EP3400014A1 - Méthodes et dispositifs pour le traitement de troubles oculaires postérieurs avec l'aflibercept et d'autres substances biologiques - Google Patents

Méthodes et dispositifs pour le traitement de troubles oculaires postérieurs avec l'aflibercept et d'autres substances biologiques

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Publication number
EP3400014A1
EP3400014A1 EP17736528.5A EP17736528A EP3400014A1 EP 3400014 A1 EP3400014 A1 EP 3400014A1 EP 17736528 A EP17736528 A EP 17736528A EP 3400014 A1 EP3400014 A1 EP 3400014A1
Authority
EP
European Patent Office
Prior art keywords
antibody
vegf
drug
aflibercept
eye
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP17736528.5A
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German (de)
English (en)
Inventor
Samirkumar PATEL
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Clearside Biomedical Inc
Original Assignee
Clearside Biomedical Inc
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Filing date
Publication date
Application filed by Clearside Biomedical Inc filed Critical Clearside Biomedical Inc
Publication of EP3400014A1 publication Critical patent/EP3400014A1/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/179—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A61K9/0051—Ocular inserts, ocular implants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • RVO is a condition that affects vision, resulting from a blockage in one of the veins returning blood flow from the retina.
  • RVO is the second most common cause of vision loss due to retinal vascular disease.
  • RVO affects 16.4 million adults worldwide, according to a 2010 study published in the journal Ophthalmology (Rogers et al. (2010). Ophthalmology 117, pp. 313-319)). Inadequately treated macular edema associated with RVO can cause significant loss in visual acuity and eventually lead to blindness.
  • the present invention provides novel methodology and devices for the treatment of macular edema associated with uveitis, macular edema following retinal vein occlusion (RVO) (also referred to herein as wet AMD associated with RVO), wet AMD, diabetic macular edema (DME), choroidal neovascularization (CNV), and/or wet AMD associated with CNV, thereby addressing key needs in the field of ocular therapeutics.
  • RVO retinal vein occlusion
  • DME diabetic macular edema
  • CNV choroidal neovascularization
  • wet AMD choroidal neovascularization
  • This invention is generally related to ophthalmic therapies, and more particularly to methods and devices that allow for infusion of a fluid drug formulation into posterior ocular tissues for targeted, localized treatment, for example, for the treatment of wet AMD or wet AMD associated with RVO or wet AMD associated with choroidal neovascularization.
  • the drug formulation includes aflibercept and is injected into SCS to provide localized drug in the choroid and retina.
  • the methods comprise administering an anti-inflammatory, an anti-VEGF, an anti-PDGF, or an anti- angiopoetin drug formulation to the SCS of a subject.
  • the methods comprise administering a biologic to a subject concomitantly or sequentially with the administration of the anti-inflammatory, anti-VEGF, anti-PDGF, or anti-angiopietin to the SCS.
  • the biologic is administered intravitreally.
  • the biologic is a VEGF modulator (e.g., aflibercept).
  • the anti-inflammatory drug formulation comprises triamcinolone acetonide (TA).
  • TA triamcinolone acetonide
  • the drug formulation administered SCS and the biologic act synergistically to improve treatment of an ocular disease in a subject.
  • choroidal neovascularization (CNV) and/or the method for treating wet AMD associated with CNV subsequent to at least one dosing session, e.g., from about 1 week to about 14 weeks after at least one dosing dession, e.g. , about 12 weeks after a dosing session, the patient experiences an improvement in visual acuity as measured by best corrected visual acuity of > 10 letters, > 15 letters or > 25 letters, as compared to patient's visual acuity prior to the at least one dosing session.
  • the method for treating macular edema associated with uveitis subsequent to at least one dosing session, e.g.
  • the patient experiences a decrease in retinal thickness (e.g., central subfield thickness) as compared to the patient's retinal thickness prior to the at least one dosing session.
  • retinal thickness e.g., central subfield thickness
  • the decrease in retinal thickness is > 25 ⁇ , > 50 ⁇ , > 75 ⁇ or > 100 ⁇ some embodiments, the methods set forth herein are carried out by inserting a distal end portion of a needle of a medical injector into a target tissue to define a delivery passageway within the target tissue and such that a distal end surface of a hub of the medical injector is in contact with a target surface of the target tissue.
  • a force is exerted (e.g., a manual force by a user) on an actuator of the medical injector when the distal end surface of the hub is in contact with the target surface.
  • the medical injector is configured such that the force is sufficient to move a distal end portion of the actuator within the medicament container when the distal end portion of the needle is disposed within a first region of the target tissue.
  • the medical injector is configured such that the force is insufficient to move the distal end portion of the actuator within the medicament container when the distal end portion of the needle is disposed within a second region of the target tissue.
  • the force has a magnitude of less than about 6 N.
  • a substance, e.g., a drug formulation in response to the exertion, is conveyed from the medicament container into the target tissue via the needle when the distal end portion of the needle is disposed within the first region of the target tissue.
  • the first region can be, for example, a suprachoroidal space of the eye, a lower portion of the sclera and/or an upper portion of the choroid. In some embodiments, the first region can be a retina of the eye.
  • a distal end portion of a needle of a medical injector is inserted into a target tissue to define a delivery passageway within the target tissue.
  • the insertion is performed such that a centerline of the needle and a surface line tangent to a target surface of the target tissue define an angle of entry of between about 75 degrees and about 105 degrees.
  • a distal end surface of a hub of the medical injector is placed into contact with a target surface of the target tissue to fluidically isolate the delivery passageway. After the distal end surface of the hub is placed into contact with the target surface, a substance, e.g., drug formulation, is conveyed into the target tissue via the needle.
  • a distal end portion of a needle of a medical injector is inserted into an eye to define a delivery passageway within a sclera of the eye.
  • a force e.g., a manual force by a user
  • a force is applied to the medical injector when a distal tip