EP4788361A1

EP4788361A1 - Extended, high dose vegf antagonist regimens for treatment of angiogenic eye disorders secondary to retinal vein occlusion

Info

Publication number: EP4788361A1
Application number: EP25842875.4A
Authority: EP
Inventors: Aditya ATHANIKAR; Alyson J. BERLINER; Sergio Casimiro DA SILVA LEAL; Karen Chu; Franco MENDOLIA; Rohini Rao; Andrea SCHULZE; Kenneth Turner; Robert L. Vitti; Jonathan WEYNE; Thomas Eissing; Joachim HOECHEL
Original assignee: Bayer Healthcare LLC; Regeneron Pharmaceuticals Inc
Current assignee: Bayer Healthcare LLC; Regeneron Pharmaceuticals Inc
Priority date: 2024-12-13
Filing date: 2025-12-12
Publication date: 2026-08-12
Also published as: AU2025308130A1; KR20260096819A; WO2026128860A1

Abstract

The present invention relates to regimens for the treatment of angiogenic eye disorders secondary to retinal vein occlusion, such as vascular permeability, macular edema, retinal hemorrhage, and neovascularization, and for treatment of retinal vein occlusion, characterized by high doses of aflibercept and lengthening intervals between doses.

Description

Extended, High Dose VEGF Antagonist Regimens for Treatment of Angiogenic Eye Disorders Secondary to Retinal Vein Occlusion

[0001] This application claims the benefit of U. S. Provisional Patent Application No.

63/733,920, filed on December 13, 2024; U. S. Provisional Patent Application No. 63/734,645, filed on December 16, 2024; U. S. Provisional Patent Application No. 63/749,365, filed on January 24, 2025; U. S. Provisional Patent Application No. 63/750,038, filed on January 27, 2025; U. S. Provisional Patent Application No. 63/773,224, filed on March 17, 2025; U. S.

Provisional Patent Application No. 63/783,889, filed on April 4, 2025; U. S. Provisional Patent Application No. 63/786,626, filed on April 10, 2025; U. S. Provisional Patent Application No. 63/820,351, filed on June 9, 2025; U. S. Provisional Patent Application No. 63/822,119, filed on June 11, 2025; U. S. Provisional Patent Application No. 63/831,016, filed on June 26, 2025; U. S. Provisional Patent Application No. 63/837,714, filed on July 2, 2025; U. S. Provisional Patent Application No. 63/844,396, filed on July 15, 2025; U. S. Provisional Patent Application No. 63/848,102, filed on July 21, 2025; U. S. Provisional Patent Application No. 63/852,134, filed on July 28, 2025; U. S. Provisional Patent Application No. 63/853,117, filed on July 29, 2025; U. S. Provisional Patent Application No. 63/874,347, filed on September 2, 2025; U. S. Provisional Patent Application No. 63/886,606, filed on September 23, 2025; U. S. Provisional Patent Application No. 63/897,539, filed on October 10, 2025; U. S. Provisional Patent Application No.

63/928,293, filed on December 1, 2025; and Canadian Patent Application No. 3291163, filed on November 3, 2025; each of which is herein incorporated by reference in its entirety.

REFERENCE TO A SEQUENCE LISTING

[0002] This application incorporates by reference a computer readable Sequence Listing in ST.26 XML format, titled 11876WO01 Sequence, created on December 12, 2025, and containing 5,501 bytes.

FIELD OF THE INVENTION

[0003] The field of the present invention relates to methods for treating or preventing angiogenic eye disorders by administering a VEGF antagonist.

BACKGROUND OF THE INVENTION

[0004] Retinal vein occlusion (RVO) is one of the most frequent causes of visual loss from diseases affecting the retinal vessels of the eye (Rogers et al., Ophthamology, 117(2):313-319, 2010). The 2 major RVO categories are central RVO (CRVO), with blockage of the single, central vein draining blood from the retina, and branch RVO (BRVO), where one or more of the branches of the central retinal vein are occluded. A less frequent subtype is hemiretinal vein occlusion (HRVO), where branches from the superior or inferior hemisphere are occluded, sharing characteristics with both CRVO and BRVO. All subtypes result in impaired venous drainage from the eye, which may lead to increased venous pressure, reduced arterial perfusion, and retinal ischemia (Brown et al., Investigate Ophthamology & Visual Science, 53(14):936, 2012; Korobelnik et al., Ophthamology, 121 (1 ):202-208, 2014; and Ogura etal., Am J Ophthalmol., 158(5):1032-1038, 2014). One result of retinal non-perfusion is an increase in the production of vascular endothelial growth factor (VEGF) (Aiello et al., N Engl J Med., 331 (22):1480-1487, 1994). The VEGF levels in aqueous humor from eyes with RVO can be more than 100 times higher than normal (Noma et al., Gurr Eye Res., 36(3):256-263, 2011 ). Increased expression of VEGF can lead to vascular permeability, macular edema, retinal hemorrhage, and neovascularization. Patients with central macular edema secondary to RVO lose visual acuity, and the visual prognosis, if untreated, is often poor (Holz etal., Br J Ophthalmol., 97(3):278-284, 2013).

[0005] Vascular endothelial growth factor mediates endothelial cell hypertrophy which leads to a reduction of capillary luminal diameter. This, in turn, results in an increase of intravascular pressure over the length of a retinal vessel. The resulting decrease in the blood flow in the retinal capillary augments ischemia and hypoxia, thereby increasing the expression of VEGF which maintains this pathogenic cycle (Aiello, supra).

SUMMARY OF THE INVENTION

[0006] The present invention provides a method (i) for treating or preventing an angiogenic eye disorder, (ii) for treating or preventing an angiogenic eye disorder secondary to retinal vein occlusion in a subject in need thereof, (iii) for improving best corrected visual acuity with an angiogenic eye disorder secondary to retinal vein occlusion in a subject in need thereof, (iv) for treating or preventing retinal vein occlusion in a subject in need thereof, and/or (v) for treating or preventing macular edema secondary to retinal vein occlusion; including administering to an eye of the subject (e.g., by intravitreal injection), one or more doses of about 8 mg (±0.8 mg) of a VEGF receptor fusion protein (preferably aflibercept) about once every 4-8, 4-12 or 8-12 weeks (± 7 days), 4 weeks (± 7 days) or 8 weeks (± 7 days) or 12 weeks (± 7 days). In one embodiment, the method is for treating or preventing macular edema secondary to retinal vein occlusion. In another embodiment, the method is for treating or preventing retinal vein occlusion in a subject in need thereof. For example, in an embodiment of the invention, the subject is administered one or more doses of about 8 mg (±0.8 mg) of a VEGF receptor fusion protein (preferably aflibercept) about once every 4 weeks (± 7 days). In an embodiment of the invention, the method includes administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept), followed by one or more secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept), followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept); wherein each secondary dose is administered about 2 to 4 weeks (preferably about 4 weeks; (± 7 days)) after the immediately preceding dose; and wherein each tertiary dose is administered about 8 weeks (± 7 days) after the immediately preceding dose. In one such embodiment, each secondary dose is administered about 4 weeks; (± 7 days) after the immediately preceding dose. In an embodiment of the invention, the method includes administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept), followed by 2 secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept), followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept); wherein each secondary dose is administered about 2 to 4 weeks (preferably about 4 weeks; (± 7 days)) after the immediately preceding dose; and wherein each tertiary dose is administered about 8 weeks after the immediately preceding dose. In one such embodiment, each secondary dose is administered about 4 weeks; (± 7 days) after the immediately preceding dose. In an embodiment of the invention, the method includes administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept), followed by 4 secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept), followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept); wherein each secondary dose is administered about 2 to 4 weeks (preferably about 4 weeks; (± 7 days)) after the immediately preceding dose; and wherein each tertiary dose is administered about 8 weeks (± 7 days) after the immediately preceding dose. In one such embodiment, each secondary dose is administered about 4 weeks; (± 7 days) after the immediately preceding dose. For example, the method includes administering to the eye of the subject, 3 doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept) in a formulation that comprises about 114.3 mg/ml VEGF receptor fusion protein (preferably aflibercept) at an interval of once every 4 weeks (± 7 days); wherein after said 3 doses, administering one or more doses of the VEGF receptor fusion protein (preferably aflibercept) at an interval which is lengthened up to about 8 or more weeks (± 7 days). In another example, the method includes administering to the eye of the subject, 5 doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept) in a formulation that comprises about 114.3 mg/ml VEGF receptor fusion protein (preferably aflibercept) at an interval of once every 4 weeks (± 7 days); wherein after said 5 doses, administering one or more doses of the VEGF receptor fusion protein (preferably aflibercept) at an interval which is lengthened up to about 8 or more weeks (± 7 days). In any of the methods of the invention administration may be via intravitreal administration. In any of the embodiments of the invention, the VEGF receptor fusion protein is aflibercept which is administered intravitreally. For instance, for any of the methods discussed in this paragraph, the VEGF receptor fusion protein may be aflibercept which is administered intravitreally to treat macular edema secondary to retinal vein occlusion.

[0007] In an embodiment of the invention, the method is for treating or preventing macular edema secondary to retinal vein occlusion in an subject; wherein the method comprises administering to an eye of the subject an intravitreal injection of 8 mg aflibercept in a volume of 70 pL every month or every 4 weeks +/- 1 week for the first 3 consecutive doses followed by one or more doses of 8 mg aflibercept administered 8 weeks (2 month) or 12 weeks (3 month) after the immediately preceding dose.

[0008] In an embodiment of the invention, the method is for treating or preventing macular edema secondary to retinal vein occlusion in an subject; wherein the method comprises administering to the eye of the subject, a single initial dose of 8 mg aflibercept, followed by two secondary doses of 8 mg aflibercept, followed by one or more tertiary doses of 8 mg aflibercept; wherein each secondary dose is administered 4 weeks or one month after the immediately preceding dose; and wherein one tertiary dose is administered 8 weeks (2 month) after the immediately preceding dose and wherein further tertiary doses are administered 8 weeks (2 month) or 12 weeks (3 month) after the immediately preceding dose.

[0009] In one embodiment each dose of 8 mg aflibercept is administered intravitreally.

[0010] In one embodiment each dose of 8 mg aflibercept is administered in a volume of 70 pL.

[0011] The present invention provides a method that includes administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks (preferably 4 weeks; (± 7 days)) after the immediately preceding dose; and wherein each tertiary dose is administered about 12 weeks after the immediately preceding dose. In one such embodiment, each secondary dose is administered about 4 weeks; (± 7 days) after the immediately preceding dose. In an embodiment of the invention, the method includes administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by 5 secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks (± 7 days) after the immediately preceding dose; and wherein each tertiary dose is administered at least 8 weeks after the immediately preceding dose. In one such embodiment the tertiary doses are administered 8 to 12 weeks after the preceding dose. In one such embodiment, the administration is via intravitreal injection and the VEGF receptor fusion protein is aflibercept. In an embodiment of the invention, the method includes administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by 5 secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks (± 7 days) after the immediately preceding dose; and wherein each tertiary dose is administered about 12 weeks (± 7 days) after the immediately preceding dose. In one such embodiment the secondary doses are administered about 4 weeks (± 7 days) after each other. In one such embodiment, the administration is via intravitreal injection and the VEGF receptor fusion protein is aflibercept.

[0012] In one embodiment, a method of the present invention may employ the same interval between tertiary doses throughout the administration of tertiary doses. In one embodiment, a method of the present invention may comprise monitoring to determine whether to shorten, maintain, or lengthen the interval between tertiary doses. The interval between doses, e.g., tertiary doses may be shortened (e.g., from about 8 weeks to about 4 weeks) if, in the judgment of the treating physician, a sufficient response to 8 mg aflibercept treatment is not maintained, e.g., based on visual or anatomical outcomes, e.g., BCVA or CST.

[0013] In an embodiment of the invention, the tertiary dosing interval of a method of the present invention is shortened from about 12 weeks (± 7 days) to about 8 week (± 7 days)s or about 4 weeks (± 7 days) or about 4-8 weeks (± 7 days); or wherein the tertiary dosing interval is shortened from about 8 weeks (± 7 days) to about 4 weeks (± 7 days); and/or lengthened from about 4 weeks (± 7 days) to about 8 weeks (± 7 days) or about 12 weeks (± 7 days) or from about 8 weeks (± 7 days) to about 12 weeks (± 7 days). In an embodiment of the invention, the tertiary dosing interval is shortened if the subject exhibits any one or more of: >5 letters loss of BCVA from best previous BCVA; >5 letters loss of BCVA from best previous BCVA with persistent or worsening macular edema; and/or >50 pm increase in CST (central subfield thickness) relative to CST measured at any previous time. In an embodiment of the invention, the tertiary dosing interval is lengthened if the subject exhibits any one or more of: Best-corrected visual acuity loss <5 letters relative to BCVA measured at any previous time; and/or CST thickness of <325 pm or <315 pm (e.g., wherein CST thickness of <325 pm or <315 pm is as measured by the Heidelberg Spectralis platform or by Cirrus or Topcon SD-OCT) and/or Central retinal thickness (CRT) of <320 pm or <300 pm (e.g., wherein CST thickness of <320 pm or <300 pm is as measured by the Heidelberg Spectralis platform or by Cirrus or Topcon SD-OCT). In one embodiment, a method of the invention may comprise such monitoring to determine whether to shorten, maintain, or lengthen the tertiary dosing interval. CRT (central retinal thickness) and CST (center subfield thickness) can be used, herein, interchangeably.

[0014] For example, in an embodiment of the invention, the method includes administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept), followed by one or more secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks (preferably 4 weeks; (± 7 days)) after the immediately preceding dose; and wherein each tertiary dose is administered about 12 weeks after the immediately preceding dose; wherein said tertiary interval is shortened if the subject exhibits any one or more of: >5 letters loss of BCVA from best previous BCVA; and >5 letters loss of BCVA from best previous BCVA with persistent or worsening macular edema. In one such embodiment, the interval between each immediately preceding secondary dose and the next is about 4 weeks (± 7 days).

[0015] In an embodiment of the invention, the method includes administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept), followed by one or more secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept), followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept); wherein each secondary dose is administered about 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 8 weeks after the immediately preceding dose; wherein said tertiary interval is shortened if the subject exhibits any one or more of: >5 letters loss of BCVA from best previous BCVA; >5 letters loss of BCVA from best previous BCVA with persistent or worsening macular edema; and/or >50 pm increase in CST relative to CST measured at any previous time. [0016] In an embodiment of the invention, the method includes administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept), followed by 2 or 4 secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept), followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept); wherein each secondary dose is administered about 4 weeks (± 7 days) after the immediately preceding dose; and wherein each tertiary dose is administered about 8 weeks (± 7 days) after the immediately preceding dose; wherein said tertiary interval is lengthened if the subject exhibits any one or more of: Best-corrected visual acuity loss <5 letters relative to BCVA measured at any previous time; and/or GST thickness of <325 pm or <315 pm.

[0017] In an embodiment of the invention, a subject discussed herein suffers from macular edema secondary to retinal vein occlusion, e.g., wherein the retinal vein occlusion is central retinal vein occlusion, branch retinal vein occlusion, or hemiretinal vein occlusion. In one embodiment, the occlusion is central retinal vein occlusion and/or branch retinal vein occlusion.

[0018] In an embodiment of the invention, the lengthening of an interval between tertiary doses is lengthened or shortened by one or more 4-week increments. In an embodiment of the invention, the interval between tertiary doses was lengthened one or more time prior. In an embodiment of the invention, the interval between tertiary doses has been lengthened one or more times prior from: about 8 weeks (± 7 days) to about 12 weeks (± 7 days), about 16 weeks (± 7 days) or about 20 weeks (± 7 days); about 12 weeks (± 7 days) to about 16 weeks (± 7 days)or about 20 weeks (± 7 days); and/or about 16 weeks (± 7 days) to about 20 weeks (± 7 days). In an embodiment of the invention, about 8 weeks is 8 weeks or about 8 weeks ± about 1 or 2 or 3 or 4 or 5 days; or is 2 months. In an embodiment of the invention, about 12 weeks is 12 weeks or about 12 weeks ± about 1 or 2 or 3 or 4 or 5 days or is 3 months. In an embodiment of the invention, about 16 weeks is 16 weeks or 12 weeks ± 1 or 2 or 3 or 4 or 5 days or 4 months. In an embodiment of the invention, about 20 weeks is 20 weeks or 20 weeks ± 1 or 2 or 3 or 4 or 5 days or 5 months. In one embodiment, the adjustment of the tertiary dose interval is to increase or decrease the interval by about 1 week ± about 1 day, provided that the new interval is at least about 4 weeks ± 1 week. In one embodiment, the adjustment of the tertiary dose interval is to increase or decrease the interval by about 4 weeks ± about 1 weeks, provided that the new interval is at least about 4 weeks ± 1 week. In one embodiment, the adjustment of the tertiary dose interval is to increase or decrease the interval by about 2 weeks ± about 1 day, provided that the new interval is at least about 4 weeks ± 1 week. [0019] In an embodiment of the invention, the <325 m or <315 pm is measured by spectral domain optical coherence tomography (SD-OCT).

[0020] In any of the embodiments describe herein, it may be that the subject is treatment naive. In one embodiment the subject is treatment- naive macular and has edema secondary to retinal vein occlusion (RVO). In an embodiment of the invention, the subject exhibits one or more of: Treatment-naive macular edema; Treatment-naive macular edema involving the foveal center secondary to RVO (BRVO, HRVO, or CRVO); a mean CST >300 pm on OCT (or >320 pm on Heidelberg Spectralis platform); and/or macular edema following RVO (e.g., CRVO, BRVO, or HRVO) involving the foveal center.

[0021] In an embodiment of the invention, the subject does not exhibit one or more of:

Evidence of macular edema due to any cause other than RVO; Diabetic retinopathy; Diabetic macular edema; Advanced age-related macular degeneration (neovascular AMD or geographic atrophy); Use of any intravitreal implantable agent in an eye; Prior treatment with ocriplasmin at any time in an eye; Prior treatment with pegcetacoplan injection or avacincaptad pegol injection in an eye; Prior treatment with retinal laser photocoagulation in an eye; Prior treatment with gene therapy and/or cell therapy in an eye; History of vitreoretinal surgery (including scleral buckle) in an eye; Any intraocular surgery, including cataract surgery, within 12 weeks (84 days) of treatment in an eye; YAG (Yttrium-aluminum-garnet) capsulotomy in an eye within 4 weeks (28 days) of treatment; IOP > 25 mm Hg in an eye; Uncontrolled glaucoma in an eye; Infectious blepharitis, keratitis, scleritis, or conjunctivitis in an eye; Any intraocular inflammation/infection (including trace, or above, cells in the anterior chamber and/or vitreous) within 12 weeks (84 days) of treatment in an eye; History of idiopathic or autoimmune uveitis in an eye;

Vitreomacular traction or epiretinal membrane in an eye evident on biomicroscopy or OCT that is affects central vision; Myopia of a spherical equivalent of 8 diopters or greater in an eye (prior to any refractive or cataract surgery, if applicable); History of corneal transplant in an eye; Any corneal dystrophy affecting the visual axis in an eye; Aphakia, or pseudophakia with absence of posterior capsule (unless it occurred as a result of a YAG posterior capsulotomy performed more than 28 days before treatment in an eye; Any history of macular hole of stage 2 and above in an eye; Current anterior segment neovascularization, vitreous hemorrhage, or tractional retinal detachment visible in an eye; Structural damage in an eye that is likely to preclude improvement in BCVA following resolution of macular edema (including atrophy of the retinal pigment epithelium, preretinal fibrosis, subretinal fibrosis or scar, significant macular ischemia, or organized hard exudates); Uncontrolled blood pressure (systolic > 160 mm Hg or diastolic > 95 mm Hg); Uncontrolled diabetes mellitus (DM), defined by hemoglobin A1c (HbA1c) >12% at treatment; History of cerebrovascular accident/transient ischemic attack or myocardial infarction/acute coronary syndrome within 6 months (180 days) of treatment; Renal failure, dialysis, or history of renal transplant; Known sensitivity to the VEGF receptor fusion protein (e.g., aflibercept), histidine, arginine, polysorbate or sucrose; Presence of systemic infection or treatment for suspected or active systemic infection; Subject is pregnant or is a breastfeeding woman; and/or Subject is a man or woman of child bearing potential who is not practicing a highly effective contraception prior to treatment or at least 4 months after cessation of treatment; wherein said highly effective contraception comprises stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal, contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to treatment;, intrauterine device; or intrauterine hormone-releasing system; bilateral tubal occlusion/ligation; vasectomy; condom plus contraceptive sponge, foam, or jelly, or diaphragm plus contraceptive sponge, foam, or jelly; and/or sexual abstinence. In an embodiment of the invention, an eye is the eye to which said VEGF receptor fusion protein is administered and/or the fellow eye.

[0022] In an embodiment of the invention, the VEGF receptor fusion protein (preferably aflibercept) is in an aqueous pharmaceutical formulation (e.g., at a concentration of about IOS-126 mg/ml), for example, including a histidine-based buffer and/or arginine (e.g., L-arginine) and/or a sugar and/or a polyol (e.g., sucrose); and/or a non-ionic surfactant such as polysorbate (e.g., polysorbate 20 or polysorbate 80); e.g., with a pH of about 5.8. In an embodiment of the invention, the VEGF receptor fusion protein (preferably aflibercept) is in an aqueous pharmaceutical formulation including: at least about 100 mg/ml of a VEGF receptor fusion protein comprising two polypeptides that each comprises an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of VEGFR2, and a multimerizing component; about 10-100 mM L-arginine; sucrose; a histidine-based buffer; and a surfactant; wherein the formulation has a pH of about 5.0 to about 6.8; wherein the VEGF receptor fusion protein has less than about 3.5% high molecular weight species immediately after manufacture and purification and/or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C. In an embodiment of the invention, the VEGF receptor fusion protein (preferably aflibercept) is in an aqueous pharmaceutical formulation including about the VEGF receptor fusion protein (e.g., at about 103-126 mg/ml, for example, 114.3 mg/ml), a histidine-based buffer and arginine. In an embodiment of the invention, the VEGF receptor fusion protein is an aqueous pharmaceutical formulation comprising about 114.3 mg/ml VEGF receptor fusion protein, histidine-based buffer and arginine. In an embodiment of the invention, the VEGF receptor fusion protein is aflibercept which is in an aqueous pharmaceutical formulation, wherein the aflibercept has less than about 3.5% high molecular weight species immediately after manufacture and purification and/or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8° C. In an embodiment of the invention, the VEGF receptor fusion protein (preferably aflibercept) is in an aqueous pharmaceutical formulation comprising: at least about 100 mg/ml of a VEGF receptor fusion protein; about 10-100 mM L-arginine; sucrose; a histidine-based buffer; and a surfactant (e.g., a non-ionic surfactant); wherein the formulation has a pH of about 5.0 to about 6.8; wherein the VEGF receptor fusion protein has less than about 3.5% high molecular weight species immediately after manufacture and purification and/or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C. In an embodiment of the invention, the VEGF receptor fusion protein (preferably aflibercept) is in an aqueous pharmaceutical formulation comprising: >100 mg/ml VEGF receptor fusion protein, histidine-based buffer and L-arginine; 140 mg/ml aflibercept; 20 mM histidine-based buffer; 5 % sucrose; 0.03 % polysorbate 20; 10 mM L-arginine; pH 5.8; 150 ± 15 mg/ml aflibercept, 10 mM phosphate-based buffer, 8 ± 0.8% (w/v) sucrose, 0.02-0.04% (w/v) polysorbate 20 and 50 mM L-arginine, pH 5.9-6.5; 103-126 mg/ml aflibercept, 10 ± 1 mM histidine-based buffer, 5 ± 0.5% (w/v) sucrose, 0.02-0.04% (w/v) polysorbate 20, and 50 ± 5 mM L-arginine, pH 5.5-6.1; 140 mg/ml aflibercept, 10 mM histidine-based buffer, 2.5 % (w/v) sucrose, 2.0 % (w/v) proline, 0.03 % (w/v) polysorbate 20 and 50 mM L-arginine, pH 5.8; 114.3 mg/ml aflibercept, 10 mM histidine-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 20 and 50 mM L-arginine, pH 5.8; >100 mg/ml aflibercept, histidine-based buffer and L-arginine; >100 mg/ml aflibercept at about pH 5.8, wherein the formulation forms <3% HMW aggregates after incubation at 5°C for 2 months; about 114.3 mg/mL aflibercept; 10 mM -50 mM histidine-based buffer, sugar, non-ionic surfactant, L-Arginine, pH 5.8; or about 114.3 mg/mL aflibercept; 10 mM His/His-HCl-based buffer, 5% sucrose, 0.03% polysorbate-20, 50 mM L-Arginine, pH 5.8. 41. In an embodiment of the invention, the VEGF receptor fusion protein is in an aqueous pharmaceutical formulation selected from the group consisting of formulations A to KKKK. In any of the embodiments set out herein, unless otherwise stated, the VEGF receptor fusion protein may be aflibercept which is present in the aqueous pharmaceutical formulation GGGG.

[0023] In an embodiment of the invention, a subject in a method as set forth herein having any one or more of: ocular or periocular infection; active intraocular inflammation; and/or hypersensitivity; is excluded from administration of the VEGF receptor fusion protein to the eye. In an embodiment of the invention, a method of the present invention further includes a step of evaluating the subject for: ocular or periocular infection; active intraocular inflammation; and/or hypersensitivity; and excluding the subject from said administration if any one or more if found in the subject. In an embodiment of the invention, a method of the present invention further includes monitoring the subject during said treatment or prevention for conjunctival hemorrhage, cataract, vitreous detachment, vitreous floaters, corneal epithelium defect and/or increased intraocular pressure.

[0024] In an embodiment of the invention, prior to each administration in a method of the present invention includes, providing: one single-dose glass vial having a protective plastic cap and a stopper containing an aqueous formulation comprising 8 mg (±0.8 mg) VEGF receptor fusion protein in about 70 microliters; one 18-gauge x 1¹/z-inch, 5-micron, filter needle that includes a tip and a bevel; one 30-gauge x ¹/z-inch injection needle; and one 1-mL Luer lock syringe having a graduation line marking for 70 microliters of volume, packaged together; then (1) visually inspecting the aqueous formulation in the vial and, if particulates, cloudiness, or discoloration are visible, then using another vial of aqueous formulation containing the VEGF receptor fusion protein; (2) removing the protective plastic cap from the vial; and (3) cleaning the top of the vial with an alcohol wipe; then using aseptic technique: (4) removing the 18-gauge x 1¹/2-inch, 5-micron, filter needle and the 1 mL syringe from their packaging; (5) attaching the filter needle to the syringe by twisting it onto the Luer lock syringe tip; (6) pushing the filter needle into the center of the vial stopper until the needle is completely inserted into the vial and the tip touches the bottom or a bottom edge of the vial; (7) withdrawing all of the VEGF receptor fusion protein vial contents into the syringe, keeping the vial in an upright position, slightly inclined, while ensuring the bevel of the filter needle is submerged into the liquid; (8) continuing to tilt the vial during withdrawal keeping the bevel of the filter needle submerged in the formulation; (9) drawing the plunger rod sufficiently back when emptying the vial in order to completely empty the filter needle; (10) removing the filter needle from the syringe and disposing of the filter needle; (11) removing the 30-gauge x ¹/z-inch injection needle from its packaging and attaching the injection needle to the syringe by firmly twisting the injection needle onto the Luer lock syringe tip; (12) holding the syringe with the needle pointing up, and checking the syringe for bubbles, wherein if there are bubbles, gently tapping the syringe with a finger until the bubbles rise to the top; and (13) slowly depressing the plunger so that the plunger tip aligns with the graduation line that marks 70 microliters on the syringe. In an embodiment of the invention, administration of the VEGF receptor fusion protein is performed by intravitreal injection under controlled aseptic conditions, which comprise surgical hand disinfection and the 11876WO01

use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent) and anesthesia and a topical broad-spectrum microbicide are administered prior to the injection.

[0025] In an embodiment of the invention, the VEGF receptor fusion protein includes amino acids 27-457 of the amino acid sequence set forth in SEQ ID NO: 2; or is aflibercept or conbercept. In an embodiment of the invention, the VEGF receptor fusion protein: (i) includes two polypeptides that comprise (1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO: 2; (2) a VEGFR2 component comprising amino acids 130-231 of SEQ ID NO: 2; and (3) a multimerization component comprising amino acids 232-457 of SEQ ID NO: 2; (ii) includes two polypeptides that comprise an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of a VEGFR2, and a multimerizing component; (iii) includes two polypeptides that comprise an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of VEGFR2, an Ig domain 4 of VEGFR2 and a multimerizing component; or (iv) includes two VEGFR1R2-FcAC1 (a) polypeptides encoded by the nucleic acid sequence of SEQ ID NO: 1. In an embodiment of the invention, the VEGF receptor fusion protein includes two polypeptides that include an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of a VEGFR2, and a multimerizing component. In any of the embodiments set out herein, unless otherwise stated, the VEGF receptor fusion protein may be aflibercept. Alternatively, in any of the embodiments set out herein, unless otherwise stated, the VEGF receptor fusion protein may be conbercept.

[0026] In an embodiment of the invention, the VEGF receptor fusion protein (preferably aflibercept) is administered to both eyes of the subject. In the alternative, the VEGF receptor fusion protein (preferably aflibercept) is administered to one eye of the subject.

[0027] In any of the embodiments set out herein, unless otherwise stated, it may be that the VEGF receptor fusion protein is present in a prefilled syringe that is then used to administered the VEGF receptor fusion protein. In an embodiment of the invention, the VEGF receptor fusion protein is administered from a syringe or a pre-filled syringe (e.g., which is glass or plastic, and/or sterile); for example, including a 30 gauge x ¹/₂-inch sterile injection needle. In some cases the pre-filled syringe is glass and sterile.

[0028] In an embodiment of the invention, a subject has previously received one or more doses of 2 mg VEGF receptor fusion protein, for example, which is in an aqueous pharmaceutical formulation, e.g., including about 40 mg/ml VEGF receptor fusion protein; e.g., including 40 mg/ml VEGF receptor fusion protein, 10 mM sodium phosphate, 40 mM NaCI, 0.03% polysorbate 20 and 5% sucrose, with a pH of 6.2. In another embodiment, a subject has not previously received VEGF receptor fusion protein. [0029] In an embodiment of the invention, the subject is administered one or more further doses of VEGF receptor fusion protein (preferably aflibercept); and/or the method further includes one or more periods of treat and extend (T& E) and/or pro re nata dosing.

[0030] In an embodiment of the invention, the VEGF receptor fusion protein (preferably aflibercept) is administered in a volume of about 100 pl or less, about 75 pl or less; about 70 pl or less; or about 50 pl; 51 pl; 52 pl; 53 pl; 54 pl; 55 pl; 56 pl; 57 pl; 58 pl; 59 pl; 60 pl; 61 pl; 62 pl; 63 pl; 64 pl; 65 pl; 66 pl; 67 pl; 68 pl; 69 pl; 70 pl (e.g., 70 ± 4 or 5 microliters); 71 pl; 72 pl; 73 pl; 74 pl; 75 pl; 76 pl; 77 pl; 78 pl; 79 pl; 80 pl; 81 pl; 82 pl; 83 pl; 84 pl; 85 pl; 86 pl; 87 pl; 88 pl; 89 pl; 90 pl; 91 pl; 92 pl; 93 pl; 94 pl; 95 pl; 96 pl; 97 pl; 98 pl; 99 pl; or 100 pl, e.g., by intravitreal injection.

[0031] In any of the embodiments set out herein, unless otherwise stated, the VEGF receptor fusion protein (preferably aflibercept) may be administered in a volume of about 100 pl or less. In any of the embodiments set out herein, unless otherwise stated, the VEGF receptor fusion protein (preferably aflibercept) may be administered in a volume of about 50pl to about 100 pl. In any of the embodiments set out herein, unless otherwise stated, the VEGF receptor fusion protein (preferably aflibercept) may be administered in a volume of about 60pl to about 80 pl.

[0032] In an embodiment of the invention, the interval between doses are adjusted (shortened, maintained or lengthened) based on visual and/or anatomic outcomes.

[0033] Preferably, herein, a VEGF receptor fusion protein is aflibercept; and/or the VEGF receptor fusion protein is administered by intravitreal injection.

[0034] In any of the embodiments set out herein, unless otherwise stated, it may be that the VEGF receptor fusion protein is aflibercept, administration is via intravitreal administration, and the injection volume is about 100 pl or less. In one such embodiment, the method is to treat or prevent or preventing macular edema secondary to retinal vein occlusion.

[0035] The present invention also provides a kit comprising a container comprising VEGF receptor fusion protein; and instructions for use of VEGF receptor fusion protein, wherein the container is a vial or a pre-filled syringe, wherein the container comprises >100 mg/mL VEGF receptor fusion protein, wherein the container comprises >114.3 mg/mL VEGF receptor fusion protein, wherein the instructions comprise instructions for the administration of aflibercept to patients with an angiogenic eye disorder secondary to RVO, wherein the instructions comprise instructions that aflibercept 8 mg (±0.8 mg) treatment is initiated with 1 injection per month (every 4 weeks) for 3 or 5 consecutive doses, wherein the instructions comprise instructions that after the initial 3 or 5 consecutive doses the injection interval may be lengthened up to every 8, 12, 16, 20 or 24 weeks, and wherein the instructions comprise instructions that the treatment interval may be adjusted based on the physician’s judgement of visual and/or anatomic outcomes. In some embodiments of the invention, the kit comprises a pre-filled syringe and instructions for use, wherein the pre-filled syringe comprises 114.3 mg/mL aflibercept and wherein the instructions for use comprise instructions for administration of 8 mg (±0.8 mg) aflibercept to patients with an angiogenic eye disorder, e.g., an angiogenic eye disorder secondary to RVO comprising: (i) that the recommended dose is 8 mg (±0.8 mg) aflibercept (equivalent to 70 microliters solution for injection), (ii) that treatment is initiated with 1 injection of 8 mg (±0.8 mg) aflibercept per month (every 4 weeks) for 3 consecutive doses, and (iii) that based on the physician’s judgement of visual and/or anatomic outcomes injection intervals may then be extended. In some embodiments of the invention the kit comprises a pre-filled syringe and instructions for use, wherein the pre-filled syringe comprises 114.3 mg/mL aflibercept and wherein the instructions for use comprise instructions for administration of 8 mg (±0.8 mg) aflibercept to patients with an angiogenic eye disorder, e.g., an angiogenic eye disorder secondary to RVO comprising (i) that the recommended dose is 8 mg (±0.8 mg) aflibercept (equivalent to 70 microliters solution for injection), (ii) that treatment is initiated with 1 injection of 8 mg (±0.8 mg) aflibercept per month (every 4 weeks) for 3 consecutive doses, (iii) that based on the physician’s judgement of visual and/or anatomic outcomes injection intervals may then be extended, (iv) if visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly, (v) the interval between two doses should not be shorter than 1 month (4 weeks), and (vi) the frequency of monitoring visits should be based on the patient's status and at the physician's discretion.

[0036] The present invention provides a method for treating or preventing macular edema following retinal vein occlusion (RVO) comprising administering 8 mg (±0.8 mg) aflibercept by intravitreal injection every 4 weeks (+/- 7 days) for the first three to five doses (e.g., 3 or 4 or 7 days), followed by 8 mg (±0.8 mg) aflibercept via intravitreal injection once every 4 to 8 weeks (+/- 1 week).

[0037] The present invention provides a method for treating or preventing macular edema following retinal vein occlusion (RVO) comprising administering 8 mg (±0.8 mg) of aflibercept in a pharmaceutical formulation comprising 114.3 mg/ml aflibercept in a volume of 0.07 mL by intravitreal injection every 4 weeks or approximately every 28 days (+/- 7 days) for the first three to five doses, followed by 8 mg (±0.8 mg) of aflibercept in a pharmaceutical formulation comprising 114.3 mg/ml aflibercept in a volume of 0.07 mL via intravitreal injection once every 4 to 8 weeks (+/- 1 week). [0038] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in an subject; wherein the methods comprise

(i) administering to the eye of the subject an intravitreal injection of 8 mg aflibercept every month or every 4 weeks for the first 3 consecutive injections and (ii) one or more further injections of 8 mg aflibercept after said first 3 consecutive injections wherein the injection interval between two consecutive injections is adjusted based on the physician’s judgement of visual and/or anatomic outcomes.

[0039] In one embodiment of the invention the method for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and/or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise (i) administering to the eye of the subject an intravitreal injection of 8 mg aflibercept every month or every 4 weeks for the first 3 consecutive injections and (ii) one or more further injections of 8 mg aflibercept after said first 3 consecutive injections wherein the injection interval between two consecutive injections is first extended to 8 weeks or 2 months for one or more injections and then adjusted based on the physicians judgement of visual and/or anatomic outcomes, wherein the treatment interval between two consecutive injections is between 4 weeks (1 month) and 20 weeks (5 months).

[0040] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in an subject in an subject; wherein the method comprises administering to the eye of the subject, a single initial dose of 8 mg aflibercept, followed by two secondary doses of said 8 mg aflibercept, followed by one or more tertiary doses of 8 mg aflibercept; wherein each secondary dose is administered 4 weeks or one month after the immediately preceding dose; and wherein the treatment interval between two consecutive tertiary doses is adjusted based on the physicians judgement of visual and/or anatomic outcomes.

[0041] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,

a single initial dose of 8 mg aflibercept, followed by;

one or more tertiary doses of 8 mg aflibercept; wherein the treatment interval between two consecutive tertiary closes is adjusted based on the physician’s judgement of visual and/or anatomic outcomes and wherein the subject has been treated with a different anti-angiogenic treatment prior to said single initial dose of 8 mg aflibercept. Such anti-angiogenic treatment is for example an anti-VEGF treatment using for e.g.

2 mg aflibercept, faricimab, ranibizumab or bevacizumab. In one embodiment of the invention the subject was treated with 2 mg aflibercept or faricimab prior to said single initial dose of 8 mg aflibercept. In one embodiment of the invention, the subject was treated with ranibizumab or bevacizumab prior to said single initial dose of 8 mg aflibercept.

[0042] Adjustment of treatment interval means that the interval between two consecutive administrations of 8 mg aflibercept is extended or shortened based on the physician’s judgement of visual and/or anatomic outcomes.

[0043] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise

(i) administering to the eye of the subject an intravitreal injection of 8 mg aflibercept every month or every 4 weeks for the first 3 consecutive injections and

(ii) one or more further injections of 8 mg aflibercept after said first 3 consecutive injections wherein the injection interval between two consecutive injections is extended based on the physician’s judgement of visual and/or anatomic outcomes.

[0044] In one embodiment of the invention the method for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise (i) administering to the eye of the subject an intravitreal injection of 8 mg aflibercept every month or every 4 weeks for the first 3 consecutive injections and (ii) one or more further injections of 8 mg aflibercept after said first 3 consecutive injections wherein the injection interval between two consecutive injections is first extended to 8 weeks or 2 months for one or more injections and then further extended to up to 16 weeks (4 months) or 20 weeks (5 months) based on the physicians judgement of visual and/or anatomic outcomes.

[0045] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in an subject in an subject; wherein the method comprises administering to the eye of the subject, a single initial dose of 8 mg aflibercept, followed by two secondary doses of said 8 mg aflibercept, followed by one or more tertiary doses of 8 mg aflibercept; wherein each secondary dose is administered 4 weeks or one month after the immediately preceding dose; and wherein the treatment interval between two consecutive tertiary doses is extended based on the physicians judgement of visual and/or anatomic outcomes.

[0046] In one embodiment of the invention, the first tertiary dose is administered 8 weeks (2 months) after the immediately preceding dose and one or more further tertiary doses are administered 8 weeks (2 months), or 12 weeks (3 months), or 16 weeks (4 months), or 20 weeks (5 months) after the immediately preceding dose. In one embodiment of the invention, the first tertiary dose is administered 8 weeks (2 months) after the immediately preceding dose and then the treatment interval between two consecutive injections is extended to up to 16 weeks (4 months) or 20 weeks (5 months) based on the physician’s judgement of visual and/or anatomic outcomes.

[0047] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,

a single initial dose of 8 mg aflibercept, followed by;

one or more tertiary doses of 8 mg aflibercept;

wherein the treatment interval between two consecutive tertiary doses is extended based on the physician’s judgement of visual and/or anatomic outcomes and

wherein the subject has been treated with a different anti-angiogenic treatment prior to said single initial dose of 8 mg aflibercept. Such anti-angiogennic treatment is for example an anti-VEGF treatment using for e.g., 2 mg aflibercept, faricimab, ranibizumab or bevacizumab. In one embodiment of the invention the subject was treated with 2 mg aflibercept or faricimab prior to said single initial dose of 8 mg aflibercept. In one embodiment of the invention, the subject was treated with ranibizumab or bevacizumab prior to said single initial dose of 8 mg aflibercept.

[0048] In various embodiments, any of the features or components of embodiments discussed above or herein may be combined, and such combinations are encompassed within the scope of the present disclosure. Any specific value discussed above or herein may be combined with another related value discussed above or herein to recite a range with the values representing the upper and lower ends of the range, and such ranges are encompassed within the scope of the present disclosure. 11876WO01

BRIEF DESCRIPTION OF THE FIGURES

[0049] Figure 1 shows an exemplary dosing schedule as discussed in Example 1. Note: Regimens including the dosing intervals embodied in the table herein for the AFL 8mg/3 and AFL 8mg/5 regimens, preferably as represented by the “X” and “T& E” marks, form part of the present invention. AFL=aflibercept, BCVA=best-corrected visual acuity, CST=central subfield thickness, DRM=dose regimen modification, KSE=key secondary endpoint, SD-OCT=spectral domain optical coherence tomography, T& E=treat and extend, Wk=week, X=active injection visit, -=no injection, 8 mg/3=8 mg Q8W after 3 initial Q4W doses, 8 mg/5=8 mg Q8W after 5 initial Q4W doses. ¹=Participants meeting rescue at Week 16 or Week 24 are thereafter dosed Q4W. Interval extension is possible from Week 32 depending on DRM. ²=Participants meeting rescue at any visit from Week 20 to Week 36 receive an active dose at that same visit and are thereafter dosed Q4W. Interval extension is possible from Week 32 depending on DRM. For participants who do not meet both criteria for shortening or extension of the interval, the dosing interval of Q8W will be maintained.

[0050] Figure 2 shows an exemplary study design as discussed in Example 1. BCVA=Best-corrected Visual Acuity, ETDRS=Early Treatment of Diabetic Retinopathy Study, Nl=non-inferiority, Q4W=every 4 weeks, Q8W=every 8 weeks, RVO=retinal vein occlusion, T& E=treat and extend.

[0051] Figure 3 shows a Study Flow Diagram for the QUANTUM study as discussed in Example 2.

[0052] Figure 4 shows a Dosing Schedule for the QUANTUM study as discussed in Example 2. Note: Regimens including the dosing intervals embodied in the table herein for the 8Q4 regimen, preferably as represented by the “X” marks, form part of the present invention.

X=scheduled injection visit; O=injection only if DRM Criteria have been met. ¹ Participant assessed for DRM Criteria at weeks 28 and 32; if DRM Criteria met at week 28 dosing interval will be shortened to q4 weeks. If DRM Criteria met at week 32, dosing interval will be shortened to q8 weeks - if met again at week 40, dosing interval will be shortened further to q4 weeks; ² no injection at week 44 if DRM Criteria not met at week 40, dosing interval will remain q8 weeks. PE=primary endpoint.

[0053] Figure 5 shows the study design of the ELARA study set forth in Example 3. Q4=once every 4 weeks, DME=diabetic macular edema, DRM=dose regimen modification, nAMD=neovascular age-related macular degeneration. [0054] Figure 6 shows the dosing plan for patients in the ELARA study. ‘Participants will be evaluated for interval modification based on DRM criteria beginning at week 24. EOS=end of study, Mand=mandatory, *= primary safety assessment, wk(s)=weeks.

[0055] Figure 7 shows free and adjusted bound aflibercept concentration versus time since first dose observed in the quasar study, stratified by dosing regimen. IVT, Intravitreal; LLOQ, Lower limit of quantitation; QxW, Every X weeks; Q4Wx3, 3 initial monthly doses; Q4Wx5, 5 initial monthly doses Blue lines represent the median of observed data at specific visits. Dashed lines represent the LLOQ.

[0056] Figure 8 shows free and adjusted bound aflibercept concentration versus time since first dose observed between weeks 4 and 18 in the participants enrolled in the CANDELA, PULSAR, PHOTON, and QUASAR studies who received high dose. IVT, intravitreal; LLOQ, Lower limit of quantitation; QxW, Every X weeks, The solid and dashed lines represent the medians of observed data and LLOQ. Numbers shown in each panel represent the medians of observed post-dose data around week 9 for CANDELA, PULSAR, and PHOTON and around week 16 for QUASAR

[0057] Figure 9 shows the distribution of ocular distribution clearance corrected for age effect in participants who received intravitreal administration of aflibercept, stratified by disease and drug product. DME, Diabetic macular edema; IVT, Intravitreal; MEfRVO, Macular edema following retinal vein occlusion; nAMD, Neovascular age-related macular degeneration; QE, Ocular distribution clearance, The boxes and whiskers delimit the interquartile and 5^th to 95^th percentile ranges. The lines within boxes represent the medians of the data. The number of records used for statistic calculations is shown above each box.

[0058] Figure 10 shows Forest plots of geometric mean ratios (90% confidence interval) of Bayesian model-based predictions of exposure metrics of free and adjusted bound aflibercept in participants from the CANDELA, PULSAR, PHOTON, and QUASAR studies, stratified by grouped disease population. AUCweek56-64, Area under the concentration curve from weeks 56 Io 64; Cmax,week8-12, Maximum concentration from weeks 8 to 12; Cmax, week56-64, Maximum concentration from weeks 56 to 64; DME, Diabetic macular edema; MEfRVO, Macular edema following retinal vein occlusion; n, Number of participants in each group; nAMD, Neovascular age-related macular degeneration; QxW, Every X weeks [or] indicates that the respective limit is included in the interval.

[0059] Figures 11 A, 11 B, 11C and 11D correspond to a case study patient’s angiograms at (Fig. 11 A) baseline, (Fig. 11 B) up to week 4 (4 weeks after aflibercept 8 mg injection #1), (Fig.

11 C) week 12, and (Fig. 11 D) up to week 36 (4 weeks after aflibercept 8 mg injection #6). [0060] Figure 12 summarizes BCVA gains in 8 mg aflibercept groups compared to aflibercept 2 mg groups at week 36 across RVO subtypes. Full analysis set. LS means were generated using a mixed model for repeated measures with baseline BCVA as a covariate. The fixed factors were treatment group (aflibercept 8q8/3, 8q8/5, 2q4); visit; and stratification variables: geographic region (Japan, Asia-Pacific, Europe, America), BL BCVA (<60 vs >60 letters), and, for the overall RVO population analysis only, RVO type (CRVO/HRVO vs BRVO). The model also included terms for the interactions between baseline BCVA and visit, and between treatment and visit. ^a Observed values (censoring data post intercurrent event). ^bMissing endpoint values imputed using a multiple imputation procedure. Estimates based on a linear regression model, within the multiple imputation procedure, adjusted for BL BCVA, BL CRT, and stratification variables (geographic region [Japan vs Asia-Pacific vs Europe vs America], BCVA score [>60 vs >60], RVO type [CRVO/HRVO vs BRVO]). ^cNominal p-values. BL, baseline; BRVO, branched retinal vein occlusion; Cl, confidence interval; CRVO, central retinal vein occlusion; ETDRS, Early Treatment Diabetic Retinopathy Study; HRVO, hemiretinal vein occlusion; LS, least squares. Both aflibercept 8 mg groups achieved non-inferior BCVA gains compared to aflibercept 2 mg at week 36, with fewer injections overall and consistent results across RVO subtypes.

[0061] Figure 13 summarizes CRT reductions in 8 mg aflibercept groups compared to aflibercept 2 mg groups at week 36, across RVO Subtypes. Full analysis set. LS means were generated using a mixed model for repeated measures with baseline CRT as a covariate. The fixed factors were treatment group (aflibercept 8q8/3, 8q8/5, 2q4), visit; and stratification variables: geographic region (Japan, Asian-Pacific, Europe, America), BL BCVA (<60 vs >60 letters), and, for the overall RVO population analysis only, RVO type (CRVO/HRVO vs BRVO). The model also included terms for the interaction between baseline CRT and visit, and treatment and visit. ^aMissing endpoint values imputed using a multiple imputation procedure. Based on a linear regression model. Non-parametric rank analysis of covariance, adjusted for BL BCVA, BL CRT, and stratification variables (geographic region [Japan vs Asian-Pacific vs Europe vs America], BCVA score [>60 vs >60], RVO type [CRVO/HRVO vs BRVO], within the multiple imputation procedure. Both aflibercept 8 mg groups achieved robust CRT reductions compared to aflibercept 2 mg at week 36, with fewer injections overall and across RVO subtypes.

[0062] Figure14 summarizes BCVA gains across CRT tertiles by RVO subtypes at week 36. Full analysis set. Observed cases excluding values after intercurrent event: Observations after the occurrence of an intercurrent event are excluded in line with the primary estimand strategy. CRT tertiles for BRVO were <452 pm, >452-<586 pm, and >586 pm and for CRVO/HRVO were <576 pm, >576-<798 pm, and >798 pm. a Safety analysis set. Patients completing Week 36. Both aflibercept 8 mg groups achieved comparable BCVA gains compared with aflibercept 2 mg at week 36, with fewer injections across baseline CRT tertiles by RVO subtypes.

[0063] Figure 15 summarizes CRT reductions across CRT tertiles by RVO subtypes at week 36. Full analysis set. Observed cases excluding values after intercurrent event: Observations after the occurrence of an intercurrent event are excluded in line with the primary estimand strategy. CRT tertiles for BRVO were <452 pm, >452-<586 pm, and >586 pm and for CRVO/HRVO were <576 pm, >576-<798 pm, and >798 pm. ^aSafety analysis set. Patients completing Week 36. Both aflibercept 8 mg groups achieved robust CRT improvements compared with aflibercept 2 mg at week 36, with fewer injections across baseline CRT tertiles by RVO subtypes.

[0064] Figure 16 summarizes patients maintaining > Q8 dosing intervals at week 36 across RVO subtypes. Safety analysis set. Patients completing Week 36. Q4, every 4 weeks; Q8, every 8 weeks. Most patients in the aflibercept 8 mg groups maintained > Q8 dosing intervals at week 36 across RVO subtypes.

[0065] Figure 17 summarizes patient last assigned dosing intervals at week 36 across RVO subtypes. Safety analysis set. Patients completing Week 36. Per study design, dosing interval extension was not possible in the 8q8/5 group until Week 40. Q12, every 12 weeks. Most patients eligible for dosing interval extension treated with aflibercept 8 mg were last assigned to Q8 or longer dosing intervals at week 36 across RVO subtypes.

[0066] Figure 18 is a comparison of ocular clearance estimates in patients assigned or not assigned to receive HD aflibercept Q4W, stratified by randomization group. HD=High dose; I VT=lntravitreal; Q4W=Every 4 weeks; Q4Wx3+Q8W=3 initial monthly doses followed by dosing every 8 weeks; Q4Wx5+Q8W=5 initial monthly doses followed by dosing every 8 weeks. The boxes and whiskers delimit the interquartile ranges and the 5th to 95th percentile ranges. The lines within boxes represent the medians of the data. The open circles represent the individual data outside the 5th to 95th percentile range. The numbers represent the number of data points within each data sub-group.

[0067] Figure 19 is a comparison of baseline central retinal thickness in patients assigned or not assigned to receive HD aflibercept Q4W, stratified by randomization group. HD=High dose; IVT=lntravitreal; Q4W=Every 4 weeks; Q4Wx3+Q8W=3 initial monthly doses followed by dosing every 8 weeks; Q4Wx5+Q8W=5 initial monthly doses followed by dosing every 8 weeks. The boxes and whiskers delimit the interquartile ranges and the 5th to 95th percentile ranges. The lines within boxes represent the medians of the data. The open circles represent the individual data outside the 5th to 95th percentile range. The numbers represent the number of data points within each data sub-group.

[0068] Figure 20 is a comparison of baseline best corrected visual acuity in patients assigned or not assigned to receive HD aflibercept Q4W, stratified by randomization group. HD=High dose; I VT=lntravitreal; Q4W=Every 4 weeks; Q4Wx3+Q8W=3 initial monthly doses followed by dosing every 8 weeks; Q4Wx5+Q8W=5 initial monthly doses followed by dosing every 8 weeks. The boxes and whiskers delimit the interquartile ranges and the 5th to 95th percentile ranges. The lines within boxes represent the medians of the data. The open circles represent the individual data outside the 5th to 95th percentile range. The numbers represent the number of data points within each data sub-group.

[0069] Figure 21 summarizes the incidence of dosing interval shortening to every 4 weeks for patients with ocular clearance estimates and baseline central retinal thickness values above and below the respective medians. CRT=Central retinal thickness; IVT=lntravitreal; Q4W=Every 4 weeks; Q4Wx3+Q8W=3 initial monthly doses followed by dosing every 8 weeks; Q4Wx5+Q8W =5 initial monthly doses followed by dosing every 8 weeks; QE = Ocular distribution clearance; Open circle indicates proportion of patients assigned to Q4W for each randomization group independently of baseline CRT and QE.

[0070] Figure 22 is a schematic representation of the structural PK/PD model. BCVA, Best visual corrected acuity; CRT, Central retinal thickness; DRM, Dosing Interval Shortening; Q_E, Ocular clearance. Note: in this schematic representation of the PK/PD model, the relation between " DRM” and “Dose" indicates that, when performing simulations, dosing of HD aflibercept (yes/no) was determined at every visit (every 4 weeks) considering the randomization group, the time since the last dose, and the dosing interval shortenings that happened during the clinical trial simulation. DRM was determined by predictions of CRT and BCVA and the DRM criteria of the respective clinical trial.

[0071] Figure 23 summarizes the ocular clearance for patients who did and did not qualify to receive high dose aflibercept every 4 weeks in the PHOTON and PULSAR studies. IVT, Intravitreal; Q4W, Every 4 weeks. The boxes and whiskers delimit the interquartile ranges and the 5th to 95th percentile range. The lines within boxes represent the medians of the data. The open circles represent the individual data outside the 5^th to 95^th percentile range. The numbers represent the number of data points within each data subgroup.

[0072] Figure 24 summarizes the baseline central retinal thickness for patients who did and did not qualify to receive high dose aflibercept every 4 weeks in the PHOTON and PULSAR 11876WO01

studies. IVT, Intravitreal; Q4W, Every 4 weeks. The boxes and whiskers delimit the interquartile ranges and the 5th to 95th percentile range. The lines within boxes represent the medians of the data. The open circles represent the individual data outside the 5^th to 95^th percentile range. The numbers represent the number of data points within each data subgroup.

[0073] Figure 25 summarizes the incidence of dosing interval shortening to every 4 weeks for patients with ocular clearance estimates and baseline central retinal thickness values above and below the respective medians. CRT, Central retinal thickness; Q4W, Every 4 weeks; QE, Ocular clearance. One patient was excluded from this plot since the baseline central retinal thickness measurement was missing. Open circles represented the proportion of patients that qualified for dosing every 4 weeks in each of the trials irrespective of the baseline central retinal thickness and the ocular clearance estimate.

[0074] Figure 26 summarizes the mean best corrected visual acuity difference when allowing every 4 weeks dosing. BCVA, Best visual corrected acuity; HD, High dose; Q4W, Every 4 weeks. Points and error bars represent the predicted mean difference in BCVA and its corresponding 95% prediction interval when comparing the Q4W protocol vs the Q8W protocol. These were obtained by computing the median and the 2.5th and 97.5th quantiles of the 100 simulated mean differences produced through the 100 replicates of the simulated trials. In this plot, positive differences represent a benefit of dose interval reduction down to every 4 weeks as compared to down to every 8 weeks, in patients who would qualify to receive HD aflibercept every 4 weeks.

[0075] Figure 27 summarizes the mean change in BCVA through Week 64-AII RVO (QUASAR).

[0076] Figure 28 summarizes the mean absolute BCVA through Week 64-AII RVO (QUASAR)

[0077] Figure 29 summarizes the mean change in BCVA through Week 64-BRVO (QUASAR)

[0078] Figure 30 summarizes the mean absolute BCVA through Week 64-BRVO (QUASAR)

[0079] Figure 31 summarizes the mean change in BCVA through Week 64-CRVO/HRVO (QUASAR)

[0080] Figure 32 summarizes the mean absolute BCVA through Week 64-CRVO/HRVO (QUASAR)

[0081] Figure 33 summarizes the mean absolute CST through Week 64-RVO (QUASAR)

[0082] Figure 34 summarizes the mean change in CST through Week 64-RVO (QUASAR)

[0083] Figure 35 summarizes the mean absolute CST through Week 64-BRVO (QUASAR)

[0084] Figure 36 summarizes the mean change in CST through Week 64-BRVO (QUASAR) 11876WO01

[0085] Figure 37 summarizes the mean absolute CST through Week 64-CRVO/HRVO (QUASAR)

[0086] Figure 38 summarizes the mean change in CST through Week 64-CRVO/HRVO (QUASAR)

[0087] Figure 39 summarizes the key-secondary endpoint-Number of active injections by Week 64 (QUASAR)

[0088] Figure 40 summarizes the key-secondary endpoint-Number of active injections by Week 64 by RVO type (QUASAR)

[0089] Figure 41 summarizes the patients maintaining Q8 through Week 64 (QUASAR)

[0090] Figure 42 summarizes the last assigned Interval at Week 64 (QUASAR)

[0091] Figure 43 summarizes the overview AEs through W64 (QUASAR)

DETAILED DESCRIPTION OF THE INVENTION

[0092] The present invention provides surprisingly effective methods for treating patients with a relatively common cause of retinal vascular disease which is associated with devastating vision loss, macular edema secondary to retinal vein occlusion (MERVO). The current treatment paradigm of monthly eye injections, for example of 2 mg Eylea, can make it challenging for patients to maintain their treatment plan, potentially leading to poor adherence and vision loss. Based, in part, on the data presented herein, aflibercept 8 mg can offer the potential to halve the number of injections needed, as compared to standard-of-care aflibercept 2 mg and other anti-VEGF therapies.

[0093] With the results from the QUASAR clinical trial (NCT05850520) to study macular edema secondary to RVO, EYLEA HD (8 mg aflibercept), with extended dosing, met the high bar of vision gains and safety seen with standard-of-care EYLEA (2 mg aflibercept). Importantly, in the most difficult to treat macular edema secondary to CRVO and HRVO subtypes, vision was not compromised, with fewer injections of aflibercept 8 mg. The QUASAR clinical trial met its primary endpoint at 36 weeks, with both groups of EYLEA HD (8 mg aflibercept) patients dosed every 8 weeks achieving non-inferior visual acuity gains compared to those receiving EYLEA® (aflibercept) Injection 2 mg dosed every 4 weeks. The EYLEA HD results were consistent across patients with branch retinal vein occlusions, and those

with central retinal or hemiretinal vein occlusions. The safety profile of EYLEA HD was similar to EYLEA in QUASAR and remained generally consistent with the known safety profile of EYLEA HD in its pivotal trials.

[0094] One of the key differences observed between QUASAR treatment arms was the ability to extend treatment intervals. At week 36, about 70% of patients in one arm had a last assigned dosing interval of every 12 weeks. By contrast, 25% of patients in the 2 mg group still required monthly injections compared with only 6% in an 8 mg arm. The number of patients who needed every-4-week dosing of aflibercept was about 3 times higher in 2 mg compared to 8 mg of aflibercept.

[0095] Standard methods in molecular biology are described Sambrook, Fritsch and Maniatis (1982 & 19892^nd Edition, 2001 3^rd Edition) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y.; Sambrook and Russell (2001) Molecular Cloning, 3^rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y.; Wu (1993) Recombinant DNA, Vol. 217, Academic Press, San Diego, Calif.). Standard methods also appear in Ausbel, etal. (2001) Current Protocols in Molecular Biology, Vols. 1-4, John Wiley and Sons, Inc. New York, N. Y., which describes cloning in bacterial cells and DNA mutagenesis (Vol. 1), cloning in mammalian cells and yeast (Vol. 2), glycoconjugates and protein expression (Vol. 3), and bioinformatics (Vol. 4).

[0096] General methods for protein purification including immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization are described (Coligan et al. (2000) Current Protocols in Protein Science, Vol. 1, John Wiley and Sons, Inc., New York). Chemical analysis, chemical modification, post-translational modification, production of fusion proteins, glycosylation of proteins are described (see e.g., Coligan et al. (2000) Current Protocols in Protein Science, Vol. 2, John Wiley and Sons, Inc., New York; Ausubel, etal.

(2001) Current Protocols in Molecular Biology, Vol. 3, John Wiley and Sons, Inc., NY, N. Y., pp.

16.0.5-16.22.17; Sigma-Aldrich, Co. (2001) Products for Life Science Research, St. Louis, Mo.; pp. 45-89; Amersham Pharmacia Biotech (2001) BioDirectory, Piscataway, N. J., pp. 384-391). Production, purification, and fragmentation of polyclonal and monoclonal antibodies are described (Coligan etal. (2001) Current Protcols in Immunology, Vol. 1, John Wiley and Sons, Inc., New York; Harlow and Lane (1999) Using Antibodies, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y.; Harlow and Lane, supra). Standard techniques for characterizing ligand/receptor interactions are available (see, e.g., Coligan et al. (2001) Current Protocols in Immunology, Vol. 4, John Wiley, Inc., New York).

[0097] Methods for flow cytometry, including fluorescence activated cell sorting (FACS), are available (see, e.g., Owens et al. (1994) Flow Cytometry Principles for Clinical Laboratory Practice, John Wiley and Sons, Hoboken, N. J.; Givan (2001) Flow Cytometry, 2^nd ed.; Wiley-Liss, Hoboken, N. J.; Shapiro (2003) Practical Flow Cytometry, John Wiley and Sons, Hoboken, N. J.). Fluorescent reagents suitable for modifying nucleic acids, including nucleic acid primers and probes, polypeptides, and antibodies, for use, e.g., as diagnostic reagents, are available (Molecular Probes (2003) Catalogue, Molecular Probes, Inc., Eugene, Oreg.; Sigma-Aldrich (2003) Catalogue, St. Louis, Mo.).

[0098] Standard methods of histology of the immune system are described (see e.g., Muller-Harmelink (ed.) (1986) Human Thymus: Histopathology and Pathology, Springer Verlag, New York, N. Y.; Hiatt et al. (2000) Color Atlas of Histology, Lippincott, Williams, and Wilkins, Phila, Pa.; Louis etal. (2002) Basic Histology: Text and Atlas, McGraw-Hill, New York, N. Y.).

[0099] Various concentrations, amounts, dosages and volumes as well as time intervals, for example between doses are mentioned herein. The scope of the present invention includes embodiments, including such concentration, amount, dosage, volume or time interval, ±10% thereof.

[0100] " Isolated" VEGF antagonists and VEGF receptor fusion proteins (e.g., aflibercept), polypeptides, polynucleotides and vectors, are at least partially free of other biological molecules from the cells or cell culture from which they are produced. Such biological molecules include nucleic acids, proteins, other VEGF antagonists and VEGF receptor fusion proteins, lipids, carbohydrates, or other material such as cellular debris and growth medium. An isolated VEGF antagonist or VEGF receptor fusion protein may further be at least partially free of expression system components such as biological molecules from a host cell or of the growth medium thereof. Generally, the term "isolated" is not intended to be limited to a complete absence of such biological molecules (e.g., minor or insignificant amounts of impurity may remain) or to an absence of water, buffers, or salts or to components of a pharmaceutical formulation that includes the VEGF antagonists or VEGF receptor fusion proteins.

[0101] “Subject” and “patient” are used interchangeably herein. A subject or patient is a mammal, for example a human, mouse, rabbit, monkey or non-human primate, preferably a human. In one embodiment the subject is human. A subject or patient may be said to be “suffering from” an angiogenic eye disorder such as macular edema secondary to retinal vein occlusion or visual impairment due to macular edema secondary to retinal vein occlusion. Retinal vein occlusion includes branch RVO (BRVO), central RVO (CRVO), and hemiretinal RVO (HRVO). Such a subject or patient has the disorder in one or both eyes. In an embodiment of the disclosure, a subject or patient (preferably, a human) has one or more of the following characteristics (presently or in the past):

• Treatment-naive macular edema;

• Treatment-naive macular edema involving the foveal center secondary to RVO (BRVO, HRVO, or CRVO); • A Mean central subfield thickness (CST) >300 pm on OCT e.g., measured by Cirrus or Topcon spectral domain optical coherence tomography (SD-OCT) (or >320 pm measured on Heidelberg Spectralis); and/or

• Macular edema following RVO (CRVO, BRVO, or HRVO) involving the foveal center.

[0102] In any of the embodiments set out herein, unless otherwise stated, the method is for treating or preventing retinal vein occlusion (RVO) in an eye of a subject in need thereof.

[0103] In any of the embodiments set out herein, unless otherwise stated, the method is for treating or preventing macular edema secondary retinal vein occlusion (RVO) in an eye of a subject in need thereof.

[0104] In any of the embodiments set out herein, unless otherwise stated, the method is for improving visual impairment or best corrected visual acuity due to an angiogenic eye disorder macular edema secondary to retinal vein occlusion in an eye of a subject in need thereof.

[0105] In one embodiment of the invention subjects suffering from retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion have not been previously treated with anti-VEGF treatment.

[0106] In one embodiment of the invention, subjects suffering from retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion have been previously treated with anti-VEGF treatment.

[0107] Such anti-VEGF treatments include but are not limited to aflibercept at a dose of 2 mg, faricimab, ranibizumab or bevacizumab. In one embodiment of the invention, said subject has been previously treated with aflibercept at a dose of 2 mg. In one embodiment of the invention said subject has been previously treated with faricimab. In one embodiment of the invention said subject has been previously treated with 2 mg aflibercept.

[0108] In any of the embodiments set out herein, unless otherwise stated, a subject may have Macular Edema Secondary to Retinal Vein Occlusion (MERVO); Retinal vein occlusion includes, for example, branch RVO (BRVO), central RVO (CRVO), and hemiretinal RVO (HRVO).

[0109] In any of the embodiments set out herein, unless otherwise stated, the subject may be one that has treatment-naive macular edema. It may be that such subjects have treatment-naive macular edema involving the foveal center secondary to RVO (e.g., BRVO, HRVO, or CRVO). [0110] In any of the embodiments set out herein, unless otherwise stated, the subject may be one that has macular edema secondary to RVO that has pre-treatment with an VEGF antagonist such as but not limited to 2 mg aflibercept, faricimab, ranibizumab or bevacizumab (e.g., >3 anti-VEGF ocular injections over the prior 5 months (-150 days). It may be that such subjects have pre-treated macular edema involving the foveal center secondary to RVO (e.g., BRVO, HRVO, or ORVO). In an embodiment of the invention, the subject is treatment-naive.

[0111] In an embodiment of the disclosure, a subject or patient (preferably, a human) does not have one or more of the following characteristics:

• Evidence of macular edema due to any cause other than RVO;

• Diabetic retinopathy;

• Diabetic macular edema;

• Advanced age-related macular degeneration (nAMD or geographic atrophy);

• Use of any intravitreal implantable agent in an eye (e.g., the eye to receive the treatment);

• Prior treatment with ocriplasmin at any time in an eye (e.g., the eye to receive the treatment);

• Prior treatment with pegcetacoplan injection or avacincaptad pegol injection in an eye (e.g., the eye to receive the treatment);

• Prior treatment with retinal laser photocoagulation in an eye (e.g., the eye to receive the treatment);

• Prior treatment with gene therapy and/or cell therapy in an eye (e.g., the eye to receive the treatment);

• History of vitreoretinal surgery (including scleral buckle) in an eye (e.g., the eye to receive the treatment);

• Any intraocular surgery, including cataract surgery, e.g., within 12 weeks (84 days) of treatment, in an eye (e.g., the eye to receive the treatment);

• YAG (Yttrium-aluminum-garnet) capsulotomy in an eye within 4 weeks (28 days) of treatment (e.g., the eye to receive the treatment);

• IOP > 25 mm Hg in an eye (e.g., the eye to receive the treatment);

• Uncontrolled glaucoma in an eye (e.g., the eye to receive the treatment);

• Infectious blepharitis, keratitis, scleritis, or conjunctivitis in an eye (e.g., the eye to receive the treatment); • Any intraocular inflammation/infection (including trace, or above, cells in the anterior chamber and/or vitreous), e.g., within 12 weeks (84 days) of the treatment, in an eye (e.g., the eye to receive the treatment);

• History of idiopathic or autoimmune uveitis in an eye (e.g., the eye to receive the treatment);

• Vitreomacular traction or epiretinal membrane in an eye evident on biomicroscopy or OCT that is affects central vision (e.g., the eye to receive the treatment);

• Myopia of a spherical equivalent of 8 diopters or greater in an eye (prior to any refractive or cataract surgery, if applicable) (e.g., the eye to receive the treatment);

• History of corneal transplant in an eye (e.g., the eye to receive the treatment);

• Any corneal dystrophy affecting the visual axis in an eye (e.g., the eye to receive the treatment);

• Aphakia, or pseudophakia with absence of posterior capsule (unless it occurred as a result of a YAG posterior capsulotomy, e.g., performed more than 28 days before treatment in an eye (e.g., the eye to receive the treatment);

• Any history of macular hole of stage 2 and above in an eye (e.g., the eye to receive the treatment);

• Current anterior segment neovascularization, vitreous hemorrhage, or tractional retinal detachment visible in an eye (e.g., the eye to receive the treatment);

• Structural damage in an eye (e.g., the eye to receive the treatment) that is likely to preclude improvement in BCVA following resolution of macular edema (including atrophy of the retinal pigment epithelium, preretinal fibrosis, subretinal fibrosis or scar, significant macular ischemia, or organized hard exudates);

• Uncontrolled blood pressure (systolic > 160 mm Hg or diastolic > 95 mm Hg);

• Uncontrolled diabetes mellitus (DM), defined by hemoglobin A1c (HbA1c) >12% at treatment;

• History of cerebrovascular accident/transient ischemic attack or myocardial infarction/acute coronary syndrome, e.g., within 6 months (180 days) of treatment; • Renal failure, dialysis, or history of renal transplant;

• Known sensitivity to any of the compounds administered to an eye (e.g., the eye to receive the treatment);

• Presence of systemic infection or treatment for suspected or active systemic infection;

• Subject is pregnant or is a breastfeeding woman; • Subject is a man or woman of child bearing potential who is not practicing a highly effective contraception prior to treatment or at least 4 months after cessation of treatment; wherein said highly effective contraception comprises stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal, contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to treatment;, intrauterine device; or intrauterine hormone-releasing system; bilateral tubal occlusion/ligation; vasectomy; condom plus contraceptive sponge, foam, or jelly, or diaphragm plus contraceptive sponge, foam, or jelly; and/or sexual abstinence.

[0112] Thus, the present disclosure includes a method for treating and/or preventing an angiogenic eye disorder, e.g., an angiogenic eye disorder secondary to retinal vein occlusion (e.g., MERVO), or treating retinal vein occlusion, in a subject in need thereof:

• that is an adult >18 years of age (or country’s legal age of adulthood if the legal age is >18 years);

• that has treatment-naive macular edema involving the foveal center secondary to RVO (e.g., BRVO, HRVO, or CRVO) diagnosed within 16 weeks (112 days) before beginning treatment;

• that has a Early Treatment Diabetic Retinopathy Study BCVA letter score of 73 to 24 (20/40 to 20/320) in at least one eye;

• that has experienced a decrease in BCVA determined to be primarily the result of RVO in at least one eye; or

• that has a mean CST >300 pm on OCT (or >320 pm on Heidelberg Spectralis) in at least one eye,

comprising administering to an eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of a VEGF receptor fusion protein, preferably aflibercept, followed by one or more (e.g., 2, 3 or 4) secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 4, 8, 12, 16, 20 or 24 weeks after the immediately preceding dose. In one such embodiment, the subject has macular edema secondary to retinal vein occlusion (MERVO). 11876WO01

VEGF Antagonists

[0113] The present invention includes methods for using a VEGF antagonist for treating or preventing angiogenic eye disorders (e.g., RVO or conditions secondary to RVO; e.g., MERVO). VEGF antagonists include molecules which interfere with the interaction between VEGF and a natural VEGF receptor, e.g., molecules which bind to VEGF or a VEGF receptor and prevent or otherwise hinder the interaction between VEGF and a VEGF receptor. Specific, exemplary VEGF antagonists include anti-VEGF antibodies, anti-VEGF receptor antibodies, and VEGF receptor fusion proteins. Though VEGF receptor fusion proteins, such as aflibercept, are preferred for use in connection with the methods set forth herein, the scope of the present invention includes such methods wherein any of the VEGF antagonists described herein (e.g., scFvs, DARPins, anti-VEGF antibodies) are used in place of such fusion proteins.

[0114] For purposes herein, a “VEGF receptor fusion protein” refers to a molecule that comprises one or more VEGF receptors or domains thereof, fused to another polypeptide, which interferes with the interaction between VEGF and a natural VEGF receptor, e.g., wherein two of such fusion polypeptides are associated thereby forming a homodimer or other multimer. Such VEGF receptor fusion proteins may be referred to as a " VEGF-Trap" or “VEGF Trap”. VEGF receptor fusion proteins within the context of the present disclosure that fall within this definition include chimeric polypeptides which comprise two or more immunoglobulin (Ig)-like domains of a VEGF receptor such as VEGFR1 (also known as Flt1 ) and/or VEGFR2 (also known as Flk1 or KDR), and may also contain a multimerizing domain (for example, an Fc domain).

[0115] An exemplary VEGF receptor fusion protein is a molecule referred to as VEGF1R2-FcAC1 (a) which is encoded by the nucleic acid sequence of SEQ ID NO:1 or nucleotides 79-1374 or 79-1371 thereof.

[0116] VEGF1R2-FcAC1(a) comprises or consists of three components:

(1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO:2;

(2) a VEGFR2 component comprising amino acids 130 to 231 of SEQ ID NO:2; and (3) a multimerization component (" FcAC1(a)") comprising amino acids 232 to 457 of SEQ ID NO:2 (with an optional lysine at the C-terminal end (K458); e.g., the C- terminal amino acids of SEQ ID NO:2, i.e., K458, may or may not be included in the VEGF receptor fusion proteins, see U. S. Patent No. 7,396,664 or 7,354,579, incorporated herein for all purposes). Note that amino acids 1 to 26 of SEQ ID NO:2 are the signal sequence. [0117] If the multimerizing component (MO) of a VEGF receptor fusion protein is derived from an IgG (e.g., lgG1 ) Fc domain, then the MO has no fewer amino acids than are in amino acids 232 to 457 of SEQ ID NO:2. Thus, the IgG of the MC cannot be truncated to be shorter than 226 amino acids.

[0118] In an embodiment of the invention, the VEGF receptor fusion protein consists of amino acids 27-458 or 27-457 of SEQ ID NO: 2, e.g., with an optional lysine at the C-terminal end (K458). Said VEGF receptor fusion protein can form a homodimer.

atggtcagctactgggacaccggggtcctgctgtgcgcgctgctcagctgtctgcttctcacaggatctagttccgg aagtgataccggtagacctttcgtagagatgtacagtgaaatccccgaaattatacacatgactgaaggaagggagc tcgtcattccctgccgggttacgtcacctaacatcactgttactttaaaaaagtttccacttgacactttgatccct gatggaaaacgcataatctgggacagtagaaagggcttcatcatatcaaatgcaacgtacaaagaaatagggcttct gacctgtgaagcaacagtcaatgggcatttgtataagacaaactatctcacacatcgacaaaccaatacaatcatag atgtggttct agtccgtctcat gaattgaactatctgttggagaaaagcttgtcttaaattgt cagcaagaact gaact aatgtggggattgacttcaactgggaatacccttcttcgaagcatcagcataagaaacttgt aaccgaga cctaaaaacccagtctgggagtgagatgaagaaatttttgagcaccttaactatagatggtgtaacccggagtgacc aaggattgtacacctgtgcagcatccagtgggctgatgaccaagaagaacagcacatttgtcagggtccatgaaaag gacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaa acccaaggacaccctcatgatctcccggacccctgaggtcacat cgtggtggtggacgtgagccacgaagaccctg aggtcaagttcaactggtacgtggacggcgtggaggtgcataat ccaagacaaagccgcgggaggagcagtacaac agcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggt ctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgt acaccctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacct cctggtcaaaggcttctatccc agcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactc cgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgct ccgtgat catgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaatga

(SEQ ID NO: 1)

MVSYWDTGVLLCALLSCLLLTGSSSGSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTS PNITVTLKKFPLDTLIPDGKRI IWDSRKGFI I SNATYKEIGLLTCEATVNGHLYKTNYLT HRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRD LKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

(SEQ ID NO: 2; signal sequence underscored; optionally lacking C-terminal K residue) [0119] In an embodiment of the invention, the VEGF receptor fusion protein comprises (1 ) an immunoglobin-like (Ig) domain 2 of a first VEGF receptor (e.g., VEGFR1 ), and

(2) an Ig domain 3 of a second VEGF receptor (e.g., VEGFR2),

(3) and, optionally, further including an Ig domain 4 of the second VEGF receptor (e.g., VEGFR2) and

(4) a multimerizing component (e.g., Fc domain of IgG including the hinge, CH2 and CH3 domains).

[0120] For example, in an embodiment of the invention, the VEGF receptor fusion protein has the following arrangement of said domains:

• [VEGFR1 Ig domain 2]-[VEGFR2 Ig domain 3]-[MC] (e.g., a homodimer thereof) or • [VEGFR1 Ig domain 2]-[VEGFR2 Ig domain 3]-[VEGFR2 Ig domain 4]-[MC] (e.g., a homodimer thereof).

[0121] In any of the embodiments set out herein, unless otherwise stated, the VEGF receptor fusion protein may, preferably, be aflibercept. In an alternative embodiment it may be conbercept.

[0122] Note that the present disclosure also includes, within its scope, high concentration formulations including, instead of a VEGF receptor fusion protein, a VEGF binding molecule or anti-VEGF antibody or antigen-binding fragments thereof or biopolymer conjugate thereof (e.g., KSI-301), e.g.,

• bevacizumab (e.g., at a concentration of about 80-90 or 88 mg/ml),

• ranibizumab (e.g., at a concentration of about 20-40 mg/ml, e.g., 21-35, 21 or 35 mg/ml), • an anti-VEGF aptamer such as pegaptanib (e.g., pegaptanib sodium),

• a single chain (e.g., V_L-V ) anti-VEGF antibody such as brolucizumab (e.g., at a concentration of about 200-400 or 200, 210, 400 or 420 mg/ml),

• an anti-VEGF DARPin such as the Abicipar Pegol DARPin (e.g., at a concentration of about 70-140, 70 or 140 mg/ml), or

• a bispecific anti-VEGF antibody, e.g., which also binds to ANG2, such as RG7716 (faricimab) (e.g., at a concentration of about 100-400, 100, 105, 400 or 420 mg/ml).

[0123] In order to minimize the repetitiveness of the embodiments discussed herein, it is contemplated that the scope of the present invention includes embodiments wherein any of the formulations discussed herein include, in place of a VEGF receptor fusion protein, an anti-VEGF antibody or antibody fragment or other VEGF binding molecule as discussed herein (e.g., substituted with an anti-VEGF DARPin) at any of the concentrations discussed herein. For example, the present invention includes a formulation having 35 or 80 mg/ml ranibizumab, a buffer, a thermal stabilizer, a viscosity reducing agent and a surfactant.

[0124] DARPins are Designed Ankyrin Repeat Proteins. DARPins generally contain three to four tightly packed repeats of approximately 33 amino acid residues, with each repeat containing a [3-turn and two anti-parallel a-helices. This rigid framework provides protein stability whilst enabling the presentation of variable regions, normally comprising six amino acid residues per repeat, for target recognition.

[0125] An “anti-VEGF” antibody or antigen-binding fragment of an antibody refers to an antibody or fragment that specifically binds to VEGF.

[0126] Illustrative VEGF receptor fusion proteins include aflibercept (sold as EYLEA or EYLEA HD, Regeneron Pharmaceuticals, Inc.) or conbercept (sold commercially by Chengdu Kanghong Biotechnology Co., Ltd.). See International patent application publication no.

W02005/121176 or W02007/112675. The terms “aflibercept” and “conbercept” include biosimilar versions thereof. A biosimilar version of a reference product (e.g., aflibercept) generally refers to a product comprising the identical amino acid sequence, but includes products which are biosimilar under the U. S. Biologies Price Competition and Innovation Act. In one embodiment, the VEGF receptor fusion protein is aflibercept or a bioequivalent thereof. In an embodiment of the invention the VEGF receptor fusion protein is aflibercept.

[0127] The present invention also includes embodiments including administering one or more further therapeutic agents in addition to VEGF antagonist, for example, administering (one or more doses of) a second VEGF antagonist, an antibiotic, anesthetic (e.g., local anesthetic) to the eye receiving an injection, a non-steroidal anti-inflammatory drug (NSAID), a steroid (e.g., a corticosteroid, dexamethasone), triamcinolone acetonide (TA), methotrexate, rapamycin, an anti-tumor necrosis factor alpha drug (e.g., infliximab), daclizumab, and/or a complement component (e.g., C3 or C5) inhibitor, e.g., systemically or intraocularly or intravitreally. In any of the embodiments where a further therapeutic agent is administered, it may be that both the VEGF antagonist and further therapeutic agent are administered in the same pharmaceutical composition. Alternatively, it may be that they are administered in separate pharmaceutical compositions. In one embodiment, it may be that the VEGF antagonist and further therapeutic agent are in separate compositions that are administered simultaneously, separately, or sequentially.

[0128] In an embodiment of the invention, a VEGF antagonist such as a VEGF receptor fusion protein, e.g., aflibercept, was expressed in a chemically defined medium (CDM). In an embodiment of the invention, one or more histidines in the VEGF antagonist (e.g., aflibercept) is

a 2-oxo-histidine (e.g., or

Pharmaceutical Formulations

[0129] The present invention includes methods in which the VEGF antagonist that is administered to the subject’s eye is contained within an aqueous pharmaceutical formulation that includes a pharmaceutically acceptable carrier. The present invention also includes a pharmaceutical formulation as set out herein for use in a method as set out herein. The pharmaceutical formulation includes a VEGF antagonist, which is preferably aflibercept, along with a pharmaceutically acceptable carrier. Other agents may be incorporated into the pharmaceutical formulation to provide improved transfer, delivery, tolerance, and the like. The term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U. S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly, in humans, preferably by intravitreal injection. The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the VEGF antagonist is administered. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences (15^thed, Mack Publishing Company, Easton, Pa., 1975), e.g., Chapter 87 by Blaug, Seymour, therein.

[0130] Pharmaceutical formulations for use in a method of the present invention can be “high concentration”. High concentration pharmaceutical formulations of the present invention include a VEGF antagonist, e.g., VEGF receptor fusion protein, at a concentration of at least 41 mg/ml, of at least 80 mg/ml, of at least 100 mg/ml, greater than about 100 mg/ml, of at least 125 mg/ml, of at least 140 mg/ml, of at least 150 mg/ml, of at least 175 mg/ml, of at least 200 mg/ml, of at least 225 mg/ml, of at least 250 mg/ml, or of at least 275 mg/ml. " High concentration” can refer to formulations that include a concentration of VEGF antagonist of from about 140 mg/ml to about 160 mg/ml, at least about 140 mg/ml but less than 160 mg/ml, from about 41 mg/ml to about 275 mg/ml, from about 70 mg/ml to about 75 mg/ml or from about 80 mg/ml to about 250 mg/ml. In some aspects, the VEGF antagonist concentration in the formulation is about any of the following concentrations: 41 mg/ml; 42 mg/ml; 43 mg/ml; 44 mg/ml; 45 mg/ml; 46 mg/ml; 47 mg/ml; 48 mg/ml; 49 mg/ml; 50mg/ml; 51 mg/ml; 52 mg/ml; 53 mg/ml; 54 mg/ml; 55 mg/ml; 56 mg/ml; 57 mg/ml; 58 mg/ml; 59 mg/ml; 60 mg/ml; 61 mg/ml; 62 mg/ml; 63 mg/ml; 64 mg/ml; 65 mg/ml; 66 mg/ml; 67 mg/ml; 68 mg/ml; 69 mg/ml; 70 mg/ml; 71 mg/ml; 72 mg/ml; 73 mg/ml; 74 mg/ml; 75 mg/ml; 76 mg/ml; 77 mg/ml; 78 mg/ml; 79 mg/ml; 80 mg/ml; 81 mg/ml; 82mg/ml; 83 mg/ml; 84 mg/ml; 85 mg/ml; 86 mg/ml; 87mg/ml; 88 mg/ml; 89 mg/ml; 90 mg/ml; 91 mg/ml; 92 mg/ml; 93 mg/ml; 94 mg/ml; 95mg/ml; 96 mg/ml; 97 mg/ml; 98 mg/ml; 99 mg/ml; 100 mg/ml; 101 mg/ml; 102 mg/ml; 103 mg/ml; 104 mg/ml; 105 mg/ml; 106mg/ml; 107 mg/ml; 108 mg/ml; 109 mg/ml; 110 mg/ml; 111 mg/ml; 112 mg/ml; 113 mg/ml; 113.3 mg/ml; 114 mg/ml; 114.1 mg/ml; 114.2 mg/ml; 114.3 mg/ml; 114.4 mg/ml; 114.5 mg/ml; 114.6 mg/ml; 114.7 mg/ml; 114.8 mg/ml; 114.9 mg/ml; 115 mg/ml; 116 mg/ml; 117 mg/ml; 118 mg/ml; 119 mg/ml; 120 mg/ml; 121 mg/ml; 122 mg/ml; 123 mg/ml; 124 mg/ml; 125 mg/ml; 126 mg/ml; 127mg/ml; 128 mg/ml; 129 mg/ml; 130 mg/ml; 131 mg/ml; 132 mg/ml; 133 mg/ml; 133.3 mg/ml; 133.4 mg/ml; 134 mg/ml; 135 mg/ml; 136 mg/ml; 137 mg/ml; 138 mg/ml; 139 mg/ml; 140 mg/ml; 141 mg/ml; 142 mg/ml; 143 mg/ml; 144 mg/ml; 145 mg/ml; 146 mg/ml; 147 mg/ml; 148 mg/ml; 149 mg/ml; 150 mg/ml; 151 mg/ml; 152 mg/ml; 153 mg/ml; 154mg/ml; 155 mg/ml; 156 mg/ml; 157mg/ml; 158 mg/ml; 159 mg/ml; 160 mg/ml; 161 mg/ml; 162 mg/ml; 163 mg/ml; 164 mg/ml; 165 mg/ml; 166 mg/ml; 167 mg/ml; 168 mg/ml; 169 mg/ml; 170 mg/ml; 171 mg/ml; 172 mg/ml; 173 mg/ml; 174 mg/ml; 175 mg/ml; 176 mg/ml; 177 mg/ml; 178 mg/ml; 179 mg/ml; 180 mg/ml; 181 mg/ml; 182 mg/ml;183 mg/ml; 184 mg/ml; 185 mg/ml; 186 mg/ml; 187 mg/ml; 188 mg/ml; 189 mg/ml; 190 mg/ml; 191 mg/ml; 192 mg/ml; 193 mg/ml; 194 mg/ml; 195 mg/ml; 196 mg/ml; 197 mg/ml; 198 mg/ml; 199 mg/ml; 200 mg/ml; 201 mg/ml; 202 mg/ml; 203 mg/ml; 204 mg/ml; 205 mg/ml; 206 mg/ml; 207 mg/ml; 208 mg/ml; 209 mg/ml; 210 mg/ml; 211 mg/ml; 212 mg/ml; 213 mg/ml; 214 mg/ml; 215 mg/ml; 216 mg/ml; 217 mg/ml; 218 mg/ml; 219 mg/ml; 220 mg/ml; 221 mg/ml; 222 mg/ml; 223 mg/ml; 224 mg/ml; 225 mg/ml; 226 mg/ml; 227 mg/ml; 228 mg/ml; 229 mg/ml; 230 mg/ml; 231 mg/ml; 232 mg/ml; 233 mg/ml; 234 mg/ml; 235 mg/ml; 236 mg/ml; 237mg/ml; 238 mg/ml; 239 mg/ml; 240 mg/ml; 241 mg/ml; 242 mg/ml; 243 mg/ml; 244 mg/ml; 245 mg/ml; 246 mg/ml; 247 mg/ml; 248 mg/ml; 249 mg/ml; 250 mg/ml; 251 mg/ml; 252 mg/ml; 253 mg/ml; 254 mg/ml; 255 mg/ml; 256 mg/ml; 257 mg/ml; 258 mg/ml; 259 mg/ml; 260 mg/ml; 261 mg/ml; 262 mg/ml; 263 mg/ml; 264 mg/ml; 265 mg/ml; 266 mg/ml; 267 mg/ml; 268 mg/ml; 269 mg/ml; 270 mg/ml; 271 mg/ml; 272 mg/ml; 273 mg/ml; 274 mg/ml; or 275 mg/ml. Other VEGF antagonist concentrations are contemplated herein, as long as the concentration functions in accordance with embodiments herein. In an embodiment of the invention, the VEGF antagonist concentration in a pharmaceutical formulation is about 100 mg/l to about 120 mg/ml aflibercept. In an embodiment of the invention, the VEGF antagonist concentration in a pharmaceutical formulation is about 110 mg/l to about 120 mg/ml aflibercept. In an embodiment of the invention, the VEGF antagonist concentration in a pharmaceutical formulation is about 114.3 mg/mL aflibercept.

[0131] In an embodiment of the invention, a pharmaceutical formulation for use in a method of the present invention is of such a concentration as to contain about 4, 6, 8, 10, 12, 14, 16, 18 or 20 mg VEGF receptor fusion protein (e.g., aflibercept), or the amount of such protein in any of the acceptable doses thereof which are discussed herein, in about 100 pl or less, about 75 pl or less or about 70 pl or less, e.g., about 50 pl; 51 pl; 52 pl; 53 pl; 54 pl; 55 pl; 56 pl; 57 pl; 58 pl; 59 pl; 60 pl; 61 pl; 62 pl; 63 pl; 64 pl; 65 pl; 66 pl; 67 pl; 68 pl; 69 pl; 70 pl; 71 pl; 72 pl; 73 pl; 74 pl; 75 pl; 76 pl; 77 pl; 78 pl; 79 pl; 80 pl; 81 pl; 82 pl; 83 pl; 84 pl; 85 pl; 86 pl; 87 pl; 88 pl; 89 pl; 90 pl; 91 pl; 92 pl; 93 pl; 94 pl; 95 pl; 96 pl; 97 pl; 98 pl; 99 pl; or 100 pl. In an embodiment of the invention, the VEGF antagonist concentration in a pharmaceutical formulation is about 8 mg (±0.8 mg) aflibercept in about 70 pl.

[0132] The present invention includes methods of using (as discussed herein) any of the formulations set forth under “Illustrative pharmaceutical formulations" herein, but wherein the concentration of the VEGF receptor fusion protein (e.g., aflibercept) is substituted with a concentration which is set forth in this section.

[0133] Buffers for use in pharmaceutical formulations herein that may be used in a method of the present invention refer to solutions that resist pH change by use of acid-base conjugates. Buffers are capable of maintaining pH in the range of from about 5.0 to about 6.8, and more typically, from about 5.8 to about 6.5, and most typically, from about 6.0 to about 6.5. In some cases, the pH of the formulation of the present invention is about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, or about 6.8. Example buffers for inclusion in formulations herein include histidine-based buffers, for example, histidine and histidine hydrochloride or histidine acetate. Buffers for inclusion in formulations herein can alternatively be phosphate-based buffers, for example, sodium phosphate, tris-based, acetate-based buffers, for example, sodium acetate or acetic acid, or can be citrate-based, for example, sodium citrate or citric acid. It is also recognized that buffers can be a mix of the above, as long as the buffer functions to buffer the formulations in the above described pH ranges. In some cases, the buffer is from about 5 mM to about 25 mM, or more typically, about 5 mM to about 15 mM. Buffers can be about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM, about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM, about 20 mM, about 21 mM, about 22 mM, about 23 mM, about 24 mM, or about 25 mM.

[0134] In an embodiment of the invention, a histidine-based buffer is prepared using histidine and histidine monohydrochloride.

[0135] In one embodiment of the invention the pharmaceutical formulation has a pH of 5.8.

[0136] In one embodiment of the invention the pharmaceutical formulation comprises a histidine-based buffer or a phosphate-based buffer.

[0137] In one embodiment of the invention the pharmaceutical formulation does not include a buffer. In this embodiment, the anti-VEGF antagonist (e.g. aflibercept) functions, itself, as a buffer.

[0138] In one embodiment of the invention the pharmaceutical formulation comprises 10 -50 mM buffer.

[0139] In one embodiment of the invention the pharmaceutical formulation comprises 10 -50 mM histidine-based buffer (e.g., 10 mM histidine-based buffer).

[0140] In one embodiment of the invention the pharmaceutical formulation comprises 10 -50 mM phosphate-based buffer.

[0141] Surfactant for use herein refers to ingredients that protect the higher concentration of VEGF antagonist, e.g., VEGF receptor fusion protein, from various surface and interfacial induced stresses. As such, surfactants can be used to limit or minimize VEGF receptor fusion protein aggregation, and promote protein solubility. Suitable surfactants herein have been shown to be non-ionic, and can include surfactants that have a polyoxyethylene moiety.

Illustrative surfactants in this category include: polysorbate 20, polysorbate 80, poloxamer 188, polyethylene glycol 3350, and mixtures thereof. Surfactants in the formulations can be present at from about 0.02% to about 0.1% weight per volume (w/v), and more typically, about 0.02% to about 0.04% (w/v). In some cases, the surfactant is about 0.02% (w/v), about 0.03% (w/v), about 0.04% (w/v), about 0.05% (w/v), about 0.06% (w/v), about 0.07% (w/v), about 0.08% (w/v), about 0.09% (w/v), or about 0.1% (w/v).

[0142] In one embodiment of the invention the pharmaceutical formulation comprises a surfactant. [0143] In one embodiment of the invention the pharmaceutical formulation comprises 0.01% to 0.04% (w/v) (e.g. 0.03% (w/v) surfactant.

[0144] In one embodiment of the invention the pharmaceutical formulation comprises 0.01% (w/v) - 0.03% (w/v) polysorbate 20 or polysorbate 80.

[0145] Thermal stabilizers for use in pharmaceutical formulations that may be used in methods set forth herein refers to ingredients that provide thermal stability against thermal denaturation of the VEGF antagonist, e.g., VEGF receptor fusion protein, as well as protect against loss of VEGF receptor fusion protein potency or activity. Suitable thermal stabilizers include sugars, and can be sucrose, trehalose, sorbitol or mannitol, or can be amino acids, for example L-proline, L-arginine (e.g., L-arginine monohydrochloride), or taurine. Additionally, thermal stabilizers may also include substituted acrylamides or propane sulfonic acid, or may be compounds like glycerol.

[0146] In one embodiment of the invention the pharmaceutical formulation comprises a sugar and/or an amino acid (e.g., L-arginine).

[0147] In one embodiment of the invention the pharmaceutical formulation comprises 2% (w/v) - 10% (w/v) sugar.

[0148] In one embodiment of the invention the pharmaceutical formulation comprises 2% (w/v) - 10% (w/v) sucrose, trehalose, sorbitol or mannitol.

[0149] In one embodiment of the invention the pharmaceutical formulation comprises 2% (w/v) - 10% (w/v) sucrose or trehalose.

[0150] In one embodiment of the invention the pharmaceutical formulation comprises 5% (w/v) sucrose.

[0151] In one embodiment of the invention the pharmaceutical formulation comprises 10 mM - 100 mM amino acid.

[0152] In one embodiment of the invention the pharmaceutical formulation comprises 10 mM - 100 mM (e.g. 10 mM -50 mM) proline, arginine (e.g., arginine monohydrochloride), or taurine.

[0153] In one embodiment of the invention the pharmaceutical formulation comprises 10 mM - 100 mM (e.g. 10 - 50 mM) arginine (e.g., arginine monohydrochloride).

[0154] In one embodiment of the invention the pharmaceutical formulation comprises 50 mM L-arginine, e.g., L-arginine monohydrochloride.

[0155] In an embodiment of the invention, a pharmaceutical formulation of the present invention includes aflibercept, e.g., greater than 100 mg/ml aflibercept, L-arginine and a histidine-based buffer. [0156] In some cases, the pharmaceutical formulations for use in a method herein include both a sugar and taurine, a sugar and an amino acid, a sugar and propane sulfonic acid, a sugar and taurine, glycerol and taurine, glycerol and propane sulfonic acid, an amino acid and taurine, or an amino acid and propane sulfonic acid. In addition, formulations can include a sugar, taurine and propane sulfonic acid, glycerol, taurine and propane sulfonic acid, as well as L-proline, taurine and propane sulfonic acid.

[0157] Embodiments herein may have thermal stabilizers present alone, each independently present at a concentration of, or present in combination at a total concentration of, from about 2% (w/v) to about 10% (w/v) or 4% (w/v) to about 10% (w/v), or about 4% (w/v) to about 9% (w/v), or about 5% (w/v) to about 8% (w/v). Thermal stabilizers in the formulation can be at a concentration of about 2% (w/v), about 2.5% (w/v), about 3% (w/v), about 4% (w/v), about 5% (w/v), about 6% (w/v), about 7% (w/v), about 8% (w/v), about 9% (w/v), about 10% (w/v) or about 20% (w/v). In an embodiment of the invention, the stabilizer is L-arginine, e.g., L-arginine monohydrochloride.

[0158] With respect to taurine and propane sulfonic acid, in an embodiment of the invention, these thermal stabilizers can be present in the formulations at about from 25 mM to about 100 mM, and more typically from about 50 mM to about 75 mM (as compared to the other thermal stabilizers).

[0159] Viscosity reducing agents typically are used to reduce or prevent protein aggregation. Viscosity reducing agents for inclusion herein include: sodium chloride, magnesium chloride, D-or L-arginine (e.g., L-arginine monohydrochloride), lysine, or mixtures thereof. When present herein, viscosity reducing agents can be present at from about 10 mM to about 100 mM, and more typically from about 30 mM to about 75 mM, and even more typically from about 40 mM to about 70 mM. In some cases, the viscosity reducing agent is present at about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM, about 95 mM or about 100 mM.

[0160] In one embodiment of the invention the pharmaceutical formulation comprises 10 mM - 100 mM amino acid or/and an inorganic salt (e.g. sodium chloride, magnesium chloride).

[0161] In one embodiment of the invention the pharmaceutical formulation comprises 10 mM - 100 mM (e.g. 10 mM -50 mM) L-arginine (e.g., L-arginine monohydrochloride).

[0162] In one embodiment of the invention the pharmaceutical formulation comprises 10 mM - 100 mM (e.g. 10 - 50 mM) arginine (e.g., L-arginine monohydrochloride). [0163] In one embodiment of the invention the pharmaceutical formulation comprises 50 mM L-arginine monohydrochloride.

[0164] In one embodiment of the invention the pharmaceutical formulation comprises 10 mM - 100 mM sodium chloride or magnesium chloride.

[0165] In one embodiment of the invention the pharmaceutical formulation comprises 10 mM - 50 mM sodium chloride or magnesium chloride.

[0166] Pharmaceutical formulations for use in a method as set forth herein can also have a pharmaceutically acceptable viscosity for ocular administration, for example, intravitreal injection. Viscosity generally refers to the measure of resistance of a fluid which is being deformed by either shear stress or tensile stress (typically measured by techniques known in the art, viscometer or rheometer, for example). Typical viscosities of formulations for use in a method set forth herein are from about 5.0 cP (centipoise) to about 15 cP, from about 11 cP to about 14 cP, from about 12 cP to about 15 cP or from about 11 cP to about 12 cP. As such, formulation viscosity herein can be about 5.0 cP, about 6.0, about 7.1 cP, about 7.2 cP, about 7.3 cP, about 7.4 cP, about 7.5 cP, about 7.6 cP, about 10 cP, about 10.5 cP, about 11.0 cP, about 11.5 cP, about 12.0 cP, about 12.5 cP, about 13.0 cP, about 13.5 cP, about 14.0 cP, about 14.5 cP, or about 15.0 cP (e.g., when measured at 20°C). In one embodiment of the invention the viscosity of the pharmaceutical formulation is 12 cP to about 15 cP at 20°C.

[0167] Various embodiments herein do not require inclusion of an inorganic salt, or other viscosity reducing agent, to maintain these highly useful viscosities. Typically, high concentration protein solutions require viscosity reducing agents to avoid protein aggregation and higher viscosity, making the formulations difficult for intravitreal injection and reducing the potency of the VEGF receptor fusion protein. As such, embodiments herein include methods of using formulations that have had substantially no, or no added, sodium chloride (NaCI), magnesium chloride (MgCk), D- or L-arginine (e.g., L-arginine hydrochloride), lysine or other viscosity reducing agent.

[0168] Osmolality is a critical attribute for injectable pharmaceutical formulations for use in a method of the present invention. It is desirable to have products match physiological osmotic conditions. Furthermore, osmolality provides confirmation of soluble content in solution. In an embodiment of the invention, the osmolality of a formulation for use in a method of the present invention is less than or equal to about 506 mmol/Kg or from about 250 to about 506 mmol/Kg, e.g., about 250, 260, 270, 280, 290, 299, 300, 310, 314, 315, 316, 324, 343, 346, 349, 369, 384, 403, 426, 430 or 506 mmol/Kg. In an embodiment of the invention, the osmolality is lower than about 250 mmol/Kg. In an embodiment of the invention, the formulation is isotonic. [0169] In an embodiment of the invention, the VEGF antagonist (e.g., aflibercept) is in an aqueous pharmaceutical composition wherein the composition characterized by a color: (i) which is no more brown-yellow than European Color Standard BY2; (ii) which is no more brownyellow than European Color Standard BY3; (iii) which is no more brown-yellow than European Color Standard BY4; (iv) which is no more brown-yellow than European Color Standard BY5; (v) which is no more brown-yellow than European Color Standard BY6; (vi) which is no more brown-yellow than European Color Standard BY7; (vi) which is between European Color Standard BY2 and BY3; (vii) which is between European Color Standard BY2 and BY4. For example, in an embodiment of the invention, the VEGF antagonist was expressed in a chemically defined medium. In an embodiment of the invention, one or more histidines on the antagonist is a 2-oxo-his.

[0170] Brown-yellow color of a composition discussed herein may be described in relation to the European Color Standards. See European Pharmacopoeia. Chapter 2.2.2. Degree of coloration of liquids. 8^th ed. EP Color is used typically in the pharmaceutical industry to assign a color rating to liquid samples indicative, for example, of product quality. The European Pharmacopoeia Color is a visual liquid color scale used in the pharmaceutical industry. EP 2.2.2. Degree of Coloration of Liquids 2 outlines the preparation of 37 separate “Reference Solutions” that belong to the following five color families: greenish-yellow (GY), yellow (Y), brownish-yellow (BY), brown (B), and red (R). Of the 7 brown-yellow standards (BY standards), BY1 is the darkest standard and BY7 is the least dark. Matching a given sample to that of a BY color standard is routinely done in the art.

[0171] Illustrative pharmaceutical formulations for use in the methods of the present invention include the following:

Formulation A: 80 mg/ml aflibercept, 10 mM histidine-based buffer, 5 % (w/v) sucrose, 0.03% (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.

Formulation B: 80 mg/ml aflibercept, 10 mM phosphate-based buffer, 5 % (w/v) sucrose, 0.03% (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.

Formulation C: 80 mg/ml aflibercept, 10 mM citrate-based buffer, 5 % (w/v) sucrose, 0.03% (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.

Formulation D: 80 mg/ml aflibercept, 10 mM histidine-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 6.2.

Formulation E: 80 mg/ml aflibercept, 10 mM phosphate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2. Formulation F: 80 mg/ml aflibercept, 10 mM citrate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.

Formulation G: 80 mg/ml aflibercept, 10 mM histidine-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.

Formulation H: 80 mg/ml aflibercept, 10 mM phosphate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.

Formulation I: 80 mg/ml aflibercept, 10 mM citrate-based buffer, 8 % (w/v) sucrose, and 0.03% (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.

Formulation J: 80 mg/ml aflibercept, 10 mM histidine-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.

Formulation K: 80 mg/ml aflibercept, 10 mM phosphate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.

Formulation L: 80 mg/ml aflibercept, 10 mM citrate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.

Formulation M: 150 mg/ml aflibercept, 10 mM histidine-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.

Formulation N: 150 mg/ml aflibercept, 10 mM phosphate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.

Formulation O: 150 mg/ml aflibercept, 10 mM citrate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.

Formulation P: 150 mg/ml aflibercept, 10 mM histidine-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 6.2.

Formulation Q: 150 mg/ml aflibercept, 10 mM phosphate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.

Formulation R: 150 mg/ml aflibercept, 10 mM citrate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2. Formulation S: 150 mg/ml aflibercept, 10 mM histidine-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.

Formulation T: 150 mg/ml aflibercept, 10 mM phosphate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 20, with a pH of 5.8 to 6.2 (e.g., 6.2), and, optionally, specifically excluding a viscosity reducing agent.

Formulation U: 150 mg/ml aflibercept, 10 mM citrate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.

Formulation V: 150 mg/ml aflibercept, 10 mM histidine-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.

Formulation W: 150 mg/ml aflibercept, 10 mM phosphate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.

Formulation X: 150 mg/ml aflibercept, 10 mM citrate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.

Formulation Y: 80 mg/ml conbercept, 10 mM histidine-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.

Formulation Z: 80 mg/ml conbercept, 10 mM phosphate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.

Formulation AA: 80 mg/ml conbercept, 10 mM citrate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.

Formulation BB: 80 mg/ml conbercept, 10 mM histidine-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 6.2.

Formulation CC: 80 mg/ml conbercept, 10 mM phosphate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.

Formulation DD: 80 mg/ml conbercept, 10 mM citrate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.

Formulation EE: 80 mg/ml conbercept, 10 mM histidine-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent. Formulation FF: 80 mg/ml conbercept, 10 mM phosphate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.

Formulation GG: 80 mg/ml conbercept, 10 mM citrate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.

Formulation HH: 80 mg/ml conbercept, 10 mM histidine-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.

Formulation II: 80 mg/ml conbercept, 10 mM phosphate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.

Formulation JJ: 80 mg/ml conbercept, 10 mM citrate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.

Formulation KK: 150 mg/ml conbercept, 10 mM histidine-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.

Formulation LL: 150 mg/ml conbercept, 10 mM phosphate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.

Formulation MM: 150 mg/ml conbercept, 10 mM citrate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.

Formulation NN: 150 mg/ml conbercept, 10 mM histidine-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 6.2.

Formulation OO: 150 mg/ml conbercept, 10 mM phosphate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.

Formulation PP: 150 mg/ml conbercept, 10 mM citrate-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.

Formulation QQ: 150 mg/ml conbercept, 10 mM histidine-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.

Formulation RR: 150 mg/ml conbercept, 10 mM phosphate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent. Formulation SS: 150 mg/ml conbercept, 10 mM citrate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.

Formulation TT: 150 mg/ml conbercept, 10 mM histidine-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.

Formulation UU: 150 mg/ml conbercept, 10 mM phosphate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.

Formulation VV: 150 mg/ml conbercept, 10 mM citrate-based buffer, 8 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.

Formulation WW: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 10 mM histidine-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 20, and 50 mM taurine, with a pH of 5.8.

Formulation XX: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine-based buffer, 4 % (w/v) proline, 0.03 % (w/v) polysorbate 20, and 50 mM arginine (e.g., arginine hydrochloride), with a pH of 5.8.

Formulation YY: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine-based buffer, 2.5 % (w/v) sucrose, 2.0 % (w/v) proline, 0.03 % (w/v) polysorbate 20, and 50 mM taurine, with a pH of 5.8.

Formulation ZZ: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 10 mM histidine-based buffer, 2.5 % (w/v) sucrose, 2.0 % (w/v) proline, 0.03 % (w/v) polysorbate 20, and 50 mM arginine (e.g., arginine hydrochloride), with a pH of 5.8.

Formulation AAA: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine-based buffer, 5 % (w/v) sucrose, 0.03% (w/v) polysorbate 20, and 50 mM PSA, with a pH of 5.8. Formulation BBB: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine-based buffer, 2.5 % (w/v) sucrose, 2.0 % (w/v) proline, 0.03 % (w/v) polysorbate 20, and 50 mM PSA, with a pH of 5.8.

Formulation CCC: 80, 100, 120 or 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 20, and 50 mM arginine (e.g., arginine hydrochloride), with a pH of 5.8.

Formulation DDD: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 10 mM histidine-based buffer, 4 % (w/v) proline, 0.03 % (w/v) polysorbate 20, and 50 mM PSA, with a pH of 5.8. Formulation EEE: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine-based buffer, 5 % (w/v) sucrose, and 0.03 % (w/v) polysorbate 20 and, optionally, no thermal stabilizer, with a pH of 5.8.

Formulation FFF: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 10mM sodium phosphate, 5 % (w/v) sucrose and 0.03 % polysorbate 20 with a pH of 6.2.

Formulation GGG: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5% sucrose; 0.03 % polysorbate 20; 50 mM sodium sulfate

Formulation HHH: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5% sucrose; 0.03 % polysorbate 20; 50 mM sodium thiocyanate

Formulation III: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose, 0.03 % polysorbate 20; 40 mM sodium citrate

Formulation JJJ: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5% Sucrose, 0.03 % polysorbate 20; 50 mM glycine

Formulation KKK: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose, 0.03 % polysorbate 20; 50 mM sodium chloride

Formulation LLL: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose; 0.03 % polysorbate 20; 50 mM lysine

Formulation MMM: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose; 0.03% polysorbate 20; 50 mM sodium aspartate

Formulation NNN: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose; 0.03 % polysorbate 20; 50 mM sodium glutamate

Formulation OOO: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose; 0.03% polysorbate 20; 50 mM sodium citrate; 50 mM arginine (e.g., arginine hydrochloride)

Formulation PPP: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose; 0.03% polysorbate 20; 50 mM glycine; 50 mM arginine (e.g., arginine hydrochloride)

Formulation QQQ: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose; 0.03% polysorbate 20; 50 mM sodium aspartate; 50 mM arginine (e.g., arginine hydrochloride)

Formulation RRR: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose; 0.03% polysorbate 20; 50 mM sodium glutamate; 50 mM arginine (e.g., arginine hydrochloride) Formulation SSS: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM His, pH 5.8; 5 % sucrose; 0.03 % polysorbate 20; 10 mM L-arginine (e.g., L-arginine hydrochloride) Formulation TTT: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM His, pH 5.8; 5 % sucrose; 0.03 % polysorbate 20; 100 mM L-arginine (e.g., L-arginine hydrochloride) Formulation UUU: 30 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 10 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, pH 6.2

Formulation VVV: 30 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, pH 6.2

Formulation WWW: 60 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 10 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, pH 6.2

Formulation XXX: 60 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, pH 6.2

Formulation YYY: 120 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 10 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, pH 6.2

Formulation ZZZ: 120 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, pH 6.2

Formulation AAAA: 120 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 10 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, 50 mM NaCI, pH 6.2

Formulation BBBB: 120 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, 50 mM NaCI, pH 6.2

Formulation CCCC: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 10 mM sodium phosphate, 5 % sucrose, 40 mM sodium chloride, 0.03 % PS20, pH 6.2

Formulation DDDD: 80 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine-based buffer, 5 % (w/v) sucrose, 0.03 % (w/v) polysorbate 20, and 50 mM L-arginine (e.g., L-arginine hydrochloride), with a pH of 5.8.

Formulation EEEE: 120.0 mg/ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., ± 12 mg/ml), 20 mM histidine-based buffer (e.g., ± 2 mM), 5 % (w/v) sucrose (e.g., ± 0.5%), 0.03 % (w/v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine (e.g., L-arginine hydrochloride) (e.g., ± 5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1).

Formulation FFFF: 113.3 mg/ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., 102-125 mg/ml), 20 mM histidine-based buffer (e.g., ± 2 mM), 5 % (w/v) sucrose (e.g., ± 0.5%), 0.03 % (w/v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine (e.g., L-arginine monohydrochloride) (e.g., ± 5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1). Formulation GGGG: 114.3 mg/ml VEGF receptor fusion protein (e.g., aflibercept) (or, 103-126 mg/ml), 10 mM histidine-based buffer, for example, including Histidine and Histidine-HCI (e.g., ± 1 mM), 5 % (w/v) sucrose (e.g., ± 0.5%), 0.03 % (w/v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine (e.g., L-arginine monohydrochloride) (e.g., ± 5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1).

Formulation HHHH: 100.0 mg/ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., ± 10 mg/ml), 20 mM histidine-based buffer (e.g., ± 2 mM), 5 % (w/v) sucrose (e.g., ± 0.5%), 0.03 % (w/v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine (e.g., L-arginine monohydrochloride) (e.g., ± 5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1).

Formulation IIII: 133.3 mg/ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., ± 13 mg/ml), 20 mM histidine-based buffer (e.g., ± 2 mM), 5 % (w/v) sucrose (e.g., ± 0.5%), 0.03 % (w/v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine (e.g., L-arginine monohydrochloride) (e.g., ± 5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1).

Formulation JJJJ: 150 mg/ml aflibercept (e.g., aflibercept) (e.g., ± 15 mg/ml), 10 mM sodium phosphate, 8% (w/v) sucrose (e.g., ± 0.8%), 0.03% (w/v) polysorbate 20 (e.g., 0.02-0.04%) and 50 mM L-arginine (e.g., arginine hydrochloride), pH 6.2 (e.g., 6.0-6.4 or 5.9-6.5).

Formulation KKKK: 114.3 mg/ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., ± 14 mg/ml), 20 mM histidine-based buffer (e.g., ± 2 mM), 5% (w/v) sucrose (e.g., ± 0.5%), 0.03% (w/v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine (e.g., arginine monohydrochloride) (e.g., ± 5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1);

[0172] See International Patent Application Publication No. WO2019/217927.

[0173] In any of the embodiments set out herein, unless otherwise stated, it may be that the VEGF receptor fusion protein is aflibercept and the pharmaceutical composition is present in is Formulation GGGG: 114.3 mg/ml VEGF receptor fusion protein (e.g., aflibercept) (or, 103-126 mg/ml), 10 mM histidine-based buffer, for example, including Histidine and Histidine-HCI (e.g., ± 1 mM), 5 % (w/v) sucrose (e.g., ± 0.5%), 0.03 % (w/v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine (e.g., L-arginine monohydrochloride) (e.g., ± 5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1).

[0174] In an embodiment of the invention, the 8 mg (±0.8 mg) VEGF receptor fusion protein, preferably aflibercept, when administered, is in an aqueous pharmaceutical formulation comprising: a VEGF receptor fusion protein comprising two polypeptides that each comprises an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of VEGFR2, and a multimerizing component (e.g., which comprises amino acids 27-457 of SEQ ID NO: 2) at a concentration of greater than about 100 mg/ml; about 5% sucrose; L-arginine (e.g., L-arginine monohydrochloride); a histidine-based buffer (e.g., containing histidine HCI); and about 0.03% surfactant; wherein the formulation has a pH of about 5.0 to about 6.8 (e.g., 5.8 to 6.5, for example 5.8). Preferably the formulation is suitable for intravitreal administration. Other components that may be included are sodium sulfate, sodium thiocyanate, glycine, NaCI, sodium aspartate and/or sodium glutamate. In an embodiment of the invention, the VEGF receptor fusion protein is at a concentration of: about 100 mg/ml; about 111.5 mg/ml; about 112.0 mg/ml; about 113.3 mg/ml; about 114.3 mg/ml; about 115.6 mg/ml; about 116.3 mg/ml; about 120 mg/ml; about 133 mg/ml; about 140 mg/ml; about 150 mg/ml; about 200 mg/ml; or about 250 mg/ml. The formulation may be characterized by (i) an osmolality of about 299 to about 506 mmol/Kg; and/or (ii) a viscosity of from about 6-15 cP at 20°C. The surfactant may be a non-ionic surfactant such as polysorbate 20, polysorbate 80, poloxamer 188, polyethylene glycol 3350 or mixtures thereof. The histidine-based buffer may be at a concentration of about 10 mM to 20 mM. In an embodiment of the invention, the VEGF receptor fusion protein has less than about 3.5% high molecular weight species immediately after manufacture and purification and/or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C.

[0175] In an embodiment of the invention, the 8 mg (±0.8 mg) VEGF receptor fusion protein is, when administered in an aqueous pharmaceutical formulation, comprising: greater than about 100 mg/ml of a VEGF receptor fusion protein comprising two polypeptides that each comprises an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of VEGFR2, and a multimerizing component (e.g., aflibercept); about 10-100 mM L-arginine; sucrose; a histidine-based buffer; and a surfactant; wherein the formulation has a pH of about 5.0 to about 6.8; wherein the VEGF receptor fusion protein has less than about 3.5% high molecular weight species immediately after manufacture and purification and/or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C.

[0176] In an embodiment of the invention, the aqueous pharmaceutical formulation includes:

• > about 100 mg/ml VEGF receptor fusion protein (e.g., aflibercept), histidine-based buffer and L-arginine;

• about 140 mg/ml aflibercept; 20 mM histidine-based buffer; 5% sucrose; 0.03 % polysorbate 20; 10 mM L-arginine; pH 5.8;

• about 150 ± 15 mg/ml aflibercept, 10 mM phosphate-based buffer, 8 ± 0.8% (w/v) sucrose, 0.02-0.04% (w/v) polysorbate 20 and 50 mM L-arginine, pH 5.9-6.5;

• about 103-126 mg/ml aflibercept, 10 ± 1 mM histidine-based buffer, 5 ± 0.5% (w/v) sucrose, 0.02-0.04% (w/v) polysorbate 20, and 50 ± 5 mM L-arginine, pH 5.5-6.1; • about 140 mg/ml aflibercept, 10 mM histidine-based buffer, 2.5 % (w/v) sucrose, 2.0 % (w/v) proline, 0.03 % (w/v) polysorbate 20 and 50 mM L-arginine, pH 5.8;

• about 114.3 mg/ml aflibercept, 10 mM histidine-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 20 and 50 mM L-arginine, pH 5.8;

• > about 100 mg/ml aflibercept, histidine-based buffer and L-arginine;

• > about 100 mg/ml aflibercept at about pH 5.8, wherein the formulation forms <3% HMW aggregates after incubation at 5°C for 2 months;

• about 114.3 mg/mL aflibercept; 10 mM - 50 mM histidine-based buffer, sugar, non-ionic surfactant, L-Arginine, pH 5.8;

or

• about 114.3 mg/mL aflibercept; 10 mM Histidine-based buffer, 5% sucrose, 0.03% polysorbate-20, 50 mM L-Arginine, pH 5.8.

[0177] In an embodiment of the invention, the 8 mg (±0.8 mg) VEGF receptor fusion protein is aflibercept, and is administered in an aqueous pharmaceutical formulation comprising: aflibercept at a concentration of at least about 100 mg/ml (e.g., about 111.5 mg/ml; 112.0 mg/ml; 113.3 mg/ml; about 114.3 mg/ml; about 115.6 mg/ml; or about 116.3 mg/ml);

a thermal stabilizer which is a sugar, an amino acid, sucrose, mannitol, sorbitol, trehalose, L-proline, glycine, glycerol, taurine or propane sulfonic acid (e.g., at about 2% (w/v) to about 10% (w/v), for example, 5% (w/v)); a buffer which is a histidine-based buffer, a phosphate-based buffer, an acetate-based buffer (e.g., at a concentration of about 5-25 mM, e.g., 10 mM or 20 mM); or a citrate-based buffer; a non-ionic surfactant, such as for example, polyoxyethylenebased, polysorbate 20, polysorbate 80, poloxamer 188 or polyethylene glycol 3350 (e.g., at a concentration of about 0.02% to about 0.1 % (w/v), e.g., 0.03% (w/v)); and a viscosity reducing agent which is NaCI, MgCh, D-arginine, L-arginine or L-lysine (e.g., at a concentration of about 10-100 mM, e.g., 50 mM), wherein the formulation has a pH of about 5.0 to about 6.8 (e.g., 5.0-6.0 or 5.8).

[0178] In an embodiment of the invention, the VEGF receptor fusion protein, e.g., aflibercept, is at a concentration in the aqueous pharmaceutical formulation of about 100 mg/ml; 101 mg/ml; 102 mg/ml; 103 mg/ml; 104 mg/ml; 105 mg/ml; 106 mg/ml; 107 mg/ml; 108 mg/ml; 109 mg/ml; 110 mg/ml; 111 mg/ml; 112 mg/ml; 113 mg/ml; 113.3 mg/ml; 114 mg/ml; 114.1 mg/ml; 114.2 mg/ml; 114.3 mg/ml; 114.4 mg/ml; 114.5 mg/ml; 114.6 mg/ml; 114.7 mg/ml; 114.8 mg/ml; 114.9 mg/ml; 115 mg/ml; 116 mg/ml; 117 mg/ml; 118 mg/ml; 119 mg/ml; 120 mg/ml; 121 mg/ml; 122 mg/ml; 123 mg/ml; 124 mg/ml; 125 mg/ml; 126 mg/ml; 127 mg/ml; 128 mg/ml; 129 mg/ml; 130 mg/ml; 131 mg/ml; 132 mg/ml; 133 mg/ml; 133.3 mg/ml; 133.4 mg/ml; 134 mg/ml; 135 mg/ml; 136 mg/ml; 137 mg/ml; 138 mg/ml; 139 mg/ml; 140 mg/ml; 141 mg/ml; 142 mg/ml; 143 mg/ml; 144 mg/ml; 145 mg/ml; 146 mg/ml; 147 mg/ml; 148 mg/ml; 149 mg/ml; 150 mg/ml; 151 mg/ml; 152 mg/ml; 153 mg/ml; 154mg/ml; 155 mg/ml; 156 mg/ml; 157mg/ml; 158 mg/ml; 159 mg/ml; 160 mg/ml; 161 mg/ml; 162 mg/ml; 163 mg/ml; 164 mg/ml; 165 mg/ml; 166 mg/ml; 167 mg/ml; 168 mg/ml; 169 mg/ml; 170 mg/ml; 171 mg/ml; 172 mg/ml; 173 mg/ml; 174 mg/ml; 175 mg/ml; 176 mg/ml; 177 mg/ml; 178 mg/ml; 179 mg/ml; 180 mg/ml; 181 mg/ml; 182 mg/ml; 183 mg/ml; 184 mg/ml; 185 mg/ml; 186 mg/ml; 187 mg/ml; 188 mg/ml; 189 mg/ml; 190 mg/ml; 191 mg/ml; 192 mg/ml; 193 mg/ml; 194 mg/ml; 195 mg/ml; 196 mg/ml; 197 mg/ml; 198 mg/ml; 199 mg/ml; 200 mg/ml; 201 mg/ml; 202 mg/ml; 203 mg/ml; 204 mg/ml; 205 mg/ml; 206 mg/ml; 207 mg/ml; 208 mg/ml; 209 mg/ml; 210 mg/ml; 211 mg/ml; 212 mg/ml; 213 mg/ml; 214 mg/ml; 215 mg/ml; 216 mg/ml; 217 mg/ml; 218 mg/ml; 219 mg/ml; 220 mg/ml; 221 mg/ml; 222 mg/ml; 223 mg/ml; 224 mg/ml; 225 mg/ml; 226 mg/ml; 227 mg/ml; 228 mg/ml; 229 mg/ml; 230 mg/ml; 231 mg/ml; 232 mg/ml; 233 mg/ml; 234 mg/ml; 235 mg/ml; 236 mg/ml; 237mg/ml; 238 mg/ml; 239 mg/ml; 240 mg/ml; 241 mg/ml; 242 mg/ml; 243 mg/ml; 244 mg/ml; 245 mg/ml; 246 mg/ml; 247 mg/ml; 248 mg/ml; 249 mg/ml; 250 mg/ml; 251 mg/ml; 252 mg/ml; 253 mg/ml; 254 mg/ml; 255 mg/ml; 256 mg/ml; 257 mg/ml; 258 mg/ml; 259 mg/ml; 260 mg/ml; 261 mg/ml; 262 mg/ml; 263 mg/ml; 264 mg/ml; 265 mg/ml; 266 mg/ml; 267 mg/ml; 268 mg/ml; 269 mg/ml; 270 mg/ml; 271 mg/ml; 272 mg/ml; 273 mg/ml; 274 mg/ml; or 275 mg/ml. In an embodiment of the invention, the VEGF receptor fusion protein, e.g., aflibercept, is at a concentration in the aqueous pharmaceutical formulation of about 80 mg/ml to about 140 mg/ml. In an embodiment of the invention, the VEGF receptor fusion protein, e.g., aflibercept, is at a concentration in the aqueous pharmaceutical formulation of about 100 mg/ml to about 120 mg/ml. In one embodiment aflibercept is at a concentration of 114.3 mg/mL.

[0179] In an embodiment of the invention, the aqueous pharmaceutical formulation includes VEGF receptor fusion protein, e.g., aflibercept, at a concentration of greater than about 100 mg/ml; sucrose, mannitol, sorbitol, trehalose; a histidine-based buffer; polysorbate 20 or polysorbate 80; and L-arginine, at a pH of about 5.0 to about 6.8; wherein the VEGF receptor fusion protein, e.g., aflibercept, has less than about 3.5% high molecular weight species immediately after manufacture and purification and/or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C.

[0180] In an embodiment of the invention, the sucrose, mannitol, sorbitol or trehalose is at a concentration of about 2-10% (w/v); the L-arginine is at a concentration of about 10-100 mM; the polysorbate 20 or polysorbate 80 is at a concentration of about 0.02-0.1% (w/v); and the histidine-based buffer is at a concentration of about 5-25 mM; at a pH of about 5.0 to about 6.8. Treatment and Administration

[0181] The present disclosure provides methods for treating and preventing angiogenic eye disorders including angiogenic eye disorders secondary to retinal vein occlusion (e.g., macular edema secondary to RVO (MERVO)), and treating retinal vein occlusion by sequentially administering one or more initial loading doses (e.g., 2 mg or more, 4 mg or more or, preferably, about 8 mg (±0.8 mg) or more of VEGF antagonist, for example, a VEGF receptor fusion protein such as aflibercept), for example, about every 2-4 or 3-5 weeks, preferably 4 weeks, optionally, followed by additional doses every 4 or 8 or 12 or 16, or 20 or 24 or 28 or 32 or 36 or 4-8 or 8-12 and/or 4-12 weeks and/or by a Pro re nata or Treat & Extend treatment regimen. In one embodiment, the doses are 8 mg (±0.8 mg) of aflibercept administered intravitreally.

[0182] In one embodiment, the doses are 8 mg (±0.8 mg) of aflibercept administered intravitreally.

[0183] As used herein, terms “injection interval” or “dosing interval” or “treatment interval” are used interchangeably and refer to the time interval between two consecutive injections of an VEGF antagonist (e.g., 8 mg aflibercept) into the eye of a subject.

[0184] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise

(i) administering to the eye of the subject one or more intravitreal injections of 8 mg (±0.8 mg) aflibercept every month or every 4 weeks ± 7 days, for example, for the first 3, 4 or 5 or 3-5 or 6 or 7 consecutive injections, preferably 3; and

(ii) one or more further injections of 8 mg (±0.8 mg) aflibercept administered once every 8 weeks ± 7 days; optionally, followed by administering one or more 8 mg injections on a Treat & Extend or Pro re nata basis or wherein the interval between doses is based on the physician’s judgement of visual and/or anatomic outcomes, e.g., starting at week 36. For example, in an embodiment of the invention, the method includes the steps of administering to the eye of the subject one or more intravitreal injections of 8 mg (±0.8 mg) aflibercept every month or every 4 weeks ± 7 days for the first 3 consecutive injections; and one or more further injections of 8 mg (±0.8 mg) aflibercept administered once every 8 weeks ± 7 days.

[0185] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise (i) administering to the eye of the subject one or more intravitreal injections of 8 mg (±0.8 mg) aflibercept every month or every 4 weeks ± 7 days; optionally, followed by administering one or more 8 mg (±0.8 mg) injections on a Treat & Extend or Pro re nata basis or wherein the interval between doses is based on the physician’s judgement of visual and/or anatomic outcomes, e.g., starting at week 36. For example, in an embodiment of the invention, the method includes the steps of administering to the eye of the subject one or more intravitreal injections of 8 mg (±0.8 mg) aflibercept every month or every 4 weeks ± 7 days wherein no doses other than every month or every 4 weeks ± 7 days is administered.

[0186] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise

(ii) one or more further injections of 8 mg (±0.8 mg) aflibercept administered once every 12 weeks ± 7 days; optionally, followed by administering one or more 8 mg injections on a Treat & Extend or Pro re nata basis or wherein the interval between doses is based on the physician’s judgement of visual and/or anatomic outcomes, e.g., starting at week 36. For example, in an embodiment of the invention, the method includes the steps of administering to the eye of the subject one or more intravitreal injections of 8 mg (±0.8 mg) aflibercept every month or every 4 weeks ± 7 days for the first 3 consecutive injections; and one or more further injections of 8 mg (±0.8 mg) aflibercept administered once every 12 weeks ± 7 days.

[0187] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise

(i) administering to the eye of the subject one or more intravitreal injections of 8 mg (±0.8 mg) aflibercept every month or every 4 weeks ± 7 days and; optionally, e.g., after the first 3, 4 or 5 or 3-5 or 6 or 7 such doses

(ii) one or more further injections of 8 mg administered on a Treat & Extend or Pro re nata basis or wherein the interval between doses is based on the physician’s judgement of visual and/or anatomic outcomes. [0188] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise

(i) administering to the eye of the subject one or more intravitreal injections of 8 mg (±0.8 mg) aflibercept every month or every 4 weeks ± 7 days for the 3, 4 or 5 or 3-5 or 6 or 7 consecutive injections; and

(ii) one or more further injections of 8 mg (±0.8 mg) aflibercept after said first consecutive injections (e.g., 3) wherein the injection interval between two consecutive injections is adjusted based on the physician’s judgement of visual and/or anatomic outcomes, e.g., by Treat & Extend or Pro re nata.

[0189] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in an subject; wherein the methods comprise

(i) administering, to the eye of the subject, one or more intravitreal injections of 8 mg aflibercept every month or every 4 weeks for the first 3 consecutive injections; and

(ii) one or more further injections of 8 mg (±0.8 mg) aflibercept after said first 3 consecutive injections wherein the injection interval between two consecutive injections is adjusted based on the physician’s judgement of visual and/or anatomic outcomes.

[0190] In one embodiment of the invention, the method for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise

(i) administering to the eye of the subject one or more intravitreal injections of 8 mg aflibercept every month or every 4 weeks for the first 3 consecutive injections and

(ii) one or more further injections of 8 mg (±0.8 mg) aflibercept after said first 3 consecutive injections, wherein the injection interval between two consecutive injections is first extended to 8 weeks or 2 months for one or more injections and then adjusted based on the physicians judgement of visual and/or anatomic outcomes, wherein the treatment interval between two consecutive injections is between 4 weeks (1 month) and 20 weeks (5 months).

[0191] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in an subject in a subject; wherein the method comprises administering to the eye of the subject,

(i) a single initial dose of 8 mg (±0.8 mg) aflibercept, followed by

(ii) two secondary doses of said 8 mg aflibercept, followed by one or more tertiary doses of 8 mg (±0.8 mg) aflibercept;

wherein each secondary dose is administered 4 weeks or one month after the immediately preceding dose; and

wherein the treatment interval between two consecutive tertiary doses is adjusted based on the physician’s judgement of visual and/or anatomic outcomes.

[0192] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,

a single initial dose of 8 mg (±0.8 mg) aflibercept, followed by;

one or more secondary and/or tertiary doses of 8 mg (±0.8 mg) aflibercept;

wherein the treatment interval between two consecutive tertiary doses is adjusted based on the physician’s judgement of visual and/or anatomic outcomes; and

wherein the subject has been treated with a different anti-angiogenic treatment prior to said single initial dose of 8 mg (±0.8 mg) aflibercept. Such anti-angiogenic treatment is for example an anti-VEGF treatment using for e.g., 2 mg aflibercept, faricimab, ranibizumab or bevacizumab. In one embodiment of the invention, the subject was treated with 2 mg aflibercept or faricimab prior to said single initial dose of 8 mg (±0.8 mg) aflibercept. In one embodiment of the invention, the subject was treated with ranibizumab or bevacizumab prior to said single initial dose of 8 mg (±0.8 mg) aflibercept (e.g., >3 anti-VEGF ocular injections over the prior 5 months (-150 days).

[0193] Adjustment of treatment interval means that the interval between two consecutive administrations of 8 mg (±0.8 mg) aflibercept is extended or shortened based on the physician’s judgement of visual and/or anatomic outcomes.

[0194] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise

(i) administering to the eye of the subject, one or more intravitreal injections of 8 mg (±0.8 mg) aflibercept every month or every 4 weeks for the first 3 consecutive injections; and (ii) one or more further injections of 8 mg (±0.8 mg) aflibercept after said first 3 consecutive injections wherein the injection interval between two consecutive injections is extended based on the physician’s judgement of visual and/or anatomic outcomes.

[0195] In one embodiment of the invention, the method for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and/or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise

(i) administering to the eye of the subject one or more intravitreal injections of 8 mg (±0.8 mg) aflibercept every month or every 4 weeks for the first 3 consecutive injections; and

(ii) one or more further injections of 8 mg (±0.8 mg) aflibercept after said first 3 consecutive injections, wherein the injection interval between two consecutive injections is first extended to 8 weeks or 2 months for one or more injections and then further extended to up to 12 weeks (3 months) or 16 weeks (4 months) or 20 weeks (5 months) based on the physicians judgement of visual and/or anatomic outcomes.

[0196] The present disclosure provides methods comprising administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by 2, 3 or 4 or 2-4 secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein; followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2, 3, 4, or 2-4 weeks (±7 days) after the immediately preceding dose; and wherein:

(a) each tertiary dose is administered about 8 weeks (±7 days) after the immediately preceding dose;

(b) one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then subsequent tertiary doses are administered about 4 weeks (±7 days) after the immediately preceding dose;

(c) 2-4 secondary doses are administered every 4 weeks and each tertiary dose is administered about 8 weeks (±7 days) after the immediately preceding dose;

(d) 2 secondary doses are administered every 4 weeks and each tertiary dose is administered about 8 weeks (±7 days) after the immediately preceding dose;

(e) 3 secondary doses are administered every 4 weeks and each tertiary dose is administered about 8 weeks (±7 days) after the immediately preceding dose;

(f) 4 secondary doses are administered every 4 weeks and each tertiary dose is administered about 8 weeks (±7 days) after the immediately preceding dose; (g) one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then subsequent tertiary doses are administered about 4 weeks (±7 days) after the immediately preceding dose;

(h) 2-4 secondary doses are administered about every 4 weeks (±7 days) and one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then subsequent tertiary doses are administered about 4 weeks (±7 days) after the immediately preceding dose;

(i) 2 secondary doses are administered about every 4 weeks (±7 days) and one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then subsequent tertiary doses are administered about 4 weeks (±7 days) after the immediately preceding dose;

(j) 3 secondary doses are administered about every 4 weeks (±7 days) and one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then subsequent tertiary doses are administered about 4 weeks (±7 days) after the immediately preceding dose;

(k) 4 secondary doses are administered about every 4 weeks (±7 days) and one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then subsequent tertiary doses are administered about 4 weeks (±7 days) after the immediately preceding dose;

(l) one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then the interval between subsequent tertiary doses are shortened to about 4 weeks (±7 days) after the immediately preceding dose;

(m) 2-4 secondary doses are administered about every 4 weeks (±7 days) and one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then the interval between subsequent tertiary doses are shortened to about 4 weeks (±7 days) after the immediately preceding dose;

(n) 2 secondary doses are administered about every 4 weeks (±7 days) and one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then the interval between subsequent tertiary doses are shortened to about 4 weeks (±7 days) after the immediately preceding dose;

(o) 3 secondary doses are administered about every 4 weeks (±7 days) and one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then the interval between subsequent tertiary doses are shortened to about 4 weeks (±7 days) after the immediately preceding dose; (p) 4 secondary doses are administered about every 4 weeks (±7 days) and one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then the interval between subsequent tertiary doses are shortened to about 4 weeks (±7 days) after the immediately preceding dose;

(q) one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then one or more subsequent tertiary doses are administered on a Treat & Extend or pro re nata basis, or are adjusted based on the physician’s judgement of visual and/or anatomic outcomes;

(r) 2 or 3 tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose and then one or more subsequent tertiary doses are administered on a Treat & Extend or pro re nata basis, or are adjusted based on the physician’s judgement of visual and/or anatomic outcomes;

(s) 4 of said secondary doses are administered, then 2 tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose and then one or more tertiary doses are administered on a Treat & Extend or pro re nata basis, or are adjusted based on the physician’s judgement of visual and/or anatomic outcomes;

(t) 2 of said secondary doses are administered, then 3 tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose and then one or more tertiary doses are administered on a Treat & Extend or pro re nata basis, or are adjusted based on the physician’s judgement of visual and/or anatomic outcomes; and/or

(u) one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose and then each subsequent tertiary dose is administered about 4 weeks (±7 days) after the immediately preceding dose; and then one or more tertiary doses are administered on a Treat & Extend or pro re nata basis, or are adjusted based on the physician’s judgement of visual and/or anatomic outcomes.

[0197] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and/or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,

a single initial dose of 8 mg (±0.8 mg) aflibercept, followed by

two secondary doses of said 8 mg (±0.8 mg) aflibercept, followed by

one or more tertiary doses of 8 mg (±0.8 mg) aflibercept;

wherein each secondary dose is administered 4 weeks or one month after the immediately preceding dose; and wherein the treatment interval between two consecutive tertiary doses is extended based on the physician’s judgement of visual and/or anatomic outcomes.

[0198] In one embodiment of the invention, the first tertiary dose or a dosing regimen set forth herein is administered 8 weeks (2 months) after the immediately preceding dose and one or more further tertiary doses are administered 8 weeks (2 months), or 12 weeks (3 months), or 16 weeks (4 months), or 20 weeks (5 months) after the immediately preceding dose. In one embodiment of the invention, the first tertiary dose is administered 8 weeks (2 months) after the immediately preceding dose and then the treatment interval between two consecutive injections is extended to up to 16 weeks (4 months) or 20 weeks (5 months) based on the physician’s judgement of visual and/or anatomic outcomes.

[0199] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and/or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,

a single initial dose of 8 mg (±0.8 mg) aflibercept, followed by;

one or more secondary or tertiary doses of 8 mg (±0.8 mg) aflibercept;

wherein the treatment interval between two consecutive secondary or tertiary doses is extended based on the physician’s judgement of visual and/or anatomic outcomes and wherein the subject has been treated with a different anti-angiogenic treatment prior to said single initial dose of 8 mg (±0.8 mg) aflibercept. Such anti-angiogenic treatment is for example an anti-VEGF treatment using for e.g., 2 mg aflibercept, faricimab, ranibizumab or bevacizumab. In one embodiment of the invention, the subject was treated with 2 mg aflibercept or faricimab prior to said single initial dose of 8 mg (±0.8 mg) aflibercept (e.g., >3 anti-VEGF ocular injections over the prior 5 months (~ 150 days). In one embodiment of the invention, the subject was treated with ranibizumab or bevacizumab prior to said single initial dose of 8 mg (±0.8 mg) aflibercept (e.g., >3 anti-VEGF ocular injections over the prior 5 months (-150 days).

[0200] In one embodiment of the invention said treatment interval between two consecutive injections is extended if the subject (i) exhibits <5 letters loss of BOVA from reference visit and/or (ii) has a CRT (central retinal thickness) <320 pm measured by Heidelberg Spectralis or < 300 pm measured by Cirrus or Topcon spectral domain optical coherence tomography (SD-OCT).

[0201] In one embodiment, the reference visit is the visit at the previous injection.

[0202] In one embodiment such reference visit is the visit at the second monthly or 4-weekly secondary dosing or the visit at 12 weeks (3 months) after initiation of treatment. [0203] In one embodiment of the invention, said treatment interval between two consecutive doses is extended by 2 or 4 or 2-4 weeks. In one embodiment of the invention, said treatment interval between two consecutive doses is extended by 2 or 4 weeks. In one embodiment of the invention said treatment interval between two consecutive doses is 4 weeks (1 month) or 8 weeks (2 month) or 12 weeks (3 months) or 16 weeks (4 months), or 20 weeks (5 months).

[0204] In one embodiment of the invention, said treatment interval between two consecutive doses is 8 weeks or 2 months. In one embodiment of the invention, said treatment interval between two consecutive doses is 12 weeks or 3 months. In one embodiment of the invention, said treatment interval between two consecutive doses is 16 weeks or 4 months. In one embodiment of the invention, said treatment interval between two consecutive doses is 20 weeks or 5 months. In one embodiment of the invention, said treatment interval between two consecutive doses is extended from 8 weeks or 2 months to 12 weeks or 3 months. In one embodiment of the invention, said treatment interval between two consecutive doses is extended from 12 weeks or 3 months to 16 weeks or 4 months. In one embodiment of the invention, said treatment interval between two consecutive doses is extended from 16 weeks or 4 months to 20 weeks or 5 months.

[0205] In one embodiment of the invention, the first tertiary dose is administered 8 weeks (2 months) after the immediately preceding dose and one or more further tertiary doses are administered 8 weeks (2 months) or 12 weeks (3 months) after the immediately preceding dose.

[0206] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise

(ii) one or more further injections of 8 mg (±0.8 mg) aflibercept after said first 3 consecutive injections wherein the injection interval between two consecutive injections is shortened based on the physician’s judgement of visual and/or anatomic outcomes.

[0207] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,

a single initial dose of 8 mg aflibercept, followed by

two secondary doses of said 8 mg aflibercept, followed by one or more tertiary doses of 8 mg aflibercept;

wherein the treatment interval between two consecutive tertiary doses is shortened based on the physician’s judgement of visual and/or anatomic outcomes.

[0208] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and/or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,

a single initial dose of 8 mg aflibercept, followed by;

one or more secondary and/or tertiary doses of 8 mg aflibercept;

wherein the treatment interval between two consecutive tertiary doses is shortened based on the physician’s judgement of visual and/or anatomic outcomes; and

wherein the subject has been treated with a different anti-angiogenic treatment prior to said single initial dose of 8 mg aflibercept. Such anti-angiogenic treatment is, for example, an anti-VEGF treatment using for e.g., 2 mg aflibercept, faricimab, ranibizumab or bevacizumab. In one embodiment of the invention the subject was treated with 2 mg aflibercept or faricimab prior to said single initial dose of 8 mg aflibercept. In one embodiment of the invention, the subject was treated with ranibizumab or bevacizumab prior to said single initial dose of 8 mg aflibercept (e.g., >3 anti-VEGF ocular injections over the prior 5 months (-150 days).

[0209] In one embodiment of the invention said treatment interval between two consecutive tertiary doses is shortened if the subject (i) exhibits >5 letters loss of BOVA from reference visit; and/or (ii) >50 pm increase in CRT (central retinal thickness) from reference visit.

[0210] In one embodiment the reference visit is the visit at the previous injection.

[0211] In one embodiment of the invention said treatment interval between two consecutive doses is shortened by 2 or 4 weeks. In one embodiment of the invention said treatment interval between two consecutive doses is shortened from 20 weeks or 5 months to 16 weeks or 4 months. In one embodiment of the invention, said treatment interval between two consecutive doses is shortened from 16 weeks or 4 months to 12 weeks or 3 months. In one embodiment of the invention, said treatment interval between two consecutive doses is shortened from 12 weeks or 3 months to 8 weeks or 2 months. In one embodiment of the invention, said treatment interval between two consecutive doses is shortened from 8 weeks or 2 months to 4 weeks or 1 month. [0212] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in a subject in a subject; wherein the method comprises administering to the eye of the subject,

a single initial dose of 8 mg aflibercept, followed by;

two secondary doses of said 8 mg (±0.8 mg) aflibercept, followed by;

one or more tertiary doses of 8 mg (±0.8 mg) aflibercept;

[0213] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,

a single initial dose of 8 mg (±0.8 mg) aflibercept, followed by;

two secondary doses of 8 mg (±0.8 mg) aflibercept, followed by;

one or more tertiary doses of 8 mg (±0.8 mg) aflibercept;

wherein the treatment interval between two consecutive tertiary doses is extended based on the physician’s judgement of visual and/or anatomic outcomes.

[0214] In one embodiment of the invention such treatment interval between two consecutive tertiary injections is extended if the subject

(i) exhibits <5 letters loss of BCVA from reference visit and/or

(ii) has a CRT (central retinal thickness) <320 pm measured by Heidelberg Spectralis or < 300 pm measured by Cirrus or Topcon spectral domain optical coherence tomography (SD-OCT). In one embodiment, such reference visit is the visit at the second monthly or 4-weekly secondary dosing or the visit at 12 weeks (3 month) after initiation of treatment.

[0215] In one embodiment the reference visit is the visit at the previous injection.

[0216] In one embodiment such reference visit is the visit at the second monthly or 4-weekly secondary dosing or the visit at 12 weeks (3 months) after initiation of treatment.

[0217] In one embodiment of the invention said treatment interval between two consecutive tertiary doses is extended by 2 or 4 or 2-4 weeks. In one embodiment of the invention the treatment interval between two consecutive tertiary closes is 4 weeks (1 month) or 8 weeks (2 month) or 12 weeks (3 month).

[0218] In one embodiment of the invention, the first tertiary dose is administered 8 weeks (2 months) after the immediately preceding dose and one or more further tertiary doses are administered 8 weeks (2 months) or 12 weeks (3 months) after the immediately preceding dose.

[0219] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,

a single initial dose of 8 mg (±0.8 mg) aflibercept, followed by

two secondary doses of said 8 mg (±0.8 mg) aflibercept, followed by

one or more tertiary doses of 8 mg (±0.8 mg) aflibercept;

[0220] In one embodiment of the invention said treatment interval between two consecutive tertiary doses is shortened if the subject

(i) exhibits >5 letters loss of BCVA from reference visit; and/or

(ii) >50 pm increase in CRT (central retinal thickness) from reference visit.

[0221] In one embodiment the reference visit is the visit at the previous injection.

[0222] In one embodiment of the invention said treatment interval between two consecutive tertiary doses is shortened by 2 or 4 weeks. In one embodiment of the invention said treatment interval between two consecutive tertiary doses is 4 weeks (1 month) or 8 weeks (2 month) or 12 weeks (3 months).

[0223] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,

a single initial dose of 8 mg (±0.8 mg) aflibercept, followed by;

one or more tertiary doses of 8 mg (±0.8 mg) aflibercept;

wherein the treatment interval between two consecutive tertiary doses is adjusted based on the physician’s judgement of visual and/or anatomic outcomes; and wherein the subject was treated with 2 mg aflibercept, faricimab, ranibizumab or bevacizumab prior to said single initial dose of 8 mg (±0.8 mg) aflibercept (e.g., >3 anti-VEGF ocular injections over the prior 5 months (-150 days).

[0224] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,

a single initial dose of 8 mg (±0.8 mg) aflibercept, followed by;

one or more tertiary doses of 8 mg (±0.8 mg) aflibercept;

wherein the treatment interval between two consecutive tertiary doses is extended based on the physician’s judgement of visual and/or anatomic outcomes; and

wherein the subject was treated with 2 mg aflibercept, faricimab, ranibizumab or bevacizumab prior to said single initial dose of 8 mg (±0.8 mg) aflibercept (e.g., >3 anti-VEGF ocular injections over the prior 5 months (-150 days).

[0225] In one embodiment of the invention said treatment interval between two consecutive tertiary doses is extended if the subject

(i) exhibits <5 letters loss of BOVA from reference visit and/or

(ii) has a CRT (central retinal thickness) <320 pm measured by Heidelberg Spectralis or < 300 pm measured by Cirrus or Topcon spectral domain optical coherence tomography (SD-OCT).

[0226] In one embodiment the reference visit is the visit at the previous injection.

[0227] In one embodiment of the invention, said treatment interval between two consecutive tertiary doses is extended by 2 or 4 or 2-4 weeks. In one embodiment of the invention, said treatment interval between two consecutive tertiary doses is 4 weeks (1 month) or 8 weeks (2 months) or 12 weeks (3 months).

[0228] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,

a single initial dose of 8 mg (±0.8 mg) aflibercept, followed by;

one or more tertiary doses of 8 mg (±0.8 mg) aflibercept;

wherein the treatment interval between two consecutive tertiary doses is shortened based on the physician’s judgement of visual and/or anatomic outcomes; and wherein the subject was treated with 2 mg aflibercept, faricimab, ranibizumab or bevacizumab prior to said single initial dose of 8 mg (±0.8 mg) aflibercept (e.g., >3 anti-VEGF ocular injections over the prior 5 months (-150 days).

[0229] In one embodiment of the invention said treatment interval between two consecutive tertiary doses is shortened if the subject

(i) exhibits >5 letters loss of BOVA from reference visit; and/or

(ii) >50 pm increase in CRT (central retinal thickness) from reference visit.

[0230] In one embodiment the reference visit is the visit at the previous injection.

[0231] In one embodiment of the invention, said treatment interval between two consecutive tertiary doses is shortened by 2 or 4 or 2-4 weeks. In one embodiment of the invention, said treatment interval between two consecutive tertiary doses is 4 weeks (1 month) or 8 weeks (2 month) or 12 weeks (3 month).

[0232] In one embodiment of the invention the subject was treated with 2 mg aflibercept or faricimab prior to said single initial dose of 8 mg (±0.8 mg) aflibercept. In one embodiment of the invention, the subject was treated with ranibizumab or bevacizumab prior to said single initial dose of 8 mg (±0.8 mg) aflibercept (e.g., >3 anti-VEGF ocular injections over the prior 5 months (-150 days).

[0233] According to the invention the treatment interval between two consecutive doses is not shorter than 1 month (4 weeks).

[0234] According to the invention retinal vein occlusion includes branch RVO (BRVO), central RVO (CRVO), and hemiretinal RVO (HRVO).

[0235] In one embodiment each injection of 8 mg aflibercept is administered intravitreally in a volume of 70 pL.

[0236] In one embodiment of the invention said treatment with 8 mg aflibercept will be discontinued if visual and/or anatomic outcomes indicate that the patient is not benefiting from continued treatment. Such visual outcomes can be decreased visual acuity or > 5 letter loss of BCVA. Such anatomic outcomes can be retinal fluid, subretinal fluid, CNV lesion size, total lesion size or central retinal thickness (CRT).

[0237] In one embodiment, a method of the present invention may comprise a period of Treat and Extend (T& E), for instance after an initial period of dosing. In one embodiment, T& E is employed during administration of tertiary doses.

[0238] In an embodiment of the invention a subject will initiate treatment with injections of 8 mg (±0.8 mg) aflibercept q4w for a total of 3, 4, or 5 or 3-5 doses, followed by extension of the treatment interval to at least 8 weeks, then beginning, e.g., at week 36, T& E is employed [0239] In an embodiment of the invention a subject will initiate treatment with injections of 8 mg (±0.8 mg) aflibercept q4w for a total of 3 or 5 doses, followed by extension of the treatment interval of 8 weeks, then beginning, e.g., at week 36, T& E is employed.

[0240] In an embodiment of the invention a subject will receive a total of 6 injections of 8 mg (±0.8 mg) aflibercept dosed every 4 weeks (e.g., from initiation through week 20) followed by an extension of the dosing interval to every 12 weeks.

[0241] The present invention encompasses methods for treating and preventing angiogenic eye disorders including angiogenic eye disorders secondary to retinal vein occlusion (e.g., macular edema secondary to RVO (MERVO)) by sequentially administering one or more (preferably 3 or 5) initial loading dose (preferably, about 8 mg (±0.8 mg) of VEGF antagonist, preferably, aflibercept) about every 4 weeks (±7 days), followed by one or more doses administered on a Treat & Extend basis. Treat & Extend may initiate at any point, for example, at week 36 from treatment initiation.

[0242] The present invention provides methods for treating or preventing angiogenic eye disorders including angiogenic eye disorders secondary to retinal vein occlusion (e.g., MERVO) by administering:

• one or more (e.g., 2 or 3 or 4 or 5 or 6) doses of about 8 mg (±0.8 mg) or more of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) about every 2-4, 2, 3, 4, or 3-5 weeks, preferably, every 4 weeks (±7 days);

• one or more (e.g., 2 or 3 or 4 or 5 or 6) doses of about 8 mg (±0.8 mg) or more of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) about every 4 weeks or every month (±7 days);

• one or more (e.g., 2 or 3 or 4 or 5 or 6) doses of about 8 mg (±0.8 mg) or more of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) about every 4 weeks (±7 days) [may be referred to herein as 8q4 or 8q4w];

• one or more (e.g., 2 or 3 or 4 or 5 or 6 or 7 or 3-5) doses of about 8 mg (±0.8 mg) or more of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) about every 2-4, 4 or 3-5 weeks, preferably, every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) or more VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) every 4 or 8 or 12 or 4-8 or 8-12 or 4-12 weeks (±7 days);

• 2 or 3 or 4 or 5 or 6 or 7 or 3-5 doses of about 8 mg (±0.8 mg) or more of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) about every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) or more VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) every 8 weeks (±7 days); optionally, after one or more doses every 8 weeks, a Treat & Extend (T& E) treatment or PRN regimen may initiate, e.g., starting about 36 weeks after treatment initiation, which may later revert to dosing every 8 weeks (±7 days);

• three doses of about 8 mg (±0.8 mg) or more of aflibercept about every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) or more aflibercept every 8 weeks (±7 days) [may be referred to herein as 3x8q4w->8q8w or 8q8/3];

• four doses of about 8 mg (±0.8 mg) or more of aflibercept about every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) or more aflibercept every 8 weeks (±7 days) [may be referred to herein as 4x8q4w->8q8w or 8q8/4];

• five doses of about 8 mg (±0.8 mg) or more of aflibercept about every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) or more aflibercept every 8 weeks (±7 days) [may be referred to herein as 5x8q4w->8q8w or 8q8/5]

• three to five doses of about 8 mg (±0.8 mg) or more of aflibercept about every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) or more aflibercept every 8 weeks (±7 days) [may be referred to herein as 3-5x8q4w->8q8w or 8q8/3-5]

• 2 or 3 or 4 or 5 or 6 or 7 doses of about 8 mg (±0.8 mg) or more of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) about every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) or more VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) every 12 weeks (±7 days);

• 2 or 3 or 4 or 5 or 6 or 7 doses of about 8 mg (±0.8 mg) or more of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) about every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) or more VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) every 12 weeks (±7 days), then one or more doses every 8 weeks (±7 days) (e.g., starting about 28 or 32 weeks after treatment initiation);

• 6 doses of about 8 mg (±0.8 mg) or more of aflibercept about every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) or more aflibercept every 12 weeks (±7 days) [may be referred to herein as 6x8q4w->8q12w],

In such embodiments each administered dose comprises 8 mg aflibercept.

[0243] In one embodiment, a method of the present invention comprises administering three doses of about 8 mg (±0.8 mg) or more of aflibercept about every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) or more aflibercept every 8 weeks (±7 days) [may be referred to herein as 3x8q4w->8q8w or 8q8/3]. In one such embodiment, administration is via intravitreal injection. In one such embodiment, each administered dose comprises 8 mg aflibercept.

[0244] In one embodiment, a method of the present invention comprises administering five doses of about 8 mg (±0.8 mg) or more of aflibercept about every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) or more aflibercept every 8 weeks (±7 days) [may be referred to herein as 3x8q4w->8q8w or 8q8/3]. In one such embodiment, administration is via intravitreal injection. In one such embodiment, each administered dose comprises 8 mg aflibercept.

[0245] The present invention provides a method for treating or preventing macular edema following retinal vein occlusion (RVO) comprising administering 8 mg (±0.8 mg) aflibercept by intravitreal injection every 4 weeks (+/- 7 days) for the first three or four to five or 3-5 doses (e.g., every 3, 4 or 5 weeks), followed by 8 mg (±0.8 mg) aflibercept via intravitreal injection once every 4 to 8 weeks (+/- 1 week). The present invention provides, for example, a method for treating or preventing macular edema following retinal vein occlusion (RVO) comprising administering 8 mg (±0.8 mg) of aflibercept in a pharmaceutical formulation comprising 114.3 mg/ml aflibercept in a volume of 0.07 mL by intravitreal injection every 4 weeks or approximately every 28 days (+/- 7 days) for the first three to five doses, followed by 8 mg (±0.8 mg) of aflibercept in a pharmaceutical formulation comprising 114.3 mg/ml aflibercept in a volume of 0.07 mL via intravitreal injection once every 4 to 8 weeks (+/- 1 week).

[0246] The dosing regimen including the about 4 or 8 or 4-8 or 8-12 or 4-12 week tertiary dosing interval may be referred to herein as a 4 or 8 or 12 or 4-8 or 8-12 or 4-12 week dosing regimen or 8q4 or 8q8 or 8q12 or 8q4-8 or 8q8-12 or 8q4-12.

[0247] In an embodiment of the disclosure, a subject begins receiving the >8 mg (±0.8 mg) maintenance doses, e.g., of about every 8 or 12 weeks, after the >8 mg (±0.8 mg) monthly loading doses with no intervening doses. The subject enters the maintenance dose phase rapidly/immediately after the loading dose phase. In an embodiment of the disclosure, the subject continues receiving the maintenance doses without any intervening doses. In one such embodiment each administered dose comprises 8 mg (±0.8 mg) aflibercept.

[0248] For example, the present disclosure also provides methods for treating angiogenic eye disorders including angiogenic eye disorders secondary to RVO (e.g., MERVO) as discussed herein including administering doses of about >8 mg (±0.8 mg) VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) in a volume of about 100 pl or less, about 75 pl or less or about 70 p.1 or less, e.g., about 50 pl; 51 pl; 52 pl; 53 pl; 54 pl; 55 pl; 56 pl; 57 pl; 58 pl; 59 pl; 60 pl; 61 pl; 62 pl; 63 pl; 64 pl; 65 pl; 66 pl; 67 pl; 68 pl; 69 pl; 70 pl; 71 pl; 72 pl; 73 pl; 74 pl; 75 >il; 76 pl; 77 pl; 78 pl; 79 JLLI; 80 pl; 81 pl; 82 pl; 83 pl; 84 j l; 85 pl; 86 pl; 87 pl; 88 pl; 89 pl; 90 pl; 91 pl; 92 pl; 93 pl; 94 pl; 95 pl; 96 pl; 97 pl; 98 pl; 99 pl; or 100 pl. In one such embodiment, the volume is about 100 pl or less. In one such embodiment, the volume is about 50 pl to about 100 pl. In one embodiment, the volume is about 60 pl to about 80 pl. In one embodiment, the volume is about 70 pl. In one such embodiment each administered dose comprises 8 mg aflibercept.

[0249] In an embodiment of the disclosure, the subject does not receive a dosing regimen modification (DRM) or does not terminate treatment for at least 1, 2, 3, 4 or 5 years.

[0250] The present disclosure also provides methods for improving visual acuity in subjects with an angiogenic eye disorder including angiogenic eye disorders secondary to RVO (e.g., MERVO) by administering, sequentially, one or more (e.g., 3 or 4 or 5 or 6) doses about every month (or about every 28 days, 28 ± 5 days or about every 4 weeks), followed by one or more doses every 4 or 8 or 12 or 4-8 or 8-12 or 4-12 weeks.

[0251] The terms "initial dose," "secondary doses," and "tertiary doses," refer to the temporal sequence of administration of the VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept). Thus, the "initial dose" is the dose which is administered at the beginning of the treatment regimen (also referred to as the "baseline dose"); the "secondary doses" are the doses which are administered after the initial dose; and the "tertiary doses" are the doses which are administered after the secondary doses. The initial, secondary, and tertiary doses may all contain the same amount of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), but will generally differ from one another in terms of frequency of administration. In certain embodiments, however, the amount of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) contained in the initial, secondary and/or tertiary doses will vary from one another (e.g., adjusted up or down as appropriate) during the course of treatment.

[0252] Thus, a dosing regimen of the present disclosure may be expressed as follows: a method for treating an angiogenic eye disorder e.g., an angiogenic eye disorder secondary to RVO (e.g., MERVO) in a subject in need thereof including administering (e.g., intravitreally) to the subject in need thereof, a single initial dose of about >8 mg (±0.8 mg) VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), for example, in a volume of about 100 pl or less, about 75 pl or less or about 70 pl or less, e.g., about 50 pl; 51 pl; 52 pl; 53 pl; 54 pl; 55 pl; 56 pl; 57 pl; 58 pl; 59 pl; 60 pl; 61 pl; 62 pl; 63 pl; 64 pl; 65 pl; 66 pl; 67 pl; 68 pl; 69 pl; 70 pl; 71 pl; 72 pl; 73 pl; 74 pl; 75 pl; 76 pl; 77 pl; 78 pl; 79 pl; 80 pl; 81 pl; 82 pl; 83 pl; 84 pl; 85 pl; 86 pl; 87 pl; 88 pl; 89 pl; 90 pl; 91 pl; 92 pl; 93 pl; 94 pl; 95 pl; 96 pl; 97 pl; 98 pl; 99 pl; or 100 pl), followed by one or more (e.g., 2, or 3 or 2-4 or 4 or 5) secondary doses of the VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), followed by one or more tertiary doses of the VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept); wherein each secondary dose is administered about 2 to 4 weeks (preferably, about every 4 weeks) after the immediately preceding dose; and wherein each tertiary dose is administered about 4 or 8 or 12 or 4-8 or 8-12 or 4-12 weeks after the immediately preceding dose. In one embodiment, the doses are administered in a 100 pel or less via intravitreal injection with the tertiary doses administered at about 8 to 12 week intervals. In one such embodiment, the secondary doses are administered at about 4 week intervals.

[0253] The present disclosure also provides methods for treating an angiogenic eye disorder including angiogenic eye disorders secondary to RVO (e.g., MERVO) including administering to a subject in need thereof about >8 mg (±0.8 mg) (for example, in about 100 |il or less, about 75 |il or less or about 70 pl or less, e.g., about 50 p.1; 51 pl; 52 pl; 53 pl; 54 pl; 55 pl; 56 pl; 57 pl; 58 pl; 59 pl; 60 pl; 61 pl; 62 pl; 63 pl; 64 pl; 65 pl; 66 pl; 67 pl; 68 pl; 69 pl; 70 pl; 71 pl; 72 pl; 73 pl; 74 pl; 75 pl; 76 pl; 77 pl; 78 pl; 79 pl; 80 pl; 81 pl; 82 pl; 83 pl; 84 pl; 85 pl; 86 pl; 87 pl; 88 pl; 89 pl; 90 pl; 91 pl; 92 pl; 93 pl; 94 pl; 95 pl; 96 pl; 97 pl; 98 pl; 99 pl; or 100 pl) of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) on a pro re nata (PRN) or Treat & Extend basis or based on the physician’s judgement of visual and/or anatomic outcomes. In an embodiment of the invention, one or more PRN doses are administered following any tertiary doses that were administered once every 4 or 8 or 12 or 4-8 or 8-12 or 4-12 weeks. Such PRN doses can be inserted into any dosing regimen discussed herein at any point, e.g., after or before an initial, secondary and/or tertiary dose.

[0254] A pro re nata (PRN) treatment protocol calls for intervals between doctor visits to remain fixed (e.g., once every 2, 3, 4, 8, 12, 16, 20 or 24 weeks) and decisions to carry out an injection of VEGF receptor fusion protein (e.g., aflibercept) to be based on the anatomic findings at each respective visit (e.g., as per OCT findings). A capped PRN dosing regimen is PRN wherein subjects must be treated at a certain minimal frequency, e.g., at least once every 2 or 3 or 4 or 6 months. Any treatment regimen set forth herein may further include one or more PRN and/or capped PRN dosing intervals.

[0255] Treat & Extend (T& E) treatment regimen is a gradual approach in which the treatment intervals between two consecutive injections are gradually extended as long as the patient's condition remains stable or improves or shortened when the patient's condition becomes worse or deteriorates. This method aims to reduce the treatment burden while maintaining the effectiveness of the therapy. Treat & Extend (T& E) regimens call for the time interval between doctor visits to be adjusted based on the patient’s clinical course — e.g., if a subject shows no sign of an active disease (e.g., the macula remains dry, without any leakage), the next one or more intervals can be extended; if there is fluid accumulation, the next interval will be shortened. At each visit following T& E, an injection of VEGF receptor fusion protein will be performed; the current clinical status only has an impact on the duration of the next injection interval. Any treatment regimen set forth herein may further include one or more T& E dosing intervals. In an embodiment of the invention, one or more T& E doses are administered following tertiary doses that were administered once every 4 or 8 or 12 or 4-8 or 8-12 or 4-12 weeks. In an embodiment of the invention, T& E is initiated after the loading dose phase of treatment.

[0256] See e.g., Lanzetta et al., Vision Academy Steering Committee. Fundamental principles of an anti-VEGF treatment regimen: optimal application of intravitreal anti-vascular endothelial growth factor therapy of macular diseases. Graefes Arch Clin Exp Ophthalmol

2017;255(7):1259-1273.

[0257] The present disclosure also provides methods for treating an angiogenic eye disorder including angiogenic eye disorders secondary to RVO by administering to a subject in need thereof a single initial dose of about 8 mg (±0.8 mg) aflibercept and, then 2 secondary doses of about 8 mg (±0.8 mg) aflibercept every month (4 weeks); and after said 3 doses (initial dose and 2 secondary doses) injection intervals between two doses of about 8 mg (±0.8 mg) aflibercept are extended based on the physician’s judgement of visual and/or anatomic outcomes.

[0258] The present disclosure also provides methods for treating an angiogenic eye disorder including angiogenic eye disorders secondary to RVO by administering to a subject in need thereof 70 pL of an pharmaceutical formulation comprising 8 mg (±0.8 mg) aflibercept, wherein after the administration of a single initial dose of about 8 mg (±0.8 mg) aflibercept 2 secondary doses of about 8 mg (±0.8 mg) aflibercept are administered every month (4 weeks). After said 3 doses (initial dose and 2 secondary doses) injection intervals between two doses of about 8 mg (±0.8 mg) aflibercept may then be extended based on the physician’s judgement of visual and/or anatomic outcomes.

[0259] In one embodiment the dosing interval after said 3 initial doses ((initial dose and 2 secondary doses) is extended if the subject exhibits (i) <5 letters loss of BOVA from reference visit; and/or (ii) CRT (central retinal thickness) is <320 pm measured by Heidelberg Spectralis or < 300 pm measured by Cirrus or Topcon spectral domain optical coherence tomography (SD-OCT).

[0260] In one embodiment, such reference visit is the visit at the second monthly or 4-weekly secondary dosing or the visit at 12 weeks (3 months) after initiation of treatment.

[0261] In one embodiment, the reference visit is the visit at the previous injection. [0262] In one embodiment, the tertiary dosing interval is extended by 2 or 4 weeks.

[0263] The present disclosure also provides methods for treating an angiogenic eye disorder including angiogenic eye disorders secondary to RVO by administering to a subject in need thereof 70 pL of an pharmaceutical formulation comprising 8 mg (±0.8 mg) aflibercept, wherein after the administration of a single initial dose of about 8 mg (±0.8 mg) aflibercept 4 secondary doses of about 8 mg (±0.8 mg) aflibercept are administered every month (4 weeks). After said 5 doses (initial dose and 4 secondary doses) injection intervals between two doses of about 8 mg (±0.8 mg) aflibercept may then be extended based on the physician’s judgement of visual and/or anatomic outcomes.

[0264] The present disclosure includes embodiments wherein, at any point during a 8q4 or 8q8 or 8q12 or 8q4-8 or 8q8-12 or 8q4-12 treatment regimen, the patient can be switched to a PRN, capped PRN or T& E regimen. The PRN, capped PRN and/or T& E may be continued indefinitely or can be stopped at any point and then the 8q4 or 8q8 or 8q12 or 8q4-8 or 8q8-12 or 8q4-12 regimen is re-initiated at any phase thereof. Any 8q4 or 8q8 or 8q12 or 8q4-8 or 8q8-12 or 8q4-12 regimen can be preceded or followed by a period of PRN, capped PRN and/or T& E.

[0265] The present disclosure includes methods wherein one or more additional, nonscheduled doses, in addition to any of the scheduled initial, secondary and/or tertiary doses of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) are administered to a subject. Such doses are typically administered at the discretion of the treating physician depending on the particular needs of the subject.

[0266] Thus, the present disclosure includes methods comprising administering the required doses as set forth herein, wherein each of the tertiary doses is administered, e.g., about 4, 8, or 12 weeks after the immediately preceding dose, wherein the treatment interval between two tertiary doses is extended (e.g., by one or more increments of 4 weeks), for example, until signs of disease activity recur or vision deteriorates and then either continuing dosing at the last tertiary interval used or the penultimate tertiary interval used.

[0267] The present disclosure includes methods comprising administering the required doses of a treatment regimen as discussed herein, wherein the treatment interval between any two tertiary doses is reduced (e.g., by one or more increments of 4 weeks), for example, until signs of disease activity decrease or vision improves (e.g., BOVA stabilizes or improves) whereupon, optionally, the interval between doses can be extended, e.g., back to a greater interval length. [0268] For example, in an embodiment of the disclosure, the interval between doses, can be extended, for example by one or more 4 week increments as appropriate in the judgment of the treating physician, for example if there is:

• <5 letter loss in BCVA, e.g., relative to BCVA at time of the previous dose or measurement (e.g., at week 12 or 16); and/or

• Central subfield thickness (CST) <315 pm on SD-OCT (or <325 pm on Spectralis SD- OCT).

[0269] For example, in an embodiment of the disclosure, the interval between doses, can be shortened (e.g., beginning at week 16 or 20 relative to treatment initiation), for example by one or more 4 week increments as appropriate in the judgment of the treating physician, for example if there is:

• BCVA loss of >5 letters, e.g., relative to BCVA at time of the previous dose or measurement (e.g., at week 12 or 16 or 24 or 32), for example, that is accompanied by persistent or worsening disease activity; and/or

• >50 micrometer increase in CST, e.g., relative to CST at time of the previous dose or measurement (e.g., at week 12 or 16).

[0270] In an embodiment of the disclosure, the interval between doses, can be shortened, for example by one or more 4 week increments as appropriate, for example if there is >5 letters loss of BCVA from e.g., relative to BCVA at time of the previous dose or measurement with persistent or worsening disease activity.

[0271] In an embodiment of the invention, the shortest interval between doses is about 4 weeks.

[0272] In an embodiment of the invention, the interval between intervals is shortened if criterial for such (e.g., BCVA loss of >5 letters, e.g., relative to BCVA at time of the previous dose or measurement (e.g., at week 12 or 16), for example, that is accompanied by persistent or worsening disease activity) are met at week 28 after treatment initiation.

[0273] In an embodiment of the disclosure, a method of treating an angiogenic eye disorder, e.g., an angiogenic eye disorder secondary to RVO (e.g., MERVO), as set forth herein includes the step of evaluating BCVA and/or CST and, optionally, lengthening or shortening the interval between doses.

[0274] In an embodiment of the invention, a tertiary dosing interval is increased or decreased at increments of 4 weeks, e.g., from 4 to 8, 8 to 12, 12 to 8 or 8 to 4. Decisions to increase or decrease a tertiary dosing interval can be made at one or more office visits to the treating physician. In an embodiment of the invention, the dosing interval is lengthened to about 16, 20, 24, 28 or 32 weeks (± 7 days).

[0275] Administration about every 4 weeks as discussed herein may be referred to as dosing about every month, about 12 times per year, about every 28 days, 30 days or 31 days.

[0276] Dosing every “month” or after a “month” refers to dosing after about 28 days, about 4 weeks, or about 28 ± 7 days and may encompass up to 5 weeks ± 7 days. Dosing every “4 weeks” or after “4 weeks” refers to dosing after about 28 days (± 7 days), about a month or about 28 (± 7 days), and may encompass up to every 5 weeks (± 7 days).

[0277] Administration about every 8 weeks as discussed herein may be referred to as dosing about every 2 months, about every other month, about 6 times per year, about every 56, 57, 58, 59, 60 or 61 or 62 days.

[0278] Dosing every “12 weeks” or after “12 weeks” refers to dosing after about 3 months, about 84 days (± 7 days), 85 days (± 7 days), 86 days (± 7 days), 87 days (± 7 days), 88 days (± 7 days), 89 days (± 7 days), or about 90 days (± 7 days). Dosing every “16 weeks” or after “16 weeks” refers to dosing after about 4 months or about 112 days (± 7 days).

[0279] Dosing every “2-4 weeks” or after “2-4 weeks” refers to dosing after about 2 weeks (± 7 days), 3 weeks (± 7 days) or, preferably, 4 weeks (± 7 days). Dosing every “8 weeks” or after “8 weeks” refers to dosing after about 2 months (± 7 days) or about 56 (± 7 days).

[0280] A dose of > 8 mg encompasses a dose of about 8 mg (± 0.8 mg) or doses exceeding 8 mg, for example, about 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg.

[0281] Any dosing frequency specified herein encompasses the specific frequency “± 5 days” (e.g., where “4 weeks” is stated, the present invention also includes embodiments such as 4 weeks ± 7 days). The term ± 7 days includes ±1, ±2, ±3, ±4 days, ±5 days, ±6 days and/or ±7 days.

[0282] " Sequentially administering" means that each dose of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) is administered to the eye of a subject at a different point in time, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks or months). The present disclosure includes methods which comprise sequentially administering to the eye of a subject a single initial dose of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), followed by one or more secondary doses of the VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), followed by one or more tertiary doses of the VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept).

[0283] Baseline values refer to values prior to or at the time of initiation of a treatment. [0284] In an embodiment of the invention, an angiogenic eye disorder is neovascular age-related macular degeneration (wet), macular edema, an angiogenic eye disorder secondary to RVO, macular edema following retinal vein occlusion, retinal vein occlusion (RVO), central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), hemiretinal vein occlusion (HRVO), diabetic macular edema (DME), choroidal neovascularization (CNV), iris neovascularization, neovascular glaucoma, post-surgical fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), optic disc neovascularization, corneal neovascularization, retinal neovascularization, vitreal neovascularization, pannus, pterygium, vascular retinopathy, diabetic retinopathy, non-proliferative diabetic retinopathy and/or proliferative diabetic retinopathy.

[0285] An "angiogenic eye disorder secondary to RVO" means any disease of the eye which is caused by or associated with the growth or proliferation of blood vessels or by blood vessel leakage following retinal vein occlusion, such as macular edema following retinal vein occlusion (ME-RVO or MERVO). Retinal vein occlusion includes central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), and hemiretinal vein occlusion (HRVO). In one embodiment, the retinal vein occlusion is selected from central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), and hemiretinal vein occlusion (HRVO). In one embodiment, it is selected from central retinal vein occlusion (CRVO), and branch retinal vein occlusion (BRVO).

[0286] The present disclosure provides methods for treating angiogenic eye disorders including angiogenic eye disorders secondary to RVO (e.g., MERVO), in a subject in need thereof, by sequentially administering an loading doses (e.g., about 8 mg (±0.8 mg) of VEGF antagonist, for example, a VEGF receptor fusion protein such as aflibercept) (e.g., about every 2-4 or 3-5 weeks, preferably every 4 weeks; preferably, three initial loading doses or five initial loading doses) followed by additional maintenance doses about every 4 or 8 or 12 or 4-8 or 8-12 or 4-12 weeks, wherein the subject achieves and/or maintains, e.g., by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92 or 96 weeks after treatment initiation:

• achieves an improvement in BCVA by week 36 of about 17 or 16 or as high as 50 letters (or more); for example, wherein the subject has received an 8q8/3 dosing regimen;

• achieves an improvement in BCVA by week 36 of about 18 or 19 or as high as 52 letters (or more); for example, wherein the subject has received an 8q8/5 dosing regimen; • achieves an improvement in BCVA by week 36 of about 17 or 18 or 16 or as high as 50 letters (or more); for example, wherein the subject has received an 8q8/3 dosing regimen; for example, wherein the subject has BRVO;

• achieves an improvement in BCVA by week 36 of about 19 or 18 or as high as 52 letters (or more); for example, wherein the subject has received an 8q8/5 dosing regimen; for example, wherein the subject has BRVO;

• achieves an improvement in BCVA by week 36 of about 16 or 17 or as high as 47 letters (or more); for example, wherein the subject has received an 8q8/3 dosing regimen; for example, wherein the subject has CRVO or HRVO;

• achieves an improvement in BCVA by week 36 of about 17 or 18 or as high as 50 letters (or more); for example, wherein the subject has received an 8q8/5 dosing regimen; for example, wherein the subject has CRVO or HRVO;

• achieves a reduction in CST by week 36 of about 363 or 233 or 318 or as high as 1259 or 233-1259 micrometers (or more); for example, wherein the subject has received an 8q8/3 dosing regimen;

• achieves a reduction in CST by week 36 of about 355 or 307 or 8 or as high as 1146 or 8-1146 micrometers (or more); for example, wherein the subject has received an 8q8/5 dosing regimen;

• achieves a reduction in CST by week 36 of about 275 or 236 or as high as 781 micrometers (or more); for example, wherein the subject has received an 8q8/3 dosing regimen; for example, wherein the subject has BRVO;

• achieves a reduction in CST by week 36 of about 284 or 255 or 8 or as high as 927 or 8-927 micrometers (or more); for example, wherein the subject has received an 8q8/5 dosing regimen; for example, wherein the subject has BRVO;

• achieves a reduction in CST by week 36 of about 458 or 439 or 38 or as high as 1259 or 38-1259 micrometers (or more); for example, wherein the subject has received an 8q8/3 dosing regimen; for example, wherein the subject has CRVO or HRVO;

• achieves a reduction in CST by week 36 of about 431 or 376 or 38 or as high as 1146 or 38-1146 micrometers (or more); for example, wherein the subject has received an 8q8/5 dosing regimen; for example, wherein the subject has CRVO or HRVO;

• A BCVA improvement of about 6, 7, 8 or 9 letters;

• Does not lose 5 or more, 10 or more or 15 or more letters BCVA; • A BCVA of about 69, 70, 71, 72 or 73 letters;

• No intraretinal fluid (IRF);

• No subretinal fluid (SRF);

• No IRF and no SRF;

• No increase in CST;

• No leakage observed on fluorescein angiography;

• A NEI-VFQ-25 total score of about 80;

• A NEI-VFQ-25 total score change from baseline of about 2 or 3;

• No significant change in intraocular pressure;

• No significant change in systolic blood pressure;

• No significant change in diastolic blood pressure;

• Non-inferior BVCA compared to that of aflibercept which is intravitreally dosed at 2 mg approximately every 4 weeks for the first 3, 4 or 5 injections followed by 2 mg approximately once every 8 weeks or once every 2 months;

• Increase in BCVA (according to ETDRS letter score) of about 7, 8 or 9 letters by week 64 from start of treatment, wherein the baseline BCVA is about 61, 62 or 63;

• BCVA (according to ETDRS letter score) of at least about 69 letters by week 36, 48, 60 or 64 from start of treatment;

• Does not lose 5, 10, 15 or 69 letters or more BCVA after week 12, 24, 36, 49, 60, 64, 72, 84 or 90 from start of treatment;

• Improvement in BCVA (according to ETDRS letter score) by week 12, 24, 36, 49, 60, 64, 72, 84 or 90 from start of treatment;

• Improvement in BVCA by week 4, week 8, week 12, week 16, week 20, week 24, week 28, week 32, week 36, week 40, week 44, or week 48 from start of treatment;

• Between weeks 48 and 64, a BCVA score (according to ETDRS letter score) of about 69, 70, 71, 72 or 73;

• Between weeks 36 and 48, a change in BCVA score (according to ETDRS letter score) from initiation of treatment of about 7, 8 or 9 wherein the BCVA at any point between week 36 to 48 is about 60 or 70; • Between weeks 48 and 64, a change in BCVA score (according to ETDRS letter score) from initiation of treatment of about 7, 8 or 9, wherein the BCVA at any point between week 48 to 64 is about 69, 70, 71, 72 or 73;

• Increase in BCVA as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart or Snellen equivalent by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 or 48 weeks from start of treatment by >4 letters, >5 letters, >6 letters, >7 letters, >8 letters, >9 letters or >10 letters;

• Does not lose 5, 10 or 15 letters by week 48 or 64 from start of treatment (according to ETDRS letter score);

• Gains at least 5, 10 or 15 letter by week 48 or 64 from start of treatment (according to ETDRS letter score);

• Improvement in BCVA, by 4 weeks after initiation of treatment, of about 4 or 5 letters (ETDRS or Snellen equivalent);

• Improvement in BCVA, by 8 weeks after initiation of treatment, of about 6 letters (ETDRS or Snellen equivalent);

• Improvement in BCVA, by 12 weeks after initiation of treatment, of about 6 or 7 letters (ETDRS or Snellen equivalent);

• Improvement in BCVA, by 16 weeks after initiation of treatment, of about 6 or 7 letters (ETDRS or Snellen equivalent);

• Improvement in BCVA, by 20 weeks after initiation of treatment, of about 6 letters (ETDRS or Snellen equivalent);

• Improvement in BCVA, by 24 weeks after initiation of treatment, of about 7 letters (ETDRS or Snellen equivalent);

• Improvement in BCVA, by 28 weeks after initiation of treatment, of about 7 or 8 letters (ETDRS or Snellen equivalent);

• Improvement in BCVA, by 32 weeks after initiation of treatment, of about 7 letters (ETDRS or Snellen equivalent);

• Improvement in BCVA, by 36 weeks after initiation of treatment, of 8 letters (ETDRS or Snellen equivalent);

• Improvement in BCVA, by 40 weeks after initiation of treatment, of about 8 letters (ETDRS or Snellen equivalent);

• Improvement in BCVA, by 44 weeks after initiation of treatment, of about 8 letters (ETDRS or Snellen equivalent); • Improvement in BCVA, by 48 weeks after initiation of treatment, of about 8 or 9 letters (ETDRS or Snellen equivalent);

• An improvement in BCVA by about week 8 after initiation of treatment which is maintained thereafter during the treatment regimen to at least week 48;

• A BCVA by 4 weeks after initiation of treatment of about 68 letters (ETDRS or Snellen equivalent);

• A BCVA by 8 weeks after initiation of treatment of about 70 letters (ETDRS or Snellen equivalent);

• A BCVA by 12 weeks after initiation of treatment of about 70 letters (ETDRS or Snellen equivalent);

• A BCVA by 16 weeks after initiation of treatment of about 71 letters (ETDRS or Snellen equivalent);

• A BCVA by 20 weeks after initiation of treatment of about 70 letters (ETDRS or Snellen equivalent) when on an 8q4 or 8q8 or 8q12 or 8q4-8 or 8q8-12 or 8q4-12 regimen;

• A BCVA by 24 weeks after initiation of treatment of about 71 letters (ETDRS or Snellen equivalent);

• A BCVA by 28 weeks after initiation of treatment of about 72 letters (ETDRS or Snellen equivalent);

• A BCVA by 32 weeks after initiation of treatment of about 71 letters (ETDRS or Snellen equivalent);

• A BCVA by 36 weeks after initiation of treatment of about 71 letters (ETDRS or Snellen equivalent);

• A BCVA by 40 weeks after initiation of treatment of about 72 letters (ETDRS or Snellen equivalent);

• A BCVA by 44 weeks after initiation of treatment of about 72 letters (ETDRS or Snellen equivalent);

• A BCVA by 48 weeks after initiation of treatment of about 73 letters (ETDRS or Snellen equivalent);

• A BCVA improvement, by week 48 following treatment initiation, of about 9 or 10 letters (ETDRS or Snellen equivalent) when baseline BCVA is about <73 ETDRS letters; • A BCVA improvement, by week 48 following treatment initiation, of about 5 or 6 letters (ETDRS or Snellen equivalent) when baseline BCVA is about >73 ETDRS letters;

• A BCVA improvement, by week 48 following treatment initiation, of about 8 or 9 letters (ETDRS or Snellen equivalent) when baseline BCVA is about <73 ETDRS letters;

• A BCVA improvement, by week 48 following treatment initiation, of about 4 or 5 letters (ETDRS or Snellen equivalent) when baseline BCVA is about >73 ETDRS letters;

• Gain of >5, >10 or >15 letters BCVA (according to ETDRS letter score) by week 12, 24, 36, 49, 60, 64, 72, 84 or 90 from start of treatment;

• Retina without fluid (total fluid, intraretinal fluid [IRF] and/or subretinal fluid [SRF]) at the foveal center and in center subfield by week 12, 24, 36, 49, 60, 64, 72, 84 or 90 from start of treatment as measured by optical coherence tomography (OCT);

• No vascular leakage as measured by fluorescein angiography (FA) by week 12, 24, 36, 49, 60, 64, 72, 84 or 90 from start of treatment;

• Maintenance of a fluid-free retina (total fluid, IRF and/or SRF at foveal center and in the center subfield) by week 12, 24, 36, 49, 60, 64, 72, 84 or 90 from start of treatment;

• Reduction in total area of fluorescein leakage within ETDRS grid (mm²) at week 48 or 64 by about 12, 13 or 14 mm² or more as measured by fluorescein angiography;

• Retina free of fluid on spectral domain optical coherence tomography (SD-OCT) by week 12, 24, 36, 49, 60, 64, 72, 84 or 90 from start of treatment;

• Retina without fluid (total fluid, intraretinal fluid [IRF] and/or subretinal fluid [SRF]) at the foveal center by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 or 48 weeks from start of treatment;

• Dry retina by week 12, 24, 36, 49, 60, 64, 72, 84 or 90 from start of treatment; • Foveal center without fluid by week 12, 24, 36, 49, 60, 64, 72, 84 or 90 from start of treatment as measured by optical coherence tomography (OCT);

• Does not have anti-drug antibodies against aflibercept after 36, 48, 60 or 64 weeks of treatment; • Improvement from pre-treatment baseline in National Eye Institute Visual Function Questionnaire (NEI-VFQ) total score; and/or

• Lack of macular edema.

[0287] In an embodiment of the invention, in a subject with an angiogenic eye disorder the subject achieves:

• By Week 12 from treatment initiation achieving an improvement in BCVA of about 1 or 2 letters e.g., in a subject with nAMD; e.g., who has been receiving 8 mg (±0.8 mg) aflibercept once every 4 weeks;

• By Week 16 from treatment initiation achieving an improvement in BCVA of about 1 or 2 letters e.g., in a subject with nAMD; e.g., who has been receiving 8 mg (±0.8 mg) aflibercept once every 4 weeks;

• By Week 20 from treatment initiation achieving an improvement in BCVA of about 7 letters e.g., in a subject with nAMD; e.g., who has been receiving 8 mg (±0.8 mg) aflibercept once every 4 weeks;

• By Week 4 from treatment initiation achieving an improvement in BCVA of about 1 or 2 letters e.g., in a subject with DME; e.g., who has been receiving 8 mg (±0.8 mg) aflibercept once every 4 weeks;

• By Week 8 from treatment initiation achieving an improvement in BCVA of about 2 or 2 letters e.g., in a subject with DME; e.g., who has been receiving 8 mg (±0.8 mg) aflibercept once every 4 weeks;

• By Week 12 from treatment initiation achieving an improvement in BCVA of about 3 or 2 letters e.g., in a subject with DME; e.g., who has been receiving 8 mg (±0.8 mg) aflibercept once every 4 weeks; and/or;

• By Week 16 from treatment initiation achieving an improvement in BCVA of about 3 letters e.g., in a subject with DME; e.g., who has been receiving 8 mg (±0.8 mg) aflibercept once every 4 weeks.

[0288] In an embodiment of the disclosure, CST and/or retinal fluid is as measured on spectral domain optical coherence tomography (SD-OCT). In an embodiment of the disclosure, any of such achievements are maintained as long as the subject is receiving the treatment regimen.

[0289] In an embodiment of the disclosure, a subject receiving a treatment for an angiogenic eye disorder, e.g., an angiogenic eye disorder secondary to RVO (e.g., MERVO), or for treatment of RVO, does not experience or is no more likely to experience than a subject receiving Eylea according to the prescribed dosage regimen: • Ocular serious TEAE (e.g., through week 96 after treatment initiation), for example, cataract subcapsular, retinal detachment, ulcerative keratitis, vitreous haemorrhage or increased intraocular pressure, angle closure glaucoma, cataract, choroidal detachment, retinal detachment, retinal haemorrhage, skin laceration and/or vitreous haemorrhage;

• TEAE intraocular inflammation (e.g., through week 96 after treatment initiation), for example, chorioretinitis, iridocyclitis, iritis, uveitis, vitreal cells and/or vitritis;

• Non-ocular serious TEAEs (e.g., through week 96 after treatment initiation), for example, acute left ventricular failure, acute myocardial infarction, cardiac arrest, coronary artery disease, myocardial infarction, covid-19 pneumonia, gangrene, pneumonia, hyponatraemia, cerebrovascular accident, acute kidney injury, acute respiratory failure, angina pectoris, chest pain, cellulitis, pneumonia, pyelonephritis acute, urinary tract infection, upper limb fracture, hyponatraemia, osteoarthritis, bladder neoplasm and/or cerebrovascular accident;

• Treatment emergent APTC event (e.g., through week 96 after treatment initiation), for example, non-fatal myocardial infarction, non-fatal stroke and/or vascular death;

• Treatment emergent hypertension events (e.g., through week 96 after treatment initiation), for example, blood pressure increased (diastolic and/or systolic), hypertension, diastolic hypertension, systolic hypertension, hypertensive crisis, hypertensive emergency, hypertensive urgency, labile hypertension and/or white coat hypertension;

• Potentially clinically significant values (e.g., through week 96 after treatment initiation), for example, systolic blood pressure>160 mmHg and an increase from baseline of >20 mmHg; and/or diastolic blood pressure >110 mmHg and an increase from baseline of >10 mmHg; and/or

• Death (e.g., through week 96 after treatment initiation), for example, due to cardiac arrest, cardio-respiratory arrest, left ventricular failure, myocardial infarction, death, sudden death, covid-19, pneumonia, diabetic metabolic decompensation, endometrial cancer, acute kidney injury, abdominal strangulated hernia, pneumonia aspiration, skull fracture, metastatic neoplasm and/or non-small cell lung cancer [0290] In one such embodiment, the subject has an angiogenic eye disorder secondary to RVO. In one such embodiment they have MERVO. [0291] Some subjects may be excluded from administration according to the present invention, based, for example, on the existence of certain exclusion criteria. For example, in an embodiment of the disclosure, the exclusion criteria are any one or more of the following:

1. Evidence of macular edema due to any cause other than RVO in an eye to be treated and/or the other eye not to be treated;

2. DME or DR, defined in a diabetic subject as diabetic retinopathy lesions in the assessable area of the retina in an eye to be treated and/or the other eye not to be treated;

3. Advanced age-related macular degeneration (nAMD or geographic atrophy) in an eye to be treated and/or the other eye not to be treated;

4. Prior ocular or systemic treatment (with an investigational or approved agent) or surgery for RVO in an eye to be treated and/or the other eye not to be treated;

5. Use of topical steroids within 4 weeks (28 days) of treatment in an eye to be treated and/or the other eye not to be treated;

6. Use of intraocular or periocular steroids, e.g., within 16 weeks (112 days) of treatment, in an eye to be treated and/or the other eye not to be treated;

7. Use of any intravitreal implantable agents (e.g., containing fluocinolone acetonide, dexamethasone or ranibizumab) in an eye to be treated and/or the other eye not to be treated;

8. Prior treatment with ocriplasmin at any time in an eye to be treated and/or the other eye not to be treated;

9. Prior treatment with pegcetacoplan injection or avacincaptad pegol injection in an eye to be treated and/or the other eye not to be treated;

10. Prior treatment with retinal laser photocoagulation in an eye to be treated and/or the other eye not to be treated;

11. Prior treatment with gene therapy and/or cell therapy in an eye to be treated and/or the other eye not to be treated;

12. History of vitreoretinal surgery (including scleral buckle) in an eye to be treated and/or the other eye not to be treated;

13. Any intraocular surgery, including cataract surgery, e.g., within 12 weeks (84 days) of treatment, in an eye to be treated and/or the other eye not to be treated;

14. YAG capsulotomy in the study eye, e.g., within 4 weeks (28 days) of treatment; 15. IOP > 25 mm Hg in an eye to be treated and/or the other eye not to be treated; 16. Uncontrolled glaucoma in an eye to be treated and/or the other eye not to be treated; (participant who has had filtration surgery in the past, or is likely to need filtration surgery in the future) based on physician assessment;

17. Evidence of infectious blepharitis, keratitis, scleritis, or conjunctivitis in an eye to be treated and/or the other eye not to be treated;

18. Any intraocular inflammation/infection (including trace, or above, cells in the anterior; chamber and/or vitreous), e.g., within 12 weeks (84 days) of treatment, in an eye to be treated and/or the other eye not to be treated;

19. History of idiopathic or autoimmune uveitis in an eye to be treated and/or the other eye not to be treated;

20. Vitreomacular traction or epiretinal membrane in an eye to be treated and/or the other eye not to be treated evident on biomicroscopy or OCT that is thought to affect central vision;

21. Myopia of a spherical equivalent of 8 diopters or greater in an eye to be treated and/or the other eye not to be treated (prior to any refractive or cataract surgery, if applicable);

22. History of corneal transplant in an eye to be treated and/or the other eye not to be treated;

23. Any corneal dystrophy affecting the visual axis in an eye to be treated and/or the other eye not to be treated based on physician assessment;

24. Aphakia, or pseudophakia with absence of posterior capsule (unless it occurred as a result of a YAG posterior capsulotomy, e.g., that was performed more than 28 days before treatment, in an eye to be treated and/or the other eye not to be treated;

25. Any history of macular hole of stage 2 and above in an eye to be treated and/or the other eye not to be treated;

26. Current anterior segment neovascularization, vitreous hemorrhage, or tractional retinal detachment visible in an eye to be treated and/or the other eye not to be treated; 27. Structural damage in an eye to be treated and/or the other eye not to be treated that is likely to preclude improvement in BCVA following the resolution of macular edema (e.g., atrophy of the retinal pigment epithelium, preretinal fibrosis, subretinal fibrosis or scar, significant macular ischemia, or organized hard exudates);

28. Uncontrolled blood pressure (e.g., systolic > 160 mm Hg or diastolic > 95 mm Hg); 29. History of cerebrovascular accident/transient ischemic attack or myocardial infarction/acute coronary syndrome, e.g., within 6 months (180 days) of treatment; 30. Renal failure, dialysis, or history of renal transplant;

31. Known sensitivity to aflibercept;

32. Presence of systemic infection or treatment for suspected or active systemic infection

33. Presence of any contraindications to Eylea;

34. Subject is a pregnant or breastfeeding woman; and/or

35. Subject is of child bearing potential and is unwilling to practice highly effective contraception

[0292] In an embodiment of the disclosure, a subject receiving VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) is monitored for adverse events (AEs) such as conjunctival hemorrhage, cataract, vitreous detachment, vitreous floaters, corneal epithelium defect and/or increased intraocular pressure. If an AE is found, the AE can be treated in the subject and treatment can either be discontinued or continued.

[0293] The methods of present disclosure can include preparatory steps that include use of • one single-dose glass vial having a protective plastic cap and a stopper containing an aqueous formulation comprising 8 mg (±0.8 mg) aflibercept in about 70 microliters;

• one 18-gauge x 1¹/2-inch, 5-micron, filter needle that includes a tip and a bevel;

• one 30-gauge x ¹/2-inch injection needle; and

• one 1-mL Luer lock syringe having a graduation line marking for 70 microliters of volume;

packaged together (kits including such items form part of the present invention). The steps can include, for example: (1) visually inspecting the aqueous formulation in the vial and, if particulates, cloudiness, or discoloration are visible, then using another vial of aqueous formulation containing the aflibercept; (2) removing the protective plastic cap from the vial; and (3) cleaning the top of the vial with an alcohol wipe; then, using aseptic technique the following steps: (4) removing the 18-gauge x 1 Va-inch, 5-micron, filter needle and the 1 mL syringe from their packaging; (5) attaching the filter needle to the syringe by twisting it onto the Luer lock syringe tip; (6) pushing the filter needle into the center of the vial stopper until the needle is completely inserted into the vial and the tip touches the bottom or a bottom edge of the vial; (7) withdrawing all of the aflibercept vial contents into the syringe, keeping the vial in an upright position, slightly inclined, while ensuring the bevel of the filter needle is submerged into the liquid; (8) continuing to tilt the vial during withdrawal keeping the bevel of the filter needle submerged in the formulation; (9) drawing the plunger rod sufficiently back when emptying the vial in order to completely empty the filter needle; (10) removing the filter needle from the syringe and disposing of the filter needle; (11) removing the 30-gauge x Vz-inch injection needle from its packaging and attaching the injection needle to the syringe by firmly twisting the injection needle onto the Luer lock syringe tip; (12) holding the syringe with the needle pointing up, and checking the syringe for bubbles, wherein if there are bubbles, gently tapping the syringe with a finger until the bubbles rise to the top; and (13) slowly depressing the plunger so that the plunger tip aligns with the graduation line that marks 70 microliters on the syringe. Preferably injection of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) as performed in methods of the present invention is performed under controlled aseptic conditions, which comprise surgical hand disinfection and the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent) and anesthesia and a topical broadspectrum microbicide are administered prior to the injection.

Treatment and Administration for neovascular (wet) age-related macular degeneration (nAMD) or visual impairment due to diabetic macular oedema (DME) [0294] The present disclosure provides methods for treating or preventing neovascular (wet) age-related macular degeneration (nAMD) or visual impairment due to diabetic macular oedema (DME) in a subject; wherein the methods comprise

(i) administering to the eye of the subject an intravitreal injection of 8 mg aflibercept every month or every 4 weeks +/- 1 week for the first 3 consecutive injections; and (ii) one or more further injections of 8 mg aflibercept after said first 3 consecutive injections wherein the injection interval between two consecutive injections is adjusted based on the physician’s judgement of visual and/or anatomic outcomes;

wherein the injection interval between two consecutive injections is at least 4 weeks or one month.

[0295] The present disclosure provides methods for treating or preventing retinal neovascular (wet) age-related macular degeneration (nAMD) or visual impairment due to diabetic macular oedema (DME) in a subject; wherein the methods comprise

(i) administering to the eye of the subject an intravitreal injection of 8 mg aflibercept every month or every 4 weeks +/- 1 week for the first 3 consecutive injections; and (ii) one or more further injections of 8 mg aflibercept after said first 3 consecutive injections wherein the injection interval between two consecutive injections is shortened based on the physician’s judgement of visual and/or anatomic outcomes

and wherein the injection interval between two consecutive injections is at least 4 weeks or one month.

[0296] The present disclosure provides methods for treating or preventing neovascular (wet) age-related macular degeneration (nAMD) or visual impairment due to diabetic macular oedema (DME) in a subject; wherein the method comprises administering to the eye of the subject, a single initial dose of 8 mg aflibercept, followed by

[0297] The present disclosure provides methods for treating or preventing neovascular (wet) age-related macular degeneration (nAMD) or visual impairment due to diabetic macular oedema (DME) in a subject; wherein the method comprises administering to the eye of the subject, a single initial dose of 8 mg aflibercept, followed by

two secondary doses of said 8 mg aflibercept, followed by

one or more tertiary doses of 8 mg aflibercept;

wherein the treatment interval between two consecutive tertiary doses is shortened based on the physician’s judgement of visual and/or anatomic outcomes and

[0298] The present disclosure provides methods for treating or preventing neovascular (wet) age-related macular degeneration (nAMD) or visual impairment due to diabetic macular oedema (DME) in a subject; wherein the method comprises administering to the eye of the subject, a single initial dose of 8 mg aflibercept, followed by;

one or more tertiary doses of 8 mg aflibercept; wherein the treatment interval between two consecutive tertiary closes is adjusted based on the physician’s judgement of visual and/or anatomic outcomes; and

wherein the subject has been treated with a different anti-angiogenic treatment prior to said single initial dose of 8 mg aflibercept; and

[0299] The present disclosure provides methods for treating or preventing neovascular (wet) age-related macular degeneration (nAMD) or visual impairment due to diabetic macular oedema (DME) in a subject; wherein the method comprises administering to the eye of the subject, a single initial dose of 8 mg aflibercept, followed by;

one or more tertiary doses of 8 mg aflibercept;

wherein the injection interval between two consecutive injections is at least 4 weeks or one month. Such anti-angiogenic treatment is, for example, an anti-VEGF treatment using for e.g., 2 mg aflibercept, faricimab, ranibizumab or bevacizumab (e.g., >3 anti-VEGF ocular injections over the prior 5 months (~ 150 days). In one embodiment of the invention, the subject was treated with 2 mg aflibercept or faricimab prior to said single initial dose of 8 mg aflibercept (e.g., >3 anti-VEGF ocular injections over the prior 5 months (—150 days). In one embodiment of the invention, the subject was treated with ranibizumab or bevacizumab prior to said single initial dose of 8 mg aflibercept (e.g., >3 anti-VEGF ocular injections over the prior 5 months (-150 days).

[0300] In one embodiment of the invention said treatment interval between two consecutive tertiary doses is shortened if the subject

(i) exhibits >5 letters loss of BCVA from reference visit; and/or

(ii) (ii) >50 pm increase in CRT (central retinal thickness) from reference visit.

In one embodiment the reference visit is the visit at the previous injection.

In one embodiment of the invention said treatment interval between two consecutive doses is shortened by 2 or 4 weeks. In one embodiment of the invention, said treatment interval between two consecutive doses is shortened from 24 weeks or 6 months to 20 weeks or 5 months. In one embodiment of the invention said treatment interval between two consecutive doses is shortened from 20 weeks or 5 months to 16 weeks or 4 months. In one embodiment of the invention, said treatment interval between two consecutive doses is shortened from 16 weeks or 4 months to 12 weeks or 3 months. In one embodiment of the invention, said treatment interval between two consecutive doses is shortened from 12 weeks or 3 months to 8 weeks or 2 months. In one embodiment of the invention, said treatment interval between two consecutive doses is shortened from 8 weeks or 2 months to 4 weeks or 1 month. In one embodiment the tertiary dose interval is shortened by 1 week, provided that the new interval is at least about 4 weeks or one month. In one embodiment, the adjustment of the tertiary dose interval is shortened by about 4 weeks, provided that the new interval is at least about 4 weeks or 1 month. In one embodiment the tertiary dose interval is shortened by 2 weeks, provided that the new interval is at least about 4 weeks or 1 month. In one embodiment the treatment interval between two consecutive doses is at least 4 weeks or one month.

Precision Dose Drug Delivery

[0301] The present invention provides methods as set forth herein wherein a VEGF antagonist (e.g., aflibercept) is delivered with a high amount of precision, e.g., with a drug delivery device (DDD) (e.g., with a 0.5 mL volume), whether pre-filled or capable of being filled from a vial, and delivering a volume of between 70 and 100 microliter with an average volume of about 81 or 82 or 81-82 microliters, e.g., with a standard deviation of about 4 or 5 or 4-5 microliters (e.g., about 4.5 or 4.46 microliters) or less. In an embodiment of the invention, the DDD is a syringe, e.g., with a 30 gauge, ¹Z> inch needle.

[0302] In one embodiment, doses of the VEGF antagonist are administered via intravitreal injection via syringe. One means for ensuring precision of a dose to be delivered with a device, such as a syringe, is by employing a syringe wherein the dose volume is device-determined. If the dose volume is device-determined, the device is designed only to deliver a single volume (e.g., 87 microliters) or a single volume with a limited amount of acceptable error (± 4-5 microliters). Thus, if used properly, the user cannot deliver the wrong dose (e.g., cannot deliver more than the intended volume from the device).

[0303] The present invention includes embodiments wherein, a precise dosage of about 8 mg (±0.8 mg) is a dose of about 9, 9.3, 9.33, 9.7, 9.8, 9.9, 9.7-9.9 mg or more ± about 0.5, or ± about 0.51 mg is delivered to a subject’s eye. The volume in which a dose is delivered can be, for example, about 70, 81, 82, 81.7, 85, 86, 87, 85-87 microliters ± about 4, 4.45, 4.5, or 5 microliters. Doses may be delivered with a dose delivery device (DDD) which is a syringe.

[0304] Highly precise doses of VEGF antagonist (e.g., aflibercept) may be delivered, for example, in a volume that is device-determined (wherein the device is a syringe), by a method that includes the steps: (a) priming the syringe (e.g., a pre-filled syringe), thereby removing air from the syringe and, thus avoiding injection of air into the eye, by advancing the plunger rod by a predetermined distance into the syringe body until advancement of the plunger rod is resisted by a stop; (b) rotating the plunger rod about a longitudinal axis; and (c) actuating the plunger rod to dispense a predetermined (device-determined) volume (e.g., about 70, 81, 82, 81.7, 85, 86, 87, 85-87 microliters, ± about 4, 4.45, 4.5, or 5 microliters) of the formulation.

[0305] In an embodiment of the invention, the drug delivery device (DDD), comprises:

• a barrel including a longitudinal axis, a proximal end region, and a distal end region, the proximal end region including an opening, wherein the barrel is configured to receive a drug therein;

• a plunger rod disposed at least partially inside the barrel and protruding from the opening, wherein the plunger rod includes a rack having a plurality of teeth; and

• a pinion having a plurality of teeth configured to engage with the plurality of teeth of the rack,

wherein rotation of the pinion against the rack moves at least a part of the plunger rod along the longitudinal axis of the barrel; for example, which further comprises a shaft affixed to the pinion, wherein rotation of the shaft rotates the pinion against the rack which may include a knob affixed to the shaft. In an embodiment of the invention, the DDD further includes a magnifier disposed on the distal end region of the barrel. In an embodiment of the invention, the DDD further includes a stopper inside the barrel, wherein the stopper is affixed to a distal end of the plunger rod. In an embodiment of the invention, the DDD further includes a circular ratchet disposed coaxially with the pinion, wherein the circular ratchet has a diameter smaller than a diameter of the pinion; a spring-loaded pawl disposed on an internal circumference of the pinion, wherein the pawl is configured to engage the ratchet; and a shaft affixed to the ratchet, wherein rotation of the shaft in one direction causes rotation of the pinion, and rotation of the shaft in a second direction does not cause rotation of the pinion for example wherein the ratchet is disposed inside the pinion. In an embodiment of the invention, the pinion includes a plurality of teeth having a first height, and a stopper tooth having a second height greater than the first height, for example, wherein the second height of the stopper tooth prevents the pinion from engaging the plurality of teeth of the rack, and/or wherein the second height of the stopper tooth is configured to contact one of the plunger rod and the rack to stop rotation of the pinion. In an embodiment of the invention, the plunger rod includes an inner column and an outer lumen, and wherein the rack is disposed on the inner column, e.g., wherein rotation of the pinion against the rack moves the inner column of the plunger rod independently of the outer lumen, and/or further including a shaft removably affixed to the pinion, wherein the shaft prevents movement of the outer lumen of the plunger rod relative to the barrel, and wherein removal of the shaft allows for movement of the outer lumen of the plunger rod relative to the barrel. In an embodiment of the invention, the plunger rod further includes a body and a flange, the flange extending partially along a longitudinal length of the body and having a width greater than a width of the body; wherein the barrel further comprises a plunger lock, the plunger lock including a through hole configured to allow the flange to pass through the second plunger lock in a specific orientation. In an embodiment of the invention, the drug delivery device (DDD), comprises:

• a barrel including a longitudinal axis, a proximal end region, a distal end region, and an interior, the proximal end region including an opening and the interior including a threaded region; and

• a plunger rod disposed at least partially inside the barrel and protruding from the opening, the plunger rod including a threaded region configured to engage the threaded region of the barrel interior,

wherein rotation of the plunger rod about the longitudinal axis of the drug delivery device moves the plunger rod along the longitudinal axis. In an embodiment of the invention, the plunger rod further includes a tab protruding from the plunger rod in a first direction and located proximally from the threaded region of the plunger rod, and wherein the threaded region in the interior of the barrel further includes a slot sized and configured to allow for the tab to pass through the threaded region in the interior of the barrel, e.g., wherein the slot includes a first segment parallel to the longitudinal axis of the drug delivery device and a second segment perpendicular to the longitudinal axis of the drug delivery device — the slot may include a third segment parallel to the longitudinal axis of the drug delivery device, wherein the second segment is in between the first segment and the third segment. In an embodiment of the invention, the tab is a first tab, and wherein the plunger rod further includes a second tab protruding from the plunger rod in a second direction opposite to the first direction, and wherein the threaded region in the interior of the barrel further includes a second slot sized and configured to allow for the second tab to pass through the threaded region in the interior of the barrel.

[0306] In an embodiment of the invention, the drug delivery device, includes:

• a barrel having a proximal end region, a distal end region, an opening in the proximal end region, an interior, and a threaded region in the interior;

• a sleeve disposed partly inside the barrel and protruding from the opening in the proximal end region of the barrel, the sleeve including a threaded region engaged with the threaded region of the barrel interior;

• a plunger rod disposed at least partially inside the sleeve; and • a stopper inside the barrel and located distally from the sleeve, the stopper connected to a distal end of the plunger rod,

wherein rotation of the sleeve in a first direction around a longitudinal axis of the drug delivery device moves the sleeve towards the distal end region of the barrel. In an embodiment of the invention, rotation of the sleeve in the first direction moves the stopper towards the distal end region of the barrel. In an embodiment of the invention; the sleeve includes an inner passage, and the stopper has a diameter larger than a diameter of the inner passage; and/or the sleeve includes a tab disposed on an exterior of the sleeve, the tab located proximally from the threaded region of the barrel interior, and wherein the tab stops movement of the sleeve towards the distal end region of the barrel, e.g., wherein the tab is configured to stop movement of the sleeve towards the distal end region of the barrel after the drug delivery device has been primed or wherein the tab is a first tab, and wherein the sleeve further includes a second tab disposed on an exterior of the sleeve, the second tab located distally from the threaded region of the barrel interior, wherein the second tab stops movement of the sleeve towards the proximal end region of the barrel.

[0307] In an embodiment of the invention, the drug delivery device, comprises:

• a barrel including a proximal end region and a distal end region, the proximal end region including an opening;

• a plunger rod including a body and a flange, the flange extending partially along a longitudinal length of the body and having a width greater than a width of the body, the plunger rod disposed at least partially inside the barrel and protruding from the opening;

• a first plunger lock disposed on the barrel, the first plunger lock configured to block the flange from entering the barrel; and

• a second plunger lock disposed in the barrel, the second plunger lock including a through hole configured to allow the flange to pass through the second plunger lock in a specific orientation.

[0308] For example, in an embodiment of the invention, the first plunger lock is removable and/or frangible. In an embodiment of the invention, a distance between the first plunger lock and the second plunger lock is equivalent to the distance that the stopper must travel to prime the drug delivery device; and/or the plunger rod is rotatable around a longitudinal axis of the drug delivery device.

Substances from such a DDD (e.g., a formulation including aflibercept as described herein), having a plunger rod and a barrel, may be dispensed as follows: • advancing the plunger rod by a predetermined distance into the barrel until advancement of the plunger rod is resisted by a stop;

• deactivating the stop; and

• actuating the plunger rod (e.g., which includes a flange, wherein the stop includes a lock that prevents the flange from entering the barrel; or which includes a flange, wherein the stop comprises a lock that prevents the flange from entering the barrel) to deliver the substance. Advancing the plunger rod may include the step of rotating a pinion against a rack disposed on the plunger rod, e.g., wherein the stop comprises a shaft removably affixed to the pinion, and wherein deactivating the stop comprises removing the shaft from the pinion. Deactivating the stop may include the step of rotating the plunger rod. In an embodiment of the invention, deactivating the stop includes the step of removing the lock and/or breaking the lock.

In an embodiment of the invention, the drug delivery device, includes:

• a barrel including a longitudinal axis, a proximal end region, and a distal end region, the proximal end region including an opening and a rack disposed on the interior of the barrel, the rack having a plurality of teeth, wherein the barrel is configured to receive a drug therein;

• a plunger rod disposed at least partially inside the barrel and protruding from the opening, wherein the plunger rod includes a rack having a plurality of teeth; a pinion having a plurality of teeth configured to engage with the plurality of teeth of the plunger rod rack; and • an inner plunger coupled to the pinion by a rod, wherein rotation of the pinion against the plunger rod rack results in movement of the inner plunger along the longitudinal axis of the barrel;

for example, wherein the teeth of the pinion are further configured to engage with the plurality of teeth of the rack disposed on the barrel. In an embodiment of the invention, the pinion is a first pinion, and further includes: a second pinion disposed coaxially with the first pinion, the second pinion having a diameter smaller than a diameter of the first pinion and a plurality of teeth configured to engage with the plurality of the teeth of the rack disposed on the barrel, wherein rotation of the first pinion results in rotation of the second pinion against the rack disposed on the barrel and in movement of the inner plunger along the longitudinal axis of the barrel.

[0309] See International patent application publication no. WO2019/118588.

[0310] In an embodiment of the invention, the drug delivery device (DDD), includes:

• a body;

• a plunger rod disposed partially inside the body;

• a protrusion extending from the plunger rod; and • a blocking component coupled to a proximal end portion of the body, wherein the blocking component is a flange piece,

wherein, when the protrusion is in a first position relative to the blocking component, the blocking component restricts distal movement of the plunger rod to a first stopping point, and when the protrusion is in a second position relative to the blocking component, the blocking component restricts distal movement of the plunger rod to a second stopping point. In an embodiment of the invention, the DDD further includes: a stopper disposed in the body, wherein distal movement of the plunger rod distally moves the stopper; and a drug substance disposed in the body in between the stopper and a distal end of the body, wherein distal movement of the plunger rod to the first stopping point primes the drug delivery device, and distal movement of the plunger rod to the second stopping point dispenses a predetermined volume of the drug substance from a distal end of the device.

[0311] In an embodiment of the invention, moving the protrusion from the first position to the second position includes twisting the plunger rod relative to the blocking component. In an embodiment of the invention, the DDD further includes: a cavity in a proximal side of the blocking component, the cavity sized and configured to receive a portion of the protrusion, wherein when the protrusion is in the second position relative to the blocking component, the protrusion is positioned proximally from the cavity, such that distal movement of the plunger rod moves the protrusion into the cavity; e.g., wherein the cavity is a first cavity, and further includes: a second cavity in a proximal side of the blocking component, the second cavity sized and configured to receive a portion of the protrusion, wherein the first and second cavity are located on opposite sides of a central longitudinal axis of the drug delivery device. In an embodiment of the invention, the plunger rod passes through an opening in the blocking component. In an embodiment of the invention the DDD further includes an actuation portion at a proximal end portion of the plunger rod, wherein the protrusion extends from the actuation portion, e.g., wherein the actuation portion includes a generally cylindrical shape having a diameter greater than a width of the remainder of the plunger rod, wherein the protrusion extends from a side of the generally cylindrical shape, and wherein the actuation portion further comprises: a thumb pad on a proximal end of the actuation portion; and a ring on an exterior surface on the side of the generally cylindrical shape; e.g., further including a proximal collar on the blocking component, wherein the actuation portion partially fits inside the proximal collar; e.g., wherein the plunger rod further includes a pair of extensions protruding distally from the actuation portion and the blocking component (e.g., which includes one or more indents formed along a bottom wall of the blocking component; and wherein a portion of each extension is configured to be received by the one or more indents upon distal movement of the plunger rod relative to the blocking component to allow distal movement of the plunger rod to the second stopping point; or, which includes one or more indents formed along a bottom wall of the blocking component; and wherein a portion of each extension is configured to be received by the one or more indents upon distal movement of the plunger rod relative to the blocking component to allow distal movement of the plunger rod to the second stopping point; or, which includes a pair of internal grooves formed along a sidewall of the blocking component; and wherein a portion of each extension is configured to be received by at least one of the pair of internal grooves upon rotation of the plunger rod relative to the blocking component to expand the extensions radially-outward from a compressed state to a relaxed state) includes a pair of openings; and wherein a portion of each extension is configured to be received by one of the pair of openings in the first stopping point. In an embodiment of the invention, the protrusion is a first protrusion, and further includes a second protrusion extending from the plunger rod in a direction opposite to the first protrusion. In an embodiment of the invention, the blocking component is slidably coupled to the body and includes a third cavity and a pair of ribs that extend into the third cavity, wherein the body includes a top flange and the pair of ribs are configured to engage the top flange received in the third cavity; wherein the pair of internal ribs are configured to apply a distally-directed force onto the top flange. In an embodiment of the invention, the blocking component is slidably coupled to the body and includes a pair of movable tabs that are configured to engage the body; and the pair of movable tabs are laterally deflectable upon receiving the body in the blocking component and are configured to apply a radially-inward directed force onto the body. In an embodiment of the invention, the blocking component further includes a pair of finger flanges, and each of the finger flanges includes a textured surface having a predefined pattern that increases a grip of the blocking component.

[0312] In an embodiment of the invention, the drug delivery device (DDD), includes:

• a body;

• a plunger rod having a distal end contacting a stopper inside the body, and a proximal end including an actuation portion with a thumb pad;

• a plurality of protrusions extending from the actuation portion; and

• a blocking component disposed on the body, the blocking component including a proximal collar having a plurality of slots,

wherein, when the protrusions and the slots are in a first configuration relative to one another, the blocking component restricts distal movement of the plunger rod to a first stopping point, and when the protrusions and the slots are in a second configuration, the blocking component restricts distal movement of the plunger rod to a second stopping point, wherein, in the second configuration, the slots are configured to receive the protrusions upon distal movement of the plunger rod. In an embodiment of the invention, the protrusions and the slots are movable from the first configuration to the second configuration by rotation of the actuation portion about a longitudinal axis in relation to the blocking component, and wherein when the protrusions and the slots are in the second configuration, the protrusions and the slots are not movable to the first configuration; and/or

a difference between the first stopping point and the second stopping point is equivalent to a distance that the stopper must travel to expel a predetermined volume of a drug product from a distal end of the body, and wherein the plunger rod is prevented from moving from the second stopping point to the first stopping point; and/or the plurality of protrusions includes two protrusions disposed symmetrically about the actuation portion; and/or the blocking component further comprises a pair of finger flanges; and/or the drug delivery device is a pre-filled syringe; and/or the drug delivery device is changeable: (a) from a pre-use state to a primed state, by longitudinally moving the plunger rod (e.g., wherein the plunger rod includes a neck disposed distally from the actuation portion, wherein the neck interfaces with an opening in the blocking component to prevent proximal movement of the plunger rod, for example, wherein the neck further interfaces with the opening in the blocking component to prevent movement of the drug delivery device from the delivery state to the primed state) until the plunger rod reaches the first stopping point; (b) from the primed state to a delivery state by rotating the plunger rod in relation to the blocking component until the protrusions and the blocking component are in the second configuration; and (c) from a delivery state to a used state by longitudinally moving the plunger rod until the plunger reaches the second stopping point, wherein the drug delivery device is not changeable from the used state to the delivery state, from the delivery state to the primed state, or from the primed state to the pre-use state. In an embodiment of the invention, when the plunger rod is at the second stopping point, the stopper does not contact a distal end of the body.

[0313] In an embodiment of the invention, a drug delivery device, includes:

• a body;

• a plunger rod, including:

• a distal portion contacting a stopper inside the body;

• a proximal end including a generally cylindrical actuation portion disposed outside of the body; and • two protrusions extending from opposite sides of the actuation portion in a symmetrical configuration; and

• a blocking component coupled to the body, the blocking component including: a collar configured to accept a distal part of the actuation portion; and two cavities in the collar having proximally-facing openings, wherein each cavity is configured to accept a distal portion of one of the two protrusions;

wherein the plunger rod is longitudinally movable and rotatable about a longitudinal axis relative to the blocking component, and

wherein, when the drug delivery device is in a pre-use state, the protrusions and the cavity openings are not longitudinally aligned, and when the drug delivery device is in a delivery state, the protrusions and the cavity openings are longitudinally aligned. In an embodiment of the invention, the blocking component further includes a finger flange, and further includes a ribbed surface on a side of the actuation portion. In an embodiment of the invention, the plunger rod further includes: two extensions protruding distally from the actuation portion; and a plurality of openings in the collar of the blocking component, wherein a portion of each extension is configured to be received by one of the plurality of openings upon distal movement of the plunger rod relative to the blocking component.

[0314] In an embodiment of the invention, a drug delivery device includes:

• a body;

• a stopper disposed inside the body;

• a sleeve having a proximal end and a distal end, the distal end being disposed inside the body, proximally from the stopper; and

• a plunger rod disposed at least partially inside the sleeve;

wherein, when the stopper is in a ready position, distal advancement of one of (a) only the sleeve, (b) only the plunger rod, or (c) both the sleeve and the plunger rod together, relative to the body advances the stopper to a primed position, and wherein, when the stopper is in the primed position, distal advancement of another of (a) only the sleeve, (b) only the plunger rod, or (c) both the sleeve and the plunger rod together, relative to the body advances the stopper to a dose completion position. For example, in an embodiment of the invention, a DDD further includes a removable blocking component (e.g., wherein the blocking component is a clip removably secured around at least a portion of the sleeve) disposed between a proximal portion of the sleeve and a proximal end of the body, the blocking component obstructing distal advancement of the sleeve relative to the body, wherein distal advancement of the sleeve relative to the body after removal of the blocking component advances the stopper to the primed position. In an embodiment of the invention, the DDD further includes a removable locking component (e.g., a pin, a tab, or a bar) that couples the plunger rod to the sleeve, wherein distal advancement of both the sleeve and the plunger rod together relative to the body advances the stopper to the primed position, wherein distal advancement of only the plunger rod relative to the body after removal of the locking component advances the stopper to the dose completion position. In an embodiment of the invention, in the dose completion position, a proximal end of the plunger rod abuts against a distal end of the sleeve, such that the plunger rod is prevented from advancing distally any further relative to the body. In an embodiment of the invention, the DDD further includes a protrusion disposed on the plunger rod; and an inner protrusion disposed on an interior wall of the sleeve distally to the protrusion of the plunger rod, wherein distal advancement of only the plunger rod relative to the body advances the stopper to the primed position and causes the protrusion of the plunger rod to contact the inner protrusion of the sleeve, and wherein distal advancement of both the plunger rod and the sleeve relative to the body, after the protrusion of the plunger rod has contacted the inner protrusion of the sleeve, advances the stopper to the dose completion position. In an embodiment of the invention, the sleeve includes a finger flange. In an embodiment of the invention, the DDD further includes a stop disposed at a proximal end of the body, the stop sized to block distal advancement of the sleeve or the plunger rod once the stopper is in the completion position.

[0315] In an embodiment of the invention, a drug delivery device, includes:

• a body;

• a plunger rod having a distal portion disposed inside the body and a proximal portion disposed outside a proximal end of the body, the proximal portion having a width greater than a width of the distal portion; and

• an obstruction that, in an obstructing position relative to the plunger rod, prevents distal advancement of the plunger rod from a primed position to a dose completion position, wherein displacement of the obstruction from the obstructing position permits distal advancement of the plunger rod to the dose completion position, for example, further including a collar affixed to a proximal end portion of the body, the collar surrounding the proximal portion of the plunger rod; and a collar projection extending radially inward from the collar, wherein the proximal portion of the plunger rod includes a channel into which the collar projection protrudes, the channel including a circumferential path and an axial dose completion path, wherein the obstruction comprises the collar projection, which, when disposed in the circumferential path of the channel, prevents distal advancement of the plunger rod to the dose completion position, and wherein displacement of the obstruction from the obstructing position comprises twisting the plunger rod about a longitudinal axis to align the collar projection with the axial dose completion path. For example, in an embodiment of the invention, the channel further includes an axial priming path offset from the axial dose completion path, and connected to the axial dose completion path by the circumferential path, and distal movement of the plunger rod such that the collar projection travels on the axial priming path advances the plunger rod to the primed position. In an embodiment of the invention, the DDD further includes a finger flange. In an embodiment of the invention, the proximal portion of the plunger rod includes a projection extending radially outward, and the drug delivery device further includes: a rotatable alignment component disposed in between the proximal portion of the plunger rod and the body, the alignment component including a channel, the channel sized and configured to accommodate the plunger rod projection, wherein the obstruction comprises a wall of the channel that blocks a distal axial path of the plunger rod projection when the plunger rod is in the primed position, and wherein displacement of the obstruction from the obstructing position comprises rotating the alignment component to remove the wall of the channel from the distal axial path of the plunger rod projection, e.g., further including a finger flange coupled to a proximal end portion of the body, wherein the rotatable alignment component is disposed between the finger flange and the proximal portion of the plunger rod. In an embodiment of the invention, the DDD further includes a flange piece disposed at the proximal end of the body, wherein the obstruction includes a removable cap that, when in the obstructing position relative to the plunger rod, is disposed partially in between the proximal portion of the plunger rod and the flange piece. In an embodiment of the invention, removal of the cap allows the proximal portion of the plunger rod to advance to a dose completion position, wherein, in the dose completion position, the proximal portion of the plunger rod contacts the flange piece. In an embodiment of the invention, the removable cap covers the proximal portion of the plunger rod when in the obstructing position. In an embodiment of the invention, the DDD further includes a collar disposed between the proximal end of the body and the proximal portion of the plunger rod, the collar defining an opening sized to accommodate the proximal portion of the plunger rod upon distal advancement of the plunger rod beyond a primed position; wherein the obstruction comprises a tab protruding radially outward from the proximal portion of the plunger rod, the tab preventing the proximal portion of the plunger rod from fitting into the opening of the collar, and wherein a depth of the collar opening coincides with a distance the plunger rod must travel to advance distally to the dose completion position, e.g., wherein displacement of the obstruction from the obstructing position comprises either removing the tab or compressing the tab into a side of the proximal portion of the plunger rod; and/or wherein the tab is a first tab, and wherein the obstruction further comprises a second tab protruding radially outward from the proximal portion of the plunger rod in a direction opposite the protruding direction of the first tab; and/or wherein the obstruction comprises a tab that, when in the obstructing position, is disposed between the body and the proximal portion of the plunger rod, and wherein the plunger rod includes a geometry disposed proximally from the tab, wherein the geometry cannot advance distally past the tab when the tab is in the obstructing position. For example, displacement of the obstruction may include removing the tab from the drug delivery device by pulling the tab. In an embodiment of the invention, the DDD further includes a flange piece, wherein a portion of the tab is disposed inside a cavity of the flange piece. In an embodiment of the invention, displacement of the obstruction comprises removing the tab from the drug delivery device by breaking the tab. In an embodiment of the invention, the obstruction includes a flange piece that, in the obstructing position, is disposed proximally from the proximal end of the body, between the proximal portion of the plunger rod and the body, and is spaced from the proximal end of the body by a removable blocking component, and wherein displacement of the obstruction from the obstructing position comprises: removing the blocking component; and shifting the flange piece distally towards the proximal end of the body. In an embodiment of the invention, the plunger rod includes a projection extending radially outward, wherein the obstruction includes a lever having an end that, in the obstructing position, is located distally from the projection and blocks distal movement of the projection and thereby distal movement of the plunger rod, and wherein displacement of the obstruction from the obstructing position comprises actuating the lever to remove the end of the lever from its location distal from the projection. In an embodiment of the invention, distal advancement of the plunger rod beyond the dose completion position is prevented by contact between the proximal portion of the plunger rod and a portion of a flange piece coupled to the body.

[0316] In an embodiment of the invention, the drug delivery device, includes:

• a body;

• a sleeve affixed to the body, the sleeve including a proximal end, a distal end, and an opening disposed in a circumferential wall of the sleeve;

• a plunger rod passing through the sleeve, the plunger rod including a distal end portion disposed inside the body, and a radially-extending protrusion;

wherein the plunger rod may be distally advanced into the body from a ready position to a primed position, wherein, in the primed position, the protrusion of the plunger rod is disposed inside the opening, and further distal advancement of the plunger rod is resisted by contact between the protrusion and a wall of the opening, and wherein pressure may be exerted on the protrusion to overcome the resistance to further distal advancement of the plunger rod. In an embodiment of the invention, the opening in the sleeve is a second opening, and the sleeve further includes a first opening disposed in the circumferential wall of the sleeve proximally from the second opening, and a third opening disposed in the circumferential wall of the sleeve distally from the second opening, wherein, in the ready position, the protrusion of the plunger rod is disposed in the first opening, and further distal advancement of the plunger rod is resisted by contact between the protrusion and a wall of the first opening, and wherein, after further distal advancement of the plunger rod past the primed position, the protrusion of the plunger rod is disposed in the third opening, and further distal advancement of the plunger rod is prevented. In an embodiment of the invention, the radially-extending protrusion is a first protrusion, and wherein the plunger rod further includes a second radially-extending protrusion opposite the first protrusion, and wherein squeezing the first and second protrusions towards one another while applying axial pressure in the distal direction on the plunger rod overcomes the resistance to further distal advancement of the plunger rod. In an embodiment of the invention, the protrusion includes a distally-tapering profile to aid in distal advancement of the plunger rod.

[0317] In an embodiment of the invention, a drug delivery device, includes:

• a body;

• a plunger rod including a distal end portion disposed inside the body and a rotatable element; and

• a sleeve affixed to the body, the sleeve including a proximal opening into which the plunger rod may be advanced,

wherein rotating the rotatable element causes distal advancement of the plunger rod to a primed position, and wherein once the plunger rod is in the primed position, further rotation of the rotatable element is resisted. In an embodiment of the invention, the DDD further includes a collar disposed at a proximal end of the body, an interior of the collar including a proximal threaded portion forming a proximal helical path, wherein the rotatable element comprises a proximal portion of the plunger rod including a protrusion, wherein the proximal portion of the plunger rod may be rotated about a longitudinal axis to cause the protrusion to travel distally along the proximal helical path, and wherein once the protrusion reaches the end of the proximal threaded portion of the collar, the plunger rod is in the primed position, e.g., wherein once the plunger rod is in the primed position, the plunger rod may be depressed axially into the body to distally advance the plunger rod to a dose completion position; and/or wherein the interior of the collar further includes a distal threaded portion, wherein threads of the distal threaded portion form a distal helical path offset from, and opposite to, the proximal helical path, wherein alignment of the protrusion with the distal helical path places the plunger rod in the primed position, and wherein rotation of the proximal portion of the plunger rod to cause the protrusion to travel distally along the distal helical path causes distal advancement of the plunger rod to a dose completion position.

[0318] A substance may be dispensed using such a DDD having a plunger rod and a body, may be done by a method including:

(a) advancing the plunger rod by a predetermined distance into the body until advancement of the plunger rod is resisted by a stop;

(b) rotating the plunger rod about a longitudinal axis; and

(c) actuating the plunger rod to dispense a predetermined volume of the substance, wherein none of steps (a), (b), and (c) are reversible. In an embodiment of the invention, the DDD further includes a flange piece having a collar, and advancing the plunger rod and actuating the plunger rod comprise pressing an actuation portion of the plunger rod into the collar of the flange piece; for example, wherein the plunger rod comprises a protrusion, and wherein the collar of the flange piece abuts against the protrusion to resist advancement of the plunger rod. For example, in an embodiment of the invention, wherein rotating the plunger rod comprises twisting an actuation portion of the plunger rod relative to the flange piece, until a protrusion on the plunger rod becomes longitudinally aligned with a cavity in the collar of the flange piece, which may further include advancing the protrusion into the cavity until the protrusion abuts a distal side of the cavity, wherein the predetermined volume of the substance is dispensed when the protrusion abuts the distal side of the cavity.

[0319] See International patent application publication no. WO2020/247686.

Products for use and manufacture of medicaments

[0320] Wherever a method of treatment is referred to herein, also provided is a VEGF receptor fusion protein for use in such a method. For instance, aflibercept for use in such a method is provided.

[0321] Wherever a method of treatment is referred to herein, also provided is use of a VEGF receptor fusion protein in the manufacture of a medicament for use in such a method. For instance, use of aflibercept in the manufacture of such a medicament is provided.

[0322] Wherever a method of treatment is referred to herein, also provided is a pharmaceutical composition for use in such a method, where the pharmaceutical composition comprises a VEGF receptor fusion protein as set out herein. Further illustrative embodiments

[0323] The following represent further illustrative embodiments of the present invention:

[1 ] A method for treating or preventing macular edema secondary to retinal vein occlusion (MERVO) comprising administering to an eye of the subject a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein;

wherein each secondary dose is administered about 2 to 4 weeks (±7 days) after the immediately preceding dose; and

wherein each tertiary dose is administered at least about four weeks (±7 days) after the immediately preceding dose.

[2] The method of [1], wherein at least two secondary doses are administered.

[3] The method of [1] or [2], wherein two to six secondary doses are administered.

[4] The method of any one of [1] to [3], wherein two secondary doses are administered.

[5] The method of any one of [1] to [3], wherein four secondary doses are administered.

[6] The method of any one of [1] to [3], wherein five secondary doses are administered.

[7] The method of any one of [1] to [6], wherein the secondary doses are administered at about monthly intervals.

[8] The method of any one of [1] to [7], wherein the tertiary doses are administered at least 8 weeks after the immediately preceding dose.

[9] The method of any one of [1] to [8], wherein the tertiary doses are administered at least 12 weeks after the immediately preceding dose.

[10] The method of any one of [1] to [9], wherein the interval of at least eight weeks between tertiary doses is maintained throughout the tertiary dosing period.

[11] The method of any one of [1] to [10], wherein the subject is assessed during administration of the tertiary doses to determine whether to length, maintain, or shorten the interval between tertiary doses.

[12] The method of any one of [1 ] to [11 ], wherein the VEGF receptor fusion protein is aflibercept.

[13] The method of any one of [1] to [12], wherein the subject is treatment naive.

[14] The method of any one of [1] to [13], wherein administration is via intravitreal injection.

[15] The method of [14], wherein the intravitreal injection volume is less than about 100 pl. [16] The method of any one of [1] to [15], wherein the retinal vein occlusion is central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO) and/or hemiretinal vein occlusion (HRVO).

[17] The method of any one of [1 ] to [16], wherein the subject is 18 years or older who have been diagnosed with macular edema secondary to RVO, involving the center of the macula, with a BCVA letter score of 73 to 24 (20/40 to 20/320) in the study eye.

EXAMPLES

[0324] The present invention includes methods for achieving any of the individual results, for example, by the period of time after treatment initiation that is indicated (e.g., improvement in BCVA by X ETDRS letters by Y days after treatment initiation) as is set forth in the Examples section in a subject having an angiogenic eye disorder, e.g., an angiogenic eye disorder secondary to retinal vein occlusion by administering a VEGF receptor fusion protein treatment regimen to the subject.

Example 1: A Randomized, Double-Masked, Active-Controlled Phase 3 Study of the Efficacy and Safety of High-Dose Aflibercept in Patients with Macular Edema Secondary to Retinal Vein Occlusion (MERVO) (QUASAR)

[0325] This is a Phase 3, multi-center, randomized, double-masked, active-controlled clinical study to assess the efficacy and safety of high dose (8 mg) aflibercept administered intravitreally (IVT) compared to 2 mg aflibercept treatment in participants with treatment-naive macular edema secondary to retinal vein occlusion (RVO). The trial is a global randomized, doublemasked, active-controlled phase III study evaluating the efficacy and safety of Eylea (aflibercept) 8 mg used with extended dosing intervals in treatment-naive patients with macular edema secondary to retinal vein occlusion including central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO) or hemiretinal vein occlusion (HRVO). The primary endpoint of this study is to document change in best corrected visual acuity (BCVA), as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score, from the date of randomization through 36 weeks of treatment. The study compares BCVA changes between patients who received Eylea 8 mg every 8 weeks following either 3 or 5 initial monthly doses compared to Eylea 2 mg every 4 weeks. Treatment intervals could be further adjusted based on treatment response continuously evaluated under clinically relevant dose regimen modification (DRM) criteria. Treatment intervals could be shortened by 4 weeks at any dosing visit if patients met DRM criteria. Treatment intervals could be extended based on DRM criteria from week 32 (for the study arms with aflibercept 2 mg and aflibercept 8 mg following 3 initial monthly doses) or week 40 (for the study arm with aflibercept 8 mg following 5 initial monthly doses). Patients will be treated up to week 60 followed by a monitoring period until week 64. The trial has enrolled more than 800 patients from 27 countries

[0326] The study population consists of men and women 18 years and older who have been diagnosed with macular edema secondary to RVO (BRVO, CRVO, or HRVO), involving the center of the macula, with a BCVA letter score of 73 to 24 (20/40 to 20/320) in the study eye.

[0327] A total of approximately 822 eligible participants with macular edema secondary to RVO are planned to be randomized in a 1:1:1 ratio to aflibercept 8 mg Q8W after 3 initial Q4W initiation doses group or aflibercept 8 mg Q8W after 5 initial Q4W initiation doses group or aflibercept 2 mg Q4W group. 804 were randomized to intervention and 802 were treated. The study consists of a screening/baseline period, and an end of study (EoS) visit at Week 64. No study intervention will be administered at the EoS visit at Week 64.

[0328] Figure 1 shows the dosing schedule.

[0329] Study visits will be scheduled Q4W throughout the study duration. At every visit until Week 60, the participants will receive an active or sham injection for masking purposes. During the first 32 weeks, the 2 mg group (2q4) will receive an active injection at every visit while the 8 mg groups will initiate treatment with injections Q4W for a total of 3 doses (8q8/3) or will initiate treatment with injections Q4W for a total of 5 doses (8q8/5), followed by extension of the treatment interval of 8 weeks. Beginning at Week 36 through Week 60, treat and extend (T& E) will be employed for the 2 mg Q4W group and 8 mg Q8W after 3 initial Q4W doses group and beginning at Week 44 through Week 60 for the 8 mg Q8W after 5 initial Q4W doses group. Extension or shortening of the dosing interval will depend on meeting dose regimen modification (DRM) criteria. The DRM criteria may also indicate active injections at Weeks 20 and 28 for participants in the 8 mg groups in the need of treatment.

[0330] The current study will investigate the efficacy and safety of aflibercept 8 mg with the intent of achieving non-inferior BCVA, while extending the dosing interval to reduce the number of injections and potentially improving visual and/or anatomic outcomes for aflibercept 8 mg vs. the currently approved aflibercept 2 mg dose regimen as well as maintaining the same safety profile as aflibercept 2 mg.

[0331] The primary, secondary, and exploratory objectives and endpoints for the study are shown in Table 1A, below. Table 1A. Objectives and Endpoints

Objectives Endpoints

Primary

• To determine if treatment with aflibercept Primary Endpoint:

8 mg Q8W provides non-inferior BCVA • Change from baseline in BCVA measured by change compared to aflibercept 2 mg Q4W the ETDRS letter score at Week 36 Secondary - Efficacy

• To determine if treatment with aflibercept Key Secondary Endpoint

8 mg Q8W requires less injections • Number of active injections from baseline to compared to aflibercept 2 mg Q4W Week 64¹

Secondary Endpoint

• Number of active injections from baseline to Week 36

• To determine the effect of aflibercept 8 mg Secondary Endpoints:

Q8W compared to aflibercept 2 mg Q4W on • Change from baseline in BCVA measured by other visual and anatomic measures of the ETDRS letter score at Week 64 response • Participant gaining at least 15 letters in BCVA from baseline at Weeks 36 and 64

• Participant achieving an ETDRS letter score of at least 69 (approximate 20/40 Snellen equivalent) at Weeks 36 and 64

• Participant having no IRF and no SRF in the center subfield at Weeks 36 and 64

• Change from baseline in GST at Weeks 36 and 64

• To assess the efficacy of aflibercept 8 mg • Change from baseline in NEI-VFQ-25 total Q8W compared to aflibercept 2 mg score at Weeks 36 and 64

aflibercept Q4W on vision-related QoL

Secondary - Safety

• To evaluate the safety of aflibercept 8 mg • Occurrence of TEAEs and SAEs through Q8W compared to aflibercept 2 mg Weeks 36 and 64

aflibercept Q4W

Secondary - Other

• To evaluate duration of effect of aflibercept • Participant dosed only Q8W through Week 36 8 mg Q8W compared to aflibercept 2 mg in the 8 mg Q8W group

aflibercept Q4W • Participant having last treatment interval >12 or of 16 weeks at Week 64

• Participant having next intended interval >12, >16 or of 20 weeks at Week 64

• To evaluate the PK of aflibercept 8 mg Q8W • Systemic exposure to aflibercept as assessed compared to aflibercept 2 mg aflibercept by plasma concentrations of free, adjusted Q4W bound and total aflibercept from baseline

through Weeks 36 and 64 Objectives Endpoints

Exploratory

• To determine the effect of aflibercept 8 mg • Participant with vision changes of at least 5, Q8W compared to aflibercept 2 mg Q4W on 10, or 15 letters in BCVA from baseline at further visual and anatomic measures of each visit

response • Participant with no IRF and no SRF in the center subfield at each visit

• Time to fluid-free retina over 36 and 64 weeks (total fluid, IRF, and/or SRF in the center subfield)

• Participant having sustained fluid-free retina over 36 and 64 weeks (total fluid, IRF, and/or SRF in the center subfield)

• Change in area of retinal ischemia at Weeks 36 and 64

• Change in the area of fluorescein leakage at Weeks 36 and 64

• To study molecular drivers of RVO or related • Evaluation of clinical efficacy parameters by diseases, clinical efficacy of aflibercept, and repertoire or frequency of genetic alterations affected molecular pathways (genomics substudy)

• Treatment related changes in circulating

biomarkers (FBR)

AE=adverse event, BCVA=best-corrected visual acuity, CST=central subfield thickness, ETDRS=Early Treatment Diabetic Retinopathy Study, FBR=future biomedical research, IRF=intraretinal fluid, NEI-VFQ-25=National Eye Institute Visual Functioning Questionnaire-25, PK=pharmacokinetics, QoL=quality of life, Q4W=every 4 weeks, Q8W=every 8 weeks, RVO=retinal vein occlusion, SAE=serious adverse event, SRF=sub-retinal fluid, TEAE=treatment-emergent adverse event

¹ Where premature treatment discontinue due to treatment related AE is considered as treatment-failure and the number of active injections from baseline to Week 64 is set to an unfavorable outcome (equal to 16, the maximum value).

[0332] The primary estimand for the primary objective is described by the following attributes:

• Population: Adult participants with treatment-naive macular edema secondary to RVO

• Endpoint: Change from baseline in BCVA measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score at Week 36

• Treatment condition:

o Aflibercept 8 mg administered with 3 initial Q4W initiation doses followed by extension of treatment interval to 8-weeks until Week 36 unless the treatment response indicates to continue with Q4W

o Aflibercept 8 mg administered with 5 initial Q4W initiation doses followed by extension of treatment interval to 8-weeks until Week 36 unless the treatment response indicates to continue with Q4W

o Aflibercept 2 mg administered Q4W [0333] A delayed active injection resulting in an injection interval up to 4 weeks longer than planned is considered to be in line with the treatment regimen of interest.

• Intercurrent events and strategies:

o Premature treatment discontinuation - addressed by the hypothetical strategy (had participants continued treatment until Week 36)

o Use of prohibited medication - addressed by the hypothetical strategy (had prohibited medications not been taken)

o Missed study intervention:

Missed active injection resulting in an injection interval up to 4 weeks longer than planned: treatment policy strategy (the effect of a missed active injection will be included in the estimate of the treatment effect)

> Missed active injection resulting in an injection interval more than 4 weeks longer than planned: hypothetical strategy (had injection not been missed or delayed by less than 4 weeks)

• Population-level summary: Difference in mean change from baseline to Week 36 in BCVA between each Aflibercept 8 mg group and the Aflibercept 2 mg group

[0334] The secondary estimand for the secondary objective is described by the following attributes:

• Population: Adult participants with treatment-naive macular edema secondary to RVO • Endpoint: Number of active injections from baseline to Week 64 where premature treatment discontinuations due to treatment related adverse event (AE) is considered as treatmentfailure and the number of injections is set to an unfavorable outcome (equal to 16, the maximum value)

• Treatment condition:

o Aflibercept 8 mg administered with 3 initial Q4W initiation doses followed by extension of treatment interval to 8-weeks and further adjustment of intervals according to treatment response

o Aflibercept 8 mg administered with 5 initial Q4W initiation doses followed by extension of treatment interval to 8-weeks and further adjustment of intervals according to treatment response

o Aflibercept 2 mg administered Q4W until Week 32, followed by adjustment of treatment intervals according to treatment response [0335] The minimum treatment interval is 4 weeks while the study duration allows the maximum treatment interval to be 16 weeks. Imperfect adherence other than premature treatment discontinuation is considered as part of the treatment.

• Intercurrent events and strategies:

o Premature treatment discontinuation

Due to lack-of-efficacy: Hypothetical strategy (had participants continued treatment until Week 64)

Due to treatment related AEs: Composite strategy (addressed in the endpoint definition)

> Due to treatment unrelated AEs and other reasons: Hypothetical strategy (had participants continued treatment until Week 64)

o Missed study intervention - addressed by treatment policy strategy (the effect of a missed active injection will be included in the estimate of the treatment effect)

• Population-level summary: Difference in mean number of active injections up to Week 64 between each Aflibercept 8 mg group and the Aflibercept 2 mg group

[0336] Dosage Regimen Modification - study visits will be scheduled Q4W throughout the study duration. At every visit until Week 60, the participants will receive an active or sham injection for masking purposes. During the first 32 weeks, the 2 mg group will receive an active injection at every visit while the 8 mg groups will initiate treatment with injections Q4W for a total of 3 doses or will initiate treatment with injections Q4W for a total of 5 doses, followed by extension of the treatment interval of 8 weeks. Beginning at Week 36 through Week 60, T& E will be employed for 8 mg groups. Extension or shortening of the dosing interval will depend on meeting DRM criteria. The DRM criteria may also indicate active injections at Weeks 20 and 28 for participants in the 8 mg groups in the need of a treatment, as shown in Table 1 B.

[0337] DRM Shortening Criteria for 8 mg Groups Before Week 32: Beginning at Weeks 16 (for aflibercept 8 mg/3 group) and 20 (for aflibercept 8 mg/5 group), participants in the 8 mg groups will be eligible to have their dosing interval shortened by 4 weeks if both the following DRM shortening criteria are met at a dosing visit:

1. Best-corrected visual acuity loss >5 letters from reference visit*, AND

2. >50 pm increase in central subfield thickness (CST) from reference visit*

*Reference visit is Week 12 for the 8 mg Q8W after 3 initial Q4W doses group and Week 16 for the 8 mg Q8W after 5 initial Q4W doses group.

[0338] For example, in case the DRM shortening criteria are met at Weeks 16 and 24, participants will have their following dosing intervals shortened to 4 weeks, thus, will receive additional active doses at Weeks 20 and 28. In case the DRM shortening criteria are met at Week 24, participants will receive an additional active dose at Week 28. The minimum interval between dosing visits is 4 weeks. The actual interval between injections may be shorter than 28 days due to the allowed visit windows. Once a participant has their treatment interval shortened to Q4W, they will continue to be treated Q4W through Week 32.

[0339] DRM Extension Criteria Starting at Weeks 32 and 40: Starting at Week 32, all participants in all three treatment groups will be eligible for interval extension (by 4-week increments) if both the following DRM extension criteria are met at a dosing visit:

1. Best-corrected visual acuity loss <5 letters from reference visit*, AND

2. CST thickness <325 pm Heidelberg Spectralis <315 pm Cirrus or Topcon spectral domain optical coherence tomography (SD-OCT)

[0340] When these criteria are met at a dosing visit, the participant receives the planned dose at that visit and has the next treatment interval extended by 4 weeks (e.g., if the last interval was 4 weeks, the next will be 8 weeks). If at a later dosing visit, the DRM extension criteria are met again, the participant receives the planned dose at that visit and the next interval will be extended by another 4 weeks (e.g., if the last interval was 8 weeks, the next will be 12 weeks). DRM Shortening Criteria Starting at Weeks 32 and 40: Additionally, starting at Week 32, participants in all three groups will have the dosing interval shortened by 4 weeks if both the following DRM shortening criteria are met at a dosing visit:

1. Best-corrected visual acuity loss >5 letters from reference visit*, AND

2. >50 pm increase in CST from reference visit*

*Reference visit is Week 12 for 8 mg Q8W after 3 initial Q4W doses group and Week 16 for 8 mg Q8W after 5 initial Q4W doses group.

[0341] For the assessment of DRM shortening and extension criteria, in case measurement is not available at the reference visit, the most recent measurement from previous visit should be used instead. For example, if Week 16 measurement is not available, the Week 12 measurement should be used instead. If both Weeks 12 and 16 measurements are not available, the Week 8 measurement should be used instead. If all Weeks 8, 12, and 16 measurements are not available, the Week 4 measurement should be used instead. In case there are no measurements at Weeks 4, 8, 12, and 16, the participant will be considered non-compliant and discontinued from the study. [0342] For participants who do not meet the criteria for shortening or extension of the interval, the current dosing interval will be maintained.

[0343] The study design is illustrated in Figure 2.

Table 1 B. Study Assessment and Procedures

Study Phase Screening Baseline Treatment

Visit 1 2 3 4 5 6 7 8 9 10 Week -3 0 4 8 12 16 20 24 28 32 Day -21 to -1 1 29 57 85 113 141 169 197 225 Window

±5 ±5 ±5 ±5 ±5 ±5 ±5 ±5 (day)^a

Administrative:

ICF X

Genomic

X

Substudy ICF^b

FBR ICF^c X

Inclusion/Exclu

X X^d

sion Eligibility

Medical History X

Demographics X

Prior and/or

Concomitant

X X X X X X X X X X

Medications/

Treatment

Randomization X

Study Intervention®:

Study

Intervention

X X X X X X X X X

(Active or

Sham)

DRM X X X X X

Assessment*

Ocular Efficacy and Safety (bilateral unless indicated):

NEI-VFQ-259 X

BCVA

(ETDRS) and X X X X X X X X X X Refraction

IOP^h X X X X X X X X X X Slit Lamp X X X X X X X X X X

Study Phase Screening Baseline Treatment

±5 ±5 ±5 ±5 ±5 ±5 ±5 ±5 (day)^a

Examination'

Indirect

Ophthalmosco X X X X X X X X X X pyi

FA, FP^k X X

SD-OCT^k X X X X X X X X X X OCT-A¹ X X X Nonocular Safety:

Physical

X

Examination

Vital Signs^m X X X X X X X X X X ECG X AEs X X X X X X X X X X Laboratory Testingⁿ:

Hematology X

Blood

X

Chemistry

Pregnancy

X X X X X X X X X X

Test

Serum Urine Urine Urine Urine Urine Urine Urine Urine Urine (WOCBP)⁰

Urinalysis,

X UPGR

Pharmacokinetics and Other Sampling:

PK Sample

X X X XP

(Sparse)^p

Genomic DNA

Sample X

(optional)¹³

Table 1-B, Continued Study Phase Treatment EoS or ED Visit 11 12 13 14 15 16 17 18 Week 36 40 44 48 52 56 60 64 Day 253 281 309 337 365 393 421 449 Window

±5 ±5 ±5 ±5 ±5 ±5 ±5 ±5 (day)^a

Administrative:

IGF

Genomic

Substudy ICF^b

FBR ICF^C

Inclusion/Exclu

sion Eligibility

Medical

History

Demographics

Prior and/or

Concomitant

X X X X X X X X

Medications/

Treatment

Randomization

Study Intervention®:

Study

Intervention

X X X X X X X

(Active or

Sham)

DRM X X X X X X X

Assessment’

Ocular Efficacy and Safety (bilateral unless indicated):

NEI-VFQ-259 X X BCVA

(ETDRS) and X X X X X X X X Refraction

IOP^h X X X X X X X X Slit Lamp

X X X X X X X X

Examination'

Indirect

Ophthalmosco X X X X X X X X pyi

FA, FP^k X X SD-OCT^k X X X X X X X X

Study Phase Treatment EoS or ED

Visit 11 12 13 14 15 16 17 18

Week 36 40 44 48 52 56 60 64

Day 253 281 309 337 365 393 421 449

Window

±5 ±5 ±5 ±5 ±5 ±5 ±5 ±5

(day)^a

OCT-A¹ X X

Nonocular Safety:

Physical

X X

Examination

Vital Signs^m X X X X X X X X

ECG X X AEs X X X X X X X X

Laboratory Testingⁿ:

Hematology X X

Blood

X X

Chemistry

Pregnancy

X X X X X X X X

Test

Urine Urine Urine Urine Urine Urine Urine Urine

(WOCBP)⁰

Urinalysis,

X X UPGR

Pharmacokinetics and Other Sampling:

PK Sample

X X

(Sparse)P

Genomic DNA

Sample

(optional)¹⁵

AE=adverse event, BCVA=best corrected visual acuity, DNA=deoxyribonucleic acid, DRM=dose regimen modification, ECG=electrocardiogram, ED=early discontinuation, EoS=end of study, ETDRS=Early Treatment Diabetic Retinopathy Study, FA=fluorescein angiography, FBR=future biomedical research, FP=fundus photography, ICF=informed consent form, IOP=intraocular pressure, I VT=intravitreally, NEI-VFQ-25=National Eye Institute Visual Functioning Questionnaire-25, OCT-A=optical coherence tomography angiography, PK=pharmacokinetics, SD-OCT=spectral domain optical coherence tomography, UPCR=urine protein:creatinine ratio, WOCBP=women of childbearing potential Footnotes for the Schedule of Activities (SoA) Tables

a. Visit schedules may deviate by up to ±5 days. Set schedule visits use baseline for the calculation.

The procedures required at each visit have to be complete within 3 days, i.e., split visits are allowed. Additionally, all procedures have to be complete within the 5-day window. Slit lamp (anterior segment), IOP measurement, and indirect ophthalmoscopy are recommended to take place on the same day as the IVT injection.

b. The optional genomic substudy ICF should be presented to participants at the screening visit and may be signed at any subsequent visit at which the participant chooses to participate after screening. The genomic DNA blood sample should be collected on Day 1/baseline (pre-injection) or at any time during the study, only from participants who consent to participate in the genomic substudy.

c. The optional FBR ICF should be presented to participants and signed at the screening visit. No additional blood sample is required - remaining blood samples (from e.g., PK) may be used. d. Inclusion/exclusion criteria will be evaluated at screening and baseline to confirm participant’s eligibility. The Investigator is responsible for confirming that any changes between screening and baseline do not affect the participant’s eligibility.

e. Following study intervention injection or sham procedure, participants will be observed for at least 30 minutes.

f. For masking purposes, assessments for DRM will be performed in all participants at all visits starting from Week 16. Actual DRMs will be implemented based on outcome at active treatment visits. g. National Eye Institute Visual Functioning Questionnaire-25 to be administered in a quiet room by a masked study-related person trained to administer this type of questionnaire, preferably before other visit procedures are performed.

h. Intraocular pressure will be measured at all study visits (bilateral). On days when study intervention is administered, IOP should be measured approximately 30 to 60 minutes (+/- 10 minutes so measure should be at least 20 minutes after IVT injection and no more than 70 minutes after IVT injection) after administration of study intervention (study eye only) by the unmasked Investigator (or designee). The exact timing is left to the discretion of the unmasked Investigator. Intraocular pressure will be measured using Goldman applanation tonometry, rebound tonometry Icare, or Tonopen and the same method of measurement must be used in each participant throughout the study.

i. Slit lamp examination will be performed bilaterally.

j. Indirect ophthalmoscopy will be performed bilaterally at all visits. On days when study intervention is administered, it should also be performed immediately after administration of study intervention (study eye only).

k. The same SD-OCT/FA/FP imaging system used at screening and Day 1 must be used at all followup visits in each participant. Images will be taken in both eyes before dosing (active or sham injection).

l. Optical coherence tomography angiography is optional at all sites that have the relevant equipment.

If OCT-A cannot be performed at screening visit, it may be done at baseline visit. m. Vital signs (body temperature, blood pressure, and heart rate) should be measured per the procedure outlined in the study manual. Vital signs should be measured prior to injection and any blood sampling. Timing of all blood pressure assessments should be within 2 hours of clock time of dosing on Day 1.

n. All samples collected for laboratory assessments should be obtained prior to administration of fluorescein, and prior to administration of study intervention.

o. For WOCBP, a negative serum pregnancy test at screening is required for eligibility. A negative urine pregnancy test is required before any treatment is administered at subsequent visits.

p. Sparse PK sampling will be performed in all participants. Any PK sampling will be done prior to dosing if scheduled at the sampling time point. An additional sample 6 days (±7 days) after third injection: Days 62 and 118.

[0344] Efficacy Assessments include ophthalmic examinations, best corrected visual acuity, slit lamp examination, intraocular pressure, spectral domain optical coherence tomography, optical coherence tomography angiography, indirect ophthaloscopy, fundus photography and fluorescein angiography, and the NEI-VFQ-25 questionnaire. Planned timepoints are provided in Table 1-B.

[0345] All ophthalmic examinations are to be conducted pre-injection in both eyes and postinjection in the study eye only, unless indicated otherwise.

[0346] Visual function will be assessed using the ETDRS protocol (Early Treatment Diabetic Retinopathy Study Research Group, 1985) starting at 4 meters. Refraction is to be done at each visit. Visual acuity examiners must be certified to ensure consistent measurement of BOVA. Any certified and trained study personnel may perform this assessment (including but not limited to ophthalmologist, optometrist, or technician). For each participant, the same examiner should perform all assessments whenever possible. Best-corrected visual acuity should be done before any other ocular procedures are performed.

[0347] Slit lamp examination will be performed bilaterally. Participants’ anterior eye structure and ocular adnexa will be examined bilaterally (pre-dose on visits with active injection) at each study visit using a slit lamp.

[0348] Intraocular pressure will be measured using Goldman applanation tonometry, rebound tonometry Icare, or Tonopen and the same method of measurement must be used in each participant throughout the study. At all visits, IOP should be measured bilaterally. On days when study intervention is administered, IOP should also be measured approximately 30 to 60 minutes (+/- 10 minutes so measure should be at least 20 minutes after IVT injection and no more than 70 minutes after IVT injection) after administration of study intervention (study eye only). If multiple post-injection measurements are performed, the final measurement before the participant leaves should be documented in the eCRF. Any injection-related increase in IOP (and treatment) should be documented in a masked fashion.

[0349] Retinal and lesion characteristics will be evaluated using spectral domain optical coherence tomography (SD-OCT). Technicians must be certified by the reading center to ensure consistency and quality in image acquisition and segmentation. For all visits where the SD-OCT procedure is scheduled, images will be captured and read by the technician and Investigator for individual treatment decisions and sent to an independent reading center where images will be read by masked readers. The participants’ eligibility to take part in the study in terms of SD-OCT will be reconfirmed by the central reading center. The same SD-OCT imaging system used at screening and Day 1 must be used at all follow-up visits in each participant. Images will be taken in both eyes before dosing (active or sham injection). All SD-OCTs will be archived electronically by the study sites as part of the source documentation.

[0350] Optical coherence tomography angiography is optional at all sites that have the relevant equipment. Technicians must be certified by the reading center to ensure consistency and quality in image acquisition. If optical coherence tomography angiography (OCT-A) cannot be performed at screening visit, it may be done at baseline visit. The same imaging modality used at screening must be used at all follow-up visits in each participant. Images will be taken in both eyes before dosing (active or sham injection). All OCT-As will be archived electronically by the study sites as part of the source documentation.

[0351] Indirect ophthalmoscopy will be performed according to local medical practice and applicable medical standards at the site. Participants’ posterior pole and peripheral retina will be examined by indirect ophthalmoscopy at each study visit pre-dose (bilateral). Post-dose evaluation should be performed as soon as possible, approximately 0 to 15 minutes after injection.

[0352] The anatomical state of the retinal vasculature of the study eye will be evaluated by fundus photography (FP) and fluorescein angiography (FA) at specified visits. Photographers must be certified by the reading center to ensure consistency and quality in image acquisition.

[0353] Fundus photography and FA images will be read by the Investigator for individual treatment decisions and sent to an independent reading center where images will be read by masked readers. The participants’ eligibility to participate in the study in terms of FA will be confirmed by the central reading center before randomization. The same FA/FP imaging system used at screening and Day 1 must be used at all subsequent visits in each participant. Images will be taken in both eyes before dosing (active or sham injection). All FA and FP images will be archived electronically at the site as part of the source documentation.

[0354] Vision-related quality of life will be assessed using the National Eye Institute Visual Functioning Questionnaire-25 (NEI-VFQ-25) questionnaire.

[0355] The study population consists of men and women 18 years and older who have been diagnosed with treatment-naive macular edema secondary to RVO (BRVO, CRVO, or HRVO), involving the center of the macula, with a BCVA letter score of 73 to 24 (20/40 to 20/320) in the study eye. Only 1 eye per participant will be enrolled in the study. The participants’ eligibility to take part in the study in terms of ocular imaging assessments will be reconfirmed by the central reading center.

[0356] Inclusion Criteria Participants are eligible to be included in the study only if all of the following criteria apply at both screening and baseline visits, except where otherwise indicated:

Age

1. Adult >18 years of age (or country’s legal age of adulthood if the legal age is >18 years) at the time of signing the informed consent.

Type of Participant and Disease Characteristics

2. Treatment-naive macular edema involving the foveal center secondary to RVO (BRVO, HRVO, or CRVO) diagnosed within 16 weeks (112 days) before the screening visit in the study eye.

3. Early Treatment Diabetic Retinopathy Study BCVA letter score of 73 to 24 (20/40 to 20/320) at screening and baseline visits in the study eye.

4. Decrease in BCVA determined to be primarily the result of RVO in the study eye.

5. Mean CST >300 pm on OCT (or >320 pm on Heidelberg Spectralis), confirmed by the reading center at screening visit and by the site at baseline visit in the study eve.

Informed Consent

6. Capable of giving signed informed consent form (ICF) by study participant or legally acceptable representative.

7. US participants will be required to have a Health Insurance Portability and Accountability Act (HIPAA) authorization; in other countries, as applicable according to national laws.

Contraception

8. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for participation in clinical studies. [0357] Exclusion Criteria - Participants are excluded from the study if any of the following criteria apply at either screening or baseline visit, except where otherwise indicated:

Medical Conditions - Per Eye

1. Concurrent disease that causes substantial decrease of BCVA, is expected to limit BCVA recovery or is likely to require medical or surgical intervention during the study in the study eye.

2. Any ocular disorders that, in the opinion of the Investigator, may confound interpretation of study results in the study eve.

3. Presence or history of the following ocular conditions:

a. Advanced age-related macular degeneration (neovascular AMD or geographic atrophy) in the study eve.

b. Diabetic macular oedema or diabetic retinopathy, defined in diabetic participants as DR lesions outside the area of the vein occlusion in the study eve and anywhere in the retina in the fellow eve.

c. Anterior segment neovascularization, vitreous haemorrhage, retinal detachment in the study eye.

d. Vitreomacular traction, epiretinal membrane or structural damage to the macula that is considered by the Investigator to significantly affect central vision or preclude improvement in vision in the study eye.

e. Macular hole of stage 2 and above in the study eye.

f. Myopia of a spherical equivalent of at least 8 diopters prior to any refractive or cataract surgery in the study eye.

g. Corneal transplant or corneal dystrophy in the study eye.

h. Idiopathic or autoimmune uveitis in the study or in the fellow eye.

4. Presence of the following ocular conditions at screening or baseline visit:

a. Significant media opacities, including cataract, that interfere with BCVA, or imaging assessments (e.g., fundus photography [FP], OCT) in the study eve. b. Aphakia, or pseudophakia with absence of posterior capsule (unless it occurred as a result of a yttrium-aluminum-garnet [YAG] posterior capsulotomy performed more than 30 days before screening visit), in the study eve.

c. Uncontrolled glaucoma (defined as IOP >25 mmHg despite treatment with anti-glaucoma medication); or

d. History or likely future need of glaucoma surgery in the study eve. e. Intraocular inflammation/infection (including trace, or above, cells in the anterior chamber and/or vitreous) within 12 weeks (84 days) of the screening visit in the study or in the fellow eye.

f. Extraocular or periocular infection or inflammation (including infectious blepharitis, keratitis, scleritis, or conjunctivitis) in the study or in the fellow eye.

Medical Conditions - Per Participant

5. Uncontrolled blood pressure (defined as systolic >160 mmHg or diastolic >95 mmHg) at screening visit or baseline visit.

6. Uncontrolled diabetes mellitus (DM), defined by hemoglobin A1c (HbA1c) >12% at screening visit.

7. History of cerebrovascular accident or myocardial infarction within 24 weeks (168 days) before the screening visit or between screening and baseline visits.

8. Renal failure requiring dialysis, or renal transplant at screening or potentially during the study.

9. Known allergy or hypersensitivity to any of the compounds/excipients in the study interventions formulations, including fluorescein used in FA.

10. Presence of any contraindications indicated in the locally approved label for aflibercept. 11. Systemic infection at the time of screening or baseline. Or systemic treatment for suspected or active systemic infection at screening or baseline visit.

12. Pregnant or breastfeeding women.

13. History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, might affect interpretation of the results of the study, renders the participant at high risk from treatment complications or is likely to interfere with full participation in the study.

14. Members of the clinical site study team and/or his/her immediate family.

Prior Therapy

15. Any prior or concomitant ocular or systemic treatment (with an investigational or approved, anti-VEGF or other agent) or surgery for RVO in the study eye.

16. Previous administration of systemic anti-angiogenic medications for any condition.

17. Prior treatment of the study eve with any of the following drugs (any route of ophthalmic administration) or procedures:

a. Anti-angiogenic drugs at any time including investigational therapy (e.g., with

anti-angiopoietin/anti-VEGF bispecific monoclonal antibodies). b. Previous use topical steroids within 4 weeks (28 days) from the screening visit, or intraocular or periocular steroids within 16 weeks (112 days) from the screening visit, or steroid implants at any time.

c. Previous treatment with intraocular or periocular implant, gene therapy, or cell therapy at any time.

d. Treatment with ocriplasmin at any time.

e. Vitreoretinal surgery (including scleral buckling) at any time.

f. Any intraocular surgery, including cataract surgery, within 12 weeks (84 days) before the screening visit.

g. Previous treatment with retinal laser photocoagulation.

18. Prior treatment of the fellow eve with any of the following:

a. Gene therapy, or cell therapy in the fellow eve at any time.

19. Any concomitant ocular or systemic administration of drugs that may interfere with or potentiate the mechanism of action of aflibercept.

Prior/Concurrent Clinical Study Experience

20. Participation in other clinical studies requiring administration of investigational treatments (other than vitamins and minerals) at the time of screening visit, or within 30 days or 5 half-lives of administration of the previous study intervention, whichever is longer.

Results (Week 36)

[0358] This study successfully met its primary endpoint at week 36, demonstrating that patients receiving aflibercept 8 mg every 8 weeks (after initial monthly doses) achieved noninferior visual acuity gains compared to those receiving the current standard therapy EYLEA 2 mg (aflibercept 2 mg) every 4 weeks. Aflibercept 8 mg was well tolerated, and its safety profile was consistent with previous clinical trials. These data demonstrated that aflibercept 8 mg had the potential to become a new standard of care in the treatment of exudative retinal diseases including patients with retinal vein occlusion, which is known to have a high VEGF load. The successful outcome of the study reinforced the capacity of aflibercept 8 mg to provide sustained disease control. Aflibercept 8 mg delivered rapid and resilient fluid control and allowed long treatment intervals with vision gains and tolerability comparable to Eylea 2 mg. For the patients, this meant less frequent injections at comparable efficacy and safety. In QUASAR, the vast majority of aflibercept 8 mg patients (approximately 90%) were extended to every 8-week dosing and maintained their interval through 36 weeks. Almost 70% were assigned every 12-week dosing at the week 32 visit, potentially further alleviating the burden associated with 11876WO01

frequent injections. Aflibercept 8 mg demonstrated rapid and robust reduction of fluid in the retina similar to EYLEA 2 mg, as measured by changes in central subfield thickness (CST) from baseline through week 36. Reduction of fluid in the retina and reducing CST were associated with disease control. The mean number of injections through week 36 was reduced to 6.1 or 6.9 injections with aflibercept 8 mg dosed every 8 weeks (following 3 or 5 initial monthly doses) versus 8.8 injections with EYLEA 2 mg dosed every 4 weeks. Despite less injections, aflibercept 8 mg every 8 weeks achieved similar efficacy and safety to EYLEA 2 mg every 4 weeks at week 36. See Table 1 -C for a summary of outcomes at 36 weeks. The safety profile of EYLEA HD (n=591) was similar to EYLEA (n=301) in the QUASAR trial and remained generally consistent with the known safety profile of EYLEA HD in its pivotal trials. Ocular treatment emergent adverse events (TEAEs) occurring in >5% of all EYLEA HD patients included increased ocular pressure (5%), and there was one case each of endophthalmitis and retinal vasculitis. The rate of intraocular inflammation was 0.5% for EYLEA HD and 1.3% for EYLEA. Hypertension at baseline was present in 66% of EYLEA HD patients and 62% of EYLEA patients. Hypertension during the trial was reported in 8.1% of EYLEA HD patients and 4.7% of EYLEA patients. Thromboembolic events (APTC) occurred in 0.5% of EYLEA HD patients and 1.7% of EYLEA patients.

[0359] The following results, set forth in Tables 1-1 to 1-17 represent observations among participants in this clinical trial at week 36. The QUASAR study met its primary endpoint, with both aflibercept 8 mg treatment arms showing non-inferior BCVA gains at week 36 compared to monthly aflibercept 2 mg (see Tables 1-6 - 1-9). At week 36, the patients in the 8q8/3 and 8q8/5 groups achieved a LS mean increase in BCVA of about 17 and 18 letters, respectively; whereas 2q4 patients achieved a LS mean increase in BCVA of about 18 letters. Aflibercept 8 mg demonstrated rapid and robust reduction of fluid in the retina, as measured by changes in central subfield thickness. Central subfield thickness is summarized in Table 1-10 and 1-11. At week 36, 8q8/3 and 8q8/5 patients achieves a mean decrease in CST of about 363 and 355 micrometers, respectively; whereas 2q4 patients achieved reduction of about 400 micrometers. Subjects in the 8q8/3 and 8q8/5 groups received fewer injections (6.1 and 6.9 injections on average among week 36 completers (safety analysis set)) than those in the 2q4 group (8.8 injections on average among week 36 completers (safety analysis set)). See Table 1-5. The vast majority of the 8 mg treated patients could maintain 8-week dosing up to week 36.

Approximately 90% of aflibercept 8 mg patients were extended to every 8-week dosing and maintained their interval through 36 weeks. See Table 1-5. Treatment exposure of patients is summarized in Tables 1-4 -1-5. Aflibercept 8 mg was well tolerated, with a safety profile consistent with previous clinical trials. Safety data through week 36 was comparable to the known safety profile of aflibercept 2 mg. Adverse events and other safety data is summarized in Tables 1-12 - 1-17. The baseline demographics and disease information for patients is summarized in Table 1-1 - 1-3.

Table 1-C. Outcomes at 36 Weeks

EYLEA HD EYLEA HD EYLEA

4-week 8-week regimen after 8-week regimen after 3 initial monthly 5 initial monthly regimen

doses doses (n=301)

(n=293) (n=298) Mean observed BCVA 17.8

17.0 letters 19.1 letters improvement letters

Least squares mean

difference in BCVA

-0.1 0.8 improvement, primary

(p<0.0001) (p<0.0001) endpoint (noninferiority p-value)*

Mean observed BCVA 72.0

72.8 letters 74.6 letters letters

Patients maintained

on every 8 -week 88% 93%

dosing interval

BCVA: best corrected visual acuity

*Non-inferiority (1 -sided) p-values are for the difference in least squares mean compared to EYLEA with margin of 4 letters. EYLEA HD groups met non-inferiority. Table 1-1. Disposition: flow of participants through study phases: Week 36 (all participants) Population group: Non-China sub-population

Number of Participants 2q4 8q8/3 8q8/5 All 8 mg Total Enrolled 1158 (100.0%) Did not complete screening 355 ( 30.7%) Primary reason ADVERSE EVENT 2 ( 0.2%) LOST TO FOLLOW-UP 1 ( <0.1 %) PHYSICIAN DECISION 1 ( <0.1%)

SCREEN FAILURE 321 ( 27.7%) WITHDRAWAL BY SUBJECT 23 ( 2.0%) OTHER 7 ( 0.6%) Participants who were re-screened 44 ( 3.8%) Primary reason for not completing initial screening

LOGISTICAL PROBLEM 1 ( 2.3%) SCREEN FAILURE 41 ( 93.2%) WITHDRAWAL BY SUBJECT 1 ( 2.3%) OTHER 1 ( 2.3%) Randomized to intervention 277 (100.0%) 267 (100.0%) 260 (100.0%) 527 (100.0%) 804 (100.0%) Study intervention never administered 1 ( 0.4%) 1 ( 0.4%) 0 1 ( 0.2%) 2 ( 0.2%) Treated 276 ( 99.6%) 266 ( 99.6%) 260 (100.0%) 526 ( 99.8%) 802 ( 99.8%) Treatment phase through Week 36

Started 276 ( 99.6%) 266 ( 99.6%) 260 (100.0%) 526 ( 99.8%) 802 ( 99.8%) Completed treatment phase through Week 36 264 ( 95.3%) 251 ( 94.0%) 239 ( 91.9%) 490 ( 93.0%) 754 ( 93.8%) Did not complete treatment phase through Week 36 12 ( 4.3%) 15 ( 5.6%) 21 ( 8.1%) 36 ( 6.8%) 48 ( 6.0%) Primary reason

ADVERSE EVENT 1 ( 0.4%) 0 1 ( 0.4%) 1 ( 0.2%) 2 ( 0.2%) DEATH 2 ( 0.7%) 2 ( 0.7%) 3 ( 1.2%) 5 ( 0.9%) 7 ( 0.9%) LOGISTICAL PROBLEM 0 1 ( 0.4%) 0 1 ( 0.2%) 1 ( 0.1%) LOST TO FOLLOW-UP 2 ( 0.7%) 3 ( 1.1%) 3 ( 1.2%) 6 ( 1.1%) 8 ( 1.0%) PROTOCOL DEVIATION 0 0 1 ( 0.4%) 1 ( 0.2%) 1 ( 0.1%) WITHDRAWAL BY SUBJECT 7 ( 2.5%) 9 ( 3.4%) 13 ( 5.0%) 22 ( 4.2%) 29 ( 3.6%) Follow-up phase

Started follow-up phase prior to Week 36 12 ( 4.3%) 15 ( 5.6%) 21 ( 8.1%) 36 ( 6.8%) 48 ( 6.0%) Completed follow-up phase through Week 36 0 0 0 0 0 Unknown if completed follow-up phase through Week 36 0 2 ( 0.7%) 1 ( 0.4%) 3 ( 0.6%) 3 ( 0.4% ) _ Number of Participants _ 2q4 8q8/3 8q8/5 All 8mg Total

Did not complete follow-up phase through Week 36 12 ( 4.3%) 13 ( 4.9%) 20 ( 7.7%) 33 ( 6.3%) 45 ( 5.6%)

Primary reason

ADVERSE EVENT 1 ( 0.4%) 0 1 ( 0.4%) 1 ( 0.2%) 2 ( 0.2%)

DEATH 2 ( 0.7%) 2 ( 0.7%) 3 ( 1.2%) 5 ( 0.9%) 7 ( 0.9%)

LOST TO FOLLOW-UP 2 ( 0.7%) 2 ( 0.7%) 2 ( 0.8%) 4 ( 0.8%) 6 ( 0.7%)

PROTOCOL DEVIATION 0 0 1 ( 0.4%) 1 ( 0.2%) 1 ( 0.1%)

WITHDRAWAL BY SUBJECT 7 ( 2.5%) 9 ( 3.4%) 13 ( 5.0%) 22 ( 4.2%) 29 ( 3.6%)

Number of participants enrolled is the number of participants who signed informed consent. In case of rescreening, rescreened participants are

counted once with their final enrollment.

Definition of completed treatment phase through week 36 = did not discontinue study intervention prior to week 36 visit, and reached the week 36

visit (either visit performed or confirmed not done).

Definition of completed follow-up phase through week 36 = end of treatment was prior to week 36, but study discontinuation date was at week 36

or later.

Follow up phase starts after date of treatment discontinuation for participant.

2q4: Aflibercept 2mg administered every 4 weeks.

8q8/3: Aflibercept 8mg administered every 8 weeks, after 3 initial injections at 4-week intervals.

8q8/5: Aflibercept 8mg administered every 8 weeks, after 5 initial injections at 4-week intervals.

All 8mg: Pooled aflibercept 8mg administered every 8 weeks, after 3 or 5 initial injections at 4-week intervals.

Table 1-2. Demographics and baseline characteristics (full analysis set)

Population group: Non-China sub-population

2q4 8q8/5 All 8mg Total N=276 (F N=260 (1C N=526 (100 N=802 (1C Sex Female 138 ( 50.0%) 128 ( 48.1%) 126 ( 48.5%) 254 ( 48.3%) 392 ( 48.9%)

Male 138 ( 50.0%) 138 ( 51.9%) 134 ( 51.5%) 272 ( 51.7%) 410 ( 51.1%) 2q4 8q8/3 8q8/5 All 8mg Total N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%) N=802 (100%) Race AMERICAN INDIAN OR ALASKA NATIVE 0 0 2 ( 0.8%) 2 ( 0.4%) 2 ( 0.2%) ASIAN 76 ( 27.5%) 64 ( 24.1%) 59 ( 22.7%) 123 ( 23.4%) 199 ( 24.8%) ASIAN INDIAN 3 ( 1.1%) 2 ( 0.8%) 3 ( 1.2%) 5 ( 1.0%) 8 ( 1.0%) CHINESE 3 ( 1.1%) 4 ( 1.5%) 3 ( 1.2%) 7 ( 1.3%) 10 ( 1.2%) JAPANESE 35 ( 12.7%) 32 ( 12.0%) 31 ( 11.9%) 63 ( 12.0%) 98 ( 12.2%) KOREAN 25 ( 9.1%) 19 ( 7.1%) 15 ( 5.8%) 34 ( 6.5%) 59 ( 7.4%) THAI 2 ( 0.7%) 2 ( 0.8%) 1 ( 0.4%) 3 ( 0.6%) 5 ( 0.6%) OTHER 8 ( 2.9%) 5 ( 1.9%) 6 ( 2.3%) 11 ( 2.1%) 19 ( 2.4%) BLACK OR AFRICAN AMERICAN 8 ( 2.9%) 7 ( 2.6%) 9 ( 3.5%) 16 ( 3.0%) 24 ( 3.0%) MULTIPLE 1 ( 0.4%) 0 1 ( 0.4%) 1 ( 0.2%) 2 ( 0.2%) NATIVE HAWAIIAN OR OTHER PACIFIC 0 0 1 ( 0.4%) 1 ( 0.2%) 1 ( 0.1%) ISLANDER NOT REPORTED 13 ( 4.7%) 22 ( 8.3%) 11 ( 4.2%) 33 ( 6.3%) 46 ( 5.7%)

WHITE 178 ( 64.5%) 173 ( 65.0%) 177 ( 68.1%) 350 ( 66.5%) 528 ( 65.8%) Ethnicity

HISPANIC OR LATINO 22 ( 8.0%) 25 ( 9.4%) 13 ( 5.0%) 38 ( 7.2%) 60 ( 7.5%) NOT HISPANIC OR LATINO 242 ( 87.7%) 227 ( 85.3%) 237 ( 91.2%) 464 ( 88.2%) 706 ( 88.0%) NOT REPORTED 12 ( 4.3%) 14 ( 5.3%) 10 ( 3.8%) 24 ( 4.6%) 36 ( 4.5%) Geographic region

Japan 34 ( 12.3%) 32 ( 12.0%) 31 ( 11.9%) 63 ( 12.0%) 97 ( 12.1%) APAC (without Japan) 41 ( 14.9%) 37 ( 13.9%) 28 ( 10.8%) 65 ( 12.4%) 106 ( 13.2%) Europe 113 ( 40.9%) 111 ( 41.7%) 114 ( 43.8%) 225 ( 42.8%) 338 ( 42.1%) America 88 ( 31.9%) 86 ( 32.3%) 87 ( 33.5%) 173 ( 32.9%) 261 ( 32.5%) Age at enrollment (years)

n 276 266 260 526 802 Mean (SD) 66.8 (11.3) 66.4 (11.6) 66.7 (11.4) 66.5 (11.5) 66.6 (11.4) Median 68.0 68.0 67.0 68.0 68.0

QI, Q3 60.0. 75.0 58.0. 75.0 58.0. 76.0 58.0. 75.0 59.0. 75.0 Min. Max 27, 89 23, 95 39, 92 23, 95 23. 95

Age group 1 (years)

<65 108 ( 39.1%) 107 ( 40.2%) 105 ( 40.4%) 212 ( 40.3%) 320 ( 39.9%) >=65 168 ( 60.9%) 159 ( 59.8%) 155 ( 59.6%) 314 ( 59.7%) 482 ( 60.1%) Age group 2 (years)

<55 35 ( 12.7%) 47 ( 17.7%) 41 ( 15.8%) 88 ( 16.7%) 123 ( 15.3%) >=55 - <65 73 ( 26.4%) 60 ( 22.6%) 64 ( 24.6%) 124 ( 23.6%) 197 ( 24.6%) >=65 - <75 96 ( 34.8%) 85 ( 32.0%) 83 ( 31.9%) 168 ( 31.9%) 264 ( 32.9%) >=75 72 ( 26.1%) 74 ( 27.8%) 72 ( 27.7%) 146 ( 27.8%) 218 ( 27.2%) 2q4 8q8/3 8q8/5 All 8mg Total N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%) N=802 (100%) Age group 3 (years) 18 - 64 108 ( 39.1%) 107 ( 40.2%) 105 ( 40.4%) 212 ( 40.3%) 320 ( 39.9%) 65 - 74 96 ( 34.8%) 85 ( 32.0%) 83 ( 31.9%) 168 ( 31.9%) 264 ( 32.9%) 75 - 84 62 ( 22.5%) 65 ( 24.4%) 60 ( 23.1%) 125 ( 23.8%) 187 ( 23.3%)

>=85 10 ( 3.6%) 9 ( 3.4%) 12 ( 4.6%) 21 ( 4.0%) 31 ( 3.9%) Weight (kg)

n 275 264 257 521 796 Mean (SD) 76.34 (19.16) 77.85 (18.82) 78.27 (19.33) 78.06 (19.06) 77.46 (19.10) Median 74.20 75.55 76.00 76.00 75.00

Q1, Q3 62.40, 87.00 64.25, 89.15 65.00, 90.00 64.50, 90.00 64.00, 88.85 Min, Max 36.0, 141.0 39.4, 152.5 37.4, 135.0 37.4, 152.5 36.0, 152.5 Height (cm)

n 276 264 257 521 797 Mean (SD) 165.61 (10.62) 166.83 (10.14) 166.90 (10.42) 166.87 (10.27) 166.43 (10.40) Median 165.00 167.00 167.00 167.00 165.50

Q1, Q3 157.00, 173.00 160.00, 175.00 160.00, 173.20 160.00, 174.00 159.00, 173.70 Min. Max 135.0. 193.0 143.0. 196.0 130.0. 201.9 130.0. 201.9 130.0. 201.9 Body mass index (kg/m2)

n 275 264 256 520 795 Mean (SD) 27.63 (5.62) 27.76 (5.24) 27.88 (5.20) 27.82 (5.22) 27.75 (5.36) Median 27.10 27.30 27.45 27.35 27.30

Q1, Q3 24.00, 30.70 24.20, 30.35 24.50, 30.70 24.40, 30.50 24.20, 30.50 Min, Max 14.8, 60.8 16.4, 43.3 14.9, 48.6 14.9, 48.6 14.8, 60.8 Body mass index (BMI) group (kg/m2)

missing 1 ( 0.4%) 2 ( 0.8%) 4 ( 1.5%) 6 ( 1.1%) 7 ( 0.9%) <=25 98 ( 35.5%) 82 ( 30.8%) 76 ( 29.2%) 158 ( 30.0%) 256 ( 31.9%) >25 to <=30 100 ( 36.2%) 111 ( 41.7%) 103 ( 39.6%) 214 ( 40.7%) 314 ( 39.2%) >30 to <=35 48 ( 17.4%) 46 ( 17.3%) 55 ( 21.2%) 101 ( 19.2%) 149 ( 18.6%) >35 29 ( 10.5%) 25 ( 9.4%) 22 ( 8.5%) 47 ( 8.9%) 76 ( 9.5%) Systolic blood pressure (mmHg)

n 276 266 260 526 802 Mean (SD) 135.55 (11.70) 135.25 (11.96) 134.69 (12.02) 134.97 (11.98) 135.17 (11.88) Median 136.00 135.50 135.00 135.00 135.50

Q1, Q3 127.75, 143.50 128.00, 143.50 127.50, 142.25 128.00, 142.50 128.00, 143.00 Min. Max 98.0. 160.0 98.0. 158.5 105.5. 177.0 98.0. 177.0 98.0. 177.0 2q4 8q8/3 8q8/5 All 8mg Total N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%) N=802 (100%) Diastolic blood pressure (mmHg) n 276 266 260 526 802 Mean (SD) 79.17 (7.75) 79.59 (8.31) 79.73 (8.28) 79.66 (8.29) 79.49 (8.10) Median 80.25 80.00 80.25 80.00 80.00 Q1, Q3 74.25, 85.00 74.50, 85.50 74.00, 86.50 74.50, 86.00 74.50, 85.50

Min, Max 57.0, 96.5 53.0, 96.0 56.0, 95.0 53.0, 96.0 53.0, 96.5 Heart rate (beats/min)

n 276 266 260 526 802

Mean (SD) 73.0 (10.0) 73.3 (11.2) 73.4 (11.0) 73.3 (11.1) 73.2 (10.7) Median 72.0 73.0 72.0 72.0 72.0

QI, Q3 67.0, 80.0 65.0, 80.0 66.0, 79.0 66.0, 80.0 66.0, 80.0 Min, Max 48, 119 48, 115 42, 107 42, 115 42, 119 Temperature (°C)

n 276 266 260 526 802 Mean (SD) 36.46 (0.35) 36.49 (0.36) 36.44 (0.35) 36.46 (0.36) 36.46 (0.35) Median 36.50 36.50 36.40 36.50 36.50

Q1, Q3 36.25, 36.70 36.30, 36.70 36.20, 36.70 36.20, 36.70 36.20, 36.70 Min. Max 34.4. 37.5 35.0. 37.3 35.3. 37.3 35.0. 37.3 34.4. 37.5 Prior Fellow Eye Treatment

No 273 ( 98.9%) 265 ( 99.6%) 258 ( 99.2%) 523 ( 99.4%) 796 ( 99.3%) Yes 3 ( 1.1%) 1 ( 0.4%) 2 ( 0.8%) 3 ( 0.6%) 6 ( 0.7%) Aflibercept 0 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) 2 ( 0.2%) Bevacizumab 2 ( 0.7%) 0 2 ( 0.8%) 2 ( 0.4%) 4 ( 0.5%) Ranibizumab 1 ( 0.4%) 0 0 0 1 ( 0.1%) Medical history of hypertension

No 101 ( 36.6%) 87 ( 32.7%) 88 ( 33.8%) 175 ( 33.3%) 276 ( 34.4%) Yes 175 ( 63.4%) 179 ( 67.3%) 172 ( 66.2%) 351 ( 66.7%) 526 ( 65.6%) Medical history of diabetes

No 221 ( 80.1%) 216 ( 81.2%) 214 ( 82.3%) 430 ( 81.7%) 651 ( 81.2%) Yes 55 ( 19.9%) 50 ( 18.8%) 46 ( 17.7%) 96 ( 18.3%) 151 ( 18.8%) Medical history of cerebrovascular disease

No 257 ( 93.1%) 244 ( 91.7%) 250 ( 96.2%) 494 ( 93.9%) 751 ( 93.6%) Yes 19 ( 6.9%) 22 ( 8.3%) 10 ( 3.8%) 32 ( 6.1%) 51 ( 6.4%) Medical history of ischaemic heart disease

No 252 ( 91.3%) 245 ( 92.1%) 242 ( 93.1%) 487 ( 92.6%) 739 ( 92.1%) Yes 24 ( 8.7%) 21 ( 7.9%) 18 ( 6.9%) 39 ( 7.4%) 63 ( 7.9%) 2q4 8q8/3 8q8/5 All 8mg Total N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%) N=802 (100%) Medical history of renal impairment Missing 7 ( 2.5%) 5 ( 1.9%) 4 ( 1.5%) 9 ( 1.7%) 16 ( 2.0%) Normal 160 ( 58.0%) 172 ( 64.7%) 162 ( 62.3%) 334 ( 63.5%) 494 ( 61.6%) Mild 90 ( 32.6%) 70 ( 26.3%) 73 ( 28.1%) 143 ( 27.2%) 233 ( 29.1%) Moderate 16 ( 5.8%) 16 ( 6.0%) 16 ( 6.2%) 32 ( 6.1%) 48 ( 6.0%)

Severe 3 ( 1.1%) 3 ( 1.1%) 5 ( 1.9%) 8 ( 1.5%) 11 ( 1.4%) Medical history of hepatic impairment

No 264 ( 95.7%) 255 ( 95.9%) 253 ( 97.3%) 508 ( 96.6%) 772 ( 96.3%)

Yes 12 ( 4.3%) 11 ( 4.1%) 7 ( 2.7%) 18 ( 3.4%) 30 ( 3.7%)

NEI-VFQ-25 total score

n 276 266 260 526 802

Mean (SD) 78.578 (17.265) 79.131 (16.909) 77.655 (17.333) 78.401 (17.119) 78.462 (17.159) Median 82.160 83.200 82.215 82.420 82.290

QI, Q3 69.270, 92.580 71.430, 92.190 69.030, 91.070 70.310, 91.410 70.050, 91.930 Min. Max 22.92, 100.00 24.22, 100.00 18.75, 100.00 18.75, 100.00 18.75, 100.00

NEI-VFQ-25 = National Eye Institute Visual Functioning Questionnaire-25

Multiple: Participants who reported that they belong to more than one race.

2q4: Aflibercept 2mg administered every 4 weeks.

Table 1-3. Baseline disease characteristics of the study eye (full analysis set)

Population group: Non-China sub-population

8q8/3 8q8/5 All 8mg Total N=276 (100%) N=266 (100%) N=526 (100%) N=802 (100%) RVO Type (a) BRVO 133 ( 48.2%) 139 ( 52.3%) 134 ( 51.5%) 273 ( 51.9%) 406 ( 50.6%) CRVO 108 ( 39.1%) 95 ( 35.7%) 91 ( 35.0%) 186 ( 35.4%) 294 ( 36.7%) HRVO 35 ( 12.7%) 32 ( 12.0%) 35 ( 13.5%) 67 ( 12.7%) 102 ( 12.7%) RVO Type (used for stratified randomization) (b) BRVO 158 ( 57.2%) 150 ( 56.4%) 147 ( 56.5%) 297 ( 56.5%) 455 ( 56.7%)

CRVO / HRVO 118 ( 42.8%) 116 ( 43.6%) 113 ( 43.5%) 229 ( 43.5%) 347 ( 43.3%) 8q8/3 8q8/5 All 8mg Total N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%) N=802 (100%) BCVA (ETDRS letters score)

n 276 266 260 526 802 Mean (SD) 53.5 (14.5) 55.2 (13.6) 55.2 (13.8) 55.2 (13.7) 54.6 (14.0) Median 56.5 57.0 58.0 57.5 57.0 Q1. Q3 43.0, 65.0 47.0, 67.0 48.0, 66.5 48.0, 67.0 46.0, 66.0 Min, Max 24, 73 24, 73 18, 74 18, 74 18, 74 Categorized BCVA (ETDRS letters score)

< 60 156 ( 56.5%) 150 ( 56.4%) 147 ( 56.5%) 297 ( 56.5%) 453 ( 56.5%) >= 60 120 ( 43.5%) 116 ( 43.6%) 113 ( 43.5%) 229 ( 43.5%) 349 ( 43.5%) Intraocular pressure (mmHg)

n 276 266 260 526 802 Mean (SD) 14.7 (3.1) 14.7 (3.1) 14.8 (2.9) 14.8 (3.0) 14.7 (3.0) Median 14.0 15.0 15.0 15.0 15.0 Q1. Q3 12.0, 17.0 13.0, 17.0 13.0, 17.0 13.0, 17.0 13.0. 17.0 Min. Max 6, 24 7, 24 7. 26 7, 26 6, 26 Central subfield thickness (CST) (um)

n 275 266 260 526 801 Mean (SD) 654.2 (239.5) 626.0 (230.6) 612.4 (216.9) 619.3 (223.8) 631.3 (229.8) Median 610.0 572.0 569.0 571.5 583.0 Q1. Q3 473.0, 767.0 458.0, 754.0 451.5, 745.0 455.0, 747.0 459.0, 759.0 Min, Max 302, 1601 272, 1499 268, 1424 268, 1499 268, 1601 Categorized CST (Central subfield thickness) missing 1 ( 0.4%) 0 1 ( 0.1%) <= Observed Median (581 um) 124 ( 44.9%) 137 ( 51.5%) 273 ( 51.9%) 397 ( 49.5%) > Observed Median (581 um) 151 ( 54.7%) 129 ( 48.5%) 253 ( 48.1%) 404 ( 50.4%) Presence of perifoveal and parafoveal ischemia by FA missing 14 ( 5.3%) 34 ( 6.5%) 57 ( 7.1%) No 56 ( 21.1%) 110 ( 20.9%) 178 ( 22.2%) Undetermined 23 ( 8.6%) 49 ( 9.3%) 76 ( 9.5%)

Yes 173 ( 65.0%) 333 ( 63.3%) 491 ( 61.2%) Total area of macular ischemia (not considering the FAZ) by FA

(mm2)

n 235 225 217 442 677 Mean (SD) 4.059 (4.827) 4.476 (4.885) 4.637 (4.971) 4.555 (4.922) 4.383 (4.891) Median 2.500 3.600 3.210 3.450 3.130 Q1. Q3 0.000, 7.200 0.000, 7.210 0.000, 8.080 0.000, 7.700 0.000, 7.630 Min, Max 0.00, 28.08 0.00, 26.86 0.00, 24.20 0.00, 26.86 0.00, 28.08 2q4 8q8/3 8q8/5 All 8mg Total N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%) N=802 (100%) Presence of retinal areas of non-perfusion outside the macula by FA

missing 13 ( 4.7%) 11 ( 4.1%) 13 ( 5.0%) 24 ( 4.6%) 37 ( 4.6%) No 69 ( 25.0%) 61 ( 22.9%) 58 ( 22.3%) 119 ( 22.6%) 188 ( 23.4%) Undetermined 25 ( 9.1%) 18 ( 6.8%) 24 ( 9.2%) 42 ( 8.0%) 67 ( 8.4%) Yes 169 ( 61.2%) 176 ( 66.2%) 165 ( 63.5%) 341 ( 64.8%) 510 ( 63.6%) BCVA = Best corrected visual acuity; BRVO = Branch retinal vein occlusion; CRVO = Central retinal vein occlusion; ETDRS = Early treatment diabetic retinopathy study; FA = Fluorescein angiography assessment; FAZ = Foveal avascular zone; HRVO = Hemiretinal vein occlusion; RVO = Retinal vein occlusion

(a) RVO type based on reading center assessment (investigator assessment is used for participnts with missing reading center data).

(b) RVO type based on investigator assessment; used for strata assignment at randomization via the IxRS system.

2q4: Aflibercept 2mg administered every 4 weeks.

Table 1-4. Exposure to intervention in study eye: Through Week 36 (safety analysis set)

Population group: Non-China sub-population

2q4 8q8/3 8q8/5 All 8mg Total

N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%) N=802 (100%)

Total number of active injections 2359 1587 1732 3319 5678

Total number of sham injections 0 712 457 1169 1169

Number of active injections

1 2 ( 0.7%) 2 ( 0.8%) 2 ( 0.8%) 4 ( 0.8%) 6 ( 0.7%)

2 1 ( 0.4%) 1 ( 0.4%) 5 ( 1.9%) 6 ( 1.1%) 7 ( 0.9%)

3 6 ( 2.2%) 3 ( 1.1%) 4 ( 1.5%) 7 ( 1.3%) 13 ( 1.6%)

4 1 ( 0.4%) 5 ( 1.9%) 3 ( 1.2%) 8 ( 1.5%) 9 ( 1.1%)

5 3 ( 1.1%) 14 ( 5.3%) 8 ( 3.1%) 22 ( 4.2%) 25 ( 3.1%)

6 3 ( 1.1%) 217 ( 81.6%) 19 ( 7.3%) 236 ( 44.9%) 239 ( 29.8%)

7 7 ( 2.5%) 10 ( 3.8%) 210 ( 80.8%) 220 ( 41.8%) 227 ( 28.3%)

8 26 ( 9.4%) 14 ( 5.3%) 9 ( 3.5%) 23 ( 4.4%) 49 ( 6.1%)

9 227 ( 82.2%) 0 0 0 227 ( 28.3%)

Number of active injections

n 276 266 260 526 802

Mean (SD) 8.5 (1.3) 6.0 (0.9) 6.7 (1.1) 6.3 (1.0) 7.1 (1.6)

Median 9.0 6.0 7.0 6.0 7.0

QI, Q3 9.0, 9.0 6.0, 6.0 7.0, 7.0 6.0, 7.0 6.0, 9.0

Min, Max 1, 9 1, 8 1, 8 1, 8 1, 9 2q4 8q8/3 8q8/5 All 8mg Total N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%) N=802 (100%) Number of sham injections 0 276 (100.0%) 5 ( 1.9%) 18 ( 6.9%) 23 ( 4.4%) 299 ( 37.3%) 1 0 23 ( 8.6%) 27 ( 10.4%) 50 ( 9.5%) 50 ( 6.2%) 2 0 25 ( 9.4%) 215 ( 82.7%) 240 ( 45.6%) 240 ( 29.9%)

3 0 213 ( 80.1%) 0 213 ( 40.5%) 213 ( 26.6%) Number of sham injections

n 276 266 260 526 802 Mean (SD) 0.0 (0.0) 2.7 (0.7) 1.8 (0.6) 2.2 (0.8) 1.5 (1.2) Median 0.0 3.0 2.0 2.0 2.0

QI, Q3 0.0, 0.0 3.0, 3.0 2.0, 2.0 2.0, 3.0 0.0, 3.0 Min, Max 0, 0 0, 3 0, 2 0, 3 0, 3 Total amount of active study drug (mg)

n 276 266 260 526 802

Mean (SD) 17.1 (2.7) 47.6 (6.9) 53.2 (8.9) 50.4 (8.4) 38.9 (17.3) Median 18.0 48.0 56.0 48.0 48.0

QI, Q3 18.0, 18.0 48.0, 48.0 56.0. 56.0 48.0, 56.0 18.0, 56.0 Min. Max 2, 18 8. 64 8, 64 8. 64 2, 64 Treatment duration (weeks)

n 276 266 260 526 802 Mean (SD) 34.90 (5.00) 35.15 (4.37) 34.28 (6.03) 34.72 (5.27) 34.78 (5.18) Median 36.00 36.00 36.00 36.00 36.00 QI, Q3 35.86, 36.21 35.71, 36.29 35.71, 36.29 35.71, 36.29 35.71, 36.29 Min, Max 4.0, 39.1 4.0, 42.1 4.0. 37.4 4.0, 42.1 4.0, 42.1 Duration (weeks) = [(date of last study intervention prior to Week 36) - (date of first study intervention) +28]/7; 28 days were added because of the minimum 4-week dosing interval in the study. Study interventions given at Week 36 or beyond are not included in this table.

2q4: Aflibercept 2 mg administered every 4 weeks.

8q8/3: Aflibercept 8 mg administered every 8 weeks, after 3 initial injections at 4-week intervals.

Table 1-5. Exposure to intervention in study eye: Through Week 36 (safety analysis

set, only participants considered as completers for Week 36)

Population group: Non-China sub-population

2q4 8q8/3 8q8/5 All 8mg Total N=264 (100%) N=251 (100%) N=239 (100%) N=490 (100%) N=754 (100%) Total number of active injections 2316 1530 1653 3183 5499 Total number of sham injections 0 694 448 1142 1142 Number of active injections 2 1 ( 0.4%) 1 ( 0.2%) 1 ( 0.1%) 3 1 ( 0.4%) 0 0 1 ( 0.1%) 4 1 ( 0.4%) 2 ( 0.8%) 1 ( 0.4%) 3 ( 0.6%) 4 ( 0.5%) 5 2 ( 0.8%) 10 ( 4.0%) 2 ( 0.8%) 12 ( 2.4%) 14 ( 1.9%) 6 1 ( 0.4%) 215 ( 85.7%) 17 ( 7.1%) 232 ( 47.3%) 233 ( 30.9%) 7 6 ( 2.3%) 10 ( 4.0%) 209 ( 87.4%) 219 ( 44.7%) 225 ( 29.8%) 8 26 ( 9.8%) 14 ( 5.6%) 9 ( 3.8%) 23 ( 4.7%) 49 ( 6.5%) 9 227 ( 86.0%) 0 0 0 227 ( 30.1%) Number of active injections n 264 754 Mean (SD) 8.8 (0.7) 7.3 (1.3) Median 9.0 7.0 Q1. Q3 6.0, 9.0

Min, Max 2, 9 Number of sham injections

0 264 (100.0%) 1 ( 0.4%) 3 ( 1.3%) 4 ( 0.8%) 268 ( 35.5%) 1 0 17 ( 6.8%) 24 ( 10.0%) 41 ( 8.4%) 41 ( 5.4%) 2 0 22 ( 8.8%) 212 ( 88.7%) 234 ( 47.8%) 234 ( 31.0%) 3 0 211 ( 84.1%) 0 211 ( 43.1%) 211 ( 28.0%) 2q4 8q8/3 8q8/5 All 8mg Total N=264 (100%) N=251 (100%) N=239 (100%) N=490 (100%) N=754 (100%) Number of sham injections n 264 251 239 490 754 Mean (SD) 0.0 (0.0) 2.8 (0.6) 1.9 (0.4) 2.3 (0.7) 1.5 (1.2) Median 0.0 3.0 2.0 2.0 2.0 QI, Q3 0.0, 0.0 3.0, 3.0 2.0, 2.0 2.0, 3.0 0.0, 3.0

Min, Max 0, 0 0, 3 0, 2 0, 3 0, 3 Total amount of active study drug (mg)

n 264 251 239 490 754 Mean (SD) 17.5 (1.5) 48.7 (4.7) 55.3 (4.2) 51.9 (5.5) 39.9 (17.0) Median 18.0 48.0 56.0 48.0 48.0

QI, Q3 18.0, 18.0 48.0, 48.0 56.0, 56.0 48.0, 56.0 18.0, 56.0 Min, Max 6, 18 32, 64 16, 64 16, 64 6, 64 Treatment duration (weeks)

n 264 251 239 490 754 Mean (SD) 35.81 (2.03) 35.96 (1.23) 35.79 (2.05) 35.88 (1.68) 35.85 (1.81) Median 36.00 36.00 36.00 36.00 36.00 QI, Q3 35.86, 36.29 35.86, 36.29 35.86, 36.29 35.86. 36.29 35.86, 36.29 Min. Max 12.4, 39.1 24.0. 42.1 8.6, 37.4 8.6, 42.1 8.6. 42.1 Participants with q8 or longer dosing interval through Week 36 (a) 220 ( 87.6%) 222 ( 92.9%) 442 ( 90.2%) 442 ( 58.6%) Participants with q4 as the last intended dosing interval (b) 66 ( 25.0%) 16 ( 6.4%) 17 ( 7.1%) 33 ( 6.7%) 99 ( 13.1%) Participants with q8 as the last intended dosing interval (b) 198 ( 75.0%) 65 ( 25.9%) 222 ( 92.9%) 287 ( 58.6%) 485 ( 64.3%) Participants with ql2 as the last intended dosing interval (b) 170 ( 67.7%) 0 170 ( 34.7%) 170 ( 22.5%) 2q4 8q8/3 8q8/5 All 8mg Total N=264 (li N-251 (100%) N=239 (100%) N=490 (100%) N=754 (100%) Participants shortened to q4 dosing interval anytime 31 ( 12.4%) 17 ( 7.1%) 48 ( 9.8%) 48 ( 6.4%) Participants shortening dosing interval at W16 17 ( 6.8%) 17 ( 3.5%) 17 ( 2.3%) Participants shortening dosing interval at W24 10 ( 4.0%) 12 ( 5.0%) 22 ( 4.5%) 22 ( 2.9%)

Participants shortening dosing interval at W32 4 ( 1.6%) 5 ( 2.1%) 9 ( 1.8%) 9 ( 1.2%) Duration (weeks) = [(date of last study intervention prior to Week 36) - (date of first study intervention) +28]/7; 28 days were added because of the minimum 4- week dosing interval in the study. Study interventions given at Week 36 or beyond are not included in this table.

Only participants that did not discontinue study intervention prior to Week 36 are included.

(a) All participants on q8 interval for whom it was not planned to have their interval shortened (according to DRM criteria until W32) prior to Week 36.

(b) Based on dose regimen modification (DRM) criteria assessed at the last visit with active injection before Week 36.

2q4: Aflibercept 2 mg administered every 4 weeks.

Table 1-6. Change from baseline in BCVA measured by the ETDRS letter score at Week 36, MMRM (full analysis set)

Population group: Non-China sub-population

Number of participants p- value of with week one-sided test 36 data: for nonp-valuc of included/ex inferiority at a one-sided LS mean (SE) chg. Arith. mean (SD) Baseline eluded due margin of 4 test for Estimate for Contrast and Treatment _ from BL chg. from BL (a) mean (a) to ICE DF Contrast (b) t-value letters two-sided 95% CI (c) 8q8/3 (N=266) 17.3 (0.7) 16.8 (11.8) 55.2 236/11 515.9 8q8/3 - 2q4 0.5452 -0.1 (-2.2, 2.0)

8q8/5 (N=260) 18.4 (0.7) 19.0 (11.6) 55.2 216/18 493.4 8q8/5 - 2q4 4.76 <.0001 0.1895 0.9 (-1.1, 2.9) Number of participants p-value of with week one-sided test

36 data: for non- p-value of included/ex inferiority at a one-sided

LS mean (SE) chg. Arith. mean (SD) Baseline eluded due margin of 4 test for Estimate for Contrast and Treatment from BL chg. from BL (a) mean (a) to ICE DF Contrast (b) t- value letters superiority two-sided 95% CI (c)

2q4 (N=276) 17.5 (0.8) 17.7 (13.4) 53.5 244/16

BL = Baseline: CI = Confidence Interval; DF = Degrees of Freedom; ICE = Intercurrent Event; LS = Least Squares: SD = Standard Deviation; SE = Standard Error.

A mixed model for repeated measurements (MMRM) was used with baseline BCVA measurement as a covariate, treatment group, visit and the stratification variables

(geographic region [Japan vs. APAC vs. Europe vs. America], baseline BCVA [<60 vs. >=60]. and RVO type [CRVO/HRVO vs BRVO]) as fixed factors, and terms for the

interaction between baseline BCVA and visit and treatment and visit. Covariance structure used: unstructured covariance structure.

Intercurrent events were handled according to primary estimand strategy'

(a) based on observed cases excluding data after ICE.

(b) The contrast also includes the interaction term for treatment x visit (at week 36, for details on the population-level summary.

(c) Estimate based on the MMRM, was computed for the differences of 8q8/3 minus 2q4 and 8q8/5 minus 2q4, respectively⁷ with two-sided 95% Cis.

2q4: Aflibercept 2mg administered every 4 weeks.

8q8/5: Aflibercept 8mg administered every⁷ 8 weeks, after 5 initial injections at 4-week intervals.

Table 1-7. Summary statistics for BCVA measured by the ETDRS letter score by visit, OC excluding values

after ICE (full analysis set)

Population group: Non-China sub-population

Value at Visit Change from Baseline Treatment Visit n Mean (SD) SEM Median QI, Q3 Min, Max n Mean (SD) SEM Median QI, Q3 Min, Max 2q4 (N=276) BASELINE 276 53.5 (14.5) 0.9 56.5 43.0, 65.0 24, 73

WEEK 4 272 65.4 (14.9) 0.9 68.0 58.0, 76.0 3, 93 272 11.9 (10.5) 0.6 11.0 5.5, 17.0 -35, 46 WEEK 8 266 68.0 (15.0) 0.9 71.0 61.0, 79.0 16, 96 266 14.5 (11.4) 0.7 13.0 7.0, 20.0 -47, 53 WEEK 12 265 68.9 (15.6) 1.0 73.0 63.0, 80.0 7, 94 265 15.6 (12.1) 0.7 15.0 9.0, 22.0 -52, 60 WEEK 16 259 70.0 (15.8) 1.0 75.0 63.0, 81.0 9, 96 259 16.6 (12.5) 0.8 16.0 10.0, 23.0 -48, 57 WEEK 20 254 70.4 (15.8) 1.0 75.0 63.0, 81.0 8. 99 254 16.9 (12.6) 0.8 16.0 10.0, 24.0 -55, 55 WEEK 24 255 70.8 (16.1) 1.0 76.0 62.0, 82.0 7. 97 255 17.2 (12.8) 0.8 17.0 10.0, 24.0 -56. 54 WEEK 28 247 71.1 (16.2) 1.0 76.0 63.0, 82.0 6. 96 247 17.5 (13.3) 0.8 16.0 10.0, 25.0 -57. 56

WEEK 32 248 70.9 (16.2) 1.0 75.0 64.0, 82.0 7, 98 248 17.3 (13.0) 0.8 17.0 10.0, 25.0 -56, 56

WEEK 36 244 71.4 (16.0) 1.0 75.0 64.0, 83.0 3, 96 244 17.7 (13.4) 0.9 17.0 1 1.0, 26.0 -60, 55 Value at Visit Change from Baseline Treatment Visit n Mean (SD) SEM Median QI, Q3 Min, Max n Mean (SD) SEM Median QI, Q3 Min, Max 8q8/3 (N=266) BASELINE 266 55.2 (13.6) 0.8 57.0 47.0, 67.0 24, 73

WEEK 4 264 66.3 (13.6) 0.8 70.0 60.0, 75.0 22, 93 264 10.9 ( 8.8) 0.5 10.0 4.0, 16.0 -13, 38 WEEK 8 262 69.2 (14.6) 0.9 73.0 62.0, 79.0 6, 91 262 13.9 (10.0) 0.6 13.0 7.0, 20.0 -18, 40 WEEK 12 258 69.9 (15.2) 0.9 74.0 61.0, 80.0 5, 95 258 14.6 (11.0) 0.7 14.0 8.0, 21.0 -19, 60 WEEK 16 253 69.7 (15.8) 1.0 73.0 63.0, 80.0 0, 96 253 14.2 (11.5) 0.7 14.0 8.0, 21.0 -25, 44 WEEK 20 252 70.8 (15.5) 1.0 74.0 63.0, 81.0 5, 95 252 15.4 (11.4) 0.7 14.5 9.0, 22.0 -19, 50 WEEK 24 247 71.1 (15.3) 1.0 75.0 64.0, 80.0 4, 95 247 15.6 (11.6) 0.7 16.0 9.0, 21.0 -21, 45 WEEK 28 242 71.8 (15.4) 1.0 75.0 65.0, 82.0 0, 97 242 16.4 (11.8) 0.8 16.0 10.0, 23.0 -24, 49 WEEK 32 239 72.0 (14.9) 1.0 75.0 64.0, 83.0 5, 96 239 16.4 (11.8) 0.8 16.0 10.0, 23.0 -25, 50 WEEK 36 236 72.4 (14.6) 1.0 75.0 67.0, 82.0 7. 96 236 16.8 (11.8) 0.8 16.0 10.0, 23.5 -22, 50 8q8/5 (N=260) BASELINE 260 55.2 (13.8) 0.9 58.0 48.0, 66.5 18, 74

WEEK 4 255 67.3 (13.3) 0.8 70.0 61.0, 77.0 24, 91 255 11.9 ( 9.5) 0.6 11.0 6.0, 16.0 -27, 41 WEEK 8 251 70.4 (12.8) 0.8 73.0 63.0, 80.0 22, 95 251 15.0 (10.3) 0.7 14.0 9.0, 21.0 -20, 47 WEEK 12 247 71.7 (13.0) 0.8 75.0 65.0, 81.0 27, 93 247 16.2 (11.4) 0.7 16.0 10.0, 22.0 -23, 51 WEEK 16 244 72.7 (13.2) 0.8 76.5 66.5, 83.0 26, 96 244 17.3 (11.6) 0.7 17.0 10.0, 24.0 -35, 53 WEEK 20 234 73.5 (12.9) 0.8 78.0 67.0, 83.0 24, 98 234 17.8 (11.6) 0.8 17.0 11.0, 25.0 -30, 53 WEEK 24 236 72.7 (14.1) 0.9 77.0 65.5, 82.0 18, 99 236 17.2 (12.4) 0.8 17.0 10.0, 25.0 -34, 57 WEEK 28 231 73.6 (14.4) 0.9 78.0 67.0, 83.0 0, 99 231 18.0 (13.5) 0.9 18.0 11.0, 25.0 -60, 58 WEEK 32 223 73.8 (13.8) 0.9 78.0 69.0, 83.0 15, 98 223 18.5 (12.5) 0.8 17.0 11.0, 26.0 -34, 53

WEEK 36 216 74.5 (12.6) 0.9 78.0 69.0, 83.0 25, 99 216 19.0 (11.6) 0.8 18.0 12.0, 26.5 -14, 52 BCVA = Best corrected visual acuity; ETDRS = Early treatment diabetic retinopathy study; ICE = Intercurrent Event

OC (observed cases) excluding values after ICE (intercurrent event): observations after the occurrence of an ICE are excluded in line with the primary estimand strategy

2q4: Aflibercept 2mg administered every 4 weeks.

Table 1-8. Change from baseline in BCVA measured by the ETDRS letter score at Week 36, MMRM by RVO Type (full analysis set)

Population group: Non-China sub-population

Number of

participants p-value of

with week one-sided test

36 data: for non- p-value of

Arith. mean included/ex inferiority at a one-sided Estimate for Contrast

LS mean (SE) (SD) chg. Baseline eluded due margin of 4 test for and two-sided 95%

RVO Type _ Treatment _ chg. from BL from BL (a) mean (a) to ICE DF Contrast (b) t-value letters superiority CI (c)

BRVO 8q8/3 (N=139) 18.0 (0.8) 17.0 (10.7) 58.9 123/4 262.4 8q8/3 - 2q4 2.69 0.0039 0.7738 -0.9 (-3.2, 1.4)

8q8/5 (N=134) 19.3 (0.7) 19.5 (10.1) 58.6 111/11 240.9 8q8/5 - 2q4 3.96 <,0001 0.3718 0.4 (-1.8, 2.5) Number of participants p-value of with week one-sided test

36 data: for non- p-value of Arith. mean included/ex inferiority at a one-sided Estimate for Contrast

RVO Type Treatment chg. from BL from BL (a) mean (a) to ICE DF Contrast (b) t-value letters superiority CI (c)

2q4 (N=133) 18.9 (0.8) 19.4 (11.4) 56.7 117/8 CRVO/HRVO 8q8/3 (N=127) 16.7 (1.2) 16.6 (13.0) 51.1 113/7 255.0 8q8/3 - 2q4 2.72 0.0035 0.3352 0.7 (-2.7, 4.2)

8q8/5 (N=126) 17.4 (1.2) 18.5 (13.0) 51.7 105/7 248.8 8q8/5 - 2q4 3.13 0.0010 0.2078 1.4 (-2.0, 4.8)

2q4 (N=143) 16.0 (1.3) 16.2 (14.9) 50.5 127/8

BL = Baseline: CI = Confidence Interval: DF = Degrees of Freedom: ICE = Intercurrent Event: LS = Least Squares: SD = Standard Deviation: SE = Standard Error.

A mixed model for repeated measurements (MMRM) was used with baseline BCVA measurement as a covariate, treatment group, visit and the stratification variables (geographic

region [Japan vs. APAC vs. Europe vs. America] and baseline BCVA [<60 vs. >=60]) as fixed factors, and terms for the interaction between baseline BCVA and visit and treatment

and visit. Covariance structure used: unstructured covariance structure.

Intercurrent events were handled according to primary estimand strategy

(a) based on observed cases excluding data after ICE.

(b) The contrast also includes the interaction term for treatment x visit (at week 36).

(c) Estimate based on the MMRM, was computed for the differences of 8q8/3 minus 2q4 and 8q8/5 minus 2q4, respectively with two-sided 95% Cis.

2q4: Aflibercept 2mg administered every 4 weeks.

8q8/3: Aflibercept 8mg administered every⁷ 8 weeks, after 3 initial injections at 4-week intervals.

Table 1-9. Summary statistics for BCVA measured by the ETDRS letter score by RVO Type and visit, OC

excluding values after ICE (full analysis set)

Population group: Non-China sub-population

Value at Visit Change from Baseline

RVO Type Treatment Visit n Mean (SD) SEM Median Q1, Q3 Min, Max n Mean (SD) SEM Median QI, Q3 Min, Max BRVO 2q4 (N=133) BASELINE 133 56.7 (13.6) 1.2 61.0 49.0, 68.0 24, 73

WEEK 4 131 69.1 (11.9) 1.0 71.0 61.0, 78.0 31, 89 131 12.3 ( 9.7) 0.8 11.0 6.0, 17.0 -6. 43 WEEK 8 128 72.2 (11.3) 1.0 75.0 65.5, 80.0 36, 96 128 15.2 (10.6) 0.9 13.0 8.0, 20.0 -6. 50 WEEK 12 125 73.4 (12.0) 1.1 76.0 68.0, 82.0 29, 94 125 16.9 (11.2) 1.0 15.0 10.0, 22.0 -7. 55 WEEK 16 123 74.7 (11.7) 1.1 78.0 69.0. 83.0 34, 96 123 17.9 (11.5) 1.0 16.0 11.0, 24.0 -10. 57 WEEK 20 123 74.8 (11.9) 1.1 78.0 70.0, 83.0 30, 99 123 18.2 (11.1) 1.0 16.0 10.0, 24.0 -4, 55 WEEK 24 122 75.4 (11.9) 1.1 78.5 69.0, 83.0 33, 97 122 18.7 (11.1) 1.0 17.0 12.0, 23.0 -5, 54 WEEK 28 117 75.9 (11.8) 1.1 78.0 72.0, 83.0 32, 96 117 19.1 (11.0) 1.0 16.0 12.0, 25.0 -3, 55 WEEK 32 119 75.5 (12.0) 1.1 79.0 69.0, 84.0 33, 98 119 18.8 (10.4) 1.0 18.0 12.0, 24.0 -2, 55 WEEK 36 117 76.0 (11.5) 1.1 79.0 70.0, 84.0 31, 96 117 19.4 (11.4) 1.0 17.0 12.0, 26.0 -5, 55 Value at Visit Change from Baseline RVO Type Treatment Visit n Mean (SD) SEM Median Q1, Q3 Min, Max n Mean (SD) SEM Median QI, Q3 Min. Max 8q8/3 (N=139) BASELINE 139 58.9 (11.2) 1.0 60.0 53.0, 68.0 25, 73

WEEK 4 139 70.1 (10.8) 0.9 73.0 64.0, 78.0 32, 90 139 11.3 ( 8.8) 0.7 10.0 5.0, 17.0 -13, 38 WEEK 8 138 73.3 (11.0) 0.9 76.0 69.0, 80.0 34, 91 138 14.5 ( 9.3) 0.8 14.0 8.0, 20.0 -4, 40 WEEK 12 135 74.6 (11.5) 1.0 77.0 70.0, 82.0 31, 95 135 15.7 (10.6) 0.9 15.0 9.0, 21.0 -8, 60 WEEK 16 131 74.0 (12.1) 1.1 76.0 69.0, 82.0 30, 95 131 14.9 ( 9.9) 0.9 14.0 8.0, 20.0 -14. 44 WEEK 20 131 75.2 (11.5) 1.0 77.0 70.0, 83.0 29, 95 131 16.0 ( 9.2) 0.8 15.0 10.0, 22.0 -2. 44 WEEK 24 130 75.5 (11.3) 1.0 78.0 70.0, 83.0 28, 95 130 16.3 (10.0) 0.9 16.0 10.0, 21.0 -18. 45 WEEK 28 127 76.2 (10.7) 0.9 78.0 70.0, 84.0 33, 97 127 17.0 ( 9.9) 0.9 17.0 10.0, 21.0 -8. 49 WEEK 32 125 75.6 (11.2) 1.0 78.0 71.0, 83.0 33, 96 125 16.2 (11.0) 1.0 16.0 10.0, 22.0 -16. 50 WEEK 36 123 76.2 (11.1) 1.0 78.0 71.0, 84.0 26, 96 123 17.0 (10.7) 1.0 16.0 10.0, 23.0 -22. 50

8q8/5 (N=134) BASELINE 134 58.6 (11.9) 1.0 61.5 52.0, 69.0 28, 73

WEEK 4 131 70.2 (10.9) 1.0 73.0 63.0, 79.0 30, 86 131 11.4 ( 7.6) 0.7 10.0 6.0, 15.0 -7, 41 WEEK 8 130 73.9 (10.1) 0.9 76.0 67.0, 81.0 44, 95 130 14.8 ( 9.0) 0.8 14.0 9.0, 20.0 -9, 47 WEEK 12 127 75.2 ( 9.7) 0.9 77.0 69.0, 82.0 48, 93 127 16.1 ( 9.5) 0.8 16.0 10.0, 22.0 -8, 47 WEEK 16 127 76.8 ( 9.9) 0.9 79.0 70.0, 84.0 49, 96 127 17.7 ( 9.8) 0.9 18.0 12.0, 23.0 -6, 53 WEEK 20 120 77.4 ( 9.2) 0.8 79.0 72.0, 84.0 49, 98 120 18.0 ( 9.5) 0.9 16.5 12.0, 24.5 -3, 53 WEEK 24 123 76.7 (11.2) 1.0 79.0 71.0, 84.0 18, 99 123 17.6 (11.2) 1.0 17.0 12.0, 24.0 -34. 57 WEEK 28 121 76.9 (13.2) 1.2 80.0 73.0, 84.0 0, 99 121 17.9 (13.6) 1.2 18.0 12.0, 25.0 -60. 58 WEEK 32 115 77.7 (10.7) 1.0 79.0 73.0, 85.0 18, 98 115 18.8 (11.6) 1.1 18.0 13.0, 25.0 -34. 53 WEEK 36 111 78.4 ( 9.3) 0.9 80.0 73.0, 84.0 51, 99 111 19.5 (10.1) 1.0 18.0 13.0, 26.0 -4. 52 CRVO/HRVO 2q4 (N=143) BASELINE 143 50.5 (14.7) 1.2 54.0 38.0, 62.0 24, 73

WEEK 4 141 62.0 (16.6) 1.4 66.0 55.0, 74.0 3, 93 141 11.6 (11.2) 0.9 11.0 5.0, 17.0 -35, 46 WEEK 8 138 64.1 (16.9) 1.4 68.0 56.0, 77.0 16, 93 138 13.8 (12.2) 1.0 13.5 6.0, 21.0 -47, 53 WEEK 12 140 64.9 (17.3) 1.5 67.0 57.5, 79.0 7, 94 140 14.5 (12.8) 1.1 14.5 8.0, 22.0 -52, 60 WEEK 16 136 65.7 (17.7) 1.5 69.5 57.5, 79.0 9, 95 136 15.4 (13.4) 1.1 16.0 8.0, 23.0 -48, 55 WEEK 20 131 66.2 (17.8) 1.6 70.0 58.0, 79.0 8, 96 131 15.6 (13.8) 1.2 16.0 9.0, 24.0 -55, 44 WEEK 24 133 66.5 (18.2) 1.6 70.0 59.0, 79.0 7, 97 133 15.9 (14.1) 1.2 17.0 8.0, 24.0 -56, 44 WEEK 28 130 66.9 (18.4) 1.6 71.0 60.0, 80.0 6, 95 130 16.1 (15.0) 1.3 16.0 8.0, 24.0 -57, 56 WEEK 32 129 66.6 (18.4) 1.6 70.0 60.0, 79.0 7, 97 129 15.9 (14.8) 1.3 17.0 7.0, 25.0 -56. 56 WEEK 36 127 67.1 (18.3) 1.6 72.0 60.0, 80.0 3, 96 127 16.2 (14.9) 1.3 16.0 8.0, 26.0 -60. 50 8q8/3 (N=127) BASELINE 127 51.1 (14.8) 1.3 52.0 40.0, 63.0 24, 73

WEEK 4 125 62.0 (15.2) 1.4 65.0 54.0, 73.0 22, 93 125 10.6 ( 8.8) 0.8 10.0 4.0, 15.0 -10, 36 WEEK 8 124 64.5 (16.5) 1.5 69.0 56.0, 76.5 6, 89 124 13.2 (10.7) 1.0 13.0 6.0, 20.0 -18, 40 WEEK 12 123 64.7 (17.1) 1.5 69.0 55.0, 77.0 5, 92 123 13.4 (11.4) 1.0 14.0 8.0, 20.0 -19, 41 WEEK 16 122 65.0 (17.9) 1.6 69.0 58.0, 79.0 0, 96 122 13.5 (12.9) 1.2 14.0 7.0, 21.0 -25, 41 WEEK 20 121 66.2 (17.8) 1.6 70.0 59.0, 79.0 5, 95 121 14.7 (13.4) 1.2 14.0 8.0, 22.0 -19, 50 WEEK 24 117 66.1 (17.5) 1.6 70.0 58.0, 79.0 4, 95 117 14.8 (13.2) 1.2 15.0 9.0, 22.0 -21, 45 WEEK 28 115 66.8 (18.1) 1.7 70.0 59.0, 80.0 0, 95 115 15.7 (13.5) 1.3 15.0 10.0, 24.0 -24, 46 WEEK 32 114 68.0 (17.3) 1.6 71.5 59.0, 81.0 5, 94 114 16.6 (12.7) 1.2 17.0 10.0, 23.0 -25, 48 WEEK 36 113 68.2 (16.8) 1.6 71.0 60.0, 80.0 7, 93 113 16.6 (13.0) 1.2 16.0 9.0, 24.0 -21, 47 Value at Visit Change from Baseline RVO Type Treatment Visit n Mean (SD) SEM Median Q1, Q3 Min, Max n Mean (SD) SEM Median QI, Q3 Min. Max 8q8/5 (N=126) BASELINE 126 51.7 (14.7) 1.3 55.5 40.0, 63.0 18, 74

WEEK 4 124 64.3 (14.9) 1.3 68.5 56.0, 74.5 24, 91 124 12.4 (11.2) 1.0 12.0 5.5, 19.0 -27, 40 WEEK 8 121 66.5 (14.2) 1.3 69.0 59.0, 77.0 22, 90 121 15.1 (11.6) 1.1 14.0 9.0, 22.0 -20, 42 WEEK 12 120 68.1 (15.0) 1.4 71.0 61.0, 80.0 27, 88 120 16.3 (13.1) 1.2 16.0 9.0, 23.0 -23, 51 WEEK 16 117 68.3 (14.9) 1.4 71.0 61.0, 80.0 26, 90 117 16.9 (13.2) 1.2 17.0 9.0, 24.0 -35. 53 WEEK 20 114 69.5 (15.0) 1.4 72.0 61.0, 82.0 24, 88 114 17.6 (13.6) 1.3 17.5 10.0, 27.0 -30. 48 WEEK 24 113 68.3 (15.7) 1.5 73.0 58.0, 80.0 20, 90 113 16.8 (13.5) 1.3 17.0 8.0, 26.0 -17. 53 WEEK 28 110 70.0 (14.9) 1.4 73.0 60.0, 82.0 14, 91 110 18.1 (13.3) 1.3 18.0 9.0, 27.0 -16. 51 WEEK 32 108 69.6 (15.4) 1.5 72.5 61.5, 80.0 15, 93 108 18.2 (13.4) 1.3 17.0 9.0, 28.5 -15. 48

WEEK 36 105 70.3 (14.2) 1.4 74.0 63.0, 82.0 25, 91 105 18.5 (13.0) 1.3 17.0 9.0, 28.0 -14. 50 BCVA = Best corrected visual acuity; BRVO = Branch retinal vein occlusion; CRVO = Central retinal vein occlusion; ETDRS = Early treatment diabetic retinopathy study; HRVO = Hemiretinal vein occlusion; ICE = Intercurrent Event; RVO = Retinal vein occlusion

2q4: Aflibercept 2mg administered every 4 weeks.

Table 1-10. Summary statistics for CST (urn) by visit, OC excluding values after ICE (full analysis set)

Population group: Non-China sub-population

_ Value at Visit Change from Baseline

Treatment Visit _ n _ Mean (SD) _ SEM Median _ QI, Q3 _ Min, Max _ n _ Mean (SD) _ SEM Median _ QI, Q3 _ Min, Max 2q4 (N=276) BASELINE 275 654.2 (239.5) 14.4 610.0 473.0, 767.0 302, 1601

WEEK 4 270 296.9 ( 82.2) 5.0 282.0 256.0, 307.0 119, 856 269 -355.6 (233.2) 14.2 -326.0 -459.0, -183.0 -1305, 246 WEEK 8 266 270.2 ( 56.5) 3.5 264.0 238.0, 291.0 115, 584 265 -381.0 (250.7) 15.4 -341.0 -510.0, -193.0 -1379, 127 WEEK 12 264 266.5 ( 64.1) 3.9 259.0 233.5, 287.0 47, 811 263 -389.0 (251.9) 15.5 -353.0 -516.0, -200.0 -1462, 72 WEEK 16 259 263.3 ( 59.5) 3.7 258.0 231.0, 282.0 20, 667 258 -393.3 (257.8) 16.0 -346.0 -525.0, -202.0 -1459, 120 WEEK 20 254 261.0 ( 60.6) 3.8 254.0 228.0, 281.0 23, 766 253 -394.8 (252.6) 15.9 -352.0 -525.0, -207.0 -1440, -4 WEEK 24 254 263.3 ( 73.8) 4.6 256.0 226.0, 281.0 20, 880 253 -393.9 (256.4) 16.1 -353.0 -524.0, -197.0 -1458, 134 WEEK 28 247 263.2 ( 72.4) 4.6 257.0 228.0, 281.0 17, 798 246 -394.3 (255.1) 16.3 -346.0 -528.0, -213.0 -1462, 71 WEEK 32 248 259.6 ( 67.1) 4.3 253.0 226.5, 277.0 29, 816 247 -397.7 (258.7) 16.5 -350.0 -530.0, -202.0 -1443, 110 WEEK 36 243 257.9 ( 67.2) 4.3 251.0 227.0. 277.0 26. 682 242 -400.2 (257.5) 16.6 -357.0 -532.0, -204.0 -1434, 74 Value at Visit Change from Baseline Treatment Visit n Mean (SD) SEM Median QI, Q3 Min, Max n Mean (SD) SEM Median QI, Q3 Min, Max 8q8/3 (N=266) BASELINE 266 626.0 (230.6) 14.1 572.0 458.0, 754.0 272, 1499

WEEK 4 262 288.4 ( 51.2) 3.2 283.5 260.0, 308.0 187, 582 262 -333.0 (224.7) 13.9 -292.5 -463.0, -171.0 -1253, 28 WEEK 8 262 271.5 ( 48.1) 3.0 268.5 244.0, 296.0 168, 512 262 -351.6 (234.2) 14.5 -304.0 -499.0, -180.0 -1261, -7 WEEK 12 258 266.3 ( 46.9) 2.9 265.0 239.0, 291.0 161, 554 258 -354.0 (237.3) 14.8 -305.0 -492.0, -178.0 -1264, -9 WEEK 16 253 291.1 ( 97.6) 6.1 269.0 240.0, 299.0 155, 793 253 -328.5 (234.9) 14.8 -286.0 -452.0, -167.0 -1212, 117 WEEK 20 252 261.6 ( 45.5) 2.9 261.0 233.5, 287.0 148, 530 252 -357.4 (234.6) 14.8 -311.0 -496.5, -180.0 -1246, 2 WEEK 24 246 270.1 ( 66.2) 4.2 262.0 236.0, 287.0 143, 717 246 -348.9 (242.4) 15.5 -300.0 -492.0, -168.0 -1244, 445 WEEK 28 241 259.4 ( 47.7) 3.1 258.0 232.0, 281.0 142, 583 241 -364.2 (237.0) 15.3 -314.0 -512.0, -186.0 -1254, 12 WEEK 32 239 265.0 ( 60.6) 3.9 259.0 234.0, 286.0 147, 765 239 -355.9 (242.7) 15.7 -313.0 -500.0, -179.0 -1250, 194 WEEK 36 236 259.7 ( 55.9) 3.6 257.0 231.0. 281.5 149. 804 236 -362.6 (239.5) 15.6 -318.0 -503.0, -186.5 -1259, 233

8q8/5 (N=260) BASELINE 260 612.4 (216.9) 13.5 569.0 451.5, 745.0 268, 1424

WEEK 4 253 286.1 ( 40.9) 2.6 281.0 260.0, 309.0 145, 537 253 -323.7 (215.2) 13.5 -279.0 -450.0, -150.0 -1102, -26 WEEK 8 251 272.9 ( 41.5) 2.6 270.0 248.0, 295.0 141, 589 251 -339.5 (220.4) 13.9 -296.0 -463.0, -166.0 -1129, -13 WEEK 12 247 266.2 ( 35.8) 2.3 265.0 243.0, 287.0 133, 383 247 -343.8 (220.5) 14.0 -293.0 -468.0, -173.0 -1124, -24 WEEK 16 244 264.6 ( 37.1) 2.4 261.5 241.0, 286.0 135, 386 244 -347.0 (224.8) 14.4 -299.0 -477.0, -171.5 -1152, -22 WEEK 20 233 261.5 ( 38.2) 2.5 258.0 238.0, 282.0 137, 405 233 -345.1 (218.6) 14.3 -304.0 -479.0, -169.0 -1162, -21 WEEK 24 235 276.1 ( 76.2) 5.0 262.0 238.0, 287.0 131, 932 235 -333.0 (232.5) 15.2 -269.0 -467.0, -151.0 -1125, 117 WEEK 28 230 260.7 ( 38.3) 2.5 258.5 234.0, 282.0 128, 408 230 -347.6 (226.5) 14.9 -294.5 -485.0, -166.0 -1138, -20 WEEK 32 222 266.0 ( 57.1) 3.8 259.0 234.0, 285.0 131, 731 222 -348.0 (235.3) 15.8 -306.0 -487.0, -169.0 -1142, 194 WEEK 36 215 260.2 ( 38.4) 2.6 257.0 233.0, 283.0 127, 413 215 -355.1 (229.5) 15.7 -307.0 -491.0, -181.0 -1146, -8 CST = Central subfield thickness: ICE = Intercurrent Event

OC (observed cases) excluding values after ICE (intercurrent event): observations after the occurrence of an ICE are excluded in line with the primary estimand strategy.

2q4: Aflibercept 2mg administered every 4 weeks.

Table 1-11. Summary statistics for CST (urn) by RVO Type and visit, OC excluding values after ICE (full analysis set) Population group: Non-China sub-population Value at Visit Change from Baseline

RVO Type _ Treatment _ Visit _ n _ Mean (SD) SEM Median _ QI, Q3 _ Min, Max n _ Mean (SD) SEM Median _ QI, Q3 _ Min, Max BRVO 2q4(N=133) BASELINE 133 555.8 (172.8) 15.0 545.0 422.0, 653.0 302, 1036

WEEK 4 130 285.4 ( 66.0) 5.8 276.5 248.0, 300.0 194, 662 130 -267.9 (177.9) 15.6 -256.5 -372.0, -150.0 -835, 246 WEEK 8 128 268.5 ( 53.5) 4.7 260.5 237.5, 288.0 186, 560 128 -281.6 (178.2) 15.8 -267.0 -376.0, -153.0 -843, 127 WEEK 12 124 267.1 ( 50.5) 4.5 258.5 237.0, 288.0 182, 477 124 -285.1 (177.9) 16.0 -273.0 -383.5, -154.0 -740, 72 WEEK 16 123 266.5 ( 51.5) 4.6 258.0 234.0, 286.0 177, 467 123 -287.3 (185.7) 16.7 -266.0 -384.0, -154.0 -832, 120 WEEK 20 123 262.6 ( 47.4) 4.3 254.0 234.0, 281.0 177, 494 123 -295.3 (184.2) 16.6 -277.0 -413.0, -155.0 -833, -4 WEEK 24 122 262.7 ( 50.0) 4.5 256.5 232.0, 282.0 181, 460 122 -291.9 (184.5) 16.7 -278.0 -388.0, -151.0 -834, 134 WEEK 28 117 261.9 ( 50.1) 4.6 257.0 232.0, 280.0 183, 516 117 -295.5 (184.6) 17.1 -281.0 -380.0, -162.0 -838, 71 WEEK 32 119 261.2 ( 48.9) 4.5 254.0 231.0, 279.0 182, 444 119 -295.3 (186.6) 17.1 -279.0 -380.0, -159.0 -849, 110 WEEK 36 117 259.7 ( 45.9) 4.2 255.0 230.0, 278.0 180, 418 117 -296.8 (186.3) 17.2 -281.0 -386.0, -156.0 -850, 74 8q8/3 (N=139) BASELINE 139 544.1 (165.1) 14.0 522.0 421.0, 640.0 272, 1008

WEEK 4 138 283.7 ( 50.7) 4.3 279.0 259.0, 302.0 187, 515 138 -257.6 (166.8) 14.2 -229.0 -350.0, -125.0 -698, 28 WEEK 8 138 269.7 ( 52.5) 4.5 264.0 241.0, 288.0 170, 512 138 -274.8 (177.5) 15.1 -244.5 -379.0, -136.0 -765, -7 WEEK 12 135 266.6 ( 48.8) 4.2 264.0 236.0, 286.0 169, 508 135 -272.3 (174.5) 15.0 -250.0 -348.0, -138.0 -772, -9 WEEK 16 131 292.1 ( 93.7) 8.2 269.0 240.0, 299.0 167, 783 131 -247.5 (171.6) 15.0 -223.0 -344.0, -125.0 -776, 63 WEEK 20 131 265.9 ( 52.6) 4.6 261.0 233.0, 289.0 168, 530 131 -273.5 (173.7) 15.2 -238.0 -367.0, -140.0 -779, 2 WEEK 24 129 278.0 ( 78.4) 6.9 264.0 241.0, 292.0 164, 717 129 -258.5 (180.6) 15.9 -235.0 -346.0, -135.0 -779, 445 WEEK 28 127 263.3 ( 54.5) 4.8 258.0 234.0, 280.0 163, 583 127 -278.7 (174.2) 15.5 -246.0 -374.0, -157.0 -786, 12 WEEK 32 125 272.1 ( 72.7) 6.5 260.0 239.0, 285.0 166, 765 125 -266.0 (177.8) 15.9 -233.0 -367.0, -141.0 -786, 194 WEEK 36 123 265.5 ( 68.1) 6.1 258.0 237.0, 275.0 161, 804 123 -275.1 (175.6) 15.8 -236.0 -382.0, -145.0 -781, 233 8q8/5 (N=134) BASELINE 134 542.4 (159.5) 13.8 509.0 429.0, 637.0 268, 1160

WEEK 4 131 286.2 ( 44.0) 3.8 281.0 259.0, 308.0 206, 537 131 -255.0 (158.6) 13.9 -233.0 -355.0, -133.0 -911, -26 WEEK 8 130 272.9 ( 37.3) 3.3 269.0 248.0, 294.0 155, 390 130 -266.3 (162.1) 14.2 -235.0 -362.0, -145.0 -930, -13 WEEK 12 127 268.8 ( 36.5) 3.2 266.0 246.0, 290.0 145, 382 127 -271.8 (163.6) 14.5 -244.0 -370.0, -148.0 -926, -24 WEEK 16 127 267.6 ( 37.1) 3.3 263.0 241.0, 289.0 149, 386 127 -273.4 (163.6) 14.5 -240.0 -374.0, -149.0 -925, -22 WEEK 20 119 263.4 ( 37.4) 3.4 258.0 238.0, 284.0 147, 382 119 -271.2 (159.0) 14.6 -240.0 -365.0, -148.0 -929, -21 WEEK 24 122 273.2 ( 50.5) 4.6 268.0 241.0, 288.0 150, 488 122 -263.6 (165.7) 15.0 -229.0 -367.0, -143.0 -924, -6 WEEK 28 120 263.8 ( 38.2) 3.5 259.0 237.0, 286.0 151, 383 120 -276.3 (165.0) 15.1 -240.5 -369.5, -151.5 -926, -20 WEEK 32 114 267.0 ( 41.1) 3.9 262.5 240.0, 286.0 151, 431 114 -276.1 (167.2) 15.7 -238.0 -372.0, -158.0 -929, -12 WEEK36 111 264.0 ( 38.3) 3.6 257.0 235.0, 286.0 199, 387 111 -284.1 (166.8) 15.8 -255.0 -377.0, -156.0 -927, -8 CRVO/HRVO 2q4 (N=143) BASELINE 142 746.4 (256.5) 21.5 699.0 573.0, 892.0 316, 1601

WEEK 4 140 307.5 ( 93.7) 7.9 284.5 263.0, 316.0 119, 856 139 -437.6 (249.0) 21.1 -409.0 -572.0, -267.0 -1305, 11 WEEK 8 138 271.8 ( 59.3) 5.0 269.0 238.0, 292.0 115, 584 137 -474.0 (272.6) 23.3 -431.0 -595.0, -297.0 -1379, -9 WEEK 12 140 265.9 ( 74.3) 6.3 259.5 228.5, 282.5 47, 811 139 -481.7 (271.9) 23.1 -445.0 -600.0, -306.0 -1462, -9 WEEK 16 136 260.4 ( 66.0) 5.7 256.5 229.0, 280.5 20, 667 135 -489.9 (276.3) 23.8 -447.0 -621.0, -308.0 -1459, -39 WEEK 20 131 259.5 ( 71.0) 6.2 254.0 226.0, 280.0 23, 766 130 -488.9 (272.4) 23.9 -444.0 -607.0, -313.0 -1440, -37 WEEK 24 132 263.8 ( 90.6) 7.9 256.0 224.0, 280.0 20, 880 131 -489.0 (277.2) 24.2 -445.0 -611.0, -313.0 -1458, -43 WEEK 28 130 264.4 ( 88.0) 7.7 256.5 226.0, 284.0 17, 798 129 -484.0 (276.8) 24.4 -441.0 -599.0, -311.0 -1462, -41 WEEK 32 129 258.1 ( 80.6) 7.1 249.0 223.0, 277.0 29, 816 128 -492.9 (279.8) 24.7 -447.5 -615.5, -315.5 -1443, -43 WEEK 36 126 256.3 ( 82.4) 7.3 248.0 226.0, 274.0 26, 682 125 -496.9 (277.2) 24.8 -458.0 -619.0, -314.0 -1434, -44 Value at Visit Change from Baseline RVO Type Treatment Visit n Mean (SD) SEM Median Q1, Q3 Min, Max n Mean (SD) SEM Median QI, Q3 Min. Max 8q8/3 (N=127) BASELINE 127 715.6 (257.9) 22.9 677.0 527.0, 858.0 305, 1499

WEEK 4 124 293.6 ( 51.4) 4.6 293.0 262.5, 313.0 194, 582 124 -417.0 (250.3) 22.5 -384.5 -541.5, -241.5 -1253, -35 WEEK 8 124 273.4 ( 42.9) 3.8 276.0 248.0, 299.5 168, 461 124 -437.1 (259.4) 23.3 -401.5 -578.0, -251.0 -1261, -40 WEEK 12 123 265.9 ( 44.9) 4.0 267.0 244.0, 292.0 161, 554 123 -443.6 (263.9) 23.8 -407.0 -578.0, -252.0 -1264, -43 WEEK 16 122 290.0 (102.0) 9.2 271.5 240.0, 300.0 155, 793 122 -415.5 (261.8) 23.7 -383.5 -564.0, -206.0 -1212, 117 WEEK 20 121 257.0 ( 35.8) 3.3 259.0 235.0, 283.0 148, 369 121 -448.1 (257.9) 23.4 -420.0 -604.0, -257.0 -1246, -40 WEEK 24 117 261.3 ( 48.3) 4.5 260.0 234.0, 284.0 143, 568 117 -448.5 (262.6) 24.3 -418.0 -610.0, -256.0 -1244, -37 WEEK 28 114 255.1 ( 38.4) 3.6 256.5 230.0, 281.0 142, 384 114 -459.4 (260.9) 24.4 -440.5 -631.0, -273.0 -1254, -42 WEEK 32 114 257.2 ( 42.6) 4.0 255.5 230.0, 286.0 147, 392 114 -454.4 (265.8) 24.9 -437.0 -635.0, -260.0 -1250, -41 WEEK 36 113 253.5 ( 37.8) 3.6 256.0 227.0, 283.0 149, 389 113 -457.9 (263.0) 24.7 -439.0 -632.0, -272.0 -1259, -38

8q8/5 (N=126) BASELINE 126 686.8 (244.1) 21.7 634.5 489.0, 879.0 313, 1424

WEEK 4 122 286.1 ( 37.6) 3.4 284.5 262.0, 309.0 145, 414 122 -397.5 (242.5) 22.0 -350.5 -576.0, -209.0 -1102, -26 WEEK 8 121 272.9 ( 45.8) 4.2 271.0 248.0, 296.0 141, 589 121 -418.2 (246.7) 22.4 -378.0 -596.0, -230.0 -1129, -35 WEEK 12 120 263.5 ( 35.0) 3.2 263.0 242.0, 286.0 133, 383 120 -420.0 (246.6) 22.5 -372.5 -623.5, -222.5 -1124, -37 WEEK 16 117 261.4 ( 37.0) 3.4 261.0 240.0, 284.0 135, 384 117 -427.0 (253.8) 23.5 -370.0 -615.0, -230.0 -1152, -37 WEEK 20 114 259.6 ( 39.1) 3.7 258.5 238.0, 280.0 137, 405 114 -422.2 (244.9) 22.9 -379.5 -602.0, -233.0 -1162, -37 WEEK 24 113 279.2 ( 96.7) 9.1 260.0 235.0, 285.0 131, 932 113 -407.9 (269.0) 25.3 -347.0 -624.0, -203.0 -1125, 117 WEEK 28 110 257.3 ( 38.2) 3.6 257.0 231.0, 276.0 128, 408 110 -425.3 (257.7) 24.6 -365.0 -623.0, -221.0 -1138, -40 WEEK 32 108 265.0 ( 70.3) 6.8 256.0 230.0, 283.0 131, 731 108 -423.7 (271.2) 26.1 -375.0 -631.5, -217.5 -1142, 194 WEEK 36 104 256.2 ( 38.4) 3.8 254.5 232.0, 276.5 127, 413 104 -431.0 (261.7) 25.7 -375.5 -647.0, -218.5 -1146, -38 BRVO = Branch retinal vein occlusion: CRVO = Central retinal vein occlusion; CST = Central subfield thickness; HRVO = Hemiretinal vein occlusion; ICE = Intercurrent Event; RVO = Retinal vein occlusion

2q4: Aflibercept 2mg administered every 4 weeks.

Table 1-12. Adverse events: overall summary of number of participants (safety analysis set)

Population group: Non-China sub-population

2q4 8q8/3 8q8/5 All 8mg

N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%)

Number (%) of participants with adverse events

Any AE 193 ( 69.9%) 182 ( 68.4%) 179 ( 68.8%) 361 ( 68.6%)

Any pre-treatment AE 20 ( 7.2%) 25 ( 9.4%) 26 ( 10.0%) 51 ( 9.7%)

Any TEAE 190 ( 68.8%) 179 ( 67.3%) 169 ( 65.0%) 348 ( 66.2%)

Any post-treatment AE 1 ( 0.4%) 0.8%) 3 ( 1.2%) 5 ( 1.0%)

Any ocular AE 95 ( 34.4%) 110 ( 41.4%) 86 ( 33.1%) 196 ( 37.3%)

Study eye 82 ( 29.7%) 97 ( 36.5%) 79 ( 30.4%) 176 ( 33.5%)

Fellow eye 48 ( 17.4%) 52 ( 19.5%) 40 ( 15.4%) 92 ( 17.5%)

Any non-ocular AE 145 ( 52.5%) 135 ( 50.8%) 146 ( 56.2%) 281 ( 53.4%) 2q4 8q8/3 8q8/5 All 8mg N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%) Any ocular TEAE 94 ( 34.1%) 107 ( 40.2%) 83 ( 31.9%) 190 ( 36.1%) Study eye 81 ( 29.3%) 94 ( 35.3%) 75 ( 28.8%) 169 ( 32.1%) Fellow eye 46 ( 16.7%) 45 ( 16.9%) 37 ( 14.2%) 82 ( 15.6%) Any non-ocular TEAE 141 ( 51.1%) 128 ( 48.1%) 137 ( 52.7%) 265 ( 50.4%) Any intervention-related TEAE 6 ( 2.2%) 12 ( 4.5%) 3 ( 1.2%) 15 ( 2.9%) Any ocular intervention-related TEAE 6 ( 2.2%) 10 ( 3.8%) 3 ( 1.2%) 13 ( 2.5%) Study eye 6 ( 2.2%) 10 ( 3.8%) 3 ( 1.2%) 13 ( 2.5%) Fellow eye 0 0 0 0 Any non-ocular intervention-related TEAE 0 2 ( 0.8%) 0 2 ( 0.4%) Any TEAE related to injection procedure 17 ( 6.2%) 32 ( 12.0%) 20 ( 7.7%) 52 ( 9.9%) Any ocular TEAE related to injection procedure 16 ( 5.8%) 32 ( 12.0%) 20 ( 7.7%) 52 ( 9.9%) Study eye 16 ( 5.8%) 32 ( 12.0%) 20 ( 7.7%) 52 ( 9.9%) Fellow eye 0 1 ( 0.4%) 0 1 ( 0.2%) Any non-ocular TEAE related to injection procedure 1 ( 0.4%) 0 0

Any TEAE related to protocol-required procedure 5 ( 1.8%) 8 ( 3.0%) 11 ( 4.2%) 3.6%) Any ocular TEAE related to protocol-required procedure 3 ( 1.1%) 4 ( 1.5%) 6 ( 2.3%) 1.9%) Study eye 3 ( 1.1%) 4 ( 1.5%) 6 ( 2.3%) 1.9%) Fellow eye 0 0 0

Any non-ocular TEAE related to protocol-required procedure 2 ( 0.7%) 4 ( 1.5%) 5 ( 1.9%) 1.7%) Any TEAE related to commercial aflibercept 2mg (of fellow eye) 0 0 0 0 Any ocular TEAE related to commercial aflibercept 2mg (of fellow eye) 0 0 0 0 Study eye 0 0 0 0 Fellow eye 0 0 0 0 Any non-ocular TEAE related to commercial aflibercept 2mg (of fellow eye) 0 0 0 0 Any TEAE leading to discontinuation of intervention 3 ( 1.1%) 2 ( 0.8%) 1.2%) 5 ( 1.0%) Any ocular TEAE leading to discontinuation of intervention 0 0 0.4%) 1 ( 0.2%) Study eye 0 0 0.4%) 1 ( 0.2%) Fellow eye 0 0 0 Any non-ocular TEAE leading to discontinuation of intervention 3 ( 1.1%) 2 ( 0.8%) 0.8%) 4 ( 0.8%) Any TEAE related to medical device 0 1 ( 0.4%) 1 ( 0.2%) Any ocular TEAE related to medical device 0 1 ( 0.4%) 1 ( 0.2%) Study eye 0 1 ( 0.4%) 1 ( 0.2%) Fellow eye 0 0 0 Any non-ocular TEAE related to medical device 0 0 0 A

ny TEAE of special interest 9 ( 3.3%) 1 ( 0.4%) 5 ( 1.0%) Any TEAE of APTC events 5 ( 1.8%) 0 3 ( 1.2%) 3 ( 0.6%) Any TEAE of hypertension 13 ( 4.7%) 22 ( 8.3%) 22 ( 8.5%) 44 ( 8.4%) Any TEAE of intraocular inflammation of study eye 4 ( 1.4%) 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) 2q4 8q8/3 8q8/5 All 8mg N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%) Any TEAE of nasal mucosal finding 2 ( 0.7%) 2 ( 0.8%) 1 ( 0.4%) 3 ( 0.6%) Maximum intensity for any ocular TEAE

Study eye

Mild 57 ( 20.7%) 69 ( 25.9%) 57 ( 21.9%) 126 ( 24.0%) Moderate 20 ( 7.2%) 23 ( 8.6%) 15 ( 5.8%) 38 ( 7.2%) Severe 4 ( 1.4%) 2 ( 0.8%) 3 ( 1.2%) 5 ( 1.0%) Fellow eye

Mild 33 ( 12.0%) 32 ( 12.0%) 30 ( 11.5%) 62 ( 11.8%) Moderate 13 ( 4.7%) 12 ( 4.5%) 7 ( 2.7%) 19 ( 3.6%) Severe 0 1 ( 0.4%) 0 1 ( 0.2%) Maximum intensity for any non-ocular TEAE

Mild 80 ( 29.0%) 80 ( 30.1%) 85 ( 32.7%) 165 ( 31.4%) Moderate 47 ( 17.0%) 35 ( 13.2%) 41 ( 15.8%) 76 ( 14.4%) Severe 14 ( 5.1%) 13 ( 4.9%) 11 ( 4.2%) 24 ( 4.6%) Any SAE 30 ( 10.9%) 24 ( 9.0%) 27 ( 10.4%) 51 ( 9.7%) Any pre-treatment SAE 2 ( 0.7%) 0 4 ( 1.5%) 4 ( 0.8%) Any TESAE 28 ( 10.1%) 23 ( 8.6%) 22 ( 8.5%) 45 ( 8.6%) Any post-treatment SAE 1 ( 0.4%) 2 ( 0.8%) 2 ( 0.8%) 4 ( 0.8%) Any ocular SAE 7 ( 2.5%) 4 ( 1.5%) 4 ( 1.5%) 8 ( 1.5%) Study eye 7 ( 2.5%) 3 ( 1.1%) 4 ( 1.5%) 7 ( 1.3%) Fellow eye 0 1 ( 0.4%) 0 1 ( 0.2%) Any non-ocular SAE 23 ( 8.3%) 21 ( 7.9%) 23 ( 8.8%) 44 ( 8.4%) Any ocular TESAE 6 ( 2.2%) 4 ( 1.5%) 4 ( 1.5%) 8 ( 1.5%) Study eye 6 ( 2.2%) 3 ( 1.1%) 4 ( 1.5%) 7 ( 1.3%) Fellow eye 0 1 ( 0.4%) 0 1 ( 0.2%) Any non-ocular TESAE 22 ( 8.0%) 20 ( 7.5%) 18 ( 6.9%) 38 ( 7.2%) Any intervention-related TESAE 2 ( 0.7%) 0 1 ( 0.4%) 1 ( 0.2%) Any ocular intervention-related TESAE 2 ( 0.7%) 0 1 ( 0.4%) 1 ( 0.2%) Study eye 2 ( 0.7%) 0 1 ( 0.4%) 1 ( 0.2%) Fellow eye 0 0 0 0 Any non-ocular intervention-related TESAE 0 0 0 0 Any TESAE related to injection procedure 3 ( 1.1%) 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Any ocular TESAE related to injection procedure 3 ( 1.1%) 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Study eye 3 ( 1.1%) 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Fellow eye 0 0 0 0 Any non-ocular TESAE related to injection procedure 0 0 0 0 Any TESAE related to protocol-required procedure 0 0 0 0 Any ocular TESAE related to protocol-required procedure 0 0 0 0 Study eye 0 0 0 0 2q4 8q8/3 8q8/5 All 8mg N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%) Fellow eye 0 0 0 0 Any non-ocular TESAE related to protocol-required procedure 0 0 0 0 Any TESAE related to commercial aflibercept 2mg (of fellow eye) 0 0 0 0 Any ocular TESAE related to commercial aflibercept 2mg (of fellow eye) 0 0 0 0 Study eye 0 0 0 0 Fellow eye 0 0 0 0 Any non-ocular TESAE related to commercial aflibercept 2mg (of fellow eye) 0 0 0 0 Any TESAE related to medical device 0 0 0 0 Any ocular TESAE related to medical device 0 0 0 0 Study eye 0 0 0 0 Fellow eye 0 0 0 0 Any non-ocular TESAE related to medical device 0 0 0 0 Any TESAE of special interest 6 ( 2.2%) 1 ( 0.4%) 3 ( 1.2%) 4 ( 0.8%) Any TESAE of APTC events 4 ( 1.4%) 0 3 ( 1.2%) 3 ( 0.6%) Any TESAE of hypertension 1 ( 0.4%) 0 0 0 Any TESAE of intraocular inflammation of study eye 2 ( 0.7%) 1 ( 0.4%) 0 1 ( 0.2%) Any TESAE of nasal mucosal finding 1 ( 0.4%) 0 0 0 Maximum intensity for any ocular TESAE

Study eye

Mild 0 0 1 ( 0.4%) 1 ( 0.2%) Moderate 4 ( 1.4%) 2 ( 0.8%) 2 ( 0.8%) 4 ( 0.8%) Severe 2 ( 0.7%) 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Fellow eye

Severe 0 1 ( 0.4%) 0 1 ( 0.2%) Maximum intensity for any non-ocular TESAE

Mild 1 ( 0.4%) 2 ( 0.8%) 3 ( 1.2%) 5 ( 1,0%) Moderate 10 ( 3.6%) 8 ( 3.0%) 6 ( 2.3%) 14 ( 2,7%) Severe 11 ( 4.0%) 10 ( 3.8%) 9 ( 3.5%) 19 ( 3,6%) Total number of deaths 2 ( 0.7%) 2 ( 0.8%) 3 ( 1.2%) 5 ( 1.0%) Any AE with outcome death 2 ( 0.7%) 2 ( 0.8%) 3 ( 1.2%) 5 ( 1.0%) Any pre-treatment AE with outcome death 0 0 0 0 Any TEAE with outcome death 2 ( 0.7%) 2 ( 0.8%) 2 ( 0.8%) 4 ( 0.8%) Any post-treatment AE with outcome death 0 0 1 ( 0.4%) 1 ( 0.2%) 2q4 8q8/3 8q8/5 All 8mg N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%) Deaths not attributed to an AE 0 0 0 0 AE = Adverse event; APTC = Anti-platelet trialists' collaboration; RVO = Retinal vein occlusion; SAE = Serious adverse event; TEAE = Treatment- emergent adverse event; TESAE = Treatment-emergent serious adverse event

Pre-treatment adverse events are defined as AEs that start before first administration of study intervention.

TEAEs are defined as AEs that started in the time frame from first injection to the last injection (active or sham) in the study plus 30 days. For the participants who have not discontinued study treatment prematurely are 'ongoing') at the Week 36 analysis, all AEs that started at first injection or later will be considered treatment-emergent.

Post-treatment adverse events are defined as AEs that start more than 30 days after the stop of study intervention.

Only the most severe intensity is counted for multiple occurrences of the same AE in one individual. 'Missing' is considered to be the lowest category of intensity.

Adverse Event of Special Interest (AES I) are arterial thromboembolic events including cerebrovascular ischemic events and cardiovascular ischemic events.

2q4: Aflibercept 2mg administered every 4 weeks.

Table 1-13. Ocular treatment-emergent adverse events of study eye: number of participants by primary system organ class and preferred term (safety analysis set)

Population group: Non-China sub-population

Primary system organ class Preferred term* 8q8/3 All 8mg MedDRA version 27.1 _ N=266 (100%) N=526 (100%)

Number (%) of participants with at least one such adverse event 169 ( 32.1%) Eye disorders 70 ( 25.4%) 82 ( 30.8%) 65 ( 25.0%) 147 ( 27.9%) Allergic keratitis 1 ( 0.4%) 0 0 0

Anterior chamber cell 1 ( 0.4%) 0 0 0

Anterior chamber disorder 0 1 ( 0.4%) 0 1 ( 0.2%) Aphakia 0 0 1 ( 0.4%) 1 ( 0.2%) Blepharitis 1 ( 0.4%) 2 ( 0.8%) 0 2 ( 0.4%) Blepharospasm 0 1 ( 0.4%) 0 1 ( 0.2%) Blindness 1 ( 0.4%) 0 1 ( 0.4%) 1 ( 0.2%) Borderline glaucoma 0 2 ( 0.8%) 0 2 ( 0.4%) Cataract 9 ( 3.3%) 4 ( 1.5%) 10 ( 3.8%) 14 ( 2.7%) Cataract cortical 0 2 ( 0.8%) 0 2 ( 0.4%) Cataract nuclear 0 0 1 ( 0.4%) 1 ( 0.2%) Chalazion 0 0 1 ( 0.4%) 1 ( 0.2%)

Ciliary muscle spasm 1 ( 0.4%) 0 0 0

Conjunctival haemorrhage 5 ( 1.8%) 9 ( 3.4%) 6 ( 2.3%) 15 ( 2.9%) Primary system organ class Preferred term* 2q4 8q8/3 8q8/5 All 8mg MedDRA version 27.1 _ N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%) Conjunctival hyperaemia 0 1 ( 0.4%) 1 ( 0.2%) Conjunctival irritation 0 0 0 Conjunctival oedema 0 0 0 Conjunctival suffusion 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Conjunctivitis allergic 3 ( 1.1%) 2 ( 0.8%) 5 ( 1.0%) Corneal disorder 1 ( 0.4%) 0 1 ( 0.2%) Corneal infiltrates 1 ( 0.4%) 0 1 ( 0.2%) Corneal scar 1 ( 0.4%) 0 1 ( 0.2%) Cystoid macular oedema 0.4%) 0 0 0 Detachment of retinal pigment epithelium 1 ( 0.4%) 0 1 ( 0.2%) Diabetic retinopathy 0.4%) 0 0 0 Dry age-related macular degeneration 0 1 ( 0.4%) 1 ( 0.2%) Dry eye 2.2%) 4 ( 1.5%) 5 ( 1.9%) 9 ( 1.7%) Dysmetropsia 1 ( 0.4%) 0 1 ( 0.2%) Epiretinal membrane 2.2%) 3 ( 1.1%) 7 ( 2.7%) 10 ( 1.9%) Eye inflammation 0.4%) 0 0 0 Eye irritation 2 ( 0.8%) 0 2 ( 0.4%) Eye pain 1.1%) 5 ( 1.9%) 3 ( 1.2%) 8 ( 1.5%) Eye pruritus 2 ( 0.8%) 0 2 ( 0.4%) Eye swelling 1 ( 0.4%) 0 1 ( 0.2%) Foreign body sensation in eyes 1 ( 0.4%) 0 1 ( 0.2%) Glaucoma 4 ( 1.5%) 1 ( 0.4%) 5 ( 1.0%) Keratic precipitates 1 ( 0.4%) 0 1 ( 0.2%) Keratitis 0 1 ( 0.4%) 1 ( 0.2%) Lenticular opacities 0 2 ( 0.8%) 2 ( 0.4%) Macular degeneration 0.7%) 1 ( 0.4%) 0 1 ( 0.2%) Macular hole 0.4%) 0 1 ( 0.4%) 1 ( 0.2%) Macular ischaemia 0.4%) 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Macular oedema 0.4%) 2 ( 0.8%) 1 ( 0.4%) 3 ( 0.6%) Macular thickening 5 ( 1.9%) 0 5 ( 1.0%) Meibomian gland dysfunction 0.4%) 0 0 0 Narrow anterior chamber angle 0 1 ( 0.4%) 1 ( 0.2%) Normal tension glaucoma 0.7%) 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Ocular discomfort 0 1 ( 0.4%) 1 ( 0.2%) Ocular hyperaemia 0.4%) 0 0 0 Ocular hypertension 1.4%) 4 ( 1.5%) 2 ( 0.8%) 6 ( 1.1%) Open angle glaucoma 1 ( 0.4%) 0 1 ( 0.2%) Optic atrophy 0 1 ( 0.4%) 1 ( 0.2%) Optic nerve cupping 1 ( 0.4%) 0 1 ( 0.2%) Optic neuropathy 0 1 ( 0.4%) 1 ( 0.2%) Posterior capsule opacification 0.4%) 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Presbyopia 0 1 ( 0.4%) 1 ( 0.2%) Pterygium 0.4%) 0 0 0 Punctate keratitis 1.8%) 4 ( 1.5%) 2 ( 0.8%) 6 ( 1.1%) Retinal artery' embolism 0 1 ( 0.4%) 1 ( 0.2%)

Retinal artery' occlusion 0.4%) 1 ( 0.4%) 0 1 ( 0.2%) Primary system organ class Preferred term* 2q4 8q8/3 8q8/5 All 8mg MedDRA version 27.1 _ N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%) Retinal collateral vessels 2 ( 0.7%) 1 ( 0.4%) 0 1 ( 0.2%) Retinal degeneration 1 ( 0.4%) 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Retinal detachment 1 ( 0.4%) 0 0 0 Retinal drusen 2 ( 0.7%) 0 0 0 Retinal exudates 1 ( 0.4%) 2 ( 0.8%) 2 ( 0.8%) 4 ( 0.8%) Retinal haemorrhage 1 ( 0.4%) 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Retinal ischaemia 1 ( 0.4%) 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Retinal oedema 2 ( 0.7%) 2 ( 0.8%) 1 ( 0.4%) 3 ( 0.6%) Retinal pigment epitheliopathy 0 1 ( 0.4%) 0 1 ( 0.2%) Retinal tear 0 1 ( 0.4%) 2 ( 0.8%) 3 ( 0.6%) Retinal vascular disorder 0 2 ( 0.8%) 1 ( 0.4%) 3 ( 0.6%) Retinal vasculitis 0 0 1 ( 0.4%) 1 ( 0.2%) Retinal vein occlusion 1 ( 0.4%) 2 ( 0.8%) 3 ( 1.2%) 5 ( 1.0%) Swelling of eyelid 0 1 ( 0.4%) 0 1 ( 0.2%) Uveitis 0 0 1 ( 0.4%) 1 ( 0.2%) Vision blurred 0 0 1 ( 0.4%) 1 ( 0.2%) Visual acuity reduced 4 ( 1.4%) 11 ( 4.1%) 7 ( 2.7%) 18 ( 3.4%) Visual field defect 0 1 ( 0.4%) 0 1 ( 0.2%) Visual impairment 0 1 ( 0.4%) 0 1 ( 0.2%) Vitreomacular interface abnormal 0 1 ( 0.4%) 0 1 ( 0.2%) Vitreoretinal traction syndrome 0 1 ( 0.4%) 0 1 ( 0.2%) Vitreous detachment 2 ( 0.7%) 8 ( 3.0%) 9 ( 3.5%) 17 ( 3.2%) Vitreous floaters 3 ( 1.1%) 4 ( 1.5%) 2 ( 0.8%) 6 ( 1.1%)

Vitreous haemorrhage 0 2 ( 0.8%) 2 ( 0.8%) 4 ( 0.8%) General disorders and administration site conditions 5 ( 1.8%) 5 ( 1.9%) 3 ( 1.2%) 8 ( 1.5%) Application site irritation 1 ( 0.4%) 0 0 0 Injection site irritation 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.8%) 3 ( 0.6%) Injection site pain 0 0 1 ( 0.4%) 1 ( 0.2%) Oedema 2 ( 0.7%) 1 ( 0.4%) 0 1 ( 0.2%) Pain 0 2 ( 0.8%) 0 2 ( 0.4%) Sensation of foreign body 1 ( 0.4%) 1 ( 0.4%) 0 1 ( 0.2%) Infections and infestations 3 ( 1.1%) 5 ( 1.9%) 4 ( 1.5%) 9 ( 1.7%) Conjunctivitis 1 ( 0.4%) 3 ( 1.1%) 2 ( 0.8%) 5 ( 1.0%) Conjunctivitis viral 0 1 ( 0.4%) 0 1 ( 0.2%) Endophthalmitis 2 ( 0.7%) 1 ( 0.4%) 0 1 ( 0.2%) Hordeolum 0 0 2 ( 0.8%) 2 ( 0.4%) Injury, poisoning and procedural complications 4 ( 1.4%) 6 ( 2.3%) 3 ( 1.2%) 9 ( 1.7%) Corneal abrasion 1 ( 0.4%) 0 2 ( 0.8%) 2 ( 0.4%) Foreign body in eye 1 ( 0.4%) 0 1 ( 0.4%) 1 ( 0.2%) Injection related reaction 1 ( 0.4%) 0 0 0

Intra-ocular injection complication 1 ( 0.4%) 4 ( 1.5%) 0 4 ( 0.8%) Primary system organ class Preferred term* 2q4 8q8/3 8q8/5 All 8mg MedDRA version 27.1 N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%)

Skin laceration 0 2 ( 0.8%) 0 2 ( 0.4%) Investigations 6 ( 2.2%) 14 ( 5.3%) 8 ( 3.1%) 22 ( 4.2%) Intraocular pressure decreased 1 ( 0.4%) 0 0 0 Intraocular pressure increased 4 ( 1.4%) 13 ( 4.9%) 8 ( 3.1%) 21 ( 4.0%) Intraocular pressure test abnormal 0 1 ( 0.4%) 0 1 ( 0.2%) Optic nerve cup/disc ratio increased 1 ( 0.4%) 0 0 0 Neoplasms benign, malignant and unspecified (incl cysts and polyps) 0 1 ( 0.4%) 0 1 ( 0.2%) Seborrhoeic keratosis 0 1 ( 0.4%) 0 1 ( 0.2%) Vascular disorders 1 ( 0.4%) 3 ( 1.1%) 1 ( 0.4%) 4 ( 0.8%) Haemorrhage 0 1 ( 0.4%) 0 1 ( 0.2%) Vascular shunt 1 ( 0.4%) 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Vein disorder 0 1 ( 0.4%) 0 1 ( 0.2%) Uncoded 1 ( 0.4%) 1 ( 0.4%) 0 1 ( 0.2%) Barley Of The Lower Eyelid 1 ( 0.4%) 0 0 0 Silicon Oil Drops In Vitreous 0 1 ( 0.4%) 0 1 ( 0.2%) Adverse events are sorted by alphabetical order of the MedDRA classification. A participant is counted only once within each primary SOC and preferred term. TEAEs are defined as AEs that started in the time frame from first injection to the last injection (active or sham) in the study plus 30 days. For the participants who have not discontinued study treatment prematurely (i.e., are 'ongoing') at the Week 36 analysis, all AEs that started at first injection or later will be considered treatment-emergent. * Reported term will be displayed in case of uncoded terms..

2q4: Aflibercept 2mg administered every 4 weeks.

Table 1-14. Non-ocular treatment-emergent adverse events: number of participants by primary system organ class and preferred term (safety analysis set)

Population group: Non-China sub-population Primary system organ class 2q4 8q8/3 8q8/5 All 8mg Preferred term* N=276 N=266 N=260 N=526 MedDRA version 27.1 (100%) (100%) (100%) (100%) Number (%) of participants with at least one such adverse event 141 ( 51.1%) 128 ( 48.1%) 137 ( 52.7%) 265 ( 50.4%) Blood and lymphatic system disorders 4 ( 1.4%) 4 ( 1.5%) 2 ( 0.8%) 6 ( 1.1%) Anaemia 2 ( 0.7%) 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Blood loss anaemia 0 0 1 ( 0.4%) 1 ( 0.2%) Iron deficiency anaemia 1 ( 0.4%) 1 ( 0.4%) 0 1 ( 0.2%) Lymphocytosis 0 1 ( 0.4%) 0 1 ( 0.2%) Monocytosis 0 1 ( 0.4%) 0 1 ( 0.2%) Neutrophilia 0 1 ( 0.4%) 0 1 ( 0.2%) Pancytopenia 1 ( 0.4%) 0 0 0 Thrombocytopenia 0 0 1 ( 0.4%) 1 ( 0.2%) Cardiac disorders 14 ( 5.1%) 10 ( 3.8%) 19 ( 3.6%) Acute myocardial infarction 1 ( 0.4%) 0 0 0 Aortic valve incompetence 1 ( 0.4%) 0 0 0 Arrhythmia 0 0 1 ( 0.4%) 1 ( 0.2%) Atrial fibrillation 1 ( 0.4%) 2 ( 0.8%) 2 ( 0.8%) 4 ( 0.8%) Atrial tachycardia 0 1 ( 0.4%) 0 1 ( 0.2%) Atrioventricular block first degree 1 ( 0.4%) 1 ( 0.4%) 0 1 ( 0.2%) Bradycardia 0 3 ( 1.1%) 0 3 ( 0.6%) Bundle branch block left 1 ( 0.4%) 1 ( 0.4%) 0 1 ( 0.2%) Bundle branch block right 0 0 1 ( 0.4%) 1 ( 0.2%) Coronary artery disease 2 ( 0.7%) 1 ( 0.4%) 0 1 ( 0.2%) Hypertensive heart disease 2 ( 0.7%) 0 0 0 Left ventricular hypertrophy 0 0 1 ( 0.4%) 1 ( 0.2%) Mitral valve incompetence 1 ( 0.4%) 0 0 0 Myocardial infarction 1 ( 0.4%) 0 1 ( 0.4%) 1 ( 0.2%) Palpitations 1 ( 0.4%) 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Sinus bradycardia 2 ( 0.7%) 0 0 0 Tachycardia 2 ( 0.7%) 0 2 ( 0.8%) 2 ( 0.4%)

Ventricular extrasystoles 0 0 1 ( 0.2%) Congenital, familial and genetic disorders 0 1 ( 0.4%) 0 1 ( 0.2%) Factor V Leiden mutation 0 1 ( 0.4%) 0 1 ( 0.2%) Ear and labyrinth disorders 2 ( 0.7%) 4 ( 1.5%) 5 ( 1.9%) 9 ( 1.7%) Deafness 1 ( 0.4%) 0 0 0 Ear inflammation 0 0 1 ( 0.4%) 1 ( 0.2%) Ear pain 1 ( 0.4%) 0 0 0 Presbyacusis 0 1 ( 0.4%) 0 1 ( 0.2%) Vertigo 0 3 ( 1.1%) 3 ( 1.2%) 6 ( 1.1%) Vertigo positional 0 0 1 ( 0.4%) 1 ( 0.2%) Endocrine disorders 1 ( 0.4%) 0 0 0 Primary system organ class 2q4 8q8/3 8q8/5 All 8mg Preferred term* N=276 N=266 N=260 N=526 MedDRA version 27.1 (100%) (100%) (100%) (100%)

Thyroid mass 1 ( 0.4%) 0 0 0 Gastrointestinal disorders 19 ( 6.9%) 16 ( 6.0%) 17 ( 6.5%) 33 ( 6.3%) Abdominal pain 1 ( 0.4%) 0 0 0 Abdominal pain upper 2 ( 0.7%) 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Chronic gastritis 0 1 ( 0.4%) 0 1 ( 0.2%) Constipation 0 1 ( 0.4%) 0 1 ( 0.2%) Crohn's disease 0 0 1 ( 0.4%) 1 ( 0.2%) Dental caries 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.8%) 3 ( 0.6%) Diarrhoea 2 ( 0.7%) 2 ( 0.8%) 1 ( 0.4%) 3 ( 0.6%) Diverticulum intestinal 0 0 1 ( 0.4%) 1 ( 0.2%) Duodenal ulcer 0 0 1 ( 0.4%) 1 ( 0.2%) Dysphagia 0 0 1 ( 0.4%) 1 ( 0.2%) Femoral hernia incarcerated 0 1 ( 0.4%) 0 1 ( 0.2%) Food poisoning 1 ( 0.4%) 0 1 ( 0.4%) 1 ( 0.2%) Gastritis 0 0 1 ( 0.4%) 1 ( 0.2%) Gastrointestinal disorder 2 ( 0.7%) 0 0 0 Gastrooesophageal reflux disease 0 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Glossitis 0 1 ( 0.4%) 0 1 ( 0.2%) Haemorrhoids 0 0 2 ( 0.8%) 2 ( 0.4%) Hiatus hernia 0 1 ( 0.4%) 0 1 ( 0.2%) Irritable bowel syndrome 2 ( 0.7%) 0 0 0 Large intestine polyp 1 ( 0.4%) 0 0 0 Lower gastrointestinal haemorrhage 0 1 ( 0.4%) 0 1 ( 0.2%) Nausea 3 ( 1.1%) 4 ( 1.5%) 3 ( 1.2%) 7 ( 1.3%) Oesophagitis 1 ( 0.4%) 0 0 0 Pancreatic disorder 0 0 1 ( 0.4%) 1 ( 0.2%) Periodontal disease 1 ( 0.4%) 0 0 0 Small intestinal obstruction 1 ( 0.4%) 0 0 0 Stomatitis 1 ( 0.4%) 0 1 ( 0.4%) 1 ( 0.2%) Toothache 1 ( 0.4%) 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Vomiting 4 ( 1.4%) 1 ( 0.4%) 0 1 ( 0.2%) General disorders and administration site conditions 10 ( 3.6%) 13 ( 4.9%) 5 ( 1.9%) 18 ( 3.4%) Application site hypersensitivity 0 1 ( 0.4%) 0 1 ( 0.2%) Asthenia 0 0 1 ( 0.4%) 1 ( 0.2%) Chest pain 2 ( 0.7%) 4 ( 1.5%) 0 4 ( 0.8%) Chills 1 ( 0.4%) 0 0 0 Fatigue 0 0 1 ( 0.4%) 1 ( 0.2%) Gait disturbance 0 0 1 ( 0.4%) 1 ( 0.2%) General physical health deterioration 1 ( 0.4%) 0 0 0 Hernia 1 ( 0.4%) 0 0 0 Incarcerated hernia 1 ( 0.4%) 0 0 0 Influenza like illness 0 2 ( 0.8%) 1 ( 0.4%) 3 ( 0.6%) Injection site bruising 0 1 ( 0.4%) 0 1 ( 0.2%) Malaise 1 ( 0.4%) 1 ( 0.4%) 0 1 ( 0.2%) Primary system organ class 2q4 8q8/3 8q8/5 All 8mg Preferred term* N=276 N=266 N=260 N=526 MedDRA version 27.1 (100%) (100%) (100%) (100%) Mass 0 0 1 ( 0.4%) 1 ( 0.2%) Oedema peripheral 2 ( 0.7%) 4 ( 1.5%) 0 4 ( 0.8%) Peripheral swelling 0 1 ( 0.4%) 0 1 ( 0.2%)

Pyrexia 3 ( 1.1%) 1 ( 0.4%) 0 1 ( 0.2%) Hepatobiliary disorders 4 ( 1.4%) 2 ( 0.8%) 5 ( 1.9%) 7 ( 1.3%) Biliary colic 0 0 1 ( 0.4%) 1 ( 0.2%) Cholecystitis acute 0 1 ( 0.4%) 0 1 ( 0.2%) Cholecystitis chronic 0 0 1 ( 0.4%) 1 ( 0.2%) Cholelithiasis 1 ( 0.4%) 0 0 0 Hepatic cyst 0 1 ( 0.4%) 0 1 ( 0.2%) Hepatic steatosis 3 ( 1.1%) 0 3 ( 1.2%) 3 ( 0.6%) Metabolic dysfunction-associated liver disease 0 0 1 ( 0.4%) 1 ( 0.2%) Immune system disorders 4 ( 1.4%) 4 ( 1.5%) 1 ( 0.4%) 5 ( 1.0%) Allergy to chemicals 0 1 ( 0.4%) 0 1 ( 0.2%) Anaphylactic reaction 0 1 ( 0.4%) 0 1 ( 0.2%) Drug hypersensitivity 1 ( 0.4%) 0 0 0 Multiple allergies 1 ( 0.4%) 0 0 0 Seasonal allergy 2 ( 0.7%) 2 ( 0.8%) 1 ( 0.4%) 3 ( 0.6%) Infections and infestations 57 ( 20.7%) 51 ( 19.2%) 55 ( 21.2%) 106 ( 20.2%) Abdominal abscess 1 ( 0.4%) 0 0 0 Acute sinusitis 1 ( 0.4%) 1 ( 0.4%) 0 1 ( 0.2%) Asymptomatic bacteriuria 1 ( 0.4%) 0 0 0 Atypical pneumonia 1 ( 0.4%) 0 0 0 Bronchitis 3 ( 1.1%) 2 ( 0.8%) 2 ( 0.8%) 4 ( 0.8%) COVID-19 6 ( 2.2%) 13 ( 4.9%) 6 ( 2.3%) 19 ( 3.6%) Chronic hepatitis C 0 0 1 ( 0.4%) 1 ( 0.2%) Chronic sinusitis 0 0 1 ( 0.4%) 1 ( 0.2%) Coronavirus infection 2 ( 0.7%) 0 0 0 Cystitis 1 ( 0.4%) 0 1 ( 0.4%) 1 ( 0.2%) Diverticulitis 0 3 ( 1.1%) 1 ( 0.4%) 4 ( 0.8%) Enterocolitis infectious 1 ( 0.4%) 0 0 0 Epididymitis 0 0 1 ( 0.4%) 1 ( 0.2%) Erysipelas 1 ( 0.4%) 0 0 0 Escherichia urinary tract infection 1 ( 0.4%) 0 0 0 Fungal infection 0 1 ( 0.4%) 0 1 ( 0.2%) Fungal skin infection 0 0 1 ( 0.4%) 1 ( 0.2%) Gastroenteritis 1 ( 0.4%) 1 ( 0.4%) 0 1 ( 0.2%) Gastroenteritis viral 0 0 1 ( 0.4%) 1 ( 0.2%) Gingivitis 1 ( 0.4%) 1 ( 0.4%) 0 1 ( 0.2%) Helicobacter infection 0 1 ( 0.4%) 0 1 ( 0.2%) Herpes dermatitis 1 ( 0.4%) 0 0 0 Herpes simplex 0 0 1 ( 0.4%) 1 ( 0.2%) Herpes zoster 3 ( 1.1%) 0 2 ( 0.8%) 2 ( 0.4%) Primary system organ class 2q4 8q8/3 8q8/5 All 8mg Preferred term* N=276 N=266 N=260 N=526 MedDRA version 27.1 (100%) (100%) (100%) (100%) Infected dermal cyst 0 1 ( 0.4%) 0 1 ( 0.2%) Infectious pleural effusion 0 1 ( 0.4%) 0 1 ( 0.2%) Influenza 6 ( 2.2%) 4 ( 1.5%) 1 ( 0.4%) 5 ( 1.0%) Localised infection 1 ( 0.4%) 1 ( 0.4%) 0 1 ( 0.2%) Lower respiratory tract infection 0 0 1 ( 0.4%) 1 ( 0.2%) Nasopharyngitis 9 ( 3.3%) 15 ( 5.6%) 14 ( 5.4%) 29 ( 5.5%) Oral candidiasis 0 1 ( 0.4%) 0 1 ( 0.2%) Oral herpes 1 ( 0.4%) 2 ( 0.8%) 1 ( 0.4%) 3 ( 0.6%) Osteomyelitis 0 0 1 ( 0.4%) 1 ( 0.2%) Otitis externa 0 1 ( 0.4%) 0 1 ( 0.2%) Periodontitis 1 ( 0.4%) 2 ( 0.8%) 1 ( 0.4%) 3 ( 0.6%) Pharyngitis 0 3 ( 1.1%) 0 3 ( 0.6%) Pneumonia 3 ( 1.1%) 3 ( 1.1%) 1 ( 0.4%) 4 ( 0.8%) Pneumonia parainfluenzae viral 0 0 1 ( 0.4%) 1 ( 0.2%) Pneumonia pseudomonal 0 0 1 ( 0.4%) 1 ( 0.2%) Pulpitis dental 1 ( 0.4%) 0 0 0 Respiratory syncytial virus infection 0 0 1 ( 0.4%) 1 ( 0.2%) Respiratory tract infection 0 1 ( 0.4%) 0 1 ( 0.2%) Rhinitis 0 1 ( 0.4%) 0 1 ( 0.2%) Sepsis 0 2 ( 0.8%) 0 2 ( 0.4%) Sinusitis 3 ( 1.1%) 1 ( 0.4%) 3 ( 1.2%) 4 ( 0.8%) Tinea cruris 1 ( 0.4%) 0 0 0 Tinea pedis 0 0 1 ( 0.4%) 1 ( 0.2%) Tonsillitis 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.8%) 3 ( 0.6%) Tooth infection 1 ( 0.4%) 0 0 0 Upper respiratory tract infection 4 ( 1.4%) 3 ( 1.1%) 1 ( 0.4%) 4 ( 0.8%) Urinary tract infection 10 ( 3.6%) 4 ( 1.5%) 11 ( 4.2%) 15 ( 2.9%) Vaginal infection 0 0 1 ( 0.4%) 1 ( 0.2%) Viral infection 1 ( 0.4%) 0 1 ( 0.4%) 1 ( 0.2%) Viral rhinitis 0 0 1 ( 0.4%) 1 ( 0.2%) Viral upper respiratory tract infection 0 0 1 ( 0.4%) 1 ( 0.2%)

Wound infection 1 ( 0.4%) 0 0 0 Injury, poisoning and procedural complications 9 ( 3.3%) 11 ( 4.1%) 10 ( 3.8%) 21 ( 4.0%) Bone contusion 0 1 ( 0.4%) 0 1 ( 0.2%) Brain herniation 0 0 1 ( 0.4%) 1 ( 0.2%) Contusion 0 0 2 ( 0.8%) 2 ( 0.4%) Fall 2 ( 0.7%) 0 3 ( 1.2%) 3 ( 0.6%) Foot fracture 1 ( 0.4%) 0 0 0 Hand fracture 0 1 ( 0.4%) 0 1 ( 0.2%) Humerus fracture 1 ( 0.4%) 0 0 0 Limb injury 1 ( 0.4%) 2 ( 0.8%) 0 2 ( 0.4%) Meniscus injury 0 1 ( 0.4%) 0 1 ( 0.2%) Muscle strain 0 1 ( 0.4%) 0 1 ( 0.2%) Oral contusion 1 ( 0.4%) 0 0 0 Pelvic fracture 1 ( 0.4%) 0 0 0 Primary system organ class 2q4 8q8/3 8q8/5 All 8mg Preferred term* N=276 N=266 N=260 N=526 MedDRA version 27.1 (100%) (100%) (100%) (100%) Post procedural swelling 1 ( 0.4%) 0 0 0 Postoperative thoracic procedure complication 0 1 ( 0.4%) 0 1 ( 0.2%) Procedural nausea 0 1 ( 0.4%) 0 1 ( 0.2%) Procedural pain 1 ( 0.4%) 0 2 ( 0.8%) 2 ( 0.4%) Skin laceration 0 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Snake bite 0 1 ( 0.4%) 0 1 ( 0.2%) Subdural haematoma 0 0 1 ( 0.4%) 1 ( 0.2%) Tendon rupture 0 0 1 ( 0.4%) 1 ( 0.2%) Upper limb fracture 0 1 ( 0.4%) 0 1 ( 0.2%)

Wrist fracture 1 ( 0.4%) 0 0 0 Investigations 11 ( 4.0%) 16 ( 6.0%) 17 ( 6.5%) 33 ( 6.3%) Alanine aminotransferase increased 0 0 1 ( 0.4%) 1 ( 0.2%) Aspartate aminotransferase increased 0 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Blood alkaline phosphatase increased 0 1 ( 0.4%) 0 1 ( 0.2%) Blood cholesterol increased 0 0 1 ( 0.4%) 1 ( 0.2%) Blood creatine increased 1 ( 0.4%) 0 0 0 Blood creatine phosphokinase increased 2 ( 0.7%) 2 ( 0.8%) 2 ( 0.8%) 4 ( 0.8%) Blood creatinine 0 0 1 ( 0.4%) 1 ( 0.2%) Blood iron decreased 0 0 1 ( 0.4%) 1 ( 0.2%) Blood potassium increased 0 0 1 ( 0.4%) 1 ( 0.2%) Blood pressure diastolic increased 1 ( 0.4%) 0 1 ( 0.4%) 1 ( 0.2%) Blood pressure increased 1 ( 0.4%) 3 ( 1.1%) 2 ( 0.8%) 5 ( 1.0%) Blood pressure systolic increased 1 ( 0.4%) 0 1 ( 0.4%) 1 ( 0.2%) Blood triglycerides increased 1 ( 0.4%) 0 0 0 Blood urea increased 1 ( 0.4%) 0 0 0 Blood urine present 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.8%) 3 ( 0.6%) Creatinine urine decreased 1 ( 0.4%) 0 0 0 Electrocardiogram QT prolonged 0 0 1 ( 0.4%) 1 ( 0.2%) Glucose urine 0 0 1 ( 0.4%) 1 ( 0.2%) Glycosylated haemoglobin increased 2 ( 0.7%) 3 ( 1.1%) 4 ( 1.5%) 7 ( 1.3%) Haematocrit decreased 1 ( 0.4%) 0 1 ( 0.4%) 1 ( 0.2%) Haematocrit increased 0 0 1 ( 0.4%) 1 ( 0.2%) Haemoglobin decreased 1 ( 0.4%) 0 1 ( 0.4%) 1 ( 0.2%) Liver function test abnormal 0 0 1 ( 0.4%) 1 ( 0.2%) Liver function test increased 0 1 ( 0.4%) 0 1 ( 0.2%) Low density lipoprotein increased 0 0 1 ( 0.4%) 1 ( 0.2%) Mean cell haemoglobin decreased 0 0 1 ( 0.4%) 1 ( 0.2%) Mean cell volume abnormal 0 1 ( 0.4%) 0 1 ( 0.2%) Monocyte count increased 1 ( 0.4%) 1 ( 0.4%) 0 1 ( 0.2%) Neutrophil count increased 0 1 ( 0.4%) 0 1 ( 0.2%) Platelet count decreased 1 ( 0.4%) 0 0 0 Protein urine present 1 ( 0.4%) 0 0 0 Red blood cell count decreased 1 ( 0.4%) 0 0 0 Red blood cells urine 0 1 ( 0.4%) 0 1 ( 0.2%) Urinary sediment present 0 1 ( 0.4%) 0 1 ( 0.2%) Primary system organ class 2q4 8q8/3 8q8/5 All 8mg Preferred term* N=276 N=266 N=260 N=526 MedDRA version 27.1 (100%) (100%) (100%) (100%) Urine analysis abnormal 0 1 ( 0.4%) 0 1 ( 0.2%) Urine ketone body present 1 ( 0.4%) 1 ( 0.4%) 0 1 ( 0.2%) Urine protein/creatinine ratio increased 3 ( 1.1%) 0 0 0 Weight decreased 0 1 ( 0.4%) 0 1 ( 0.2%) Weight increased 1 ( 0.4%) 0 0 0 White blood cell count increased 0 2 ( 0.8%) 0 2 ( 0.4%)

White blood cells urine positive 1 ( 0.4%) 1 ( 0.4%) 0 1 ( 0.2%) Metabolism and nutrition disorders 22 ( 8.0%) 9 ( 3.4%) 18 ( 6.9%) 27 ( 5.1%) Acidosis 0 0 1 ( 0.4%) 1 ( 0.2%) Dehydration 1 ( 0.4%) 0 0 0 Diabetes mellitus 0 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Dyslipidaemia 1 ( 0.4%) 0 3 ( 1.2%) 3 ( 0.6%) Glucose tolerance impaired 0 1 ( 0.4%) 0 1 ( 0.2%) Gout 2 ( 0.7%) 0 1 ( 0.4%) 1 ( 0.2%) Hypercholesterolaemia 5 ( 1.8%) 3 ( 1.1%) 6 ( 2.3%) 9 ( 1.7%) Hyperkalaemia 0 1 ( 0.4%) 0 1 ( 0.2%) Hyperlipidaemia 5 ( 1.8%) 1 ( 0.4%) 3 ( 1.2%) 4 ( 0.8%) Hypertriglyceridaemia 1 ( 0.4%) 0 1 ( 0.4%) 1 ( 0.2%) Hyperuricaemia 1 ( 0.4%) 1 ( 0.4%) 0 1 ( 0.2%) Hypervolaemia 0 0 1 ( 0.4%) 1 ( 0.2%) Hypoglycaemia 2 ( 0.7%) 0 0 0 Hypokalaemia 1 ( 0.4%) 2 ( 0.8%) 0 2 ( 0.4%) Hyponatraemia 0 1 ( 0.4%) 0 1 ( 0.2%) Metabolic syndrome 1 ( 0.4%) 0 0 0 Obesity 0 0 1 ( 0.4%) 1 ( 0.2%) Overweight 1 ( 0.4%) 0 0 0 Type 2 diabetes mellitus 3 ( 1.1%) 0 4 ( 1.5%) 4 ( 0.8%) Vitamin B complex deficiency 0 0 1 ( 0.4%) 1 ( 0.2%) Vitamin D deficiency 0 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Musculoskeletal and connective tissue disorders 23 ( 8.3%) 21 ( 7.9%) 16 ( 6.2%) 37 ( 7.0%) Arthralgia 6 ( 2.2%) 3 ( 1.1%) 4 ( 1.5%) 7 ( 1.3%) Arthritis 0 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Back pain 4 ( 1.4%) 2 ( 0.8%) 3 ( 1.2%) 5 ( 1.0%) Bursitis 2 ( 0.7%) 0 0 0 Dupuytren's contracture 0 0 1 ( 0.4%) 1 ( 0.2%) Foot deformity 1 ( 0.4%) 0 0 0 Haemarthrosis 0 0 1 ( 0.4%) 1 ( 0.2%) Intervertebral disc degeneration 1 ( 0.4%) 0 0 0 Joint effusion 0 0 1 ( 0.4%) 1 ( 0.2%) Joint swelling 0 2 ( 0.8%) 0 2 ( 0.4%) Muscle disorder 1 ( 0.4%) 0 0 0 Muscle spasms 2 ( 0.7%) 0 1 ( 0.4%) 1 ( 0.2%) Musculoskeletal pain 1 ( 0.4%) 0 0 0 Musculoskeletal stiffness 0 0 1 ( 0.4%) 1 ( 0.2%) Primary system organ class 2q4 8q8/3 8q8/5 All 8mg Preferred term* N=276 N=266 N=260 N=526 MedDRA version 27.1 (100%) (100%) (100%) (100%) Myalgia 2 ( 0.7%) 0 0 0 Myositis 1 ( 0.4%) 0 0 0 Osteoarthritis 3 ( 1.1%) 1 ( 0.4%) 3 ( 1.2%) 4 ( 0.8%) Osteoporosis 1 ( 0.4%) 2 ( 0.8%) 0 2 ( 0.4%) Pain in extremity 1 ( 0.4%) 3 ( 1.1%) 2 ( 0.8%) 5 ( 1.0%) Plantar fasciitis 0 1 ( 0.4%) 0 1 ( 0.2%) Rheumatic disorder 1 ( 0.4%) 0 0 0 Rheumatoid arthritis 0 3 ( 1.1%) 0 3 ( 0.6%) Rotator cuff syndrome 0 1 ( 0.4%) 0 1 ( 0.2%) Scoliosis 0 1 ( 0.4%) 0 1 ( 0.2%) Spinal osteoarthritis 1 ( 0.4%) 2 ( 0.8%) 1 ( 0.4%) 3 ( 0.6%) Systemic lupus erythematosus 0 1 ( 0.4%) 0 1 ( 0.2%) Tendon pain 1 ( 0.4%) 0 0 0 Tenosynovitis 0 0 1 ( 0.4%) 1 ( 0.2%)

Vertebral lateral recess stenosis 1 ( 0.4%) 0 0 0 Neoplasms benign, malignant and unspecified (incl cysts and polyps) 6 ( 2.2%) 4 ( 1.5%) 3 ( 1.2%) 7 ( 1.3%) Benign breast neoplasm 0 0 1 ( 0.4%) 1 ( 0.2%) Cancer fatigue 1 ( 0.4%) 0 0 0 Colon cancer 0 0 1 ( 0.4%) 1 ( 0.2%) Leiomyoma 1 ( 0.4%) 0 0 0 Lipoma 0 1 ( 0.4%) 0 1 ( 0.2%) Lung neoplasm malignant 0 0 1 ( 0.4%) 1 ( 0.2%) Metastases to lymph nodes 0 0 1 ( 0.4%) 1 ( 0.2%) Metastatic neoplasm 1 ( 0.4%) 0 0 0 Oesophageal carcinoma 0 1 ( 0.4%) 0 1 ( 0.2%) Prostate cancer metastatic 0 0 1 ( 0.4%) 1 ( 0.2%) Prostate cancer stage II 0 1 ( 0.4%) 0 1 ( 0.2%) Squamous cell carcinoma of lung 1 ( 0.4%) 0 0 0 Squamous cell carcinoma of skin 1 ( 0.4%) 0 0 0 T-cell lymphoma 1 ( 0.4%) 0 0 0 Uterine leiomyoma 0 1 ( 0.4%) 0 1 ( 0.2%) Nervous system disorders 18 ( 6.5%) 17 ( 6.4%) 17 ( 6.5%) 34 ( 6.5%) Amnesia 0 1 ( 0.4%) 0 1 ( 0.2%) Atypical migraine 1 ( 0.4%) 0 0 0 Carotid arteriosclerosis 0 1 ( 0.4%) 0 1 ( 0.2%) Carotid artery occlusion 1 ( 0.4%) 0 0 0 Carotid artery stenosis 0 0 1 ( 0.4%) 1 ( 0.2%) Cerebellar infarction 1 ( 0.4%) 0 0 0 Cerebellar stroke 1 ( 0.4%) 0 0 0 Cerebral infarction 1 ( 0.4%) 0 1 ( 0.4%) 1 ( 0.2%) Cerebrovascular accident 1 ( 0.4%) 0 0 0 Cerebrovascular disorder 0 1 ( 0.4%) 0 1 ( 0.2%) Cervical radiculopathy 1 ( 0.4%) 2 ( 0.8%) 0 2 ( 0.4%) Cognitive disorder 0 0 1 ( 0.4%) 1 ( 0.2%) Primary system organ class 2q4 8q8/3 8q8/5 All 8mg Preferred term* N=276 N=266 N=260 N=526 MedDRA version 27.1 (100%) (100%) (100%) (100%) Dementia 1 ( 0.4%) 0 0 0 Dementia Alzheimer's type 0 1 ( 0.4%) 0 1 ( 0.2%) Dizziness 4 ( 1.4%) 0 4 ( 1.5%) 4 ( 0.8%) Epilepsy 1 ( 0.4%) 1 ( 0.4%) 0 1 ( 0.2%) Facial paralysis 1 ( 0.4%) 0 0 0 Haemorrhage intracranial 1 ( 0.4%) 0 0 0 Headache 5 ( 1.8%) 6 ( 2.3%) 6 ( 2.3%) 12 ( 2.3%) Hypoaesthesia 1 ( 0.4%) 0 0 0 Lacunar infarction 1 ( 0.4%) 0 0 0 Lumbar radiculopathy 0 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Memory impairment 0 0 1 ( 0.4%) 1 ( 0.2%) Paraesthesia 1 ( 0.4%) 0 0 0 Peripheral nerve palsy 0 1 ( 0.4%) 0 1 ( 0.2%) Post herpetic neuralgia 0 1 ( 0.4%) 0 1 ( 0.2%) Sciatica 1 ( 0.4%) 3 ( 1.1%) 1 ( 0.4%) 4 ( 0.8%) Syncope 0 0 3 ( 1.2%) 3 ( 0.6%)

Vertebral artery stenosis 0 0 1 ( 0.4%) 1 ( 0.2%) Psychiatric disorders 5 ( 1.8%) 3 ( 1.1%) 2 ( 0.8%) 5 ( 1.0%) Anxiety 1 ( 0.4%) 2 ( 0.8%) 0 2 ( 0.4%) Depression 2 ( 0.7%) 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Euphoric mood 1 ( 0.4%) 0 0 0 Insomnia 0 0 1 ( 0.4%) 1 ( 0.2%) Mental status changes 1 ( 0.4%) 0 0 0 Sleep disorder 1 ( 0.4%) 0 0 0 Renal and urinary disorders 7 ( 2.5%) 7 ( 2.6%) 5 ( 1.9%) 12 ( 2.3%) Acute kidney injury 1 ( 0.4%) 0 0 0 Calculus bladder 0 0 1 ( 0.4%) 1 ( 0.2%) Chronic kidney disease 0 0 1 ( 0.4%) 1 ( 0.2%) Cystitis noninfective 0 0 1 ( 0.4%) 1 ( 0.2%) Diabetic nephropathy 0 0 1 ( 0.4%) 1 ( 0.2%) Dysuria 1 ( 0.4%) 0 0 0 Haematuria 0 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Nephrolithiasis 2 ( 0.7%) 1 ( 0.4%) 0 1 ( 0.2%) Nephropathy 1 ( 0.4%) 0 0 0 Nocturia 0 1 ( 0.4%) 0 1 ( 0.2%) Proteinuria 1 ( 0.4%) 3 ( 1.1%) 0 3 ( 0.6%) Ureterolithiasis 1 ( 0.4%) 0 0 0 Urinary incontinence 0 1 ( 0.4%) 0 1 ( 0.2%) Urinary retention 1 ( 0.4%) 0 0 0 Urinary tract discomfort 0 0 1 ( 0.4%) 1 ( 0.2%) Urine abnormality 0 1 ( 0.4%) 0 1 ( 0.2%) Reproductive system and breast disorders 5 ( 1.8%) 2 ( 0.8%) 3 ( 1.2%) 5 ( 1.0%) Benign prostatic hyperplasia 0 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Primary system organ class 2q4 8q8/3 8q8/5 All 8mg Preferred term* N=276 N=266 N=260 N=526 MedDRA version 27.1 (100%) (100%) (100%) (100%) Gynaecomastia 1 ( 0.4%) 0 0 0 Heavy menstrual bleeding 0 1 ( 0.4%) 0 1 ( 0.2%) Infertility 1 ( 0.4%) 0 0 0 Ovarian cyst 1 ( 0.4%) 0 0 0 Pelvic organ prolapse 1 ( 0.4%) 0 0 0 Prostatitis 1 ( 0.4%) 0 0 0 Prostatomegaly 0 0 1 ( 0.4%) 1 ( 0.2%)

Uterine haemorrhage 0 0 1 ( 0.4%) 1 ( 0.2%) Respiratory, thoracic and mediastinal disorders 12 ( 4.3%) 12 ( 4.5%) 7 ( 2.7%) 19 ( 3.6%) Asthma 1 ( 0.4%) 0 0 0 Chronic obstructive pulmonary disease 0 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Cough 4 ( 1.4%) 2 ( 0.8%) 2 ( 0.8%) 4 ( 0.8%) Dyspnoea 1 ( 0.4%) 0 0 0 Epistaxis 2 ( 0.7%) 2 ( 0.8%) 1 ( 0.4%) 3 ( 0.6%) Nasal congestion 1 ( 0.4%) 0 1 ( 0.4%) 1 ( 0.2%) Oropharyngeal pain 0 3 ( 1.1%) 1 ( 0.4%) 4 ( 0.8%) Paranasal sinus mucosal hypertrophy 0 1 ( 0.4%) 0 1 ( 0.2%) Respiratory failure 0 0 1 ( 0.4%) 1 ( 0.2%) Rhinitis allergic 2 ( 0.7%) 0 1 ( 0.4%) 1 ( 0.2%) Rhinorrhoea 0 1 ( 0.4%) 0 1 ( 0.2%) Sleep apnoea syndrome 1 ( 0.4%) 2 ( 0.8%) 0 2 ( 0.4%) Skin and subcutaneous tissue disorders 8 ( 2.9%) 7 ( 2.6%) 7 ( 2.7%) 14 ( 2.7%) Acne 0 1 ( 0.4%) 0 1 ( 0.2%) Actinic keratosis 0 2 ( 0.8%) 0 2 ( 0.4%) Cutaneous symptom 0 0 1 ( 0.4%) 1 ( 0.2%) Dermatitis 1 ( 0.4%) 0 0 0 Dermatitis contact 0 0 1 ( 0.4%) 1 ( 0.2%) Dry skin 0 1 ( 0.4%) 0 1 ( 0.2%) Eczema 1 ( 0.4%) 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Eczema asteatotic 1 ( 0.4%) 0 0 0 Hyperkeratosis 1 ( 0.4%) 0 0 0 Miliaria 1 ( 0.4%) 1 ( 0.4%) 0 1 ( 0.2%) Pruritus 0 2 ( 0.8%) 0 2 ( 0.4%) Rash 0 0 1 ( 0.4%) 1 ( 0.2%) Skin irritation 1 ( 0.4%) 0 0 0 Skin swelling 1 ( 0.4%) 0 0 0 Skin ulcer 0 0 1 ( 0.4%) 1 ( 0.2%) Stasis dermatitis 0 0 1 ( 0.4%) 1 ( 0.2%) Urticaria 1 ( 0.4%) 0 2 ( 0.8%) 2 ( 0.4%) Social circumstances 1 ( 0.4%) 0 0 0 Menopause 1 ( 0.4%) 0 0 0 Primary system organ class 2q4 8q8/3 8q8/5 All 8mg Preferred term* N=276 N=266 N=260 N=526 MedDRA version 27.1 (100%) (100%) (100%) (100%) Surgical and medical procedures 0 1 ( 0.4%) 3 ( 1.2%) 4 ( 0.8%) Medical induction of coma 0 0 1 ( 0.4%) 1 ( 0.2%) Skin neoplasm excision 0 1 ( 0.4%) 0 1 ( 0.2%) Spinal fusion surgery 0 0 1 ( 0.4%) 1 ( 0.2%)

Tooth extraction 0 0 1 ( 0.4%) 1 ( 0.2%) V a scul ar di sorders 16 ( 5.8%) 23 ( 8.6%) 24 ( 9.2%) 47 ( 8.9%) Aortic aneurysm 0 1 ( 0.4%) 0 1 ( 0.2%) Aortic dilatation 1 ( 0.4%) 0 0 0 Arteriosclerosis 0 2 ( 0.8%) 0 2 ( 0.4%) Blood pressure fluctuation 1 ( 0.4%) 0 0 0 Brachiocephalic arteriosclerosis 0 0 1 ( 0.4%) 1 ( 0.2%) Deep vein thrombosis 1 ( 0.4%) 0 0 0 Embolism venous 0 0 1 ( 0.4%) 1 ( 0.2%) Essential hypertension 1 ( 0.4%) 0 0 0 Giant cell arteritis 1 ( 0.4%) 0 0 0 Hypertension 10 ( 3.6%) 19 ( 7.1%) 19 ( 7.3%) 38 ( 7.2%) Hypertensive emergency 1 ( 0.4%) 0 0 0 Hypotension 1 ( 0.4%) 1 ( 0.4%) 0 1 ( 0.2%) Peripheral arterial occlusive disease 0 0 1 ( 0.4%) 1 ( 0.2%) Peripheral artery occlusion 0 0 1 ( 0.4%) 1 ( 0.2%) Peripheral vascular disorder 0 0 1 ( 0.4%) 1 ( 0.2%) Scalp haematoma 1 ( 0.4%) 0 0 0 Thrombophlebitis 0 0 1 ( 0.4%) 1 ( 0.2%) Vein rupture 1 ( 0.4%) 0 0 0 Encoded 2 ( 0.7%) 1 ( 0.4%) 6 ( 2.3%) 7 ( 1.3%) Abnormal Urine Analysis (Blood, Leucocyte Esterase, app. Cloudy, Bacteria, squamous Epithelial Cells, 0 0 1 ( 0.4%) 1 ( 0.2%) Wbc Cells)

Basal Cell Skin Cancer 0 0 1 ( 0.4%) 1 ( 0.2%) Left Hip Labral Tear 0 0 1 ( 0.4%) 1 ( 0.2%) Normal Pressure Hydrocephalus 1 ( 0.4%) 0 0 0 Pain In 'Hie Lower Jaw Premolar On The Left Side 1 ( 0.4%) 0 0 0 Thalassemia 0 1 ( 0.4%) 0 1 ( 0.2%) Urinary Creatinine At Visit 11 (313 Mg/ DI) 0 0 1 ( 0.4%) 1 ( 0.2%) Urine Protein At Week 11 (39.4 Mg/ DI) 0 0 1 ( 0.4%) 1 ( 0.2%) Vertigo Due To Tension 0 0 1 ( 0.4%) 1 ( 0.2%) Primary system organ class 2q4 8q8/3 8q8/5 All 8mg Preferred term* N=276 N=266 N=260 N=526 MedDRA version 27.1 (100%) (100%) (100%) (100%)

Worsening Of Hypercholesterinaenia 0 0 1 ( 0.4%) 1 ( 0.2%) Adverse events are sorted by alphabetical order of the MedDRA classification.

A participant is counted only once within each primary SOC and preferred term.

TEAEs are defined as AEs that started in the time frame from first injection to the last injection (active or sham) in the study plus 30 days. For the participants who have not discontinued study treatment prematurely (i.e., are 'ongoing') at the Week 36 analysis, all AEs that started at first injection or later will be considered treatment-emergent.

* Reported term will be displayed in case of uncoded terms..

2q4: Aflibercept 2mg administered every 4 weeks.

Table 1-15. Ocular treatment-emergent serious adverse events of study eye: number of participants by primary system organ class and preferred term (safety analysis set)

Population group: Non-China sub-population

Primary system organ class

Preferred term 2q4 8q8/3 8q8/5 All 8mg

MedDRA version 27.1 _ N: =276 (100%) N=266 (100%) N=260 (100%) N=526 (100%)

Number (%) of participants with at least one such adverse event 6 ( 2.2%) 3 ( 1.1%) 4 ( 1.5%) 7 ( 1.3%)

Eye disorders 4 ( 1.4%) 0 4 ( 1.5%) 4 ( 0.8%)

Cataract 0 0 1 ( 0.4%) 1 ( 0.2%)

Macular hole 1 ( 0.4%) 0 0 0

Retinal artery occlusion 1 ( 0.4%) 0 0 0

Retinal detachment 1 ( 0.4%) 0 0 0

Retinal vasculitis 0 0 1 ( 0.4%) 1 ( 0.2%)

Retinal vein occlusion 0 0 1 ( 0.4%) 1 ( 0.2%)

Visual acuity reduced 1 ( 0.4%) 0 1 ( 0.4%) 1 ( 0.2%)

General disorders and administration site conditions 0 1 ( 0.4%) 0 1 ( 0.2%)

Oedema 0 1 ( 0.4%) 0 1 ( 0.2%)

Infections and infestations 2 ( 0.7%) 1 ( 0.4%) 0 1 ( 0.2%)

Endophthalmitis 2 ( 0.7%) 1 ( 0.4%) 0 1 ( 0.2%)

Injury, poisoning and procedural complications 0 1 ( 0.4%) 0 1 ( 0.2%) Primary system organ class Preferred term 2q4 8q8/3 8q8/5 All 8mg MedDRA version 27.1 N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%)

Skin laceration 0 1 ( 0.4%) 0 1 ( 0.2%) Adverse events are sorted by alphabetical order of the MedDRA classification.

A participant is counted only once within each primary SOC and preferred term.

TES AEs are defined as serious AEs that started in the time frame from first injection to the last injection (active or sham) in the study plus 30 days. For the participants who have not discontinued study treatment prematurely (i.e., are 'ongoing') at the Week 36 analysis, all AEs that started at first injection or later will be considered treatment-emergent.

2q4: Aflibercept 2mg administered every 4 weeks.

Table 1-16. Non-ocular treatment-emergent serious adverse events: number of participants by primary system organ class and preferred term (safety analysis set)

Population group: Non-China sub-population

Primary system organ class

Preferred term* 2q4 8q8/3 8q8/5 All 8mg MedDRA version 27.1 N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%) Number (%) of participants with at least one such adverse event 22 ( 8.0%) 20 ( 7.5%) 18 ( 6.9%) 38 ( 7.2%) Blood and lymphatic system disorders 1 ( 0.4%) 0 0 0 Pancytopenia 1 ( 0.4%) 0 0 0 Cardiac disorders 1 ( 0.4%) 3 ( 1.1%) 1 ( 0.4%) 4 ( 0.8%) Acute myocardial infarction 1 ( 0.4%) 0 0 0 Atrial fibrillation 0 1 ( 0.4%) 0 1 ( 0.2%) Bradycardia 0 2 ( 0.8%) 0 2 ( 0.4%) Coronary artery disease 0 1 ( 0.4%) 0 1 ( 0.2%) Myocardial infarction 0 0 1 ( 0.4%) 1 ( 0.2%) Ear and labyrinth disorders 0 1 ( 0.4%) 0 1 ( 0.2%) Vertigo 0 1 ( 0.4%) 0 1 ( 0.2%) Gastrointestinal disorders 1 ( 0.4%) 3 ( 1.1%) 1 ( 0.4%) 4 ( 0.8%) Abdominal pain upper 0 0 1 ( 0.4%) 1 ( 0.2%) Femoral hernia incarcerated 0 1 ( 0.4%) 0 1 ( 0.2%) Hiatus hernia 0 1 ( 0.4%) 0 1 ( 0.2%) Lower gastrointestinal haemorrhage 0 1 ( 0.4%) 0 1 ( 0.2%) Primary system organ class Preferred term* 2q4 8q8/3 8q8/5 All 8mg MedDRA version 27.1 _ N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%)

Small intestinal obstruction 1 ( 0.4%) 0 0 0 General disorders and administration site conditions 2 ( 0.7%) 0 0 0 General physical health deterioration 1 ( 0.4%) 0 0 0 Incarcerated hernia 1 ( 0.4%) 0 0 0 Hepatobiliary disorders 0 2 ( 0.8%) 1 ( 0.4%) 0.6%) Cholecystitis acute 0 1 ( 0.4%) 0 0.2%) Cholecystitis chronic 0 0 1 ( 0.4%) 0.2%) Hepatic cyst 0 1 ( 0.4%) 0 0.2%) Immune system disorders 0 1 ( 0.4%) 0.2%) Anaphylactic reaction 0 1 ( 0.4%) 0.2%) Infections and infestations 5 ( 1.8%) 7 ( 2.6%) 5 ( 1.9%) 2.3%) Bronchitis 0 0 1 ( 0.4%) 0.2%) COVID-19 1 ( 0.4%) 1 ( 0.4%) 0 0.2%) Diverticulitis 0 2 ( 0.8%) 0 0.4%) Gastroenteritis 0 1 ( 0.4%) 0 0.2%) Herpes zoster 1 ( 0.4%) 0 0 Infectious pleural effusion 0 1 ( 0.4%) 0 0.2%) Localised infection 1 ( 0.4%) 0 0 Osteomyelitis 0 0 1 ( 0.4%) 0.2%) Pneumonia 2 ( 0.7%) 1 ( 0.4%) 0 0.2%) Pneumonia parainfluenzae viral 0 0 1 ( 0.4%) 0.2%) Pneumonia pseudomonal 0 0 1 ( 0.4%) 0.2%) Sepsis 0 2 ( 0.8%) 0 0.4%) Urinary tract infection 0 0 1 ( 0.4%) 0.2%) Injury, poisoning and procedural complications 2 ( 0.7%) 3 ( 1.2%) 1.0%) Brain herniation 0 0 1 ( 0.4%) 0.2%) Humerus fracture 1 ( 0.4%) 0 0 Pelvic fracture 1 ( 0.4%) 0 0 Postoperative thoracic procedure complication 0 1 ( 0.4%) 0 0.2%) Procedural pain 0 0 1 ( 0.4%) 0.2%) Snake bite 0 1 ( 0.4%) 0 0.2%) Subdural haematoma 0 0 1 ( 0.4%) 0.2%)

Tendon rupture 0 0 1 ( 0.4%) 0.2%) Investigations 0 0 1 ( 0.4%) 1 ( 0.2%) Blood urine present 0 0 1 ( 0.4%) 1 ( 0.2%) Metabolism and nutrition disorders 1 ( 0.4%) 0 1 ( 0.4%) 1 ( 0.2%) Hypoglycaemia 1 ( 0.4%) 0 0 0 Primary system organ class Preferred term* 2q4 8q8/3 8q8/5 All 8mg MedDRA version 27.1 N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%)

Type 2 diabetes mellitus 0 0 1 ( 0.4%) 1 ( 0.2%) Musculoskeletal and connective tissue disorders 0 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Haemarthrosis 0 0 1 ( 0.4%) 1 ( 0.2%) Osteoarthritis 0 1 ( 0.4%) 0 1 ( 0.2%) Neoplasms benign, malignant and unspecified (incl cysts and polyps) 3 ( 1.1%) 2 ( 0.8%) 3 ( 1.2%) 5 ( 1.0%) Colon cancer 0 0 1 ( 0.4%) 1 ( 0.2%) Lung neoplasm malignant 0 0 1 ( 0.4%) 1 ( 0.2%) Metastatic neoplasm 1 ( 0.4%) 0 0 0 Oesophageal carcinoma 0 1 ( 0.4%) 0 1 ( 0.2%) Prostate cancer metastatic 0 0 1 ( 0.4%) 1 ( 0.2%) Prostate cancer stage II 0 1 ( 0.4%) 0 1 ( 0.2%) Squamous cell carcinoma of lung 1 ( 0.4%) 0 0 0

T-cell lymphoma 1 ( 0.4%) 0 0 0 Nervous system disorders 5 ( 1.8%) 2 ( 0.8%) 1 ( 0.4%) 3 ( 0.6%) Atypical migraine 1 ( 0.4%) 0 0 0 Cerebellar infarction 1 ( 0.4%) 0 0 0 Cerebellar stroke 1 ( 0.4%) 0 0 0 Cerebral infarction 0 0 1 ( 0.4%) 1 ( 0.2%) Cerebrovascular accident 1 ( 0.4%) 0 0 0 Epilepsy 1 ( 0.4%) 1 ( 0.4%) 0 1 ( 0.2%) Haemorrhage intracranial 1 ( 0.4%) 0 0 0 Lacunar infarction 1 ( 0.4%) 0 0 0 Sciatica 0 1 ( 0.4%) 0 1 ( 0.2%) Psychiatric disorders 1 ( 0.4%) 1 ( 0.4%) 0 1 ( 0.2%) Anxiety 0 1 ( 0.4%) 0 1 ( 0.2%) Mental status changes 1 ( 0.4%) 0 0 0 Renal and urinary disorders 1 ( 0.4%) 0 3 ( 1.2%) 3 ( 0.6%) Calculus bladder 0 0 1 ( 0.4%) 1 ( 0.2%) Diabetic nephropathy 0 0 1 ( 0.4%) 1 ( 0.2%) Nephrolithiasis 1 ( 0.4%) 0 0 0 Urinary tract discomfort 0 0 1 ( 0.4%) 1 ( 0.2%) Reproductive system and breast disorders 1 ( 0.4%) 0 2 ( 0.8%) 2 ( 0.4%) Benign prostatic hyperplasia 0 0 1 ( 0.4%) 1 ( 0.2%) Pelvic organ prolapse 1 ( 0.4%) 0 0 0 Uterine haemorrhage 0 0 1 ( 0.4%) 1 ( 0.2%) Respiratory, thoracic and mediastinal disorders 1 ( 0.4%) 0 1 ( 0.4%) 1 ( 0.2%) Chronic obstructive pulmonary disease 0 0 1 ( 0.4%) 1 ( 0.2%) Primary system organ class Preferred term* 2q4 8q8/3 8q8/5 All 8mg MedDRA version 27.1 N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%) Epistaxis 1 ( 0.4%) 0 0 0

Respiratory failure 0 0 1 ( 0.4%) 1 ( 0.2%) Surgical and medical procedures 0 0 1 ( 0.4%) 1 ( 0.2%) Medical induction of coma 0 0 1 ( 0.4%) 1 ( 0.2%) Vascular disorders 2 ( 0.7%) 0 1 ( 0.4%) 1 ( 0.2%) Giant cell arteritis 1 ( 0.4%) 0 0 0 Hypertensive emergency 1 ( 0.4%) 0 0 0 Peripheral artery occlusion 0 0 1 ( 0.4%) 1 ( 0.2%) Uncoded 0 0 1 ( 0.4%) 1 ( 0.2%) Left Hip Labral Tear 0 0 1 ( 0.4%) 1 ( 0.2%) Adverse events are sorted by alphabetical order of the MedDRA classification. A participant is counted only once within each primary SOC and preferred term. TES AEs are defined as serious AEs that started in the time frame from first injection to the last injection (active or sham) in the study plus 30 days. For the participants who have not discontinued study treatment prematurely (i.e., are 'ongoing') at the Week 36 analysis, all AEs that started at first injection or later will be considered treatment-emergent. * Reported term will be displayed in case of uncoded terms..

2q4: Aflibercept 2mg administered every 4 weeks.

Table 1-17. Deaths: number of participants with adverse events with fatal outcome by primary system organ class and preferred term (safety analysis set)

Population group: Non-China sub-population

Primary system organ class Preferred term 2q4 8q8/3 8q8/5 All 8mg MedDRA version 27.1 N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%)

Number (%) of participants with at least one such adverse event 2 ( 0.7%) 2 ( 0.8%) 3 ( 1.2%) 5 ( 1.0%) Infections and infestations 1 ( 0.4%) 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Bronchitis 0 0 1 ( 0.4%) 1 ( 0.2%) Pneumonia 1 ( 0.4%) 0 0 0

Sepsis 0 1 ( 0.4%) 0 1 ( 0.2%) Primary system organ class Preferred term 2q4 8q8/3 8q8/5 All 8mg MedDRA version 27.1 N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%) Injury, poisoning and procedural complications 0 0 1 ( 0.4%) 1 ( 0.2%)

Brain herniation 0 0 1 ( 0.4%) 1 ( 0.2%) Neoplasms benign, malignant and unspecified (incl cysts and polyps) 0 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) Oesophageal carcinoma 0 1 ( 0.4%) 0 1 ( 0.2%) Prostate cancer metastatic 0 0 1 ( 0.4%) 1 ( 0.2%) Nervous system disorders 1 ( 0.4%) 0 0 0

Haemorrhage intracranial 1 ( 0.4%) 0 0 0 Adverse events are sorted by alphabetical order of the MedDRA classification.

2q4: Aflibercept 2mg administered every 4 weeks.

Results at week 36 (updated)

[0360] Aflibercept 8 mg groups achieved robust visual outcomes, with non-inferior BCVA gains compared with the aflibercept 2 mg group at Week 36. Most patients in the aflibercept 8 mg groups maintained their assigned Q8 intervals through Week 36. Robust and comparative CRT changes from BL were observed in the 8q8/3, 8q8/5, and 2q4 groups at Week 36.

Aflibercept 8 mg was well tolerated with a safety profile consistent with the established safety of aflibercept 2 mg in patients with RVO, with no new safety signals. Of the 892 patients randomly assigned and treated, nearly 94% completed the 36-Week study visit. See Table 1-18.

Table 1-18. Summary of Patient Disposition at Week 36

2q4 8q8/3 8q8/5 Total

Randomized, n 302 294 298 894

T reated 301 (99.7) 293 (99.7) 298 (100) 892 (99.8)

Completing Week 36 287 (95.0) 278 (94.6) 273 (91.6) 838 (93.7)

Discontinued before Week 36 14 (4.6) 15 (5.1) 25 (8.4) 54 (6.0)

Reasons for discontinuation

Withdrawal by subject 8 (2.6) 8 (2.7) 16 (5.4) 32 (3.6)

Adverse events 2 (0.7) 0 2 (0.7) 4 (0.4)

Death 2 (0.7) 2 (0.7) 3 (1.0) 7 (0.8)

Lost to follow-up 2 (0.7) 3 (1.0) 3 (1.0) 8 (0.9) a

Other 0 2 (0.7) 1 (0.3) 3 (0.3)

Data are n (%) unless otherwise indicated. ^alncludes “logistical problem”, “physician decision”, and “protocol deviation”. Categories were combined to maintain masking of individual patients

[0361] The baseline demographics and disease characteristics were balanced between the three treatment groups. Overall, the mean age was 66 years and 48% of patients were female, with a baseline BCVA of approximately 55 letters. See Table 1-19.

Table 1-19. Baseline Demographics and Disease Characteristics

2q4 8q8/3 8q8/5 Total (n=301) (n=293) (n=298) (n=892) Age (years) 65.9 (11.7) 65.8 (11.5) 65.8 (11.5) 65.9 (11.6) Female, n (%) 144 (47.8) 136 (46.4) 146 (49.0) 426 (47.8) Race, n (%)

Asian 101 (33.6) 91 (31.1) 97 (32.6) 289 (32.4) Black or African American 8 (2.7) 7 (2.4) 9 (3.0) 24 (2.7) White 178 (59.1) 173 (59.0) 177 (59.4) 528 (59.2) a

Other 1 (0.3) 0 4 (1-3) 5 (0.6) Not reported 13 (4.3) 22 (7.5) 11 (3.7) 46 (5.2) Hispanic or Latino, n (%) 22 (7.3) 25 (8.5) 14 (4.7) 61 (6.8) Medical history of hypertension, n

187 (62.1) 192 (65.5) 196 (65.8) 575 (64.5) (%)

RVO type, n (%)

BRVO 149 (49.5) 159 (54.3) 159 (53.4) 467 (52.4) CRVO 117 (38.9) 99 (33.8) 102 (34.2) 318 (35.7) HRVO 35 (11.6) 35 (11.9) 37 (12.4) 107 (12.0) BCVA (ETDRS letters) 54.1 (14.3) 55.2 (13.6) 55.4 (13.4) 54.9 (13.8) CRT (pm)' 651 (240) 626 (230) 609 (213) 629 (229)

Full analysis set. Data are mean (SD) unless otherwise indicated. ^a ncludes American Indian or Alaskan native, native Hawaiian or other Pacific Islander, and Multiple. ^bReading center assessed ^c2q4, n=300; Total, n=891. SD, standard deviation.

[0362] At Week 36, the robust BCVA gains demonstrated with aflibercept 8 mg were noninferior (with a margin of 4 letters) to aflibercept 2 mg. Least squares mean differences compared to 2q4 were -0.1 and 0.8 for 8q8/3 and 8q8/5, respectively, with nominal p-values less than 0.0001 for both treatment groups. See Tables 1-20 and 1-21.

Table 1-20. BCVA Change over Time (LS mean change in BCVA from baseline (ETDRS letters))

Week 2q4 (n=301) 8q8/3 (n=293) 8q8/5 (n=298) 0 0.0 0.0 0.0 4 11.6 10.8 11.9 8 14.1 14.1 14.8 12 15.2 15 16

16 16.1 14.7 16.9

20 16.6 16 17.6

24 17 16.3 16.9

28 17.3 16.9 17.9

32 17.3 17 17.7

36 17.5 17.4 18.3

Full analysis set. MMRM. LS means were generated for the full analysis set using a mixed model for repeated measures with baseline CRT as a covariate; treatment group (aflibercept 8q8/3, 8q8/5, 2q4), visit, and stratification variables (geographic region [Japan vs Asian-Pacific vs Europe vs America], BL BCVA [<60 vs >60 letters], RVO type [CRVO/HRVO vs BRVO]) as fixed factors; and terms for the interaction between baseline CRT and visit and treatment and visit. BL, baseline; Cl, confidence interval; LS, least squares; MMRM, mixed model for repeated measurements.

Table 1-21. Summary of BCVA Change at Week 36

Difference

LS mean 1 -sided test for

in LS 2-sided Absolute mean change from non-inferiority at

means 95% Cl BCVA at Week 36 BL at Week 36 4-letter margin

versus 2q4

2q4 17.5 72.0

-2.0,

8q8/3 17.4 -0.1 p<0.0001 72.8

1.9

-1.1,

8q8/5 18.3 0.8 p<0.0001 74.6

2.7

[0363] The robust decrease in CRT from baseline to Week 36 was comparative between the aflibercept 8 mg and aflibercept 2 mg treatment groups, ranging from -371 to -370 pm. See Tables 1-22 and 1-23.

Table 1-22. Central Retinal Thickness Changes over Time (LS mean change in CRT from baseline (micrometers))

Week 2q4 8q8/3 8q8/5

0 0.0 0.0 0.0 4 -334.5 -342.4 -342.5 8 -358.6 -359.2 -357.6 12 -362.3 -364.3 -364.2

16 -365.7 -341.6 -365.7

20 -367.3 -369.2 -368

24 -366.3 -359.8 -353.3

28 -366.8 -370.8 -369

32 -369.5 -364.7 -363.2

36 -370.8 -370.9 -369.5

Full analysis set. LS means were generated for the full analysis set using a mixed model for repeated measures with baseline CRT as a covariate; treatment group (aflibercept 8q8/3, 8q8/5, 2q4), visit, and stratification variables (geographic region [Japan vs Asian-Pacific vs Europe vs America], BL BCVA [<60 vs >60 letters], RVO type [CRVO/HRVO vs BRVO]) as fixed factors; and terms for the interaction between baseline CRT and visit and treatment and visit. MMRM.

Table 1-23. Absolute Mean CRT (micrometers) at Week 36 Group Absolute mean CRT (micrometers) 2q4 257

8q8/3 258

8q8/5 259

[0364] Most, 94%, of patients treated with aflibercept 8 mg maintained every 8 weeks dosing intervals through Week 36. See Table 1-24.

Table 1-24 Maintenance of Q8 Dosing Interval Through Week 36

Group Q4 dosing interval Q8 dosing interval 8q8/3 (n=293) 11.5% 88.5%

8q8/5 (n=298) 6.6% 93.4%

[0365] Most patients treated with aflibercept 8 mg and aflibercept 2 mg had a last assigned dosing interval of 8 weeks or greater at Week 36. At Week 36, 69% of patients in the 8q8/3 group were last assigned to an every 12-week dosing interval and approximately, 25% of patients were assigned to an every 8-week dosing interval. 93% of patients in the 8q8/5 group were last assigned to every 8-week dosing intervals, however this treatment group did not have the option to extend their dosing intervals until Week 40 of the study. Approximately 76% of patients randomly assigned to the 2q4 group achieved a last assigned dosing interval of every 8 weeks at Week 36. The observed durability and robust response to aflibercept 8 mg was achieved with fewer active injections compared with aflibercept 2 mg, with a mean of 6.0 and 6.7 active injections in the 8q8/3 and 8q8/5 groups compared with a mean of 8.5 active injections for the 2q4 group through Week 36. See Tables 1 -25 and 1 -26.

Table 1-25. Last Assigned Dosing Interval at Week 36

Group Q4 dosing interval Q8 dosing interval Q12 dosing interval 2q4 (n=301) 24.4 75.6

8q8/3 (n=293) 6.1 24.8 69.1

8q8/5 (n=298) 6.6 93.4

Patients completing Week 36: 2q4 n=287; 8q8/3 n=278, 8q8/5 n=273. ^aFull analysis set. Q12, every 12 weeks.

Table 1-26. Mean Number of Injections through Week 36^a

2q4 8q8/3 8q8/5

8.5 6.0 6.7

[0366] Aflibercept 8 mg was well-tolerated with a safety profile consistent with the established safety of aflibercept 2 mg in patients with RVO, with no new safety signals.

Table 1-27. Ocular and Non-Ocular Safety through Week 36

N (SAF) 301 293 298 591

98 117 97 214 Ocular TEAEs, n (%)

(32.6%) (39.9%) (32.6%) (36.2%) Ocular SAEs, n (%) 8 (2.7%) 4 (1.4%) 4 (1.3%) 8 (1.4%) Intraocular inflammation, n (%) 4 (1.3%) 2 (0.7%) 1 (0.3%) 3 (0.5%)

Anterior chamber cell 1 (0.3%) 0 0 0 Eye inflammation 1 (0.3%) 0 0 0 Iritis 0 1 (0.3%) 0 1 (0.2%) Uveitis 1 (0.3%) 1 (0.2%)

0 0

Endophthalmitis 2 (0.7%) 1 (0.3%) 0 1 (0.2%) Non-ocular SAEs, n (%) 26 (8.6%) 22 (7.5%) 28 (9.4%) 50 (8.5%)

APTC events, n (%) 5 (1.7%) 0 3 (1.0%) 3 (0.5%)

11876WO01 Deaths, n (%) 2 (0.7%) 2 (0.7%) 3 (1.0%) 5 (0.8%)

[0367] Study of Week 36 efficacy outcomes by baseline (BL) characteristics in the QUASAR trial. Study of Week 36 efficacy outcomes by baseline (BL) characteristics in the QUASAR trial. Aflibercept 8 mg provided robust visual gains in patients with MEfRVO, regardless of baseline characteristics. In QUASAR (NGT05850520), patients with treatment-naive MEfRVO were randomly assigned to aflibercept 8 mg every 8 weeks after 3 (8q8/3; n=293) or 5 (8q8/5; n=298) initial monthly injections versus 2 mg every 4 weeks (2q4; n=301). The treatment effects of 8q8/3 and 8q8/5 versus 2q4 on the primary endpoint of mean change from baseline in best-corrected visual acuity (BOVA) at Week 36 were evaluated by baseline characteristics (e.g. age, sex, ethnicity, BCVA, central retinal thickness [CRT]). The primary endpoint of non-inferiority in BCVA gains at Week 36 was met, with fewer active injections with 8q8/3 and 8q8/5 versus 2q4. Improvements in BCVA with 8q8/3 and 8q8/5 were comparable to that of 2q4, regardless of baseline age, sex, ethnicity, BCVA, or CRT. The safety profile of aflibercept 8 mg was consistent with the established safety profile of aflibercept 2 mg.

[0368] Results from the QUASAR study: Comparable vision gains with aflibercept 8 mg and 2 mg in treatment-naive macular edema secondary to retinal vein occlusion [0369] The purpose of this study was to determine the effect of baseline age, sex, race, ethnicity, retinal vein occlusion (RVO) subtype, best-corrected visual acuity (BCVA), and central subfield retinal thickness (CRT) on the efficacy of aflibercept 8 mg and aflibercept 2 mg in the QUASAR (NCT05850520) trial in patients with treatment-naive macular edema following RVO.

[0370] QUASAR is an ongoing, 64-week, randomized, double-masked, active-controlled, Phase 3 study of adult patients with macular edema secondary to RVO (including branch (BRVO), central (CRVO), and hemiretinal vein occlusion (HRVO) subtypes). QUASAR is a global study being conducted in 237 sites across 27 countries.

[0371] In QUASAR, patients were randomly assigned 1:1:1 to receive aflibercept 8 mg injection administered every 8 weeks, after 3 initial monthly injections (8q8/3) or 5 initial monthly injections (8q8/5), or aflibercept 2 mg every 4 weeks (2q4). The dosing intervals could be shortened by 4 weeks starting from Week (W) 16 for the 8q8/3 group, from W24 for the 8q8/5 group, and from W40 for the 2q4 group, and extended by 4 weeks from W32 for the 8q8/3 and 2q4 groups and from W40 for the 8q8/5 group, based on defined dosing regimen modification criteria for shortening and extension. The minimum dosing interval was 4 weeks. The effect of aflibercept on the primary endpoint of mean change from baseline in BCVA was assessed

according to baseline age (<55, >55-65, >65-75, and >75 years), sex, race (Asian and White), ethnicity (Hispanic and non-Hispanic), RVO subtype (BRVO and CRVO/HRVO), BCVA letter score categories (<60 letters and >60 letters), and CRT categories (<581 pm and >581 pm). The number of active injections from baseline and dosing intervals were analyzed descriptively.

[0372] BCVA gains from baseline with aflibercept 8q8/3 and 8q8/5 were comparable to those of 2q4 at W36, regardless of baseline age, sex, race, ethnicity, or RVO subtype. Least squares mean (standard error [SE]) change from baseline BCVA letter scores at W36 were comparable by baseline BCVA category across the aflibercept 8q8/3 and 8q8/5 versus 2q4 treatment groups (<60 letters: 21.0 [1.1] and 22.1 [1.0] vs 21.2 [1.1]; >60 letters: 13.0 [0.7] and 13.5 [0.7] vs 13.0 [0.9], respectively). Likewise, least squares mean (SE) change from baseline BCVA letter scores at W36 were similar by baseline CRT category across the aflibercept 8q8/3 and 8q8/5 versus 2q4 treatment groups (<581 pm: 14.0 [1.0] and 15.9 [0.8] vs 16.4 [0.7]; >581 pm: 20.9 [1.0] and 20.7 [1.1] vs 18.7 [1.2], respectively). The observed BCVA gains were achieved with fewer mean active injections with aflibercept 8q8/3 (6.1) and 8q8/5 (6.9) versus 2q4 (8.8). Most patients, 90.9% (8q8/3: 246/278 [88.5%]; 8q8/5: 255/273 [93.4%]), who were treated with aflibercept 8 mg and who completed W36 maintained 8-week dosing intervals. The latest BCVA and durability results with data collected at later timepoints in the study will also be presented.

[0373] In patients with macular edema secondary to RVO, similar BCVA gains were achieved with aflibercept 8 mg compared to aflibercept 2 mg in all subgroups regardless of baseline characteristic evaluated. These outcomes were consistent with the full study population. The majority (90.9%) of patients treated with aflibercept 8 mg maintained 8-week dosing intervals through W36. Overall, aflibercept 8 mg provides robust visual outcomes with fewer active injections compared with aflibercept 2 mg.

[0374] Study to describe outcomes in patients with CRVO/HRVO or BRVO receiving intravitreal aflibercept 8mg every 8 weeks (W), after 3 (8q8/3) or 5 (8q8/5) initial monthly injections vs 2mg every 4 W (2q4). Aflibercept 8mg achieved robust vision gains and anatomic improvements comparable to 2mg in patients with CRVO/HRVO or BRVO, with fewer injections. In QUASAR (NCT05850520), patients were randomly assigned to receive 8q8/3 (n=293), 8q8/5 (n=298), or 2q4 (n=301). Visual, anatomic, and interval extension outcomes were evaluated by RVO subgroup: CRVO/HRVO or BRVO. Improvement in BCVA from baseline to Week 36 was comparable with 8q8/3 and 8q8/5 vs 2q4 in patients with CRVO/HRVO (least squares mean change [letters]: +16.6 and +17.2 vs +15.9) and BRVO (+18.3 and +19.2 vs +19.0), with fewer mean (SD) injections (CRVO/HRVO: 6.1 [0.5] and 6.9

[0.6] vs 8.7 [0.9] and BRVO: 6.1 [0.6] and 6.9 [0.5] vs 8.8 [0.6]). Similar reduction in CRT was observed in all 3 arms in both subgroups. Most patients receiving 8q8/3 and 8q8/5 maintained q8 dosing in both groups (CRVO/HRVO: 88.4% and 91.1% and BRVO: 88.6% and 95.3%). No new safety signals were identified.

[0375] A high proportion of patients in both aflibercept 8mg groups achieved >5- 10- and 15-letter gains at Week 36 with fewer injections than the 2q4 group. See Table 1-28.

Table 1-28. Proportion of Patients With >5-, 10- or 15-Letter Loss or Gain at Week 36

2q4 8q8/3 8q8/5

(n=301) (n=293) (n=298)

>15-letter loss 1.4 1.8 0

>10-letter loss 1.8 2.6 0.8

>5-letter loss 3.6 4.4 2.3

>5-letter gain 89.7 87.9 91

>10-letter gain 79 76.1 80.8

>15-letter gain 59.1 58.5 62.8

FAS, observed cases.

Results at week 36 (updated)

[0376] There were 1282 enrolled participants in 27 countries/regions (Europe, America, Japan and APAC), of whom 388 participants were screen failures.

[0377] Overall, 894 participants at 237 sites were randomized and 892 participants were treated. Of these, 838 participants completed the treatment phase through Week 36.

[0378] 50 participants did not complete the study through Week 36, with no notable differences between the treatment groups with regard to the reasons for premature discontinuation. The most common reasons for discontinuation were withdrawal by subject and lost to follow-up.

[0379] Of note, the number of participants for whom the primary reason for not completing study through Week 36 was reported as “Adverse event” are not necessarily the same as the number of participants with ocular or non-ocular TEAEs resulting in discontinuation of study intervention, because for the participants who discontinued study intervention due to a TEAE, the participant could have remained in the study beyond Week 36 or, if discontinued, the primary reason for discontinuation could be a different reason other than AE (e.g. death).

[0380] Overall, 168 (18.8%) participants reported important protocol deviations. The most frequent (>5%) important protocol deviations were related to the “treatment deviations” category.

[0381] In general, the frequency of participants with important protocol deviations from baseline through Week 36 was similar across the treatment groups, except for “treatment deviations” which were more common in the 8q8/3 group (14.6%) than in the 2q4 and 8q8/5 groups (9.9% and 8.4%, respectively).

[0382] The FAS (Full Analysis Set) and SAF (Safety Analysis Set) populations were identical comprising 892 participants each.

[0383] Overall, the 3 treatment groups were well balanced and there were no clinically relevant differences across the treatment groups for the demographics or disease characteristics at baseline.

The following numerical differences were noted between treatment groups:

• History of mild renal impairment was more prevalent in the 2q4 group compared to the All 8 mg (31.2% vs 25.5%, respectively).

• Most participants in all treatment groups were Not Hispanic or Latino, although there were slightly more in the 8q8/5 group compared to the 2q4 and 8q8/3 groups (91.6%, 88.7% and 86.7%, respectively); however, no differences were noted when comparing 2q4 vs All 8 mg groups (88.7% vs 89.2%, respectively).

• History of hypertension was slightly less prevalent in the 2q4 group compared to the All 8 mg (62.1% vs 65.7%, respectively).

[0384] The overall proportion of male and female participants was 52.2% and 47.8%, respectively. The mean age was 65.9 years (range 23 to 95 years) overall. Most participants were White (59.2%) or Asian (32.4%) and of Not Hispanic or Latino (89.0%) ethnic origin.

[0385] Overall, no substantial differences in demographics and baseline characteristics were observed across the different RVO types (BRVO and CRVO/HRVO), except for minor differences in sex, race, history of diabetes and renal impairment that were considered not clinically relevant.

The following differences (>5%) were noted by RVO type:

• The proportion of female participants was higher in BRVO participants than for CRVO/HRVO participants (53.1% vs 41.9%, respectively).

• The proportion of participants of Asian race was higher for BRVO type than for CRVO/HRVO type (38.8% vs 25.4%, respectively)

• The proportion of participants with medical history of normal renal function was higher for BRVO than for CRVO/HRVO types (67.9% vs 59.3%, respectively).

• The proportion of participants with medical history of diabetes was lower for BRVO than for CRVO/HRVO types (12.6% vs 25.2%, respectively).

Overall, no notable differences were noted across treatment groups.

Based on reading center assessment, the proportion of participants diagnosed with macular edema secondary to BRVO, CRVO and HRVO were 52.4%, 35.7% and 12.0%, respectively.

[0386] Overall, the 2q4, 8q8/3 and 8q8/5 groups were well balanced with respect to the specific baseline disease characteristics of the study eye.

[0387] The mean (SD) BCVA using ETDRS letter score averaged over all treatment groups at baseline was 54.9 (13.8) letters; 55.7% of participants had an ETDRS letter score <60 and 44.3% of >60 letters. The mean (SD) value averaged over all treatment groups at baseline for intraocular pressure in the study eye was 14.7 (3.1) mmHg, and for CST was 628.8 (228.5) pm. The following differences (>5%) were noted between treatment groups:

• CRVO type based on reading center assessment was slightly more prevalent in the 2q4 group (38.9% participants) compared to the 8q8/3 and 8q8/5 groups (33.8% and 34.2%, respectively). However, RVO types were well balanced across all treatment groups when using investigator assessment for strata assignment at randomization.

• Most participants in all treatment groups had perifoveal and parafoveal ischemia by FA, although there were slightly less in the 2q4 group compared to the “All 8 mg” group (59.1% vs 65.0%, respectively).

• The mean values of CST at baseline were slightly higher in the 2q4 group (651.0 pm) compared to 8q8/3 and 8q8/5 groups (626.1 and 609.2 pm, respectively).

[0388] A similar distribution in baseline disease characteristics of the study eye were observed across the different RVO types, except for the following differences (>5%):

• The mean (SD) BCVA using ETDRS letter score averaged over all treatment groups at baseline was slightly higher in participants with BRVO type (58.2 [12.0] letters) compared to CRVO/HRVO type (51.3 [14.7] letters); with more participants having a ETDRS letter score >60 letters (53.7% vs 33.9%, respectively).

• The mean (SD) value averaged over all treatment groups at baseline for CST in the study eye was lower in participants with BRVO type (547.2 [166.8] pm) than with CRVO/HRVO type (718.7 [252.5] pm).

Overall, no notable differences were noted across treatment groups.

[0389] Ocular medical history findings in the study eye included the primary SOCs Eye disorders and Surgical and medical procedures. In total, retinal vein occlusion, cataract, macular oedema, vitreous detachment and cataract operation were the most frequently (>10%) reported ocular medical history findings in the study eye.

[0390] The incidence of non-ocular medical history findings was generally similar between the 2q4, the 8q8/3, and the 8q8/5 groups. Overall, 91.5% of the total population of the SAP had at least one non-ocular medical history finding. The most commonly reported SOO (>30%) was Vascular disorders, followed by Metabolism and nutrition disorders, and Surgical and medical procedures. Non-ocular medical history findings by PT reported in >10% of the total population were hypertension, hypercholesterolaemia, hyperlipidaemia, type 2 diabetes mellitus, and gastrooesophageal reflux disease.

[0391] Prior medication was medication that was taken before the start of the study drug intake, regardless of when it ended.

[0392] There was no clinically relevant difference in use of prior medications between treatment groups.

The most frequently (>80%) used prior medications by ATC class were:

• Drugs for the sensory organs (99.7%), in particular “ophthalmologicals” (99.7%)

• Various drugs (99.2%), in particular “diagnostic agents” (98.7%), and

• Drugs for the cardiovascular system (82.8%).

[0393] Concomitant medication was medication that was taken during the treatment phase, between the first and last study drug intake, regardless of when it started or ended.

[0394] The use of concomitant medication through Week 36 was well balanced across the treatment groups; no differences >10% points across the treatment groups were noted for any medication class or subclass.

[0395] The most frequently used concomitant medications (>80% by ATC class) belonged to the following ATC classes:

• Sensory Organs (100%), in particular “ophthalmologicals” (100%)

• Various (98.2%), in particular “diagnostic agents” (98.0%)

• Alimentary Tract and Metabolism (88.2%), in particular “stomatological preparations” (81.5%)

• Cardiovascular System (91.1%)

• Dermatologicals (96.7%),

• Respiratory system (88.2%), and

• Nervous system (80%).

[0396] The mean number of active injections through Week 36 in the SAP population was 8.5, 6.0 and 6.7 in the 2q4, 8q8/3 and 8q8/5 treatment groups, respectively. For those 838 participants completing the Week 36 treatment period (Week 36 completers), the mean number of active injections was 8.8, 6.1 and 6.9 in the 2q4, 8q8/3 and 8q8/5 treatment groups, respectively.

[0397] Among the Week 36 completers, the target dosing interval of Q8 was maintained through Week 36 in 90.9% of participants in the All 8 mg group.

[0398] From Week 32 participants meeting DRM criteria in the 2q4 and 8q8/3 groups could have their intervals extended by 4 weeks to Q8 and Q12, respectively. At Week 36, 75.6% of participants in the 2q4 group had a last intended interval of Q8 compared to 93.4% in the 8q8/5 group; whereas 93.9% of participants in the 8q8/3 group had a last intended interval of >8 weeks (24.8% and 69.1% with a last intended interval of Q8 and Q12, respectively) at Week 36. For participants in the 8q8/5group the dosing interval extension was not allowed until Week 40. Less than 10% of participants in the All 8 mg group met criteria for shortening to Q4 dosing interval. For participants in the 2q4 group the dosing interval shortening was not allowed until Week 40.

[0399] No substantial differences in the exposure to study intervention was observed across the different RVO types.

[0400] From baseline through Week 36, few participants reported fellow eye injections, which were at similar frequencies across all treatment groups (2q4: 3.0%; 8q8/3: 1.7%; 8q8/5: 1.7%); the mean (SD) number of injections was 3.7 (1.9), 3.4 (2.8) and 4.8 (2.3) in the 2q4, 8q8/3 and 8q8/5 groups, respectively.

[0401] Mean treatment compliance through Week 36 was high (>96%) in each of the 3 treatment groups and >81% of participants in each group received >90 to <100% of the total number of planned injections [sham or active] in the study eye through Week 36.

[0402] The change from baseline in BCVA measured by the ETDRS letter score at Week 36 was the primary efficacy endpoint. In the primary analysis using an MMRM, both 8q8/3 and 8q8/5 treatments demonstrated non-inferiority to 2q4 treatment with respect to the primary efficacy endpoint using the noninferiority margin of 4 letters with LS mean (i.e. estimated, adjusted mean) change from baseline in BCVA of 17.4 letters (8q8/3) and 18.3 letters (8q8/5) versus 17.5 letters in the 2q4 group. The differences in LS mean changes from baseline in BCVA at Week 36 (with corresponding 95% Cl) were -0.1 (-2.0, 1.9) and 0.8 (-1.1, 2.7) letters

for 8q8/3 and 8q8/5, respectively compared to 2q4. The p-values for the non-inferiority test at a margin of 4 letters were both <0.0001 for 8q8/5 vs. 2q4 (statistical hypothesis #1 in the hierarchical testing procedure) and for 8q8/3 vs. 2q4 (statistical hypothesis #2 in the hierarchical testing procedure). The lower confidence limits were greater than -4 and the p-values lower than 0.025 (1 -sided statistical tests), allowing the conclusion of non-inferiority (Table 1-29). The LS mean increases in BCVA over time were similar across all groups and minor numerical differences were not considered clinically relevant.

Table 1-29. Change from baseline in BCVA measured by the ETDRS letter score at Week 36 in the study eye, MMRM (full analysis set)

2q4 8q8/3 8q8/5 N = 301 N = 293 N = 298 Baseline mean ^(a) 54.1 55.2 55.4 Number of participants with Week 36 data (included/excluded 264/17 260/12 248/18

due to ICE)

Arithmetic mean (SD) change from baseline ^(al 17.8 (13.1) 17.0 (11.8) 19.1 (11.2) LS mean (SE) change from baseline 17.5 (0.7) 17.4 (0.7) 18.3 (0.6) Contrast b) 8q8/3 -2q4 8q8/5 -2q4 Estimate for contrast and two-sided 95% CI ^(c) -0.1 (-2.0. 1.9) 0.8 (-1.1, 2.7) p- value of one-sided test for non-inferiority at a margin of 4 <.0001 <.0001

letters

APAC = Asia-Pacific; BCVA = best-corrected visual acuity; Cl = Confidence Interval; ETDRS = early treatment diabetic retinopathy study; ICE = intercurrent event; LS = least squares; MMRM = mixed model for repeated measurements; RVO = retinal vein occlusion; SD = Standard Deviation; SE = Standard Error. A MMRM was used with baseline BCVA measurement as a covariate, treatment group, visit and the stratification variables (geographic region [Japan vs. APAC vs. Europe vs. America], baseline BCVA [<60 vs. >60], and RVO type [CRVO/HRVO vs BRVO]) as fixed factors, and terms for the interaction between baseline BCVA and visit and treatment and visit. Covariance structure used: unstructured covariance structure. ICEs were handled according to primary estimand strategy based on observed cases excluding data after ICE.

(a) based on observed cases excluding data after ICE.

(b) The contrast also includes the interaction term for treatment x visit (at week 36, for details on the population-level summary).

[0403] The number of active injections from baseline to Week 36 was analyzed using the analysis described for the key secondary endpoint (/.e. number of active injections from baseline

to Week 64). ICEs were handled similarly as described for the secondary estimand. However, for the composite strategy for the ICE “premature discontinuation of study intervention due to intervention related AEs”, the value for the number of injections was set to 9 (the maximum possible by Week 36).

[0404] A numerically lower number of active injections were administered to the 8q8/3 and 8q8/5 groups (6.1 and 6.9, respectively) compared to the 2q4 group (8.8 active injections). The estimated difference in the LS mean number of active injections from baseline to Week 36 suggests a clinically meaningful reduction for both HD groups in comparison with 2q4 treatment (8q8/3: -2.7; 8q8/5: -1.8; Table 1-30).

Table 1-30. Number of active injections from baseline to Week 36, Main Analysis (full analysis set)

2q4 8q8/3 8q8/5 (N=301) (N=293) (N=298)

LS mean (SE) number of active injections 8.8 (0.0) 6.1 (0.0) 6.9 (0.0) Contrast ^(a) _8q8/3. _{2q4 8}q8/5 - 2q4 Estimate for contrast and two-sided 95% Cl ^(a)

-2.7 (-2.8, -2.6) -1.8 (-1.9, -1.7) p-value ^(b)

<.0001 <.0001 APAC = Asia-Pacific; ANCOVA = Analysis of covariance; BCVA = best-corrected visual acuity; Cl = Confidence Interval; CST = Central subfield thickness; ICE = intercurrent events; LS = least-square; SE Standard Error.

Missing endpoint values were imputed using a multiple imputation approach

A non-parametric rank ANCOVA was used on each imputed data, adjusting for baseline BCVA, baseline CST, and the stratification variables (geographic region [Japan + APAC vs. Europe vs. America], BCVA score [<60 vs. >60], and RVO type [CRVO/HRVO vs. BRVO]) and results were combined using Rubin's rule.

ICEs were handled according to secondary estimand strategy

Based on the application of Rubin's rule after fitting a linear regression model adjusted for the same covariates as the non- parametric rank ANCOVA on each imputed dataset.

(a) Nominal p-value based on the non-parametric rank ANCOVA applied to each imputed dataset and combined using Rubin's rule.

[0405] An arithmetic mean number of 8.5, 6.0 and 6.7 active injections for the 2q4, 8q8/3 and 8q8/5 groups, respectively, were administered from baseline to Week 36 based on OC.

[0406] The proportion of participants achieving visual and anatomic measures of response at Week 36 is depicted in Table 1 -31.

[0407] In the FAS, the proportions of participants gaining at least 15 letters in BCVA from baseline at Week 36 using OC excluding values after ICE were similar in the 2q4 and 8q8/3

groups (59.8% and 58.8%, respectively) and slightly higher in the 8q8/5 treatment group (64.9%); the small numerical differences between the treatment groups were not clinically meaningful (Table 1-31). Similar results were observed in the corresponding analysis based on OC.

Table 1-31. Proportion of participants gaining at least 15 letters in BCVA from baseline at Week 36, OC excluding values after ICE (full analysis set)

Visual and anatomic measures 2q4 8q8/3 8q8/5

N=301 N=293 N=298 Num/Den (%) Num/Den (%) Num/Den (%) Participants who gained at least 15 letters 158/264 (59.8%) 153/260 (58.8%) 161/248 (64.9%) ICE = intercurrent events; IRF = intraretinal fluid; OC = observed cases; SRF = subretinal fluid OC excluding values after ICE: observations after the occurrence of an ICE are excluded in line with the primary estimand strategy

Missing cases were not included in the denominator when calculating proportions. See Definition of terms for treatment group description.

[0408] The proportions of participants achieving an ETDRS letter score of at least 69 letters (approximate 20/40 Snellen equivalent) at Week 36 using OC excluding values after ICE were numerically higher in the 8q8/3 and 8q8/5 groups (72.7% and 76.2%, respectively) compared to 2q4 group (67.8%) (Table 1-32). Similar results were observed in the corresponding analysis based on OC.

Table 1-32. Proportion of participants achieving ETDRS letter score of at least 69 at Week 36, OC excluding values after ICE (full analysis set)

Visual and anatomic measures 2q4 8q8/3 8q8/5

N=301 N=293 N=298 Num/Den (%) Num/Den (%) Num/Den (%) Participants who achieved letter score 179/264 (67.8%) 189/260 (72.7%) 189/248 (76.2%) of at least 69 letters

ICE = intercurrent events; IRF = intraretinal fluid; OC = observed cases; SRF = subretinal fluid OC excluding values after ICE: observations after the occurrence of an ICE are excluded in line with the primary estimand strategy

Missing cases were not included in the denominator when calculating proportions.

[0409] Overall, the proportions of participants with no retinal fluid (no IRF and no SRF) in the central subfield at Week 36 using OC excluding values after ICE was high (>80%) and similar

across the 3 treatment groups; the small numerical differences between the treatment groups were not clinically meaningful (Table 1-33). Similar results were observed in the corresponding analysis based on OC.

Table 1-33. Proportion of participants having no retinal fluid in the central subfield at Week 36, OC excluding values after ICE (full analysis set)

Visual and anatomic measures 2q4 8q8/3 8q8/5

N=301 N=293 N=298 Num/Den (%) Num/Den (%) Num/Den (%) Participants with no IRF and no SRF in 221/264 (83.7%) 211/260 (81.2%) 202/247 (81.8%) central subfield

[0410] Similar LS mean decreases from baseline were observed in all treatment groups at Week 36, (-370.8, -370.9 and -369.5 pm in 2q4, 8q8/3 and 8q8/5 groups, respectively). The estimated difference in LS mean changes in CST from Baseline at Week 36 (95% Cis) based on the MMRM in the FAS were minimal, i.e., -0.1 (-10.0, 9.8) pm for8q8/3 vs. 2q4 and of 1.2 (-7.7, 10.2) pm for 8q8/5 vs. 2q4 (Table 1 -34). The LS mean decreases from baseline in CST over time were similar across all groups with generally minor numerical differences that were not considered clinically meaningful.

Table 1-34. Change from baseline in CST (pm) at Week 36, MMRM (full analysis set)

2q4 N = 301 8q8/3 N = 293 8q8/5 N = 298 Baseline mean ^(a) 651.0 626.1 609.2 Number of participants with Week 36 data 262/17 260/11 247/18 (included/excluded due to ICE)

Arithmetic mean (SD) change from baseline <^a) -397.3 (257.7) -365.9 (239.9) -351.0 (225.4) LS mean (SE) change from baseline -370.8 (3.9) -370.9 (3.1) -369.5 (2.3) Contrast <^b> 8q8/3 - ²q^{4 8}9^8/5 - ²q⁴ Estimate for contrast and two- sided 95% Cl ^(c) '0-1 (-10.0, 9.8) 1.2 (-7.7, 10.2) P-value (d) 0.9804 0.7863

APAC = Asia-Pacific; BCVA = best-corrected visual acuity; Cl = confidence interval; CST =

central subfield retinal thickness; ICE = intercurrent events; LS = least squares; MMRM = mixed model for repeated measurements; RVO = retinal vein occlusion; SD = standard deviation; SE = standard error

A MMRM was used with baseline CST measurement as a covariate, treatment group, visit and the stratification variables (geographic region [Japan vs. APAC vs. Europe vs. America], baseline BCVA [<60 vs >60], and RVO type [CRVO/HRVO vs BRVO]) as fixed factors, and terms for the interaction between baseline CST and visit and treatment and visit. Covariance structure used: unstructured covariance structure.

ICEs were handled according to primary estimand strategy

(a) Based on observed cases excluding data after ICE

(b) The contrast also includes the interaction term for treatment x visit (at week 36, for details on the population-level summary

(c) Estimate based on the MMRM model, was computed for the differences of 8q8/3 minus 2q4 and 8q8/5 minus 2q4, respectively with two-sided 95% Cis.

(d) p-value for the two-sided test.

[0411] Both aflibercept 8 mg groups achieved rapid and sustained reductions in CRT, of -371 pm in the overall RVO population and importantly with less injections. Fluctuations were minimal (<25 microns). The results in RVO subtypes were similar. Anatomic improvements were not compromised with the reduced number of injections of aflibercept 8 mg compared to monthly 2 mg. Table 1-34A.

Table 1-34A. Change in CRT Over Time (LSmean change in CRT

from BL (pm))

Overall RVO Population

Week 2q4 (n=301 ) 8q8/3 (n=293) 8q8/5 (n=298)

0 0.0 0.0 0.0

4 -334.5 -342.4 -342.5

8 -358.6 -359.2 -357.6

12 -362.3 -364.3 -364.2

16 -365.7 -341.6 -365.7

20 -367.3 -369.2 -368

24 -366.3 -359.8 -353.3

28 -366.8 -370.8 -369

32 -369.5 -364.7 -363.2

36 -370.8 -370.9 -369.5

BRVC Subtype

2q4 (n=149) 8q8/3 (n=159) 8q8/5 (n=159)

0 0.0 0.0 0.0

4 -262.4 -266.8 -263.8

8 -277.1 -280.1 -277.6

12 -280.3 -283.2 -281.4

16 -281.1 -260.5 -282.2

20 -284.1 -284.7 -284.6

24 -284 -272.4 -275.6

28 -285 -287.1 -284.3

32 -286.1 -278.6 -281.7

36 -287.3 -286 -284.7

CRVO/HRVO Subtype

2q4 (n=152) 8q8/3 (n=134) 8q8/5 (n=139)

0 0.0 0.0 0.0

4 -414.7 -425.9 -429.5

8 -448.1 -446.3 -445.4

12 -453 -453.6 -455.1

16 -459.1 -430.9 -457.1

20 -458.9 -462.5 -459.5

24 -457.7 -457.3 -437.4

28 -457.1 -463.6 -461.9

32 -461.7 -460.8 -452

36 -463.2 -465.6 -462.4

Full analysis set. LS means were generated using a mixed model for repeated measures with baseline CRT as a covariate. The fixed factors were treatment group (aflibercept 8q8/3, 8q8/5, 2q4), visit, and stratification variables (geographic region [Japan vs Asian-Pacific vs Europe vs America], BL BCVA [<60 vs >60 letters], and for the overall RVO population only RVO type [CRVO/HRVO vs BRVO]).

The model also included terms for the interaction between baseline CRT and visit, and treatment and visit.

^aSafety analysis set. Patients completing Week 36.

[0412] The change from baseline in NEI-VFQ-25 total score at Week 36 was analyzed using an ANCOVA model similar to the approach used for the primary endpoint sensitivity analysis [0413] The mean NEI-VFQ-25 total score at baseline was similar across the 3 treatment groups, ranging from 78.15 to 79.39. Mean increases from baseline were observed in all groups at Week 36 with generally minor numerical differences across treatment groups that were not considered clinically meaningful. The estimated contrasts (95% Cl) for the 2-sided test, using the MMRM in the FAS were of -0.36 (-2.1, 1.40) points for 8q8/3 vs. 2q4 and of 0.65 (-1.2, 2.45) points for 8q8/5 vs. 2q4 (Table 1 -35).

Table 1-35. Change from baseline in NEI-VFQ-25 total score at Week 36, ANCOVA (full analysis set)

2q4 N = 301 8q8/3 N = 293 8q8/5 N = 298 Baseline mean ^(a) 78.98 79.39 78.15 Number of participants with Week 36 data 263/17 259/12 249/17 (included/excluded due to ICE)

Arithmetic mean (SD) change from baseline ^(b) 6.00 (13.03) 5.65 (11.37) 7.32 (12.50) LS mean (SE) change from baseline 6.27 (0.67) 5.91 (0.61) 6.92

(0.63) Contrast 8q8/3 - 2q4 8q8/5 - 2q4 Estimate for contrast and two- sided 95% Cl ^(c) -0.36 (-2.1, 1.40) 0.65 (-1.2, 2.45) P-value ^(d) 0.6869 0.4792 ANCOVA = Analysis of covariance; APAC = Asia-Pacific; BCVA = best-corrected visual acuity; ICE = intercurrent events; Cl = confidence interval; LS = least squares; NEI-VFQ-25 = National Eye Institute Visual Functioning Questionnaire-25; RVO = retinal vein occlusion; SD = standard deviation, SE = standard error

An ANCOVA was used with baseline NEI-VFQ-25 total score measurement as a covariate, treatment group and the stratification variables (geographic region [Japan vs. APAC vs. Europe vs. America], baseline BCVA [<60 vs. >60], and RVO

type [CRVO/HRVO vs BRVO]) as fixed factors.

Data after occurrence of an ICE was excluded in line with the sensitivity estimand strategy (a) Based on observed assessments

(b) Based on observed assessment excluding data after ICEs.

(c) Estimate based on the ANCOVA model, was computed for the differences of 8q8/3 minus 2q4 and 8q8/5 minus 2q4, respectively with two-sided 95% Cis.

(d) p-value for the two-sided test.

[0414] A total of 501 (90.9%) participants in the All 8 mg group were able to maintain every 8 weeks dosing through Week 36, while maintaining visual and anatomic outcomes.

[0415] Arithmetic mean changes in BCVA from baseline observed at each visit until Week 36 using OC excluding values after ICE in all treatment groups were consistent with the main analysis at Week 3. The arithmetic mean as well as the LS mean increases in BCVA over time were similar across all groups with minor numerical differences not being considered of clinical relevance.

[0416] Across all treatment groups and visits, more than 89% of participants gained letters. The proportion of participants gaining at least 5 letters ranged from 78.8%, 73.5% and 81.2% at Week 4 to 89.8%, 88.8% and 91.9% at Week 36 in the 2q4, 8q8/3 and 8q8/5 groups, respectively. Overall, a numerically lower proportion of participants in the 2q4 and 8q8/3 groups gained >10 letters or >15 letters compared to the 8q8/5 group, with only small numerical differences between the groups. Few participants (<6% across all treatment groups) lost 5 or more letters through Week 36 regardless of treatment group.

[0417] The proportions of participants gaining or losing at least 5, 10 or 15 letters in BCVA from baseline at Week 36 using OC were comparable to those using OC excluding values after ICE.

[0418] The proportions of participants with dry retina (no retinal fluid) increased from approximately 0% at baseline to >50% at Week 4 and >80% at Week 36 in all 3 treatment

groups. Similar results were observed for the proportion of participants with no IRF and no SRF in central subfield by visit, using OC.

[0419] The median time to fluid-free retina (total fluid, IRF, and/or SRF in the central subfield) was 4 weeks in all 3 treatment groups. There were no clinically meaningful differences between the HD treatment groups and the 2q4 group with respect to the time to fluid-free retina (no IRF and no SRF), time to IRF-free retina, or time to SRF-free retina over 36 weeks.

[0420] Sustained fluid-free retina over week 36 was defined by having no IRF or SRF in the central subfield at 2 consecutive visits, and at all subsequent study visits.

[0421] The proportion of participants with sustained fluid-free retina (no IRF and no SRF) using OC excluding values after ICE, was numerically higher in the 2q4 group (79.5%) compared to 8q8/3 and 8q8/5 groups (68.0% and 72.2%, respectively); these differences were not considered of clinical relevance. Likewise, the proportion of participants with sustained IRF-free retina at Week 36 was numerically higher in the 2q4 group (79.5%) compared to the HD groups (68.8% and 72.2%, respectively). The proportion of participants with sustained SRF-free retina was high (>98.5%) and similar across all 3 treatment groups.

[0422] Similar results were observed for the proportion of participants with total sustained fluid-free retina, IRF-free retina, and SRF-free retina at Week 36 assessed using OC.

[0423] The mean (SD) change in area of retinal ischemia from baseline to Week 36 using the OC excluding values after ICE were 0.30 (4.86) mm² and -0.38 (4.25) mm² in the 8q8/3 and 8q8/5 groups, respectively, vs 0.67 (5.58) in the 2q4 group. The differences across treatment groups were not considered clinically meaningful. Results were consistent with those using OC.

[0424] The mean (SD) change in area of fluorescein leakage from baseline to Week 36 using the OC excluding values after ICE were -10.02 (6.39) mm² and -10.43 (6.47) mm² in the 8q8/3 and 8q8/5 groups, respectively, vs -10.35 (7.66) in the 2q4 group. The differences across treatment groups were not considered clinically meaningful. Results were consistent with those using OC.

[0425] A supportive exploratory subgroup analysis for BRVO and CRVO/HRVO for the primary efficacy variable “Change from baseline for BCVA in ETDRS letter score at Week 36” was performed using an MMRM similar to the main analysis in the FAS (Table 1-36).

[0426] The analysis using MMRM showed no substantial differences across the different RVO types. In BRVO participants, LS mean change from baseline in BCVA measured by ETDRS letter score at Week 36 in the 2q4, 8q8/3 and 8q8/5 groups were of 19.0, 18.3 and 19.2 letters, respectively; the corresponding results in participants with CRVO/HRVO were 15.9, 16.6 and 17.2 letters, respectively. The estimated differences (95% Cis) in LS mean changes were -0.8 (-

2.9, 1.4) letters for 8q8/3 vs. 2q4 and 0.2 (-1.9, 2.2) letters for 8q8/5 vs. 2q4 in participants with BRVO. The corresponding differences in participants with CRVO/HRVO were 0.6 (-2.6, 3.9) letters for 8q8/3 vs. 2q4 and 1.3 (-2.0, 4.5) letters for 8q8/5 vs. 2q4. In both RVO type groups the results observed were consistent with those in the pooled RVO group, meeting the criteria for non-inferiority pre-defined for the overall population (i.e. lower limit of the 95% Cl greater than -4).

[0427] Arithmetic mean changes in BCVA from baseline were observed across the different RVO types in all treatment groups at each visit through Week 36 using OC excluding values after ICE. Similar results were observed using OC.

Table 1-36. Change from baseline in BCVA measured by the ETDRS letter score at Week 36, MMRM by RVO Type (full analysis set)

RVO Type BRVO CRVO/HRVO

2q4 8q8/3 8q8/5 2q4 8q8/3 8q8/5 N = 149 N = 159 N = 159 N = 152 N = 134 N = 139 Baseline mean ^(a) 57.3 58.6 58.5 51.0 51.3 51.8 Number of participants with 131/8 140/5 134/11 133/9 120/7 114/7 Week 36 data (included/excluded

due to ICE)

Arithmetic mean (SD) change 19.4 (11.0) 17.4 (10.9) 19.5 (10.0) 16.2 (14.7) 16.5 (12.7) 18.6 (12.6) from baseline ^(a)

LS mean (SE) change 19.0 (0.8) 18.3 (0.8) 19.2 (0.7) 15.9 (1.2) 16.6 (1.1) 17.2 (1.2) from baseline

Contrast ^(b) 8q8/3 - 2q4 8q8/5 - 2q4 8q8/3 - 2q4 8q8/5 - 2q4 Estimate for contrast -0.8 0.2 0.6 1.3 and two-sided 95% Cl '^ci (-2.9, 1.4) (-1 -9, 2.2) (-2.6, 3.9) (-2.0, 4.5) Nominal p-value of one-sided test 0.0018 <.0001 0.0027 0.0008 for non-inferiority at a margin of 4

letters

APAC = Asia-Pacific; BCVA = best-corrected visual acuity; Cl = Confidence Interval; ETDRS = early treatment diabetic retinopathy study; ICE = intercurrent events; LS = least-squares; MMRM = mixed model for repeated measurements; RVO = retinal vein occlusion; SD = Standard Deviation; SE = Standard Error.

A MMRM was used with baseline BCVA measurement as a covariate, treatment group, visit and the stratification variables (geographic region [Japan vs. APAC vs. Europe vs. America] and baseline BCVA [<60 vs >60]) as fixed factors, and terms for the interaction between baseline BCVA and visit and treatment and visit. Covariance structure used: unstructured covariance structure.

ICEs were handled according to primary estimand strategy based on observed cases excluding data after ICE.

The contrast also includes the interaction term for treatment x visit (at week 36).

Estimate based on the MMRM, was computed for the differences of 8q8/3 minus 2q4 and 8q8/5 minus 2q4, respectively with two-sided 95% Cis.

[0428] The primary endpoint of non-inferiority compared to monthly aflibercept 2 mg was met. Both aflibercept 8 mg groups achieved rapid and sustained BCVA gains, importantly, with fewer injections compared with 2 mg. The 8q8/3 group had a mean number of active injections of 6.1, while patients in the 2 mg group received 8.8 injections. There were comparable proportions of patients with the BRVO and CRVO/HRVO subtypes in QUASAR, similar outcomes were observed including robust vision gains and reduced number of injections with aflibercept 8 mg. Importantly, vision was not compromised with the reduced number of injections, especially in the harder to treat CRVO/HRVO subtype. See Table 1-36A.

Table 1-36A. LSmean Change in BCVA Over Time (LS mean change in BCVA from

BL (ETDRS letters))

Overall RVO Population

Week 2q4 (n=301) 8q8/3 (n=293) 8q8/5 (n=298)

0 0.0 0.0 0.0

4 11.6 10.8 11.9

8 14.1 14.1 14.8

12 15.2 15 16

16 16.1 14.7 16.9

20 16.6 16 17.6

24 17 16.3 16.9

28 17.3 16.9 17.9

32 17.3 17 17.7

36 17.5 17.4 18.3

BRVC Subtype

2q4 (n=149) 8q8/3 (n=159) 8q8/5 (n=159)

0 0.0 0.0 0.0

4 11.8 11.2 11.4

8 14.7 14.7 14.9

12 16.2 16 16.2

16 17.2 15.4 17.6

20 17.5 16.8 18.1

24 18.2 17.1 17.8

28 18.6 17.8 18.2

32 18.6 17.4 18.5

36 19 18.3 19.2

CRVO/HRVO Subtype

2q4 (n=152) 8q8/3 (n=134) 8q8/5 (n=139)

0 0.0 0.0 0.0

4 11.3 10.4 12.5

8 13.3 13.4 14.8

12 14.2 13.8 15.8

16 15 13.9 16.1

20 15.6 15.1 17.1

24 15.8 15.5 15.9

28 16 15.9 17.5

32 15.9 16.7 17

36 15.9 16.6 17.2

Full analysis set. LS means were generated using a mixed model for repeated measures with baseline BCVA as a covariate. The fixed factors were treatment group (aflibercept 8q8/3, 8q8/5, 2q4); visit; and stratification variables: geographic region (Japan, Asian-Pacific, Europe, America), BL BCVA (<60 vs >60 letters), and, for the overall RVO population analysis only, RVO type (CRVO/HRVO vs BRVO).

The model also included terms for the interactions between baseline BCVA and visit, and between treatment and visit.

^aObserved values (censoring data post intercurrent event).

^bSafety analysis set. Patients completing Week 36.

^cNominal p-values.

BL, baseline; BRVO, branch retinal vein occlusion; CRVO, central retinal vein occlusion;

ETDRS, Early Treatment Diabetic Retinopathy Study;

HRVO, hemiretinal vein occlusion; LS, least squares.

[0429] Subgroup analyses for the primary efficacy endpoint (changes from baseline in BCVA at Week 36), using an MMRM similar to the main analysis in the FAS, were consistent with those observed in the overall population for all subgroups assessed (baseline BCVA, age at enrollment, sex, geographic regions, ethnicity, race, and baseline CST.

[0430] As expected, there is some variability across the subgroups and several subgroups are too small to draw meaningful conclusions (e.g., the >55-<65 age, Hispanic or Latino or Japan subgroups).

[0431] Overall, no clinically meaningful differences between the subgroup population and the total population were observed.

[0432] The LS mean number of active injections administered from baseline to Week 36 were similar across 2q4, 8q8/3 and 8q8/5 groups in BRVO (8.8, 6.1 and 6.9, respectively) and CRVO/HRVO (8.7, 6.1 and 6.9, respectively) participants.

[0433] The results using OC are consistent.

[0434] In BRVO participants, similar improvements in mean change from baseline to Week 36 in CST were observed using OC excluding values after ICE in all treatment groups with minor numerical differences not clinically meaningful. In CRVO/HRVO participants, a larger reduction

in mean CST was observed in the 2q4 group (-498.8 vs -461.2 and -429.0 pm in the 8q8/3 and 8q8/5 groups, respectively) which was not considered clinically meaningful due to the higher baseline CST values in the 2q4 group.

[0435] All safety endpoints were analyzed using the SAF: 892 treated participants (99.8% of all randomized).

[0436] The incidence of TEAEs reported during the study was similar across the treatment groups (Table 1-37). The results of the subgroup analyses by RVO types for ocular TEAEs in the study eye and non-ocular TEAEs were generally comparable to those seen in the entire safety population and did not suggest clinically relevant differences among the treatment groups.

[0437] The analyses of vital signs and electrocardiogram (EGG) data (including QT interval) did not show any clinically meaningful changes over time within the All 8mg group and the 2q4 group or differences between the groups, and there were no clinically relevant findings in clinical laboratory evaluations and no relevant imbalances among treatment groups.

[0438] An overall summary of AEs through Week 36 is presented in Table 1-37.

[0439] In total, similar proportions of participants experienced TEAEs: 386 (65.3%) participants in the All 8mg group (196 [66.9%] in the 8q8/3 group and 190 [63.8%] in the 8q8/5 group) and 201 (66.8%) in the 2q4 group.

[0440] The frequency of ocular TEAEs was slightly higher in the 8q8/3 group (39.9%) compared to the 8q8/5 group (32.6%) or the 2q4 group (32.6%).

[0441] With regard to last assigned dosing intervals, comparable trends were observed for the RVO subtypes. See Table 1-36B.

Table 1-36B. Last Assigned Dosing Interval for BRVO and CRVO/HRVO Subtypes at Week 36 (%)

BRVO Q4 Q8 Q12

2q4 (n=141) 20.6 79.4

8q8/3 (n=149) 6.0 25.5 71.9 CRVO/HRVO

2q4 (n=146) 28.1 68.5

8q8/3 (n=129) 6.2 24.0 69.8

Safety analysis set. Patients completing Week 36. Per study design, dosing interval extension was not possible in the 8q8/5 group until Week 40.

Table 1-37. Adverse events: overall summary of number of participants (safety analysis

set)

8q8/3 N=293 8q8/5 N=298 All 8ma N=591 2q4 N=301

(100%) (100%) (100%) (100%)

Number (%) of participants with adverse events Any

AE 206 (68.4%) 200 (68.3%) 203 (68.1%) 403 (68.2%) Any pre-treatment AE 25 (8.3%) 28 (9.6%) 30 (10.1%) 58 (9.8%) Any TEAE 201 (668%) 196 (66 9%) 190 (63 8%) 386 (65 3%) Any post-treatment AE 1 (0.3%) 2 (0.7%) 3 (1.0%) 5 (0.8%) Any ocular TEAE 98 (32.6%) 1 17 (39.9%) 97 (32.6%) 214 (36.2%) Study eye 85 (28.2%) 103 (35.2%) 86 (28.9%) 189 (32.0%) Fellow eye 47 (15.6%) 49 (16.7%) 41 (13.8%) 90 (15.2%) Any non-ocular TEAE 151 (50.2%) 138 (47.1%) 152 (51.0%) 290 (49.1%) Any intervention-related TEAE 7 (2.3%) 14 (4.8%) 7 (2.3%) 21 (3.6%) Any ocular intervention-related TEAE 6 (2.0%) 12 (4.1%) 6 (2.0%) 18 (3.0%) Study eye 6 (2.0%) 12 (4.1%) 6 (2.0%) 18 (3.0%) Fellow eye 0 0 0 0 Any non-ocular intervention-related TEAE 1 (0.3%) 2 (0.7%) 1 (0.3%) 3 (0.5%) Any TEAE related to injection procedure 20 (6.6%) 38 (13.0%) 25 (8.4%) 63 (10.7%) Any ocular TEAE related to injection procedure 19 (6.3%) 38 (13.0%) 25 (8.4%) 63 (10.7%) Study eye 19 (63%) 38 (13 0%) 25 (8 4%) 63 (10 7%) Fellow eye 0 1 (0.3%) 0 1 (0.2%) Any non-ocular TEAE related to injection 1 (0.3%) 0 0 0 procedure

Any TEAE related to protocol-required procedure 6 (2.0%) 9 (3.1%) 11 (3.7%) 20 (3.4%) Any ocular TEAE related to protocol-required procedure 3 (1.0%) 5 (1.7%) 6 (2.0%) 1 1 (1.9%) Study eye 3 (1.0%) 5 (1.7%) 6 (2.0%) 11 (1.9%) Fellow eye 0 0 0 0 Any non-ocular TEAE related to protocol- 3 (1.0%) 4 (1.4%) 5 (1.7%) 9 (1.5%) required procedure

Any TEAE related to commercial aflibercept 2mg 0 0 0 0 (of fellow eye)

Any TEAE leading to discontinuation of 4 (1.3%) 2 (0 7%) 4 (1.3%) 6 (1 0%) intervention

Any ocular TEAE leading to discontinuation of intervention 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Study eye 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Fellow eye 0 0 0 0 Any non-ocular TEAE leading to discontinuation 3 (1.0%) 2 (0.7%) 3 (1.0%) 5 (0.8%) of intervention

Any TEAE related to medical device 0 1 (0.3%) 0 1 (0.2%) Any ocular TEAE related to medical device 0 1 (0.3%) 0 1 (0.2%) Study eye 0 1 (0.3%) 0 1 (0.2%) Fellow eye 0 0 0 0

Any non-ocular TEAE related to medical device 0 0 0 0 Any TEAE of special interest 9 (30%) 1 (0 3%) 5 (1 7%) 6 (1 0%) Any TEAE of APTC events 5 (1.7%) 0 3 (1.0%) 3 (0.5%) Any TEAE of hypertension 14 (4.7%) 24 (8.2%) 24 (8.1%) 48 (8.1%) Any TEAE of intraocular inflammation of study eye 4 (1.3%) 2 (0.7%) 1 (0.3%) 3 (0.5%) Any TEAE of nasal mucosal finding 2 (0.7%) 2 (0.7%) 1 (0.3%) 3 (0.5%) Maximum intensity for any ocular TEAE Study

eye

Mild 58 (193%) 76 (25 9%) 66 (22 1%) 142 (24 0%) Moderate 21 (7.0%) 25 (8.5%) 17 (5.7%) 42 (7.1%) Severe 6 (2.0%) 2 (0.7%) 3 (1.0%) 5 (0.8%) Fellow eye

Mild 33 (11.0%) 35 (11.9%) 34 (11.4%) 69 (11.7%) Moderate 14 (4.7%) 13 (4.4%) 7 (2.3%) 20 (3.4%) Severe 0 1 (0.3%) 0 1 (0.2%) Maximum intensity for any non-ocular TEAE

84 (27.9%) 86 (29.4%) 95 (31.9%) 181 (30.6%) Mild

Moderate 51 (16.9%) 38 (13.0%) 45 (15.1%) 83 (14.0%) Severe 16 (5.3%) 14 (4.8%) 12 (4.0%) 26 (4.4%) Any SAE 34 (11 3%) 25 (8 5%) 32 (10 7%) 57 (9 6%) Any pre-treatment SAE 2 (0.7%) 0 5 (1.7%) 5 (0.8%) Any TESAE 32 (10.6%) 24 (8.2%) 26 (8.7%) 50 (8.5%) Any post-treatment SAE 1 (0.3%) 2 (0.7%) 2 (0.7%) 4 (0.7%) Any ocular SAE 8 (2.7%) 4 (1.4%) 4 (1.3%) 8 (1.4%) Study eye 8 (2.7%) 3 (1.0%) 4 (1.3%) 7 (1.2%) Fellow eye 0 1 (0.3%) 0 1 (0.2%) Any non-ocular SAE 26 (8.6%) 22 (7.5%) 28 (9.4%) 50 (8.5%) Any ocular TESAE 7 (2.3%) 4 (1.4%) 4 (1.3%) 8 (1.4%) Study eye 7 (2.3%) 3 (1.0%) 4 (1.3%) 7 (1.2%) Fellow eye 0 1 (0.3%) 0 1 (0.2%) Any non-ocular TESAE 25 (8.3%) 21 (7.2%) 22 (7.4%) 43 (7.3%) Any intervention-related TESAE 2 (0.7%) 0 1 (0.3%) 1 (0.2%) Any ocular intervention-related TESAE 2 (0 7%) 0 1 (0 3%) 1 (0 2%) Study eye 2 (0.7%) 0 1 (0.3%) 1 (0.2%) Fellow eye 0 0 0 0 Any non-ocular intervention-related TESAE 0 0 0 0 Any TESAE related to injection procedure 4 (1.3%) 1 (0.3%) 1 (0.3%) 2 (0.3%) Any ocular TESAE related to injection procedure 4 (1.3%) 1 (0.3%) 1 (0.3%) 2 (0.3%) Study eye 4 (1.3%) 1 (0 3%) 1 (0 3%) 2 (0 3%) Fellow eye 0 0 0 0 Any non-ocular TESAE related to injection procedure 0 0 0 0 Any TESAE related to protocol-required procedure 0 0 0 0

Any TESAE related to commercial aflibercept 2mg (of 0 0 0 0 fellow eye)

Any TESAE related to medical device 0 0 0 0 Any TESAE of special interest 6 (2.0%) 1 (0.3%) 4 (1.3%) 5 (0.8%) Any TESAE of APTC events 4 (1.3%) 0 3 (1.0%) 3 (0.5%) Any TESAE of hypertension ^a 1 (0.3%) 0 0 0 Any TESAE of intraocular inflammation of study 2 (0.7%) 1 (0.3%) 0 1 (0.2%) eye ^a

Any TESAE of nasal mucosal finding ^a 1 (0.3%) 0 0 0 Maximum intensity for any ocular TESAE Study

eye

Mild 0 0 1 (0.3%) 1 (0.2%) Moderate 4 (1.3%) 2 (0.7%) 2 (0.7%) 4 (0.7%) Severe 3 (1.0%) 1 (0.3%) 1 (0.3%) 2 (03%) Fellow eye Severe

0 1 (0.3%) 0 1 (0.2%) Maximum intensity for any non-ocular TESAE Mild

1 (0.3%) 2 (0.7%) 3 (1.0%) 5 (0.8%) Moderate 10 (3.3%) 8 (2.7%) 9 (3.0%) 17 (2.9%) Severe 14 (4.7%) 11 (3.8%) 10 (3.4%) 21 (3.6%) Total number of deaths 2 (0.7%) 2 (0.7%) 3 (1.0%) 5 (0.8%) Any AE with outcome death 2 (0.7%) 2 (0.7%) 3 (1.0%) 5 (0.8%) Any pre-treatment AE with outcome death 0 0 0 0 Any TEAE with outcome death 2 (0.7%) 2 (0.7%) 2 (0.7%) 4 (0.7%) Any post-treatment AE with outcome death 0 0 1 (0.3%) 1 (0.2%) Deaths not attributed to an AE 0 0 0 0 AE = Adverse event; APTC = Anti-platelet trialists' collaboration; RVO = Retinal vein occlusion; SAE = Serious adverse event; TEAE = Treatment-emergent adverse event; TESAE = Treatment-emergent serious adverse event

TEAEs are defined as AEs that started in the time frame from first injection to the last injection (active or sham) in the study plus 30 days. For the participants who have not discontinued study treatment prematurely (/.e., are 'ongoing') at the Week 36 analysis, all AEs that started at first injection or later will be considered treatment-emergent.

Adverse Event of Special Interest (AESI) are arterial thromboembolic events including cerebrovascular ischemic events and cardiovascular ischemic events.

a: Based on grouped MedDRA PTs

[0442] Table 1-38 summarizes the 10 most frequent PTs in each treatment group with their

associated SOCs for ocular TEAEs in the study eye through Week 36.

[0443] Ocular TEAEs in the study eye were reported in 189 (32.0%) participants in the All 8mg group (103 [35.2%] in the 8q8/3 group and 86 [28.9%] in the 8q8/5 group) and 85 (28.2%) participants in the 2q4 group. The most frequently reported ocular TEAE in the study eye was IOP increased, which was reported in numerically higher proportion of participants in the All 8 mg group (31 [5.2%] participants: 16 [5.5%] and 15 [5.0%] for the 8q8/3 and 8q8/5 groups, respectively) than in the 2q4 group (5 [1.7%] participants). None of the IOP increased events were serious or led to discontinuation of study intervention, most were mild or moderate in intensity and resolved without sequela. IOP increased was assessed as not related to the study intervention in the majority of participants who experienced such events. All other ocular TEAEs in the study eye were reported in <5% of participants in any treatment group.

[0444] In general, no clinically meaningful differences were observed in type of TEAEs or their frequencies between the All 8mg and 2q4 groups, and reported events were consistent with the known safety profile of aflibercept.

Table 1-38. Number (%) of participants with ocular TEAEs in the study eye: 10 most frequent PTs in each treatment group with their associated SOCs: (safety analysis set)

Primary System Organ Class 2q4 8q8/5

Preferred term N=301 8q8/3 N=298 All 8mg MedDRA version 27.1 (100%) N=293 (100%) (100%) N=591 (100%) Number (%) of participants with at least one such 85 (28.2%) 103 (35.2%) 86 (28.9%) 189 (32.0%) adverse event Eye disorders 73 (24 3%) 90 (30 7%) 70 (23 5%) 160 (27 1%) Cataract 9 (3.0%) 5 (1.7%) 10 (34%) 15 (2.5%) Conjunctival haemorrhage 6 (2.0%) 10 (3.4%) 7 (23%) 17 (2.9%) Dry eye 6 (2.0%) 4 (1.4%) 5 (1 7%) 9 (1.5%) Epiretinal membrane 6 (2.0%) 3 (1.0%) 7 (23%) 10 (1.7%) Punctate keratitis 5 (1.7%) 4 (1.4%) 2 (0 7%) 6 (1.0%) Conjunctivitis allergic 4 (1.3%) 3 (1.0%) 2 (0 7%) 5 (0.8%) Ocular hypertension 4 (1.3%) 4 (1 4%) 2 (0 7%) 6 (1 0%) Visual acuity reduced 4 (1.3%) 12 (4.1%) 8 (2 7%) 20 (3.4%) Eye pain 3 (1.0%) 5 (1.7%) 4 (1.3%) 9 (1.5%) Vitreous floaters 3 (1.0%) 4 (1.4%) 2 (0 7%) 6 (1.0%) Vitreous detachment 2 (0.7%) 8 (2.7%) 9 (30%) 17 (2.9%) Glaucoma 0 4 (1.4%) 1 (0.3%) 5 (0.8%) Macular thickening 0 5 (1.7%) 0 5 (0.8%) Injury, poisoning and procedural complications 4 (1.3%) 8 (2.7%) 3 (1.0%) 11 (1.9%) I ntra-ocular injection complication 1 (0.3%) 5 (1.7%) 0 5 (0.8%) Investigations 7 (2.3%) 17 (5.8%) 15 (50%) 32 (5.4%)

Intraocular pressure increased 5 (1.7%) 16 (5.5%) 15 (5.0%) 31 (5.2%)

[0445] The results of the subgroup analyses by RVO types (CRVO/HRVO and BRVO) for ocular TEAEs in the study eye show slightly higher incidences in the CRVO/HRVO due to a numerically higher proportion of participants reporting Epiretinal membrane and Visual acuity reduced in the CRVO/HRVO subgroup than in the BRVO subgroup. In addition, more PTs types were reported in the CRVO/HRVO subgroup under the SOC Eye disorders, but most of them were infrequently reported (<2% of participants in any treatment group).

[0446] However, no clinically relevant differences were observed within either subgroup even though numerical differences across the treatment groups were occasionally observed.

[0447] Overall, ocular TEAEs in the fellow eye were reported in 90 (15.2%) participants in the All 8mg group (49 [16.7%] in the 8q8/3 group and 41 [13.8%] in the 8q8/5 group) and 47 (15.6%) participants in the 2q4 group. The most frequently reported ocular TEAEs in the fellow eye were Cataract (11 [1.9%] participants in the All 8mg group and 9 [3.0%] in the 2q4 group). Ocular TEAEs in the fellow eye were reported infrequently for all other PTs and were generally balanced across the treatment groups.

[0448] Table 1-39 summarizes the 10 most frequent PTs in each treatment group with their associated SOC for non-ocular TEAEs through Week 36.

[0449] Non-ocular TEAEs were reported in 290 (49.1%) participants in the All 8mg group (138 [47.1%] in the 8q8/3 group and 152 [51.0%] in the 8q8/5 group) and 151 (50.2%) participants in the 2q4 group. The majority of the TEAEs were in the SOC of Infections and infestations; however, the most common TEAE was Hypertension, which was reported in 6.6% of participants in the All 8mg group (6.5% and 6.7% for the 8q8/3 and 8q8/5 groups, respectively) and 3.3% of participants in the 2q4 group. This is consistent with the imbalance in incidence of non-ocular medical history of Hypertension with 61.9% in the All 8mg group compared to 57.5% in the 2q4 group. All cases of Hypertension were non-serious, assessed as not related to study intervention, almost all were mild or moderate intensity, and no clinically relevant changes in BP measurements were observed. All other non-ocular TEAEs were reported in <5.0% of participants in any treatment group (Table 1-39).

[0450] No clinically meaningful differences were observed in type of TEAEs or their frequencies between the All 8mg and 2q4 groups.

Table 1-39. Number (%) of participants for non-ocular TEAEs: 10 most frequent PTs in

each treatment group with their associated SOCs (safety analysis set)

Primary System Organ Class

2q4 8q8/3 8q8/5 All 8mg N=301 (100%) N=293 (100%) N=298 (100%) N=591 (100%) Number (%) of participants with at least one such 151 (502%) 138 (47.1%) 152 (51.0%) 290 (49.1%) adverse event

Gastrointestinal disorders 21 (70%) 16 (5.5%) 18 (6.0%) 34 (5.8%) Vomiting 5 (1 7%) 1 (0.3%) 0 1 (0.2%) Nausea 4 (1.3%) 4 (1.4%) 3 (1.0%) 7 (1.2%) General disorders and administration site conditions 1 1 (3 7%) 13 (4.4%) 8 (2.7%) 21 (3.6%) Chest pain 2 (0 7%) 4 (1.4%) 1 (0.3%) 5 (0.8%) Oedema peripheral 2 (0 7%) 4 (1.4%) 0 4 (0.7%) Infections and infestations 58 (193%) 54 (18.4%) 57 (19.1%) 1 11 (18.8%) Urinary tract infection 10 (3.3%) 4 (1.4%) 11 (3.7%) 15 (2.5%) Nasopharyngitis 9 (30%) 15 (5.1%) 14 (4.7%) 29 (4.9%) COVID-19 6 (20%) 13 (4.4%) 6 (2.0%) 19 (3.2%) Influenza 6 (20%) 4 (1 4%) 1 (0 3%) 5 (0 8%) Upper respiratory tract infection 5 (1 7%) 3 (1.0%) 3 (1.0%) 6 (1.0%) Pharyngitis 0 4 (1.4%) 0 4 (0.7%) Investigations 17 (5 6%) 19 (6.5%) 23 (7.7%) 42 (7.1%) Blood pressure increased 2 (0 7%) 5 (1.7%) 2 (0.7%) 7 (1.2%) Metabolism and nutrition disorders 24 (80%) 9 (3.1%) 22 (7.4%) 31 (5.2%) Hyperlipidaemia 7 (23%) 1 (0.3%) 3 (1.0%) 4 (0.7%) Hypercholesterolaemia 5 (1 7%) 3 (1.0%) 7 (2.3%) 10 (1.7%) Type 2 diabetes mellitus 5 (1 7%) 0 4 (1.3%) 4 (0.7%) Musculoskeletal and connective tissue disorders 24 (80%) 22 (7.5%) 17 (5.7%) 39 (6.6%) Arthralgia 6 (20%) 3 (1.0%) 4 (1.3%) 7 (1.2%) Nervous system disorders 19 (63%) 17 (5.8%) 19 (6.4%) 36 (6.1%) Headache 5 (1 7%) 6 (2.0%) 6 (2.0%) 12 (2.0%) Respiratory, thoracic and mediastinal disorders 13 (43%) 15 (5.1 %) 8 (2.7%) 23 (3.9%) Cough 4 (1.3%) 4 (1.4%) 2 (0.7%) 6 (1.0%) Vascular disorders 16 (53%) 23 (7.8%) 26 (8.7%) 49 (8.3%) Hypertension 10 (3.3%) 19 (6.5%) 20 (6.7%) 39 (6.6%)

[0451] The results of the subgroup analyses by RVO types (CRVO/HRVO and BRVO) for non- ocular TEAEs were similar to those seen in the entire safety population and did not suggest clinically relevant differences among the treatment groups.

[0452] The relationship of AEs to the study intervention was assessed by the masked investigator, and was a clinical decision based on all available information.

[0453] Ocular study intervention-related TEAEs in the study eye were reported in 18 (3.0%) participants in the All 8mg group (12 [4.1%] and 6 [2.0%] for the 8q8/3 and 8q8/5 groups,

respectively) and 6 (2.0%) participants in the 2q4 group (Table 1-40). These events were generally of low frequency and mostly reported for single participants only. The events that were reported for more than 2 participants in any treatment group were IOP increased and Visual acuity reduced. IOP increased was reported in 8 (1.4%) participants in the All 8mg group (5 [1.7%] and 3 [1.0%] for the 8q8/3 and 8q8/5 groups, respectively) and 1 (0.3%) participant in the 2q4 group. Visual acuity reduced was reported in 2 (0.7%) participants each in the 8q8/3 group and the 2q4 group. Of the 4 events of Visual acuity reduced judged to be related to study intervention, 2 were resolved, 1 is resolving, and 1 has not resolved at the time of this report.

Table 1-40. Ocular treatment-emergent intervention-related adverse events of study eye: number of participants by primary system organ class and preferred term (safety analysis set)

Primary system organ class Preferred term 2q4 N=301 8q8/3 8q8/5 All 8mg MedDRA version 27.1 (100%) N=293 N=298 N=591

(100%) (100%) (100%) Number (%) of participants with at least one such adverse 6 (2.0%) 12 (4.1%) 6 (2.0%) 18 (3.0%) event Eye disorders 4 (1.3%) 6 (2.0%) 3 (1.0%) 9 (1.5%) Anterior chamber disorder 0 1 (0.3%) 0 1 (0.2%) Blindness 0 0 1 (0.3%) 1 (0.2%) Conjunctival haemorrhage 0 0 1 (0.3%) 1 (0.2%) Epiretinal membrane 1 (0.3%) 0 0 0 Eye inflammation 1 (0.3%) 0 0 0 Macular degeneration 2 (0.7%) 0 0 0 Macular oedema 0 1 (0.3%) 0 1 (0.2%) Macular thickening 0 1 (0.3%) 0 1 (0.2%) Retinal vasculitis 0 0 1 (0.3%) 1 (0.2%) Visual acuity reduced 2 (0.7%) 2 (0.7%) 0 2 (0.3%) Vitreous detachment 0 1 (0.3%) 0 1 (0.2%) Infections and infestations 1 (0.3%) 0 0 0 Endophthalmitis 1 (0.3%) 0 0 0 Injury, poisoning and procedural complications 0 1 (0.3%) 0 1 (0.2%) I ntra-ocular injection complication 0 1 (0.3%) 0 1 (0.2%) Investigations 1 (0.3%) 5 (1.7%) 3 (1.0%) 8 (1.4%)

Intraocular pressure increased 1 (0.3%) 5 (1.7%) 3 (1.0%) 8 (1.4%) A participant is counted only once within each primary SOC and preferred term.

[0454] Through Week 36, no ocular study intervention-related TEAE in the fellow eye was reported in any treatment group

[0455] Non-ocular study intervention-related TEAEs was reported in 2 (0.7%) participants in

the 8q8/3 group (Atrioventricular block first degree and Headache, respectively), and 1 (0.3%) participant each in the 8q8/5 group (Rash) and 2q4 group (Haemoglobin increased).

[0456] The relationship of AEs to the IVT injection procedure was assessed by the masked investigator, and was a clinical decision based on all available information.

[0457] Overall, the proportions of participants with ocular TEAEs related to IVT injection procedure in the study eye were slightly higher in the All 8mg group (63 [10.7%]; 38 [13.0%] and 25 [8.4%] for the 8q8/3 and 8q8/5 groups, respectively) than in the 2q4 group (19 [6.3%]) (Table 1-41). These events were generally of low frequency and mostly reported for single participants only. The most common ocular IVT-injection-related TEAEs, reported in >5 participants in total, were Conjunctival haemorrhage, IOP increased, and Eye pain. All events were non-serious except for 6 events, which were serious (Endophthalmitis in 2 participants in the 2q4 group and 1 participant in the 8q8/3 group, Macular hole and Retinal detachment each in 1 participant in the 2q4 group, and Cataract in 1 participant in the 8q8/5 group).

Table 1-41. Ocular treatment-emergent intravitreal injection procedure-related adverse events of study eye: number of participants by primary system organ class and preferred term (safety analysis set)

Primary system organ class 2q4 8q8/3 8q8/5 All 8mg N=301 N=293 N=298 N=591 (100%) (100%) (100%) (100%) Number (%) of participants with at least one such adverse 19 (6.3%) 38 (13.0%) 25 (84%) 63 (10.7%) event Eye disorders 13 (4.3%) 25 (8.5%) 17 (57%) 42 (7.1%) Blepharitis 0 1 (0.3%) 0 1 (0.2%) Blindness 0 0 1 (0.3%) 1 (0.2%) Cataract 0 0 1 (0.3%) 1 (0.2%) Conjunctival haemorrhage 5 (1.7%) 8 (2.7%) 6 (20%) 14 (2.4%) Conjunctival hyperaemia 0 0 1 (0.3%) 1 (02%) Conjunctival irritation 1 (0.3%) 0 0 0 Conjunctival oedema 1 (0.3%) 0 0 0 Conjunctival suffusion 0 1 (0.3%) 1 (0.3%) 2 (0.3%) Corneal disorder 0 1 (0.3%) 0 1 (0.2%) Dry eye 0 1 (0.3%) 0 1 (0.2%) Epiretinal membrane 0 0 2 (07%) 2 (0.3%) Eye pain 2 (0.7%) 3 (1.0%) 2 (07%) 5 (0.8%) Lenticular opacities 0 0 1 (0.3%) 1 (0.2%) Macular hole 1 (0.3%) 0 0 0 Macular oedema 0 1 (0.3%) 0 1 (0.2%) Ocular hypertension 0 2 (0.7%) 1 (0.3%) 3 (0.5%)

Punctate keratitis 2 (0.7%) 2 (0.7%) 0 2 (0.3%) Retinal artery occlusion 0 1 (0.3%) 0 1 (0.2%) Retinal detachment 1 (0.3%) 0 0 0 Retinal tear 0 1 (0.3%) 0 1 (0.2%) Vitreoretinal traction syndrome 0 1 (0.3%) 0 1 (0.2%) Vitreous detachment 0 3 (1.0%) 1 (0.3%) 4 (0.7%) Vitreous floaters 2 (0.7%) 2 (0.7%) 0 2 (0.3%) Vitreous haemorrhage 0 1 (0.3%) 1 (0.3%) 2 (0.3%) Vitreous opacities 0 0 1 (0.3%) 1 (0.2%) General disorders and administration site conditions 1 (0.3%) 4 (1.4%) 2 (0.7%) 6 (1.0%) Injection site irritation 1 (0.3%) 1 (0.3%) 1 (0.3%) 2 (0.3%) Injection site pain 0 0 1 (0.3%) 1 (0.2%) Pain 0 2 (0.7%) 0 2 (0.3%) Sensation of foreign body 0 1 (0.3%) 0 1 (0.2%) Infections and infestations 2 (0.7%) 1 (0.3%) 1 (0.3%) 2 (0.3%) Conjunctivitis 0 0 1 (0.3%) 1 (0.2%) Endophthalmitis 2 (0.7%) 1 (0.3%) 0 1 (0.2%) Injury, poisoning and procedural complications 1 (0.3%) 3 (1.0%) 0 3 (0.5%) Injury corneal 0 1 (0.3%) 0 1 (0.2%) Intra-ocular injection complication 1 (0.3%) 2 (0.7%) 0 2 (0.3%) Investigations 3 (1.0%) 9 (3.1%) 6 (2.0%) 15 (2.5%) Intraocular pressure increased 3 (1.0%) 9 (3.1%) 6 (2.0%) 15 (2.5%) A participant is counted only once within each imary SOC and preferred term.

[0458] Ocular IVT-injection-related TEAEs in the fellow eye through Week 36 were reported in 1 (0.3%) participant in the 8q8/3 group (Eye irritation).

[0459] Non-ocular IVT-injection-related TEAEs through Week 36 were reported in 1 (0.3%) participant in the 2q4 group (Headache)

[0460] The relationship of TEAEs to other study procedures was assessed by the masked investigator, and was a clinical decision based on all available information.

[0461] Ocular protocol-required procedures-related TEAEs in the study eye were reported in 11 (1.9%) participants in the All 8mg group (5 [1.7%] and 6 [2.0%] for the 8q8/3 and 8q8/5 groups, respectively) and 3 (1.0%) participants in the 2q4 group. All of the events were reported for single participants only except for Intraocular pressure increased (2 participants in the 8q8/3 and 8q8/5 groups, respectively) and Conjunctival haemorrhage (1 participant in each of the treatment group).

[0462] Through Week 36, no ocular protocol-required procedures-related TEAE in the fellow eye was reported in any treatment group.

[0463] Non-ocular protocol-required procedures-related TEAEs through Week 36 were

reported in 9 (1.5%) participants in All 8mg group (4 [1.4%] and 5 [1.7%] for the 8q8/3 and 8q8/5 groups, respectively) and 3 (1.0%) participants in the 2q4 group. All of the events were reported in single participants only except for Nausea (3 participants in the 8q8/5 group, and 1 participant each in the 8q8/3 group and 2q/4 group).

[0464] Once the fellow eye received 2 mg aflibercept treatment during the study, TEAEs and serious TEAEs were also assessed as related/not related to the commercial 2 mg aflibercept treatment in the fellow eye.

[0465] No ocular or non-ocular TEAE related to fellow eye treatment with 2 mg aflibercept was reported in any treatment group through Week 36.

[0466] Overall, the intensities of ocular TEAEs in the study eye were similar between the All 8mg group and the 2q4 group, although the proportions of participants with mild TEAEs were slightly higher in the All 8mg groups compared to the 2q4 group.

[0467] The maximum intensity of ocular TEAEs in the study eye was mostly mild (24% in the All 8mg group [25.9% and 22.1% for the 8q8/3 and 8q8/5 groups, respectively] and 19.3% in the 2q4 group) or moderate (7.1% in the All 8mg group [8.5% and 5.7% for the 8q8/3 and 8q8/5 groups, respectively] and 7.0% in the 2q4 group).

[0468] Severe ocular TEAEs in the study eye were reported in 5 (0.8%) participants in the All 8mg group (2 [0.7%] and 3 [1.0%] for the 8q8/3 and 8q8/5 groups, respectively) and 6 (2.0%) participants in the 2q4 group. All the severe ocular TEAEs were reported in single participants except for Cataract (2 participants in the 8q8/5 group) (Table 1-42).

Table 1-42. All severe ocular TEAEs by PT with their associated SOCs: number (%) of participants (safety analysis set)

Primary System Organ Class 8q8/3 8q8/5 All 8mg 2q4 N=293 N=298 N=591 N=301 (100%) (100%) (100%) (100%) Number (%) of participants with at least one such adverse event 6 (2.0%) 2 (0.7%) 3 (1.0%) 5 (0.8%) Eye disorders 5 (1.7%) 0 3 (1.0%) 3 (0.5%) Blindness 1 (0.3%) 0 0 0 Cataract 0 0 2 (0.7%) 2 (0.3%) Macular hole 1 (0.3%) 0 0 0 Posterior capsule opacification 1 (0.3%) 0 0 0 Retinal artery occlusion 1 (0.3%) 0 0 0 Retinal detachment 1 (0.3%) 0 0 0 Retinal vein occlusion 0 0 1 (0.3%) 1 (0.2%) Infections and infestations 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Endophthalmitis 0 1 (0.3%) 0 1 (0.2%)

Tooth abscess 1 (0.3%) 0 0 0 Investigations 0 1 (0.3%) 0 1 (0.2%) Intraocular pressure increased 0 1 (0.3%) 0 1 (02%)

[0469] Overall, the intensities of ocular TEAEs in the fellow eye were similar between the All 8 mg group and the 2q4 group.

[0470] The maximum intensity of ocular TEAEs in the fellow eye was mostly mild (11.7% in the All 8mg group [11.9% and 11.4% for the 8q8/3 and 8q8/5 groups, respectively] and 11.0% in the 2q4 group) or moderate (3.4% in the All 8mg group [4.4% and 2.3% for the 8q8/3 and 8q8/5 groups, respectively] and 4.7% in the 2q4 group). Severe ocular TEAEs in the fellow eye were reported in 1 (0.3%) participant in the 8q8/3 group with events of Choroidal detachment, Flat anterior chamber of eye, Glaucoma, and Intraocular pressure increased.

[0471 ] Overall, the intensities of non-ocular TEAEs were similar between the All 8mg group and the 2q4 group. The maximum intensity of non-ocular TEAEs was mostly mild (30.6% in the All 8mg group [29.4% and 31.9% for the 8q8/3 and 8q8/5 groups, respectively] and 27.9% in the 2q4 group) or moderate (14.0% in the All 8mg group [13.0% and 15.1% for the 8q8/3 and 8q8/5 groups, respectively] and 16.9% in the 2q4 group). Severe non-ocular TEAEs were reported in 26 (4.4%) participants in the All 8mg group (14 [4.8%] and 12 [4.0%] for the 8q8/3 and 8q8/5 groups, respectively) and 16 (5.3%) participants in the 2q4 group. All severe non-ocular TEAEs were reported in single participants except for Bradycardia and Sepsis (both in 2 participants in the 8q8/3 group), and Type 2 diabetes mellitus (2 participants in the 2q4 group) (Table 1-43).

Table 1-43. All severe non-ocular TEAEs by PT with their associated SOCs: number (%) of participants (safety analysis set)

Primary System Organ Class Preferred term 2q4 8q8/3 8q8/5 All 8mg MedDRA version 27.1 N=301 N=293 N=298 N=591

(100%) (100%) (100%) (100%) Number (%) of participants with at least one such adverse event 16 (5.3%) 14 (4.8%) 12 (4.0%) 26 (4.4%) Blood and lymphatic system disorders 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Blood loss anaemia 0 0 1 (0.3%) 1 (0.2%) Pancytopenia 1 (0.3%) 0 0 0 Cardiac disorders 0 2 (0.7%) 1 (0.3%) 3 (0.5%) Bradycardia 0 2 (0.7%) 0 2 (0.3%) Coronary artery disease 0 1 (0.3%) 0 1 (0.2%) Myocardial infarction 0 0 1 (0.3%) 1 (02%) Gastrointestinal disorders 1 (0.3%) 3 (1.0%) 0 3 (0.5%) Femoral hernia incarcerated 0 1 (0.3%) 0 1 (0.2%)

Hiatus hernia 0 1 (0.3%) 0 1 (0.2%) Lower gastrointestinal haemorrhage 0 1 (0.3%) 0 1 (0.2%) Small intestinal obstruction 1 (0.3%) 0 0 0 General disorders and administration site conditions 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Chest pain 0 1 (0.3%) 0 1 (0.2%) Incarcerated hernia 1 (0.3%) 0 0 0 Hepatobiliary disorders 0 1 (0.3%) 1 (0.3%) 2 (0.3%) Cholecystitis acute 0 1 (0.3%) 0 1 (0.2%) Cholecystitis chronic 0 0 1 (0.3%) 1 (0.2%) Infections and infestations 2 (0.7%) 5 (1.7%) 2 (0.7%) 7 (1.2%) Abdominal abscess 1 (0.3%) 0 0 0 Bronchitis 0 0 1 (0.3%) 1 (0.2%) COVID-19 0 1 (0.3%) 0 1 (0.2%) Diverticulitis 0 1 (0.3%) 0 1 (0.2%) Gastroenteritis 0 1 (0.3%) 0 1 (02%) Infectious pleural effusion 0 1 (0.3%) 0 1 (0.2%) Pneumonia 1 (0.3%) 0 0 0 Pneumonia pseudomonal 0 0 1 (0.3%) 1 (0.2%) Sepsis 0 2 (0.7%) 0 2 (0.3%) Injury, poisoning and procedural complications 0 1 (0.3%) 2 (0.7%) 3 (0.5%) Brain herniation 0 0 1 (0.3%) 1 (0.2%) Procedural pain 0 0 1 (0.3%) 1 (02%) Rib fracture 0 1 (0.3%) 0 1 (0.2%) Subdural haematoma 0 0 1 (0.3%) 1 (0.2%) Investigations 1 (0.3%) 0 0 0 Haemoglobin increased 1 (0.3%) 0 0 0 Metabolism and nutrition disorders 2 (0.7%) 0 0 0 Diabetic ketoacidosis 1 (0.3%) 0 0 0 Type 2 diabetes mellitus 2 (0.7%) 0 0 0 Musculoskeletal and connective tissue disorders 2 (0.7%) 1 (0.3%) 2 (0.7%) 3 (0.5%) Arthralgia 0 0 1 (0.3%) 1 (0.2%) Back pain 0 0 1 (0.3%) 1 (0.2%) Intervertebral disc compression 1 (0.3%) 0 0 0 Myalgia 1 (0.3%) 0 0 0 Pain in extremity 0 1 (0.3%) 0 1 (0.2%) Vertebral lateral recess stenosis 1 (0.3%) 0 0 0 Neoplasms benign, malignant and unspecified (incl cysts and 2 (0.7%) 1 (0.3%) 4 (1.3%) 5 (0.8%) polyps)

0 0 1 (0.3%) 1 (0.2%) Colon cancer

Lung neoplasm malignant 0 0 1 (0.3%) 1 (0.2%) Metastatic neoplasm 1 (0.3%) 0 0 0 Oesophageal carcinoma 0 1 (0.3%) 0 1 (0.2%) Prostate cancer metastatic 0 0 1 (0.3%) 1 (0.2%) Rectal cancer 0 0 1 (0.3%) 1 (0.2%) Squamous cell carcinoma of lung 1 (0.3%) 0 0 0 Nervous system disorders 5 (1.7%) 1 (0.3%) 0 1 (0.2%)

Atypical migraine 1 (0.3%) 0 0 0 Cerebellar infarction 1 (0.3%) 0 0 0 Cerebellar stroke 1 (0.3%) 0 0 0 Cerebrovascular accident 1 (0.3%) 0 0 0 Epilepsy 0 1 (0.3%) 0 1 (0.2%) Haemorrhage intracranial 1 (0.3%) 0 0 0 Headache 1 (0.3%) 0 0 0 Lacunar infarction 1 (0.3%) 0 0 0 Psychiatric disorders 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Anxiety 0 1 (0.3%) 0 1 (0.2%) Mental status changes 1 (0.3%) 0 0 0 Renal and urinary disorders 2 (0.7%) 0 0 0 Acute kidney injury 1 (0.3%) 0 0 0 Diabetic nephropathy 1 (0.3%) 0 0 0 Reproductive system and breast disorders 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Pelvic organ prolapse 1 (0.3%) 0 0 0 Uterine haemorrhage 0 0 1 (0.3%) 1 (0.2%) Respiratory, thoracic and mediastinal disorders 0 1 (0.3%) 1 (0.3%) 2 (0.3%) Chronic obstructive pulmonary disease 0 0 1 (0.3%) 1 (02%) Respiratory failure 0 0 1 (0.3%) 1 (0.2%) Sleep apnoea syndrome 0 1 (0.3%) 0 1 (0.2%) Surgical and medical procedures 0 0 2 (0.7%) 2 (0.3%) Medical induction of coma 0 0 1 (0.3%) 1 (0.2%) Spinal fusion surgery 0 0 1 (0.3%) 1 (0.2%) Vascular disorders 2 (0.7%) 1 (0.3%) 0 1 (0.2%) Giant cell arteritis 1 (0.3%) 0 0 0 Hypertension 0 1 (0.3%) 0 1 (0.2%) Hypertensive emergency 1 (0.3%) 0 0 0

[0472] Through Week 36, there were 7 deaths reported in this study, evenly distributed across the treatment groups (Table 1-44), and all were associated with an SAE. None of the underlying AEs were assessed to be related to study intervention or study procedure. All AEs with fatal outcome were reported for single participants and all were TEAEs except for the Bronchitis with fatal outcome for the participant in the 8q8/5 group which was a post-treatment AE.

[0473] Overall, the deaths reported were consistent with concurrent medical conditions and the complications of these conditions associated with an older population.

Table 1-44. Deaths: number of participants with adverse events with fatal outcome by

primary system organ class and preferred term (safety analysis set)

Primary system organ class Preferred term 2q4 8q8/3 8q8/5 All 8mg MedDRA version 27.1 N=301 N=293 N=298 N=591 (100%) (100%) (100%) (100%) Number (%) of participants with at least one such adverse 2 (0.7%) 2 (0.7%) 3 (1.0%) 5 (0.8%) event

Infections and infestations 1 (0.3%) 1 (0.3%) 1 (0.3%) 2 (0.3%) Bronchitis 0 0 1 (0.3%) 1 (0.2%) Pneumonia 1 (0.3%) 0 0 0 Sepsis 0 1 (0.3%) 0 1 (0.2%) Injury, poisoning and procedural complications 0 0 1 (0.3%) 1 (0.2%) Brain herniation 0 0 1 (0.3%) 1 (0.2%) Neoplasms benign, malignant and unspecified (incl cysts and 0 1 (0.3%) 1 (0.3%) 2 (0.3%) polyps)

Oesophageal carcinoma 0 1 (0.3%) 0 1 (0.2%) Prostate cancer metastatic 0 0 1 (0.3%) 1 (0.2%) Nervous system disorders 1 (0.3%) 0 0 0 Haemorrhage intracranial 1 (0.3%) 0 0 0

[0474] The proportion of participants with ocular serious TEAEs in the study eye was low in all treatment groups and numerically lower in the All 8mg group (7 [1.2%]: 3 [1.0%] and 4 [1.3%] for the 8q8/3 and 8q8/5 groups, respectively) than in the 2q4 group 7 (2.3%) participants. Most of these events were reported in single participants except for Endophthalmitis (2 participants in the 2q/4 group and 1 in the 8q8/3 group), Macular hole (2 participants in the 2q4 group), and Visual acuity reduced (1 participant each in the 8q8/5 group and the 2q/4 group) (Table 1-45).

[0475] The maximum intensity of these SAEs was mostly moderate (4 [0.7%] participants in the All 8mg group: 2 [0.7%] for each the 8 mg group, and 4 (1.3%) participants in the 2q4 group) or severe (2 [0.3%] in the All 8mg group: 1 [0.3%] for each the 8 mg group, and 3 [1.0%] participants in the 2q4 group).

[0476] Six of the events were assessed to be related to IVT injection procedure (Endophthalmitis in 2 participants in the 2q4 group and 1 participant in the 8q8/3 group, Macular hole and Retinal detachment each in 1 participant in the 2q4 group, and Cataract in 1 participant in the 8q8/5 group). Three of the events were assessed to be related to the study intervention (Retinal vasculitis in 1 participant in the 8q8/5 group, and Visual acuity reduced and Endophthalmitis each in 1 participant in the 2q4 group).

[0477] Endophthalmitis: 5 days after receiving the preceding dose of study intervention, a participant in the 2q4 group experienced an event of moderate Endophthalmitis, which was assessed to be related to study intervention and the IVT injection procedure. The event didn’t

lead to any dose change of the study intervention, and it recovered/resolved with sequelae after 24 days.

[0478] Endophthalmitis: 3 days after receiving the preceding dose of study intervention, a participant in the 2q4 group experienced an event of moderate Endophthalmitis, which was assessed to be related to IVT injection. Study intervention was interrupted, and the recorded outcome was recovered/resolved at the time of this report.

[0479] Endophthalmitis: 2 days after the last dose of study intervention, a participant in the 8q8/3 group experienced an event of severe Endophthalmitis, which was assessed to be related to IVT injection. Mechanical vitrectomy was performed, and other remedial therapy was administered. The event didn’t lead to any dose change of the study intervention, and it recovered/resolved with sequelae after 16 days.

[0480] Macular hole: 25 days after the last dose of study intervention, a participant in the 2q4 group experienced an event of severe Macular hole, which was assessed to be related to IVT injection. Study intervention was withdrawn, and the recorded outcome was not recovered/not resolved at the time of this report.

[0481] Retinal detachment: 27 days after receiving the preceding dose of study intervention, a participant in the 2q4 group experienced an event of severe Retinal detachment, which was assessed to be related to IVT injection. Study intervention was interrupted, and the recorded outcome was recovering/resolving at the time of this report.

[0482] Cataract: 28 days after receiving the preceding dose of study intervention, a participant in the 8q8/5 group experienced an event of severe Cataract, which was assessed to be related to IVT injection. Study intervention was interrupted, and the recorded outcome was recovered/resolved with sequelae after 4 days.

[0483] Retinal vasculitis: approximately 1 month after the 2nd dose of study intervention, a 52-year- old male participant in the 8q8/5 group experienced an event reported as retinal vasculitis, which was assessed as related to study intervention by the Investigator. There were no signs or symptoms of a concurrent intraocular infection, and no medical history of systemic vasculitis was reported. A systemic cause (e.g., Behcet disease or others) was not found based on performed laboratory investigation (ESR/CRP/PPD/ ACE/test for VDRL/Toxoplasmosis/HIV/HSV/RF/ANA/ANCA). Study intervention was withdrawn, and the participant remained in the study for follow-up; the participant was started on dexamethasone intravitreal implant (Ozurdex) treatment and received intravitreal anti-VEGF treatment (ranibizumab, bevacizumab) and improved.

[0484] The review of the examination with FA/fundoscopy and OCT showed vessel staining

and multiple cotton wool spots without inflammatory cells. Some evidence of vessel staining was already noted at baseline, which is typical for RVO. At time of event larger veins show more prominent staining, but no evidence of significant increase in non-perfusion. There were no indications of worsening of RVO nor other explanation why vision was reduced. Further followup will be collected.

[0485] Visual acuity reduced: about 1 month after receiving the preceding dose of study intervention, a participant in the 2q4 group experienced an event of moderate Visual acuity reduced, which was assessed to be related to study intervention. Study intervention was interrupted, and the recorded outcome was not recovered/not resolved at the time of this report.

Table 1-45. Ocular serious TEAEs in the study eye: number of participants by primary system organ class and preferred term (safety analysis set)

Primary system organ class 2q4 8q8/3 8q8/5 All 8mg N=301 N=293 N=298 N=591 (100%) (100%) (100%) (100%) Number (%) of participants with at least one such adverse 7 (2.3%) 3 (1.0%) 4 (1.3%) 7 (1.2%) event

Eye disorders 5 (1.7%) 0 4 (1.3%) 4 (0.7%) Cataract 0 0 1 (0.3%) 1 (0.2%) Macular hole 2 (0.7%) 0 0 0 Retinal artery occlusion 1 (0.3%) 0 0 0 Retinal detachment 1 (0.3%) 0 0 0 Retinal vasculitis 0 0 1 (0.3%) 1 (0.2%) Retinal vein occlusion 0 0 1 (0.3%) 1 (0.2%) Visual acuity reduced 1 (0.3%) 0 1 (0.3%) 1 (0.2%) General disorders and administration site conditions 0 1 (0.3%) 0 1 (0.2%) Oedema 0 1 (0.3%) 0 1 (0.2%) Infections and infestations 2 (0.7%) 1 (0.3%) 0 1 (0.2%) Endophthalmitis 2 (0.7%) 1 (0.3%) 0 1 (0.2%) Injury, poisoning and procedural complications 0 1 (0.3%) 0 1 (0.2%) Skin laceration 0 1 (0.3%) 0 1 (0.2%)

[0486] The results of the subgroup analyses by RVO types for ocular serious TEAEs in the study eye show slightly higher incidences in the CRVO/HRVO subgroup than in the BRVO subgroup, which was mainly driven by more PTs types were reported in the CRVO/HRVO subgroup, for which almost all were reported in single participants.

[0487] Ocular serious TEAEs in the fellow eye were reported in 1 (0.3%) participant in the 8q8/3 group with a total of 3 events (Choroidal detachment, Flat anterior chamber of eye, and

Glaucoma). All three events were severe in intensity, but none were assessed to be related to study intervention or IVT injection procedure. The events of Flat anterior chamber of eye and Glaucoma were resolved, and the Choroidal detachment is resolving by Week 36.

[0488] Non-ocular serious TEAEs were reported with similar frequencies across the treatment groups: 43 (7.3%) participants in the All 8mg group (21 [7.2%] and 22 [7.4%] for the 8q8/3 and 8q8/5 groups, respectively) and 25 (8.3%) participants in the 2q4 group.

[0489] The majority of these TEAEs were reported in single participants only. Non-ocular serious TEAEs reported in >1 participant in any treatment group through Week 36 are presented in Table 1-46. Across the treatment groups, the most frequent non-ocular serious TEAEs was Pneumonia, which was reported in 1 (0.3%) participant in the 8q8/3 group and 2 (0.7%) participants in the 2q4 group. None of the non-ocular serious TEAEs was assessed to be related to study intervention or IVT injection procedure.

[0490] The maximum intensity of these SAEs was mostly moderate (17 [2.9%] participants in the All 8mg group: 8 [2.7%] and 9 [3.0%] for the 8q8/3 and 8q8/5 groups, respectively and 10 [3.3%] in 2q4 group) or severe (21 [3.6%] participants in the All 8mg group: 11 [3.8%] and 10 [3.4%] for the 8q8/3 and 8q8/5 groups, respectively and 14 [4.7%] in 2q4 group).

Table 1-46. Non-ocular treatment-emergent SAEs occurring in > 1 participant in all treatment group with their associated SOCs through Week 36 (safety analysis set) Primary System Organ Class Preferred term 2q4 8q8/3 8q8/5 All 8mg MedDRA version 27.1 N=301 N=293 N=298 N=591

(100%) (100%) (100%) (100%) Number (%) of participants with at least one such adverse 25 (8.3%) 21 (7.2%) 22 (7.4%) 43 (7.3%) event

Cardiac disorders

Bradycardia 0 2 (0.7%) 0 2 (0.3%) Infections and infestations

COVID-19 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Diverticulitis 0 2 (0.7%) 0 2 (0.3%) Herpes zoster 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Osteomyelitis 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Pneumonia 2 (0.7%) 1 (0.3%) 0 1 (0.2%) Sepsis 0 2 (0.7%) 0 2 (0.3%) Metabolism and nutrition disorders

Type 2 diabetes mellitus 2 (0.7%) 0 1 (0.3%) 1 (0.2%) Nervous system disorders

Epilepsy 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Renal and urinary disorders

Diabetic nephropathy 1 (0.3%) 0 1 (0.3%) 1 (0.2%)

[0491] The results of the subgroup analyses by RVO types for non-ocular serious TEAEs show slightly higher incidences in the CRVO/HRVO subgroup than in the BRVO subgroup. This was mainly driven by more PTs under the SOC Infections and infestations were reported in the CRVO/HRVO subgroup, and most of these events were reported in single participants.

[0492] Ocular and non-ocular TEAEs resulting in discontinuation of study intervention through Week 36 are summarized below.

[0493] Ocular TEAEs in the study eye leading to discontinuation of study intervention were reported in 1 (0.3%) participant each in the 8q8/5 group (Retinal vasculitis) and the 2q4 group (Macular hole).

[0494] Ocular TEAEs in the fellow eye leading to discontinuation of study intervention was not reported.

[0495] Non-ocular TEAEs leading to discontinuation of study intervention was reported in 5 (0.8%) participants in the All 8mg group (2 [0.7%] and 3 [1.0%] for the 8q8/3 and 8q8/5 groups, respectively) and 3 (1.0%) participants in the 2q4 group. They were Acute coronary syndrome, Chest pain, Pneumonia, Sepsis, Brain herniation, Subdural haematoma, Oesophageal carcinoma, Prostate cancer metastatic, Haemorrhage intracranial, Headache, and Giant cell arteritis. No specific safety trend was observed, and all events were reported in single participants.

[0496] Table 1-47 displays AESI as collected on the CRF, which are arterial thromboembolic events (ATEs) including cerebrovascular ischemic events and cardiovascular ischemic events. The proportion of participants with AESI was low and numerically lower in the All 8mg group (6 [1.0%] participants: 1 [0.3%] and 5 [1.7%] for the 8q8/3 and 8q8/5 groups, respectively) than in the 2q4 group (9 [3.0%]). All AESI were reported in single participants except for Coronary artery disease (1 participant each in the 8q8/3 and 2q4 groups) and Cerebral infarction (1 participant each in the 8q8/5 and 2q4 groups) (Table 1-47).

Table 1-47. Treatment-emergent adverse events of special interest: number of participants by primary system organ class and preferred term (safety analysis set) Primary system organ class Preferred term 2q4 8q8/3 8q8/5 All 8mg MedDRA version 27.1 N=301 N=293 N=298 N=591

(100%) (100%) (100%) (100%) Number (%) of participants with at least one such adverse 9 (3.0%) 1 (0.3%) 5 (1.7%) 6 (1.0%) event

Cardiac disorders 2 (0.7%) 1 (0.3%) 2 (0.7%) 3 (0.5%) Acute coronary syndrome 0 0 1 (0.3%) 1 (0.2%) Acute myocardial infarction 1 (0.3%) 0 0 0 Coronary artery disease 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Myocardial infarction 0 0 1 (0.3%) 1 (0.2%) Eye disorders 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Retinal artery embolism 0 0 1 (0.3%) 1 (0.2%) Retinal artery occlusion 1 (0.3%) 0 0 0 Nervous system disorders 6 (2.0%) 0 1 (0.3%) 1 (0.2%) Atypical migraine 1 (0.3%) 0 0 0 Carotid artery occlusion 1 (0.3%) 0 0 0 Cerebellar infarction 1 (0.3%) 0 0 0 Cerebellar stroke 1 (0.3%) 0 0 0 Cerebral infarction 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Cerebrovascular accident 1 (0.3%) 0 0 0 Haemorrhage intracranial 1 (0.3%) 0 0 0 Lacunar infarction 1 (0.3%) 0 0 0 Vascular disorders 0 0 1 (0.3%) 1 (0.2%) Peripheral artery occlusion 0 0 1 (0.3%) 1 (0.2%) Table displays adverse events of special interest as collected on the ORF. Adverse Event of Special Interest (AESI) are arterial thromboembolic events including cerebrovascular ischemic events and cardiovascular ischemic events.

[0497] Potential ATEs were evaluated by a masked adjudication committee according to criteria formerly applied and published by the Antiplatelet Trialists’ Collaboration (APTC). ATEs as defined by the APTC criteria include Nonfatal myocardial infarction, Nonfatal stroke (ischemic or hemorrhagic), or Death resulting from vascular or unknown causes.

[0498] Three (1.0%) participants in the 8q8/5 group and 5 (1.7%) participants in the 2q4 group reported adjudicated APTC events (Table 1 -48).

Table 1-48: Treatment-emergent adverse events: number of participants with APTC event by primary system organ class and preferred term (safety analysis set)

Primary system organ class Preferred term 2q4 8q8/3 8q8/5 All 8mg Med DRA version 27.1 N=301 N=293 N=298 N=591

(100%) (100%) (100%) (100%) Number (%) of participants with at least one such adverse 5 (1.7%) 0 3 (1.0%) 3 (0.5%) event

Cardiac disorders 2 (0.7%) 0 1 (0.3%) 1 (0.2%) Acute myocardial infarction 1 (0.3%) 0 0 0 Myocardial infarction 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Injury, poisoning and procedural complications 0 0 1 (0.3%) 1 (0.2%) Brain herniation 0 0 1 (0.3%) 1 (02%)

Nervous system disorders 3 (1.0%) 0 1 (0.3%) 1 (0.2%) Cerebellar infarction 1 (0.3%) 0 0 0 Cerebellar stroke 1 (0.3%) 0 0 0 Cerebral infarction 0 0 1 (0.3%) 1 (0.2%) Cerebrovascular accident 1 (0.3%) 0 0 0 Haemorrhage intracranial 1 (0.3%) 0 0 0 Lacunar infarction 1 (0.3%) 0 0 0

[0499] TEAEs related to hypertension events were reported in slightly higher proportion of participants in the All 8mg group (8.1%) than in the 2q4 group (4.7%) (Table 1-49). This is consistent with the imbalance in incidence of non-ocular medical history of Hypertension with 61.9% in the All 8mg group compared to 57.5% in the 2q4 group. Overall, approximately 60% of participants in all treatment groups had a medical history of Hypertension.

Table 1-49. Treatment-emergent adverse events: number of participants with Hypertension by primary system organ class and preferred term (safety analysis set) Primary system organ class Preferred term 2q4 8q8/3 8q8/5 All 8mg Med DR A version 27.1 N=301 N=293 N=298 N=591

(100%) (100%) (100%) (100%) Number (%) of participants with at least one such adverse 14 (4.7%) 24 (8.2%) 24 (8.1%) 48 (8.1%) event

Cardiac disorders 2 (0.7%) 0 0 0 Hypertensive heart disease 2 (0.7%) 0 0 0 Eye disorders 0 0 1 (0.3%) 1 (0.2%) Retinopathy hypertensive 0 0 1 (0.3%) 1 (0.2%) Investigations 3 (1.0%) 5 (1.7%) 4 (1.3%) 9 (1.5%) Blood pressure diastolic increased 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Blood pressure increased 2 (0.7%) 5 (1.7%) 2 (07%) 7 (1.2%) Blood pressure systolic increased 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Vascular disorders 12 (4.0%) 19 (6.5%) 20 (6.7%) 39 (6.6%) Essential hypertension 1 (0.3%) 0 0 0 Hypertension 10 (3.3%) 19 (6.5%) 20 (6.7%) 39 (6.6%) Hypertensive emergency 1 (0.3%) 0 0 0

[0500] The proportion of participants with TEAEs related to intraocular inflammation in the study eye was low and generally similar among the treatment groups (Table 1-50).

Table 1-50. Treatment-emergent adverse events: number of participants with Intraocular inflammation of study eye by primary system organ class and preferred term (safety analysis set) Primary system organ class Preferred term 2q4 8q8/3 8q8/5 All 8mg Med DR A version 27.1 N=301 N=293 N=298 N=591

(100%) (100%) (100%) (100%) Number (%) of participants with at least one such adverse 4 (1.3%) 2 (0.7%) 1 (0.3%) 3 (0.5%) event. E_ye d,.isord,ers 2 ( '0.7%) ' 1 ( '0.3%) ' 1 ( '03%) ' 2 ( '0.3%) ' Anterior chamber cell 1 (0.3%) 0 0 0 Eye inflammation 1 (0.3%) 0 0 0 Iritis 0 1 (0.3%) 0 1 (0.2%) Uveitis 0 0 1 (0.3%) 1 (0.2%) Infections and infestations 2 (0.7%) 1 (0.3%) 0 1 (0.2%) Endophthalmitis 2 (0.7%) 1 (0.3%) 0 1 (0.2%)

[0501] Due to findings from the preclinical toxicology studies for 8 mg aflibercept, an assessment was performed in the clinical program for events related to nasal mucosa. The only TEAE related to nasal mucosal findings was Epistaxis, which was reported for 2 (0.7%) participants each in the 8q8/3 and 2q4 groups and 1 (0.3%) participant in the 8q8/5 group. None of the events were considered related to the study intervention, the IVT injection procedure, the fellow eye treatment, or protocol-required procedures.

Table 1-51. Treatment-emergent adverse events: number of participants with Nasal mucosal events by primary system organ class and preferred term (safety analysis set) Primary system organ class Preferred term 2q4 8q8/3 8q8/5 All 8mg Med DR A version 27.1 N=301 N=293 N=298 N=591

(100%) (100%) (100%) (100%) Number (%) of participants with at least one such adverse 2 (07%) 2 (07%) 1 (0.3%) 3 (05%) event

Respiratory, thoracic and mediastinal disorders 2 (0.7%) 2 (0.7%) 1 (0.3%) 3 (0.5%) Epistaxis 2 (0.7%) 2 (0.7%) 1 (0.3%) 3 (0.5%)

[0502] Ocular TEAEs in the study eye and non-ocular TEAEs (both serious and non-serious) reported in the study through Week 36 were analyzed by the following subgroups: age at enrollment, sex, geographic region, ethnicity, race, baseline BCVA, baseline CST, medical history (including hypertension, diabetes, cerebrovascular disease, ischaemic heart disease, renal impairment, and hepatic impairment), and RVO type.

[0503] In general, the results of the treatment group comparisons of ocular TEAEs in the study eye through Week 36 within the subgroups considered for safety analyses were generally comparable to those in the entire study population and did not suggest medically relevant

differences among the treatment groups. The majority of events were reported in 1 or 2 participants in each group.

[0504] Larger differences across the treatment groups that were occasionally observed within the subgroups, for example the age group subgroup, must be interpreted with caution in view of the smaller subgroup sizes. In most subgroups, these differences were not consistently observed.

[0505] Treatment group comparisons of ocular serious TEAEs in the study eye through Week 36 within the subgroups must be interpreted with caution in view of the low group sizes and the low number of SAEs observed.

[0506] In general, the results of the treatment group comparisons of non-ocular TEAEs through Week 36 within the subgroups considered for safety analyses were generally comparable to those in the entire study population and did not suggest medically relevant differences among the treatment groups.

[0507] Similar to the ocular TEAEs, larger differences across the treatment groups that were occasionally seen within the subgroups, for example the age, and geographic region, must be interpreted with caution in view of the lower subgroup sizes. In most subgroups, these differences were not consistently observed.

[0508] Treatment group comparisons of non-ocular serious TEAEs in the study eye through Week 36 within the subgroups must also be interpreted with caution in view of the low group sizes and the low number of SAEs observed.

[0509] All abnormal laboratory test results (whether captured as part of the study procedures or as ancillary collections) considered clinically significant by the investigator were to be reported as AEs.

[0510] Pre-defined treatment-emergent hematological and clinical chemistry laboratory abnormalities were analyzed separately as presented in Table 1-52.

Table 1-52. Selected pre-defined treatment-emergent laboratory abnormalities by laboratory parameter and visit: numbers of participants (safety analysis set)

Pre-defined

treatment- 2q4 8q8/3 8q8/5 All 8mg Parameter emergent lab (N=301) (N=293) (N=298) (N=591) Category Parameter abnormalities Num/Den(%) Num/Den(%) Num/Den(%) Num/Den(%) Hematology Hematocrit Males: <37%, 3/249 (1.2%) 1/238 (0.4%) 2/239 (0.8%) 3/477 (0.6%) Females: <32%

Males: >55%, 13/245 (5.3%) 14/ 234 (6.0%) 14/231 (6.1%) 28/465 (6.0%) Females: >50% Hemoglobin Decrease from 9/252 (3.6%) 6/239 (2.5%) 8/242 (3.3%) 14/481 (2.9%) baseline >2.0 g/dL Males: <11.5 5/ 252 (2.0%) 1/238 (0.4%) 3/236 (1.3%) 4/474 (0.8%) g/dL, Females: <9.5 g/dL Males: >18.5 0/250 0/239 0/241 0/480 g/dL, Females: >16.5 g/dL Neutrophils Non-Black: <1.5 0/242 0/227 0/237 0/464

GIGA/L, Black: <1.0 GIGA/L

0/250 0/238 0/240 0/478 Monocytes >0.7 10³/uL 0/250 0/238 0/240 0/478

Eosinophils >0.5 10³/uL or 0/250 0/238 0/240 0/478

> ULN if ULN

>0.5 10³/uL

Basophils >0.1 10³/uL 0/250 0/238 0/240 0/478 Platelets <100 10³/uL 0/241 0/236 0/237 0/473

RBC >6 10⁶/uL 0/251 0/239 0/242 0/481

WBC >16.0 GIGA/L 0/251 0/239 0/242 0/481

Non-Black: <3.0 0/244 0/229 0/239 0/468 GIGA/L, Black:

<2.0 GIGA/L

General Chloride <80 mmol/L 0/271 1/261 (0.4%) 0/257 1/518 (0.2%) chemistry

>115 mmol/L 0/271 0/261 0/257 0/518 Potassium <3 mmol/L 0/269 0/253 1/257 (0.4%) 1/510 (0.2%) >5.5 mmol/L 1/271 (0.4%) 1/252 (0.4%) 2/256 (0.8%) 3/508 (0.6%) Sodium £129 mmol/L 2/271 (0.7%) 1/262 (0.4%) 1/259 (0.4%) 2/521 (0.4%) >160 mmol/L 0/272 1/262 (0.4%) 0/261 1/523 (0.2%) Creatinine >150 umol/L 4/270 (1.5%) 3/257 (1.2%) 3/255 (1.2%) 6/512 (1.2%) (>1.7 mg/dL)

Increase from 12/272 (4.4%) 16/260 (6.2%) 12/258 (4.7%) 28/518 (5.4%) baseline >30%

Glucose Hyperglycaemia: 9/264 (3.4%) 5/251 (2.0%) 0/253 5/504 (1.0%) >11.1 mmol/L

(5200 mg/dL)

Hypoglycaemia: 1/268 (0.4%) 6/254 (2.4%) 6/253 (2.4%) 12/507 (2.4%) <3.9 mmol/L

(<70.3 mg/dL)

and < LLN

Albumin <2.5 g/dL 0/274 0/263 0/262 0/525

AST >3 ULN 0/268 0/254 0/252 0/506

ALT >3 ULN 0/268 0/255 1/253 (0.4%) 1/508 (0.2%) ALT and Total ALT >3 ULN and 0/269 0/255 0/253 0/508

Total Bilirubin >2

Bilirubin ULN

Alkaline Phosphatase >1.5 ULN 0/270 2/261 (0.8%) 0/256 2/517 (0.4%)

Total >1.5 ULN 0/269 2/257 (0.8%) 0/251 2/508 (0.4%) Bilirubin

Conjugated >35% total 0/269 0/257 0/254 0/511 bilirubin bilirubin (when

total bilirubin

>1.5 ULN)

Blood Urea >1.5 ULN 1/266 (0.4%) 6/256 (2.3%) 8/252 (3.2%) 14/508 (2.8%) Nitrogen

Total £7.74 mmol/L 5/265 (1.9%) 3/261 (1.1%) 6/249 (2.4%) 9/510 (1.8%) Cholesterol (>299.3 mg/dL)

Triglycerides >4.6 mmol/L 5/265 (1.9%) 1/253 (0.4%) 4/247 (1.6%) 5/500 (1.0%) (>407.3 mg/dL)

Uric Acid Hyperuricemia: 15/236 (6.4%) 20/226 (8.8%) 21/216 (9.7%) 41/442 (9.3%) >408 umol/L

(>6.86 mg/dL)

Hypouricemia: 0/270 0/257 0/254 0/511

<120 umol/L

(<2.02 mg/dL)

CPK >3 ULN 1/267 (0.4%) 1/252 (0.4%) 3/253 (1.2%) 4/505 (0.8%) The denominator (Den) represents the number of participants with no pre-defined abnormal lab assessment at baseline who also have a valid lab value post baseline.

The numerator (Num) represents the number of participants with a pre-defined abnormal lab assessment post baseline who also had no pre-defined abnormal lab assessment at baseline.

[0511] The proportions of participants with high abnormalities in the hematology variables were generally low (<10%) in all treatment groups, with the exception of hematology variables Erythrocytes Mean Corpuscular Volume (28.8% in the All 8mg group [31.5% and 26.1% for the 8q8/3 and 8q8/5 groups, respectively] and 30.2% in the 2q4 group) and Hematocrit (18.3% for the All 8mg group [18.8% and 17.7% in the 8q8/3 and 8q8/5 groups, respectively] and 15.1% in the 2q4 group). There were no relevant differences in the proportions of participants with high abnormalities between the All 8mg group and the 2q4 group for any hematology variable.

[0512] The proportions of participants with low abnormalities in the hematology variables were generally low (<10%) and balanced across the treatment groups.

[0513] Pre-defined selected laboratory abnormalities were only reported in the hematology variables Hematocrit and Hemoglobin and the incidences of these abnormalities were generally low (with the highest incidence of 6.1%) and balanced across the treatment groups (Table 1-52).

[0514] The proportions of participants with high abnormalities in the clinical chemistry variables were generally low (<10%) in all treatment groups, except for Hemoglobin A1C in all treatment groups (19.3% in the All 8mg group [17.4% and 21.4% in the 8q8/3 and 8q8/5 groups, respectively] and 18.0% in the 2q4 group), Triglycerides in all treatment groups (16.4% in All 8mg group [15.8% and 17.0% in the 8q8/3 and 8q8/5 groups, respectively] and 13.8% in the 2q4 group), Cholesterol in all treatment groups (15.0% in the All 8mg group [12.0% and 18.2% in the 8q8/3 and 8q8/5 groups, respectively] and 17.6% in the 2q4 group), Blood Urea Nitrogen in the 8q8/3 and 2q4 groups (11.9% and 12.2%, respectively), and high density lipoprotein (HDL) Cholesterol in the 2q4 groups (10.2%). However, there were no relevant differences in the proportions of participants with high abnormalities between the All 8mg group and the 2q4 group for any clinical chemistry variable.

[0515] The proportions of participants with low abnormalities in the clinical chemistry variables were generally low (<10%) in all treatment groups, except for Creatinine in the 8q8/3 group (13.3%), HDL Cholesterol in the 8q8/5 and 2q4 groups (11.8% for both), and Bicarbonate in the 8q8/5 and 2q/4 groups (12.7% and 10.5%, respectively). However, there were no relevant differences in the proportions of participants with low abnormalities between the All 8mg group and the 2q4 group for any clinical chemistry variable.

[0516] Pre-defined selected clinical chemistry laboratory abnormalities are summarized in Table

1-52. The incidences of these abnormalities were generally low (<5%), with the exception of Uric Acid in all treatment groups (9.3% in the All 8mg group [8.8% and 9.7% in the 8q8/3 and 8q8/5 groups, respectively] and 6.4% in the 2q4 group) and Creatinine in the 8q8/3 group (6.2%). The incidences were all generally balanced across the treatment groups.

[0517] The proportions of participants with high abnormalities in the urinalysis variables were generally low (<10%) in all treatment groups, except for Protein in the 2q4 group (11.1%), and Protein/Creatinine in the 8q8/3 and 2q4 groups (11.5% and 18.3%, respectively). There were no relevant differences in the proportions of participants with high abnormalities between the All 8mg group and the 2q4 group for any urinalysis variable.

[0518] The proportions of participants with low abnormalities in the clinical chemistry variables Creatinine and Protein/Creatinine were generally low (with the highest incidence of 7.5%) and

balanced across the treatment groups. No low abnormalities were observed for Protein and Specific Gravity.

[0519] There were no pre-defined selected laboratory test abnormalities defined for the urinalysis variables. All clinically relevant laboratory abnormalities were reported as AEs.

[0520] There were no clinically meaningful findings in the vital signs measurements, physical examination assessments, or other observations related to safety in this study. The assessments and observations were comparable across treatment groups.

[0521] The following analyses of these routinely assessed vital sign variables provide complementary safety information.

[0522] The mean change from baseline in SBP was similar across the treatment groups with numerically small mean decreases in all treatment groups through Week 36, and no relevant differences were seen across the treatment groups.

[0523] There were no notable differences across the treatment groups for the pre-defined treatment- emergent potentially clinically significant values (PCSVs) for SBP, with a low frequency in all treatment groups (<2.5% for PCSVs decrease, and <8.0% for PCSVs increase) (Table 1-53). Overall, no consistent trend of changes in SBP was observed during the study.

Table 1-53. Treatment-emergent potentially clinically significant values for systolic blood pressure at any visit (safety analysis set)

Pre-defined treatment-emergent 2q4(N=301) 8q8/3 (N=293) 8q8/5 (N=298) All 8mg potentially clinically significant Num/Den(%) Num/Den(%) Num/Den(%) (N=591)

values Num/Den(%) SBP <95 mmHg and decrease from 5/ 299 (1.7%) 5/ 291 (1.7%) 7/ 296 (2.4%) 12/ 587 (2.0%) baseline >20 mmHg

SBP >160 mmHg and increase from 22/299 (7.4%) 23/291 (7.9%) 15/296 (5.1%) 38/587 (6.5%) baseline >20 mmHg

The denominator (Den) represents the number of participants at baseline without an abnormal blood pressure assessment, and at least one valid blood pressure value after start of treatment. Participants with missing or abnormal values at baseline are not included in the denominator. The numerator (Num) represents the number of participants with at least one abnormal blood pressure assessment after the start of treatment, and without an abnormal blood pressure assessment at baseline.

Participants with at least one treatment-emergent potentially clinically significant value (PCSV) of SBP are displayed.

[0524] The mean change from baseline in DBP was similar across the treatment groups with numerically slight mean decreases in all treatment groups through Week 36, and no relevant differences were seen across the treatment groups.

[0525] Pre-defined treatment-emergent PCSVs (increase or decrease) for DBP were only sporadically reported (<1.0% of participants in any treatment group) (Table 1-54). Overall, no consistent trend of changes in DBP was observed during the study.

Table 1-54. Treatment-emergent potentially clinically significant values for diastolic blood pressure at any visit (safety analysis set)

2q4(N=301) 8q8/3 (N=293) 8q8/5 (N=298) All 8mg Pre-defined treatment-emeraent ⁹ Num/Den(%) Num/Den(%) Num/Den(%) (N=591) potentially clinically significant values Num/Den(%) DBP <45 mmHg and decrease from 2/299 (0.7%) 1/ 291 (0.3%) 0/ 296 1/587 (0.2%) baseline >10 mmHg DBP >110 mmHg and increase from 1/299 (0.3%) 3/291 (1.0%) 3/296 (1.0%) 6/587 (1.0%) baseline >10 mmHg

Participants with at least one treatment-emergent potentially clinically significant value (PCSV) of blood pressure are displayed.

[0526] The mean change from baseline in heart rate was comparable across the treatment groups with numerically slight mean decreases in all treatment groups through Week 36.

There was no trend of change over time in any of the treatment groups with regard to body temperature.

[0527] Clinically relevant ECG alterations that occurred during the course of the study were reported as AEs. The following analyses of the cardiac conduction times provide complementary safety information.

[0528] The mean changes from baseline to Week 36 in heart rate by ECG were small and similar across the treatment groups and did not show relevant systematic changes over time. The PR intervals showed small mean increases (2.4 ms in the All 8mg group and 1.03 ms in the 2q4 group) with large SD values from baseline to Week 36, which were similar in extent in all treatment groups and not clinically relevant.

[0529] None of the treatment groups showed clinically relevant mean changes in QRS duration from baseline to Week 36 (0.33 ms in the All 8mg group and -0.16 ms in the 2q4 group).

Maximum QRS durations at Week 36 ranged from 158 ms (8q8/5 group) to 196 ms (2q4 group).

[0530] The RR interval showed slight mean increases (23.44 ms in the All 8mg and 17.44 ms in the 2q4 group) with large SD values from baseline to Week 36, which were similar in extent in all treatment groups and not clinically relevant.

[0531] There were no clinically relevant mean changes in QT interval from baseline to Week 36 (4.59 ms in the All 8mg group and 3.25 ms in the 2q4 group). Maximum and minimum changes were more pronounced in the 8q8/3 group. Maximum QT intervals at Week 36 ranged from 503 ms (2q4 group) to 545 ms (8q8/3 group), which were lower than the maximum interval at baseline (551 in the 2q8 group).

vQTcB interval of up to 519 ms (8q8/5 group) and 551 ms (2q4 group) were already observed at baseline. Mean changes in QTcB interval from baseline to Week 36 were small and not clinically relevant (-0.64 ms in the All 8mg group and -0.24 ms in the 2q4 group). Maximum individual QTcB values at Week 36 ranged from 500 ms (8q8/3 group) to 525 ms (8q8/5 group).

[0532] QTcF interval of up to 518 ms (8q8/3 group) and 551 ms (2q4 group) were already observed at baseline. Mean changes in QTcF interval from baseline to Week 36 were small and not clinically relevant (1.15 ms in the All 8mg group and 0.94 ms in the 2q4 group). Maximum individual QTcF values at Week 36 ranged from 495 ms (8q8/5 group) to 503 ms (2q4 group).

[0533] Overall, there were no clinically relevant differences between the All 8mg group and the 2q4 group and no signs of a systematic trend towards QTc prolongation with either Bazett’s or Fridericia’s correction.

[0534] The proportion of participants with a normal ECG at baseline who transitioned to an abnormal ECG at Week 36 was 17.8% in the All 8mg group and 21.6% in the 2q4 group. The proportion of participants with an abnormal ECG at baseline who transitioned to a normal ECG at Week 36 was much larger: 51.4% in the All 8 mg and 57.1% in the 2q4 group.

[0535] Overall, there were no patterns or trends in the ECG assessments that suggest drug-related ECG changes or differences across the treatment groups.

[0536] Any clinically relevant ECG findings were captured as non-ocular TEAEs. The only TEAE that was clearly associated with morphological ECG findings was Electrocardiogram QT prolonged under the SOC Investigations, which was mild in intensity and non-serious (reported in a single participant in the 8q8/5 group).

[0537] All clinically relevant findings during the course of the study were to be reported as ocular AEs. The following analyses of the results of intraocular pressure, and flare and cell in the anterior chamber provide complementary safety information.

[0538] No relevant mean or median changes from baseline to Week 36 or relevant differences

across the treatment groups were observed in the analysis of the pre- injection IOP data.

[0539] The number of participants meeting IOP criteria at any visit in the study eye is presented in Table 1-54. The proportions of participants meeting IOP criteria were generally low in all treatment groups but slightly higher in the All 8mg group compared to the 2q4 group for all criteria except for the most clinically relevant IOP assessment of >35 mmHg (pre- or post-dose), for which the incidences were balanced between the All 8mg group (1.0%) and the 2q4 group (0.3%).

Table 1-55. Number of participants meeting intraocular pressure criteria at any visit through Week 36- study eye (safety analysis set)

2q4 8q8/3 8q8/5 All 8mg N=301 N=293 N=298 N=591 (100%) (100%) (100%) (100%) Participants with >10 mmHg increase in pre-dose IOP from baseline 4 (1.3%) 13 (4.4%) 11 (3.7%) 24 (4.1%) Participants with pre-dose IOP >21 mmHg 19 (6.3%) 34 (11.6%) 41 (13.8%) 75 (12.7%) Participants with pre-dose IOP S25 mmHg 5 (1.7%) 11 (3.8%) 12 (4.0%) 23 (3.9%) Participants with pre- or post-dose IOP S35 mmHg 1 (0.3%) 3 (1.0%) 3 (1.0%) 6 (1.0%)

[0540] Clinically relevant changes in IOP values (in both eyes) were reported as ocular TEAEs under the SOC Investigations and included Intraocular pressure decreased, Intraocular pressure increased, and Intraocular pressure test abnormal.

[0541] IOP increased in the study eye was reported in 31 (5.2%) participants in the All 8mg group (16 [5.5%] and 15 [5.0%] for the 8q8/3 and 8q8/5, respectively) and 5 (1.7%) participants in the 2q4 group. None of the IOP increased events were serious or led to discontinuation of study intervention, most were mild or moderate in intensity and resolved without sequela.

[0542] Severe IOP increased was reported in 1 participant in the 8q8/3 group.

[0543] IOP decreased in the study eye was reported for 1 participant in the 2q4 group and was of mild intensity. IOP test abnormal in the study eye was reported for 1 participant in the 8q8/3 group and was also of mild intensity.

[0544] The analyses of the semi-quantitative grading for anterior chamber flare and anterior chamber cells using the categories 0, trace, 1 +, 2+, 3+, and 4+, did not show relevant differences across the treatment groups at baseline or at subsequent visits through Week 36.

[0545] Anterior chamber flare was reported very infrequently and did not exceed a maximum grade of 1+, which occurred occasionally in one participant in the 8q8/5 group at baseline, in one participant in the 8q8/3 group at Week 20, and in 2 participants at baseline and in single

participants from Week 4 to 20 in the 2q4 group. Since Week 28, no anterior chamber flare was detected in any of the treatment group.

[0546] Anterior chamber cells were only sporadically detected in all treatment groups over time, with a maximum intensity of 2+ (in a single participant in the 8q8/5 group at Week 12). No anterior chamber cell was detected in any treatment group since Week 28.

[0547] There was no pregnancy reported during this study.

[0548] The PK data presented in this report are based on almost all PK samples taken up to Week 24 and about 30% of PK samples at Week 36. Owing to time needed for sample shipment, bioanalysis and population PK analysis, not all samples taken up to Week 36 could be considered for the database release of this Week 36 report. A PK analysis based on all scheduled samples up to Week 36 is planned to be presented in the Week 64 report.

[0549] Systemic exposure to free and adjusted bound aflibercept (at expected maximum plasma concentration after the 5^th or 4^th IVT administration depending on the treatment regimen, and during elimination phase from plasma) were determined by sparse sampling. The concentration-time data for free and adjusted bound aflibercept up to Week 36 as based on the available samples are described below. A more detailed pharmacokinetic analysis was performed using a population approach (popPK by non-linear mixed effect modeling) designed to handle sparse data. This evaluation is reported separately.

[0550] Since total aflibercept is the sum of free and adjusted bound aflibercept, the main results and conclusions described here are transferable to the total aflibercept concentration. Therefore, PK results for total aflibercept are not discussed in detail here.

[0551] The PKS was used for the descriptive statistics of the PK assessment of free, adjusted bound, and total aflibercept concentration. The PKS included 883 (98.8%) participants who had at least one non-missing PK assessment following the first dose of study intervention.

[0552] The bioanalytical methods used to determine free and bound aflibercept concentrations in plasma as well as the assay performance are described in detail in the bioanalytical report.

[0553] T able 1 -56 summarizes the plasma concentration-time data for free aflibercept after IVT administration of aflibercept. Concentrations of free aflibercept in plasma were, on average and as expected, higher for the 8q8/3 and 8q8/5 groups than the 2q4 group. When interpreting the concentration data, the time of PK sampling after the most recent dose needs to be considered. While the PK samples taken in Weeks 4, 12, and 36 were taken nominally 4 weeks after the most recent dose, the Week 24 samples were taken nominally 8 weeks after the most recent dose. Due to the allowed DRM /dosing interval shortening in participants meeting pre-defined criteria, some of the participants might have taken their PK sample at this timepoint only 4 weeks after

the most recent dose. In contrast, the PK samples linked to Week 16, had to be taken 1 to 10 days after dosing in Week 16. This range of time after dose explains the high variability of the Week 16 free aflibercept concentrations. The proximity to the most recent dose explains why highest concentrations were measured at this timepoint. With the exception of this timepoint and the Week 12 PK samples in the All 8mg dose group, the majority of concentrations in plasma was below the lower limit of quantitation (< LLOQ).

[0554] Exploratory analysis of subgroups with respect to age, body mass index (BMI), medical history of renal impairment, medial history of hepatic impairment, ethnicity (Latino/Hispanic vs. not Latino/Hispanic), and race (White vs. Black or African American vs. Asian vs. Other/Not reported) did not reveal any meaningful differences for free aflibercept concentrations. When comparing the mean values in the different groups, the smaller numbers of participants per group as well as the high variability of data should be considered.

Table 1-56. Summary statistics for concentrations of free aflibercept (ng/mL) in plasma: Up to Week 36 (pharmacokinetic analysis set)

n > Geom. Arithm.

Treatment Visit n LLOQ Mean (SD) Mean (SD) 2q4 Baseline 295 2 N. C 0.2 (3.2)

Week 4 290 8 N. C 0.6 (3.8)

Week 12 291 19 N C 24 (148)

Week 16 272 212 26.8 (2.3) 35.9 (34.8)

Week 24 278 14 N. C 1.1 (4.8)

Week 36 75 1 N. C. 0.2 (2.0)

8q8/3 Baseline 278 1 N. C. 0.4 (6.4)

Week 4 279 140 N. C 13.3 (14.9)

Week 12 279 201 20.8 (2.0) 24.1 (20.4)

Week 16 271 238 93.8 (3.1) 147.0 (135.3)

Week 24 265 15 N. C 1.3 (5.6)

Week 36 72 41 N. C. 16.8 (16.9)

8q8/5 Baseline 284 2 N. C. 0.2 (2.3)

Week 4 282 140 N. C 13.0 (14.9)

Week 12 276 199 21.1 (2.1) 24.8 (22.1)

Week 16 268 261 129.1 (2.5) 180.7 (155.4)

Week 24 268 15 N. C 1.3 (5.3)

Week 36 75 40 N. C. 13.7 (13.9)

All 8mg Baseline 562 3 N. C 0.3 (4.8)

Week 4 561 280 N. C 13.1 (14.9)

Week 12 555 400 20.9 (2.0) 24.4 (21.2)

Week 16 539 499 109.9 (2.8) 163.7 (146.5)

Week 24 533 30 N. C 1.3 (5.5) 11876WO01 Week 36 147 81 N. C 15.2 (15.4)

CV: Coefficient of variation, LLOQ: Lower Limit of Quantitation, SD: Standard Deviation, NE: Not Evaluable N. C.: not calculated (less than 2/3 of values per timepoint are > LLOQ for geometric mean calculation).

Values which were under lower limit of quantitation (< LLOQ), half the value of the LLOQ was used for analysis. For arithmetic statistics use, values under LLOQ were set to 0 instead of half LLOQ value.

For free aflibercept assay: LLOQ = 15.6 ng/mL.

[0555] Table 1-57 summarizes the plasma concentration-time data for adjusted bound aflibercept after IVT administration of aflibercept. Concentrations of adjusted bound aflibercept in plasma were, on average and as expected, higher for the 8q8/3 and 8q8/5 groups than the 2q4 group. In all groups, mean adjusted bound aflibercept concentrations increased from baseline to Week 12. For the other timepoints, the different time after the most recent dose needs to be considered. In contrast to free aflibercept, most bound concentrations (except at baseline) could be quantified with concentrations > LLOQ.

[0556] Exploratory analysis of subgroups with respect to age, body mass index (BMI), medical history of renal impairment, medial history of hepatic impairment, ethnicity (Latino/Hispanic vs. not Latino/Hispanic), and race (White vs. Black or African American vs. Asian vs. Other / Not reported) did not reveal any meaningful differences for adjusted bound aflibercept concentrations. When comparing the mean values in the different groups, the smaller numbers of participants per group as well as the high variability of data should be considered.

Table 1-57. Summary statistics for concentrations of adjusted bound aflibercept (ng/mL) in plasma: Up to Week 36 (pharmacokinetic analysis set)

n > LLOQ Geom. Mean Arithm. Mean (SD) Treatment Visit n (SD)

2q4 Baseline 295 4 N. C 1.5 (15.3)

Week 4 290 285 91.4 (1.7) 103.2 (56.8)

Week 12 291 288 150.4 (1.7) 169.1 (83.2)

Week 16 273 273 210.1 (1.6) 232.5 (111.9)

Week 24 278 276 165.1 (1.7) 187.6 (94.4)

Week 36 85 84 169.1 (1.7) 189.9 (86.3)

8q8/3 Baseline 278 6 N. C 6.5 (59.8)

Week 4 279 278 272.1 (1.6) 297.0 (110.7)

Week 12 279 276 431.7 (1.7) 476.5 (180.8)

Week 16 271 271 342.0 (1.7) 383.0 (166.0)

Week 24 265 262 179.4 (1.9) 215.7 (131.8)

Week 36 89 89 355.6 (1.6) 397.1 (177.3) 11876WO01 8q8/5 Baseline 286 6 N. C 4.3 (37.3)

Week 4 282 278 261.3 (1.8) 291.2 (114.3)

Week 12 276 274 433.0 (1.7) 475.6 (179.4)

Week 16 268 268 569.8 (1.5) 610.4 (224.2)

Week 24 268 263 202.0 (2.0) 245.4 (143.3)

Week 36 91 89 310.1 (2.1) 363.4 (149.3)

All 8mg Baseline 564 12 N. C 5.4 (49.7)

Week 4 561 556 266.6 (1.7) 294.1 (112.5)

Week 12 555 550 432.3 (1.7) 476.0 (179.9)

Week 16 539 539 440.8 (1.7) 496.1 (227.5)

Week 24 533 525 190.4 (2.0) 230.6 (138.4)

Week 36 180 178 331.8 (1.9) 380.1 (164.2)

For bound aflibercept assay: LLOQ = 31.3 ng/mL.

[0557] Conclusion. Treatment with HD aflibercept at intervals of 8 weeks (administered with 3 or 5 initial Q4 doses) provided non-inferior BCVA gains at Week 36 compared to treatment with aflibercept 2 mg every 4 weeks, while achieving an average reduction of up to 2 active injections in the HD groups compared to the 2q4 group through Week 36. Overall, 90.9% of participants treated with HD aflibercept through Week 36 were maintained on a treatment interval of every 8 weeks through Week 36 while maintaining visual and anatomic outcomes. Furthermore, the last intended interval at Week 36 was 8 weeks for 75.6% of participants in the 2q4 group, while in the 8q8/3 group it was >8 weeks for 93.9% of participants and 12 weeks for 69% of participants. Review of the safety data did not reveal any new safety signals or adverse trends in the All 8mg aflibercept groups compared to the 2 mg group. The ocular and systemic safety profile of aflibercept HD was consistent with the established safety profile of aflibercept 2 mg and 8mg. Robust efficacy and safety was demonstrated in all RVO types (BRVO and CRVO/HRVO)

Results at week 36 (updated)

[0558] In a case study, a patient that had the BRVO subtype was randomly assigned to the 8q8/3 group and had a baseline BCVA of 35 letters and CRT of 925 p.m. Extensive leakage was visible at baseline. Baseline characteristics of the patient are set forth in Table 1 -57A.

Table 1-57A. Baseline Patient Characteristics

Age, years 52

Gender Female

Ethnicity White

Type of RVO BRVO, right eye

Treatment arm 8q8/3

Baseline BCVA,

35

ETDRS letters

Baseline CRT, pm 925

Past medical history None

Past ocular history None

[0559] The patient’s baseline angiogram is set forth in Figure 11 A. The angiogram shows extensive leakage of fluorescein.

[0560] The patient’s angiogram at week 4, 4 weeks after the first injection, is set forth in Figure 11 B. By Week 4, which corresponds to the second initial dose of aflibercept, the patient’s BCVA and CRT markedly improved, with a 25 letter gain in BCVA and 660 pm decrease of CRT from baseline. In addition, there is complete resolution of intraretinal fluid and subretinal fluid. See Table 1-57B.

Table 1-57B. Patient Characteristics at Week 4

BCVA, ETDRS letters

60 (+25)

(Change from baseline)

CRT, pm

265 (-660)

(Change from baseline)

Current treatment interval Q4

[0561] The patient’s angiogram at week 12, a reference visit with no aflibercept 8 mg injection given, is set forth in Figure 11 G. There was no detectable leakage of fluorescein at week 12. By the Week 12 reference visit, the patient’s BCVA and CRT continued to improve from baseline and there remained no detectable leakage of fluorescein with no intraretinal fluid and subretinal fluid on OCT. See Table 1-57C.

Table 1-57C. Patient Characteristics at Week 12

BCVA, ETDRS letters 65

(Change from baseline) (+30)

CRT, pm

258 (-667)

(Change from baseline)

Current treatment interval Q8

[0562] The patient’s angiogram at week 36, 4 weeks after aflibercept 8 mg injection #6, is set forth in Figure 11 D. There was no detectable leakage of fluorescein at week 36. The improvements were maintained through Week 36, with a BCVA of 85 letters and CRT of 250 pm and there remained no detectable leakage of fluorescein with an absence of intraretinal fluid and subretinal fluid. The patient’s treatment interval was maintained at every 8 weeks. See Table 1-57D.

Table 1-57D. Patient Characteristics at Week 36

BCVA, ETDRS letters 85

(Change from baseline) (+50)

CRT, pm

250 (-675)

(Change from baseline)

Current treatment interval Q8

[0563] The mean change from baseline in BCVA at Week 36 was generally comparable across treatment groups when evaluated within subgroups by age and sex. Table 1-57E and Table 1-57F.

Table 1-57E. Mean Change in BCVA at Week 36 by Age^A, Sex and Race^a

2q4 8q8/3 8q8/5

Female 17.1 16.8 19

Male 18.5 17.2 19.2

Asian 18.2 16.5 18.6

White 17.7 17.3 19.4

<55 yrs of age 21.4 21.5 22.4

>55-<65 yrs of age 20.5 18.2 20.3

>65-<75 yrs of age 16.9 16.4 17.1

>75 yrs of age 13.6 13.6 18.1

Full analysis set. Observed values (censoring data post intercurrent event).

^aThe subgroup Black or African American race could not be evaluated due to small sample size (8, 7 and 9 patients in the 2q4, 8q8/3 and 8q8/5 groups, respectively).

^AFull analysis set. Observed values (censoring data post intercurrent event). SD, standard deviation

Table 1-57F. Standard Deviation of Mean Change in BCVA at Week 36 by Age^A, Sex and Race^a SD SD SD2q4 8q8/3 8q8/5

Female 13.6 12.3 11.3

Male 12.5 11.3 11.2

Asian 13 11 9.3

White 11.8 12.3 12.2

<55 yrs of age 10.9 10 9.8

>55-<65 yrs of age 14.1 11.5 11.8

>65-<75 yrs of age 11.7 11.4 10.9

>75 yrs of age 14.1 12.6 11.7

Full analysis set. Observed values (censoring data post intercurrent event).

Aflibercept 8 mg for Retinal Vein Occlusion: Outcomes of the QUASAR Phase 3 Randomized Trial by RVO Type, CRVO/HRVO, or BRVO

[0564] As set forth in Figure 12, both Aflibercept 8 mg groups achieved non-inferior BCVA gains compared to Aflibercept 2 mg at week 36, with fewer injections overall and consistent results across RVO subtypes. Both aflibercept 8 mg groups achieved robust CRT reductions, compared to Aflibercept 2 mg at week 36, with fewer injections overall and across RVO subtypes. See

Figure 13. As set forth in Figure 14, both aflibercept 8 mg groups achieved comparable BCVA gains compared with Aflibercept 2 mg at week 36, with fewer injections across baseline CRT tertiles by RVO subtypes. Also, both Aflibercept 8 mg groups achieved robust CRT improvements compared with Aflibercept 2 mg at week 36, with fewer injections across baseline CRT tertiles by RVO subtypes. See Figure 15. Most patients in the Aflibercept 8 mg groups maintained > Q8 dosing intervals at week 36 across RVO subtypes. See Figure 16. Also, most patients eligible for dosing interval extension treated with Aflibercept 8 mg were last assigned to q8w or longer dosing intervals at week 36 across RVO subtypes. See Figure 17.

Impact of baseline (BL) best-corrected visual acuity on visual and anatomic outcomes among patients with retinal vein occlusion (RVO): Post hoc analysis of the Phase 3 QUASAR trial

[0565] The impact of baseline (BL) best-corrected visual acuity (BCVA) on clinical outcomes following treatment with aflibercept 8 mg versus 2 mg in patients with macular edema following branch or central/hemi retinal vein occlusion (MEfBRVO or MEfCRVO/HRVO) was assessed. In QUASAR (NCT05850520), treatment-naive patients with MEfBRVO or MEfCRVO/HRVO were assigned 1:1:1 to aflibercept 8 mg every 8 weeks after 3 (8q8/3; n=293) or 5 (8q8/5; n=298) initial monthly doses or aflibercept 2 mg every 4 weeks (2q4; n=301 ). Visual and anatomic outcomes were evaluated through Week 36 by BL BCVA tertiles for each RVO subtype (MEfBRVO [n=467], T1: <55; T2: >55-<65; and T3: >65 letters; MEfCRVO/HRVO [n=425], T1: <47; T2: >47-<59; and T3: >59 letters). In MEfBRVO, patients across treatment groups within each tertile achieved similar BCVA at Week 36 with mean change from BL (letters) for 8q8/3, 8q8/5, and 2q4, respectively, of +24.8, +25.8, and +27.2 in T1; +17.3, +18.9, and +16.7 in T2; and +12.1, +13.5, and +13.6 in T3. Mean BL central retinal thickness (CRT) (pm) for 8q8/3, 8q8/5, and 2q4, respectively, was 623.1, 603.9, and 647.1 in T1; 556.1, 518.1, and 526.6 in T2; and 482.2, 498.7, and 475.1 in T3. At Week 36, mean CRT (pm) was improved from BL to a similar level across treatment groups within each tertile, respectively, as follows: 249.3, 249.1, and 250.8 in T1; 255.1, 257.7, and 254.1 in T2; and 277.8, 278.4, and 268.4 in T3. Eyes in 8q8/3 and 8q8/5 received fewer injections versus 2q4 (6.0 and 6.9 vs 8.9 in T1; 6.1 and 7.0 vs 8.9 in T2; and 6.1 and 6.9 vs 8.7 injections in T3, respectively). Most patients in the 8q8/3 and 8q8/5 groups maintained > Q8 dosing through Week 36 across all tertiles (T 1: 89.4% and 93.9%; T2: 86.7% and 94.4%; and T3: 89.5% and 97.8%, respectively). Fewer patients treated with 8q8/3 and 8q8/5 versus 2q4 met criteria for Q4 dosing at Week 36 in all tertiles (T1: 6.4%, 6.1% vs 26.0%; T2: 6.7%, 5.6% vs 14.6%; and T3: 5.3%, 2.2% vs 20.0%; respectively). Results were

similar for MEfCRVO/HRVO. Aflibercept 8 mg resulted in robust improvements in BCVA and CRT at Week 36 in patients with MEfBRVO or MEfCRVO/HRVO, with fewer injections versus aflibercept 2 mg across BL BCVA tertiles. Substantially fewer patients required Q4 dosing with aflibercept 8 mg versus 2 mg at Week 36.

Impact of baseline (BL) central retinal thickness (CRT) on visual and anatomic outcomes in patients with macular edema following retinal vein occlusion: Post hoc analysis of the Phase 3 QUASAR trial through Week 36

[0566] The impact of BL central retinal thickness (CRT) on clinical outcomes following treatment with aflibercept 8 mg and 2 mg in patients with macular edema following branch or central/hemi retinal vein occlusion (MEfBRVO or MEfCRVO/HRVO) through Week (Wk) 36 was assessed. As discussed herein, in QUASAR (NCT05850520), patients with treatment-naive MEfBRVO or MEfCRVO/HRVO were randomized to aflibercept 8 mg every 8 weeks after 3 (8q8/3; n=293) or 5 (8q8/5; n=298) initial monthly injections or aflibercept 2 mg every 4 weeks (2q4; n=301 ). Outcomes were evaluated through Wk 36 by BL CRT tertiles in MEfBRVO (n=467) (tertile [T] 1: <452 pm, T2: >452 to <586 pm, and T3: >586 pm) and MEfCRVO/HRVO (n=425) (T 1: <576 pm, T2: >576 to <798 pm, and T3: >798 pm) through Wk 36. In MEfBRVO, patients across treatment groups within each tertile achieved comparable BCVA at Wk 36, with mean BCVA gains (letters) from BL for 8q8/3, 8q8/5, and 2q4, respectively, of 13.6, 16.8, and 17.4 in T1; 16.1, 18.3, and 18.2 in T2; and 22.4, 23.0, and 23.2 in T3. Mean BL CRT (pm) for 8q8/3, 8q8/5, and 2q4, respectively, was 377.6, 386.2, and 381.2 in T1; 520.6, 511.8, and 532.3 in T2; and 744.0, 714.8, and 755.9 in T3. At Wk 36, mean CRT (pm) was improved to a similar level across treatment groups within all tertiles as follows, respectively: 255.4, 263.2, and 257.2 in T1; 276.3, 266.3, and 262.5 in T2; and 255.5, 254.6, and 253.0 in T3. Eyes treated with 8q8/3 and 8q8/5 received fewer injections versus 2q4 (6.0 and 6.8 vs 8.8 in T1; 6.0 and 7.0 vs 8.8 in T2; and 6.2 and 7.0 vs 8.8 in T3, respectively). Most patients in the 8q8/3 and 8q8/5 groups maintained >q8 dosing through Wk 36 across all tertiles (T1: 91.8% and 96.1%; T2: 90.0% and 95.7%, and T3: 84.0% and 94.1%, respectively). Fewer patients treated with 8q8/3 and 8q8/5 versus 2q4 required Q4 dosing at Wk 36 across all tertiles (T 1: 2.0%, 3.9% vs 11.1%; T2: 6.0%, 4.3% vs 24.1%; and T3: 10.0%, 5.9% vs 26.2%; respectively). Similar results were observed in MEfCRVO/HRVO. Aflibercept 8 mg demonstrated robust visual and anatomic improvements in patients with MEfBRVO and MEfCRVO/HRVO, regardless of BL CRT, with fewer injections versus aflibercept 2 mg across all BL CRT tertiles through Wk 36. Substantially fewer patients required Q4 dosing with aflibercept 8 mg versus 2 mg at Wk 36. 11876WO01

[0567] In summary:

• Aflibercept 8q8/3 and 8q8/5 groups achieved non-inferior BCVA gains and robust reductions in CRT with fewer injections than in the aflibercept 2q4 group at Week 36, and consistent results across BRVO and CRVO/HRVO subtypes;

• Mean BCVA gains and CRT improvements were similar across baseline CRT tertiles with fewer injections after treatment with aflibercept 8 mg compared with aflibercept 2 mg across BRVO and CRVO/HRVO subtypes;

• Approximately 94% of patients across both RVO subtypes in the aflibercept 8q8/3 group were last assigned to >8-week dosing intervals at Week 36;

• The safety profile of aflibercept 8 mg in patients with macular edema secondary to RVO was consistent with the established safety profile of aflibercept 2 mg and 8 mg.

Results at week 64

[0568] Results at week 64 of the QUASAR clinical trial are summarized below. The QUASAR study met the key secondary endpoint at week 64:

• Aflibercept 8 mg treatment every 8 weeks after initial monthly doses required 2-3 less injections than aflibercept 2mg

• The majority of 8 mg-treated patients could be extended to Q16 or longer

Efficacy in BCVA and CST could be maintained through week 64 in all arms. Non-inferiority was maintained for BCVA through week 64 for both 8 mg arms. Safety data through week 64 was comparable to the known safety profile of aflibercept 2 mg and 8 mg.

At week 64, among patients in the 8q8/3 arm, 88.1% maintained q8 dosing whereas 11.9% were shortened to q4; and among patients in the 8q8/5 arm, 91.0% of patients were maintained on q8 dosing whereas 9.0% of patients were shortened to q4 dosing (Patients completing Week 64: 2q4 n=270; 8q8/3 n=269, 8q8/5 n=256).

[0569] The disposition of QUASAR patients at week 64, including the non-China subpopulation, are set forth in Table 1-58 and Table 1-58A.

Table 1-58. Disposition: flow of participants through study phases: Week 64 (all participants)

Number of Participants 2q4 8q8/3 8q8/5 All 8mg Total

Enrolled 1282 (100.0%) Did not complete screening 388 (30.3%) Primary reason

ADVERSE EVENT 2 (0.2%) LOST TO FOLLOW-UP 2 (0.2%) PHYSICIAN DECISION 1 (<0.1%) SCREEN FAILURE 353 (27.5%) WITHDRAWAL BY SUBJECT 25 (2.0%) OTHER 5 (0.4%) Participants who were re-screened 46 (3.6%) Primary reason for not completing initial screening

LOGISTICAL PROBLEM 1 (2.2%) SCREEN FAILURE 43 (93.5%) WITHDRAWAL BY SUBJECT 1 (2.2%) OTHER 1 (2.2%) Randomized to intervention 302 (100.0%) 294 (100.0%) 298 (100.0%) 592 (100.0%) 894 (100.0%) Study intervention never administered 1 (0.3%) 1 (0.3%) 0 1 (0.2%) 2 (0.2%) Treated 301 (99.7%) 293 (99.7%) 298 (100.0%) 591 (99.8%) 892 (99.8%) Treatment phase through Week 64

Started 301 (99.7%) 293 (99.7%) 298 (100.0%) 591 (99.8%) 892 (99.8%) Completed treatment phase through Week 64 270 (89.4%) 269 (91.5%) 256 (85.9%) 525 (88.7%) 795 (88.9%) Did not complete treatment phase through Week 64 31 (10.3%) 24 (8.2%) 42 (14.1%) 66 (11.1%) 97 (10.9%) Primary reason

ADVERSE EVENT 3 (1.0%) 2 (0.7%) 4 (1.3%) 6 (1.0%) 9 (1.0%) DEATH 3 (1.0%) 2 (0.7%) 5 (1.7%) 7 (1.2%) 10 (1.1%) LOGISTICAL PROBLEM 2 (0.7%) 1 (0.3%) 0 1 (0.2%) 3 (0.3%) LOST TO FOLLOW-UP 5 (1.7%) 4 (1.4%) 4 (1.3%) 8 (1.4%) 13 (1.5%) PHYSICIAN DECISION 0 2 (0.7%) 0 2 (0.3%) 2 (0.2%) PROTOCOL DEVIATION 0 0 1 (0.3%) 1 (0.2%) 1 (0.1%) WITHDRAWAL BY SUBJECT 18 (6.0%) 13 (4.4%) 28 (9.4%) 41 (6.9%) 59 (6.6%) Follow-up phase

Started follow-up phase prior to Week 64 301 (99.7%) 293 (99.7%) 298 (100.0%) 591 (99.8%) 892 (99.8%) Completed follow-up phase through Week 64 270 (89.4%) 268 (91.2%) 256 (85.9%) 524 (88.5%) 794 (88.8%) Did not complete follow-up phase through Week 64 31 (10.3%) 25 (8.5%) 42 (14.1%) 67 (11.3%) 98 (11.0%) Primary reason

ADVERSE EVENT 3 (1.0%) 2 (0.7%) 3 (1.0%) 5 (0.8%) 8 (0.9%) DEATH 3 (1.0%) 2 (0.7%) 5 (1.7%) 7 (1.2%) 10 (1.1%) LOGISTICAL PROBLEM 2 (0.7%) 2 (0.7%) 0 2 (0.3%) 4 (0.4%) LOST TO FOLLOW-UP 5 (1.7%) 4 (1.4%) 5 (1.7%) 9 (1.5%) 14 (1.6%) PHYSICIAN DECISION 0 2 (0.7%) 0 2 (0.3%) 2 (0.2%) PROTOCOL DEVIATION 0 0 1 (0.3%) 1 (0.2%) 1 (0.1%) WITHDRAWAL BY SUBJECT 18 (6.0%) 13 (4.4%) 28 (9.4%) 41 (6.9%) 59 (6.6%) N

umber of participants enrolled is the number of participants who signed informed consent. In case of rescreening, rescreened participants are counted once with their final enrollment.

Definition of completed treatment phase through week 64 = did not discontinue study intervention prior to week 64 visit, and reached the week 64 visit (either visit performed or confirmed not done). Definition of completed follow-up phase through week 64 = did answer YES to the question 'Did the subject complete the study?' on the 'End of study' form.

Follow up phase starts after date of treatment discontinuation or treatment phase completeness for participant.

2q4: Aflibercept 2mg administered every 4 weeks.

8q8/3: Aflibercept 8mg administered every 8 weeks, after 3 initial injections at 4-week intervals. 8q8/5: Aflibercept 8mg administered every 8 weeks, after 5 initial injections at 4-week intervals. All 8mg: Pooled aflibercept 8mg administered every 8 weeks, after 3 or 5 initial injections at 4-week intervals.

Table 1-58A. Disposition: flow of participants through study phases: Week 64 (all

participants)

Population group: Non-China sub-population

Number of Participants 2q4 8q8/3 8q8/5 All 8 mg Total Enrolled 1158 (100.0%) Did not complete screening 354 (30.6%) Primary reason

ADVERSE EVENT 2 (0.2%) LOST TO FOLLOW-UP 2 (0.2%) PHYSICIAN DECISION 1 (<0.1%) SCREEN FAILURE 321 (27.7%) WITHDRAWAL BY SUBJECT 23 (2.0%) OTHER 5 (0.4%) Participants who were re-screened 44 (3.8%) Primary reason for not completing initial screening

LOGISTICAL PROBLEM 1 (2.3%) SCREEN FAILURE 41 (93.2%) WITHDRAWAL BY SUBJECT 1 (2.3%) OTHER 1 (2.3%) Randomized to intervention 277 (100.0%) 267 (100.0%) 260 (100.0%) 527 (100.0%) 804 (100.0%) Study intervention never administered 1 (0.4%) 1 (0.4%) 0 1 (0.2%) 2 (0.2%) Treated 276 (99.6%) 266 (99.6%) 260 (100.0%) 526 (99.8%) 802 (99.8%) Treatment phase through Week 64

Started 276 (99.6%) 266 (99.6%) 260 (100.0%) 526 (99.8%) 802 (99.8%) Completed treatment phase through Week 64 250 (90.3%) 243 (91.0%) 226 (86.9%) 469 (89.0%) 719 (89.4%) Did not complete treatment phase through Week 64 26 (9.4%) 23 (8.6%) 34 (13.1%) 57 (10.8%) 83 (10.3%) Primary⁷ reason

ADVERSE EVENT 2 (0.7%) 2 (0.7%) 3 (1.2%) 5 (0.9%) 7 (0.9%) DEATH 3 (1.1%) 2 (0.7%) 5 (1.9%) 7 (1.3%) 10 (1.2%) LOGISTICAL PROBLEM 2 (0.7%) 1 (0.4%) 0 1 (0.2%) 3 (0.4%) LOST TO FOLLOW-UP 5 (1.8%) 4 (1.5%) 4 (1.5%) 8 (1.5%) 13 (1.6%) PHYSICIAN DECISION 0 2 (0.7%) 0 2 (0.4%) 2 (0.2%) PROTOCOL DEVIATION 0 0 1 (0.4%) 1 (0.2%) 1 (0.1%) WITHDRAWAL BY SUBJECT 14 (5.1%) 12 (4.5%) 21 (8.1%) 33 (6.3%) 47 (5.8%) Follow-up phase

Started follow-up phase prior to Week 64 276 (99.6%) 266 (99.6%) 260 (100.0%) 526 (99.8%) 802 (99.8%) Completed follow-up phase through Week 64 250 (90.3%) 242 (90.6%) 226 (86.9%) 468 (88.8%) 718 (89.3%) Did not complete follow-up phase through Week 64 26 (9.4%) 24 (9.0%) 34 (13.1%) 58 (11.0%) 84 (10.4%) Primary reason

ADVERSE EVENT 2 (0.7%) 2 (0.7%) 2 (0.8%) 4 (0.8%) 6 (0.7%) DEATH 3 (1.1%) 2 (0.7%) 5 (1.9%) 7 (1.3%) 10 (1.2%) LOGISTICAL PROBLEM 2 (0.7%) 2 (0.7%) 0 2 (0.4%) 4 (0.5%) LOST TO FOLLOW-UP 5 (1.8%) 4 (1.5%) 5 (1.9%) 9 (1.7%) 14 (1.7%) PHYSICIAN DECISION 0 2 (0.7%) 0 2 (0.4%) 2 (0.2%) PROTOCOL DEVIATION 0 0 1 (0.4%) 1 (0.2%) 1 (0.1%)

WITHDRAWAL BY SUBJECT 14 (5.1%) 12 (4.5%) 21 (8.1%) 33 (6.3%) 47 (5.8%) Number of participants enrolled is the number of participants who signed informed consent. In case of rescreening, rescreened participants are counted once with their final enrollment.

2q4: Aflibercept 2mg administered every 4 weeks.

8q8/3: Aflibercept 8mg administered every 8 weeks, after 3 initial injections at 4-week intervals. 8q8/5: Aflibercept 8mg administered every 8 weeks, after 5 initial injections at 4-week intervals. All 8mg: Pooled aflibercept 8mg administered every 8 weeks, after 3 or 5 initial injections at 4-week 11876WO01 intervals.

[0570] The intervention eye exposure of QUASAR patients at week 64, including that of the non-China subpopulation, are set forth in Table 1-59 and Table 1-59A and Table 1-59B. The exposure of QUASAR patients with BRVO and CRVO/HRVO, at week 64, are summarized in Table 1-59 C, D, E and F. Exposure of patients with any fellow eye treatment is summarized in Table 1-59G.

Table 1-59. Exposure to intervention in study eye: Through Week 64 (safety analysis set, only participants considered as completers for Week 64)

2q4 8q8/3 8q8/5 All 8 mg N=270 (100%) N=269(100%) N=256(100%) N=525(100%) Total number of active injections 3158 2273 2411 4684 Total number of sham injections 1053 1950 1600 3550 Number of active injections

3 1 (0.4%) 0 0 0 6 1 (0.4%) 1 (0.4%) 0 1 (0.2%) 7 0 8 (3.0%) 1 (0.4%) 9 (1.7%) 8 1 (0.4%) 203 (75.5%) 12 (4.7%) 215 (41.0%) 9 2 (0.7%) 28 (10.4%) 169 (66.0%) 197 (37.5%) 10 13 (4.8%) 9 (3.3%) 52 (20.3%) 61 (11.6%) 11 148 (54.8%) 8 (3.0%) 8 (3.1%) 16 (3.0%) 12 51 (18.9%) 5 (1.9%) 8 (3.1%) 13 (2.5%) 13 22 (8.1%) 3 (1.1%) 2 (0.8%) 5 (1.0%) 14 9 (3.3%) 2 (0.7%) 3 (1.2%) 5 (1.0%) 15 11 (4.1%) 2 (0.7%) 1 (0.4%) 3 (0.6%) 16 11 (4.1%) 0 0 0 Number of active injections

n 270 269 256 525 Mean (SD) 11.7 (1.6) 8.4 (1.2) 9.4 (1.0) 8.9 (1.2) Median 11.0 8.0 9.0 9.0 Q1. Q3 11.0, 12.0 8.0, 8.0 9.0, 10.0 8.0, 9.0 Min, Max 3, 16 6, 15 7, 15 6, 15 Number of sham injections

0 23 (8.5%) 0 0 0 1 7 (2.6%) 2 (0.7%) 3 (1.2%) 5 (1.0%) 2 13 (4.8%) 4 (1.5%) 3 (1.2%) 7 (1.3%) 3 29 (10.7%) 5 (1.9%) 6 (2.3%) 11 (2.1%) 4 57 (21.1%) 7 (2.6%) 11 (4.3%) 18 (3.4%) 5 141 (52.2%) 13 (4.8%) 21 (8.2%) 34 (6.5%) 6 0 14 (5.2%) 60 (23.4%) 74 (14.1%) 7 0 44 (16.4%) 152 (59.4%) 196 (37.3%) 8 0 180 (66.9%) 0 180 (34.3%) Number of sham injections

n 270 269 256 525 Mean (SD) 3.9 (1.6) 7.2 (1.4) 6.3 (1.2) 6.8 (1.4) Median 5.0 8.0 7.0 7.0 Q1. Q3 3.0, 5.0 7.0, 8.0 6.0, 7.0 6.0, 8.0 Min, Max 0, 5 1, 8 1, 7 1, 8

Total amount of active study drug (mg)

n 270 269 256 525 Mean (SD) 23.4 (3.2) 67.5 (10.1) 75.3 (8.2) 71.3 (10.0) Median 22.0 64.0 72.0 72.0 Q1. Q3 22.0, 24.0 64.0, 64.0 72.0, 80.0 64.0, 72.0 Min, Max 6, 32 48, 120 56, 120 48, 120 Treatment duration (weeks)

n 270 269 256 525 Mean (SD) 63.73 (3.40) 64.12 (0.97) 63.99 (1.16) 64.06 (1.06) Median 64.00 64.00 64.00 64.00 Q1. Q3 63.86, 64.29 64.00, 64.43 63.86, 64.29 63.86, 64.43 Min, Max 12.4, 68.0 56.0, 68.0 52.3, 66.9 52.3, 68.0 Participants with q8 or longer dosing interval from Week 32 through 189 (70.0%)

Week 64 (a)

Participants with q8 or longer dosing interval through Week 64 (b) 237 (88.1%) 233 (91.0%) 470 (89.5%) Participants shortened to q4 dosing interval anytime (c) 21 (7.8%) 32 (11.9%) 23 (9.0%) 55 (10.5%) Participants extended dosing interval anytime (d) 252 (93.3%) 245 (91.1%) 232 (90.6%) 477 (90.9%) Participants never extended dosing interval (e) 18 (6.7%) 24 (8.9%) 24 (9.4%) 48 (9.1%) Participants with q4 as the last intended dosing interval (f) 21 (7.8%) 11 (4.1%) 10 (3.9%) 21 (4.0%) Participants with q8 as the last intended dosing interval (f) 39 (14.4%) 26 (9.7%) 27 (10.5%) 53 (10.1%) Participants with ql2 as the last intended dosing interval (f) 75 (27.8%) 59 (21.9%) 60 (23.4%) 119 (22.7%) Participants with ql6 as the last intended dosing interval (f) 135 (50.0%) 64 (23.8%) 159 (62.1%) 223 (42.5%) Participants with q20 as the last intended dosing interval (f) 109 (40.5%)

Participants with q8 or longer as the last intended dosing interval (f) 249 (92.2%) 258 (95.9%) 246 (96.1%) 504 (96.0%) Participants with q 12 or longer as the last intended dosing interval (f) 210 (77.8%) 232 (86.2%) 219 (85.5%) 451 (85.9%) Participants with ql6 or longer as the last intended dosing interval (f) 135 (50.0%) 173 (64.3%) 159 (62.1%) 332 (63.2%) Participants with q4 as the last completed dosing interval 35 (13.0%) 13 (4.8%) 9 (3.5%) 22 (4.2%) Participants with q8 as the last completed dosing interval 52 (19.3%) 37 (13.8%) 46 (18.0%) 83 (15.8%) Participants with ql2 as the last completed dosing interval 183 (67.8%) 68 (25.3%) 201 (78.5%) 269 (51.2%) Participants with ql6 as the last completed dosing interval 151 (56.1%)

Participants with q8 or longer as the last completed dosing interval 235 (87.0%) 256 (95.2%) 247 (96.5%) 503 (95.8%) Participants with q!2 or longer as the last completed dosing interval 183 (67.8%) 219 (81.4%) 201 (78.5%) 420 (80.0%)

Duration (weeks) = [(date of last study intervention prior to Week 64 ) - (date of first study intervention) +28]/7; 28 days were added because of the minimum 4-week dosing interval in the study.

Only participants that did not discontinue study intervention prior to Week 64 are included.

(a) All participants on 2q4 extended to 8-week interval at the W32 visit for whom it was not planned to have their interval shortened to 4-week interval (according to DRM criteria until Week 60) prior to Week 64.

(b) All participants on 8q8 with 8-week or longer interval for whom it was not planned to have their interval shortened to 4-week interval (according to DRM criteria until Week 60) prior to Week 64. (c) For 2q4 this includes participants that were extended to q8 dosing interval and subsequently shortened back to q4.

(d) All participants for whom it was planned to have their interval extended (according to DRM criteria until Week 60) prior to Week 64.

(e) All participants for whom it was not planned to have their interval extended (according to DRM criteria until Week 60) prior to Week 64.

(f) Based on DRM criteria assessed at the last visit with active injection before Week 64.

2q4: Aflibercept 2 mg administered every 4 weeks.

8q8/5: Aflibercept 8mg administered every 8 weeks, after 5 initial injections at 4-week intervals. All 8mg: Pooled aflibercept 8mg administered every 8 weeks, after 3 or 5 initial injections at 4-week

intervals

See also Figure 43.

Table 1-68A. Adverse events: overall summary of number of participants (safety analysis set) _ _ _

Population group: Non-China sub-population

2q4 8q8/3 8q8/5 All 8mg \-276 \-266 \-260 N=526 (100%) (100%) (100%) (100%)

Number (%) of participants with adverse events Any AE 229 (83.0%) 213 (80.1%) 204 (78.5%) 417 (79.3%) Any pre-treatment AE 20 (7.2%) 26 (9.8%) 28 (10.8%) 54 (10.3%) Any TEAE 223 (80.8%) 209 (78.6%) 198 (76.2%) 407 (77.4%) Any post-treatment AE 17 (6.2%) 10 (3.8%) 9 (3.5%) 19 (3.6%) Any ocular AE 138 (50.0%) 140 (52.6%) 115 (44.2%) 255 (48.5%) Study eye 123 (44.6%) 126 (47.4%) 106 (40.8%) 232 (44.1%) Fellow eye 69 (25.0%) 68 (25.6%) 56 (21.5%) 124 (23.6%) Any non-ocular AE 185 (67.0%) 172 (64.7%) 173 (66.5%) 345 (65.6%) Any ocular TEAE 136 (49.3%) 137 (51.5%) 113 (43.5%) 250 (47.5%) Study eye 121 (43.8%) 123 (46.2%) 103 (39.6%) 226 (43.0%) Fellow eye 67 (24.3%) 61 (22.9%) 53 (20.4%) 114 (21.7%) Any non-ocular TEAE 177 (64.1%) 165 (62.0%) 168 (64.6%) 333 (63.3%) Any intervention-related TEAE 8 (2.9%) 13 (4.9%) 5 (1.9%) 18 (3.4%) Any ocular intervention-related TEAE 6 (2.2%) 12 (4.5%) 4 (1.5%) 16 (3.0%) Study eye 6 (2.2%) 12 (4.5%) 4 (1.5%) 16 (3.0%) Fellow eye 0 0 0 0 Any non-ocular intervention-related TEAE 2 (0.7%) 3 (1.1%) 1 (0.4%) 4 (0.8%) Any TEAE related to injection procedure 21 (7.6%) 39 (14.7%) 28 (10.8%) 67 (12.7%) Any ocular TEAE related to injection procedure 20 (7.2%) 39 (14.7%) 28 (10.8%) 67 (12.7%) Study eye 20 (7.2%) 39 (14.7%) 28 (10.8%) 67 (12.7%) Fellow eye 1 (0.4%) 1 (0.4%) 0 1 (0.2%) Any non-ocular TEAE related to injection procedure 2 (0.7%) 1 (0.4%) 0 1 (0.2%) Any TEAE related to protocol-required procedure 5 (1.8%) 12 (4.5%) 16 (6.2%) 28 (5.3%) Any ocular TEAE related to protocol-required procedure 3 (1.1%) 7 (2.6%) 11 (4.2%) 18 (3.4%) Study eye 3 (1.1%) 7 (2.6%) 11 (4.2%) 18 (3.4%) Fellow eye 0 0 0 0 Any non-ocular TEAE related to protocol-required procedure 3 (1.1%) 5 (1.9%) 5 (1.9%) 10 (1.9%) Any TEAE related to commercial aflibercept 2mg (of fellow eye) 0 0 0 0 Any ocular TEAE related to commercial aflibercept 2mg (of fellow 0 0 0 0 eye)

Any TEAE leading to discontinuation of intervention 4 (1.4%) 3 (1.1%) 5 (1.9%) 8 (1.5%) Any ocular TEAE leading to discontinuation of intervention 0 0 2 (0.8%) 2 (0.4%) Study eye 0 0 2 (0.8%) 2 (0.4%) Fellow eye 0 0 0 0 Any non-ocular TEAE leading to discontinuation of intervention 4 (1.4%) 3 (1.1%) 3 (1.2%) 6 (1.1%) Any TEAE related to medical device 0 1 (0.4%) 2 (0.8%) 3 (0.6%) Any ocular TEAE related to medical device 0 1 (0.4%) 2 (0.8%) 3 (0.6%) Study eye 0 1 (0.4%) 2 (0.8%) 3 (0.6%) Fellow eye 0 0 0 0 Any non-ocular TEAE related to medical device 0 0 0 0 Any TEAE of special interest 9 (3.3%) 2 (0.8%) 7 (2.7%) 9 (1.7%) Any TEAE of APTC events 6 (2.2%) 2 (0.8%) 6 (2.3%) 8 (1.5%) Any TEAE of hypertension 19 (6.9%) 35 (13.2%) 27 (10.4%) 62 (11.8%) Any TEAE of intraocular inflammation of study eye 4 (1.4%) 3 (1.1%) 2 (0.8%) 5 (1.0%) Any TEAE of nasal mucosal finding 2 (0.7%) 3 (1.1%) 1 (0.4%) 4 (0.8%)

Maximum intensity for any ocular TEAE

Study eye

Mild 80 (29.0%) 80 (30.1%) 80 (30.8%) 160 (30.4%) Moderate 37 (13.4%) 41 (15.4%) 19 (7.3%) 60 (11.4%)

Severe 4 (1.4%) 2 (0.8%) 4 (1.5%) 6 (1.1%) Fellow eye

Mild 53 (19.2%) 47 (17.7%) 44 (16.9%) 91 (17.3%) Moderate 14 (5.1%) 13 (4.9%) 9 (3.5%) 22 (4.2%) Severe 0 1 (0.4%) 0 1 (0.2%)

Maximum intensity for any non-ocular TEAE

Mild 97 (35.1%) 94 (35.3%) 99 (38.1%) 193 (36.7%) Moderate 60 (21.7%) 54 (20.3%) 52 (20.0%) 106 (20.2%) Severe 20 (7.2%) 17 (6.4%) 17 (6.5%) 34 (6.5%) Any SAE 45 (16.3%) 36 (13.5%) 40 (15.4%) 76 (14.4%) Any pre-treat ment SAE 2 (0.7%) 0 4 (1.5%) 4 (0.8%) Any TESAE 40 (14.5%) 34 (12.8%) 34 (13.1%) 68 (12.9%) Any post-treatment SAE 7 (2.5%) 3 (1.1%) 3 (1.2%) 6 (1.1%) Any ocular SAE 8 (2.9%) 6 (2.3%) 5 (1.9%) 11 (2.1%) Study eye 8 (2.9%) 6 (2.3%) 5 (1.9%) 11 (2.1%) Fellow eye 0 1 (0.4%) 0 1 (0.2%) Any non-ocular SAE 37 (13.4%) 31 (11.7%) 35 (13.5%) 66 (12.5%) Any ocular TESAE 6 (2.2%) 5 (1.9%) 5 (1.9%) 10 (1.9%) Study eye 6 (2.2%) 5 (1.9%) 5 (1.9%) 10 (1.9%) Fellow eye 0 1 (0.4%) 0 1 (0.2%) Any non-ocular TESAE 34 (12.3%) 30 (11.3%) 29 (11.2%) 59 (11.2%) Any intervention-related TESAE 2 (0.7%) 1 (0.4%) 2 (0.8%) 3 (0.6%) Any ocular intervention-related TESAE 2 (0.7%) 0 1 (0.4%) 1 (0.2%) Study eye 2 (0.7%) 0 1 (0.4%) 1 (0.2%) Fellow eye 0 0 0 0 Any non-ocular intervention-related TESAE 0 1 (0.4%) 1 (0.4%) 2 (0.4%) Any TESAE related to injection procedure 3 (1.1%) 1 (0.4%) 1 (0.4%) 2 (0.4%) Any ocular TESAE related to injection procedure 3 (1.1%) 1 (0.4%) 1 (0.4%) 2 (0.4%) Study eye 3 (1.1%) 1 (0.4%) 1 (0.4%) 2 (0.4%) Fellow eye 0 0 0 0 Any non-ocular TESAE related to injection procedure 0 0 0 0 Any TESAE related to protocol-required procedure 0 0 0 0 Any ocular TESAE related to protocol-required procedure 0 0 0 0 Study eye 0 0 0 0 Fellow eye 0 0 0 0 Any non-ocular TESAE related to protocol-required procedure 0 0 0 0 Any TESAE related to commercial aflibercept 2mg (of fellow eye) 0 0 0 0 Any ocular TESAE related to commercial aflibercept 2mg (of fellow 0 0 0 0 eye)

Any TESAE related to medical device 0 0 0 0 Any ocular TESAE related to medical device 0 0 0 0 Study eye 0 0 0 0 Fellow eye 0 0 0 0 Any non-ocular TESAE related to medical device 0 0 0 0 Any TESAE of special interest 6 (2.2%) 1 (0.4%) 5 (1.9%) 6 (1.1%) Any TESAE of APTC events 4 (1.4%) 1 (0.4%) 5 (1.9%) 6 (1.1%) Any TESAE of hypertension 2 (0.7%) 0 0 0 Any TESAE of intraocular inflammation of study eye 2 (0.7%) 2 (0.8%) 0 2 (0.4%) Any TESAE of nasal mucosal finding 1 (0.4%) 0 0 0 Maximum intensity for any ocular TESAE

Study eye Mild 0 0 1 (0.4%) 1 (0.2%) Moderate 4 (1.4%) 3 (1.1%) 2 (0.8%) 5 (1.0%) Severe 2 (0.7%) 2 (0.8%) 2 (0.8%) 4 (0.8%) Fellow eye

Severe 0 1 (0.4%) 0 1 (0.2%)

Maximum intensity for any non-ocular TESAE

Mild 3 (1.1%) 4 (1.5%) 4 (1.5%) 8 (1.5%) Moderate 14 (5.1%) 15 (5.6%) 10 (3.8%) 25 (4.8%) Severe 17 (6.2%) 11 (4.1%) 15 (5.8%) 26 (4.9%) Total number of deaths 3 (1.1%) 2 (0.8%) 5 (1.9%) 7 (1.3%) Any AE with outcome death 3 (1.1%) 2 (0.8%) 5 (1.9%) 7 (1.3%) Any pre-treatment AE with outcome death 0 0 0 0 Any⁷ TEAE with outcome death 3 (1.1%) 2 (0.8%) 3 (1.2%) 5 (1.0%) Any post-treatment AE with outcome death 0 0 2 (0.8%) 2 (0.4%) Deaths not attributed to an AE 0 0 0 0

2q4: Aflibercept 2mg administered every 4 weeks.

Table 1-69. Ocular treatment-emergent adverse events of study eye: number of participants by primary system organ class and preferred term (safety analysis set)

Primary' system organ class

Preferred term 2q4 8q8/3 8q8/5 All 8mg MedDRA version 28.0 N=301 (100%) N=293 (100%) N=298 (100%) N=591 (100%) Number (%) of participants with at least one such adverse event 127 (42.2%) 134 (45.7%) 118 (39.6%) 252 (42.6%) Eye disorders 112 (37.2%) 118 (40.3%) 102 (34.2%) 220 (37.2%) Allergic keratitis 1 (0.3%) 0 0 0 Amaurosis fugax 0 1 (0.3%) 0 1 (0.2%) Angle closure glaucoma 1 (0.3%) 0 0 0 Anterior chamber cell 1 (0.3%) 0 0 0 Anterior chamber disorder 0 1 (0.3%) 0 1 (0.2%) Aphakia 1 (0.3%) 0 2 (0.7%) 2 (0.3%) Blepharitis 2 (0.7%) 2 (0.7%) 2 (0.7%) 4 (0.7%) Blepharospasm 0 1 (0.3%) 1 (0.3%) 2 (0.3%) Blindness 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Borderline glaucoma 0 2 (0.7%) 1 (0.3%) 3 (0.5%) Cataract 17 (5.6%) 11 (3.8%) 18 (6.0%) 29 (4.9%) Cataract cortical 0 2 (0.7%) 0 2 (0.3%) Cataract nuclear 0 0 1 (0.3%) 1 (0.2%) Cataract subcapsular 1 (0.3%) 0 0 0 Chalazion 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Chorioretinal folds 0 1 (0.3%) 0 1 (0.2%) Ciliary muscle spasm 1 (0.3%) 0 0 0 Conjunctival haemorrhage 8 (2.7%) 14 (4.8%) 12 (4.0%) 26 (4.4%) Conjunctival hyperaemia 0 0 1 (0.3%) 1 (0.2%) Conjunctival irritation 1 (0.3%) 0 0 0 Conjunctival oedema 2 (0.7%) 0 0 0 Conjunctival suffusion 0 1 (0.3%) 1 (0.3%) 2 (0.3%) Conjunctivitis allergic 5 (1.7%) 4 (1.4%) 3 (1.0%) 7 (1.2%) Corneal disorder 0 1 (0.3%) 0 1 (0.2%) Corneal erosion 0 1 (0.3%) 1 (0.2%) Corneal infiltrates 0 1 (0.3%) 1 (0.2%) Corneal oedema 0 1 (0.3%) 1 (0.2%) Corneal scar 1 (0.3%) 1 (0.3%) o 1 (0.2%) Cystoid macular oedema 2 (0.7%) 3 (1.0%) 1 (0.3%) 4 (0.7%) Detachment of retinal pigment epithelium 0 1 (0.3%) 0 1 (0.2%) Diabetic retinopathy 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Dry age-related macular degeneration 0 0 1 (0.3%) 1 (0.2%) Dry eye 9 (3.0%) 4 (1.4%) 9 (3.0%) 13 (2.2%) Dysmetropsia 0 1 (0.3%) 0 1 (0.2%) Ectropion 0 1 (0.3%) 0 1 (0.2%) Epiretinal membrane 6 (2.0%) 6 (2.0%) 10 (3.4%) 16 (2.7%) Exophthalmos 0 0 1 (0.3%) 1 (0.2%) Eye inflammation 1 (0.3%) 0 0 0 Eye irritation 0 2 (0.7%) 0 2 (0.3%) Eye pain 3 (1.0%) 5 (1.7%) 4 (1.3%) 9 (1.5%) Eye pruritus 0 3 (1.0%) 0 3 (0.5%) Eye swelling 0 1 (0.3%) 0 1 (0.2%) Eyelid oedema 1 (0.3%) 0 0 0 Flat anterior chamber of eye 0 0 1 (0.3%) 1 (0.2%) Foreign body sensation in eyes 0 1 (0.3%) 0 1 (0.2%) Glaucoma 1 (0.3%) 5 (1.7%) 2 (0.7%) 7 (1.2%) Glaucomatous optic neuropathy 1 (0.3%) 0 0 0 Iritis 0 1 (0.3%) 0 1 (0.2%) Keratic precipitates 0 1 (0.3%) 0 1 (0.2%) Keratitis 0 1 (0.3%) 1 (0.3%) 2 (0.3%) Lacrimation increased 3 (1.0%) 0 0 0 Lens dislocation 0 0 1 (0.3%) 1 (0.2%) Lenticular opacities 0 0 2 (0.7%) 2 (0.3%) Lid margin discharge 1 (0.3%) 0 0 0 Macular degeneration 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Macular hole 2 (0.7%) 0 1 (0.3%) 1 (0.2%) Macular ischaemia 1 (0.3%) 2 (0.7%) 1 (0.3%) 3 (0.5%) Macular oedema 6 (2.0%) 10 (3.4%) 5 (1.7%) 15 (2.5%) Macular thickening 8 (2.7%) 12 (4.1%) 1 (0.3%) 13 (2.2%) Meibomian gland dysfunction 1 (0.3%) 0 0 0 Narrow anterior chamber angle 0 1 (0.3%) 1 (0.3%) 2 (0.3%) Normal tension glaucoma 3 (1.0%) 2 (0.7%) 1 (0.3%) 3 (0.5%) Ocular discomfort 0 0 1 (0.3%) 1 (0.2%) Ocular hyperaemia 1 (0.3%) 0 0 0 Ocular hypertension 5 (1.7%) 5 (1.7%) 3 (1.0%) 8 (1.4%) Ocular rosacea 1 (0.3%) 0 0 0 Open angle glaucoma 0 2 (0.7%) 0 2 (0.3%) Optic atrophy 2 (0.7%) 0 1 (0.3%) 1 (0.2%) Optic nerve cupping 0 2 (0.7%) 0 2 (0.3%) Optic neuropathy 0 0 1 (0.3%) 1 (0.2%) Photopsia 0 1 (0.3%) 0 1 (0.2%) Posterior capsule opacification 1 (0.3%) 1 (0.3%) 2 (0.7%) 3 (0.5%) Presbyopia 0 0 1 (0.3%) 1 (0.2%) Pterygium 1 (0.3%) 0 0 0 Punctate keratitis 7 (2.3%) 4 (1.4%) 2 (0.7%) 6 (1.0%) Retinal artery⁷ embolism 0 0 1 (0.3%) 1 (0.2%) Retinal artery occlusion 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Retinal collateral vessels 2 (0.7%) 1 (0.3%) 0 1 (0.2%) Retinal degeneration 1 (0.3%) 1 (0.3%) 1 (0.3%) 2 (0.3%) Retinal depigmentation 1 (0.3%) 0 0 0 Retinal detachment 1 (0.3%) 0 0 0 Retinal drusen 3 (1.0%) 0 0 0 Retinal exudates 1 (0.3%) 2 (0.7%) 2 (0.7%) 4 (0.7%)

Retinal haemorrhage 1 (0.3%) 3 (1.0%) 3 (1.0%) 6 (1.0%) Retinal ischaemia 1 (0.3%) 1 (0.3%) 1 (0.3%) 2 (0.3%) Retinal oedema 2 (0.7%) 3 (1.0%) 1 (0.3%) 4 (0.7%) Retinal pigment epitheliopathy 0 1 (0.3%) 0 1 (0.2%) Retinal tear 1 (0.3%) 1 (0.3%) 2 (0.7%) 3 (0.5%) Retinal vascular disorder 0 2 (0.7%) 2 (0.7%) 4 (0.7%) Retinal vasculitis 0 0 1 (0.3%) 1 (0.2%) Retinal vein occlusion 2 (0.7%) 4 (1.4%) 4 (1.3%) 8 (1.4%) Retinoschisis 0 1 (0.3%) 0 1 (0.2%) Subretinal fluid 0 0 1 (0.3%) 1 (0.2%) Superior limbic keratoconjunctivitis 0 0 1 (0.3%) 1 (0.2%) Swelling of eyelid 0 1 (0.3%) 0 1 (0.2%) Uveitis 0 0 2 (0.7%) 2 (0.3%) Vision blurred 0 3 (1.0%) 1 (0.3%) 4 (0.7%) Visual acuity reduced 12 (4.0%) 16 (5.5%) 9 (3.0%) 25 (4.2%) Visual field defect 0 2 (0.7%) 0 2 (0.3%) Visual impairment 0 2 (0.7%) 1 (0.3%) 3 (0.5%) Vitreomacular interface abnormal 0 1 (0.3%) 0 1 (0.2%) Vitreoretinal traction syndrome 0 3 (1.0%) 1 (0.3%) 4 (0.7%) Vitreous detachment 4 (1.3%) 9 (3.1%) 10 (3.4%) 19 (3.2%) Vitreous floaters 4 (1.3%) 6 (2.0%) 3 (1.0%) 9 (1.5%) Vitreous haemorrhage 0 3 (1.0%) 2 (0.7%) 5 (0.8%) Vitreous opacities 0 1 (0.3%) 2 (0.7%) 3 (0.5%) Vitritis 0 2 (0.7%) 0 2 (0.3%) Xerophthalmia 0 1 (0.3%) 1 (0.3%) 2 (0.3%) General disorders and administration site conditions 7 (2.3%) 6 (2.0%) 10 (1.7%) Application site irritation 1 (0.3%) 1 (0.3%) 1 (0.2%) Injection site irritation 1 (0.3%) 2 (0.7%) 4 (0.7%) Injection site pain 1 (0.3%) 0 1 (0.2%) Oedema 3 (1.0%) 1 (0.3%) 1 (0.2%) Pain 0 2 (0.7%) 1 (0.3%) 3 (0.5%)

Sensation of foreign body 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Immune system disorders 1 (0.3%) 3 (1.0%) 2 (0.7%) 5 (0.8%) Drug hypersensitivity 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Iodine allergy 0 1 (0.3%) 1 (0.3%) (0.3%) Seasonal allergy 0 2 (0.7%) 0 2 (0.3%) Infections and infestations 8 (2.7%) 7 (2.4%) 5 (1.7%) 12 (2.0%) Adenoviral conjunctivitis 0 1 (0.3%) 0 1 (0.2%) Conjunctivitis 2 (0.7%) 3 (1.0%) 3 (1.0%) 6 (1.0%) Conjunctivitis viral 0 1 (0.3%) 0 1 (0.2%) Endophthalmitis 3 (1.0%) 1 (0.3%) 0 1 (0.2%) Hordeolum 2 (0.7%) 1 (0.3%) 2 (0.7%) 3 (0.5%) Infective keratitis 1 (0.3%) 0 0 0 Tooth abscess 1 (0.3%) 0 0 0 Injury, poisoning and procedural complications 6 (2.0%) 10 (3.4%) 7 (2.3%) 17 (2.9%) Corneal abrasion 1 (0.3%) 1 (0.3%) 5 (1.7%) 6 (1.0%) Eye injury 0 1 (0.3%) 0 1 (0.2%) Foreign body in eye 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Injection related reaction 1 (0.3%) 0 0 0 Injury corneal 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Intra-ocular injection complication 1 (0.3%) 5 (1.7%) 0 5 (0.8%) Overdose 1 (0.3%) 0 0 0 Posterior capsule rupture 0 0 1 (0.3%) 1 (0.2%) Skin laceration 0 2 (0.7%) 0 2 (0.3%) Investigations 11 (3.7%) 20 (6.8%) 16 (5.4%) 36 (6.1%) Intraocular pressure decreased 1 (0.3%) 0 0 0 Intraocular pressure increased 8 (2.7%) 19 (6.5%) 16 (5.4%) 35 (5.9%) Intraocular pressure test abnormal 0 1 (0.3%) 0 1 (0.2%) Optic nerve cup/disc ratio increased 2 (0.7%) 0 0 0 Neoplasms benign, malignant and unspecified (incl cysts and polyps} 0 1 (0.3%) 1 (0.3%) 2 (0.3%) Melanocytic: naevus 0 1 (0.3%) 1 (0.2%) Seborrhoeic keratosis 1 (0.3%) 0 1 (0.2%) Nervous system disorders 1 (0.3%) 0 1 (0.2%) Hypotonia 1 (0.3%) 0 1 (0.2%) Skin and subcutaneous tissue disorders 0 0

An gioedema 0 0 Vascular disorders 2 (0.7%) 3 (1.0%) 1 (0.3%) 4 (0.7%) Haemorrhage 0 1 (0.3%) 0 1 (0.2%) Vascular shunt 1 (0.3%) 1 (0.3%) 1 (0.3%) 2 (0.3%) Vasodilatation 1 (0.3%) 0 0 0 Vein disorder 0 1 (0.3%) 0 1 (0.2%)

Adverse events are sorted by alphabetical order of the MedDRA classification.

A participant is counted only once within each primary SOC and preferred term.

2q4: Aflibercept 2mg administered every 4 weeks.

Table 1-69A. Ocular treatment-emergent adverse events of study eye: number of participants by primary system organ class and preferred term (safety analysis set) Population group: Non-China sub-population

Primary' system organ class

Preferred term 2q4 8q8/3 8q8/5 All 8mg MedDRA version 28.0 N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%) Number (%) of participants with at least one such adverse event 121 (43.8%) 123 (46.2%) 103 (39.6%) 226 (43.0%) Eye disorders 108 (39.1%) 109 (41.0%) 92 (35.4%) 201 (38.2%) Allergic keratitis 1 (0.4%) 0 0 0 Amaurosis fugax 0 1 (0.4%) 0 1 (0.2%) Angle closure glaucoma 1 (0.4%) 0 0 0 Anterior chamber cell 1 (0.4%) 0 0 0 Anterior chamber disorder 0 1 (0.4%) 0 1 (0.2%) Aphakia 0 0 2 (0.8%) 2 (0.4%) Blepharitis 2 (0.7%) 2 (0.8%) 2 (0.8%) 4 (0.8%) Blepharospasm 0 1 (0.4%) 0 1 (0.2%) Blindness 1 (0.4%) 0 1 (0.4%) 1 (0.2%) Borderline glaucoma 0 2 (0.8%) 0 2 (0.4%) Cataract 17 (6.2%) 10 (3.8%) 18 (6.9%) 28 (5.3%) Cataract cortical 0 2 (0.8%) 0 2 (0.4%) Cataract nuclear 0 0 1 (0.4%) 1 (0.2%) Cataract subcapsular 1 (0.4%) 0 0 0 Chalazion 1 (0.4%) 0 1 (0.4%) 1 (0.2%) Chorioretinal folds 0 1 (0.4%) 0 1 (0.2%) Ciliary muscle spasm 1 (0.4%) 0 0 0 Conjunctival haemorrhage 7 (2.5%) 12 (4.5%) 11 (4.2%) 23 (4.4%) Conjunctival hyperaemia 0 0 1 (0.4%) 1 (0.2%) Conjunctival irritation 1 (0.4%) 0 0 0 Conjunctival oedema 2 (0.7%) 0 0 0 Conjunctival suffusion 0 1 (0.4%) 1 (0.4%) 2 (0.4%) Conjunctivitis allergic 5 (1.8%) 4 (1.5%) 3 (1.2%) 7 (1.3%) Corneal disorder 0 1 (0.4%) 0 1 (0.2%) Corneal erosion 0 1 (0.4%) 0 1 (0.2%) Corneal infiltrates 0 1 (0.4%) 0 1 (0.2%) Corneal oedema 0 1 (0.4%) 0 1 (0.2%)

Corneal scar 1 (0.4%) 1 (0.4%) 0 1 (0.2%) Cystoid macular oedema 2 (0.7%) 3 (1.1%) 1 (0.4%) 4 (0.8%) Detachment of retinal pigment epithelium 0 1 (0.4%) 0 1 (0.2%) Diabetic retinopathy 1 (0.4%) 0 1 (0.4%) 1 (0.2%) Dry age-related macular degeneration 0 0 1 (0.4%) 1 (0.2%) Dry⁷ eye 9 (3.3%) 4 (1.5%) 7 (2.7%) 11 (2.1%) Dysmetropsia 0 1 (0.4%) 0 1 (0.2%) Ectropion 0 1 (0.4%) 0 1 (0.2%) Epiretinal membrane 6 (2.2%) 6 (2.3%) 10 (3.8%) 16 (3.0%) Exophthalmos 0 0 1 (0.4%) 1 (0.2%) Eye inflammation 1 (0.4%) 0 0 0 Eye irritation 0 2 (0.8%) 0 2 (0.4%) Eye pain 3 (1.1%) 5 (1.9%) 3 (1.2%) 8 (1.5%) Eye pruritus 0 3 (1.1%) 0 3 (0.6%) Eye swelling 0 1 (0.4%) 0 1 (0.2%) Eyelid oedema 1 (0.4%) 0 0 0 Foreign body sensation in eyes 0 1 (0.4%) 0 1 (0.2%) Glaucoma 1 (0.4%) 5 (1.9%) 1 (0.4%) 6 (1.1%) Glaucomatous optic neuropathy 1 (0.4%) 0 0 0 Keratic precipitates 0 1 (0.4%) 0 1 (0.2%) Keratitis 0 1 (0.4%) 1 (0.4%) 2 (0.4%) Lacrimation increased 3 (1.1%) 0 0 0 Lens dislocation 0 0 1 (0.4%) 1 (0.2%) Lenticular opacities 0 0 2 (0.8%) 2 (0.4%) Lid margin discharge 1 (0.4%) 0 0 0 Macular degeneration 1 (0.4%) 1 (0.4%) 0 1 (0.2%) Macular hole 1 (0.4%) 0 1 (0.4%) 1 (0.2%) Macular ischaemia 1 (0.4%) 2 (0.8%) 1 (0.4%) 3 (0.6%) Macular oedema 6 (2.2%) 10 (3.8%) 4 (1.5%) 14 (2.7%) Macular thickening 8 (2.9%) 12 (4.5%) 1 (0.4%) 13 (2.5%) Meibomian gland dysfunction 1 (0.4%) 0 0 0 Narrow anterior chamber angle 0 1 (0.4%) 1 (0.4%) 2 (0.4%) Normal tension glaucoma 3 (1.1%) 2 (0.8%) 1 (0.4%) 3 (0.6%) Ocular discomfort 0 0 1 (0.4%) 1 (0.2%) Ocular hyperaemia 1 (0.4%) 0 0 0 Ocular hypertension 5 (1.8%) 5 (1.9%) 3 (1.2%) 8 (1.5%) Ocular rosacea 1 (0.4%) 0 0 0 Open angle glaucoma 0 2 (0.8%) 0 2 (0.4%) Optic atrophy 2 (0.7%) 0 1 (0.4%) 1 (0.2%) Optic nerve cupping 0 2 (0.8%) 0 2 (0.4%) Optic neuropathy 0 0 1 (0.4%) 1 (0.2%) Photopsia 0 1 (0.4%) 0 1 (0.2%) Posterior capsule opacification 1 (0.4%) 1 (0.4%) 2 (0.8%) 3 (0.6%) Presbyopia 0 0 1 (0.4%) 1 (0.2%) Pterygium 1 (0.4%) 0 0 0 Punctate keratitis 7 (2.5%) 4 (1.5%) 2 (0.8%) 6 (1.1%) Retinal artery embolism 0 0 1 (0.4%) 1 (0.2%) Retinal artery occlusion 1 (0.4%) 1 (0.4%) 0 1 (0.2%) Retinal collateral vessels 2 (0.7%) 1 (0.4%) 0 1 (0.2%) Retinal degeneration 1 (0.4%) 1 (0.4%) 1 (0.4%) 2 (0.4%) Retinal depigmentation 1 (0.4%) 0 0 0 Retinal detachment 1 (0.4%) 0 0 0 Retinal drusen 3 (1.1%) 0 0 0 Retinal exudates 1 (0.4%) 2 (0.8%) 2 (0.8%) 4 (0.8%) Retinal haemorrhage 1 (0.4%) 3 (1.1%) 2 (0.8%) 5 (1.0%) Retinal ischaemia 1 (0.4%) 1 (0.4%) 1 (0.4%) 2 (0.4%) Retinal oedema 2 (0.7%) 3 (1.1%) 1 (0.4%) 4 (0.8%) Retinal pigment epitheliopathy 0 1 (0.4%) 0 1 (0.2%) Retinal tear 1 (0.4%) 1 (0.4%) 2 (0.8%) 3 (0.6%) Retinal vascular disorder 0 2 (0.8%) 2 (0.8%) 4 (0.8%) Retinal vasculitis 0 0 1 (0.4%) 1 (0.2%) Retinal vein occlusion 2 (0.7%) 4 (1.5%) 4 (1.5%) 8 (1.5%) Retinoschisis 0 1 (0.4%) 0 1 (0.2%) Subretinal fluid 0 0 1 (0.4%) 1 (0.2%) Superior limbic keratoconjunctivitis 0 0 1 (0.4%) 1 (0.2%) Swelling of eyelid 0 1 (0.4%) 0 1 (0.2%) Uveitis 0 0 2 (0.8%) 2 (0.4%)

Vision blurred 0 2 (0.8%) 1 (0.4%) 3 (0.6%) Visual acuity reduced 10 (3.6%) 15 (5.6%) 7 (2.7%) 22 (4.2%) Visual field defect 0 2 (0.8%) 0 2 (0.4%) Visual impairment 0 2 (0.8%) 1 (0.4%) 3 (0.6%) Vitreomacular interface abnormal 0 1 (0.4%) 0 1 (0.2%) Vitreoretinal traction syndrome 0 1 (0.4%) 0 1 (0.2%) Vitreous detachment 4 (1.4%) 9 (3.4%) 10 (3.8%) 19 (3.6%) Vitreous floaters 4 (1.4%) 6 (2.3%) 3 (1.2%) 9 (1.7%) Vitreous haemorrhage 0 2 (0.8%) 2 (0.8%) 4 (0.8%) Vitreous opacities 0 1 (0.4%) 1 (0.4%) 2 (0.4%) Vitritis 0 2 (0.8%) 0 2 (0.4%) General disorders and administration site conditions 7 (2.5%) 6 (2.3%) 4 (1.5%) 10 (1.9%) Application site irritation 1 (0.4%) 1 (0.4%) 0 1 (0.2%) Injection site irritation 1 (0.4%) 2 (0.8%) 2 (0.8%) 4 (0.8%) Injection site pain 1 (0.4%) 0 1 (0.4%) 1 (0.2%) Oedema 3 (1.1%) 1 (0.4%) 0 1 (0.2%) Pain 0 2 (0.8%) 1 (0.4%) 3 (0.6%) Sensation of foreign body 1 (0.4%) 1 (0.4%) 0 1 (0.2%) Immune system disorders 1 (0.4%) 3 (1.1%) 2 (0.8%) 5 (1.0%) Drug hypersensitivity 1 (0.4%) 0 1 (0.4%) 1 (0.2%) Iodine allergy 0 1 (0.4%) 1 (0.4%) 2 (0.4%) Seasonal allergy 0 2 (0.8%) 0 2 (0.4%) Infections and infestations 6 (2.2%) 7 (2.6%) 4 (1.5%) 11 (2.1%) Adenoviral conjunctivitis 0 1 (0.4%) 0 1 (0.2%) Conjunctivitis 1 (0.4%) 3 (1.1%) 2 (0.8%) 5 (1.0%) Conjunctivitis viral 0 1 (0.4%) 0 1 (0.2%) Endophthalmitis 2 (0.7%) 1 (0.4%) 0 1 (0.2%) Hordeolum 2 (0.7%) 1 (0.4%) 2 (0.8%) 3 (0.6%) Infective keratitis 1 (0.4%) 0 0 0 Tooth abscess 1 (0.4%) 0 0 0 Injury, poisoning and procedural complications 6 (2.2%) 9 (3.4%) 7 (2.7%) 16 (3.0%) Corneal abrasion 1 (0.4%) 1 (0.4%) 5 (1.9%) 6 (1.1%) Eye injury 0 1 (0.4%) 0 1 (0.2%) Foreign body in eye 1 (0.4%) 0 1 (0.4%) 1 (0.2%) Injection related reaction 1 (0.4%) 0 0 0 Injury corneal 1 (0.4%) 0 0 0 Intra-ocular injection complication 1 (0.4%) 5 (1.9%) 0 5 (1.0%) Overdose 1 (0.4%) 0 0 0 Posterior capsule rupture 0 0 1 (0.4%) 1 (0.2%) Skin laceration 0 2 (0.8%) 0 2 (0.4%) Investigations 9 (3.3%) 17 (6.4%) 8 (3.1%) 25 (4.8%) Intraocular pressure decreased 1 (0.4%) 0 0 0 Intraocular pressure increased 6 (2.2%) 16 (6.0%) 8 (3.1%) 24 (4.6%) Intraocular pressure test abnormal 0 1 (0.4%) 0 1 (0.2%) Optic nerve cup/disc ratio increased 2 (0.7%) 0 0 0 Neoplasms benign, malignant and unspecified (incl cysts and polyps) 0 1 (0.4%) 1 (0.4%) 2 (0.4%) Melanocytic naevus 0 0 1 (0.4%) 1 (0.2%) Seborrhoeic keratosis 0 1 (0.4%) 0 1 (0.2%) Nervous system disorders 0 1 (0.4%) 0 1 (0.2%) Hypotonia 0 1 (0.4%) 0 1 (0.2%) Skin and subcutaneous tissue disorders 1 (0.4%) 0 0 0 Angioedema 1 (0.4%) 0 0 0 Vascular disorders 2 (0.7%) 3 (1.1%) 1 (0.4%) 4 (0.8%) Haemorrhage 0 1 (0.4%) 0 1 (0.2%) Vascular shunt 1 (0.4%) 1 (0.4%) 1 (0.4%) 2 (0.4%)

Vasodilatation 1 (0.4%) 0 0 0 |

Vein disorder | 0 | 1 (0.4%) | 0 | 1 (0.2%) | Adverse events are sorted by alphabetical order of the MedDRA classification.

A participant is counted only once within each primary SOC and preferred term.

2q4: Aflibercept 2mg administered every 4 weeks.

Table 1-70. Non-ocular treatment-emergent adverse events: number of participants by primary system organ class and preferred term (safety analysis set)

Primary system organ class Preferred term 2q4 All 8mg MedDRA version 28.0 _ N=301 (100% N=591 (100 Number (%) of participants with at least one such adverse event 189 (62.8%) 368 (62.3%) Blood and lymphatic system disorders 5 (1.7%) 11 (1.9%) Anaemia 2 (0.7%) 5 (0.8%) Blood loss anaemia 0 1 (0.2%) Eosinophilia 1 0 0 Iron deficiency anaemia 1 (0.3%) 1 (0.2%) Lymphocytosis 1 (0.3%) 1 (0.2%) Monocytosis o 1 (0.3%) 1 (0.2%) Neutrophilia o 1 (0.3%) 1 (0.2%) Pancytopenia 1 (0.3%) 0 0 Platelet disorder 0 0 1 (0.2%) Retroperitoneal lymphadenopathy 1 (0.3%) 0 0 Thrombocytopenia 0 0 1 (0.2%)

Thrombocytosis 0 0 1 (0.2%) Cardiac disorders 16 (5.3%) 17 (5.8%) 19 (6.4%) 36 (6.1%) Acute coronary syndrome 0 0 1 (0.3%) 1 (0.2%) Acute myocardial infarction 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Angina unstable 1 (0.3%) 0 0 0 Aortic valve incompetence 1 (0.3%) 0 0 0 Arrhythmia 0 0 1 (0.3%) 1 (0.2%) Arteriosclerosis coronary artery 0 0 1 (0.3%) 1 (0.2%) Atrial fibrillation 1 (0.3%) 2 (0.7%) 4 (1.3%) 6 (1.0%) Atrial tachycardia 0 1 (0.3%) 0 1 (0.2%) Atrioventricular block first degree 2 (0.7%) 1 (0.3%) 0 1 (0.2%) Bradycardia 0 3 (1.0%) 0 3 (0.5%) Bundle branch block left 2 (0.7%) 1 (0.3%) 0 1 (0.2%) Bundle branch block right 0 0 1 (0.3%) 1 (0.2%) Cardiac failure 0 0 1 (0.3%) 1 (0.2%) Cardiac failure acute 0 1 (0.3%) 0 1 (0.2%) Coronary artery disease 2 (0.7%) 2 (0.7%) 3 (1.0%) 5 (0.8%) Hypertensive heart disease 2 (0.7%) 0 0 0

Left ventricular enlargement 0 0 1 (0.3%) 1 (0.2%) Left ventricular hypertrophy 0 0 2 (0.7%) (0.3%) Mitral valve incompetence 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Mitral valve prolapse 0 1 (0.3%) 0 1 (0.2%) Myocardial infarction 1 (0.3%) 1 (0.3%) 1 (0.3%) 2 (0.3%) Myocardial ischaemia 0 0 1 (0.3%) 1 (0.2%) Palpitations 1 (0.3%) 1 (0.3%) 1 (0.3%) 2 (0.3%) Prinzmetal angina 0 1 (0.3%) 0 1 (0.2%) Sinus bradycardia 2 (0.7%) 3 (1.0%) 1 (0.3%) 4 (0.7%) Sinus tachycardia 1 (0.3%) 0 0 0 Tachycardia 2 (0.7%) 0 3 (1.0%) 3 (0.5%) Tricuspid valve incompetence 0 0 1 (0.3%) 1 (0.2%) Ventricular dyssynchrony 0 0 1 (0.3%) 1 (0.2%)

Ventricular extrasystoles 0 1 (0.3%) 0 1 (0.2%) Congenital, familial and genetic disorders 0 2 (0.7%) 1 (0.3%) 3 (0.5%) Aberrant aortic arch 0 0 1 (0.3%) 1 (0.2%) Factor V Leiden mutation 0 1 (0.3%) 0 1 (0.2%) Thalassaemia 0 1 (0.3%) 0 1 (0.2%) Ear and labyrinth disorders 4 (1.3%) 7 (2.4%) 9 (3.0%) 16 (2.7%) Deafness 1 (0.3%) 0 0 0 Deafness transitory 0 0 1 (0.3%) 1 (0.2%) Ear inflammation 0 0 1 (0.3%) 1 (0.2%) Ear pain 1 (0.3%) 0 0 0 Presbyacusis 0 1 (0.3%) 0 1 (0.2%) Tinnitus 0 1 (0.3%) 0 1 (0.2%) Vertigo 2 (0.7%) 5 (1.7%) 6 (2.0%) 11 (1.9%) Vertigo positional 0 0 1 (0.3%) 1 (0.2%) Endocrine disorders 2 (0.7%) 1 (0.3%) 2 (0.7%) 3 (0.5%) Autoimmune thyroiditis 1 (0.3%) 0 0 0 Goitre 0 1 (0.3%) 0 1 (0.2%) Hypothyroidism 0 0 1 (0.3%) 1 (0.2%) Primary hyperaldosteronism 0 0 1 (0.3%) 1 (0.2%) Thyroid mass 1 (0.3%) 0 0 0 Gastrointestinal disorders 36 (12.0%) 27 (9.2%) 24 (8.1%) 51 (8.6%) Abdominal discomfort 1 (0.3%) 0 0 0 Abdominal distension 0 0 1 (0.2%) Abdominal hernia 1 (0.3%) 0 0 Abdominal pain 1 (0.3%) 0 0 Abdominal pain upper 3 (1.0%) 1 (0.3%) 2 (0.3%) Burning mouth syndrome 1 (0.3%) 0 0 Chronic gastritis 0 1 (0.3%) 2 (0.3%) Constipation 3 (1.0%) 1 (0.3%) 5 (0.8%) Crohn's disease 0 1 (0.3%) 1 (0.2%) Dental caries 3 (1.0%) 4 (1.3%) 5 (0.8%) Diarrhoea 4 (1.3%) 1 (0.3%) 4 (0.7%) Diverticulum 0 1 (0.3%) 1 (0.2%) Diverticulum intestinal 0 1 (0.3%) 1 (0.2%) Diverticulum intestinal haemorrhagic 1 0 0 0 Duodenal stenosis 0 1 (0.3%) 0 1 (0.2%) Duodenal ulcer 0 0 1 (0.3%) 1 (0.2%) Duodenogastric reflux 0 0 1 (0.3%) 1 (0.2%) Dyspepsia 1 (0.3%) 0 0 Dysphagia 0 1 (0.3%) 2 (0.3%) Femoral hernia incarcerated 0 0 1 (0.2%) Flatulence 0 0 1 (0.2%) Food poisoning 1 (0.3%) 1 (0.3%) 1 (0.2%) Gastritis 0 1 (0.3%) 1 (0.2%) Gastrointestinal disorder 2 (0.7%) 0 0 0 Gastrooesophageal reflux disease 1 (0.3%) 2 (0.7%) 1 (0.3%) 3 (0.5%) Glossitis 0 1 (0.3%) 0 1 (0.2%) Haemorrhoids 1 (0.3%) 0 2 (0.7%) 2 (0.3%) Hiatus hernia 0 1 (0.3%) 0 1 (0.2%) Irritable bowel syndrome 2 1 (0.3%) 0 1 (0.2%) Large intestine polyp 1 0 0 0 Lower gastrointestinal haemorrhage 0 1 (0.3%) 0 1 (0.2%) Mouth ulceration 0 0 1 (0.3%) 1 (0.2%) Nausea 6 4 (1.4%) 3 (1.0%) 7 (1.2%) Noninfective gingivitis 1 0 0 0 Oesophagitis 1 0 0 0 Pancreatic disorder 0 1 (0.3%) 1 (0.2%) Periodontal disease 2 0 0 Pulpless tooth 0 0 1 (0.2%) Small intestinal obstruction 1 0 0 Stomatitis 1 1 (0.3%) 1 (0.2%) Toothache 2 2 (0.7%) 3 (0.5%) Vomiting 6 1 (0.3%) 2 (0.3%)

General disorders and administration site conditions 15 (5.0%) 17 (5.8%) 11 (3.7%) 28 (4.7%) Application site hypersensitivity 0 1 (0.3%) 0 1 (0.2%) Asthenia 0 0 1 (0.3%) 1 (0.2%) Catheter site pain 0 1 (0.3%) 0 1 (0.2%) Chest pain 2 (0.7%) 4 (1.4%) 2 (0.7%) 6 (1.0%) Chills 1 (0.3%) 0 0 0 Cyst 0 0 1 (0.3%) 1 (0.2%) Fatigue 0 0 1 (0.3%) 1 (0.2%) Gait disturbance 0 0 1 (0.3%) 1 (0.2%) General physical health deterioration 1 (0.3%) 0 0 0 Hernia 1 (0.3%) 0 0 0

Ill-defined disorder 1 (0.3%) 0 0 0 Incarcerated hernia 1 (0.3%) 0 0 0 Influenza like illness 1 (0.3%) 2 (0.7%) 2 (0.7%) 4 (0.7%) Injection site bruising 0 1 (0.3%) 0 1 (0.2%) Malaise 1 (0.3%) 2 (0.7%) 1 (0.3%) 3 (0.5%) Mass 0 0 1 (0.3%) 1 (0.2%) Oedema 0 1 (0.3%) 0 1 (0.2%) Oedema due to renal disease 1 (0.3%) 0 0 0 Oedema peripheral 3 (1.0%) 4 (1.4%) 0 4 (0.7%) Peripheral swelling 0 1 (0.3%) 0 1 (0.2%) Pyrexia 4 (1.3%) 3 (1.0%) 1 (0.3%) 4 (0.7%) Hepatobiliary disorders 6 (2.0%) 2 (0.7%) 5 (1.7%) 7 (1.2%) Biliary colic 0 0 1 (0.3%) 1 (0.2%) Cholecystitis 1 (0.3%) 0 0 0 Cholecystitis acute 0 1 (0.3%) 0 1 (0.2%) Cholecystitis chronic 0 0 1 (0.3%) 1 (0.2%) Cholelithiasis 2 (0.7%) 0 0 0 Hepatic cyst 0 1 (0.3%) 0 1 (0.2%) Hepatic steatosis 4 (1.3%) 0 3 (1.0%) 3 (0.5%) Metabolic dysfunction-associated liver disease 0 0 1 (0.3%) 1 (0.2%) Immune system disorders 7 (2.3%) 7 (2.4%) 4 (1.3%) 11 (1.9%) Allergy to arthropod sting 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Allergy to chemicals 0 1 (0.3%) 0 1 (0.2%) Anaphylactic reaction 0 1 (0.3%) 0 1 (0.2%) Contrast media allergy 0 1 (0.3%) 0 1 (0.2%) Contrast media reaction 1 (0.3%) 0 0 0 Drug hypersensitivity 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Hypersensitivity 0 0 1 (0.3%) 1 (0.2%) Multiple allergies 1 (0.3%) 0 0 0 Seasonal allergy 3 (1.0%) 2 (0.7%) 3 (1.0%) 5 (0.8%) Infections and infestations 92 (30.6%) 83 (28.3%) 93 (31.2%) 176 (29.8%) Abdominal abscess 1 (0.3%) 0 0 0 Acute sinusitis 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Appendicitis 0 0 1 (0.3%) 1 (0.2%) Arthritis infective 1 (0.3%) 0 0 0 Asymptomatic bacteriuria 1 (0.3%) 0 0 0 Atypical pneumonia 2 (0.7%) 0 0 0 Bacterial urethritis 1 (0.3%) 0 0 0 Bacterial vaginosis 0 0 1 (0.3%) 1 (0.2%) Borrelia infection 0 0 1 (0.3%) 1 (0.2%) Bronchitis 4 (1.3%) 6 (2.0%) 7 (2.3%) 13 (2.2%) COVID-19 9 (3.0%) 17 (5.8%) 12 (4.0%) 29 (4.9%) Candida infection 1 (0.3%) 0 0 0 Cellulitis 0 1 (0.3%) 0 1 (0.2%) Chronic hepatitis C 0 0 1 (0.3%) 1 (0.2%) Chronic sinusitis 0 0 1 (0.3%) 1 (0.2%) Colonic abscess 0 0 1 (0.3%) 1 (0.2%) Coronavirus infection 3 (1.0%) 0 0 0 Cystitis 1 (0.3%) 0 2 (0.7%) 2 (0.3%) Diverticulitis 0 3 (1.0%) 2 (0.7%) 5 (0.8%) Ear infection 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Enterocolitis infectious 1 (0.3%) 0 0 0 Epididymitis 0 0 1 (0.3%) 1 (0.2%) Erysipelas 1 (0.3%) 0 0 0

Escherichia urinary tract infection 1 (0.3%) 0 0 Folliculitis 0 0 1 (0.3%) 1 (0.2%) Fungal infection 0 1 (0.3%) 0 1 (0.2%) Fungal skin infection 0 0 2 (0.7%) 2 (0.3%) Gastroenteritis 2 (0.7%) 2 (0.7%) 0 2 (0.3%) Gastroenteritis viral 0 0 2 (0.7%) 2 (0.3%) Gingivitis 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Helicobacter infection 0 1 (0.3%) 0 1 (0.2%) Herpes dermatitis 1 (0.3%) 0 0 0 Herpes simplex 0 0 1 (0.3%) 1 (0.2%) Herpes virus infection 1 (0.3%) 0 0 0 Herpes zoster 7 (2.3%) 2 (0.7%) 4 (1.3%) 6 (1.0%) Impetigo 0 0 1 (0.3%) 1 (0.2%) Infected cyst 0 1 (0.3%) 0 1 (0.2%) Infected dermal cyst 0 1 (0.3%) 1 (0.3%) 2 (0.3%) Infectious pleural effusion 0 1 (0.3%) 0 1 (0.2%) Influenza 13 (4.3%) 11 (3.8%) 6 (2.0%) 17 (2.9%) Localised infection 0 1 (0.3%) 0 1 (0.2%) Lower respiratory tract infection 0 0 1 (0.3%) 1 (0.2%) Nasopharyngitis 20 (6.6%) 25 (8.5%) 27 (9.1%) 52 (8.8%) Onychomycosis 0 0 1 (0.3%) 1 (0.2%) Oral candidiasis 0 1 (0.3%) 0 1 (0.2%) Oral herpes 2 (0.7%) 2 (0.7%) 1 (0.3%) 3 (0.5%) Oropharyngeal candidiasis 0 0 1 (0.3%) 1 (0.2%) Osteomyelitis 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Otitis externa 0 1 (0.3%) 1 (0.3%) 2 (0.3%) Otitis media 1 (0.3%) 0 0 0 Paronychia 0 0 1 (0.3%) 1 (0.2%) Periodontitis 2 (0.7%) 3 (1.0%) 1 (0.3%) 4 (0.7%) Pharyngitis 0 4 (1.4%) 1 (0.3%) 5 (0.8%) Pharyngitis streptococcal 1 (0.3%) 0 0 0 Pneumonia 4 (1.3%) 6 (2.0%) 5 (1.7%) 11 (1.9%) Pneumonia aspiration 1 (0.3%) 0 0 0 Pneumonia parainfluenzae viral 0 0 1 (0.3%) 1 (0.2%) Pneumonia pseudomonal 0 0 1 (0.3%) 1 (0.2%) Pulpitis dental 1 (0.3%) 0 0 0 Respiratory syncytial virus infection 0 0 1 (0.3%) 1 (0.2%) Respiratory tract infection 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Rhinitis 2 (0.7%) 1 (0.3%) 1 (0.3%) 2 (0.3%) Sepsis 0 2 (0.7%) 1 (0.3%) 3 (0.5%) Sinusitis 5 (1.7%) 4 (1.4%) 4 (1.3%) 8 (1.4%) Tinea cruris 1 (0.3%) 0 0 0 Tinea pedis 0 0 1 (0.3%) 1 (0.2%) Tonsillitis 1 (0.3%) 1 (0.3%) 2 (0.7%) 3 (0.5%) Tooth abscess 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Tooth infection 2 (0.7%) 0 1 (0.3%) 1 (0.2%) Upper respiratory tract infection 8 (2.7%) 8 (2.7%) 3 (1.0%) 11 (1.9%) Urinary tract infection 13 (4.3%) 8 (2.7%) 15 (5.0%) 23 (3.9%) Vaginal infection 0 0 2 (0.7%) 2 (0.3%) Viral infection 2 (0.7%) 1 (0.3%) 3 (1.0%) 4 (0.7%) Viral rhinitis 0 0 1 (0.3%) 1 (0.2%) Viral upper respiratory tract infection 0 0 1 (0.3%) 1 (0.2%) Wound infection 2 (0.7%) 0 0 0

Injury poisoning and procedural complications 20 (6.6%) 19 (6.5%) 20 (6.7%) 39 (6.6%) Abdominal injury⁷ 1 (0.3%) 0 0 0 Animal bite 0 2 (0.7%) 0 2 (0.3%) Bone contusion 0 1 (0.3%) 0 1 (0.2%) Brain herniation 0 0 1 (0.3%) 1 (0.2%) Cartilage injury 0 0 1 (0.3%) 1 (0.2%) Contusion 0 4 (1.3%) 7 (1.2%) Fall 3 (1.0%) 4 (1.3%) 6 (1.0%) Foot fracture 2 (0.7%) 0 0 Fractured coccyx 0 1 (0.3%) 0 1 (0.2%) Hand fracture 0 1 (0.3%) 0 1 (0.2%) Head injury 1 (0.3%) 0 0 0 Humerus fracture 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Injury 1 (0.3%) 0 0 0 Joint dislocation 1 (0.3%) 0 0 0

Joint injury 0 0 2 (0.7%) 2 (0.3%) Ligament sprain 1 (0.3%) 0 2 (0.7%) 2 (0.3%) Limb injury 2 (0.7%) 2 (0.7%) 0 2 (0.3%) Meniscus injury 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Mouth injury 1 (0.3%) 0 0 0 Multiple injuries 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Muscle strain 0 1 (0.3%) 0 1 (0.2%) Oral contusion 1 (0.3%) 0 0 0 Overdose 1 (0.3%) 0 0 0 Pelvic fracture 1 (0.3%) 0 0 0 Periorbital haemorrhage 1 (0.3%) 0 0 0

Post procedural swelling 1 (0.3%) 0 0 0 Postoperative thoracic procedure complication 0 1 (0.3%) 0 1 (0.2%) Procedural nausea 0 1 (0.3%) 0 1 (0.2%) Procedural pain 3 (1.0%) 0 2 (0.7%) 2 (0.3%) Radius fracture 0 0 1 (0.3%) 1 (0.2%) Rib fracture 0 2 (0.7%) 1 (0.3%) 3 (0.5%) Skin abrasion 1 (0.3%) 0 0 0

Skin laceration 0 1 (0.3%) 1 (0.3%) 2 (0.3%) Snake bite 0 1 (0.3%) 0 1 (0.2%) Subdural haematoma 0 0 1 (0.3%) 1 (0.2%) Tendon injury 0 0 1 (0.3%) 1 (0.2%) Tendon rupture 0 0 1 (0.3%) 1 (0.2%) Tooth fracture 0 0 1 (0.3%) 1 (0.2%) Upper limb fracture 0 1 (0.3%) 0 1 (0.2%) Wrist fracture 1 (0.3%) 0 0 0 Investigations 24 (8.0%) 38 (13.0%) 29 (9.7%) 67 (11.3%) Alanine aminotransferase increased 0 2 (0.7%) 1 (0.3%) 3 (0.5%) Aspartate aminotransferase increased 0 2 (0.7%) 2 (0.7%) 4 (0.7%) Bacterial test positive 0 0 1 (0.3%) 1 (0.2%) Bilirubin conjugated increased 0 0 1 (0.3%) 1 (0.2%) Blood albumin increased 0 1 (0.3%) 1 (0.2%) Blood alkaline phosphatase abnormal 1 (0.3%) 0 0 0 Blood alkaline phosphatase increased 0 1 (0.3%) 2 (0.7%) 3 (0.5%) Blood bilirubin increased 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Blood cholesterol increased 1 (0.3%) 2 (0.7%) 2 (0.7%) 4 (0.7%) Blood creatine increased 1 (0.3%) 0 0 0 Blood creatine phosphokinase increased 4 (1.3%) 4 (1.4%) 5 (1.7%) 9 (1.5%) Blood creatinine decreased 0 0 1 (0.3%) 1 (0.2%) Blood glucose increased 1 (0.3%) (1.0%) 1 (0.3%) 4 (0.7%) Blood iron decreased 0 1 (0.3%) 1 (0.2%) Blood potassium increased 0 1 (0.3%) 1 (0.2%) Blood pressure diastolic increased 1 (0.3%) 2 (0.7%) 4 (0.7%) Blood pressure increased 3 (1.0%) 4 (1.3%) 10 (1.7%) Blood pressure systolic increased 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Blood triglycerides increased 1 (0.3%) 1 (0.3%) 3 (0.5%) Blood urea increased 1 (0.3%) 1 (0.3%) 2 (0.3%) Blood uric acid increased 0 2 (0.7%) 2 (0.3%) Blood urine present 1 (0.3%) 3 (1.0%) 4 (0.7%) Creatine urine increased 0 0 1 (0.2%) Creatinine urine decreased 1 (0.3%) 0 0 Creatinine urine increased 2 (0.7%) 1 (0.3%) 1 (0.2%) Electrocardiogram QT prolonged 0 1 (0.3%) 1 (0.2%) Electrocardiogram ST segment depression 0 0 1 (0.2%) Electrocardiogram T wave abnormal 0 1 (0.3%) 1 (0.2%) Fungal test positive 0 1 (0.3%) 1 (0.2%) Glucose urine 0 0 1 (0.3%) 1 (0.2%) Glucose urine present 0 0 1 (0.3%) 1 (0.2%) Glycosylated haemoglobin increased 2 (0.7%) 4 (1.4%) 5 (1.7%) 9 (1.5%) Haematocrit decreased 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Haematocrit increased 0 0 1 (0.3%) 1 (0.2%) Haemoglobin decreased 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Haemoglobin increased 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Heart rate increased 0 1 (0.3%) 0 1 (0.2%) Hepatic enzyme increased 0 1 (0.3%) 0 1 (0.2%) Interferon gamma release assay positive 0 1 (0.3%) 0 1 (0.2%) Liver function test abnormal 0 0 1 (0.3%) 1 (0.2%) Liver function test increased 0 1 (0.3%) 0 1 (0.2%)

Low density lipoprotein increased 0 0 1 (0.3%) 1 (0.2%) Mean cell haemoglobin decreased 0 0 1 (0.3%) 1 (0.2%) Mean cell volume abnormal 0 1 (0.3%) 0 1 (0.2%) Monocyte count increased 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Neutrophil count increased 0 1 (0.3%) 0 1 (0.2%) Nitrite urine present 0 0 1 (0.3%) 1 (0.2%) Platelet count decreased 1 (0.3%) 0 0 0 Protein total increased 0 0 1 (0.3%) 1 (0.2%) Protein urine present 4 (1.3%) 1 (0.3%) 1 (0.3%) 2 (0.3%) Red blood cell count decreased 1 (0.3%) 0 0 0

Red blood cell count increased 0 1 (0.3%) 0 1 (0.2%) Red blood cells urine 0 1 (0.3%) 0 1 (0.2%) Red blood cells urine positive 0 0 1 (0.3%) 1 (0.2%) Reticulocyte count increased 0 0 1 (0.3%) 1 (0.2%) Urinary sediment present 1 (0.3%) 1 (0.3%) 1 (0.3%) 2 (0.3%) Urine analysis abnormal 1 (0.3%) 1 (0.3%) 1 (0.3%) 2 (0.3%) Urine ketone body present 1 (0.3%) 0 0 0 Urine protein/creatinine ratio increased 4 (1.3%) 1 (0.3%) 2 (0.7%) 3 (0.5%) Urine transitional cells present 0 0 1 (0.3%) 1 (0.2%) Urobilinogen urine increased 1 (0.3%) 0 0 0 Weight decreased 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Weight increased 1 (0.3%) 0 0 0 White blood cell count increased 0 2 (0.7%) 0 2 (0.3%) White blood cells urine positive 1 (0.3%) 1 (0.3%) 1 (0.3%) 2 (0.3%) Metabolism and nutrition disorders 31 (10.3%) 15 (5.1%) 27 (9.1%) 42 (7.1%) Acidosis 0 0 1 (0.3%) 1 (0.2%) Dehydration 1 (0.3%) 0 0 0 Diabetes mellitus 1 (0.3%) 2 (0.7%) 2 (0.7%) 4 (0.7%) Diabetic ketoacidosis 1 (0.3%) 0 0 0 Diabetic ketosis 1 (0.3%) 0 0 0 Dyslipidaemia 2 (0.7%) 0 3 (1.0%) 3 (0.5%) Glucose tolerance impaired 0 2 (0.7%) 0 2 (0.3%) Gout 3 (1.0%) 0 1 (0.3%) 1 (0.2%) Hyperchol esterol aemi a 5 (1.7%) 5 (1.7%) 8 (2.7%) 13 (2.2%) Hyperglycaemia 0 0 1 (0.3%) 1 (0.2%) Hyperkalaemia 0 1 (0.3%) 0 1 (0.2%) Hyperlipidaemia 9 (3.0%) 3 (1.0%) 3 (1.0%) 6 (1.0%) Hypertriglyceridaemia 1 (0.3%) 0 2 (0.7%) 2 (0.3%) Hyperuricaemia 3 (1.0%) 1 (0.3%) 0 1 (0.2%) Hypervolaemia 0 0 1 (0.3%) 1 (0.2%) Hypoglycaemia 2 (0.7%) 0 0 0 Hypokalaemia 1 (0.3%) 2 (0.7%) 2 (0.7%) 4 (0.7%) Hyponatraemia 1 (0.3%) 1 (0.3%) 1 (0.3%) 2 (0.3%) Hypovolaemia 0 0 1 (0.3%) 1 (0.2%) Lipid metabolism disorder 0 1 (0.3%) 1 (0.3%) 2 (0.3%) Metabolic syndrome 1 (0.3%) 0 0 0 Obesity 0 0 1 (0.3%) 1 (0.2%) Overweight 1 (0.3%) 0 0 0 Type 2 diabetes mellitus 6 (2.0%) 1 (0.3%) 5 (1.7%) 6 (1.0%) Vitamin B complex deficiency 0 0 1 (0.3%) 1 (0.2%) Vitamin D deficiency 1 (0.3%) 1 (0.3%) 1 (0.3%) 2 (0.3%) Musculoskeletal and connective tissue disorders 32 (10.6%) 35 (11.9%) 25 (8.4%) 60 (10.2%) Arthralgia 7 (2.3%) 6 (2.0%) 6 (2.0%) 12 (2.0%) Arthritis 1 (0.3%) 4 (1.4%) 1 (0.3%) 5 (0.8%) Back pain 7 (2.3%) 3 (1.0%) 5 (1.7%) 8 (1.4%) Bursitis 3 (1.0%) 0 0 0 Dupuytren's contracture 0 0 1 (0.3%) 1 (0.2%) Foot deformity 1 (0.3%) 0 0 0 Gouty tophus 0 0 1 (0.3%) 1 (0.2%) Groin pain 0 1 (0.3%) 0 1 (0.2%) Haemarthrosis 0 0 1 (0.3%) 1 (0.2%) Intervertebral disc compression 1 (0.3%) 0 0 0 Intervertebral disc degeneration 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Intervertebral disc disorder 1 (0.3%) 0 0 0

Joint effusion 0 0 1 (0.3%) 1 (0.2%) Joint swelling 0 2 (0.7%) 0 2 (0.3%) Muscle contracture 0 0 1 (0.3%) 1 (0.2%)

Muscle disorder 1 (0.3%) 0 0 0 Muscle spasms 2 (0.7%) 0 1 (0.3%) 1 (0.2%) Musculoskeletal pain 1 (0.3%) 0 0 0 Musculoskeletal stiffness 0 0 1 (0.3%) 1 (0.2%) Myalgia 4 (1.3%) 0 0 0 Myofascitis 0 0 1 (0.3%) 1 (0.2%) Myositis 1 (0.3%) 0 0 0 Neck pain 0 1 (0.3%) 0 1 (0.2%) Osteoarthritis 5 (1.7%) 2 (0.7%) 3 (1.0%) 5 (0.8%) Osteoporosis 1 (0.3%) 2 (0.7%) 0 2 (0.3%) Pain in extremity 1 (0.3%) 5 (1.7%) 2 (0.7%) 7 (1.2%) Periarthritis 1 (0.3%) 0 0 0 Plantar fasciitis 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Rheumatic disorder 1 (0.3%) 0 0 0 Rheumatoid arthritis 0 3 (1.0%>) 0 3 (0.5%) Rotator cuff syndrome 0 1 (0.3%) 0 1 (0.2%) Sacroiliitis 0 0 1 (0.3%) 1 (0.2%) Scoliosis 0 2 (0.7%) 0 2 (0.3%) Spinal osteoarthritis 1 (0.3%) 4 (1.4%) 1 (0.3%) 5 (0.8%) Spinal pain 0 0 1 (0.3%) 1 (0.2%) Systemic lupus erythematosus 0 1 (0.3%) 0 1 (0.2%) Temporomandibular pain and dysfunction syndrome 0 1 (0.3%) 0 1 (0.2%) Tendon pain 1 (0.3%) 0 0 0 Tenosynovitis 0 0 1 (0.3%) 1 (0.2%) Vertebral foraminal stenosis 0 1 (0.3%) 0 1 (0.2%) Vertebral lateral recess stenosis 1 (0.3%) 0 0 0 Neoplasms benign, malignant and unspecified (incl cysts and polyps) 9 (3.0%) 7 (2.4%) 4 (1.3%) 11 (1.9%) Basal cell carcinoma 1 (0.3%) 0 0 0 Benign breast neoplasm 0 0 1 (0.3%) 1 (0.2%) Bladder cancer 0 1 (0.3%) 0 1 (0.2%) Bladder neoplasm 0 1 (0.3%) 0 1 (0.2%) Cancer fatigue 1 (0.3%) 0 0 0 Colon cancer 0 0 1 (0.3%) 1 (0.2%) Gastrointestinal submucosal tumour 0 1 (0.3%) 0 1 (0.2%) Leiomyoma 1 (0.3%) 0 0 0 Lipoma 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Lung neoplasm malignant 0 0 1 (0.3%) 1 (0.2%) Metastases to lymph nodes 0 0 1 (0.3%) 1 (0.2%) Metastatic neoplasm 1 (0.3%) 0 0 0 Oesophageal carcinoma 0 0 1 (0.2%) Prostate cancer metastatic 0 1 1 (0.2%) Prostate cancer stage II 0 0 1 (0.2%) Rectal cancer 0 1 1 (0.2%) Seborrhoeic keratosis 1 (0.3%) 0 0 Small cell lung cancer 0 1 (0.3%) 0 1 (0.2%) Squamous cell carcinoma 1 (0.3%) 0 0 0 Squamous cell carcinoma of lung 1 (0.3%) 0 0 0 Squamous cell carcinoma of skin 1 (0.3%) 0 0 0 T-cell lymphoma 1 (0.3%) 0 0 0

Uterine leiomyoma 0 1 (0.3%) 0 1 (0.2%) Nervous system disorders 25 (8.3%) 28 (9.6%) 26 (8.7%) 54 (9.1%) Amnesia 0 1 (0.3%) 0 1 (0.2%) Atypical migraine 1 (0.3%) 0 0 0 Carotid arteriosclerosis 0 1 (0.3%) 1 (0.3%) 2 (0.3%) Carotid artery disease 0 0 1 (0.3%) 1 (0.2%) Carotid artery occlusion 1 (0.3%) 0 0 0 Carotid artery stenosis 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Carpal tunnel syndrome 0 1 (0.3%) 0 1 (0.2%) Cerebellar infarction 1 (0.3%) 0 0 0 Cerebellar stroke 1 (0.3%) 0 0 0 Cerebral infarction 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Cerebrovascular accident 1 (0.3%) 0 0 0 Cerebrovascular disorder 0 1 (0.3%) 0 1 (0.2%) Cervical radiculopathy 1 (0.3%) 2 (0.7%) 2 (0.7%) 2 (0.3%) Cognitive disorder 0 0 1 (0.3%) 1 (0.2%) Dementia 3 (1.0%) 0 0 0 Dementia Alzheimer's type 0 1 (0.3%) 0 1 (0.2%)

Diabetic neuropathy 1 (0.3%) 0 0 0 Dizziness 5 (1.7%) 3 (1.0%) 4 (1.3%) 7 (1.2%) Epilepsy 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Facial paralysis 1 (0.3%) 0 0 0 Haemorrhage intracranial 1 (0.3%) 0 0 0 Haemorrhagic stroke 0 0 1 (0.3%) 1 (0.2%) Headache 8 (2.7%) 10 (3.4%) 7 (2.3%) 17 (2.9%) Hydrocephalus 0 0 1 (0.3%) 1 (0.2%) Hypoaesthesia 2 (0.7%) 0 0 0 Intercostal neuralgia 0 1 (0.3%) 0 1 (0.2%) Lacunar infarction 1 (0.3%) 0 0 0 Lumbar radiculopathy 1 (0.3%) 1 (0.3%) 1 (0.3%) 2 (0.3%) Memory impairment 0 0 1 (0.3%) 1 (0.2%) Neuropathy peripheral 0 0 1 (0.3%) 1 (0.2%) Neurosarcoidosis 0 1 (0.3%) 0 1 (0.2%) Normal pressure hydrocephalus 1 (0.3%) 0 0 0 Occipital neuralgia 0 0 1 (0.3%) 1 (0.2%) Paraesthesia 1 (0.3%) 2 (0.7%) 1 (0.3%) 3 (0.5%) Peripheral nerve palsy 0 1 (0.3%) 0 1 (0.2%) Post herpetic neuralgia 0 1 (0.3%) 1 (0.3%) 2 (0.3%) Sciatica 1 (0.3%) 3 (1.0%) 1 (0.3%) 4 (0.7%) Seizure 2 (0.7%) 0 1 (0.3%) 1 (0.2%) Spinal claudication 0 1 (0.3%) 0 1 (0.2%) Syncope 0 1 (0.3%) 4 (1.3%) 5 (0.8%) Transient ischaemic attack 1 (0.3%) 0 0 0 Vascular dementia 1 (0.3%) 0 0 0 Vertebral artery stenosis 0 0 1 (0.3%) 1 (0.2%) Psychiatric disorders 7 (2.3%) 6 (2.0%) 6 (2.0%) (2.0%) Anxiety 2 (0.7%) 3 (1.0%) 0 (0.5%) Completed suicide 1 (0.3%) 0 0 Depression 2 (0.7%) 2 (0.7%) 3 (1.0%) (0.8%) Euphoric mood 1 (0.3%) 0 0 Insomnia 0 1 (0.3%) 1 (0.3%) (0.3%) Mental status changes 1 (0.3%) 0 0 Sleep disorder 1 (0.3%) 0 1 (0.3%) (0.2%)

Tension 0 0 1 (0.3%) (0.2%) Renal and urinary disorders 21 (7.0%) 13 (4.4%) 10 (3.4%) 23 (3.9%) Acute kidney injury 1 (0.3%) 0 0 0 Bladder pain 0 1 (0.3%) 0 1 (0.2%) Calculus bladder 0 0 1 (0.3%) 1 (0.2%) Calculus urethral 0 0 1 (0.3%) 1 (0.2%) Chronic kidney disease 3 (1.0%) 0 1 (0.3%) 1 (0.2%) Cystitis interstitial 1 (0.3%) 0 0 0 Cystitis noninfective 0 0 1 (0.3%) 1 (0.2%) Diabetic nephropathy 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Dysuria 1 (0.3%) 0 0 0 Glomerulonephritis chronic 1 (0.3%) 0 0 0 Glycosuria 1 (0.3%) 0 0 0 Haematuria 1 (0.3%) 3 (1.0%) 1 (0.3%) 4 (0.7%) Hypertensive nephropathy 1 (0.3%) 0 0 0 Nephrolithiasis 4 (1.3%) 4 (1.4%) 1 (0.3%) 5 (0.8%) Nephropathy 1 (0.3%) 0 0 0 Nephrotic syndrome 0 1 (0.3%) 0 1 (0.2%) Nocturia 0 1 (0.3%) 0 1 (0.2%) Proteinuria 5 (1.7%) 4 (1.4%) 0 4 (0.7%) Renal cyst 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Ureterolithiasis 1 (0.3%) 1 (0.3%) 1 (0.3%) 2 (0.3%) Urethral caruncle 0 0 1 (0.3%) 1 (0.2%) Urinary incontinence 0 1 (0.3%) 1 (0.3%) 2 (0.3%) Urinary retention 1 (0.3%) 0 0 0 Urinary tract discomfort 0 0 1 (0.3%) 1 (0.2%) Urine abnormality 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Reproductive system and breast disorders (2.0%) 3 (1.0%) 6 (2.0%) 9 (1.5%) Benign prostatic hyperplasia (0.3%) 2 (0.7%) 1 (0.3%) 3 (0.5%) Dysmenorrhoea (0.3%) 0 0 0 Genitourinary syndrome of menopause 0 0 1 (0.2%) Gynaecomastia 1 0 0 0 Heavy menstrual bleeding 0 1 (0.3%) 0 1 (0.2%) Infertility 1 0 0 0 Ovarian cyst 1 0 0 0 Pelvic organ prolapse 1 0 0 0 Prostatitis 1 0 0 0 Prostatomegaly 0 0 2 (0.7%) 2 (0.3%) Uterine haemorrhage 0 0 1 (0.3%) 1 (0.2%) Vaginal prolapse 0 0 1 (0.3%) 1 (0.2%) V

ulval eczema 0 0 1 (0.3%) 1 (0.2%) Respiratory, thoracic and mediastinal disorders 18 (6.0%) 21 (7.2%) 11 (3.7%) 32 (5.4%) Asthma 2 (0.7%) 1 (0.3%) 0 1 (0.2%) Bronchitis chronic 0 0 1 (0.3%) 1 (0.2%) Chronic obstructive pulmonary disease 0 1 (0.3%) 1 (0.3%) 2 (0.3%) Cough 7 (2.3%) 6 (2.0%) 3 (1.0%) 9 (1.5%) Dyspnoea 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Dyspnoea exertional 0 0 1 (0.3%) 1 (0.2%) Epistaxis 2 (0.7%) 3 (1.0%) 1 (0.3%) 4 (0.7%) Hypoxia 0 0 1 (0.3%) 1 (0.2%) Interstitial lung disease 1 (0.3%) 0 0 0 Nasal congestion 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Oropharyngeal pain 1 (0.3%) 4 (1.4%) 1 (0.3%) 5 (0.8%) Paranasal sinus hypersecretion 0 1 (0.3%) 0 1 (0.2%) Paranasal sinus mucosal hypertrophy 0 1 (0.3%) 0 1 (0.2%) Pulmonary mass 0 1 (0.3%) 0 1 (0.2%) Respiratory failure 0 0 1 (0.3%) 1 (0.2%) Rhinitis allergic 2 (0.7%) 0 1 (0.3%) 1 (0.2%) Rhinorrhoea 0 1 (0.3%) 0 1 (0.2%) Sleep apnoea syndrome 1 (0.3%) 2 (0.7%) 0 2 (0.3%) Throat irritation 1 (0.3%) 0 0 0

Skin and subcutaneous tissue disorders 11 (3.7%) 10 (3.4%) 10 (3.4%) 20 (3.4%) Acne 0 1 (0.3%) 0 1 (0.2%) Actinic keratosis 0 2 (0.7%) 0 2 (0.3%) Cutaneous symptom 0 0 1 (0.3%) 1 (0.2%) Dermatitis 3 (1.0%) 0 0 0 Dermatitis allergic 1 (0.3%) 0 0 0 Dermatitis contact 0 0 1 (0.3%) 1 (0.2%) Diabetic foot 0 1 (0.3%) 0 1 (0.2%) Dry skin 0 1 (0.3%) 0 1 (0.2%) Eczema 1 (0.3%) 1 (0.3%) 2 (0.7%) 3 (0.5%) Eczema asteatotic 1 (0.3%) 0 0 0 Hyperkeratosis 1 (0.3%) 0 0 0 Miliaria 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Photosensitivity reaction 0 0 1 (0.3%) 1 (0.2%) Pruritus 0 2 (0.7%) 0 2 (0.3%) Rash 0 1 (0.3%) 3 (1.0%) 4 (0.7%) Rash macular 0 1 (0.3%) 0 1 (0.2%) Skin irritation 1 (0.3%) 0 0 0

Skin swelling 1 (0.3%) 0 0 0

Skin ulcer 0 0 1 (0.3%) 1 (0.2%) Stasis dermatitis 0 0 2 (0.7%) 2 (0.3%) Urticaria 1 (0.3%) 0 2 (0.7%) 2 (0.3%) Social circumstances 1 (0.3%) 0 0 0 Menopause 1 (0.3%) 0 0 0 Surgical and medical procedures 3 (1.0%) 4 (1.3%) 7 (1.2%) Hernia repair 1 (0.3%) 0 1 (0.2%) Hip arthroplasty 1 (0.3%) 0 1 (0.2%) Medical induction of coma 0 1 (0.3%) 1 (0.2%) Skin neoplasm excision 1 (0.3%) 0 1 (0.2%) Spinal fusion surgery 0 1 (0.3%) 1 (0.2%) Tooth extraction 0 2 (0.7%) 2 (0.3%) Vascular disorders 39 (13.3%) 31 (10.4%) 70 (11.8%)

Aneurysm 1 (0.3%) 0 0 0 Aortic aneurysm 0 1 (0.3%) 0 1 (0.2%) Aortic arteriosclerosis 0 1 (0.3%) 1 (0.3%) 2 (0.3%) Aortic dilatation 1 (0.3%) 0 0 0 Aortic stenosis 0 1 (0.3%) 0 1 (0.2%) Arteriosclerosis 0 2 (0.7%) 0 2 (0.3%) Blood pressure fluctuation 1 (0.3%) 0 0 0 Brachiocephalic arteriosclerosis 0 0 1 (0.3%) 1 (0.2%) Circulatory collapse 1 (0.3%) 0 0 0 Deep vein thrombosis 1 (0.3%) 0 0 0 Embolism venous 0 0 1 (0.3%) 1 (0.2%) Essential hypertension 1 (0.3%) 0 0 0 Flushing 0 1 (0.3%) 0 1 (0.2%) Giant cell arteritis 1 (0.3%) 0 0 0 Hypertension 15 (5.0%) 31 (10.6%) 25 (8.4%) 56 (9.5%) Hypertensive crisis 0 1 (0.3%) 0 1 (0.2%) Hypertensive emergency 1 (0.3%) 0 0 0 Hypertensive urgency 1 (0.3%) 0 0 0 Hypotension 0 1 (0.3%) 0 1 (0.2%) Ischaemia 1 (0.3%) 0 0 0 Peripheral arterial occlusive disease 0 0 1 (0.3%) 1 (0.2%) Peripheral artery occlusion 0 0 1 (0.3%) 1 (0.2%) Peripheral vascular disorder 0 0 1 (0.3%) 1 (0.2%) Scalp haematoma 1 (0.3%) 0 0 0

Thro mbophl ebit i s 0 0 1 (0.3%) 1 (0.2%) Vein collapse 1 (0.3%) 0 0 0

Adverse events are sorted by alphabetical order of the MedDRA classification.

A participant is counted only once within each primary SOC and preferred term.

2q4: Aflibercept 2mg administered every 4 weeks.

Table 1-70A. Non-ocular treatment-emergent adverse events: number of participants by primary system organ class and preferred term (safety analysis set)

Population group: Non-China sub-population _

Primary system organ class

Preferred term 2q4 8q8/3 8q8/5 All 8mg MedDRA version 28.0 N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%) Number (%) of participants with at least one such adverse event 177 (64.1%) 165 (62.0%) 168 (64.6%) 333 (63.3%) Blood and lymphatic system disorders 5 (1.8%) 4 (1.5%) 6 (2.3%) 10 (1.9%) Anaemia 2 (0.7%) 1 (0.4%) 3 (1.2%) 4 (0.8%) Blood loss anaemia 0 0 1 (0.4%) 1 (0.2%) Eosinophilia 1 (0.4%) 0 0 0

Iron deficiency anaemia 2 (0.7%) 1 (0.4%) 0 1 (0.2%) Lymphocytosis 0 1 (0.4%) 0 1 (0.2%) Monocytosis 0 1 (0.4%) 0 1 (0.2%) Neutrophilia 0 1 (0.4%) 0 1 (0.2%) Pancytopenia 1 (0.4%) 0 0 0 Platelet disorder 0 0 1 (0.4%) 1 (0.2%) Thrombocytopenia 0 0 1 (0.4%) 1 (0.2%) Thrombocytosis 0 0 1 (0.4%) 1 (0.2%) Cardiac disorders 15 (5.4%) 15 (5.6%) 14 (5.4%) 29 (5.5%) Acute myocardial infarction 1 (0.4%) 0 1 (0.4%) 1 (0.2%) Angina unstable 1 (0.4%) 0 0 0 Aortic valve incompetence 1 (0.4%) 0 0 0

Arrhythmia 0 0 1 (0.4%) 1 (0.2%) Atrial fibrillation 1 (0.4%) 2 (0.8%) 4 (1.5%) 6 (1.1%) Atrial tachycardia 0 1 (0.4%) 0 1 (0.2%) Atrioventricular block first degree 1 (0.4%) 1 (0.4%) 0 1 (0.2%) Bradycardia 0 3 (1.1%) 0 3 (0.6%) Bundle branch block left 2 (0.7%) 1 (0.4%) 0 1 (0.2%) Bundle branch block right 0 0 1 (0.4%) 1 (0.2%) Cardiac failure 0 0 1 (0.4%) 1 (0.2%) Cardiac failure acute 0 1 (0.4%) 0 1 (0.2%) Coronary artery disease 2 (0.7%) 2 (0.8%) 2 (0.8%) 4 (0.8%) Hypertensive heart disease 2 (0.7%) 0 0 0

Left ventricular hypertrophy 0 0 1 (0.4%) 1 (0.2%) Mitral valve incompetence 1 (0.4%) 0 0 0 Mitral valve prolapse 0 1 (0.4%) 0 1 (0.2%) Myocardial infarction 1 (0.4%) 1 (0.4%) 1 (0.4%) 2 (0.4%) Myocardial ischaemia 0 0 1 (0.4%) 1 (0.2%) Palpitations 1 (0.4%) 1 (0.4%) 1 (0.4%) 2 (0.4%) Prinzmetal angina 0 1 (0.4%) 0 1 (0.2%) Sinus bradycardia 2 (0.7%) 1 (0.4%) 1 (0.4%) 2 (0.4%) Sinus tachycardia 1 (0.4%) 0 0 0 Tachycardia 2 (0.7%) 0 2 (0.8%) 2 (0.4%) Ventricular extrasystoles 0 1 (0.4%) 0 1 (0.2%) Congenital, familial and genetic disorders 0 2 (0.8%) 1 (0.4%) 3 (0.6%) Aberrant aortic arch 0 0 1 (0.4%) 1 (0.2%) Factor V Leiden mutation 0 1 (0.4%) 0 1 (0.2%) Thalassaemia 0 1 (0.4%) 0 1 (0.2%) Ear and labyrinth disorders 4 (1.4%) 6 (2.3%) 9 (3.5%) 15 (2.9%) Deafness 1 (0.4%) 0 0 0 Deafness transitory 0 0 1 (0.4%) 1 (0.2%) Ear inflammation 0 0 1 (0.4%) 1 (0.2%) Ear pain 1 (0.4%) 0 0 0 Presbyacusis 0 1 (0.4%) 0 1 (0.2%) Vertigo 2 (0.7%) 5 (1.9%) 6 (2.3%) 11 (2.1%) Vertigo positional 0 0 1 (0.4%) 1 (0.2%) Endocrine disorders 1 (0.4%) 1 (0.4%) 1 (0.4%) 2 (0.4%) Goitre 0 1 (0.4%) 0 1 (0.2%) Hypothyroidism 0 0 1 (0.4%) 1 (0.2%) Thyroid mass 1 (0.4%) 0 0 0 Gastrointestinal disorders 35 (12.7%) 24 (9.0%) 23 (8.8%) 47 (8.9%) Abdominal discomfort 1 (0.4%) 0 0 0 Abdominal hernia 1 (0.4%) 0 0 0 Abdominal pain 1 (0.4%) 0 0 0 Abdominal pain upper 3 (1.1%) 1 (0.4%) 1 (0.4%) 2 (0.4%) Burning mouth syndrome 1 (0.4%) 0 0 0 Chronic gastritis 0 1 (0.4%) 1 (0.4%) 2 (0.4%) Constipation 3 (1.1%) 3 (1.1%) 1 (0.4%) 4 (0.8%) Crohn's disease 0 0 1 (0.4%) 1 (0.2%) Dental caries 3 (1.1%) 1 (0.4%) 4 (1.5%) 5 (1.0%) Diarrhoea 4 (1.4%) 3 (1.1%) 1 (0.4%) 4 (0.8%) Diverticulum 0 0 1 (0.4%) 1 (0.2%) Diverticulum intestinal 0 0 1 (0.4%) 1 (0.2%) Diverticulum intestinal haemorrhagic 1 (0.4%) 0 0 0 Duodenal stenosis 0 1 (0.4%) 0 1 (0.2%) Duodenal ulcer 0 0 1 (0.4%) 1 (0.2%) Duodenogastric reflux 0 0 1 (0.4%) 1 (0.2%) Dyspepsia 1 (0.4%) 0 0 0 Dysphagia 0 1 (0.4%) 1 (0.4%) 2 (0.4%) Femoral hernia incarcerated 0 1 (0.4%) 0 1 (0.2%) Food poisoning 1 (0.4%) 0 1 (0.4%) 1 (0.2%) Gastritis 0 0 1 (0.4%) 1 (0.2%) Gastrointestinal disorder 2 (0.7%) 0 0 0 Gastrooesophageal reflux disease 1 (0.4%) 2 (0.8%) 1 (0.4%) 3 (0.6%) Glossitis 0 1 (0.4%) 0 1 (0.2%) Haemorrhoids 1 (0.4%) 0 2 (0.8%) 2 (0.4%)

Hiatus hernia 0 1 (0.4%) 0 1 (0.2%) Irritable bowel syndrome 2 (0.7%) 1 (0.4%) 0 1 (0.2%) Large intestine polyp 1 (0.4%) 0 0 0 Lower gastrointestinal haemorrhage 0 1 (0.4%) 0 1 (0.2%) Nausea 5 (1.8%) 4 (1.5%) 3 (1.2%) 7 (1.3%) Noninfective gingivitis 1 (0.4%) 0 0 0 Oesophagitis 1 (0.4%) 0 0 0 Pancreatic disorder 0 0 1 (0.4%) 1 (0.2%) Periodontal disease 2 (0.7%) 0 0 0 Pulpless tooth 0 1 (0.4%) 0 1 (0.2%) Small intestinal obstruction 1 (0.4%) 0 0 0 Stomatitis 1 (0.4%) 0 1 (0.4%) 1 (0.2%) Toothache 2 (0.7%) 1 (0.4%) 2 (0.8%) 3 (0.6%) Vomiting 5 (1.8%) 1 (0.4%) 1 (0.4%) 2 (0.4%) General disorders and administration site conditions 12 (4.3%) 17 (6.4%) 8 (3.1%) 25 (4.8%) Application site hypersensitivity 0 1 (0.4%) 0 1 (0.2%) Asthenia 0 0 1 (0.4%) 1 (0.2%) Catheter site pain 0 1 (0.4%) 0 1 (0.2%) Chest pain 2 (0.7%) 4 (1.5%) 1 (0.4%) 5 (1.0%) Chills 1 (0.4%) 0 0 0 Fatigue 0 0 1 (0.4%) 1 (0.2%) Gait disturbance 0 0 1 (0.4%) 1 (0.2%) General physical health deterioration 1 (0.4%) 0 0 0 Hernia 1 (0.4%) 0 0 0 Incarcerated hernia 1 (0.4%) 0 0 0 Influenza like illness 0 2 (0.8%) 1 (0.4%) 3 (0.6%) Injection site bruising 0 1 (0.4%) 0 1 (0.2%) Malaise 1 (0.4%) 2 (0.8%) 1 (0.4%) 3 (0.6%) Mass 0 0 1 (0.4%) 1 (0.2%) Oedema 0 1 (0.4%) 0 1 (0.2%) Oedema due to renal disease 1 (0.4%) 0 0 0 Oedema peripheral 3 (1.1%) 4 (1.5%) 0 4 (0.8%) Peripheral swelling 0 1 (0.4%) 0 1 (0.2%) Pyrexia 3 (1.1%) 3 (1.1%) 1 (0.4%) 4 (0.8%) Hepatobiliary disorders 4 (1.4%) 2 (0.8%) 5 (1.9%) 7 (1.3%) Biliary colic 0 0 1 (0.4%) 1 (0.2%) Cholecystitis 1 (0.4%) 0 0 0 Cholecystitis acute 0 1 (0.4%) 0 1 (0.2%) Cholecystitis chronic 0 0 1 (0.4%) 1 (0.2%) Cholelithiasis 1 (0.4%) 0 0 0 Hepatic cyst 0 1 (0.4%) 0 1 (0.2%) Hepatic steatosis 3 (1.1%) 0 3 (1.2%) 3 (0.6%) Metabolic dysfunction-associated liver disease 0 0 1 (0.4%) 1 (0.2%) Immune system disorders 7 (2.5%) 6 (2.3%) 4 (1.5%) 10 (1.9%) Allergy to arthropod sting 1 (0.4%) 1 (0.4%) 0 1 (0.2%) Allergy to chemicals 0 1 (0.4%) 0 1 (0.2%) Anaphylactic reaction 0 1 (0.4%) 0 1 (0.2%) Contrast media reaction 1 (0.4%) 0 0 0 Drug hypersensitivity 1 (0.4%) 1 (0.4%) 0 1 (0.2%) Hypersensitivity 0 0 1 (0.4%) 1 (0.2%) Multiple allergies 1 (0.4%) 0 0 0 Seasonal allergy 3 (1.1%) 2 (0.8%) 3 (1.2%) 5 (1.0%) Infections and infestations 90 (32.6%) 78 (29.3%) 89 (34.2%) 167 (31.7%) Abdominal abscess 1 (0.4%) 0 0 0 Acute sinusitis 1 (0.4%) 1 (0.4%) 0 1 (0.2%) Appendicitis 0 0 1 (0.4%) 1 (0.2%) Arthritis infective 1 (0.4%) 0 0 0 Asymptomatic bacteriuria 1 (0.4%) 0 0 0 Atypical pneumonia 2 (0.7%) 0 0 0 Bacterial urethritis 1 (0.4%) 0 0 0 Bacterial vaginosis 0 0 1 (0.4%) 1 (0.2%) Borrelia infection 0 0 1 (0.4%) 1 (0.2%) Bronchitis 4 (1.4%) 5 (1.9%) 7 (2.7%) 12 (2.3%) COVID-19 9 (3.3%) 17 (6.4%) 12 (4.6%) 29 (5.5%)

Candida infection 1 (0.4%) 0 0 0 Cellulitis 0 1 (0.4%) 0 1 (0.2%) Chronic hepatitis C 0 0 1 (0.4%) 1 (0.2%) Chronic sinusitis 0 0 1 (0.4%) 1 (0.2%) Colonic abscess 0 0 1 (0.4%) 1 (0.2%) Coronavirus infection 3 (1.1%) 0 0 0 Cystitis 1 (0.4%) 0 2 (0.8%) 2 (0.4%) Diverticulitis 0 3 (1.1%) 2 (0.8%) 5 (1.0%) Ear infection 1 (0.4%) 0 1 (0.4%) 1 (0.2%) Enterocolitis infectious 1 (0.4%) 0 0 0 Epididymitis 0 0 1 (0.4%) 1 (0.2%) Erysipelas 1 (0.4%) 0 0 0 Escherichia urinary tract infection 1 (0.4%) 0 0 0 Folliculitis 0 0 1 (0.4%) 1 (0.2%) Fungal infection 0 1 (0.4%) 0 1 (0.2%) Fungal skin infection 0 0 2 (0.8%) 2 (0.4%) Gastroenteritis 2 (0.7%) 2 (0.8%) 0 2 (0.4%) Gastroenteritis viral 0 0 2 (0.8%) 2 (0.4%) Gingivitis 1 (0.4%) 1 (0.4%) 0 1 (0.2%) Helicobacter infection 0 1 (0.4%) 0 1 (0.2%) Herpes dermatitis 1 (0.4%) 0 0 0 Herpes simplex 0 0 1 (0.4%) 1 (0.2%) Herpes virus infection 1 (0.4%) 0 0 0 Herpes zoster 6 (2.2%) 2 (0.8%) 3 (1.2%) 5 (1.0%) Impetigo 0 0 1 (0.4%) 1 (0.2%) Infected cyst 0 1 (0.4%) 0 1 (0.2%) Infected dermal cyst 0 1 (0.4%) 1 (0.4%) 2 (0.4%) Infectious pleural effusion 0 1 (0.4%) 0 1 (0.2%) Influenza 13 (4.7%) 11 (4.1%) 6 (2.3%) 17 (3.2%) Localised infection 0 1 (0.4%) 0 1 (0.2%) Lower respiratory tract infection 0 0 1 (0.4%) 1 (0.2%) Nasopharyngitis 19 (6.9%) 25 (9.4%) 27 (10.4%) 52 (9.9%) Onychomycosis 0 0 1 (0.4%) 1 (0.2%) Oral candidiasis 0 1 (0.4%) 0 1 (0.2%) Oral herpes 2 (0.7%) 2 (0.8%) 1 (0.4%) 3 (0.6%) Oropharyngeal candidiasis 0 0 1 (0.4%) 1 (0.2%) Osteomyelitis 1 (0.4%) 0 1 (0.4%) 1 (0.2%) Otitis externa 0 1 (0.4%) 1 (0.4%) 2 (0.4%) Paronychia 0 0 1 (0.4%) 1 (0.2%) Periodontitis 2 (0.7%) 3 (1.1%) 1 (0.4%) 4 (0.8%) Pharyngitis 0 3 (1.1%) 1 (0.4%) 4 (0.8%) Pharyngitis streptococcal 1 (0.4%) 0 0 0 Pneumonia 4 (1.4%) 5 (1.9%) 4 (1.5%) 9 (1.7%) Pneumonia aspiration 1 (0.4%) 0 0 0 Pneumonia parainfluenzae viral 0 0 1 (0.4%) 1 (0.2%) Pneumonia pseudomonal 0 0 1 (0.4%) 1 (0.2%) Pulpitis dental 1 (0.4%) 0 0 0 Respiratory syncytial virus infection 0 0 1 (0.4%) 1 (0.2%) Respiratory tract infection 1 (0.4%) 1 (0.4%) 0 1 (0.2%) Rhinitis 1 (0.4%) 1 (0.4%) 1 (0.4%) 2 (0.4%) Sepsis 0 2 (0.8%) 1 (0.4%) 3 (0.6%) Sinusitis 5 (1.8%) 3 (1.1%) 4 (1.5%) 7 (1.3%) Tinea cruris 1 (0.4%) 0 0 0 Tinea pedis 0 0 1 (0.4%) 1 (0.2%) Tonsillitis 1 (0.4%) 1 (0.4%) 2 (0.8%) 3 (0.6%) Tooth abscess 1 (0.4%) 1 (0.4%) 0 1 (0.2%) Tooth infection 2 (0.7%) 0 1 (0.4%) 1 (0.2%) Upper respiratory tract infection 7 (2.5%) 6 (2.3%) 1 (0.4%) 7 (1.3%) Urinary tract infection 13 (4.7%) 8 (3.0%) 15 (5.8%) 23 (4.4%) Vaginal infection 0 0 1 (0.4%) 1 (0.2%) Viral infection 2 (0.7%) 1 (0.4%) 3 (1.2%) 4 (0.8%) Viral rhinitis 0 0 1 (0.4%) 1 (0.2%) Viral upper respiratory tract infection 0 0 1 (0.4%) 1 (0.2%) Wound infection 2 (0.7%) 0 0 0 Injury, poisoning and procedural complications 20 (7.2%) 16 (6.0%) 18 (6.9%) 34 (6.5%) Abdominal injury 1 (0.4%) 0 0 0 Animal bite 0 1 (0.4%) 1 (0.2%) Bone contusion 0 1 (0.4%) 1 (0.2%)

Brain herniation 0 0 1 (0.4%) 1 (0.2%) Cartilage injury⁷ 0 0 1 (0.4%) 1 (0.2%) Contusion 0 2 (0.8%) 4 (1.5%) 6 (1.1%) Fall 3 (1.1%) 2 (0.8%) 4 (1.5%) 6 (1.1%) Foot fracture 2 (0.7%) 0 0 0 Fractured coccyx 0 1 (0.4%) 0 1 (0.2%) Hand fracture 0 1 (0.4%) 0 1 (0.2%) Head injury 1 (0.4%) 0 0 0 Humerus fracture 1 (0.4%) 0 1 (0.4%) 1 (0.2%) Injury 1 (0.4%) 0 0 0

Joint dislocation 1 (0.4%) 0 0 0

Joint injury 0 0 1 (0.4%) 1 (0.2%) Ligament sprain 1 (0.4%) 0 2 (0.8%) 2 (0.4%) Limb injury 2 (0.7%) 2 (0.8%) 0 2 (0.4%) Meniscus injury' 1 (0.4%) 1 (0.4%) 0 1 (0.2%) Mouth injury 1 (0.4%) 0 0 0 Multiple injuries 1 (0.4%) 0 0 0 Muscle strain 0 1 (0.4%) 0 1 (0.2%) Oral contusion 1 (0.4%) 0 0 0 Overdose 1 (0.4%) 0 0 0 Pelvic fracture 1 (0.4%) 0 0 0 Periorbital haemorrhage 1 (0.4%) 0 0 0

Post procedural swelling 1 (0.4%) 0 0 0 Postoperative thoracic procedure complication 0 1 (0.4%) 0 1 (0.2%) Procedural nausea 0 1 (0.4%) 0 1 (0.2%) Procedural pain 3 (1.1%) 0 2 (0.8%) 2 (0.4%) Rib fracture 0 1 (0.4%) 1 (0.4%) 2 (0.4%) Skin abrasion 1 (0.4%) 0 0 0

Skin laceration 0 1 (0.4%) 1 (0.4%) 2 (0.4%) Snake bite 0 1 (0.4%) 0 1 (0.2%) Subdural haematoma 0 0 1 (0.4%) 1 (0.2%) Tendon rupture 0 0 1 (0.4%) 1 (0.2%) Tooth fracture 0 0 1 (0.4%) 1 (0.2%) Upper limb fracture 0 1 (0.4%) 0 1 (0.2%) Wrist fracture 1 (0.4%) 0 0 0 Investigations 18 (6.5%) 29 (10.9%) 24 (9.2%) 53 (10.1%) Alanine aminotransferase increased 0 2 (0.8%) 1 (0.4%) 3 (0.6%) Aspartate aminotransferase increased 0 2 (0.8%) 1 (0.4%) 3 (0.6%) Bacterial test positive 0 0 1 (0.4%) 1 (0.2%) Blood alkaline phosphatase abnormal 1 (0.4%) 0 0 0 Blood alkaline phosphatase increased 0 1 (0.4%) 1 (0.4%) 2 (0.4%) Blood cholesterol increased 1 (0.4%) 2 (0.8%) 1 (0.4%) 3 (0.6%) Blood creatine increased 1 (0.4%) 0 0 0 Blood creatine phosphokinase increased 4 (1.4%) 3 (1.1%) 4 (1.5%) 7 (1.3%) Blood creatinine decreased 0 0 1 (0.4%) 1 (0.2%) Blood glucose increased 1 (0.4%) 0 0 0 Blood iron decreased 0 0 1 (0.4%) 1 (0.2%) Blood potassium increased 0 0 1 (0.4%) 1 (0.2%) Blood pressure diastolic increased 1 (0.4%) 2 (0.8%) 2 (0.8%) 4 (0.8%) Blood pressure increased 2 (0.7%) 3 (1.1%) 4 (1.5%) 7 (1.3%) Blood pressure systolic increased 1 (0.4%) 0 1 (0.4%) 1 (0.2%) Blood triglycerides increased 1 (0.4%) 2 (0.8%) 0 2 (0.4%) Blood urea increased 1 (0.4%) 1 (0.4%) 0 1 (0.2%) Blood urine present 1 (0.4%) 1 (0.4%) 3 (1.2%) 4 (0.8%) Creatine urine increased 0 1 (0.4%) 0 1 (0.2%) Creatinine urine decreased 1 (0.4%) 0 0 0 Creatinine urine increased 0 0 1 (0.4%) 1 (0.2%) Electrocardiogram QT prolonged 0 0 1 (0.4%) 1 (0.2%) Electrocardiogram ST segment depression 0 1 (0.4%) 0 1 (0.2%) Electrocardiogram T wave abnormal 0 0 1 (0.4%) 1 (0.2%) Fungal test positive 0 0 1 (0.4%) 1 (0.2%) Glucose urine 0 0 1 (0.4%) 1 (0.2%) Glucose urine present 0 0 1 (0.4%) 1 (0.2%) Glycosylated haemoglobin increased 2 (0.7%) 3 (1.1%) 4 (1.5%) 7 (1.3%) Haematocrit decreased 1 (0.4%) 0 1 (0.4%) 1 (0.2%) Haematocrit increased 0 0 1 (0.4%) 1 (0.2%) Haemoglobin decreased 1 (0.4%) 0 1 (0.4%) 1 (0.2%) Heart rate increased 0 1 (0.4%) 0 1 (0.2%)

Hepatic enzyme increased 0 1 (0.4%) 0 1 (0.2%) Interferon gamma release assay positive 0 1 (0.4%) 0 1 (0.2%) Liver function test abnormal 0 0 1 (0.4%) 1 (0.2%) Liver function test increased 0 1 (0.4%) 0 1 (0.2%) Low density' lipoprotein increased 0 0 1 (0.4%) 1 (0.2%) Mean cell haemoglobin decreased 0 0 1 (0.4%) 1 (0.2%) Mean cell volume abnormal 0 1 (0.4%) 0 1 (0.2%) Monocyte count increased 1 (0.4%) 1 (0.4%) 0 1 (0.2%) Neutrophil count increased 0 1 (0.4%) 0 1 (0.2%) Nitrite urine present 0 0 1 (0.4%) 1 (0.2%) Platelet count decreased 1 (0.4%) 0 0 0 Protein urine present 2 (0.7%) 1 (0.4%) 1 (0.4%) 2 (0.4%) Red blood cell count decreased 1 (0.4%) 0 0 0

Red blood cells urine 0 1 (0.4%) 0 1 (0.2%) Red blood cells urine positive 0 0 1 (0.4%) 1 (0.2%) Reticulocyte count increased 0 0 1 (0.4%) 1 (0.2%) Urinary sediment present 1 (0.4%) 1 (0.4%) 1 (0.4%) 2 (0.4%) Urine analysis abnormal 1 (0.4%) 1 (0.4%) 1 (0.4%) 2 (0.4%) Urine ketone body present 1 (0.4%) 0 0 0 Urine protein/creatinine ratio increased 4 (1.4%) 1 (0.4%) 1 (0.4%) 2 (0.4%) Urine transitional cells present 0 0 1 (0.4%) 1 (0.2%) Weight decreased 0 1 (0.4%) 0 1 (0.2%) Weight increased 1 (0.4%) 0 0 0 White blood cell count increased 0 2 (0.8%) 0 2 (0.4%) White blood cells urine positive 1 (0.4%) 1 (0.4%) 1 (0.4%) 2 (0.4%) Metabolism and nutrition disorders 29 (10.5%) 15 (5.6%) 24 (9.2%) 39 (7.4%) Acidosis 0 0 1 (0.4%) 1 (0.2%) Dehydration 1 (0.4%) 0 0 0 Diabetes mellitus 1 (0.4%) 2 (0.8%) 2 (0.8%) 4 (0.8%) Dyslipidaemia 2 (0.7%) 0 3 (1.2%) 3 (0.6%) Glucose tolerance impaired 0 2 (0.8%) 0 2 (0.4%) Gout 3 (1.1%) 0 1 (0.4%) 1 (0.2%) Hypercholesterolaemia 5 (1.8%) 5 (1.9%) 8 (3.1%) 13 (2.5%) Hyperglycaemi a 0 0 1 (0.4%) 1 (0.2%) Hyperkalaemia 0 1 (0.4%) 0 1 (0.2%) Hyperlipidaemia 7 (2.5%) 3 (1.1%) 3 (1.2%) 6 (1.1%) Hy'pertriglyceridaemia 1 (0.4%) 0 1 (0.4%) 1 (0.2%) Hy'peruricaemia 2 (0.7%) 1 (0.4%) 0 1 (0.2%) Hy'pervolaemia 0 0 1 (0.4%) 1 (0.2%) Hy'pogly caemia 2 (0.7%) 0 0 0 Hy'pokalaemia 1 (0.4%) 2 (0.8%) 0 2 (0.4%) Hyponatraemia 1 (0.4%) 1 (0.4%) 1 (0.4%) 2 (0.4%) Hypovolaemia 0 0 1 (0.4%) 1 (0.2%) Lipid metabolism disorder 0 1 (0.4%) 0 1 (0.2%) Metabolic syndrome 1 (0.4%) 0 0 0 Obesity- 0 0 1 (0.4%) 1 (0.2%) Overweight 1 (0.4%) 0 0 0 Type 2 diabetes mellitus 4 (1.4%) 1 (0.4%) 5 (1.9%) 6 (1.1%) Vitamin B complex deficiency 0 0 1 (0.4%) 1 (0.2%)

Vitamin D deficiency 0 1 (0.4%) 1 (0.4%) 2 (0.4%) Musculoskeletal and connective tissue disorders 30 (10.9%) 34 (12.8%) 23 (8.8%) 57 (10.8%) Arthralgia 7 (2.5%) 6 (2.3%) 6 (2.3%) 12 (2.3%) Arthritis 1 (0.4%) 3 (1.1%) 1 (0.4%) 4 (0.8%) Back pain 6 (2.2%) 3 (1.1%) 5 (1.9%) 8 (1.5%) Bursitis 3 (1.1%) 0 0 0 Dupuytren's contracture 0 0 1 (0.4%) 1 (0.2%) Foot deformity 1 (0.4%) 0 0 0 Gouty tophus 0 0 1 (0.4%) 1 (0.2%) Groin pain 0 1 (0.4%) 0 1 (0.2%) Haemarthrosis 0 0 1 (0.4%) 1 (0.2%) Intervertebral disc compression 1 (0.4%) 0 0 0 Intervertebral disc degeneration 1 (0.4%) 0 0 0 Intervertebral disc disorder 1 (0.4%) 0 0 0

Joint effusion 0 0 1 (0.4%) 1 (0.2%) Joint swelling 0 2 (0.8%) 0 2 (0.4%) Muscle contracture 0 0 1 (0.4%) 1 (0.2%) Muscle disorder 1 (0.4%) 0 0 0

Muscle spasms 2 (0.7%) 0 1 (0.4%) 1 (0.2%) Musculoskeletal pain 1 (0.4%) 0 0 0 Musculoskeletal stiffness 0 0 1 (0.4%) 1 (0.2%) Myalgia 4 (1.4%) 0 0 0 Myositis 1 (0.4%) 0 0 0 Neck pain 0 1 (0.4%) 0 1 (0.2%) Osteoarthritis 5 (1.8%) 2 (0.8%) 3 (1.2%) 5 (1.0%) Osteoporosis 1 (0.4%) 2 (0.8%) 0 2 (0.4%) Pain in extremity 1 (0.4%) 5 (1.9%) 2 (0.8%) 7 (1.3%) Plantar fasciitis 1 (0.4%) 1 (0.4%) 0 1 (0.2%) Rheumatic disorder 1 (0.4%) 0 0 0 Rheumatoid arthritis 0 3 (1.1%) 0 3 (0.6%) Rotator cuff syndrome 0 1 (0.4%) 0 1 (0.2%) Sacroiliitis 0 0 1 (0.4%) 1 (0.2%) Scoliosis 0 2 (0.8%) 0 2 (0.4%) Spinal osteoarthritis 1 (0.4%) 4 (1.5%) 1 (0.4%) 5 (1.0%) Spinal pain 0 0 1 (0.4%) 1 (0.2%) Systemic lupus erythematosus 0 1 (0.4%) 0 1 (0.2%) Temporomandibular pain and dysfunction syndrome 0 1 (0.4%) 0 1 (0.2%) Tendon pain 1 (0.4%) 0 0 0 Tenosynovitis 0 0 1 (0.4%) 1 (0.2%) Vertebral foraminal stenosis 0 1 (0.4%) 0 1 (0.2%) Vertebral lateral recess stenosis 1 (0.4%) 0 0 0 Neoplasms benign, malignant and unspecified (incl cysts and polyps) 9 (3.3%) 3 (1.2%) 10 (1.9%) Basal cell carcinoma 1 (0.4%) 0 0 Benign breast neoplasm 0 0 1 (0.4%) 1 (0.2%) Bladder cancer 0 1 (0.4%) 0 1 (0.2%) Bladder neoplasm 0 1 (0.4%) 0 1 (0.2%) Cancer fatigue 1 (0.4% ) 0 0 0 Colon cancer 0 0 1 (0.4%) 1 (0.2%) Gastrointestinal submucosal tumour 0 1 (0.4%) 0 1 (0.2%) Leiomyoma 1 (0.4%) 0 0 0 Lipoma 1 (0.4%) 1 (0.4%) 0 1 (0.2%) Lung neoplasm malignant 0 0 1 (0.4%) 1 (0.2%) Metastases to lymph nodes 0 0 1 (0.4%) 1 (0.2%) Metastatic neoplasm 1 (0.4%) 0 0 0 Oesophageal carcinoma 0 1 (0.4%) 0 1 (0.2%) Prostate cancer metastatic 0 0 1 (0.4%) 1 (0.2%) Prostate cancer stage II 0 1 (0.4%) 0 1 (0.2%) Seborrhoeic keratosis 1 (0.4%) 0 0 0 Small cell lung cancer 0 1 (0.4%) 0 1 (0.2%) Squamous cell carcinoma 1 (0.4%) 0 0 0 Squamous cell carcinoma of lung 1 (0.4%) 0 0 0 Squamous cell carcinoma of skin 1 (0.4%) 0 0 0 T-cell lymphoma 1 (0.4%) 0 0 0

Uterine leiomyoma 0 1 (0.4%) 0 1 (0.2%) Nervous system disorders 24 (8.7%) 28 (10.5%) 23 (8.8%) 1 (9.7%) Amnesia 0 1 (0.4%) 0 1 (0.2%) Atypical migraine 1 (0.4%) 0 0 0 Carotid arteriosclerosis 0 1 (0.4%) 0 1 (0.2%) Carotid artery disease 0 0 1 (0.4%) 1 (0.2%) Carotid artery occlusion 1 (0.4%) 0 0 0 Carotid artery stenosis 1 (0.4%) 0 1 (0.4%) 1 (0.2%) Carpal tunnel syndrome 0 1 (0.4%) 0 1 (0.2%) Cerebellar infarction 1 (0.4%) 0 0 0 Cerebellar stroke 1 (0.4%) 0 0 0 Cerebral infarction 1 (0.4%) 0 1 (0.4%) 1 (0.2%) Cerebrovascular accident 1 (0.4%) 0 0 0 Cerebrovascular disorder 0 1 (0.4%) 0 1 (0.2%) Cervical radiculopathy 1 (0.4%) 2 (0.8%) 0 2 (0.4%) Cognitive disorder 0 0 1 (0.4%) 1 (0.2%) Dementia 3 (1.1%) 0 0 0 Dementia Alzheimer's type 0 1 (0.4%) 0 1 (0.2%) Dizziness 5 (1.8%) 3 (1.1%) 4 (1.5%) 7 (1.3%) Epilepsy 1 (0.4%) 1 (0.4%) 0 1 (0.2%) Facial paralysis 1 (0.4%) 0 0 0 Haemorrhage intracranial 1 (0.4%) 0 0 0 Haemorrhagic stroke o 1 (0.4%) 1 (0.2%) Headache (2.9%) 10 (3.8%) 6 (2.3%) 16 (3.0%) Hydrocephalus 0 1 (0.4%) 1 (0.2%) Hypoaesthesia (0.7%) 0 0 0 Intercostal neuralgia 1 (0.4%) 0 1 (0.2%) Lacunar infarction (0.4%) 0 0 0 Lumbar radiculopathy (0.4%) 1 (0.4%) 1 (0.4%) (0.4%) Memory' impairment 0 1 (0.4%) 1 (0.2%) Neuropathy peripheral 0 1 (0.4%) 1 (0.2%) Neurosarcoidosis 1 (0.4%) 0 1 (0.2%) Normal pressure hydrocephalus (0.4%) 0 0 0 Occipital neuralgia 0 1 (0.4%) 1 (0.2%) Paraesthesia (0.4%) 2 (0.8%) 1 (0.4%) 3 (0.6%) Peripheral nerve palsy 1 (0.4%) 0 1 (0.2%) Post herpetic neuralgia 1 (0.4%) 0 1 (0.2%) Sciatica (0.4%) 3 (1.1%) 1 (0.4%) 4 (0.8%) Seizure (0.7%) 0 1 (0.4%) 1 (0.2%) Spinal claudication 1 (0.4%) 0 1 (0.2%) Syncope 1 (0.4%) 4 (1.5%) 5 (1.0%) Transient ischaemic attack (0.4%) 0 0 0 Vascular dementia (0.4%) 0 0 0 Vertebral artery stenosis 0 1 (0.4%) 1 (0.2%) Psychiatric disorders 7 (2.5%) 6 (2.3%) 11 (2.1%) Anxiety 2 (0.7%) 0 2 (0.4%) Completed suicide 1 (0.4%) 0 0 Depression 2 (0.7%) 3 (1.2%) 5 (1.0%) Euphoric mood 1 (0.4%) 0 0 Insomnia 0 1 (0.4%) 1 (0.4%) 2 (0.4%) Mental status changes 1 (0.4%) 0 0 0 Sleep disorder 1 (0.4%) 0 1 (0.4%) 1 (0.2%) Tension 0 0 1 (0.4%) 1 (0.2%) Renal and urinary' disorders 17 (6.2%) 13 (4.9%) 10 (3.8%) 23 (4.4%) Acute kidney' injury 1 (0.4%) 0 0 0 Bladder pain 0 1 (0.4%) 0 1 (0.2%) Calculus bladder 0 0 1 (0.4%) (0.2%) Calculus urethral 0 0 1 (0.4%) (0.2%) Chronic kidney disease 3 (1.1%) 0 1 (0.4%) (0.2%) Cystitis interstitial 1 (0.4%) 0 0 Cystitis noninfective 0 0 1 (0.4%) (0.2%) Diabetic nephropathy 0 0 1 (0.4%) (0.2%) Dysuria 1 (0.4%) 0 0 Glycosuria 1 (0.4%) 0 0 Haematuria 1 (0.4%) 3 (1.1%) 1 (0.4%) (0.8%) Nephrolithiasis 3 (1.1%) 4 (1.5%) 1 (0.4%) (1.0%) Nephropathy 1 (0.4%) 0 0 Nephrotic syndrome 0 1 (0.4%) 0 (0.2%) Nocturia 0 1 (0.4%) 0 (0.2%) Proteinuria 5 (1.8%) 4 (1.5%) 0 (0.8%) Renal cyst 1 (0.4%) 1 (0.4%) 0 (0.2%) Ureterolithiasis 1 (0.4%) 1 (0.4%) 1 (0.4%) (0.4%) Urethral caruncle 0 0 1 (0.4%) (0.2%) Urinary incontinence 0 1 (0.4%) 1 (0.4%) (0.4%) Urinary retention 1 (0.4%) 0 0 Urinary tract discomfort 0 0 1 (0.4%) (0.2%)

Urine abnormality 0 0 1 (0.4%) (0.2%) Reproductive system and breast disorders 6 (2.2%) 3 (1.1%) 6 (2.3%) 9 (1.7%) Benign prostatic hyperplasia 1 (0.4%) 2 (0.8%) 1 (0.4%) 3 (0.6%) Dysmenorrhoea 1 (0.4%) 0 0 0 Genitourinary syndrome of menopause 0 0 1 (0.4%) 1 (0.2%) Gynaecomastia 1 (0.4%) 0 0 0 Heavy' menstrual bleeding 0 1 (0.4%) 0 1 (0.2%) Infertility 1 (0.4%) 0 0 0 Ovarian cyst 1 (0.4%) 0 0 0 Pelvic organ prolapse 1 (0.4%) 0 0 0 Prostatitis 1 (0.4%) 0 0 0 Prostat omegaly 2 (0.8%) 2 (0.4%) Uterine haemorrhage 1 (0.4%) 1 (0.2%) Vaginal prolapse 1 (0.4%) 1 (0.2%) V

ulval eczema 1 (0.4%) 1 (0.2%) Respiratory, thoracic and mediastinal disorders 17 (6.2%) 18 (6.8%) 10 (3.8%) 28 (5.3%) Asthma 2 (0.7%) 1 (0.4%) 0 1 (0.2%) Chronic obstructive pulmonary disease 0 1 (0.4%) 1 (0.4%) 2 (0.4%) Cough 7 (2.5%) 4 (1.5%) 3 (1.2%) 7 (1.3%) Dyspnoea 1 (0.4%) 1 (0.4%) 0 1 (0.2%) Dyspnoea exertional 0 0 1 (0.4%) 1 (0.2%) Epistaxis 2 (0.7%) 3 (1.1%) 1 (0.4%) 4 (0.8%) Hypoxia 0 0 1 (0.4%) 1 (0.2%) Interstitial lung disease 1 (0.4%) 0 0 0 Nasal congestion 1 (0.4%) 0 1 (0.4%) 1 (0.2%) Oropharyngeal pain 1 (0.4%) 4 (1.5%) 1 (0.4%) 5 (1.0%) Paranasal sinus hypersecretion 0 1 (0.4%) 0 1 (0.2%) Paranasal sinus mucosal hypertrophy 0 1 (0.4%) 0 1 (0.2%) Respiratory failure 0 0 1 (0.4%) 1 (0.2%) Rhinitis allergic 2 (0.7%) 0 1 (0.4%) 1 (0.2%) Rhinorrhoea 0 1 (0.4%) 0 1 (0.2%) Sleep apnoea syndrome 1 (0.4%) 2 (0.8%) 0 2 (0.4%) Skin and subcutaneous tissue disorders 10 (3.6%) 10 (3.8%) 8 (3.1%) 18 (3.4%) Acne 0 1 (0.4%) 0 1 (0.2%) Actinic keratosis 0 2 (0.8%) 0 2 (0.4%) Cutaneous symptom 0 0 1 (0.4%) 1 (0.2%) Dermatitis 3 (1.1%) 0 0 0 Dermatitis contact 0 0 1 (0.4%) 1 (0.2%) Diabetic foot 0 1 (0.4%) 0 1 (0.2%) Dry skin 0 1 (0.4%) 0 1 (0.2%) Eczema 1 (0.4%) 1 (0.4%) 1 (0.4%) 2 (0.4%) Eczema asteatotic 1 (0.4%) 0 0 0 Hyperkeratosis 1 (0.4%) 0 0 0 Miliaria 1 (0.4%) 1 (0.4%) 0 1 (0.2%) Photosensitivity reaction 0 0 1 (0.4%) 1 (0.2%) Pruritus 0 2 (0.8%) 0 2 (0.4%) Rash 0 1 (0.4%) 2 (0.8%) 3 (0.6%) Rash macular 0 1 (0.4%) 0 1 (0.2%) Skin irritation 1 (0.4%) 0 0 0

Skin swelling 1 (0.4%) 0 0 0

Skin ulcer 0 0 1 (0.4%) 1 (0.2%) Stasis dermatitis 0 0 1 (0.4%) 1 (0.2%) Urticaria 1 (0.4%) 0 2 (0.8%) 2 (0.4%) Social circumstances 1 (0.4%) 0 0 o Menopause 1 (0.4%) 0 0 o Surgical and medical procedures 0 3 (1.1%) 4 (1.5%) 7 (1.3%) Hernia repair 0 1 (0.4%) 0 1 (0.2%) Hip arthroplasty 0 1 (0.4%) 0 1 (0.2%) Medical induction of coma 0 0 1 (0.4%) 1 (0.2%) Skin neoplasm excision 0 1 (0.4%) 0 1 (0.2%) Spinal fusion surgery 0 0 1 (0.4%) 1 (0.2%) Tooth extraction 0 0 2 (0.8%) 2 (0.4%) Vascular disorders 22 (8.0%) 39 (14.7%) 28 (10.8%) 67 (12.7%) Aneurysm 1 (0.4%) 0 0 0 Aortic aneurysm 0 1 (0.4%) 0 1 (0.2%) Aortic arteriosclerosis 0 1 (0.4%) 0 1 (0.2%) Aortic dilatation 1 (0.4%) 0 0 0 Aortic stenosis 0 1 (0.4%) 0 1 (0.2%) Arteriosclerosis 0 2 (0.8%) 0 2 (0.4%) Blood pressure fluctuation 1 (0.4%) 0 0 0 Brachiocephalic arteriosclerosis 0 0 1 (0.4%) 1 (0.2%) Circulatory collapse 1 (0.4%) 0 0 0 Deep vein thrombosis 1 (0.4%) 0 0 0 Embolism venous 0 0 1 (0.4%) 1 (0.2%)

Essential hypertension 1 (0.4%) 0 0 0 Flushing 0 1 (0.4%) 0 1 (0.2%) Giant cell arteritis 1 (0.4%) 0 0 0 Hypertension 15 (5.4%) 31 (11.7%) 23 (8.8%) 54 (10.3%) Hypertensive crisis 0 1 (0.4%) 0 1 (0.2%) Hypertensive emergency 1 (0.4%) 0 0 0 Hypertensive urgency 1 (0.4%) 0 0 0 Hypotension 0 1 (0.4%) 0 1 (0.2%) Ischaemia 1 (0.4%) 0 0 0 Peripheral arterial occlusive disease 0 0 1 (0.4%) 1 (0.2%) Peripheral artery occlusion 0 0 1 (0.4%) 1 (0.2%) Peripheral vascular disorder 0 0 1 (0.4%) 1 (0.2%) Scalp haematoma 1 (0.4%) 0 0 0 'thrombophlebitis 0 0 1 (0.4%) 1 (0.2%) Vein collapse 1 (0.4% ) 0 0 0 Adverse events are sorted by alphabetical order of the MedDRA classification.

A participant is counted only once within each primary SOC and preferred term.

2q4: Aflibercept 2mg administered every 4 weeks.

Table 1-71. Ocular treatment-emergent serious adverse events of study eye: number of participants by primary system organ class and preferred term (safety analysis set) Primary system organ class

Preferred term 2q4 8q8/3 8q8/5 All 8mg MedDRA version 28.0 N=301 (100%) N=293 (100%) N=298 (100%) N=591 (100%) Number (%) of participants with at least one such adverse event 8 (2.7%) 5 (1.7%) 5 (1.7%) 10 (1.7%) Eye disorders 5 (1.7%) 2 (0.7%) 4 (1.3%) 6 (1.0%) Cataract 0 0 1 (0.3%) 1 (0.2%) Glaucoma 0 1 (0.3%) 0 1 (0.2%) Macular hole 2 (0.7%) 0 0 0 Retinal artery occlusion 1 (0.3%) 0 0 0 Retinal detachment 1 (0.3%) 0 0 0 Retinal vasculitis 0 0 1 (0.3%) 1 (0.2%) Retinal vein occlusion 0 0 1 (0.3%) 1 (0.2%) Visual acuity reduced 1 (0.3% ) 0 1 (0.3%) 1 (0.2%) Vitritis 0 1 (0.3%) 0 1 (0.2%) General disorders and administration site conditions 0 1 (0.3%) 0 1 (0.2%) Oedema 0 1 (0.3%) 0 1 (0.2%) Infections and infestations 3 (1.0% ) 1 (0.3%) 0 1 (0.2%) Endophthalmitis 3 (1.0%) 1 (0.3%) 0 1 (0.2%) Injury, poisoning and procedural complications 0 1 (0.3%) 1 (0.3%) 2 (0.3%) Posterior capsule rupture 0 0 1 (0.3%) 1 (0.2%) Skin laceration 0 1 (0.3%) 0 1 (0.2%)

Adverse events are sorted by alphabetical order of the MedDRA classification.

A participant is counted only once within each primary SOC and preferred term.

TESAEs are defined as serious AEs that started in the time frame from first injection to the last injection (active or sham) in the study plus 30 days.

2q4: Aflibercept 2mg administered every 4 weeks.

Table 1-71 A. Ocular treatment-emergent serious adverse events of study eye: number of participants by primary system organ class and preferred term (safety analysis set) Population group: Non-China sub-population

Primary system organ class

Preferred term 2q4 8q8/3 8q8/5 All 8mg MedDRA version 28.0 N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%) Number (%) of participants with at least one such adverse event 6 (2.2%) 5 (1.9%) 5 (1.9%) 10 (1.9%) Eye disorders 4 (1.4%) 2 (0.8%) 4 (1.5%) 6 (1.1%) Cataract 0 0 1 (0.4%) 1 (0.2%) Glaucoma 0 1 (0.4%) 0 1 (0.2%) Macular hole 1 (0.4%) 0 0 0

Retinal artery occlusion 1 (0.4%) 0 0 0

Retinal detachment 1 (0.4%) 0 0 0

Retinal vasculitis 0 0 1 (0.4%) 1 (0.2%) Retinal vein occlusion 0 0 1 (0.4%) 1 (0.2%) Visual acuity reduced 1 (0.4%) 0 1 (0.4%) 1 (0.2%) Vitritis 0 1 (0.4%) 0 1 (0,2%) General disorders and administration site conditions 0 1 (0.4%) 0 1 (0.2%) Oedema 0 1 (0.4%) 0 1 (0.2%) Infections and infestations 2 (0.7%) 1 (0.4%) 0 1 (0.2%) Endophthalmitis 2 (0.7%) 1 (0.4%) 0 1 (0.2%) Injury, poisoning and procedural complications 0 1 (0.4%) 1 (0.4%) 2 (0.4%) Posterior capsule rupture 0 0 1 (0.4%) 1 (0.2%)

Skin laceration 0 1 (0.4%) 0 1 (0.2%) Adverse events are sorted by alphabetical order of the MedDRA classification.

A participant is counted only once within each primary SOC and preferred term.

2q4: Aflibercept 2mg administered every 4 weeks.

Table 1-72. Non-ocular treatment-emergent serious adverse events: number of participants by primary system organ class and preferred term (safety analysis set)

Primary’ system organ class

Preferred term 2q4 8q8/3 8q8/5 All 8mg MedDRA version 28.0 N=301 (100%) N=293 (100%) N=298 (100%) N=591 (100%) Number (%) of participants with at least one such adverse event 36 (12.0%) 33 (11.3%) 33 (11.1%) 66 (11.2%) Blood and lymphatic system disorders 2 (0.7%) 0 0 0

Iron deficiency anaemia 1 (0.3%) 0 0 0 Pancytopenia 1 (0.3%) 0 0 0 Cardiac disorders 2 (0.7%) 6 (2.0%) 6 (2.0%) 12 (2.0%) Acute coronary⁷ syndrome 0 0 1 (0.3%) 1 (0.2%) Acute myocardial infarction 1 (0.3%) 0 0 0

Primary' system organ class

Preferred term “ 2q4 8q8/3 8q8/5 All 8mg MedDRA version 28.0 N=301 (100%) N=293 (100%) N=298 (100%) N=591 (100%) Angina unstable 1 (0.3%) 0 0 0 Atrial fibrillation 0 1 (0.3%) 1 (0.3%) 2 (0.3%) Bradycardia 0 2 (0.7%) 0 2 (0.3%) Cardiac failure 0 0 1 (0.3%) 1 (0.2%) Cardiac failure acute 0 1 (0.3%) 0 1 (0.2%) Coronary artery disease 0 1 (0.3%) 1 (0.3%) 2 (0.3%) Myocardial infarction 0 1 (0.3%) 1 (0.3%) 2 (0.3%) Myocardial ischaemia 0 0 1 (0.3%) 1 (0.2%) Prinzmetal angina 0 1 (0.3%) 0 1 (0.2%) Ear and labyrinth disorders 0 1 (0.3%) 0 1 (0.2%) Vertigo 0 1 (0,3%) 0 1 (0.2%) Endocrine disorders 0 0 1 (0.3%) 1 (0.2%) Primary hyperaldosteronism 0 0 1 (0.3%) 1 (0.2%) Gastrointestinal disorders 2 (0.7%) 5 (1.7%) 2 (0.7%) 7 (1.2%) Abdominal distension 0 1 (0.3%) 0 1 (0.2%) Abdominal pain upper 0 0 1 (0.3%) 1 (0.2%) Diverticulum 0 0 1 (0.3%) 1 (0.2%) Diverticulum intestinal haemorrhagic 1 (0.3%) 0 0 0 Duodenal stenosis 0 1 (0.3%) 0 1 (0.2%) Femoral hernia incarcerated 0 1 (0.3%) 0 1 (0.2%) Hiatus hernia 0 1 (0.3%) 0 1 (0.2%) Lower gastrointestinal haemorrhage 0 1 (0.3%) 0 1 (0.2%) Small intestinal obstruction 1 (0.3%) 0 0 0 General disorders and administration site conditions 3 (1.0%) 0 1 (0.3%) 1 (0.2%) Chest pain 0 0 1 (0.3%) 1 (0.2%) General physical health deterioration 1 (0.3%) 0 0 0 Incarcerated hernia 1 (0.3%) 0 0 0 Oedema due to renal disease 1 (0.3%) 0 0 0 Hepatobiliary⁷ disorders 0 2 (0.7%) 1 (0.3%) 3 (0.5%) Cholecystitis acute 0 1 (0.3%) 0 1 (0.2%) Cholecystitis chronic 0 0 1 (0.3%) 1 (0.2%) Hepatic cyst 0 1 (0.3%) 0 1 (0.2%) Immune system disorders 0 1 (0.3%) 0 1 (0.2%) Anaphylactic reaction 0 1 (0.3%) 0 1 (0.2%) Infections and infestations 6 (2.0%) 8 (2.7%) 12 (4.0%) 20 (3.4%) Appendicitis 0 0 1 (0.3%) 1 (0.2%) Bronchitis 0 0 1 (0.3%) 1 (0.2%) COVID-19 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Diverticulitis 0 2 (0.7%) 1 (0.3%) 3 (0.5%) Gastroenteritis 0 1 (0.3%) 0 1 (0.2%) Herpes zoster 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Infected dermal cyst 0 0 1 (0.3%) 1 (0.2%) Infectious pleural effusion 0 1 (0.3%) 0 1 (0.2%) Osteomyelitis 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Pneumonia 2 (0.7%) 2 (0,7%) 1 (0.3%) 3 (0.5%) Pneumonia aspiration 1 (0.3%) 0 0 0 Pneumonia parainfluenzae viral 0 0 1 (0.3%) 1 (0.2%) Pneumonia pseudomonal 0 0 1 (0.3%) 1 (0.2%) Sepsis 0 2 (0.7%) 1 (0.3%) 3 (0.5%) Tooth infection 0 0 1 (0.3%) 1 (0.2%) Urinary tract infection 0 0 1 (0.3%) 1 (0.2%) Injury, poisoning and procedural complications 5 (1.7%) 4 (1.4%) 3 (1.0%) 7 (1.2%) Brain herniation 0 0 1 (0.3%) 1 (0.2%) Cartilage injury 0 0 1 (0.3%) 1 (0.2%) Fall 1 (0.3%) 0 0 0 Humerus fracture 1 (0.3%) 0 0 0

Primary' system organ class

Preferred term “ 2q4 8q8/3 8q8/5 All 8mg MedDRA version 28.0 N=301 (100%) N=293 (100%) N=298 (100%) N=591 (100%) Multiple injuries 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Overdose 1 (0.3%) 0 0 0 Pelvic fracture 1 (0.3%) 0 0 0 Postoperative thoracic procedure complication 0 1 (0.3%) 0 1 (0.2%) Procedural pain 0 0 1 (0.3%) 1 (0.2%) Rib fracture 0 1 (0.3%) 1 (0.3%) 2 (0.3%) Snake bite 0 1 (0.3%) 0 1 (0.2%) Subdural haematoma 0 0 1 (0.3%) 1 (0.2%) Tendon rupture 0 0 1 (0.3%) 1 (0.2%) Investigations 0 0 1 (0.3%) 1 (0.2%) Blood urine present 0 0 1 (0.3%) 1 (0.2%) Metabolism and nutrition disorders 2 (0.7%) 0 1 (0.3%) 1 (0.2%) Hypoglycaemia 1 (0.3%) 0 0 0

Type 2 diabetes mellitus 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Musculoskeletal and connective tissue disorders 2 (0.7%) 2 (0.7%) 1 (0.3%) 3 (0.5%) Haemarthrosis 0 0 1 (0.3%) 1 (0.2%) Intervertebral disc compression 1 (0.3%) 0 0 0 Osteoarthritis 1 (0.3%) 1 (0.3%) 0 1 (0.2%) Vertebral foraminal stenosis 0 1 (0.3%) 0 1 (0.2%) Neoplasms benign, malignant and unspecified (incl cysts and polyps) 3 (1.0%) 4 (1.4%) 4 (1.3%) 8 (1.4%) Bladder cancer 0 1 (0.3%) 0 1 (0.2%) Bladder neoplasm 0 1 (0.3%) 0 1 (0.2%) Colon cancer 0 0 1 (0.3%) 1 (0.2%) Lung neoplasm malignant 0 0 1 (0.3%) 1 (0.2%) Metastatic neoplasm 1 (0.3%) 0 0 0 Oesophageal carcinoma 0 1 (0.3%) 0 1 (0.2%) Prostate cancer metastatic 0 0 1 (0.3%) 1 (0.2%) Prostate cancer stage II 0 1 (0.3%) 0 1 (0.2%) Rectal cancer 0 0 1 (0.3%) 1 (0.2%) Small cell lung cancer 0 1 (0.3%) 0 1 (0.2%) Squamous cell carcinoma of lung 1 (0.3%) 0 0 0

T-cell lymphoma 1 (0.3%) 0 0 0 Nervous system disorders 7 (2.3%) 4 (1.4%) 3 (1.0%) 7 (1.2%) Atypical migraine 1 (0.3%) 0 0 0 Cerebellar infarction 1 (0.3%) 0 0 0 Cerebellar stroke 1 (0.3%) 0 0 0 Cerebral infarction 0 0 1 (0.3%) 1 (0.2%) Cerebrovascular accident 1 (0.3%) 0 0 0 Epilepsy 1 (0.3%) 1 (0,3%) 0 1 (0.2%) Haemorrhage intracranial 1 (0.3%) 0 0 0 Haemorrhagic stroke 0 0 1 (0.3%) 1 (0.2%) Lacunar infarction 1 (0.3%) 0 0 0 Normal pressure hydrocephalus 1 (0.3%) 0 0 0 Sciatica 0 1 (0.3%) 0 1 (0.2%) Seizure 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Spinal claudication 0 1 (0.3%) 0 1 (0.2%) Syncope 0 1 (0.3%) 0 1 (0.2%) Transient ischaemic attack 1 (0.3%) 0 0 0 Psychiatric disorders 2 (0.7%) 1 (0.3%) 0 1 (0.2%) Anxiety 0 1 (0,3%) 0 1 (0.2%) Completed suicide 1 (0.3%) 0 0 0 Mental status changes 1 (0.3%) 0 0 0 Renal and urinary disorders 2 (0.7%) 1 (0,3%) 3 (1.0%) 4 (0.7%) Calculus bladder 0 0 1 (0.3%) 1 (0.2%) Diabetic nephropathy 1 (0.3%) 0 1 (0.3%) 1 (0.2%) Nephrolithiasis 1 (0.3%) 0 0 0 Ureterolithiasis 0 1 (0.3%) 1 (0.3%) 2 (0.3%)

Primary' system organ class

Preferred term 2q4 8q8/3 8q8/5 All 8mg MedDRA version 28.0 N=301 (100%) N=293 (100%) N=298 (100%) N=591 (100%) Urinary tract discomfort 0 0 1 (0.3%) 1 (0.2%) Reproductive system and breast disorders 1 (0.3%) 0 2 (0.7%) 2 (0.3%) Benign prostatic hyperplasia 0 0 1 (0.3%) 1 (0.2%) Pelvic organ prolapse 1 (0.3%) 0 0 0 Uterine haemorrhage 0 0 1 (0.3%) 1 (0.2%) Respiratory, thoracic and mediastinal disorders 2 (0.7%) 0 2 (0.7%) 2 (0.3%) Asthma 1 (0.3%) 0 0 0 Chronic obstructive pulmonary disease 0 0 1 (0.3%) 1 (0.2%) Dyspnoea exertional 0 0 1 (0.3%) 1 (0.2%) Epistaxis 1 (0.3%) 0 0 0 Respiratory failure 0 0 1 (0.3%) 1 (0.2%) Surgical and medical procedures 0 1 (0.3%) 1 (0.3%) 2 (0.3%) Hip arthroplasty 0 1 (0.3%) 0 1 (0.2%) Medical induction of coma 0 0 1 (0.3%) 1 (0.2%) Vascular disorders 4 (1.3%) 0 1 (0.3%) 1 (0.2%) Circulatory collapse 1 (0.3%) 0 0 0 Giant cell arteritis 1 (0.3%) 0 0 0 Hypertensive emergency 1 (0.3%) 0 0 0 Hypertensive urgency 1 (0.3%) 0 0 0 Peripheral artery occlusion 0 0 1 (0.3%) 1 (0.2%)

Adverse events are sorted by alphabetical order of the MedDRA classification.

A participant is counted only once within each primary SOC and preferred term.

2q4: Aflibercept 2mg administered every 4 weeks.

Table 1-72A. Non-ocular treatment-emergent serious adverse events: number of participants by primary system organ class and preferred term (safety analysis set) Population group: Non-China sub-population

Primary system organ class

Preferred term 2q4 8q8/3 8q8/5 All 8mg MedDRA version 28.0 N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%) Number (%) of participants with at least one such adverse event 34 (12.3%) 30 (11.3%) 29 (11.2%) 59 (11.2%) Blood and lymphatic system disorders 2 (0.7%) 0 0 0

Iron deficiency anaemia 1 (0.4%) 0 0 0 Pancytopenia 1 (0.4%) 0 0 0 Cardiac disorders 2 (0.7%) 6 (2.3%) 5 (1.9%) 11 (2.1%) Acute myocardial infarction 1 (0.4%) 0 0 0 Angina unstable 1 (0.4%) 0 0 0 Atrial fibrillation 0 1 (0.4%) 1 (0.4%) 2 (0.4%) Bradycardia 0 2 (0.8%) 0 2 (0.4%) Cardiac failure 0 0 1 (0.4%) 1 (0.2%) Cardiac failure acute 0 1 (0.4%) 0 1 (0.2%) Coronary artery disease 0 1 (0.4%) 1 (0.4%) 2 (0.4%) Myocardial infarction 0 1 (0.4%) 1 (0.4%) 2 (0.4%) Myocardial ischaemia 0 0 1 (0.4%) 1 (0.2%)

Prinzmetal angina 0 1 (0.4%) 0 1 (0.2%) Ear and labyrinth disorders 0 1 (0.4%) 0 1 (0.2%) Vertigo 0 1 (0.4%) 0 1 (0.2%) Gastrointestinal disorders 2 (0.7%) 4 (1.5%) 2 (0.8%) 6 (1.1%) Abdominal pain upper 0 0 1 (0.4%) 1 (0.2%) Diverticulum 0 0 1 (0.4%) 1 (0.2%) Diverticulum intestinal haemorrhagic 1 (0.4%) 0 0 0 Duodenal stenosis 0 1 (0.4%) 0 1 (0.2%) Femoral hernia incarcerated 0 1 (0.4%) 0 1 (0.2%) Hiatus hernia 0 1 (0.4%) 0 1 (0.2%) Lower gastrointestinal haemorrhage 0 1 (0.4%) 0 1 (0.2%) Small intestinal obstruction 1 (0.4%) 0 0 0 General disorders and administration site conditions 3 (1.1%) 0 1 (0.4%) 1 (0.2%) Chest pain 0 0 1 (0.4%) 1 (0.2%) General physical health deterioration 1 (0.4%) 0 0 0 Incarcerated hernia 1 (0.4%) 0 0 0 Oedema due to renal disease 1 (0.4%) 0 0 0 Hepatobiliary disorders 0 2 (0.8%) 1 (0.4%) 3 (0.6%) Cholecystitis acute 0 1 (0.4%) 0 1 (0.2%) Cholecystitis chronic 0 0 1 (0.4%) 1 (0.2%) Hepatic cyst 0 1 (0.4%) 0 1 (0.2%) Immune system disorders 0 1 (0.4%) 0 1 (0.2%) Anaphylactic reaction 0 1 (0.4%) 0 1 (0.2%) Infections and infestations 8 (3.0%) 11 (4.2%) 19 (3.6%) Appendicitis 0 0 1 (0.4%) 1 (0.2%) Bronchitis 0 0 1 (0.4%) 1 (0.2%) COVID-19 1 (0.4%) 1 (0.4%) 0 1 (0.2%) Diverticulitis 0 2 (0.8%) 1 (0.4%) 3 (0.6%) Gastroenteritis 0 1 (0.4%) 0 1 (0.2%) Herpes zoster 1 (0.4%) 0 0 0 Infected dermal cyst 0 0 1 (0.4%) 1 (0.2%) Infectious pleural effusion 0 1 (0.4%) 0 1 (0.2%) Osteomyelitis 1 (0.4%) 0 1 (0.4%) 1 (0.2%) Pneumonia 2 (0.7%) 2 (0.8%) 1 (0.4%) 3 (0.6%) Pneumonia aspiration 1 (0.4%) 0 0 0 Pneumonia parainfluenzae viral 0 0 1 (0.4%) 1 (0.2%) Pneumonia pseudomonal 0 0 1 (0.4%) 1 (0.2%) Sepsis 0 2 (0.8%) 1 (0.4%) 3 (0.6%) Tooth infection 0 0 1 (0.4%) 1 (0.2%)

Urinary tract infection 0 0 1 (0.4%) 1 (0.2%) Injury, poisoning and procedural complications 5 (1.8%) 2 (0.8%) 3 (1.2%) 5 (1.0%) Brain herniation 0 0 1 (0.4%) 1 (0.2%) Cartilage injury 0 0 1 (0.4%) 1 (0.2%) Fall 1 (0.4%) 0 0 0 Humerus fracture 1 (0.4%) 0 0 0 Multiple injuries 1 (0.4%) 0 0 0 Overdose 1 (0.4%) 0 0 0

Pelvic fracture 1 (0.4%) 0 0 0 Postoperative thoracic procedure complication 0 1 (0.4%) 0 1 (0.2%) Procedural pain 0 0 1 (0.4%) 1 (0.2%) Rib fracture 0 0 1 (0.4%) 1 (0.2%) Snake bite 0 1 (0.4%) 0 1 (0.2%) Subdural haematoma 0 0 1 (0.4%) 1 (0.2%) Tendon rupture 0 0 1 (0.4%) 1 (0.2%) Investigations 0 0 1 (0.4%) 1 (0.2%) Blood urine present 0 0 1 (0.4%) 1 (0.2%) Metabolism and nutrition disorders 1 (0.4%) 0 1 (0.4%) 1 (0.2%)

Hypoglycaemia 1 (0.4%) 0 0 0

Type 2 diabetes mellitus 0 0 1 (0.4%) 1 (0.2%) Musculoskeletal and connective tissue disorders 2 (0.7%) 2 (0.8%) 1 (0.4%) 3 (0.6%) Haemarthrosis 0 0 1 (0.4%) 1 (0.2%) Intervertebral disc compression 1 (0.4%) 0 0 0 Osteoarthritis 1 (0.4%) 1 (0.4%) 0 1 (0.2%) Vertebral foraminal stenosis 0 1 (0.4%) 0 1 (0.2%) Neoplasms benign, malignant and unspecified (incl cysts and polyps) 3 (1.1%) 4 (1.5%) 3 (1.2%) 7 (1.3%) Bladder cancer 0 1 (0.4%) 0 1 (0.2%) Bladder neoplasm 0 1 (0.4%) 0 1 (0.2%) Colon cancer 0 0 1 (0.4%) 1 (0.2%) Lung neoplasm malignant 0 0 1 (0.4%) 1 (0.2%) Metastatic neoplasm 1 (0.4%) 0 0 0 Oesophageal carcinoma 0 1 (0.4%) 0 1 (0.2%) Prostate cancer metastatic 0 0 1 (0.4%) 1 (0.2%) Prostate cancer stage II 0 1 (0.4%) 0 1 (0.2%) Small cell lung cancer 0 1 (0.4%) 0 1 (0.2%) Squamous cell carcinoma of lung 1 (0.4%) 0 0 0

T-cell lymphoma 1 (0.4%) 0 0 0 Nervous system disorders 7 (2.5%) 4 (1.5%) 3 (1.2%) 7 (1.3%) Atypical migraine 1 (0.4%) 0 0 0 Cerebellar infarction 1 (0.4%) 0 0 0 Cerebellar stroke 1 (0.4%) 0 0 0 Cerebral infarction 0 0 1 (0.4%) 1 (0.2%) Cerebrovascular accident 1 (0.4%) 0 0 0 Epilepsy 1 (0.4%) 1 (0.4%) 0 1 (0.2%) Haemorrhage intracranial 1 (0.4%) 0 0 0 Haemorrhagic stroke 0 0 1 (0.4%) 1 (0.2%) Lacunar infarction 1 (0.4%) 0 0 0 Normal pressure hydrocephalus 1 (0.4%) 0 0 0 Sciatica 0 1 (0.4%) 0 1 (0.2%) Seizure 1 (0.4%) 0 1 (0.4%) 1 (0.2%) Spinal claudication 0 1 (0.4%) 0 1 (0.2%) Syncope 0 1 (0.4%) 0 1 (0.2%) Transient ischaemic attack 1 (0.4%) 0 0 0 Psychiatric disorders 2 (0.7%) 1 (0.4%) 0 1 (0.2%) Anxiety 0 1 (0.4%) 0 1 (0.2%) Completed suicide 1 (0.4%) 0 0 0 Mental status changes 1 (0.4%) 0 0 0 Renal and urinary disorders 1 (0.4%) 1 (0.4%) 3 (1.2%) 4 (0.8%) Calculus bladder 0 0 1 (0.4%) 1 (0.2%) Diabetic nephropathy 0 0 1 (0.4%) 1 (0.2%) Nephrolithiasis 1 (0.4%) 0 0 0 Ureterolithiasis 0 1 (0.4%) 1 (0.4%) 2 (0.4%) Urinary tract discomfort 0 0 1 (0.4%) 1 (0.2%) Reproductive system and breast disorders 1 (0.4%) 0 2 (0.8%) 2 (0.4%) Benign prostatic hyperplasia 0 0 1 (0.4%) 1 (0.2%) Pelvic organ prolapse 1 (0.4%) 0 0 0 Uterine haemorrhage 0 0 1 (0.4%) 1 (0.2%) Respiratory, thoracic and mediastinal disorders 2 (0.7%) 0 2 (0.8%) 2 (0.4%) Asthma 1 (0.4%) 0 0 0 Chronic obstructive pulmonary disease 0 0 1 (0.4%) 1 (0.2%) Dyspnoea exertional 0 0 1 (0.4%) 1 (0.2%) Epistaxis 1 (0.4%) 0 0 0 Respiratory failure 0 0 1 (0.4%) 1 (0.2%) Surgical and medical procedures 0 1 (0.4%) 1 (0.4%) 2 (0.4%) Hip arthroplasty 0 1 (0.4%) 0 1 (0.2%) Medical induction of coma 0 0 1 (0.4%) 1 (0.2%) Vascular disorders 4 (1.4%) 0 1 (0.4%) 1 (0.2%) Circulatory collapse 1 (0.4%) 0 0 0 Giant cell arteritis 1 (0.4%) 0 0 0 Hypertensive emergency 1 (0.4%) 0 0 0 Hypertensive urgency 1 (0.4%) 0 0 0

Peripheral artery occlusion 0 0 1 (0.4%) 1 (0.2%) Adverse events are sorted by alphabetical order of the MedDRA classification.

A participant is counted only once within each primary SOC and preferred term.

2q4: Aflibercept 2mg administered every 4 weeks.

Table 1-73. Deaths: number of participants with adverse events with fatal outcome by primary system organ class and preferred term (safety analysis set)

Primary system organ class

Preferred term 2q4 8q8/3 8q8/5 All 8mg MedDRA version 28.0 N=301 (100%) N=293 (100%) N=298 (100%) N=591 (100%) Number (%) of participants with at least one such adverse event 3 (1.0%) 2 (0.7%) 5 (1.7%) 7 (1.2%) Cardiac disorders 0 0 2 (0.7%) 2 (0.3%) Cardiogenic shock 0 0 1 (0.3%) 1 (0.2%) Myocardial ischaemia 0 0 1 (0.3%) 1 (0.2%) Infections and infestations 1 (0.3%) 1 (0.3%) 1 (0.3%) 2 (0.3%) Bronchitis 0 0 1 (0.3%) 1 (0.2%) Pneumonia 1 (0.3%) 0 0 0

Sepsis 0 1 (0.3%) 0 1 (0.2%) Injury, poisoning and procedural complications 0 0 1 (0.3%) 1 (0.2%) Brain herniation 0 0 1 (0.3%) 1 (0.2%) Neoplasms benign, malignant and unspecified (incl cysts and polyps) 0 1 (0.3%) 1 (0.3%) 2 (0.3%) Oesophageal carcinoma 0 1 (0.3%) 0 1 (0.2%) Prostate cancer metastatic 0 0 1 (0.3%) 1 (0.2%) Nervous system disorders 1 (0.3%) 0 0 0 Haemorrhage intracranial 1 (0.3%) 0 0 0 Psychiatric disorders 1 (0.3%) 0 0 0 Completed suicide 1 (0.3%) 0 0 0

Adverse events are sorted by alphabetical order of the MedDRA classification.

2q4: Aflibercept 2mg administered every 4 weeks.

Table 1-73A. Deaths: number of participants with adverse events with fatal outcome by primary system organ class and preferred term (safety analysis set)

Population group: Non-China sub-population

Primary system organ class

Preferred term 2q4 8q8/3 8q8/5 All 8mg MedDRA version 28.0 N=276 (100%) N=266 (100%) N=260 (100%) N=526 (100%) Number (%) of participants with at least one such adverse event 3 (1.1%) 2 (0.8%) 5 (1.9%) 7 (1.3%) Cardiac disorders 0 0 2 (0.8%) 2 (0.4%) Cardiogenic shock 0 0 1 (0.4%) 1 (0.2%) Myocardial ischaemia 0 0 1 (0.4%) 1 (0.2%) Infections and infestations 1 (0.4%) 1 (0.4%) 1 (0.4%) 2 (0.4%) Bronchitis 0 0 1 (0.4%) 1 (0.2%) Pneumonia 1 (0.4%) 0 0 0

Sepsis 0 1 (0.4%) 0 1 (0.2%) Injury⁷, poisoning and procedural complications 0 0 1 (0.4%) 1 (0.2%) Brain herniation 0 0 1 (0.4%) 1 (0.2%) Neoplasms benign, malignant and unspecified (incl cysts and polyps) 0 1 (0.4%) 1 (0.4%) 2 (0.4%) Oesophageal carcinoma 0 1 (0.4%) 0 1 (0.2%) Prostate cancer metastatic 0 0 1 (0.4%) 1 (0.2%) Nervous system disorders 1 (0.4%) 0 0 0 Haemorrhage intracranial 1 (0.4%) 0 0 0 Psychiatric disorders 1 (0.4%) 0 0 0 Completed suicide 1 (0.4%) 0 0 0 Adverse events are sorted by alphabetical order of the MedDRA classification.

2q4: Aflibercept 2mg administered every 4 weeks.

Example 2: A Phase 3 Randomized, Double-Masked, Active controlled Study of the Efficacy and Safety of 8 Mg Aflibercept in Participants with Macular Edema Following Retinal Vein Occlusion (MERVO) (QUANTUM)

[0578] This is a Phase 3, multi-center, randomized, double-masked, active-controlled study to assess the efficacy and safety of aflibercept 8 mg in participants with macular edema following retinal vein occlusion (MEfRVO).

[0579] Study Design. A total of approximately 840 participants who meet all eligibility criteria will be randomized 1:1 (n=~420 per group) to receive a total of 6 injections of either aflibercept 8 mg or ranibizumab 0.5 mg dosed every 4 weeks (from baseline through week 20), followed by an extension of the dosing interval to every 12 weeks. Participants with treatment-naive RVO criteria for disease activity.

[0580] The primary endpoint will be assessed at week 24, and the end of study will be at week 52. Primary endpoint: Change from baseline in BCVA measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score at week 24.

[0581] The estimand of primary interest is described by the following attributes:

• Population: Participants with treatment-naive RVO with disease

activity meeting the inclusion/exclusion criteria.

• Variable: Change from baseline to week 24 in BCVA in the study

eye

• Treatment condition: aflibercept 8 mg (treatment) or ranibizumab

0.5 mg (control) every 4 weeks through week 24 regardless of

whether or not the participant experiences any intercurrent events

before week 24.

• Intercurrent events and strategies:

o Premature discontinuation from treatment (treatment

policy)

o Missed injection (treatment policy)

o Use of prohibited medication (treatment policy)

o Wrong study treatment administered (treatment policy)

o Death (composite)

• Population-level summary: Difference in mean change from

baseline to week 24 in BCVA between 8q4 and Rq4.

Secondary Objective: To evaluate the safety of 8q4 compared to Rq4 dosed

every 4 weeks

• Secondary Endpoint: Occurrence of treatment-emergent adverse events (TEAEs) and serious AEs (SAEs) through week 24

[0582] Participants will be stratified by retinal vein occlusion (RVO) type (CRVO/HRVO vs BRVO), baseline CRT (> 650 microns vs < 650 microns) on spectral domain optical coherence tomography (SD-OCT), and baseline BCVA (>50 letters vs < 50 letters). Only 1 eye per participant will be enrolled as the study eye.

[0583] Participants will be followed every 4 weeks from day 1 through week 52. At the week 28 and 32 visits, participants will have the dosing interval shortened if the following Dose Regimen Modification (DRM) Criteria are met: > 5 letter loss of BCVA from best previous BCVA with persistent or worsening disease activity.

[0584] Participants meeting DRM criteria at week 28 will have their closing interval shortened to every 4 weeks and will receive injections at the week 28, 32, 36, 40, 44 and 48 visits. vParticipants first meeting DRM criteria at the week 32 visit will have their dosing interval shortened to every 8 weeks and will receive injections at the week 32 and 40 visits.

[0585] Additionally, these participants will be re-assessed for DRM criteria at this week 40 visit.

• If these participants meet the DRM criteria again at the week 40 visit, their dosing interval will be shortened further to every 4 weeks, and they will receive subsequent injections at the week 44 and 48 visits.

• If these participants do not meet DRM criteria at the week 40 visit, their dosing interval will remain at every 8 weeks, and they will receive their next injection at the week 48 visit.

[0586] Participants who do not meet DRM criteria mentioned above will receive injections at the week 32 and 44 visits. The primary analysis will occur once all participants have completed week 24 (or prematurely discontinued), with the final analysis occurring after all participants have completed the study at week 52 (or prematurely discontinued).

[0587] Safety will be assessed by ophthalmic exams, intraocular pressure ( IOP), collection of vital signs, AEs, and clinical laboratory assessments.

[0588] In all participants, blood samples for the measurement of drug concentrations (pharmacokinetics [PK]) and anti-drug antibody (ADA) will be obtained on day 1 prior to the first treatment and at prespecified time points throughout the course of the study. In addition, a DNA sample will be collected from those who sign the informed consent form (IGF) for the optional genomic substudy. A future biomedical research (FBR) substudy may be conducted for participants who sign the optional FBR IGF.

[0589] The study flow diagram and dosing schedules are presented in Figure 3 and Figure 4.

[0590] Objectives, Endpoints & Estimands. The primary objective of this study is to determine if treatment with aflibercept 8 mg dosed every 4 weeks (8q4) provides non-inferior improvement in best corrected visual acuity (BCVA) compared to ranibizumab 0.5 mg dosed every 4 weeks (Rq4). Objectives and endpoints are summarized below in Table 2-1.

Table 2-1. Study Objectives, Endpoints, and Estimands

Objectives Endpoints Primary

• To determine if treatment with • Change from baseline in BCVA measured aflibercept 8 mg dosed every 4 weeks by the ETDRS letter score at week 24 (8q4) provides non-inferior BCVA

change compared to ranibizumab 0.5

mg dosed every 4 weeks

(Rq4)

Secondary

• To evaluate the safety of 8q4 compared to • Occurrence of TEAEs and SAEs through Rq4 week 24

dosed every 4 weeks

Exploratory

• To determine the effect of treatment with • Change from baseline in CRT at weeks 24 8q4 compared to Rq4 on anatomic and and 52

functional measures of response • Participants without retinal fluid (IRF and/or SRF) in the center subfield at weeks 24 and 52

• Participants gaining and losing > 5, 10, and 15 letters at weeks 24 and 52

• Participants achieving an ETDRS letter score of at least 69 letters (approximate 20/40 Snellen equivalent) at weeks 24 and 52

• Change from baseline in leakage area on FA at weeks 24 and 52

• Change from baseline in area of capillary non-perfusion at weeks 24 and 52

• Participants maintaining q12 interval from week 20 through week 52

• Participants meeting DRM criteria

• Incidence and titer of ADA to aflibercept through week 52

• Incidence of NAb to aflibercept through week 52

• Systemic concentrations of

• To evaluate the immunogenicity and aflibercept as assessed through

PK of aflibercept week 24

• To study drivers of RVO or related Endpoints will be assessed in an exploratory diseases, the mechanism of action of manner at week 52.

aflibercept, and the VEGF pathway,

including genomic associations with

clinical or biomarker

response

8q4=aflibercept 8 mg every 4 weeks followed by an extension of the dosing interval to every 12 weeks after week 24; Rq4=ranibizumab 0.5 mg dosed every 4 weeks followed by an extension of the dosing interval to every 12 weeks after week 24; ADA=anti-drug antibody; BCVA=best corrected visual acuity; GRT=central retinal thickness; DRM=dose regimen modification;

ETDRS=Early Treatment Diabetic Retinopathy Study; FA=fluorescein angiography;

IRF=intraretinal fluid; NAb=neutralizing antibody; PK=pharmacokinetics; q12=every 12 weeks; RVO=retinal vein occlusion; SAE=serious adverse event; SRF=subretinal fluid;

TEAE=treatment-emergent adverse event; VEGF=vascular endothelial growth factor

[0591] Study duration. The duration of the study for a participant is approximately 52 weeks, excluding the screening period. The definition for End of Study (EOS) is the last visit of the last participant in the study.

[0592] Treatments. Aflibercept (8 mg) administered by intravitreal (IVT) injection every 4 weeks, followed by extension of the dosing interval to every 12 weeks following the week 20 visit. Participants meeting DRM criteria at prespecified visits will have their dosing interval shortened to every 8 weeks and/or every 4 weeks through the week 48 visit.

[0593] The Reference Drug, Ranibizumab (0.5 mg), is administered by IVT injection every 4 weeks, followed by extension of the dosing interval to every 12 weeks following the week 20 visit. Participants meeting DRM criteria at prespecified visits will have their dosing interval shortened to every 8 weeks and/or every 4 weeks through the week 48 visit.

[0594] Instructions on dose preparation are provided in the pharmacy manual. Aflibercept will be provided as a single-use glass vial designed to provide 8 mg (0.07 mL of 114.3 mg/mL solution) for IVT injection. Ranibizumab may be provided either as a single-use vial or a prefilled syringe to sites for the 0.05 mL for IVT injection. Refer to your local product insert for information. See Table 2-2 for the study treatments administered. Throughout this protocol, study treatment includes both aflibercept 8 mg and the ranibizumab 0.5 mg.

Table 2-2. Study Treatments Administered

Intervention Label Aflibercept Ranibizumab

Intervention Name Aflibercept 8 mg Ranibizumab 0.5 mg Intervention Description IVT injection IVT injection

Type Biologic Biologic

Dose Formulation Liquid formulation Liquid formulation

Unit Dose Strength(s) 114.3 mg/mL 10 mg/mL

Dosage Level(s) 8 mg (70 pL) 0.5 mg (50 pL)

Route of Administration IVT IVT

Frequency Every 4 weeks followed by extension Every 4 weeks followed by extension of the dosing interval to every 12 of the dosing interval to every 12 weeks after week 20 through week weeks after week 20 through week 52 52

Use Experimental Active comparator (control) IMP IMP IMP

Sourcing Provided centrally by the sponsor Provided centrally by the sponsor

IMP=Investigational Medicinal Product; IVT=Intravitreal

[0595] Fellow eye treatment will be allowed with aflibercept 8 mg at the investigator’s discretion for RVO, DME, DR, or nAMD and will be provided only through IWRS (Interactive web response system). The treated fellow eye will not be considered an additional study eye. Participants who receive treatment for the fellow eye will not be required to be withdrawn from the study.

[0596] Procedures and Assessments. Efficacy and safety procedures: ocular examination including BCVA ETDRS and refraction, intraocular pressure (IOP), slit lamp examination, indirect ophthalmoscopy, SD-OCT, fluorescein angiography (FA), and fundus photography (FP), ophthalmic exams, physical examination, vital signs, electrocardiogram (ECG), AEs, clinical laboratory assessments, PK, and immunogenicity. Optional genomic and FBR (future biomedical research) substudies will be conducted for those participants who sign the optional ICFs (informed consent forms).

[0597] Statistical Plan. For this phase 3 study, a total sample size of 840 participants randomized 1:1 to aflibercept 8 mg or ranibizumab 0.5 mg groups (i.e., 420 participants per group) is planned. The sample size calculation is based on testing the non-inferiority of aflibercept 8 mg compared to ranibizumab 0.5 mg with respect to the primary endpoint of change from baseline in BCVA at week 24 and to ensure large enough subgroup sample sizes in each subtype of RVO (CRVO/HRVO vs BRVO). Assuming a standard deviation (SD) of 14 letters (based on results from the COPERNICUS, GALILEO, and VIBRANT studies for aflibercept and the BRAVO and CRUISE studies for ranibizumab), a non-inferiority margin of 4 letters, and 10% drop-out rate, using 420 participants per group provides 97.5% power for the comparison of aflibercept 8 mg and ranibizumab 0.5 mg using a 2-sample t-test at alpha=0.025 (1 -sided).

[0598] A meta-analysis of randomized clinical trials in RVO comparing ranibizumab 0.5 mg to no anti-VEGF treatment of at least 6-months follow-up found that the difference in mean change

from baseline in BCVA at 6 months was 12.3 letters (95% confidence interval [Cl]: 10.03, 14.58). Based on the lower bound of this Cl, using a 4 letter non-inferiority margin means that at least 60% (»1 -[4/10.03]) of the assumed treatment effect in the ranibizumab 0.5 mg group should be retained in the aflibercept 8 mg group.

[0599] The following primary hypothesis will be tested:

Primary Hypothesis:

• Null hypothesis: aflibercept 8 mg is inferior to ranibizumab 0.5 mg (active-control) with respect to the mean change from baseline in BCVA at week 24: HO: p1 < p0-4

• Alternative hypothesis: aflibercept 8 mg is non-inferior to ranibizumab 0.5 mg (activecontrol) with respect to the mean change from baseline in BCVA at week 24: H1: p1 > p0-4

where pO, p1, are the mean change in BCVA from baseline at week 24 for ranibizumab 0.5 mg q4 and aflibercept 8 mg q4, respectively, and 4 letters is the non-inferiority margin.

[0600] For the analysis of the primary efficacy endpoint, ie, change in BCVA from baseline to week 24, the full analysis set (FAS), which is defined to include all randomized participants who received at least 1 dose of study treatment, will be used. A mixed model for repeated measurements (MMRM) will be used with baseline BCVA measurement as a covariate, treatment group, RVO type (CRVO/HRVO vs BRVO), baseline CRT (> 650 microns vs < 650 microns), baseline BCVA (>50 letters vs < 50 letters), and visit as fixed factors, as well as terms for the interaction between baseline BCVA and visit and between treatment and visit. A Kenward-Roger approximation will be used for the denominator degrees of freedom.

Furthermore, an unstructured covariance structure will be used. If the model does not converge, an appropriate covariance structure will be used instead. In line with the primary estimand and approach to handling of intercurrent events, no explicit imputation of missing BCVA measurements will be performed with the exception of the ICE of death. All other missing BCVA measurements are assumed to be missing at random and will be handled implicitly by the MMRM model.

[0601] To assess non-inferiority, the treatment difference at week 24 based on the least squares means from the MMRM will be used; 2-sided 95% Cl for this comparison will be reported. Aflibercept 8 mg will be considered to be non-inferior to ranibizumab 0.5 mg if the lower bound of this 95% Cl lies above -4 letters. Furthermore, if this lower confidence bound lies above 0 letters, superiority of aflibercept 8 mg will be concluded.

[0602] Dosage modification. Participants will be followed every 4 weeks from day 1 through week 52. At the week 28 and 32 visits, participants will have the dosing interval shortened if the following DRM (Dose Regimen Modification) Criteria are met (see Figure 4):

• 5 letter loss of BOVA from best previous BCVA with persistent or worsening disease activity

[0603] Participants meeting DRM criteria at week 28 will have their dosing interval shortened to every 4 weeks and will receive injections at the week 28, 32, 36, 40, 44, and 48 visits.

[0604] Participants first meeting DRM criteria at the week 32 visit will have their dosing interval shortened to every 8 weeks and will receive injections at the week 32 and 40 visits.

[0605] Additionally, these participants will be re-assessed for DRM criteria at this week 40 visit.

[0606] Participants who do not meet DRM criteria mentioned above will receive injections at the week 32 and 44 visits.

[0607] Study and Study Treatment Discontinuation. A participant may withdraw from study treatment or the study at any time at his/her own request or may be withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, or administrative reasons. This is expected to be uncommon.

[0608] Participants must be withdrawn if any of the following occurs:

• Relevant laboratory abnormality or SAEs, if the sponsor or investigator sees this as • medical reason to warrant withdrawal

• An AE (ocular or nonocular) that, from the participant’s or the investigator’s view, is severe enough to require withdrawal from the study. The investigator must notify the sponsor immediately if a participant is withdrawn because of an AE/SAE

• At the discretion of the treating investigator. The development of conditions which would have prevented a participant’s entry into the study according to the selection criteria is no reason per se for withdrawal. However, the withdrawal in such cases remains at the discretion of the treating investigator

• Decision by the investigator or sponsor that termination is in the participant’s best medical interest or administrative decision for a reason other than an AE/SAE

• A female participant becomes pregnant

• Lost to follow-up

• Decision by the sponsor to halt the entire study

Participants may be withdrawn if any of the following occurs:

• If any treatment for MEfRVO other than study interventions is given in the study eye • If systemic anti-angiogenic agents are taken by the participant during the study

• If, in the investigator’s opinion, continuation in the study would be harmful to the participant’s well-being

• At the specific request of the sponsor and in liaison with the investigator (e.g., obvious noncompliance or safety concerns)

[0609] Participants who permanently discontinue from study treatment should be encouraged to remain in the study. Those who agree and do not withdraw from the study will be asked to return to the clinic for all remaining study visits per the visit schedule.

[0610] Participants who permanently discontinue from study treatment and who opt to withdraw from the study will be asked to complete study assessments.

Table 2-3. Schedule of Events

Study Procedure V1 V1’V2 V2 V3 V4 V5 V6 V6.1 V7 V8 V9 V10 V11 V12 V13 V14 V15

Screening/BL BL PE EOS Screening ^1:

on same day

Week 0 0 4 8 12 16 ~17 20 24 28 32 36 40 44 48 52 Study Day -21 to -1 1 1 29 57 85 113 117 141 169 197 225 253 281 309 337 365 Window (day) ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 Informed

Consent (IGF) X X

Pharmacogenomic

X X

substudy IGF

(optional)³

Future

Biomedical X X

Research ICF

(optional)⁴

Inclusion/Exclusion X X X

Medical History X X

Demographics X X

Concomitant

medications X X X X X X X X X X X X X X X X X Randomization X X

Study Treatment X X X X X X X O⁷ X⁷-⁸ 0 O⁷ X⁸ O

Administration⁶-⁶ DRM

Criteria X X

Assessment⁷

BCVA (ETDRS)

and refraction X X X X X X X X X X X X X X X X IOP^a X X X X X X X X X X X X X X X X Slit lamp exam X X X X X X X X X X X X X X X X Indirect

ophthalmoscopy¹⁰ X X X X X X X X X X X X X X X X FA, FP¹¹ X X X X X X SD-OCT¹² X X X X X X X X X X X X X X X X Physical exam¹³ X X

Vital signs¹⁴ X X X X X X X X¹⁴ X X X X X X X X X ECG X X X

Adverse events X X X X X X X X X X X X X X X X X Hematology¹⁵ X X X Blood Chemistry¹⁵ X X X Pregnancy

Test¹⁶ (Urine X X X X X X X X X X X X X X only)

Urinalysis X X X PK samples¹⁵ X¹⁷ X¹⁷ X X X X X Immunogenicity

Sample X¹⁷ X¹⁷ X X (ADA)¹⁵

Genomic DNA

sample X¹⁷ X¹⁷

(optional)³

V=visit; BL=base ine

ADA=anti-drug antibodies; BCVA=Best corrected visual acuity; DRM=Dose regimen modification; ECG=electrocardiogram; EOS=end of study; ETDRS=Early Treatment Diabetic Retinopathy Study; FA=fluorescein angiography; FBR=future biomedical research; FP=fundus photography; ICF=informed consent form; IOP=lntraocular pressure; PE=primary endpoint; PK=pharmacokinetics; SD-OCT=spectral domain optical coherence tomography

Footnotes for Table 2-3

1. The screening and baseline visits may be conducted separately (visit 1 and visit 2) or may be combined (visit 1/2). When the 2 visits are combined, all assessments defined for visit 1 and visit 2 will be performed on the same day.

2. Visit 6.1 is based on the week 16 visit. This PK collection should be conducted no more than 7 days after the week 16 dose. While not mandatory, every effort should be made to bring participants back to the clinical study site for the collection of this blood sample. Transportation to and from the site will be provided if needed.

3. The optional pharmacogenomic sub-study ICF should be presented to participants at the screening visit and may be signed at any subsequent visit at which the participant chooses to participate. The genomic DNA sample should be collected prior to treatment on day 1 or at any study visit from participants who have signed the sub-study ICFs.

4. The ICF for FBR should be presented to participants and signed at the screening visit.

5. Refer to pharmacy manual for study treatment injection guidelines. Following study treatment injection, participants will be observed for approximately 30 minutes.

6. Study Treatment Administration: X=scheduled injection visit; O=injection only if DRM criteria have been met.

7. Participants’ study eye will be assessed for DRM criteria at weeks 28, 32, and 40 as applicable. If DRM criteria are met, the participant will be dosed at that visit and subsequent doses will be given based on the details herein.

8. For study eyes that do not meet DRM criteria, a scheduled dose will be administered at the week 32 and week 44 visits.

9. IOP will be measured at all study visits (bilaterally). On days when study treatment is administered, IOP should be measured pre-dose (bilaterally) by the masked investigator or designee and approximately 30 minutes after administration of study treatment (study eye only) by the unmasked investigator. IOP will be measured using applanation tonometry (e.g., Goldmann applanation tonometry, Perkins tonometer), combined applanation and indentation (e.g., Tono-pen®), or rebound tonometry (e.g., Icare) and the same method of measurement must be used for each participant throughout the study.

10. Indirect ophthalmoscopy will be performed pre-dose bilaterally at all visits by the masked investigator. On days when study treatment is administered, it should also be performed immediately after administration of study treatment (study eye only) by the unmasked investigator.

11. FA and FP should be performed bilaterally and prior to administration of study treatment, when applicable. For FA, the study eye will be the transit eye and images should be collected using the widest field available.

12. Wherever possible, the same SD-OCT imaging system should be used for each participant throughout the study. Images will be taken in both eyes and prior to administration of study treatment, when applicable.

13. The physical examination includes height and weight.

14. Vital signs (BP, HR, and temperature) should be measured pre-injection. BP assessments will be taken using AOBP with the Microlife WatchBP Office AFIB BP device (or comparable).

BP assessments will be taken by the device in triplicate and a mean measure as displayed will be recorded in the EDC. For visit 6.1, only BP and heart rate will be measured. No temperature measures are required.

15. All PK, ADA, and laboratory samples should be obtained prior to administration of fluorescein and prior to administration of study treatment. PK and ADA samples may also be drawn at any other scheduled visit or any unscheduled visit in case of an unexpected SAE. Residual samples from the PK and ADA blood draws may be used for FBR, provided the participant has signed the FBR consent form.

16. For women of childbearing potential, a negative urine pregnancy test at screening and on day 1 is required for eligibility and at any visit before treatment is administered in either eye. 17. Blood draw should be performed only if the participant will be randomized, but prior to administering study treatment, at the specified visits.

18. The EOS visit (visit 15, week 52) will also represent the early termination visit.

Example 3: A Phase 3b Single-arm Study of Aflibercept 8 mg in Participants with Neovascular Age Related Macular Degeneration (nAMD) or diabetic macular edema (DME)-ELARA

[0611] Aflibercept administered at 8 mg by IVT injection of 70 pL (0.07 mL) at a concentration of 114.3 mg/mL, was approved for the treatment of nAMD, DME, and DR. The 8 mg regimen can be dosed at intervals of every 12 to 16 weeks in nAMD and DME or 12 weeks in DR. This extended durability reduces the burden of care for patients by reducing the number of injections per year. While such treatments allow extended dosing intervals of 8 weeks or longer in the vast majority of patients, there remains a patient population that may still require more frequent dosing, as often as every 4 weeks after the 3 initial monthly doses, either to establish or maintain disease control. A factor in the need for more frequent dosing is likely the individual rate of ocular clearance; in fact, the population PK model has demonstrated that a faster estimated ocular clearance was associated with qualifying for dose interval shortening in PULSAR and PHOTON. This study evaluated the effect of aflibercept 8 mg dosed every 4 weeks in participants with nAMD or DME previously treated with anti-VEGF injections.

Study Design

[0612] This is a phase 3b, multicenter, single-arm study to assess the safety and measures of efficacy of treatment with aflibercept 8 mg dosed every 4 weeks (8q4) in participants with nAMD

or DME previously treated with intravitreal (IVT) anti-vascular endothelial growth factor (VEGF) injections.

[0613] This study consists of a screening/enrollment visit, a treatment period, and an end-of-study (EOS) visit at week 96.

[0614] Eligibility will be assessed at the screening visit on day 1. Participants with nAMD or DME are eligible for screening if they have been previously treated with >3 anti-VEGF injections over the prior 5 months (-150 days). A total of up to 1000 participants (-500 participants with nAMD and -500 participants with DME) who meet all eligibility criteria will be enrolled.

[0615] The screening visit should be held approximately 4 to 7 weeks (25 to 49 days) after the most recent anti-VEGF injection and, for eligible participants, the initial study treatment will occur on the same day. Participants will receive a total of 7 injections of aflibercept 8q4, from baseline through week 24.

[0616] To assess the ability to extend dosing intervals with aflibercept 8 mg in this population, Dose Regimen Modification (DRM) criteria will be used to assess potential dose interval extensions, as well as subsequent dose interval shortening at each visit beginning at week 24. The minimum interval between injections is 4 weeks (28 days).

Dosage Regimen Modifications for Extending Intervals

[0617] Beginning at week 24, participants will be evaluated for dose interval extension. Dose intervals will be extended by 2 weeks when DRM-E criteria are met at any dosing visit as long as the dose interval has not been shortened previously. For participants who have had their dose interval shortened previously, the dose interval will only be extended by 1 week increments and only after a minimum of 12 weeks (84 days) has passed.

[0618] Participants will be eligible for interval extension if the following criteria are met at any dosing visit:

nAMD

• No retinal fluid in central subfield

AND

• No new onset foveal neovascularization or foveal hemorrhage

AND

• No interval shortening within the last 12 weeks (84 days)

DME

• CST <300 pm (<320 pm on Spectralis®)

AND

• <10 pm increase (worsening) from lowest (best) previous CST value

AND

• No interval shortening within the last 12 weeks (84 days)

Dosage Regimen Modifications for Shortening Intervals

[0619] If a participant’s interval has been extended, then the dose interval may be shortened by 1 week if the DRM-S criteria are met. If the DRM-S criteria are met at either a dosing or a non-dosing visit, the participant will be dosed, and the subsequent interval will be shortened to the time from the most recent dose minus 1 week. The minimum interval between injections will be every 4 weeks.

[0620] Participants will be eligible for interval shortening (by 1-week increments), if one of the following criteria are met at any scheduled visit:

nAMD

• Any new retinal fluid in the central subfield

OR

• New onset foveal neovascularization or foveal hemorrhage

OR

• >5 letter loss in BOVA from best previous attributable to recurrent or persistent disease

DME

• >25 pm increase in CST from previous visit

OR

• >10 letter loss in BCVA from best previous attributable to recurrent or persistent disease

[0621] DRM-E and DRM-S criteria will be assessed by the investigator. Participants who do not meet the above criteria for interval extension or shortening at a given visit will continue treatment at the current interval.

[0622] Participants will be seen every 4 weeks through week 24. After week 24, participants will return for dosing visits scheduled based on their DRM assessments. Dosing visits should be scheduled as close to the planned date as possible. Mandatory visits will occur approximately

every 12 weeks through the EOS visit for all participants, regardless of dosing schedule.

Mandatory visits can be moved to within the +/- 16-day visit window to be combined with dosing visits when the visit windows overlap (except visit 13, week 96). Participants may be seen for unscheduled visits at the investigator’s discretion at any time.

[0623] The primary analysis will occur once all participants have completed week 24 (or prematurely discontinued), with the final analysis occurring after all participants have completed the study at week 96 (or prematurely discontinued). Additional analyses may be performed at other timepoints, e.g., week 48.

[0624] Safety will be assessed by ophthalmic exams, collection of vital signs (including heart rate [HR] and blood pressure [BP]), and by evaluating the occurrence of AEs and SAEs.

Study Duration

[0625] The duration of the study for a participant is approximately 96 weeks. The definition for EOS is the last visit of the last participant in the study.

Population

[0626] The sample size for this study is up to 1000 participants (-500 participants with nAMD and -500 participant with DME).

[0627] Participants with nAMD or DME previously treated with at least 3 anti-VEGF injections in the 5 months (-150 days) prior to screening.

Inclusion Criteria for Participants with nAMD

1. Men or women >50 years of age

2. History of CNV lesions secondary to nAMD in the study eye, requiring continued anti-VEGF treatment, as determined by the investigator. Participants with polypoidal choroidal vasculopathy or retinal angiomatous proliferation in the study eye are eligible to participate in the study, and their condition should be documented.

Inclusion Criteria for Participants with DME

1. Men or women >18 years of age

2. History of DME with central involvement (in the central subfield on SD-OCT) in the study eye, requiring continued anti-VEGF treatment, as determined by the investigator

Inclusion Criteria for All Participants

1. Previously treated with >3 anti-VEGF IVT injections in the study eye in the 5 months (-150 days) prior to visit 1

2. History of response to anti-VEGF IVT injections in the study eye such that continued treatment is warranted.

3. Willing and able to comply with clinic visits and study-related procedures

4. Provide informed consent signed by study participant

Exclusion Criteria for Participants with nAMD

1. Evidence of CNV due to any cause other than nAMD in either eye

2. Subretinal hemorrhage in the study eye >~50% of the total lesion area per investigator 3. DME or DR, defined in the diabetic participants with nAMD as DR lesions in the assessable area of the retina in the study eye

Exclusion Criteria for Participants with DME

1. Evidence of macular edema due to any other cause other than diabetes mellitus in the study eye

2. Advanced age-related macular degeneration (nAMD or geographic atrophy) in the study eye 3. Active proliferative DR in the study eye

4. PRP or macular laser photocoagulation in the study eye within 12 weeks (84 days) of visit 1

Exclusion Criteria for All Participants

1. Prior IVT investigational agents in study eye

2. Prior IVT investigational agents in fellow eye

3. Prior treatment with pegcetacoplan injection or avacincaptad pegol injection at any time in the study eye

4. [INTENTIONALLY LEFT BLANK]

5. Prior treatment with gene therapy and/or cell therapy in the study eye

6. Prior treatment with gene therapy and/or cell therapy in the fellow eye

7. Use of topical steroids in the study eye within 4 weeks (28 days) of visit 1

8. Previous use of intraocular or periocular corticosteroids in the study eye within 120 days of visit 1

9. Use of any IVT implantable agents (e.g., Iluvien®, Ozurdex®, Susvimo®) at any time in the study eye

10. Treatment with ocriplasmin in the study eye at any time

11. YAG capsulotomy in the study eye within 14 days of visit 1

12. History of vitreoretinal surgery (including scleral buckling) in the study eye

13. Any other intraocular surgery in the study eye within 12 weeks (84 days) of visit 1

14. IOP >25 mm Hg in the study eye

15. Evidence of infectious blepharitis, keratitis, scleritis, or conjunctivitis in study eye

16. Any intraocular inflammation/infection in study eye within 90 days of visit 1

17. Any intraocular inflammation/infection in fellow eye within 90 days of visit 1

18. Any history of macular hole of stage 2 and above in the study eye

19. Concurrent disease that causes substantial decrease of BCVA, is expected to limit BCVA recovery, or is likely to require medical or surgical intervention during the study in the study eye 20. Structural damage in the study eye that is likely to preclude improvement in BCVA following the resolution of macular edema (e.g., atrophy of the retinal pigment epithelium, preretinal fibrosis, subretinal fibrosis or scar, significant macular ischemia, or organized hard exudates) 21. Current iris neovascularization, vitreous hemorrhage, ortractional retinal detachment visible in the study eye

22. Inability to perform ophthalmic exams, obtain fundus photographs, FA, or OCT (e.g., due to media opacity, allergy to fluorescein dye or lack of venous access) in the study eye

23. History of corneal transplant in the study eye

24. Any corneal dystrophy affecting the visual axis in the study eye

25. Aphakia, or pseudophakia with absence of posterior capsule (unless it occurred as a result of a YAG posterior capsulotomy) in the study eye

26. Any concurrent ocular condition in the study eye which could either increase the risk to the participant beyond what is to be expected from standard procedures of IVT injections, or which otherwise may interfere with the injection procedure or with evaluation of efficacy or safety 27. Any prior systemic anti-VEGF administration

28. Uncontrolled BP (defined as systolic >140 mm Hg or diastolic >90 mm Hg)

29. History of cerebrovascular accident or myocardial infarction within 180 days of visit 1 30. Renal failure, dialysis, or history of renal transplant

31. Known sensitivity to any of the compounds of the study formulation

32. History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect interpretation of the results of the study or render the participant at high risk for treatment complications

33. Members of the clinical site study team and/or his/her immediate family, unless prior approval granted by the sponsor

34. Participation in an investigational study within 30 days prior to screening visit that involved treatment with any drug (excluding vitamins and minerals) or device

35. Pregnant or breastfeeding women.

36. Men and WOCBP* who are unwilling to practice highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 4 months (120 days) after the last dose. Highly effective contraceptive measures include:

a. stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening;

b. IUD; IUS;

c. bilateral tubal occlusion/ligation;

d. vasectomy**

e. condom plus contraceptive sponge, foam, or jelly, or diaphragm plus contraceptive sponge, foam, or jelly; and/or

f. sexual abstinence!, t- Pregnancy testing and contraception are required for WOCBP. Pregnancy testing and contraception are not required for women who are post-menopausal or permanently sterile. *WOCBP are defined as women who are fertile following menarche until becoming postmenopausal, unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.

A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A FSH level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a postmenopausal state. The above definitions are according to the CTFG guidance. Pregnancy testing and contraception are not required for women with documents hysterectomy or tubal ligation.

**Vasectomized partner (provided that the male vasectomized partner is the sole sexual partner of the WOCBP study participants) or vasectomized study participants must have received medical assessment of the surgical success for the procedure.

fSexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the participant.

^Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and LAM are not acceptable methods of contraception. Female condom and male condom should not be used together.

Study Eye Population

[0628] Only 1 eye per participant will be enrolled as the study eye. For participants who meet eligibility criteria in both eyes, the eye that is expected to require more frequent treatment should be chosen as the study eye based on investigator discretion. The study eye selection will be decided based on the investigator’s discretion at baseline and must not be changed during the course of the study. The non-study eye is then considered as the “fellow eye.”

Treatment

[0629] Aflibercept (8 mg) administered by IVT injection every 4 weeks, followed by dosing interval extension and shortening after week 24 through the week 96 visit, with a minimum dosing interval of 4 weeks.

Table 3-1. Study Intervention(s) Administered

Intervention Label Aflibercept

Intervention Name Aflibercept 8 mg

Intervention Description IVT injection

Type Biologic

Dose Formulation Liquid formulation

Unit Dose Strength(s) 114.3 mg/mL

Dosage Level(s) 8 mg (70 pL)

Route of Administration IVT

Frequency Every 4 weeks through week 24, followed by “treat- and-extend” based on DRM criteria.

Use Experimental

Intervention Label Aflibercept

IMP IMP

Sourcing Provided centrally by the sponsor

Abbreviations: DRM=dose regimen modification; IMP= investigational medicinal product; IVT= intravitreal.

[0630] Fellow eye treatment will be allowed with aflibercept 8 mg at the investigator’s discretion and supplied through IWRS. The treated fellow eye will not be considered an additional study eye. There is no alternative rescue treatment defined for this study.

Concomitant Medications

[0631] All of the participants took at least 1 concomitant medication, with 103 (81.7%) participants taking medications coded to the ATC level 2 class of Ophthalmologicals. Four (3.2%) participants had treatment-emergent ocular procedures in the study eye including Cataract operation, Laser surgery, Vitrectomy, and Paracentesis eye procedure. Two (1.6%) participants had treatment-emergent ocular procedures in the fellow eye including Paracentesis eye procedure and Laser surgery. It should be noted that some instances of Paracentesis eye procedure were erroneously categorized as non-ocular, and 1 participant received an anterior chamber paracentesis that was not coded prior to the database lock. On further investigation, it was determined that 5 participants received at least 1 Paracentesis eye procedure in the study eye, and of these participants, 3 received at least 1 Paracentesis eye procedure in the fellow eye. These participants were all enrolled at the same site, and all but 1 received this procedure for prophylaxis of increased IOP post IVT injection. Only 1 Paracentesis eye procedure was performed in the study eye in response to an AE of Elevated IOP.

Procedures and Assessments

[0632] Safety and efficacy procedures: ocular examination including BOVA and refraction, intraocular pressure (IOP), slit-lamp examination, indirect ophthalmoscopy, fluorescein angiography (FA), and fundus photography (FP), SD-OCT, ophthalmic exams, vital signs, and evaluating the occurrence of AEs and SAEs.

Statistical Plan

[0633] The sample size of up to 1000 participants (-500 participants with nAMD and -500 participants with DIVIE) will provide information on safety in these populations.

[0634] For the primary analysis, participants with at least one ocular TEAE (and serious TEAE) in the study eye and participants with at least one non-ocular TEAE (and serious TEAE) through week 24 will be summarized using descriptive statistics in the SAF population. The SAF population includes all enrolled participants who received at least 1 injection of aflibercept 8 mg during the study. Exploratory efficacy endpoints will be analyzed descriptively.

Primary Objective

• To evaluate the safety of aflibercept 8 mg

Exploratory Objective

• To determine the effect of aflibercept 8 mg on anatomic and functional measures of response • To determine if these participants can extend their dosing intervals after week 24 through week 96

• To continue to evaluate the safety of aflibercept 8 mg through the end of the study

Primary Endpoint

• Occurrence of TEAEs and serious TEAEs through week 24

Exploratory Endpoints

• Change[PM182] in BCVA from baseline at weeks 24 and 96

• Gain or loss of >5, 10, and 15 letters at weeks 24 and 96

• Change in CST from baseline at weeks 24 and 96

• Presence or absence of fluid (IRF and/or SRF) at the center subfield and/or foveal center at weeks 24 and 96

• Extension of dosing interval past 4 weeks at any point after week 24 through week 96

• Occurrence of TEAEs and serious TEAEs through week 96 Table 3-2. Schedule of Events

V V V V V MV MV D MV MVs D MV EOS MV Study Procedure* V1¹ V7² DVs² DVs² DVs² DVs²

2 3 4 5 6 8 9 Vs² 10 11 Vs² 12 13¹² e k s 0 4 8 12 16 20 24 28-35 3 37-47 3 49- 3 61-71 3 73- W e ( ) 3

36 48 60 72 84 85-95 96

59 83

197- 267- 351- 435- 519- 603- Study Day 1 29 57 85 113 141 169 253 337 421 505 589 673

239 323 407 491 575 659 Window (days) ±5 ±5 ±5 ±5 ±5 ±5 ±2 ±16 ±2 ±16 ±2 ±16 ±2 ±16 ±2 ±16 ±2 ±5 Informed Consent

X

(ICF)

Inclusion/

X

Exclusion

Medical History X

Demographics X

Concomitant

X X X X X X X X X X X X X X X X X X X medications

2

DRM Assessment X X X X X X X X X X X X

Study

4 X X X X X X X x² x^2,3 x² x^2,3 x² X²’³ x² X²’³ x² X²’³ x²

Drug Administration

5

BCVA/ refraction X X X X X X X X X X X X X X X X X X X 6

IOP X X X X X X X X X X X X X X X X X X X

Slit-lamp exam X X X X X X X X X X X X X X X X X X X Indirect

X X X X X X X X X X X X X X X X X X X

ophthalmoscopy⁷

FA, FP⁸ X X X X X 9

SD-OCT X X X X X X X X X X X X X X X X X X X 10

Vital signs X X X X X X X X X X X X X X X X X X X Adverse events X X X X X X X X X X X X X X X X X X X Pregnancy Test¹¹ X X X X X X X X X X X X X X X X X X

(Urine only)

⁺V=visit; DVs=dosing visits (Based on DRM); MV=mandatory visit

1. Participants who meet all eligibility criteria will be treated on the same day. Screening should take place approximately 4 to 7 weeks (25 to 49 days) after the last treatment.

2. Participants’ study eye will be assessed based on DRM criteria starting at week 24. If DRM criteria are met, the participant will be dosed at that visit and the next dose will be given at the updated interval. Subsequently, dosing visits will be scheduled as needed based on an individual participant’s dosing interval, as determined by DRM assessments. Dosing visits should be scheduled as close to the planned dosing date as possible and will be combined with Mandatory visits as appropriate; it is expected that participants only complete the visits that coincide with their dosing schedule and the mandatory visits (see footnote #3).

3. Participants will return at least every 12 weeks for mandatory visits, regardless of whether a dose is required at that visit. However, whenever possible, the Mandatory visits (except visit 13, week 96) should be moved to be combined with a dosing visit if the dosing visit is scheduled 1) at the same time point, 2) 1 or 2 weeks before, or 3) 1 or 2 weeks after, given that the visit window for the Mandatory visit is +/-16 days. If a participant is scheduled for both a dosing visit 2 weeks before AND 2 weeks after a Mandatory visit, the Mandatory visit should be conducted with the earlier dosing visit, when possible.

4. Following study drug injection, participants will be observed for approximately 30 minutes. 5. Participants enrolled at sites that are participating in the optional autorefraction visual acuity substudy may undergo additional visual function tests.

6. IOP will be measured at all study visits (bilaterally). On days when the study drug is administered, IOP should be measured predose (bilaterally) and approximately 30 minutes after administration of study drug (study eye only). IOP will be measured using applanation tonometry (e.g., Goldmann applanation tonometry, Perkins tonometer), combined applanation and indentation (e.g., Tono-pen®), or rebound tonometry (e.g., Icare), and the same method of measurement must be used in each participant throughout the study.

7. Indirect ophthalmoscopy will be performed pre-dose bilaterally at all visits. On days when study drug is administered, it should also be performed immediately after administration of study drug (study eye only).

8. FA and FP should be performed prior to administration of study drug, when applicable. For FA, the study eye will be the transit eye and images should be collected using the widest field available. If available, sites should also submit an optional ultra-widefield color photograph for DME participants.

9. Wherever possible, the same SD-OCT imaging system should be used at all study visits in each participant. Images will be taken in both eyes before dosing at each required visit.

10. Vital signs (HR and BP) should be measured pre-injection. When possible, BP assessments will be taken using AOBP with the Microlife WatchBP Office AFIB BP device (or comparable). BP assessments will be taken by the device in triplicate and a mean measure as displayed will be recorded in the EDC.

11. For WOCBP, a negative urine pregnancy test at screening is required for eligibility and before treatment is administered in either eye at subsequent visits.

12. The EOS visit (visit 13, week 96) cannot be combined with a dosing visit. This visit will also represent the early termination visit.

Results

[0635] The change in BOVA from baseline is the only exploratory endpoint. No primary efficacy analyses were performed. The mean (SD) BCVA (measured by ETDRS letter score) at baseline was 71.8 (12.0) (n=126). The mean change in BCVA from baseline using OC at week 4 was 0.2 letters (n=126); at week 8 was 0.4 letters (n=124); at week 12 was 1.6 letters (n=121 ); at week 16 was 1.9 letters (n=57) and at week 20 was 7.0 letters (n=1 ) (see Table 3-3).

Table 3-3. Summary of BCVA Score by Visit (OC) (SAF)

Value at Visit Change from Baseline Mean Min: Mean Min: Indication Visit n (SD) Median Q1: Q3 Max n (SD) Median Q1: Q3 Max nAMD Baseline 77 70.9 74.0 62.0: 29: 94

(N=77) (12.7) 79.0

Week 4 77 70.2 74.0 63.0: 0: 94 77 -0.7 0.0 -3.0: -90: 16

(14.8) 80.0 (1 1.5) 4.0 Week 8 76 70.8 74.0 65.0: 10: 92 76 -0.3 1.0 -3.0: -80: 15

(13.8) 79.5 (10.9) 4.0 Week 74 72.6 74.0 67.0: 33: 93 74 1.4 (6.0) 1.0 -3.0: -17: 21 12 (1 1.6) 80.0 5.0 Week 33 72.6 74.0 68.0: 30: 92 33 1.2 (6.7) 1.0 -4.0: -7: 23 16 (12.8) 82.0 4.0 Week 1 69.0 (-) 69.0 69.0: 69: 69 1 7.0 (-) 7.0 7.0: 7.0 7: 7 20 69.0

DME Baseline 49 73.1 75.0 66.0: 45: 94

(N=49) (10.8) 80.0

Week 4 4974.6 (9.6) 77.0 67.0: 50: 95 49 1.5 (5.1) 1.0 -1.0: -1 1: 17

80.0 4.0 Week 8 4874.3 (9.6) 76.0 67.5: 53: 92 48 1.6 (6.0) 2.0 -1.5: -17: 17

81.5 5.5 Week 4775.0 (8.3) 75.0 68.0: 55: 89 47 1.9 (6.3) 2.0 -1.0: -12: 20 12 81.0 6.0 Week 2475.0 (8.3) 75.5 68.0: 55: 88 24 3.0 (6.7) 3.0 -1.0: -7: 22 16 82.0 5.0 Week 0 0

20

Total Baseline 126 71.8 74.0 64.0: 29: 94

(N=126) (12.0) 80.0

Week 4 126 71.9 75.0 65.0: 0: 95 126 0.2 (9.5) 0.0 -2.0: -90: 17

(13.1) 80.0 4.0 Week 8 124 72.1 75.0 66.5: 10: 92 124 0.4 (9.4) 1.0 -2.0: -80: 17

(12.4) 80.0 5.0 Week 121 73.5 74.0 68.0: 33: 93 121 1.6 (6.1) 2.0 -2.0: -17: 21 12 (10.5) 80.0 5.0

Value at Visit Change from Baseline Mean Min: Mean Min: Indication Visit n (SD) Median Q1: Q3 Max n (SD) Median Q1: Q3 Max Week 57 73.6 75.0 68.0: 30: 92 57 1.9 (6.7) 1.0 -3.0: -7: 23 16 (11.1) 82.0 5.0 Week 1 69.0 (-) 69.0 69.0: 69: 69 1 7.0 (-) 7.0 7.0: 7.0 7: 7 20 69.0

Abbreviations: DME=diabetic macular edema; nAMD=neovascular age-related macular degeneration; OC=observed cases; Q1=quartile 1; Q3=quartile 3; SAF=safety analysis set; SD=standard deviation.

[0636] Other data relating to this study are summarized in the Tables below.

Table 3-4. Demographics and Baseline Characteristics (SAF)

nAMD DME Total (N=77) (N=49) (N=126) Age (years)

n 77 49 126 Mean (SD) 77.7 (8.6) 61.3 (9.1) 71.3 (11.9) Median 77.0 61.0 72.0 Q1: Q3 73.0: 84.0 55.0: 69.0 62.0: 81.0 Min: Max 60: 98 40: 85 40: 98 Age Group, n (%)

<55 years 0 11 11 (8.7%)

(22.4%)

>55 - <65 years 6 (7.8%) 20 26

(40.8%) (20.6%) >65 - <75 years 20 16 36

(26.0%) (32.7%) (28.6%) >75 - <85 years 34 1 (2.0%) 35

(44.2%) (27.8%) >85 years 17 1 (2.0%) 18

(22.1%) (14.3%) Ethnicity, n (%)

Hispanic or Latino 6 (7.8%) 3 (6.1%) 9 (7.1%) Not Hispanic or Latino 71 46 117

(92.2%) (93.9%) (92.9%) Not Reported 0 0 0 Race, n (%)

White 74 38 112

(96.1%) (77.6%) (88.9%) Black or African American 1 (1.3%) 8 9 (7.1%)

(16.3%)

nAMD DME Total (N=77) (N=49) (N=126) Asian 1 (1.3%) 2 (4.1%) 3 (2.4%) American Indian or Alaska Native 0 1 (2.0%) 1 (0.8%) Native Hawaiian or Other Pacific 0 0 0 Islander

Not Reported 0 0 0 Other 0 0 0 Multiple 1 (1.3%) 0 1 (0.8%) Sex, n (%)

Male 35 25 60

(45.5%) (51.0%) (47.6%) Female 42 24 66

(54.5%) (49.0%) (52.4%)

Abbreviations: DME=diabetic macular edema; Max=maximum; Min=minimum; nAMD=neovascular age-related macular degeneration; Q1 = quartile 1; Q3=quartile 3;

SD=standard deviation; SAF=safety analysis set

Table 3-4A. Baseline Disease Characteristics (SAF)

nAMD DME Total (N=77) (N=49) (N=126) BCVA in study eye (ETDRS letters)

n 77 49 126 Mean (SD) 70.9 (12.7) 73.1 (10.8) 71.8 (12.0) Median 74.0 75.0 74.0 Q1: Q3 62.0: 79.0 66.0: 80.0 64.0: 80.0 Min: Max 29: 94 45: 94 29: 94 BCVA category in study eye, n (%)

<38 letters 2 (2.6%) 0 2 (1.6%) >38 - <73 letters 36 (46.8%) 22 (44.9%) 58 (46.0%) >73 letters 39 (50.6%) 27 (55.1%) 66 (52.4%) IOP in study eye (mmHg)

n 77 49 126 Mean (SD) 14.6 (3.1) 14.9 (3.2) 14.7 (3.1) Median 14.0 15.0 14.0 Q1: Q3 12.0: 17.0 12.0: 17.0 12.0: 17.0 Min: Max 9: 21 9: 22 9: 22 SBP (mmHg)

n 77 49 126 Mean (SD) 128.9 (10.2) 125.1 (13.0) 127.4 (11.5) Median 130.0 129.0 130.0 Q1: Q3 123.0: 137.0 120.0: 134.0 120.0: 137.0

nAMD DME Total (N=77) (N=49) (N=126) Min: Max 104: 160 87: 140 87: 160 DBP (mmHg)

n 77 49 126 Mean (SD) 71.3 (9.6) 73.2 (10.5) 72.1 (10.0) Median 72.0 75.0 72.0 Q1: Q3 65.0: 79.0 66.0: 80.0 65.0: 80.0 Min: Max 52: 89 43: 88 43: 89 History of hypertension, n (%)

Yes 63 (81.8%) 37 (75.5%) 100 (79.4%) No 14 (18.2%) 12 (24.5%) 26 (20.6%) History of cerebrovascular disease, n

(%)

Yes 2 (2.6%) 6 (12.2%) 8 (6.3%) No 75 (97.4%) 43 (87.8%) 118 (93.7%) History of ischaemic heart disease, n

(%)

Yes 6 (7.8%) 5 (10.2%) 11 (8.7%) No 71 (92.2%) 44 (89.8%) 115 (91.3%) Abbreviations: BCVA=best-corrected visual acuity; DBP=diastolic blood pressure;

DME=diabetic macular edema; ETDRS=early treatment diabetic retinopathy study;

IOP=intraocular pressure; Max=maximum; Min=minimum; nAMD=neovascular age-related macular degeneration; Q1 =quartile; Q3=quartile; SAF=safety analysis set; SBP=systolic blood pressure; SD=standard deviation.

Table 3-5. Administration of Study Treatment in the Study Eye (SAF)

nAMD DME Total (N=77) (N=49) (N=126) Duration of treatment exposure (weeks) [1]

n 77 49 126 Mean (SD) 17.6 (3.1) 18.0 (2.3) 17.8 (2.8) Median 16.7 17.0 16.7 Q1: Q3 16.1: 20.0 16.0: 20.0 16.0: 20.0 Min: Max 4: 24 12: 21 4: 24 Total number of administrations of study 335 217 552 treatment

Number of administrations of study treatment

n 77 49 126 Mean (SD) 4.4 (0.8) 4.4 (0.6) 4.4 (0.7) Median 4.0 4.0 4.0 Q1: Q3 4.0: 5.0 4.0: 5.0 4.0: 5.0 Min: Max 1: 6 3: 5 1: 6

nAMD DME Total (N=77) (N=49) (N=126) Number of administrations of study treatment,

n(%) 1 2 (2.6%) 0 2(1.6%) 2 0 0 0 3 1 (1.3%) 2 (4.1%) 3 (2.4%) 4 41 (53.2%) 24 (49.0%) 65 (51.6%) 5 32 (41.6%) 23 (46.9%) 55 (43.7%)

6 1 (1.3%) 0 1 (0.8%) [1] Duration of treatment exposure is defined as: [(last study treatment date) - (first study treatment date) + 28]/7 (28 days are added because of the minimum 4-week dosing interval in the study).

Abbreviations: DME=diabetic macular edema; Max=maximum; Min=minimum; nAMD=neovascular age-related macular degeneration; Q1 =quartile; Q3=quartile; SAF=safety analysis set; SD=standard deviation.

Table 3-6. Overview of Treatment-Emergent Adverse Events (SAF)

nAMD DME Total (N=77) (N=49) (N=126) Participants with at least one

TEAE 25 (32.5%) 27 (55.1%) 52 (41.3%) Ocular 15 (19.5%) 12 (24.5%) 27 (21.4%) Study eye 11 (14.3%) 9 (18.4%) 20 (15.9%) Fellow eye 7 (9.1%) 9 (18.4%) 16 (12.7%) Non-ocular 16 (20.8%) 20 (40.8%) 36 (28.6%) Study treatment-related TEAE 2 (2.6%) 0 2 (1.6%) Ocular 2 (2.6%) 0 2 (1.6%) Study eye 2 (2.6%) 0 2 (1.6%) Non-ocular 0 0 0 Injection procedure-related TEAE 5 (6.5%) 6 (12.2%) 11 (8.7%) Ocular 5 (6.5%) 6 (12.2%) 11 (8.7%) Study eye 5 (6.5%) 4 (8.2%) 9 (7.1%) Non-ocular 0 1 (2.0%) 1 (0.8%) TEAE leading to study treatment 0 0 0 discontinuation

Ocular 0 0 0 Study eye 0 0 0

Non-ocular 0 0 0 TEAE with maximum severity

Ocular

Study eye

nAMD DME Total (N=77) (N=49) (N=126) Mild 9 (11.7%) 7 (14.3%) 16 (12.7%) Moderate 1 (1.3%) 2 (4.1%) 3 (2.4%) Severe 1 (1.3%) 0 1 (0.8%) Non-ocular

Mild 11 (14.3%) 11 (22.4%) 22 (17.5%) Moderate 4 (5.2%) 6 (12.2%) 10 (7.9%) Severe 1 (1.3%) 3 (6.1%) 4 (3.2%) TE-SAE 2 (2.6%) 4 (8.2%) 6 (4.8%) Ocular 1 (1.3%) 0 1 (0.8%) Study eye 1 (1.3%) 0 1 (0.8%) Fellow eye 0 0 0

Non-ocular 1 (1.3%) 4 (8.2%) 5 (4.0%) Study treatment-related TE-SAE 0 0 0 Ocular 0 0 0 Study eye 0 0 0

Non-ocular 0 0 0 Injection procedure-related TE-SAE 1 (1.3%) 0 1 (0.8%) Ocular 1 (1.3%) 0 1 (0.8%) Study eye 1 (1.3%) 0 1 (0.8%) Non-ocular 0 0 0 TEAE leading to death 0 0 0

TE intraocular inflammation event of study 1 (1.3%) 0 1 (0.8%) eye

TE hypertension event 2 (2.6%) 0 2 (1.6%) TEAEs up to 30 days after the last dose of study treatment were summarized for participants who withdrew from the study. All TEAEs were summarized for ongoing participants.

Abbreviations: DME=diabetic macular edema; nAMD=neovascular age-related macular degeneration; SAE=serious adverse event; SAF=safety analysis set; TEAE=treatment-emergent adverse event; TE=treatment-emergent.

Table 3-7. Ocular Treatment-Emergent Adverse Events in the Study Eye by Primary System Organ Class and Preferred Term (SAF)

Primary System Organ Class nAMD DME Total Preferred Term (N=77) (N=49) (N=126) Number of participants with at least one such 11 (14.3%) 9 (18.4%) 20 (15.9%) TEAE, n (%)

Eye disorders 11 (14.3%) 9 (18.4%) 20 (15.9%) Conjunctival haemorrhage 5 (6.5%) 2 (4.1%) 7 (5.6%) Vitreous floaters 0 4 (8.2%) 4 (3.2%) Eye pain 2 (2.6%) 0 2 (1.6%) Ocular hypertension 0 2 (4.1%) 2 (1.6%) Cataract 0 1 (2.0%) 1 (0.8%) Dry eye 1 (1.3%) 0 1 (0.8%) Ectropion 1 (1.3%) 0 1 (0.8%) Eye inflammation 1 (1.3%) 0 1 (0.8%) Foreign body sensation in eyes 1 (1.3%) 0 1 (0.8%) Posterior capsule opacification 0 1 (2.0%) 1 (0.8%) Retinal detachment 1 (1.3%) 0 1 (0.8%) Vitreous detachment 1 (1.3%) 0 1 (0.8%) Investigations 1 (1.3%) 0 1 (0.8%) Intraocular pressure increased 1 (1.3%) 0 1 (0.8%) TEAEs up to 30 days after the last dose of study treatment were summarized for participants who withdrew from the study. All TEAEs were summarized for ongoing participants.

The table is sorted in descending order by the frequency of system organ class and preferred term in the total group.

Abbreviations: DME=diabetic macular edema; MedDRA=Medical Dictionary for Regulatory Activities; nAMD=neovascular age-related macular degeneration; SAF=safety analysis set; TEAE=treatment-emergent adverse event.

Table 3-8. Summary and Change from Baseline to Pre-dose Intraocular Pressure in Study Eye (mmHg) (SAF)

Value at Visit Change from Baseline Mean Min: Mean Min: Indication Visit n (SD) Median Q1: Q3 Max n (SD) Median Q1: Q3 Max nAMD Baseline 77 14.6 14.0 12.0: 9: 21

(N=77) (3.1) 17.0

Week 4 77 14.3 14.0 12.0: 9: 21 77-0.3 (2.9) 0.0 -2.0: -10: 5

(3.1) 16.0 2.0 Week 8 76 14.4 14.0 12.0: 10: 24 76-0.1 (3.3) 0.0 -1.5: -9: 8

(2.8) 16.5 2.0 Week 74 14.7 15.0 12.0: 8: 21 74 0.1 (3.4) 1.0 -2.0: -10: 7 12 (3.0) 17.0 2.0

Value at Visit Change from Baseline Mean Min: Mean Min: Indication Visit n (SD) Median Q1: Q3 Max n (SD) Median Q1: Q3 Max Week 33 13.7 13.0 12.0: 7: 21 33-0.6 (3.3) 0.0 -3.0: -10: 5 16 (3.2) 16.0 1.0 Week 1 15.0 (-) 15.0 15.0: 15: 15 1 4.0 (-) 4.0 4.0: 4.0 4: 4 20 15.0

DME Baseline 49 14.9 15.0 12.0: 9: 22

(N=49) (3.2) 17.0

Week 4 49 14.6 14.0 12.0: 9: 21 49-0.2 (3.4) 0.0 -2.0: -8: 6

(3.2) 17.0 2.0 Week 8 48 14.8 15.0 13.0: 7: 21 48 0.0 (3.6) 0.0 -2.5: -12: 7

(3.2) 17.0 3.0 Week 47 14.9 15.0 13.0: 9: 22 47 0.0 (3.1) -1.0 -2.0: -8: 7 12 (3.2) 17.0 2.0 Week 24 15.0 15.0 13.0: 10: 23 24 0.1 (3.3) 0.5 -2.0: -6: 5 16 (3.0) 17.0 3.0 Week 0 0

20

Total Baseline 126 14.7 14.0 12.0: 9: 22

(N=126) (3.1) 17.0

Week 4 126 14.4 14.0 12.0: 9: 21 126-0.3 (3.1) 0.0 -2.0: -10: 6

(3.1) 17.0 2.0 Week 8 124 14.6 14.0 13.0: 7: 24 124-0.1 (3.4) 0.0 -2.0: -12: 8

(2.9) 17.0 2.0 Week 121 14.8 15.0 12.0: 8: 22 121 0.0 (3.3) 0.0 -2.0: -10: 7 12 (3.1) 17.0 2.0 Week 57 14.3 13.0 12.0: 7: 23 57-0.3 (3.3) 0.0 -2.0: -10: 5 16 (3.2) 16.0 2.0 Week 1 15.0 (-) 15.0 15.0: 15: 15 1 4.0 (-) 4.0 4.0: 4.0 4: 4 20 15.0

Abbreviations: DME=diabetic macular edema; nAMD=neovascular age-related macular degeneration; Q1 =quartile 1; Q3=quartile 3; SAF=safety analysis set; SD=standard deviation

[0637] At the time of the data cutoff, a total of 126 participants were enrolled into the study and treated with a mean of 4.4 (range 1 to 6) 8 mg IVT injections, with a treatment exposure of 4 to 24 weeks in the study eye.

[0638] At the data cutoff, there were no new safety signals identified. The safety profile is consistent with other studies conducted with aflibercept (8 mg and 2 mg) in participants with DME, nAMD and DR. Overall, 20 (15.9%) participants reported ocular TEAEs in the study eye, (1 1 [14.3%] participants in the nAMD group and 9 [18.4%] participants in the DME group). The majority of the reported ocular TEAEs were mild in severity, and the only severe ocular TEAE was an SAE of Retinal detachment in the study eye of 1 participant from the nAMD group.

Retinal detachment was assessed by the investigator as not related to the study drug and related to the injection procedure. No action was taken with the study drug due to the SAE and the outcome was reported as resolved with sequelae. The TEAEs of Conjunctival haemorrhage and Eye inflammation, reported in 1 participant each from the nAMD group, were considered to be related to study drug by the investigator. Conjunctival haemorrhage was also observed as the most frequently reported TEAE related to the Injection Procedure. These ocular TEAEs are consistent with TEAEs typically seen with IVT injections. There were 5 (4.0%) participants who experienced non-ocular SAEs; with none considered related to study drug or injection procedure by the investigator. There were no study-drug-related serious TEAEs. There were no deaths reported.

[0639] Change from baseline in IOP and BCVA were summarized and no significant safety concerns were identified. Based on this data review, no new safety concerns for aflibercept 8 mg were identified.

[0640] As of the data cutoff, treatment with aflibercept 8 mg every 4 weeks was well tolerated with no new safety signals identified. The observed TEAEs occurred at low rates. Ocular TEAEs were mostly mild in severity and all but 2 were unrelated to study drug. There were no deaths reported.

• As of the data cutoff, there were no new safety signals with aflibercept 8 mg dosed every 4 weeks (8q4) in participants with nAMD or DME.

Results at week 24

[0641] Preliminary findings from 417 previously treated patients with nAMD or DME showed meaningful improvements in BCVA and CST were achieved with aflibercept 8q4 at Week 24. Furthermore, the safety profile of aflibercept 8q4 through Week 24 was consistent with the established safety profile of both aflibercept 2 mg and 8 mg. See Table 3-9 and Table 3-10.

Table 3-9. Mean change in BCVA (ETDRS letters) in nAMD and DME Cohorts

Week nAMD (n=242)‘ DME (n=175)*

0 0 0.0

4 0.2 1.5

8 0.5 2

12 1.2 2.1

16 1.7 2.4

20 2 3.2

24 2.3 2.9

Mean BCVA at BL: 70.0 11876WO01 # Mean BCVA at BL: 71.4

Table 3-10. Mean change in CST, pm

Week nAMD (n=236)^A DME (n=175)^$

0 0 0.0

4 -27.33 -30.85

8 -28.02 -32.77

12 -28.88 -37.94

16 -30.5 -42.71

20 -30.45 -45.26

24 -32.27 -48.96

^A Mean CST at BL: 259.9

$ Mean CST at BL: 333.6

Observed cases.

nAMD: n=242 for mean change in BCVA; n=236 for mean change in CST; DME: n=175 for both mean change in BCVA and CST.

BCVA, best-corrected visual acuity; BL, baseline; CST, central subfield thickness; ETDRS, Early Treatment Diabetic Retinopathy Study.

Example 4: Population Pharmacokinetic Analysis of Aflibercept in Patients with Macular Edema Secondary to Retinal Vein Occlusion

[0642] The objectives of this analysis were to:

• Evaluate and potentially refine the previously developed population pharmacokinetic (PK) model for aflibercept

• Characterize the PK of free and adjusted bound aflibercept in patients with macular edema following retinal vein occlusion (MEfRVO) in comparison to patients with neovascular (wet) age-related macular degeneration (nAMD) or diabetic macular edema (DME)

• Compare the accumulation of free and adjusted bound aflibercept in plasma after 3 or 5 initial monthly intravitreal (IVT) injections

Summary of Observed Data

[0643] The dataset used for this PK analysis was constructed by adding the data available at the time of the database lock performed at week 36 of the QUASAR study to an existing analysis dataset previously built using the data from 16 other clinical trials. Participants enrolled in the QUASAR study experienced MEfRVO and were randomized to repeated IVT administrations of 2-mg aflibercept every 4 weeks (Q4W) or high dose (HD) aflibercept every 8

weeks (Q8W) (following either 3 or 5 initial monthly injections). As such, the QUASAR study contributed PK information collected in a disease population and dosing regimens of HD aflibercept that were not represented in the prior analysis dataset.

[0644] This PK analysis evaluated concentrations of aflibercept that was free in plasma or bound to vascular endothelial growth factor (VEGF). For purpose of analysis, the concentrations of aflibercept bound to VEGF were expressed in terms of mass unit of aflibercept in the aflibercept: VEGF complex per unit of volume and were referred to as adjusted bound aflibercept.

[0645] Overall, the analysis dataset included free and adjusted bound aflibercept concentrations in plasma collected in 17 clinical studies: 1 study in MEfRVO (QUASAR), 13 studies in nAMD or DME (VGFT-QD-0305, VGFT-QD-0306, VGFT-QD-0307, VGFT-QD-0502 part A and part C, VGFT-OD-512, VGFT-QD-603, VGFT-QD-0702. PK, VGFT-QD-0706. PK, 311523, 91745, CANDELA, PHOTON, and PULSAR), 2 studies in healthy male subjects (PDY6655 and PDY6656), and 1 study in participants with solid tumors or lymphoma (TED6113).

[0646] This dataset comprised 883 participants with MEfRVO, 1,662 participants with nAMD, 968 participants with DME, 76 healthy participants, and 38 oncology participants. A total of 19,238 free aflibercept concentrations and 19,296 adjusted bound aflibercept concentrations were included, with 61.7% and 16.1% of samples below the lower limit of quantitation (LLOQ) respectively. Across studies conducted in participants with nAMD, DME, or MEfRVO, PK data were mostly collected using sparse sampling schedules, with limited samples obtained shortly after administration. Among the participants to the QUASAR study included in the analysis dataset, 299 participants received 2 mg aflibercept Q4W, 290 participants received HD aflibercept Q8W following 3 monthly initial injections, and 294 participants received HD aflibercept Q8W following 5 monthly initial injections. While >92% of participants with MEfRVO had concentrations of free and/or adjusted bound aflibercept measured up to the week 24 visit of the QUASAR study, only 264 out of 883 participants (-30.0%) had measured concentrations in samples collected at the week 36 visit.

[0647] The population median age was 70 years across all studies, with a median baseline body weight of 75.3 kg. Average age and body weight differed across disease populations. For instance, median age values were respectively 13 or 9 years lower in participants with DME or MEfRVO than in participants with nAMD. Median body weight values were respectively 9.3 or 2.3 kg higher in participants with DME or MEfRVO than in participants with nAMD. Median baseline concentrations of albumin in serum were similar across all patient populations included

in the analysis population (4.40 g/dL). The analysis population included slightly more male (51.4%) than female participants (48.6%). The majority of the participants were classified as white (74.0%), while the rest of the population was divided between participants classified as Asians (19.6%), Black or African American (2.67%), American Indian or Alaska Native (0.138%), Native Hawaiian or other Pacific Islander (0.110%), other categories (0.634%), and unreported categories (2.81%). Additionally, most participants had normal renal function (31.6%) or mild impairment (50.4%) as well as normal hepatic function (91.9%).

[0648] The free and adjusted bound aflibercept concentration versus time data collected in participants with MEfRVO are presented in Figure 7. The distribution of trough concentrations of free and adjusted bound aflibercept at weeks 4 and 12 was generally similar across the CANDELA, PULSAR, PHOTON, and QUASAR studies, with no marked difference in the QUASAR study compared to the other studies. Comparison of non-trough concentrations measured after IVT administrations around week 9 in CANDELA, PULSAR, and PHOTON and around week 16 in QUASAR indicates that the median of adjusted bound aflibercept concentrations were slightly lower in QUASAR than in CANDELA and PULSAR (Figure 8), despite some participants in QUASAR having received 5 versus 3 initial monthly doses of HD aflibercept. The trend was less obvious when comparing QUASAR and PHOTON data, as only a limited number of participants in the PHOTON study contributed data after aflibercept administration.

Methodology

[0649] The analysis dataset was prepared by Regeneron Pharmacometrics Statistical Programming using SAS version 9.4. Population PK analyses were conducted using NONMEM® version 7.5.0 for model optimization and R version 4.2.2 for model-based simulations, data processing, summary and visualization.

[0650] A previously developed population PK model for aflibercept after intravenous (IV), subcutaneous (SC), and IVT administration was amended to streamline the existing NONMEM code and implement several technical improvements. This refactored model was then refined using the analysis dataset and used to test whether the ocular clearance and/or systemic disposition of aflibercept were different in MEfRVO compared to other diseases.

[0651] The existing model was a semi-mechanistic model describing the disposition of free aflibercept using a 3-compartment model with a nonlinear binding to VEGF, a linear clearance and an additional nonlinear clearance pathway hypothesized to represent the saturable uptake of anti-VEGF trap such as aflibercept by circulating platelets. Elimination of the adjusted bound

aflibercept was described by a linear clearance. The transfer of free aflibercept from the study and fellow eyes to the circulation was described by a linear ocular distribution clearance (QE) and was considered reversible, while the absorption from the SC injection site was described by a unidirectional first-order process.

[0652] Using the individual Bayesian parameter estimates of the refined PK model (thereafter referred to as final PK model), dense free and adjusted bound aflibercept concentrations versus time profiles in plasma were predicted for all participants in the CANDELA, PULSAR, PHOTON, and QUASAR studies assuming Q8W IVT administrations of HD aflibercept following 3 initial monthly injections. Numerical integration of the individual profiles was performed to calculate exposure metrics for free and adjusted bound aflibercept after the 3rd administration and after the last administration at week 56. Exposure metrics were then compared using geometric mean ratios (GM Rs) and associated 90% confidence interval (Cl) in subgroups defined by disease population, age tertile, body weight quintile, tertile of albumin concentration in serum, renal function, hepatic function, racial classification, and Japanese origin.

[0653] In the subset of participants with MEfRVO who received 5 initial monthly IVT injections of aflibercept in the QUASAR study, accumulation ratio (AR) at the 3^rd and 5^th dose intervals relative to the 1 ^st dose interval were compared to evaluate and compare the accumulation of free and adjusted bound aflibercept after 3 or 5 initial monthly IVT injections.

[0654] Stochastic simulations were also conducted in a population of 5,000 virtual participants with nAMD, 5,000 virtual participants with DME, 5,000 virtual participants with MEfRVO to explore the PK of free aflibercept in the eye after single IVT administration of 2-mg or HD aflibercept or repeated IVT administration of 2-mg aflibercept Q4W or HD aflibercept Q8W following 3 initial monthly injections. To further explore the impact of the maximum binding rate of free aflibercept to VEGF (V_max) on aflibercept PK, stochastic simulations were also conducted in the same virtual population to generate dense concentrations versus time profiles for free and adjusted bound aflibercept in plasma after repeated dosing, and to compare exposure metrics predicted when the proportional shift in V_max for participants with MEfRVO included in the final PK model was or was not implemented.

Results and Discussion

[0655] Following refactoring of the model code, the population PK analysis concluded that the typical value of QE was not statistically different in participants with MEfRVO, nAMD, and DME. In contrast, the inclusion of proportional shifts in V_max for participants with MEfRVO and healthy participants led to a statistically significant improvement of the objective functions, and visible Fidff fdjd bdflibtttxrre eecso auseoun aecep

11876WO01 improvements of the predictive performance of the model assessed by prediction-corrected visual predictive check (pcVPC), especially in the data strata associated with adjusted bound aflibercept concentrations in participants with nAMD or DME. The parameter estimates of the final PK model selected in the current analysis are presented in Table 4-1.

Table 4-1. Parameter Estimates of the Final Pharmacokinetic Model for Aflibercept Magnitude

of Shrinkage Parameter Estimate 95% Cl RSE(%)

Variability (%) (%)

FIVT: Bioavailability after IVT injection 0.703,

0.713 0.761% - - (unitless)^a 0.724

QE: Ocular clearance for 2-mg aflibercept 0.552,

0.596 3.93% - - (mL/day)^a 0.638

QE ~ Proportional effect of HD aflibercept 0.603,

0.648 3.72% - - on QE (unitless)^a 0.697

QE ~ Power effect of age on QE -1.61, - -1.35 7.99% - - (unitless)^a 1.16

Vi: Volume of the eye (mL)^a 4.00 Fixed 0% - - 0.0400,

K20: Elimination rate constant (1/day)^b 0.0807 29.5% - - 0.126

K20 ~ Power effect of body weight on K20 -1.45,

-0.192 234% - - (unitless)^b 0.714

V2: Volume of the central compartment 4.69,

4.99 2.79% - - (L)^b 5.22

V2 ~ Power effect of body weight on V2 0.590,

0.872 19.3% - - (unitless)^b 1.22

V3: Volume of the first peripheral 0.792,

1.08 17.0% - - compartment (L)^b 1.56

V3 ~ Power effect of body weight on V3 0.257,

1.08 51.3% - - (unitless)^b 2.71

Vs: Volume of the second peripheral 0.769,

1.18 39.8% - - compartment (L)^b 2.07

Vs ~ Power effect of body weight on V8 -0.962,

1.16 135% - - (unitless)^b 7.40

0.425,

Qi: First distribution clearance (L/day)^b 0.849 29.2% - - 1.26

0.0442,

Q2: Second distribution clearance (L/day)^b 0.0763 23.7% - - 0.110

Iidiidlibili Fidff fdjd bdflibtttttnernaaravu vyxre eecso auseoun aercep- 11876WO01 Vmax.p: Maximum binding rate to platelets 0.0148,

0.0310 35.3% - - (mg/day/L)^b 0.0649

Km.p: Amount of free aflibercept at half 2.16,

42.7 159% - - Vmax,p (mg)^b 214

K?o: Elimination rate constant from 0.00762,

0.0265 99.0% - - platelets (1/day)^b 0.105

Fsc: Bioavailability after SC injection 0.487,

0.536 5.26% - - (unitless)^b 0.601

KS2: Rate of absorption after SC injection 0.296,

0.368 10.5% - - (1/day)^b 0.430

V4: Volume of the central compartment 4.69,

4.99 2.79% - - (L)^{b c} 5.22

V4 ~ Power effect of body weight on V2 0.590,

0.872 19.3% - - (unitless)^{b c} 1.22

Vmax: Maximum binding rate to VEGF in

0.212,

participants with nAMD, DME, or tumors 0.218 1.73% - - 0.227

(mg/day/L)^a

Vmax ~ Proportional effect on Vmax for 0.602,

0.631 2.38% - - healthy participants (unitless)^a 0.660

Vmax ~ Proportional effect on Vmax for 0.656,

0.682 1.97% - - participants with MEfRVO (unitless)^a 0.704

K_m: Concentration of free aflibercept at 0.272,

0.411 16.8% - - half Vmax (mg/L)^b 0.510

0.0339,

K40: Elimination rate constant (1/day)^d 0.0350 1.87% - - 0.0364

K40 ~ Power effect of body weight on K40 -0.251, - -0.153 27.8% - - (unitless)^d 0.0768

K40 ~ Power effect of serum albumin on -0.989, - -0.767 14.0% - - K40 (unitless)^d 0.599

0.331,

0.469 16.9% 77.4% 32.3% co2 in Qe^a 0.644

0.0917,

0.207 54.1% 48.0% 25.2% co2 in K20^b 0.622

-0.144, - Covariance(co2 in V2 and V4, co² in K2o)^b -0.0727 38.9% - - 0.0239

0.0251,

0.0618 34.7% 25.3% 15.8% w2 in V2 and V4^b 0.106

0.0804,

0.104 16.7% 33.1% 40.6% C02 in Vmax^a 0.149

0.278,

0.629 26.4% 36.8% 16.7% co2 in Fsc^b 0.910

Ridlibili fdjd bd Ridlibili f fflibttttesaaraor aseonu vyuuesaaraorree aerepu vy

x - _ _ 11876WO01

0.261,

0.852 43.0% 116% 1,00e-10% co2 in Ke2^b 1.46

0.0372,

co2 in K4o^d 0.0452 9.42% 21.5% 43.3%

0.0555

after IV + SC dosing when LLOQ 0.00495,

0.0250 52.9% - is 0.0313 mg/L^d 0.0342 40.3,

after IV + SC dosing when 0.364, 89.5%

0.403 5.97% - LLOQ is 0.0313 mg/L^d 0.461

after IV + SC dosing when LLOQ 0.00591,

0.00786 11.8% - is 0.0156 mg/Ld 0.00913 35.7,

after IV + SC dosing when 0.324, 61.8%

0.357 4.18% - LLOQ is 0.0156 mg/L^d 0.384

after IVT dosing when LLOQ is 0.00590,

0.00664 5.55% - 0.0156 mg/L^a 0.00724 41.5,

after IVT dosing when LLOQ is 0.386, 59.4%

0.415 3.39% - 0.0156 mg/L^a 0.435

after IV + SC dosing when LLOQ 0.0162,

0.0206 10.9% - is 0.0315 mg/L^d 0.0241 16.7,

after IV + SC dosing when 0.152, 67.5%

0.167 5.07% - LLOQ is 0.0315 mg/L^d 0.186

after IVT dosing when LLOQ is 0.0172,

0.0215 10.4% - 0.0315 mg/La 0.0256 16.4,

after IVT dosing when LLOQ is 0.121, 70.2%

0.162 12.5% - 0.0315 mg/L^a 0.194

after IVT dosing when LLOQ is 0.0131,

0.0263 27.3% - 0.0224 mg/L^a 0.0355

20.6, 119%

after IVT dosing when LLOQ is 0.189,

0.206 5.31% - 0.0224 mg/L^a 0.231

^a estimates obtained from run077

^b estimates obtained from run431

^c set to the same values as V2-related estimates

^d estimates obtained from run463

Cl, Confidence interval; HD, High dose (8 mg IVT cohorts); IV, Intravenous; IVT, Intravitreal; LLOQ, Lower limit of quantitation; MEfRVO, Macular edema following retinal vein occlusion; RSE, Relative standard error; SC, Subcutaneous; VEGF, Vascular endothelial growth factor; o, Standard deviation; co², Variance Estimates of fixed-effect parameters are presented in the natural scale; interindividual variability terms are reported as variances around the log of the parameters or the logit of FSC. Magnitudes of residual variability are provided as ranges calculated at the maximum observed concentration of either free aflibercept or adjusted bound

aflibercept and their respective LLOQ values based on route of administration. RSE are presented in the logit scale for FIVT and F_SC and in the natural scale for all other parameters. The following pairs of parameters were high correlated: V_max: Maximum binding rate to VEGF and I IV in Vmax (r² = 0.925)

[0656] The typical values of the parameters of the final PK models influenced by covariates can be calculated as follows:

= 0.596 x 0.648^HD X 1 /weighty'⁵⁸

V 76 7

/weishtf®-¹⁵³ /ALB'... x (.

76 / \ 4.3,

« 0.218 X 0.63 X 0,682^MBmw where HD is 1 after IVT administration of HD aflibercept and 0 otherwise; Healthy is 1 in healthy participants and 0 otherwise; and MEfRVO is 1 in participants with MEfRVO and 0 otherwise. In the final PK model, the typical estimates of QE and associated ocular elimination rate were estimated to be 35.2% slower after the injection of HD aflibercept than after 2 mg aflibercept, corresponding to a 54.2% increase in ocular half-life of elimination (Table 4-2). All estimates of fixed effects related to QE differed by < 12.3% in the final population PK model compared to those obtained in the previously reported population PK model. The re-estimation of Vmax on the full analysis population and the addition of proportional shifts for participants with MEfRVO and healthy participants resulted in a 30.5% increase in the typical estimate of V_max which, in the final PK model, is representative of participants with nAMD, DME, or tumors. Vmax was estimated to be typically 36.9% and 31.8% lower in healthy participants and participants with MEfRVO than in participants with nAMD, DME, or tumors.

Importantly, after accounting for difference in age distribution and associated covariate effect on QE, the distribution of individual estimates of QE for the final PK model was similar across participants with MEfRVO, nAMD, or DME (Figure 9). This indicated that the ocular clearance of aflibercept is predicted to be typically similar in patients of identical age, regardless of MEfRVO, nAMD, or DME disease.

Table 4-2. Typical Estimate and 95% Confidence Interval of the Ocular Distribution Clearance, Elimination Rate, and Half-Life of Elimination for the Final Pharmacokinetic Model

Drug Product Ocular Distribution Clearance Ocular Elimination Rate Ocular Elimination Half-life (mL/day) (1/day) (day)

2 mg 0.596 0.149 4.65

(0.570, 0.624) (0.142, 0.156) (4.87, 4.44)

High Dose 0.387 0.0966 7.17

(0.362, 0.413) (0.0905, 0.103) (7.66, 6.72)

[0657] Metrics of free aflibercept systemic exposures predicted after repeated Q8W administrations (following 3 initial monthly IVT administrations) increased by 31 to 34% in participants with MEfRVO compared to participants with nAMD or DME, using Bayesian estimates of PK parameters. In contrast, metrics of adjusted bound aflibercept exposures were predicted to decrease by 10 to 11% in participants with MEfRVO compared to participants with nAMD or DME (Figure 10). Average body weights were approximately 4 kg lower in the participants with MEfRVO compared to the participants with nAMD or DME included in this comparison (Table 4-3). In absence of difference of Vmax across populations, the difference of body weights between participants with MEfRVO and the participants with nAMD or DME are predicted to result in 8 to 11% increases in free and adjusted bound exposures. Therefore, these small magnitude differences in exposure metrics were more likely driven by the typically smaller values in Vmax for participants with MEfRVO compared to participants with nAMD or DME, as suggested by the marginal differences in free aflibercept concentrations versus time profiles and related exposure metrics observed in stochastic simulations ignoring the proportional shift in Vmax for participants with MEfRVO. Overall, this suggested that the PK of aflibercept was not substantially different in participants with MEfRVO, nAMD, or DME.

Table 4-3. Summary of Bayesian Model-Predicted Exposure Metrics, Stratified by Grouped Disease Population in Participants from the CANDELA, PULSAR, PHOTON, and QUASAR Studies

Disease population n Body weight AUCweek56-64 (mgxday/L) Cmax,week56-64 (mg/L) Cmax,week8-12

(kg) (mg/L)

Free aflibercept

nAMD / DME 168 80.9 (24.0%) 2.64 (56.4%) 0.179 (44.4%) 0.198 (46.4%)

7

MEfRVO 88 76.7 (24.1%) 3.53 (48.5%) 0.236 (41.0%) 0.259 (41.4%)

3

Adjusted bound aflibercept

nAMD / DME 168 80.9 (24.0%) 30.9 (43.6%) 0.745 (38.8%) 1.07 (37.1%)

7

MEfRVO 88 76.7 (24.1%) 27.2 (35.8%) 0.658 (32.2%) 0.934 (31.4%)

3

A

UCweek56-64₅ Ar6cl UDC er the concentration curve from wee ks 56 to 64; CV, Coefficient of variation; C_max.week8-12, Maximum concentration from weeks 8 to 12; Cmax,week56-64, Maximum concentration from weeks 56 to 64; DME, Diabetic macular edema; HD, High dose; MEfRVO, Macular edema following retinal vein occlusion; n, Number of participants; nAMD, Neovascular age-related macular degeneration

Note: Data are presented as arithmetic mean (CV%). Exposures were simulated using post-hoc pharmacokinetic estimates of participants from the CANDELA, PULSAR, PHOTON, and QUASAR studies assuming 3 monthly injections of aflibercept HD followed by one injection every 8 weeks for all participants.

[0658] Finally, model-based predictions indicated that, on average, free aflibercept did not further accumulate in plasma after 3 or 5 monthly IVT doses in participants with MEfRVO.

Average ARs based upon area under the concentration (AUG) determined within dose intervals were estimated to be 1.06 after 3 and 5 monthly IVT doses of 2-mg aflibercept and 1.14 and 1.15 after 3 and 5 monthly IVT doses of HD aflibercept. In contrast, slightly increased accumulation of adjusted bound aflibercept was predicted after 5 versus 3 IVT doses in participants with MEfRVO. Average ARs of adjusted bound aflibercept increased from 2.09 to 2.30 after 3 and 5 monthly IVT doses of 2-mg aflibercept and from 2.25 to 2.48 after 3 and 5 monthly IVT doses of HD aflibercept, representing an approximately 10% increase in accumulation. Similar results were obtained using stochastic simulations in a combined population of virtual patients with nAMD, DME, or MEfRVO. Average ARs of free aflibercept were estimated to be 1.09 after 3 and 5 monthly IVT doses of 2-mg aflibercept and 1.20 and 1.22 after 3 and 5 monthly IVT doses of HD aflibercept. Average ARs of adjusted bound aflibercept increased from 2.06 to 2.27 after 3 and 5 monthly IVT doses of 2-mg aflibercept and from 2.35 to 2.67 after 3 and 5 monthly IVT doses of HD aflibercept, representing an approximately 10 to 14% increase in accumulation (Table 4-4).

Table 4-4. Accumulation Ratios After the Third and Fifth Dose in 15,000 Virtual Patients with Neovascular Age-Related Macular Degeneration, Diabetic Macular Edema or Macular

Edema Following Retinal Vein Occlusion Receiving 5 Monthly Intravitreal Injections of 2-mg or High Dose Aflibercept

Analyte Dosing regimen Metric Mean Median Median Median (SD) 90%PI) (95%PI) (99%PI) ARweek8-12 1.09 1.03 (1.01, 1.03 (1.00, 1.03 (unitless) (0.142) 1.38) 1.53) (1.00,

1.82) 2 mg Q4Wx5

ARweek16-20 1.09 1.03 (1.01, 1.03 (1.00, 1.03 (unitless) (0.166) 1.40) 1.59) (1 -00,

2.03) Free aflibercept

ARweek8-12 1.20 1.10 (1.01, 1.10 (1.01, 1.10 (unitless) (0.242) 1.73) 1.91) (1.01,

2.23) 8 mg Q4Wx5

ARweek16-20 1.22 1.10 (1.01, 1.10 (1.01, 1.10 (unitless) (0.307) 1.86) 2.15) (1 -01,

2.74) ARweek8-12 2.06 1.95 (1.53, 1.95 (1.47, 1.95 (unitless) (0.459) 2.98) 3.29) (1 -36,

3.90) 2 mg Q4Wx5

ARweek16-20 2.27 2.12 (1.57, 2.12 (1.50, 2.12 (unitless) (0.650) 3.52) 4.03) (1.37, Adjusted bound 5.19) aflibercept ARweek8-12 2.35 2.21 (1.64, 2.21 (1.57, 2.21

8 mg Q4Wx5 (unitless) (0.596) 3.55) 3.88) (1 -44,

4.46) ARweek16-20 2.67 2.43 (1.70, 2.43 (1.61, 2.43 (unitless) (0.912) 4.50) 5.16) (1 -45,

6.48)

ARweekx-Y, Accumulation ratio between weeks X and Y, based upon area under the concentration versus time curves, relative to first dose interval (between weeks 0 and 4); QxW, Every X weeks; PI, Prediction interval; SD, Standard deviation

Conclusions

[0659] An existing population PK model for free and adjusted bound aflibercept after SC, IV, and IVT administration was refined using data collected in participants with MEfRVO enrolled in the QUASAR studies. The distribution of estimated QE was similar across participants with MEfRVO, nAMD, and DME, once the differences that exist in age between the populations were taken into account. In the final PK model, the typical estimates of QE and associated ocular 11876WO01 elimination rate were estimated to be 35.2% slower after the injection of HD aflibercept than after 2 mg aflibercept. Additionally, this analysis indicated that there was a 31 to 34% increase in systemic exposure to free aflibercept and a 10 to 11% decrease in systemic exposure to adjusted bound aflibercept, in participants with MEfRVO compared to participants with nAMD or DME after Q8W administration of HD aflibercept administrations following 3 initial monthly IVT injections. Additionally, this analysis indicated that, free aflibercept does not typically accumulate further in plasma between 3 and 5 initial monthly IVT injections, and the accumulation of adjusted bound aflibercept after 5 initial monthly IVT injections was approximately 10 to 14% greater than following 3 monthly IVT injections.

Example 5: Pharmacometric Analysis of Aflibercept in Patients with Macular Edema Secondary to Retinal Vein Occlusion

[0660] The efficacy and safety of HD aflibercept were evaluated in 1 phase 2 study in patients with nAMD (CANDELA) and 2 phase 3 studies in patients with nAMD (PULSAR) and patients with DME and DR (PHOTON). More recently, the efficacy and safety of HD aflibercept have been assessed in patients with MEfRVO in the phase 3 pivotal QUASAR study.

[0661] Across the Phase 3 studies, different HD aflibercept dosing regimens and dose regimen modification criteria were investigated. In the PHOTON and PULSAR studies, patients randomized to HD aflibercept were scheduled to receive 3 initial monthly IVT injections of HD aflibercept, and thereafter injections either every 12 weeks or every 16 weeks. After the 3 initial monthly injections, patients who met protocol-specified criteria underwent dosing interval shortening (by 4-week increments) down to a minimum dosing interval of 8 weeks. Starting at the second year of the PULSAR and PHOTON studies, patients who met protocol-specified criteria were eligible to undergo dosing interval extensions by 4-week increments. In the QUASAR study, patients who were randomized to receive IVT injections of HD aflibercept were scheduled to either 3 or 5 initial monthly injections and thereafter received injections every 8 weeks. In contrast to PHOTON and PULSAR, patients who met protocol-specified criteria underwent dosing interval shortening down to a dosing interval of 4 weeks. Criteria for dose interval shortening were defined as described below:

• In PULSAR, starting at week 16, participants receiving HD aflibercept had the dosing interval shortened if both the following DRM criteria were met:

o 5 letters loss in BCVA from week 12

o 25 pm increase in CRT from Week 12 or new foveal hemorrhage or new foveal neovascularization

• In PHOTON, starting at week 16, participants receiving HD aflibercept had the dosing interval shortened by 4-week increments if both the following DRM criteria were met at dosing visits:

o 10 letter loss in BCVA from week 12 in association with persistent or worsening DME, and

o 50 pm increase in CRT from week 12

• In QUASAR, starting at week 16 for participants in the Q4Wx3+Q8W group and starting at week 24 for participants in the Q4Wx5+Q8W group, participants had the dosing interval shortened by 4-week increments if both the following DRM criteria were met at dosing visits:

• 5 letter loss in BCVA from reference visit*, and

• 50 pm increase in CRT from reference visit

Reference visits were at week 12 for participants in the Q4Wx3+Q8W group and week 20 for participants in the Q4Wx5+Q8W group.

[0662] Previous analyses have indicated that fast ocular clearance and high baseline CRT are predictors for the need of dose interval shortenings in patients with DME or nAMD. In addition, a recent analysis of the PHOTON and PULSAR studies indicated that patients who would have qualified to receive HD aflibercept Q4W (but did not due to the protocol-defined minimum dosing interval of 8 weeks) had a faster ocular clearance than those who would not have qualified to receive HD aflibercept Q4W. The exploratory analysis presented herein focused on patients with MEfRVO from the QUASAR study who received HD aflibercept. In particular, an exploratory analysis was performed comparing the characteristics of patients whose dosing interval was shortened to Q4W against the characteristics of patients whose dosing interval was not shortened to Q4W.

METHODOLOGY-Data

[0663] The analysis dataset used for the pharmacometric analyses included data collected during the conduct of the QUASAR study. The master PK/PD dataset was constructed by including PD-related data into the population PK analysis dataset used in the popPK analysis of the QUASAR study, as well as the QE-estimates from the final popPK model. 11876WO01 METHODOLOGY-Missing Data and Imputations

[0664] Missing QE values in participants who were not included in the popPK analysis were imputed based upon the final popPK model, considering the participant age and the typical parameter estimates using the following equation:

where -7.42494 is the log of the typical QE for a 71 -year-old patient receiving aflibercept 2 mg drug product, -0.433374 is the log of the coefficient for the HD-effect on QE, and -1.34949 is the log of the coefficient for the age-effect on QE.

METHODOLOGY-Data Analyses

[0665] Analyses were exploratory and intended to be descriptive, and no statistical testing was performed. Summary of the following patient characteristics were computed and summarized in statistics and graphical representations:

• QE estimates

• Baseline CRT (note that CST evaluated in QUASAR is analogous to CRT)

• Baseline BCVA

[0666] All summary statistics and graphical representations were produced so that distributions could be compared between patients assigned to Q4W and patients not assigned to Q4W. In addition, stratification per randomized dosing regimen (Q4Wx3+Q8W vs Q4Wx5+Q8W) was performed.

RESULTS AND DISCUSSION-Summary of Patient Characteristics

[0667] A summary of patient characteristics is presented in Table 5-1. Most of the patient characteristics show no obvious difference between patients assigned to receive HD aflibercept Q4W and patients not assigned to receive HD aflibercept Q4W. It was noticeable that median QE estimates were 32.3% higher in patients assigned to receive HD aflibercept Q4W as compared to those that were not assigned to receive HD aflibercept Q4W. This observation was in line with findings from a previous exposure-response analysis in patients with DME and nAMD. It was also noticeable that baseline CRT was 6.5% higher in patients assigned to receive HD aflibercept Q4W as compared to those that were not assigned to receive HD aflibercept Q4W. This observation was also in line with findings from a previous

exposure-response analysis in patients with DME and nAMD.

[0668] It should also be noted that the proportion of patients assigned to receive HD aflibercept Q4W was higher when patients received 3 (Q4Wx3+Q8W) versus 5 (Q4Wx5+Q8W) initial monthly injections. This finding was expected given that patients in the 8 mg IVT Q4Wx3+Q8W arm were eligible for dose interval shortening for a longer period of time (from week 16 to week 36) as compared to patients in the 8 mg IVT Q4Wx5+Q8W (from week 24 to week 36).

Table 5-1. Summary of Patient Characteristics for Patients in the QUASAR Study, Stratified by Assignment to HD Aflibercept Q4W

Assigned to Not assisted to Q4W Overall VarUMe <xtwp nr Statisnc Q4W (n~58} (n- 5«) foassdamixanea gtotsp, §^rvrowx3+qsw S3 {SOW; Ml (S«.1M) 293 (!«&) N (%) S mg 1VT Q4WX5*QSW IS (6,04%> 280 ^4.0%;: 298 (1.9W Median «.3M 9.418 9,429 Ooidas efestratK* (wLrday)

?5, F» 9.2S3, L2§ 9.216, 1.94 9,217, til Ceatsai Retinas Thickness Median m 521 574 as baseline (ptn) P5, H>5 3dd_? 940 358, 1953 349, 1058 Best Coxrected Vassal Acuisy Median 595 579 589 at baselsw (lettess) P5, PR5. M4..72.6 279. 72.9 279, 72.9 Fellow eve treatment with aflifeareepl. Yes 1 (W (M ’> (M0%) 19 (IWi) N (%)?<o 49 (S.43%) 532 (91 8%) 581 (19W? Sas, Female 359 (91 §%! 283 (19W> N (M) M9e 3? 383 (913%) 398 ( 18W>

Median d4,5 979 979 Ag«{V!

P5, FR5 C * S3,d M 9. 858 483183.9 Hispatdo os Latino 2 <5. L’⁵<.; 37 (£4.9%) 39 (11XM) Ethakiiy, N >:%.! Not Htspaisie as Latino 4- (S,?») 493 (91.3531 548 (19W Not sep>sned I M (9L7%) 12 (1 < W Median MS 759 75.0 Body weighs s&g)

F5_:P5>$ 8,?..<>, ns 51 A MO 51.2, m Median 4.49 4.59 4.59 Alfoasnti (g.-dk)

P5, P95 4.14, ISO 4.19. 5 99 4 19, 599 Median 884 99? §9.7 hstisnated GrK (ml,.4nM-l, sam2)

?5, 4S.3, 19S 524, M3 51.8, 111 Median IS.9 199 19.9 Sisun^Uwst^w (U-L )

P5, F$S 19 A 505 9.89, 48.9 9.90, 48.5 Median ® 5 21,9 219 Aspartate Mirniwftsw (b^: -1. j P5, PS5 15 4. 34.4 13,9, 4932 1311453.9 Median §2.«3 78.9 79,9 Alht&ae ghoaphatase tU. Ej?s,m 4SA 543 599, 125 47 5. 120 Median 0345 (J499 0.499 Biliraidn (pmol-Tl P5_:?5>3 9181, G. S2<5 9,199, 1.91 0.198, 1,90 NawiiS! 4? (S.8W 496 (91.3%) 543 H09%} Hepatic fencifoa.

Mdd 3 (O s%) 43(93.3%) 45 (199%) Moderate O iW; 3 (MOA- 3 (19-Wl GFR » Gfensendat- Sltraiioss rate; HD »!tsg8 dose; IVT “ Ia«avnteal; P5 « pesrettilk; P45 ™ 95dt pesyentile; QW “ Bay 4 weeks: Q4W3e-Q8'<9-” 3 sasuel monlMy dotes followed by dc-si&s: eves')- 8 weeks

11876WO01 RESULTS AND DISCUSSION-Metrics of Interest

[0669] Plots exploring the distribution of QE estimates, baseline CRT and baseline BOVA across patients who were or were not assigned to receive HD aflibercept Q4W in the QUASAR study are presented in Figure 18, Figure 19, and Figure 20, respectively.

[0670] The proportion of patients assigned to HD aflibercept Q4W was low in both of the HD aflibercept arms: 10.9% in the Q4Wx3+Q8W arm and 6.0% in the Q4Wx5+Q8W arm. It was noticeable that QE estimates were consistently higher in the groups of patients assigned to receive HD aflibercept Q4W as compared to those that were not (29.1% higher in the Q4Wx3+Q8W arm and 35.9% higher in the Q4Wx5+Q8W arm; Figure 18). Figure 19 suggests a trend towards higher baseline CRT in the groups of patients assigned to receive HD aflibercept Q4W as compared to those that were not. This difference was more noticeable in the Q4Wx5+Q8W arm (13.1% higher) as compared to the Q4Wx3+Q8W arm (3.4% higher). On the other hand, baseline BCVA did not show a consistent trend across randomization arms.

Patients assigned to receive HD aflibercept Q4W in the Q4Wx5+Q8W arm had a 6% lower baseline BCVA and patients assigned to receive HD aflibercept Q4W in the Q4Wx3+Q8W arm had a 5.3% higher baseline BCVA, as compared to patients not assigned to receive HD aflibercept Q4W (Figure 20).

[0671] Given the observed relationships of QE-estimates and baseline CRT values with dosing interval shortening to Q4W, an additional exploratory plot was conducted to investigate the interplay of both factors. As shown in Figure 21, the subsets of patients with both

QE-estimates and baseline CRT above their respective median presented the highest incidence of dosing interval shortening to Q4W. In addition, a general trend was observed where lower QE-estimates and lower baseline CRT are associated with a lower incidence of dosing interval shortening to Q4W. This observation was consistent across randomization groups and aligned with the findings of exposure-response analyses in patients with DME and nAMD.

CONCLUSIONS

[0672] The analyses presented herein focused on the patients in QUASAR study who received HD aflibercept. In this study, dosing intervals could be shortened to 4 weeks if patients met protocol-specified criteria.

[0673] The results of these analyses indicate that patients with MEfRVO with high baseline CRT show a higher incidence of dosing interval shortening to Q4W than patients with low baseline CRT, and that those with high QE show a higher incidence of dosing interval shortening to Q4W than patients with low QE. In addition, patients with MEfRVO with both high

baseline CRT and high QE showed the highest incidence of dosing interval shortening. These results align with the findings of exposure-response analyses in patients with DME and nAMD.

Example 6: Population Pharmacokinetic-Pharmacodynamic Analysis of High Dose Aflibercept in Patients with Age-Related Macular Degeneration and Patients with Diabetic Macular Edema

[0674] The objectives were to:

• Explore the characteristics of patients enrolled in the PHOTON and PULSAR studies who met Dosing Interval Shortening (DRM) criteria after receiving high dose (HD) aflibercept every 8 weeks (Q8W).

• Develop pharmacokinetic/pharmacodynamic (PK/PD) models characterizing the relationships between aflibercept concentrations in the eye with central retinal thickness (CRT) and best visual corrected acuity (BCVA) over time during the first year of the PULSAR and PHOTON studies for patients receiving HD aflibercept.

• Investigate through simulations the duration of effect after dosing HD aflibercept across the range of ocular clearance (QE) values observed in PHOTON and PULSAR studies.

• Infer through clinical trial simulations the expected benefit of HD aflibercept dose-interval shortening down to every 4 weeks (Q4W) in patients that fail to maintain response i.e., patients that still meet DRM criteria after having their dosing interval shortened to Q8W.

Summary of Data:

[0675] The analysis dataset used for the Exposure-Response (E-R) analyses described herein included data collected during the first year of the PULSAR and PHOTON studies.

Pertinent details regarding the design and sampling schedules of the included studies are summarized in Table 6-1.

Table 6-1. Summary of Design and Sampling Schedules of PHOTON and PULSAR Studies Study Cnde/NCT Study Pharmscakinetic anti Dosing Regimens

Nmnber/Pl»a$e Papulation Pharmacodynamic Ssunplitig Schedule VGFTe-HD-DM&-1934 DME 2 xtig IVT QS W after 5 Q4\V PK: predase, 4 IP, $ iF, days 2\ 3^, 5^fc. (PHOTON)/ inirial doses 8^!>, 15®, 22^s‘, 29, 66-64, weeks 12, 28, and NCTaM29503.^;Ph3Se 8 mg IVTQ12W or QiW after 48

2/3’ 3 Q4W initial doses; shortening PD: screening and prior to all sham or of dose interval allowed starting active dose

week 16; extension of dose

interval allowed starting week

52

S6-5321-. W5S tiAMO 2 mg IVT QS W after 3 Q41V PK: predose, 4 IF, 3 IF, days 22 3\ 5\ (PI1DSAR)/ initial doses 8’, 15222>, ’29, 60-64, weeks 12, 28, and NCTO442371 &■ Pirn® 3» 8 mg IVT Qi 2W nr Q IW after 48

3 Q4W tsniial doses: shortening PIT screening:md prior to all shatn or of dose interval allowed starting active dose

week 16; extension of dose

interval allowed starting week

52

’ Fellow eye treatment was. allowed dining the study with 2 xng dose of aflibercept.

® Ooh’ collected in PK su s dy

DME, Diabetic macular edema; IVT, Iniravibeal; uANfD. Neovascuiar age-related macular degeneration:

PD, Fham odynamic(s); PK, PliannacoMnedcfs); PRN, as needed: QxW, Every X weeks

[0676] Data was split to create one subset for PHOTON data, and one subset for PULSAR data. These data subsets included only data pertaining to patients which received HD aflibercept, and only data collected before the start of the second year after randomization. Data included pharmacokinetic (PK) post-hoc QE estimates obtained from the final population PK model for free and adjusted bound concentrations in plasma after intravenous (IV), subcutaneous (SC), and intravitreal (IVT) dosing. Characteristics of patients included in these data subsets are presented in Table 6-2. Table 6-2. Summary of Patient Characteristics

_v.... Group or PHOTON PULSAR Overall Statistic (n~491) (a ~6“3) (a ~ 1164) Disease, nAMD 0 (0%) S?3 (m) 673 (57.8%) N(%) DME 491 (190%) 0(0%} 491 (42.2%) Plarated dosins re^imea. 8mgIVTQ4WX3'K)izW 328(66.3%) 33^(49.8%.! 663 ($7.0%) N(%) 8 mg 1VT QtWX3^H6W 163 (33.2%) 338 (50.2%) Sill (43.0%) Sex, Male 309(62.9%) 311 (46.2%) 620 ($3.3%) N(%) Female 182 (37.1%) 362(53.8%) $4406.7%)

Median 0.508 0.366 O.420 Grata clearance tntl/dav)

P5, P95 0.266, 0.978 0.216,0.6$! 0.227,0.826 _t. Median 65.8 62.0 630 Baseline best cmreeted visual acmtv (leters ' P5, P95 41.5, 76.0 32.6, 76.0 36.0,76.0 Metes 431 390 409 Baseline mitral reimai tlnckness (um) P5 P95 360,663 249, 669 266, 668

Missing I 0 1 DME. Diabetic Macular Edema:. IVT, Eiteitreat a.. Number N, Number of records;

nAMD, Neovascular age-related macular degenerate; Q> AV, Even* X weeks

[0677] The analysis data subsets included dosing records and records for 3 different pharmacodynamic (PD) endpoints (Table 6-3):

• CRT of study eye.

• BCVA of study eye

• Loss to follow-up: loss to follow-up was defined for this analysis as patients not providing BCVA or CRT observations for more than 1 year since randomization. Patients that did provide BCVA and/or CRT samples beyond 1 year after randomization were considered censored on day 365. Patients that did not provide BCVA and/or CRT samples beyond 1 year after randomization were considered as lost to follow-up at the time of their last observation. Table 6-3. Master PK/PD Dataset Records. \.att.a,l»,k Group P ^F (, HOTON PVLSAR Overall.» - 491 ) { a - 6 O) (ii 1 IM) IWag 2713(1?.<$%) 3807(16.3%) 6520 (16,8%) Record ivpe BCVA 6140(39.7%) 9456 (40.558) 15596 (.40.2%)

CRT 6109(59.5%) 9433 (40.4%) 15542(40.0%)

Mew-op 491 (3.18%) 673(2.80%) 1164(3.00%) BCVA, Best visual corrscted acuity; CRT. Cexitrat retutai. thxlcness; n, J rfit of p«Htta^ttts/{X3tjent»sabjecfe;

N. Number of recunfe; PK PI>, 3%axmo)ldtie6c.^taxuice6ywmc

Methodology:

[0678] A series of exploratory analyses were performed:

• Exploration of trends over time for CRT and BCVA change from baseline across the different studies and randomization groups, as well as across C -estimates and baseline CRT measurements.

• Exploration of the dynamic relationship between CRT and BCVA across Ck-estimates and baseline CRT measurements through hysteresis plots.

• Exploration of the relationship between patients that would have or would have not qualified for Q4W dosing with Q_E post-hoc estimates, and baseline CRT measurements and baseline BCVA scores.

• Exploration of loss to follow-up during the first year of treatment.

[0679] Here, patients qualifying for Q4W dosing were those patients in the PHOTON and PULSAR studies who met the criteria for further DRM even after receiving HD aflibercept Q8W, but could not be dosed Q4W as per study protocol.

[0680] Thereafter, 2 independent sets of models were developed for diabetic macular edema (DME) (PHOTON study) and neovascular age-related macular degeneration (nAMD) (PULSAR study) patients. PK/PD models describing the relationship between drug concentration in the study eye and the PD endpoints CRT and BCVA were developed. Each model was developed in a sequential manner. First, longitudinal PK/PD models were fitted to describe the relationship between aflibercept concentration in the eye and CRT. Next, the individual post-hoc estimates of the PK/PD parameters were used to expand the previously developed models to describe BCVA observations. Finally, a parametric time-to-event model was developed to describe the rate at which patients were lost to follow-up.

[0681] The PK/PD model described herein (see schematic representation in Figure 22) was built upon a simplified 1 -compartment PK model describing the drug concentration in the eye.

The dynamics of CRT over-time were described utilizing a turn-over model in which drug effect was implemented on the input process. The dynamics of BCVA over time were described by means of a latent variable representing the underlying vision of the patient, and governed by a turn-over model. CRT effect on vision was implemented on the output process. The latent variable vision was thereafter transformed into a BCVA value constrained to be between 0 and 100 with a maximum effect (Emax)-like function. Finally, a parametric drop-out model was developed to account for loss-to-follow-up of patients during the observation period, and the influence of BCVA and CRT over time were investigated as predictors of loss to follow-up.

Alternative structural models and adaptations were to be considered if the above-described structure was found not to adequately describe the observed data. Regarding DRM, this was taken into consideration for model evaluation and for model application purposes, i.e., when running simulations, CRT and BCVA predictions were used to control the DRM as defined in the respective clinical trial protocols of the PHOTON and PULSAR studies.

[0682] Statistical models for inter-individual variability (I IV) in the model were specified using an exponential model. The statistical model for residual variability on CRT was specified either with a proportional or a combined additive and proportional model. The residual variability model for BCVA was specified using a logit model and back transforming into a 0 to 100 scale.

Multiple criteria were applied to assess the performance of the PK/PD models, including patterns in standard goodness-of-fit (GOF) diagnostic plots, precision in final parameter estimates (>3 significant digits, reasonable relative standard error [RSE]) and pharmacological plausibility. The adequacy of the population model to describe the observed data was evaluated by simulation-based visual predictive checks (VPCs).

[0683] Two model applications were performed:

• Model Application 1 intended to investigate the impact of QE on drug effect over time and illustrate how Q_E relates to the proportion of patients that may need dosing Q4W. For this purpose, stochastic simulations of drug concentrations in the eye after a single administration of HD aflibercept were performed, and the resulting drug effect was computed. QE values were re-sampled from the analysis populations. The individual ETA values were sampled from a normal distribution considering the variance estimated in the final models. Thereafter, the proportion of patients maintaining drug effect above 50% of the maximum effect was computed over time to illustrate how this proportion differed at 4 and 8 weeks after dosing across the QE-quartiles.

• Model Application 2 intended to infer the expected benefit of dosing as often as Q4W, as compared to only as often as Q8W, for those patients that fail to maintain pharmacological

response and require a more intense treatment. In this analysis, patients requiring a more intense treatment are those patients who would have qualified for a dosing interval shortening down to 4 weeks when considering the DRM criteria in the PHOTON and PULSAR studies. Qualifying for dosing every 4 weeks was defined as meeting the respective DRM criteria even after dosing interval shortening to Q8W (from every 12 weeks [Q12W] or every 16 weeks [Q16W] per randomization group). Benefit was assessed in terms of predicted BOVA difference at the end of the first 1-year period after randomization. For this purpose, individual patient-level data (randomization group and individual post-hoc QE-estimates) were used to develop simulation datasets. Thereafter, PK/PD simulations were performed in such a way that dosing was dynamically adapted based on simulated CRT and BCVA outcomes and on the respective DRM criteria of the PHOTON and PULSAR studies. For each of the original studies, 2 sets of 100 simulations were performed: 1) considering the original trial protocols where the shortest dosing interval allowed was 8 weeks (Q8W protocol), and 2) considering modified trial protocols where the shortest dosing interval allowed was 4 weeks (Q4W protocol). Q8W protocol simulations and the Q4W protocol simulations used the same simulation seeds so that each of the 100 simulation sets was representing a hypothetical and ideal study, where each of the patients in the PULSAR and PHOTON studies was treated through both protocols and served as their own control when comparing the results obtained with these 2 protocols. The outcomes for simulated patients that qualified for dosing Q4W were used to compute the individual-level differences when using the Q8W protocols or the Q4W protocols.

Results and Discussion:

[0684] The PK/PD analyses presented are motivated by the fact that a small proportion of patients fail to maintain pharmacological response when dosed HD aflibercept in intervals of 8 weeks and could potentially benefit from receiving HD aflibercept Q4W. Patients in the PHOTON and PULSAR studies who met DRM criteria after receiving HD aflibercept Q8W, but were not dosed Q4W as per study protocol were considered as patients qualifying for Q4W dosing in the analyses presented here. The proportion of patients qualifying for Q4W dosing was low in both studies: 1.4% in the PHOTON study and 5.8% in the PULSAR study.

[0685] It was noticeable that QE-estimates (drug clearance from the ocular compartment) were consistently higher in the Q4W qualifying patients as compared to non-Q4W qualifying patients across both studies (Figure 23) (20.8% higher in the PHOTON study and 34.2% higher in the PULSAR study). Thus, it is expected that Q4W dosing with HD aflibercept could maintain therapeutic concentrations in the eye during the dosing interval for some of these patients,

overcoming a fast ocular clearance. Regarding baseline CRT, a trend towards higher baseline CRT was observed in the Q4W qualifying patients as compared to non-Q4W qualifying patients (Figure 24). Assessment of the relationship between patients qualifying or not qualifying for Q4W dosing and their baseline CRT measurements and QE-estimates showed that the subgroup of patients with high baseline CRT measurements and high QE-estimates had the highest proportion of patients qualifying to receive HD aflibercept Q4W, while patients with low baseline CRT measurements and low QE-estimates had the lowest proportion of patients qualifying to receive HD aflibercept Q4W (Figure 25). These results are consistent with previous E-R analysis which concluded that the rate of DRM in PHOTON and PULSAR participants was dependent on the disease population (likely related to the study-specific criteria for DRM), baseline CRT measurements, and QE-estimates.

CRT Model Development

[0686] The developed CRT models for the PHOTON and PULSAR studies were structurally equivalent. The CRT dynamics over-time were described by means of a turn-over model consisting of a zero-order input rate (Kin_CR_T) and first order output constant (Koutarr). Drug effect on this dynamic system was implemented on the input process. Among the tested implementations of drug effect on KITICRT, the final implementation considered a

mono-exponential decrease from KinCRT at baseline to a minimum Kin_CRT if maximum effect was achieved. Drug effect was implemented as follows:

^{1 +} V?7v — ^: - ¹ )

where Kin_CRT is the zero-order rate constant governing the input to CRT, C_eye is the aflibercept concentration in the eye, Kin_CRT-BL is the zero-order rate constant governing the input to CRT in the absence of aflibercept, KIN_CRT~MAX is the zero-order rate constant governing the input to CRT when maximum effect is achieved, and K_CRT is the drug effect coefficient.

[0687] Parameter estimates are presented in Table 6-4 and Table 6-5 for the PHOTON and PULSAR studies, respectively.

Table 6-4. Parameter Estimates of Central Retinal Thickness Final Model for the PHOTON Study

Bootstrap mean Desmptkm Est tinate (9t?^8 ^,_rI.)^r

Baseline CRT (JUM) 43? 428 (384. 44?)

Kto-CRT-BL: Input rate for CRT at baseline (inivdsy) 16.- I 13.8 (7,09, 17.7)

Kto-CRT-tnax: Input rate for CRT when maximum effect is achieved,..

(p day) j 8.83 (4.66, 11.1)

K-CRT: Drug effect coefficient on Kin CRT (toLtog) 34. 5 68.8 (3.95. 331)

HV in Baseline CRT (%CV) 23,. 3 24.1 (22.5, 26.8)

HV to K CRT (WV) 1 67.4(52.5.87.3) riHV to Kto CRT-BL. IIV to Baseline CRT) 0.4 ’9 0.503 (0.315.0.670) IIV in Kto CRT-BL (%CV) 113 122 (110. 162) r(HV to Kto CRT-max. IIV in Baseline CRT) 0,3- IS 0.371 (0.176, 0,574) r(HV in Kto CRT-max, IIV in Kin CRT-BL) 0.9’ 55 0.967 (0,951, 0,982) HV to Kto CRT-max (%C V) 105 115 (102, 158) t'(HV to K CRT, IIV to Baseline CRT) 0.1« 56 0.174 (-0,0139, 0.362} r(HV to K CRT. IIV to Kto CRT-BL) 0.2< 57 0.270 (0.0212, 0.500) r(HV to K CRT. IIV to Kto CRT -max) 0,3' '7 0.371 (0.128, 0,572)

Proportional (%CV) 10.- I 10.2 (9.22, 11.0) %CV. Coefficient of variation expressed as a percent; 98RSE, Relative standard error expresses) as a percent; BL, Baseline; CI, Confidence interval: cov, Covariance: CRT. Central reitoal tin ckness;

. Itoer-todhidual variability: r, Pearsc-ris conelation coefficient

Sto kage: IIV m Baseline CRT (3.20H), HV in K CRT (25.1 ). IIV to Kto CRT-BL (I5.3H), HV to Kto CRT- max (15.4 )

Table 6-5. Parameter Estimates of Central Retinal Thickness Final Model for the PULSAR Study

D „escri,pt,i,on „ Es,ti.mate Bootstrap mean Baseline CRT (pat) 37? 394 (376,408) Kia_. CRT_. BL: Input rate for CRT at baseline (payday} 29.3 32.9 (27.0, 40.3} Kin. C, RT. max; hip® rate for CRT v^enmaxiinnm effect is acliieved 2(?.(-⁵ 2..i..9 (I /. /, 2P.9? (pn<'aay) K CRT; Drug effect coefficient on Kin CRT (mLfoig) O.?82 0.83? (0.324, 1.47) HV in Baseline CRT (%CV) 29.8 28,9 (26.7. 31.8) r(HV in Kin. CRT BL. IIV in Baseline CRT) 0.321 0.226 (0.157, 0,321) SV m Kin CRT BL (%CV) 57.5 ^rS. S (57,5, 98.6) i(HV mkm_CR.ljmax. II v m Basefoie CRT) -0.09199 _{r r}z-_{ft. A} '

ifHV in Kin CRT niax. IIV in Kin CRT BL) 0.888 0,940 (0,888, 0.964) Uv in Kin_CRT_inax ( CV) 59,5 80,3 (59.4. 102) r BV in K CRT, IIV ia Baseline CRT) -0.0518 -7.40e-04 (-0.233.0.195) j(IIV in K CRT, IIV ni Kia_CRT_BL) 0,130 0.111 (-0.0989, 0.338) r(HV ia K CRT, IIV i K. CRT.max) 0.330 0,255 (0,0265,.469) IIV in K CRT (T'SCV) 53.3 59.6 (51.<>. 72.9) Prop&t’ifoii (%CV) 9.62 9.54 (8.96, 10.1)

‘J-ftCV, Coefficient &f wiatioa expressed as a percent; %RSE. Relative standard eaer expressed as a percent; BL, Baseline; CI, Confidence interval: eov, Covariance: CRT. Central retinal thickness:

IIV, luier-hidividniii variability; r, Pearsen's conelation coefficient

Shrinkage: HV ia Baseline CRT (4.63%), HV ia Kia CRTJ3L (24.6%), ITV in Kin CRT _max (20.7 ), HV in K„CRT(I9.2%)

BCVA Model Development

[0688] The developed BCVA models for the PHOTON and PULSAR studies were structurally similar. The model developed for the PULSAR study included a disease progression component which the model for the PHOTON study did not include.

[0689] The dynamics over time of BCVA were described in both studies by means of a latent variable representing the underlying vision of the patient (Vision) governed by a turn-over model consisting of a zero-order input rate (Kin_Vision) and first order output constant (Koutv_isiOn). Drug effect on this dynamic system was implemented on the output process. Among the tested implementations of drug effect on Kout_Vist_0n, the final implementation considered that the ratio of

the difference between CRT at a particular time and the CRT floor (here considered 140 pm), and the difference between baseline CRT and the CRT floor, to explain the changes in Kout as CRT changed over the course of the studies. This ratio was created with the intention of defining the fraction of CRT that was not reduced considering that the maximum CRT reduction could lead to but no less than 140 pm. Drug effect was implemented as follows:

= Kout„,i,_x,^_L X? o—

where Koutvision is the first order output constant, Koutvisi_0n-BL is the first order output constant at baseline, CRTBL is CRT at baseline, and Kvision is the coeffient governing the effect of CRT and CRT at baseline on Kout_ViSt_an. The final models indicated that the lower the achieved ratio CRT-140)/(C7? T_BL-140), the lower the Kout_Vision would be and thus, the higher the vision and BCVA would be.

[0690] Regarding baseline vision, this was defined as a function of baseline CRT as follows: V

ision^ ~

where Vision_BL is the vision at baseline, CRTBL is the CRT at baseline, and KcRT- i ton is the coefficient governing the effect of CRT at baseline on the Vision_B. The final models indicated that the higher the baseline CRT, the lower the baseline vision and resulting baseline BCVA.

[0691] It was observed that, for a subgroup of patients in the PULSAR study, BCVA profiles decreased below their individual baseline in what seemed to be a progression of the disease (ie, further loss of vision from baseline). Therefore, a disease progression component was incorporated to the model for the PULSAR study in such a way that Kin_visitm was described by

the following differential equation:

where t is time, K_viSiOn is the elimination rate constant governing disease progression and Kian-cey is the coefficient governing the effect of aflibercept concentration in the eye on disease progression. In addition, 2 sub-populations were identified in terms of the K_Kin-c_eye. A mixture model was implemented so that patients could pertain to either of these 2 sub-populations and have one of two K_Kin-ce_ye. A small sub-population (-11%) was assigned to K_Km-ce_ye value that was 99% lower than the value for the larger sub-population (-89%). This lower K^n-coye implies that a much higher concentration of drug is needed to achieve inhibition of disease progression.

[0692] Final model parameters are presented in Table 6-6 and Table 6-7 for the PHOTON and PULSAR studies, respectively.

Table 6-6. Parameter Estimates of Best Corrected Visual Acuity Final Model for the PHOTON Study.

Descriptfcm Estimate %RSE Kout_vision: Elimination rate eonslant for vision (/day) 0.0844 6.40 V5: vision to achieve 50 BCVA points (Baitless) 0.540 3.43 K vision: CRT effect coefficient an Kent vision Cnm) 0.709 14.4 Box-Cox _eta I: box-cox tian fonnat oa parameter for UV n baseline vision (untiless) - -O. S42 199 Bax-Cox_eta2: box-cox traasfonnxtion parameter for HV in Kjvisioa (tmitiess) -0.346 329

KCV: Baseline CRT effect on baseline vision (qm) -8.00171 11.4 I1V in ssef e vision (%CV) 40.0 7.79 r(HV in Revision. HV ia baseline vision) 0,269 28.0 BVin K^ isimrdiCV) 83.2 13.4 HVmKatt_wion %CV) 152 14.9 Additive logit 0.0362 6,39 %CV, Coefficient of variation expressed as a percent; Relative standard error expressed as a percent; BCVA, Best corrected visual acmtv; COT, Covariance CRT, Central retinal u caess; SV, Inter- dividnai variability; r. Pearson’s tGiTelaUon. coefficient

Shrinkage; HV in baseline vision (5.3?%), nv in K_vision (18.4%). HV inKont visinn (43,2 )

Table 6-7. Parameter Estimates of Best Corrected Visual Acuity Final Model for the PULSAR Study.

Description Estimate %

RS£ Knut -Vision: Elniuiiafion rate constant for vision (/day) 0.0211 1.39 VSO: vision to achieve 50 BCV points (ittiitfess) 0.615 4.37 K_yision: CRT etTecteiiefficieni nKoui vision V'BIH 0.85.$ 341 Box-C'ox etsl: box cox tiansfor ation pacantoter for HV in baseline vision (unitless) -0.677 19.0 K. CV: Baseline CRT effect on baseline vis n (.(.tai) 0.999 10.1 DPROG: disease js’ogrression rate (/day) 0.00204 3.32 K_CONC1 Drug effect coe.fident on disease m?gcassioit for jxipnlanon 1 (inltag) 60.0 551 Pl: Pr jortioii of patients opulatimi I (tinitless) 0,891 5.26 K CONC2: Drag effect eoeficient on disease progression for population 2 (mL/mg) 0.00570 10.9 irv m DPRt tiHCV) 215 14.8 HV in baseline visum (%CV) 47.3 7.37 i'(HV ia K vision, HV in baseline vision) 9.0350 122 HV in K vision ( CV) 100 6.80 HV in Kaui-Vision (%CV) 87.1 12.3 Additive logit 0.0377 0

4S1 %CV, Coefficient of variation expressed as a percent; %R$E, Relative siaatad error expressed as a percent; BCVA, Best corrected visual acuity, w, Co iance; CRT, Cental reiinsl thickness; HV, Inter- isidual vserisibiSttv; r, Pearson’s correlation coefficient

Shortage: HV in DPR. OG (37.6%), HV in DPROG (71.1%). 8V in teeline vision (632%), HV in baseline vision (4.62%), HV in K yis n (23,3%X HV ia K vis {26.5%), HV ia Kout vi$ioa (33.3%), HV in Kuut visioa (27.1%)

Loss to follow-up Model Development

[0693] To test the influence of outcomes (CRT and BCVA) on the probability of losing patients to follow-up, a parametric survival model was developed. The analyses concluded that neither CRT nor BCVA had a significant impact on the probability of losing follow-up.

Performance evaluation of final model

[0694] The predictive performance of the final joint model was evaluated by comparing simulated change from baseline for BCVA and for CRT with observed changes from baseline considering the full joint model and DRMs. In addition, the predictive performance in terms of the capacity of the model to predict dose regimen modifications was assessed by comparing the number of doses received during the first year after randomization between the observed and simulated data. These 3 evaluations were considered successful and thus the model was considered adequate to be used for the model applications. Thus, by this complex scientific

procedure a new simulator was developed and qualified for the intended use to address questions that were not tested in the PHOTON and PULSAR studies.

Model Applications

[0695] The PK/PD models presented are designed to build a bridge between QE and risk of dose interval shortening, by describing: 1) the relationship between Q_E and exposure in the eye over time, 2) how the exposure in the eye determines the duration of the effect in terms of CRT and in consequence BCVA, and finally, 3) how the duration of the effect on CRT and BCVA determines the need for DRM. To fulfill the objectives of the analyses presented, 2 model applications (Model Application 1 and Model Application 2) were considered.

Model Application 1

[0696] Model Application 1 used the developed PK/PD models to explore how drug clearance out of the eye drives the decline of effect over time during a dosing interval. For these simulations, relative drug effect on CRT was computed as follows:

E

ffect ~.1 ™ exp'

where K_CRT is the coefficient controlling the effect of intraocular aflibercept concentration on KincRT, and Concentration_eye is the effective intraocular aflibercept concentration. On the other hand, relative drug effect on disease progression (based on the PULSAR BCVA model) was computed as follows:

E

ffect ~~ 1

Where Kef disease -progression is the coefficient controlling the effect of intraocular aflibercept Concentration on K disease-progression- [0697] The simulations of drug concentration and relative effect on CRT from Model Application 1 show that most patients maintain intraocular drug concentration at effective levels when dosing at intervals longer than Q4W, such as Q8W, Q12W and Q16W. These simulations also indicate that patients with fast QE have more rapidly declining intraocular aflibercept concentration, which over even a Q8W dose interval are not able to maintain effective concentrations and have a higher probability of requiring dosing Q4W to maintain effective concentrations.

[0698] Furthermore, PULSAR-based results include representations of drug effect on BCVA, particularly the inhibition of disease progression. It must be noted that disease progression inhibition illustrated by Model Application 1 only applies to nAMD patients, as this model

component was only identifiable in the model developed using the PULSAR study data. Here, the model identified 2 sub-populations in terms of the effect of the drug on disease progression: sub-population 1 (89% of the patients), and sub-population 2 (11% of the patients). Based on this analysis, sub-population 2 has a need for higher drug concentrations in the eye to inhibit disease progression as compared to population 1. As illustrated by Model Application 1, all subgroups of patients in sub-population 1 maintain inhibition of disease progression over the 4 and 8 week period post-dose. Conversely, some patients in sub-population 2 do not maintain inhibition of disease progression over the 4 and 8 week period, especially those with fast ocular clearance. These results indicate that some patients in sub-population 2 are in need of higher concentrations of aflibercept in the eye to retain effective concentrations longer, and that those with high QE-estimates are particularly likely to benefit from receiving HD aflibercept as often as Q4W, as compared to Q8W, to maintain the inhibition of disease progression.

Model Application 2

[0699] Model Application 2 used the developed PK/PD models to infer through simulations the expected (model-based) benefit of dosing Q4W as compared to Q8W for patients that require a more intense treatment. In this context, patients that require a more intense treatment are defined as patients that meet the criteria for further shortening of their dosing interval even when being dosed Q8W (after already having their dosing interval shortened from Q12W or Q16W at the beginning of the study). With regard to the assessment of benefit, it was evaluated in terms of a predicted BCVA difference at the end of the first 1-year period after randomization when comparing a dosing paradigm that allows dosing HD aflibercept as often as Q4W, compared to the Q8W interval allowed in the PHOTON and PULSAR studies. The results of these simulations are presented in Figure 26. This figure illustrates the distribution of the mean benefit obtained in each of the 100 clinical trial simulations. The distributions for the 100 simulations of the PHOTON (DME) and for the PULSAR (nAMD)-based trials do not cross 0, and indicate that dosing Q4W would have a benefit for patients who meet DRM criteria after receiving HD aflibercept Q8W, with a mean gain in BCVA of ~5.5 letters and ~2.5 letters in DME and nAMD patients, respectively.

[0700] This expectation was further reinforced by an additional set of simulations. Individual post-hoc estimates were used to simulate BCVA profiles over time for the subset of patients in the PHOTON and PULSAR studies that qualified for Q4W dosing, when 1) dosing Q4W and 2) dosing Q8W, after qualifying for Q4W dosing (as compared to full clinical trial simulations presented in Model Application 2). Simulated BCVA scores at the end of the last Q8W dosing

interval of the first year after randomization were compared at the individual level between these 2 dosing paradigms. Results of these simulations indicate that the mean BCVA gain would have been of 2 letters for the 7 patients in the PHOTON study and of 3.2 letters for the 39 patients in the PULSAR study that qualified for Q4W dosing. These results are aligned with the full clinical trial simulations presented in Model Application 2 and reinforce the confidence in the results of Model Application 2.

Qualifying Patients as Compared to Dosing under the Original Study Protocols

[0701] These results highlight the importance of considering a dosing of HD aflibercept every 4 weeks for patients who need it. Some patients have high exposure requirements and for them a Q4W dosing of HD aflibercept is expected to result in improved vision. Furthermore, dosing of HD aflibercept Q4W could prevent irreversible vision loss for those patients with nAMD who have high exposure needs.

Conclusions:

[0702] A small proportion of patients in the PHOTON and PULSAR trials failed to maintain pharmacological response when dosed HD aflibercept Q8W. These patients would have qualified to receive HD aflibercept Q4W but did not receive it given the clinical trial protocol did not allow for it. The analyses presented in this report show that the incidence of patients failing to maintain pharmacological response when dosed HD aflibercept Q8W in the PHOTON and PULSAR trials was highest in those patients with both high baseline CRT and fast ocular clearance.

[0703] The developed PK/PD models successfully described the observed data from PHOTON and PULSAR studies, and characterized the relationship between aflibercept concentrations in the eye with CRT and BCVA. Furthermore, the models could predict dose regimen modifications in these trials by predicting how patients would meet dose regimen modification criteria. The model was deemed appropriate to investigate the duration of a pharmacological effect and the potential benefit of shortening the dose interval to Q4W for those patients that fail to maintain response in PHOTON and PULSAR studies when dosed HD aflibercept Q8W.

[0704] The simulations presented in this report show that most patients maintain effective drug concentrations for a long period of time and are not expected to suffer a loss in efficacy when receiving HD aflibercept with dose intervals longer than 4 weeks. However, these simulations also indicate that a small proportion of patients could benefit from receiving HD

aflibercept Q4W. In particular, patients with fast ocular clearance have a higher chance of requiring closing Q4W to maintain effective concentrations.

[0705] The clinical trial simulations presented in this report consistently point towards a benefit of dosing Q4W for patients who would have qualified for Q4W dosing in the PHOTON and PULSAR studies. Simulations indicate that by allowing dosing Q4W for patients with DME and patients with nAMD who fail to maintain response when already being dosed Q8W we should expect a mean gain in BOVA of ~5.5 letters and ~2.5 letters, respectively, for these patients. It must be noted that the modeling presented here also indicates that exposures below the individual patients’ needs can result in irreversible vision loss for nAMD patients. The risk of this happening would be reduced by dosing HD aflibercept Q4W.

[0706] The results presented highlight the importance of considering dosing of HD aflibercept every 4 weeks for some patients. Patients being identified by functional loss could benefit by shortening their dosing interval from a longer interval.

[0707] Some patients may have a high threshold concentration and for them a higher rate of treatment like Q4W dosing of HD aflibercept is essential to improve or retain their vision. In particular, in the nAMD population, a Q4W dosing could prevent irreversible vision loss for those patients.

*****

[0708] All references cited herein are incorporated by reference to the same extent as if each individual publication, database entry (e.g., Genbank sequences or GenelD entries), patent application, or patent, was specifically and individually indicated to be incorporated by reference. This statement of incorporation by reference is intended by Applicants to relate to each and every individual publication, database entry (e.g., Genbank sequences or GenelD entries), patent application, or patent, each of which is clearly identified in even if such citation is not immediately adjacent to a dedicated statement of incorporation by reference. The inclusion of dedicated statements of incorporation by reference, if any, within the specification does not in any way weaken this general statement of incorporation by reference. Citation of the references herein is not intended as an admission that the reference is pertinent prior art, nor does it constitute any admission as to the contents or date of these publications or documents.

Claims

We claim:

1. A method

(i) for treating or preventing an angiogenic eye disorder, neovascular age related macular degeneration or diabetic macular edema;

(ii) for treating or preventing an angiogenic eye disorder secondary to retinal vein occlusion in a subject in need thereof,

(iii) for improving best corrected visual acuity with an angiogenic eye disorder secondary to retinal vein occlusion in a subject in need thereof,

(iv) for treating or preventing retinal vein occlusion in a subject in need thereof, and/or

(v) for treating or preventing macular edema secondary to retinal vein occlusion; comprising or consisting of administering to an eye of the subject, one or more doses of about 8 mg (±0.8 mg) of a VEGF receptor fusion protein about once every

4-8 weeks (±7 days),

4 weeks (±7 days),

8 weeks (±7 days),

4 weeks (±7 days) and then 8 weeks (±7 days),

4 weeks (±7 days) and then 8 weeks (±7 days) and then 4 weeks (±7 days),

12 weeks (±7 days),

16 weeks (±7 days),

20 weeks (±7 days),

24 weeks (±7 days), and/or

32 weeks (±7 days).

2. The method of claim 1,

(i) comprising administering to an eye of the subject, one or more doses of about 8 mg (±0.8 mg) of a VEGF receptor fusion protein about once every 4 weeks (±7 days);

(ii) comprising administering to an eye of the subject, one or more doses of about 8 mg (±0.8 mg) of a VEGF receptor fusion protein about once every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein on a Treat & Extend or Pro re nata basis or are adjusted based on the physician’s judgement of visual and/or anatomic outcomes;

(iii) comprising administering to an eye of the subject, 7 doses of about 8 mg (±0.8 mg) of a VEGF receptor fusion protein about once every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein on a Treat & Extend or Pro re nata basis or are adjusted based on the physician’s judgement of visual and/or anatomic outcomes;

(iv) consisting of administering to an eye of the subject, one or more doses of about 8 mg (±0.8 mg) of a VEGF receptor fusion protein about once every 4 weeks (±7 days);

or

(v) consisting of administering to an eye of the subject, one or more doses of about 8 mg (±0.8 mg) of a VEGF receptor fusion protein about once every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein on a Treat & Extend or Pro re nata basis or are adjusted based on the physician’s judgement of visual and/or anatomic outcomes;

and/or

(vi) consisting of administering to an eye of the subject, 7 doses of about 8 mg (±0.8 mg) of a VEGF receptor fusion protein about once every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein on a Treat & Extend or Pro re nata basis or are adjusted based on the physician’s judgement of visual and/or anatomic outcomes;

optionally, with respect to any of (i)-(vi), wherein, no doses are administered at an interval of greater than about 4 weeks.

3. The method of any one of the preceding claims, comprising administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein;

wherein each secondary dose is administered about 2, 3, 4 or 2 to 4 weeks (±7 days) after the immediately preceding dose; and

wherein each tertiary dose is administered about

4-8 weeks (±7 days),

4 weeks (±7 days),

8 weeks (±7 days),

12 weeks (±7 days),

16 weeks (±7 days),

20 weeks (±7 days),

24 weeks (±7 days), and/or

32 weeks (±7 days),

after the immediately preceding dose;

and/or on a Treat & Extend or Pro re nata basis or are adjusted based on the physician’s judgement of visual and/or anatomic outcomes.

4. The method of any one of the preceding claims, comprising administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by 2, 3, 4, 5, or 6 or 2-6 secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein;

wherein each secondary dose is administered about 2, 3, 4, or 2-4 weeks (±7 days) after the immediately preceding dose; and

wherein each tertiary dose is administered about 8 weeks (±7 days) after the immediately preceding dose;

optionally, wherein no doses are administered greater than about 8 weeks (±7 days) after the immediately preceding dose; and/or

optionally, wherein the tertiary doses are followed by one or more doses administered:

• about every 4 weeks (±7 days),

• on a Treat & Extend basis;

• on a Pro re nata basis; or

• which are adjusted based on the physician’s judgement of visual and/or anatomic outcomes.

5. The method of claim 4, wherein the tertiary doses are followed by one or more doses administered:

• about every 4 weeks (±7 days),

• on a Treat & Extend basis;

• on a Pro re nata basis; or

• which are adjusted based on the physician’s judgement of visual and/or anatomic

outcomes.

6. The method of any one of the preceding claims, comprising administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by 2 or 3 or 4 or 2-4 secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein;

optionally, wherein the tertiary doses are followed by one or more doses administered about every 4 weeks (±7 days); and/or

optionally, wherein tertiary doses are followed by one or more doses administered on a Treat & Extend or on a Pro re nata basis or are adjusted based on the physician’s judgement of visual and/or anatomic outcomes.

7. The method of any one of the preceding claims, comprising administering to the eye of the subject, 3-5 doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein in a formulation that comprises about 114.3 mg/ml VEGF receptor fusion protein at an interval of once every 4 weeks (±7 days); wherein after said 3 doses, administering one or more doses of the VEGF receptor fusion protein at an interval which is lengthened up to 8 or more weeks (±7 days); optionally, further comprising administering to the eye one or more doses about every 4 weeks (±7 days).

8. The method of any one of the preceding claims, comprising administering to the eye of the subject, 3 doses or 4 doses or 5 doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein in a formulation that comprises about 114.3 mg/ml VEGF receptor fusion protein at an interval of once every 4 weeks (±7 days); wherein after said 5 doses, administering one or more doses of the VEGF receptor fusion protein at an interval which is lengthened up to 8 or more weeks (±7 days); optionally, further comprising administering to the eye one or more doses about every 4 weeks (±7 days).

9. The method of any one of claims 1 or 3, comprising administering, to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein;

wherein each tertiary dose is administered about 12 weeks (±7 days) after the immediately preceding dose;

optionally, wherein no doses are administered greater than about 12 weeks (±7 days) after the immediately preceding dose; and/or

optionally, wherein tertiary doses are followed by one or more doses administered on a Treat & Extend or Pro re nata basis or are adjusted based on the physician’s judgement of visual and/or anatomic outcomes.

10. The method of any one of claims 1, 3 or 9, comprising administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by 5 secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein;

11. The method of any one of the preceding claims comprising administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by 5 secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein;

wherein:

(a) each tertiary dose is administered about 12 weeks (±7 days) after the immediately preceding dose;

(b) each tertiary dose is administered about 8 weeks (±7 days) after the immediately preceding dose;

(c) one tertiary dose is administered about 12 weeks (±7 days) after the immediately preceding dose and then each subsequent tertiary dose is administered about 8 weeks (±7 days) after the immediately preceding tertiary dose; or

(d) one tertiary dose is administered about 8 weeks (±7 days) after the immediately preceding dose, and then each subsequent tertiary dose is administered about 12 weeks (±7 days) after the immediately preceding tertiary dose; and/or

(e) one tertiary dose is administered about 12 weeks (±7 days) after the immediately preceding dose, then each subsequent tertiary dose administered about 8 weeks (±7 days) after the immediately preceding tertiary dose; and then each subsequent tertiary dose is administered about 4 weeks (±7 days) after the immediately preceding tertiary dose.

12. The method of claim 11 wherein one tertiary dose is administered about 12 weeks (±7 days) after the immediately preceding dose by week 36 from treatment initiation.

13. The method of claim 1, comprising administering to the eye of the subject,

a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by 2, 3 or 4 or 2-4 secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein; followed by

one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2, 3, 4, or 2-4 weeks (±7 days) after the immediately preceding dose; and

wherein:

(f) 4 secondary doses are administered every 4 weeks and each tertiary dose is administered about 8 weeks (±7 days) after the immediately preceding dose;

(g) one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then subsequent tertiary doses are administered about 4 weeks (±7 days) after the immediately preceding dose;

(o) 3 secondary doses are administered about every 4 weeks (±7 days) and one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then the interval between subsequent tertiary doses are shortened to about 4 weeks (±7 days) after the immediately preceding dose;

(p) 4 secondary doses are administered about every 4 weeks (±7 days) and one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then the interval between subsequent tertiary doses are shortened to about 4 weeks (±7 days) after the immediately preceding dose;

(u) one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose and then each subsequent tertiary dose is administered about 4 weeks (±7

days) after the immediately preceding dose; and then one or more tertiary doses are administered on a Treat & Extend or pro re nata basis, or are adjusted based on the physician’s judgement of visual and/or anatomic outcomes.

14. A method for treating or preventing an angiogenic eye disorder in a subject in need thereof comprising administering to an eye of the subject one or more doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein about once every 4 weeks (±7 days).

15. The method of any one of the preceding claims wherein the angiogenic eye disorder is neovascular age-related macular degeneration (wet), macular edema, macular edema following retinal vein occlusion, retinal vein occlusion (RVO), hemiretinal vein occlusion, central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), diabetic macular edema (DME), choroidal neovascularization (CNV), iris neovascularization, neovascular glaucoma, post-surgical fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), optic disc neovascularization, corneal neovascularization, retinal neovascularization, vitreal neovascularization, pannus, pterygium, vascular retinopathy, diabetic retinopathy, non-proliferative diabetic retinopathy and/or proliferative diabetic retinopathy.

16. The method of any one of the preceding claims, wherein one or more secondary doses is 2 doses, 3 doses or 4 doses or 5 doses or 6 doses or 7 doses.

17. The method of any one of the preceding claims, wherein secondary doses are administered with about 4 weeks (±7 days) after the immediately preceding dose.

18. The method of any one of the preceding claims, wherein, after one or more tertiary doses are administered, the tertiary dosing interval is

• shortened from about 12 weeks to about 8 weeks or about 4 weeks or about 4-8 weeks;

or wherein the tertiary dosing interval is shortened from about 8 weeks to about 4 weeks; or

• lengthened from about 4 weeks to about 8, 12, 16, 20, 24, 28, or 32 weeks or from about 8 weeks to about 12, 16, 20, 24, 28, or 32 weeks.

19. The method of any one of the preceding claims, wherein, after one or more tertiary doses are administered, the tertiary dosing interval is shortened if the subject exhibits any one or more of:

• >5 letters loss of BCVA from best previous BCVA;

• >5 letters loss of BCVA from best previous BCVA with persistent or worsening macular edema; and/or

• >50 pm increase in CST relative to CST measured at any previous time.

20. The method of any one of the preceding claims, wherein said tertiary dosing interval is lengthened if the subject exhibits any one or more of:

• Best-corrected visual acuity loss <5 letters relative to BCVA measured at any previous time; and/or

• CST thickness of <300 pm, <320 pm, <325 pm or <315 pm.

21. The method of claim 20 wherein CST thickness is as measured by Heidelberg Spectralis or Cirrus or Topcon SD-OCT.

22. The method of any one of the preceding claims, comprising administering to the eye of the subject,

a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by

one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2, 3, 4 or 2-4 weeks (±7 days) after the immediately preceding dose; and

wherein said tertiary dosing interval is shortened if the subject exhibits any one or more of:

• >5 letters loss of BCVA from best previous BCVA; and/or

• >5 letters loss of BCVA from best previous BCVA with persistent or worsening macular edema.

23. The method of any one of the preceding claims, comprising administering to the eye of the subject,

a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein;

wherein each secondary dose is administered about 4 weeks (±7 days) after the immediately preceding dose; and

• >5 letters loss of BOVA from best previous BOVA;

• >50 pm increase in GST relative to GST measured at any previous time.

24. The method of any one of the preceding claims, comprising administering to the eye of the subject,

a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by 2, 3 or 4 or 2-4 secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by

one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein; wherein each secondary dose is administered about 4 weeks (±7 days) after the immediately preceding dose; and

wherein said tertiary dosing interval is lengthened if the subject exhibits any one or more of:

• GST thickness of <325 pm or <315 pm.

25. The method of any one of the preceding claims, wherein the subject suffers from macular edema secondary to retinal vein occlusion.

26. The method of any one of the preceding claims, wherein the retinal vein occlusion is central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), and/or hemiretinal vein occlusion (HRVO).

27. The method of any one of the preceding claims, wherein lengthening or shortening the interval between tertiary doses is lengthened or shortened about one or more or 2, 3, 4, 5, 6 or 7 times by about one or more 4-week increments.

28. The method of any one or the preceding claims, wherein the interval between tertiary doses was lengthened or shortened one or more or 2, 3, 4 or 5 times prior.

29. The method of any one or the preceding claims, wherein the interval between tertiary doses was lengthened one or more or 2, 3, 4, 5 or 6 times prior from:

about 8 weeks to about 12, 16, 20, 24, 28, 32 or 36 weeks;

about 12 weeks to about 16, 20, 24, 28, 32 or 36 weeks; and/or

about 16 weeks to about 20, 24, 28, 32 or 36 weeks.

30. The method of any one of the preceding claims, wherein about 8 weeks (±7 days) is 8 weeks.

31. The method of any one of the preceding claims, wherein about 12 weeks (±7 days) is 12 weeks.

32. The method of any one of the preceding claims, wherein the <325 pm or <315 pm is measured by spectral domain optical coherence tomography (SD-OCT).

33. The method of any one of the preceding claims, wherein the subject exhibits one or more of:

• Having had at least 3 injections of a VEGF antagonist or VEGF receptor fusion protein within the past 5 months;

• Having had at least 3 injections of about 2 mg VEGF receptor fusion protein within the past 5 months;

• Having had at least 3 injections of about 8 mg VEGF receptor fusion protein within the past 5 months;

• Treatment-naive macular edema;

• Treatment-naive macular edema involving the foveal center secondary to RVO;

• Treatment-naive macular edema involving the foveal center secondary to BRVO, HRVO and/or CRVO;

• A Mean CST >300 pm on OCT or >320 pm on Heidelberg Spectralis;

• Macular edema following RVO involving the foveal center;

• Macular edema following BRVO, CRVO and/or HRVO involving the foveal center;

• A BCVA or about 46, 55, 57, 66 or 46-66 letters;

• A CST of about 459, 583, 631, 759 or 459-759, >581 or <581 micrometers;

• Perifoveal and/or parafoveal ischemia;

• Macular ischemia;

• Macular ischemia with an area of about 0, 3, 4, 28 or 0-28 mm²;

• Retinal areas of non-perfusion outside the macula;

• A history of CNV lesions secondary to nAMD; and/or

• A history of DME with central involvement.

34. The method of any one of the preceding claims, wherein the subject does not exhibit one or more of:

• Evidence of macular edema due to any cause other than RVO;

• Diabetic retinopathy;

• Diabetic macular edema;

• Advanced age-related macular degeneration (nAMD or geographic atrophy);

• Use of any intravitreal implantable agent in an eye;

• Prior treatment with ocriplasmin at any time in an eye;

• Prior treatment with pegcetacoplan injection or avacincaptad pegol injection at any time in an eye;

• Prior treatment with retinal laser photocoagulation at any time in an eye;

• Prior treatment with gene therapy and/or cell therapy at any time in an eye;

• History of vitreoretinal surgery at any time in an eye;

• Any intraocular surgery, including cataract surgery, within 12 weeks of treatment in an eye;

• YAG (Yttrium-aluminum-garnet) capsulotomy in an eye within 4 weeks of treatment; • IOP > 25 mm Hg in an eye;

• Uncontrolled glaucoma in an eye;

• Infectious blepharitis, keratitis, scleritis, or conjunctivitis in an eye;

• Any intraocular inflammation/infection within 12 weeks of treatment in an eye;

• History of idiopathic or autoimmune uveitis in an eye;

• Vitreomacular traction or epiretinal membrane in an eye evident on biomicroscopy or OCT that affects central vision;

• Myopia of a spherical equivalent of 8 diopters or greater in an eye;

• History of corneal transplant in an eye;

• Any corneal dystrophy affecting the visual axis in an eye;

• Aphakia, or pseudophakia with absence of posterior capsule, unless it occurred as a result of a YAG posterior capsulotomy performed more than 28 days before treatment in an eye;

• Any history of macular hole of stage 2 and above in an eye;

• Current anterior segment neovascularization, vitreous hemorrhage, or tractional retinal detachment visible in an eye;

• Structural damage in an eye that is likely to preclude improvement in BCVA following resolution of macular edema;

• Uncontrolled blood pressure;

• History of cerebrovascular accident/transient ischemic attack or myocardial infarction/acute coronary syndrome within 6 months (180 days) of treatment;

• Renal failure, dialysis, or history of renal transplant;

• Known sensitivity to the VEGF receptor fusion protein, histidine, arginine, polysorbate or sucrose;

• Subject is pregnant or is a breastfeeding woman;

• Subject is a man or woman of child bearing potential who is not practicing a highly effective contraception prior to treatment or at least 4 months after cessation of treatment; wherein said highly effective contraception comprises stable use of combined estrogen and progestogen containing hormonal contraception by oral, intravaginal or transdermal route or progestogen-only hormonal, contraception, by oral, injectable, implantable route associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to treatment; intrauterine device; or intrauterine hormone-releasing system;

bilateral tubal occlusion/ligation; vasectomy; condom plus contraceptive sponge, foam, or jelly, or diaphragm plus contraceptive sponge, foam, or jelly; and/or sexual abstinence.

• Subretinal hemorrhage in the study eye >~50% of the total lesion area

• DME or DR, defined in the diabetic participants with nAMD as DR lesions in the assessable area of the retina

• Evidence of macular edema due to any other cause other than diabetes mellitus in the eye

• Advanced age-related macular degeneration (nAMD or geographic atrophy) in the eye • Active proliferative DR in the eye; and/or

• Panretinal photocoagulation (PRP) or macular laser photocoagulation in the eye within 12 weeks (84 days);

optionally, wherein treatment is paused and/or terminated if the subject develops any one or more thereof after treatment initiation.

35. The method of claim 34 wherein an eye is the eye to which said VEGF receptor fusion protein is administered and/or the fellow eye.

36. The method of any one of the preceding claims, wherein the VEGF receptor fusion protein is in an aqueous pharmaceutical formulation comprising a histidine-based buffer, phosphate-based buffer, citrate-based buffer, phosphate/citrate-based buffer and/or acetate-based buffer.

37. The method of any one of the preceding claims, wherein the VEGF receptor fusion protein is in an aqueous pharmaceutical formulation comprising arginine.

38. The method of any one of the preceding claims, wherein VEGF receptor fusion protein is in an aqueous pharmaceutical formulation comprising:

at least about 100 mg/ml of a VEGF receptor fusion protein comprising two polypeptides that each comprises an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of VEGFR2, and a multimerizing component;

about 10-100 mM L-arginine;

sucrose;

a histidine-based buffer; and

a surfactant;

wherein the formulation has a pH of about 5.0 to about 6.8; wherein the VEGF receptor fusion protein has less than about 3.5% high molecular weight species immediately after manufacture and purification and/or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C.

39. The method of any one of the preceding claims, wherein a subject having any one or more of:

ocular or periocular infection;

active intraocular inflammation; and/or

hypersensitivity;

is excluded from administration of the VEGF receptor fusion protein to the eye.

40. The method of claim 39, further comprising a step of evaluating the subject for:

ocular or periocular infection;

active intraocular inflammation; and/or

hypersensitivity;

and excluding the subject from said administration if any one or more is found in the subject.

41. The method of any one of the preceding claims, further comprising monitoring the subject during said treatment or prevention for conjunctival hemorrhage, cataract, vitreous detachment, vitreous floaters, corneal epithelium defect and/or increased intraocular pressure.

42. The method of any one of the preceding claims, comprising, prior to each administration, providing:

• one single-dose glass vial having a protective plastic cap and a stopper containing an aqueous formulation comprising 8 mg (±0.8 mg) VEGF receptor fusion protein in about 70 microliters;

• one 30-gauge x ¹/2-inch injection needle; and

packaged together; then

(1) visually inspecting the aqueous formulation in the vial and, if particulates, cloudiness, or discoloration are visible, then using another vial of aqueous formulation containing the VEGF receptor fusion protein;

(2) removing the protective plastic cap from the vial; and

(3) cleaning the top of the vial with an alcohol wipe; then

using aseptic technique:

(4) removing the 18-gauge x 1¹/2-inch, 5-micron, filter needle and the 1 mL syringe from their packaging;

(5) attaching the filter needle to the syringe by twisting it onto the Luer lock syringe tip;

(6) pushing the filter needle into the center of the vial stopper until the needle is completely inserted into the vial and the tip touches the bottom or a bottom edge of the vial;

(7) withdrawing all of the VEGF receptor fusion protein vial contents into the syringe, keeping the vial in an upright position, slightly inclined, while ensuring the bevel of the filter needle is submerged into the liquid;

(8) continuing to tilt the vial during withdrawal keeping the bevel of the filter needle submerged in the formulation;

(9) drawing the plunger rod sufficiently back when emptying the vial in order to completely empty the filter needle;

(10) removing the filter needle from the syringe and disposing of the filter needle; (11) removing the 30-gauge x ¹/2-inch injection needle from its packaging and attaching the injection needle to the syringe by firmly twisting the injection needle onto the Luer lock syringe tip;

(12) holding the syringe with the needle pointing up, and checking the syringe for bubbles, wherein if there are bubbles, gently tapping the syringe with a finger until the bubbles rise to the top; and

(13) slowly depressing the plunger so that the plunger tip aligns with the graduation line that marks 70 microliters on the syringe.

43. The method of any one of the preceding claims, wherein administration of the VEGF receptor fusion protein is performed by intravitreal injection under controlled aseptic conditions, which comprise surgical hand disinfection and the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent) and anesthesia and a topical broad-spectrum microbicide are administered prior to the injection. 11876WO01

44. The method of any one of the preceding claims, wherein the VEGF receptor fusion protein comprises amino acids 27-457 of the amino acid sequence set forth in SEQ ID NO: 2.

45. The method of any one of the preceding claims, wherein the VEGF receptor fusion protein is selected from the group consisting of: aflibercept and conbercept.

46. The method of any one of the preceding claims, wherein the VEGF receptor fusion protein:

(i) comprises two polypeptides that comprise (1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO: 2; (2) a VEGFR2 component comprising amino acids 130-231 of SEQ ID NO: 2; and (3) a multimerization component comprising amino acids 232-457 of SEQ ID NO: 2;

(ii) comprises two polypeptides that comprise an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of a VEGFR2, and a multimerizing component;

(iii) comprises two polypeptides that comprise an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of VEGFR2, an Ig domain 4 of VEGFR2 and a multimerizing component; or

(iv) comprises two VEGFR1 R2-FcAC1 (a) polypeptides encoded by the nucleic acid sequence of SEQ ID NO: 1.

47. The method of any one of the preceding claims, wherein the VEGF receptor fusion protein comprises two polypeptides that comprise an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of a VEGFR2, and a multimerizing component.

48. The method of any one of the preceding claims, wherein the VEGF receptor fusion protein is in an aqueous pharmaceutical formulation selected from the group consisting of formulations A to KKKK.

49. The method of any one of the preceding claims, wherein the VEGF receptor fusion protein is in an aqueous pharmaceutical formulation comprising about 114.3 mg/ml VEGF receptor fusion protein.

50. The method of any one of the preceding claims, comprising administering the VEGF receptor fusion protein to both eyes of the subject.

51. The method of any one of the preceding claims, wherein the VEGF receptor fusion protein is administered from a pre-filled syringe.

52. The method of claim 51, wherein the pre-filled syringe is glass or plastic, and/or sterile.

53. The method of any one of the preceding claims, wherein the VEGF receptor fusion protein is intravitreally injected with a 30 gauge x ¹/₂-inch sterile injection needle.

54. The method of any one of the preceding claims, wherein the subject has previously received one or more doses of 2 mg VEGF receptor fusion protein.

55. The method of claim 54, wherein the 2 mg VEGF receptor fusion protein is in an aqueous pharmaceutical formulation comprising 40 mg/ml VEGF receptor fusion protein.

56. The method of any one of claims 54-55, wherein the 2 mg of VEGF receptor fusion protein is in an aqueous pharmaceutical formulation comprising: 40 mg/ml VEGF receptor fusion protein, 10 mM sodium phosphate, 40 mM NaCI, 0.03% polysorbate 20 and 5% sucrose, with a pH of 6.2.

57. The method of any one of the preceding claims, wherein one or more further doses of VEGF receptor fusion protein are administered.

58. The method of any one of the preceding claims, wherein 8 mg (±0.8 mg) of VEGF receptor fusion protein is in an aqueous pharmaceutical formulation that comprises a sugar or polyol.

59. The method of any one of the preceding claims, wherein 8 mg (±0.8 mg) of VEGF receptor fusion protein in an aqueous pharmaceutical formulation that comprises sucrose, trehalose or both sugar and trehalose.

60. The method of any one of the preceding claims, wherein 8 mg (±0.8 mg) of VEGF receptor fusion protein is in an aqueous pharmaceutical formulation that has a pH of about 5.8.

61. The method of any one of the preceding claims, wherein 8 mg (±0.8 mg) of VEGF receptor fusion protein is in an aqueous pharmaceutical formulation comprising about 103-126 mg/ml VEGF receptor fusion protein, histidine-based buffer and arginine.

62. The method of any one of the preceding claims, wherein 8 mg (±0.8 mg) of VEGF receptor fusion protein is an aqueous pharmaceutical formulation comprising about 114.3 mg/ml VEGF receptor fusion protein, histidine-based buffer and arginine.

63. The method of any one of the preceding claims, wherein the VEGF receptor fusion protein is aflibercept in an aqueous pharmaceutical formulation, wherein the aflibercept has less than about 3.5% high molecular weight species immediately after manufacture and purification and/or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C.

64. The method of any one of the preceding claims, wherein the VEGF receptor fusion protein is in an aqueous pharmaceutical formulation comprising:

at least about 100 mg/ml of a VEGF receptor fusion protein;

about 10-100 mM L-arginine;

sucrose;

a histidine-based buffer; and

a surfactant;

wherein the formulation has a pH of about 5.0 to about 6.8;

wherein the VEGF receptor fusion protein has less than about 3.5% high molecular weight species immediately after manufacture and purification and/or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C.

65. The method any one of the preceding claims, wherein the VEGF receptor fusion protein is in an aqueous pharmaceutical formulation comprising:

• >100 mg/ml VEGF receptor fusion protein, histidine-based buffer and L-arginine;

• 140 mg/ml aflibercept; 20 mM histidine-based buffer; 5 % (w/v) sucrose; 0.03 % (w/v) polysorbate 20; 10 mM L-arginine; pH 5.8;

• 150 ± 15 mg/ml aflibercept, 10 mM phosphate-based buffer, 8 ± 0.8% (w/v) sucrose, 0.02-0.04% (w/v) polysorbate 20 and 50 mM L-arginine, pH 5.9-6.5;

• 103-126 mg/ml aflibercept, 10 ± 1 mM histidine-based buffer, 5 ± 0.5% (w/v) sucrose, 0.02-0.04% (w/v) polysorbate 20, and 50 ± 5 mM L-arginine, pH 5.5-6.1;

• 140 mg/ml aflibercept, 10 mM histidine-based buffer, 2.5 % (w/v) sucrose, 2.0 % (w/v) proline, 0.03 % (w/v) polysorbate 20 and 50 mM L-arginine, pH 5.8;

• 114.3 mg/ml aflibercept, 10 mM histidine-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 20 and 50 mM L-arginine, pH 5.8;

• >100 mg/ml aflibercept, histidine-based buffer and L-arginine;

• >100 mg/ml aflibercept at about pH 5.8, wherein the formulation forms <3% HMW aggregates after incubation at 5°C for 2 months;

• about 114.3 mg/mL aflibercept; 10 mM - 50 mM histidine-based buffer, sugar, non-ionic surfactant, L-Arginine, pH 5.8; or

• about 114.3 mg/mL aflibercept; 10 mM His/His-HCl-based buffer, 5% sucrose, 0.03% polysorbate-20, 50 mM L-Arginine, pH 5.8.

66. The method of any one of the preceding claims, wherein the VEGF receptor fusion protein is administered in a volume of about 100 pl or less, about 75 pl or less; about 70 pl or less; or about 50 pl; 51 pl; 52 pl; 53 pl; 54 pl; 55 pl; 56 pl; 57 pl; 58 pl; 59 pl; 60 pl; 61 pl; 62 pl; 63 pl; 64 pl; 65 pl; 66 pl; 67 pl; 68 pl; 69 pl; 70 pl; 71 pl; 72 pl; 73 pl; 74 pl; 75 pl; 76 pl; 77 pl; 78 pl; 79 pl; 80 pl; 81 pl; 82 pl; 83 pl; 84 pl; 85 pl; 86 pl; 87 pl; 88 pl; 89 pl; 90 pl; 91 pl; 92 pl; 93 pl; 94 pl; 95 pl; 96 pl; 97 pl; 98 pl; 99 pl; or 100 pl.

67. The method of claim 66, wherein the VEGF receptor fusion protein is administered in a volume of about 70 ± 4 or 5 microliters.

68. The method of any one of the preceding claims, wherein the interval between doses are adjusted (shortened or lengthened) or maintained based on visual and/or anatomic outcomes.

69. The method of any one of the preceding claims, further including one or more periods of treat and extend (T& E) and/or Pro re nata dosing.

70. The method of any one of the preceding claims, wherein the VEGF receptor fusion protein is aflibercept.

71. The method of any one of the preceding claims wherein the VEGF receptor fusion protein is administered by intravitreal injection.

72. The method of any one of the preceding claims wherein the subject receives about 6 or 7 injections of VEGF receptor fusion protein over the first 36 weeks of treatment.

73. The method of any one of the preceding claims wherein the subject:

• achieves an improvement in BCVA by week 36 of about 17 or 16 or as high as 50 letters (or more) wherein the subject has received an 8q8/3 dosing regimen;

• achieves an improvement in BCVA by week 36 of about 18 or 19 or as high as 52 letters (or more) wherein the subject has received an 8q8/5 dosing regimen;

• achieves an improvement in BCVA by week 36 of about 17 or 18 or 16 or as high as 50 letters (or more) wherein the subject has received an 8q8/3 dosing regimen wherein the subject has BRVO;

• achieves an improvement in BCVA by week 36 of about 19 or 18 or as high as 52 letters (or more) wherein the subject has received an 8q8/5 dosing regimen wherein the subject has BRVO;

• achieves an improvement in BCVA by week 36 of about 16 or 17 or as high as 47 letters (or more) wherein the subject has received an 8q8/3 dosing regimen wherein the subject has CRVO or HRVO;

• achieves an improvement in BCVA by week 36 of about 17 or 18 or as high as 50 letters (or more) wherein the subject has received an 8q8/5 dosing regimen wherein the subject has CRVO or HRVO;

• achieves a reduction in CST by week 36 of about 363 or 233 or 318 or as high as 1259 or 233-1259 micrometers (or more) wherein the subject has received an 8q8/3 dosing regimen;

• achieves a reduction in CST by week 36 of about 355 or 307 or 8 or as high as 1146 or 8-1146 micrometers (or more) wherein the subject has received an 8q8/5 dosing regimen;

• achieves a reduction in CST by week 36 of about 275 or 236 or as high as 781 micrometers (or more) wherein the subject has received an 8q8/3 dosing regimen wherein the subject has BRVO;

• achieves a reduction in CST by week 36 of about 284 or 255 or 8 or as high as 927 or 8-927 micrometers (or more) wherein the subject has received an 8q8/5 dosing regimen wherein the subject has BRVO;

• achieves a reduction in CST by week 36 of about 458 or 439 or 38 or as high as 1259 or 38-1259 micrometers (or more) wherein the subject has received an 8q8/3 dosing regimen wherein the subject has CRVO or HRVO; and/or

• achieves a reduction in CST by week 36 of about 431 or 376 or 38 or as high as 1146 or 38-1146 micrometers (or more) wherein the subject has received an 8q8/5 dosing regimen wherein the subject has CRVO or HRVO.

74. A method for treating or preventing macular edema following retinal vein occlusion (RVO) comprising administering 8 mg (±0.8 mg) aflibercept by intravitreal injection every 4 weeks (± 7 days) for the first three to five doses, followed by 8 mg (±0.8 mg) aflibercept via intravitreal injection once every 8 weeks (± 1 week), optionally, followed by 8 mg (±0.8 mg) aflibercept via intravitreal injection once every 4 weeks (± 1 week).

75. The method of claim 74 wherein three to five weeks is 3 weeks, 4 weeks or 5 weeks.

76. A method for treating or preventing macular edema following retinal vein occlusion (RVO) comprising administering 8 mg (±0.8 mg) of aflibercept in a pharmaceutical formulation comprising 114.3 mg/ml aflibercept in a volume of 0.07 mL by intravitreal injection every 4 weeks or approximately every 28 days (± 7 days) for the first three to five doses, followed by 8 mg (±0.8 mg) of aflibercept in a pharmaceutical formulation comprising 114.3 mg/ml aflibercept in a volume of 0.07 mL via intravitreal injection once every 8 weeks (± 1 week), optionally, followed by 8 mg (±0.8 mg) aflibercept via intravitreal injection once every 4 weeks (± 1 week).

77. The method of any one of the preceding claims for treating Macular Edema Following Retinal Vein Occlusion (RVO) comprising administering 8 mg aflibercept in a 0.07 ml volume of aqueous pharmaceutical formulation that comprises 114.3 mg/mL aflibercept by intravitreal injection every 4 weeks (approximately every 28 days ± 7 days) for the first three to five doses, followed by 8 mg aflibercept in a 0.07 mL volume of said formulation via intravitreal injection once every 8 weeks, ± 1 week, optionally, followed by 8 mg (±0.8 mg) aflibercept via intravitreal injection once every 4 weeks (± 1 week).

78. The method of claim 77 further comprising, after one or more of said doses once every 8 weeks +/- 1 week resuming administering said doses of 8 mg aflibercept in a 0.07 ml volume of aqueous pharmaceutical formulation that comprises 114.3 mg/mL aflibercept by intravitreal injection, every 4 weeks (approximately every 28 days ± 7 days).

79. The method of any one of the preceding claims wherein said aflibercept is provided in a kit that comprises

(a)

one single-dose vial comprising 0.07 mL of aqueous pharmaceutical formulation comprising 8 mg aflibercept which is at a concentration of 114.3 mg/mL;

one 18-gauge x 1¹/2-inch, 5-micron, filter needle

one 30-gauge x ¹/2-inch injection needle; and

one 1 mL syringe;

or

(b)

one single-dose vial comprising 0.07 mL of aqueous pharmaceutical formulation comprising 8 mg aflibercept which is at a concentration of 114.3 mg/mL.

80. The method of claim 80 wherein the kit further comprises prescribing information.

81. A method of any one of the preceding claims for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in an subject; wherein the methods comprise

(i) administering to the eye of the subject an intravitreal injection of 8 mg aflibercept every month or every 4 weeks for the first 3 consecutive injections; and

(ii) one or more further injections of 8 mg aflibercept after said first 3 consecutive injections; wherein the injection interval between two consecutive injections is adjusted based on the physician’s judgement of visual and/or anatomic outcomes.

82. A method of any one of the preceding claims for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment

due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise

(ii) one or more further injections of 8 mg aflibercept after said first 3 consecutive injections; wherein the injection interval between two consecutive injections is first extended to 8 weeks or 2 months for one or more injections and then adjusted based on the physician’s judgement of visual and/or anatomic outcomes;

wherein the treatment interval between two consecutive injections is between 4 weeks (1 month) and 20 weeks (5 months).

83. A method of any one of the preceding claims for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,

a single initial dose of 8 mg aflibercept; followed by

two secondary doses of said 8 mg aflibercept; followed by

one or more tertiary doses of 8 mg aflibercept;

84. A method of any one of the preceding claims for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,

a single initial dose of 8 mg aflibercept, followed by;

one or more tertiary doses of 8 mg aflibercept;

wherein the subject has been treated with a different anti-angiogenic treatment prior to said single initial dose of 8 mg aflibercept.

85. The method of claim 84 wherein the anti-angiogenic treatment is 2 mg aflibercept, faricimab, ranibizumab or bevacizumab.

86. The method of claim 84 wherein the subject was treated with 2 mg aflibercept or faricimab prior to said single initial dose of 8 mg aflibercept.

87. The method of claim 84 wherein the subject was treated with ranibizumab or bevacizumab prior to said single initial dose of 8 mg aflibercept.

88. The method of any one of claims 84-87 wherein adjustment of treatment interval is extending or shortening the interval between doses based on the physician’s judgement of visual and/or anatomic outcomes.

89. A method of any one of the preceding claims for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise administering to the eye of the subject an intravitreal injection of

(i) 8 mg aflibercept every month or every 4 weeks for the first 3 consecutive injections; and (ii) one or more further injections of 8 mg aflibercept after said first 3 consecutive injections; wherein the injection interval between two consecutive injections is extended based on the physician’s judgement of visual and/or anatomic outcomes.

90. A method of any one of the preceding claims for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise administering to the eye of the subject an intravitreal injection of

(i) 8 mg aflibercept every month or every 4 weeks for the first 3 consecutive injections; and (ii) one or more further injections of 8 mg aflibercept after said first 3 consecutive injections; wherein the injection interval between two consecutive injections is first extended to 8 weeks or 2 months for one or more injections and then further extended to up to 16 weeks (or 4 months) or 20 weeks (or 5 months) based on the physician’s judgement of visual and/or anatomic outcomes.

91. A method of any one of the preceding claims, for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in an subject in an subject; wherein the method comprises administering to the eye of the subject,

a single initial dose of 8 mg aflibercept, followed by

92. The method of any one of claims 91, wherein the first tertiary dose is administered 8 weeks (2 months) after the immediately preceding dose and one or more further tertiary doses are administered 8 weeks (2 months), or 12 weeks (3 months), or 16 weeks (4 months), or 20 weeks (5 month) after the immediately preceding dose.

93. The method of any one of claims 91-92, wherein the first tertiary dose is administered 8 weeks (2 months) after the immediately preceding dose and then the treatment interval between two consecutive injections is extended to up to 16 weeks (4 months) or 20 weeks (5 months) based on the physician’s judgement of visual and/or anatomic outcomes.

93. A method of any one of the preceding claims for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,

a single initial dose of 8 mg aflibercept, followed by;

one or more tertiary doses of 8 mg aflibercept;

94. The method of any one of claims 93, wherein the anti-angiogenic treatment is 2 mg aflibercept, faricimab, ranibizumab or bevacizumab.

95. The method of any one of claims 93, wherein the subject was treated with 2 mg aflibercept or faricimab prior to said single initial dose of 8 mg aflibercept.

96. The method of any one of claims 93, wherein the subject was treated with ranibizumab or bevacizumab prior to said single initial dose of 8 mg aflibercept.

97. The method of any one of claims 93-96 wherein said treatment interval between two consecutive doses is 8 weeks or 2 months.

98. The method of any one of claims 93-96 wherein said treatment interval between two consecutive doses is 12 weeks or 3 months.

99. The method of any one of claims 93-96 wherein said treatment interval between two consecutive doses is 16 weeks or 4 months.

100. The method of any one of claims 93-96 wherein said treatment interval between two consecutive doses is 20 weeks or 5 months.

101. The method of any one of claims 93-96 wherein said treatment interval between two consecutive doses is extended from 8 weeks or 2 months to 12 weeks or 3 months.

102. The method of any one of claims 93-96 wherein said treatment interval between two consecutive doses is extended from 12 weeks or 3 months to 16 weeks or 4 months.

103. The method of any one of claims 93-96 wherein said treatment interval between two consecutive doses is extended from 16 weeks or 4 months to 20 weeks or 5 months.

104. A method of any one of the preceding claims, for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,

a single initial dose of 8 mg aflibercept, followed by

two secondary doses of said 8 mg aflibercept, followed by

one or more tertiary doses of 8 mg aflibercept;

105. A method of any one of the preceding claims for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and /or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,

a single initial dose of 8 mg aflibercept, followed by;

one or more tertiary doses of 8 mg aflibercept;

wherein the treatment interval between two consecutive tertiary doses is shortened based on the physician’s judgement of visual and/or anatomic outcomes and wherein the subject has been treated with a different anti-angiogenic treatment prior to said single initial dose of 8 mg aflibercept.

106. The method of claim 105 wherein the anti-angiogenic treatment is 2 mg aflibercept, faricimab, ranibizumab or bevacizumab.

107. The method of claim 105 wherein the anti-angiogenic treatment is 2 mg aflibercept or faricimab prior to said single initial dose of 8 mg aflibercept.

108. The method of claim 105 wherein the anti-angiogenic treatment is ranibizumab or bevacizumab prior to said single initial dose of 8 mg aflibercept

109. The method of any one of the preceding claims, for treating or preventing neovascular (wet) age-related macular degeneration (nAMD) or visual impairment due to diabetic macular oedema (DME) in a subject; wherein the methods comprise administering to the eye of the subject

an intravitreal injection of 8 mg aflibercept every month or every 4 weeks +/- 1 week for the first 3 consecutive injections; and

one or more further injections of 8 mg aflibercept after said first 3 consecutive injections wherein the injection interval between two consecutive injections is adjusted based on the physician’s judgement of visual and/or anatomic outcomes;

110. The method of any one of the preceding claims, for treating or preventing neovascular (wet) age-related macular degeneration (nAMD) or visual impairment due to diabetic macular oedema (DME) in a subject; wherein the methods comprise administering to the eye of the subject an intravitreal injection of

8 mg aflibercept every month or every 4 weeks +/- 1 week for the first 3 consecutive injections; and

one or more further injections of 8 mg aflibercept after said first 3 consecutive injections; wherein the injection interval between two consecutive injections is shortened based on the physician’s judgement of visual and/or anatomic outcomes; and

111. The method of any one of the preceding claims for treating or preventing neovascular (wet) age-related macular degeneration (nAMD) or visual impairment due to diabetic macular oedema (DME) in a subject; wherein the method comprises administering to the eye of the subject, a single initial dose of 8 mg aflibercept, followed by

two secondary doses of said 8 mg aflibercept, followed by

one or more tertiary doses of 8 mg aflibercept;

112. The method of any one of the preceding claims for treating or preventing neovascular (wet) age-related macular degeneration (nAMD) or visual impairment due to diabetic macular oedema (DME) in a subject; wherein the method comprises administering to the eye of the subject,

a single initial dose of 8 mg aflibercept, followed by

two secondary doses of said 8 mg aflibercept, followed by

one or more tertiary doses of 8 mg aflibercept;

113. The method of any one of the preceding claims for treating or preventing neovascular (wet) age-related macular degeneration (nAMD) or visual impairment due to diabetic macular oedema (DME) in a subject; wherein the method comprises administering to the eye of the subject, a single initial dose of 8 mg aflibercept, followed by;

one or more tertiary doses of 8 mg aflibercept;

114. The method of any one of the preceding claims for treating or preventing neovascular (wet) age-related macular degeneration (nAMD) or visual impairment due to diabetic macular oedema (DME) in a subject; wherein the method comprises administering to the eye of the subject, a single initial dose of 8 mg aflibercept, followed by;

one or more tertiary doses of 8 mg aflibercept;

115. The method of any one of claims 113-114 wherein the anti-angiogenic treatment is 2 mg aflibercept, faricimab, ranibizumab or bevacizumab.

116. The method of any one of claims 113-114, wherein the subject was treated with 2 mg aflibercept or faricimab prior to said single initial dose of 8 mg aflibercept.

117. The method of any one of claims 113-114wherein the subject was treated with ranibizumab or bevacizumab prior to said single initial dose of 8 mg aflibercept.

118. The method of any one of claims 109-117, wherein the interval between two consecutive tertiary doses is shortened if the subject

(i) exhibits >5 letters loss of BCVA from reference visit; and/or

(ii) >50 pm increase in CRT (central retinal thickness) from reference visit,

wherein the reference visit is the visit at the previous injection.

119. The method of any one of claims 109-118, wherein the interval between two consecutive doses is shortened by 2 or 4 weeks.

120. The method of any one of claims 109-118, wherein the interval between two consecutive doses is shortened from 24 weeks or 6 months to 20 weeks or 5 months.

121. The method of any one of claims 109-118, wherein the interval between two consecutive doses is shortened from 20 weeks or 5 months to 16 weeks or 4 months.

122. The method of any one of claims 109-118, wherein the interval between two consecutive doses is shortened from 16 weeks or 4 months to 12 weeks or 3 months.

123. The method of any one of claims 109-118, wherein the interval between two consecutive doses is shortened from 12 weeks or 3 months to 8 weeks or 2 months.

124. The method of any one of claims 109-118, wherein the interval between two consecutive doses is shortened from 8 weeks or 2 months to 4 weeks or 1 month.

125. The method of any one of claims 109-118, wherein the interval between doses is shortened by 1 week, provided that the new interval is at least about 4 weeks or one month.

126. The method of any one of claims 109-118, wherein the tertiary dose interval is shortened by 4 weeks, provided that the new interval is at least about 4 weeks or 1 month.

127. The method of any one of claims 109-118, wherein the tertiary dose interval is shortened by 2 weeks, provided that the new interval is at least about 4 weeks or 1 month.

128. The method of any one of claims 109-118, wherein the interval between two consecutive doses is at least 4 weeks or one month.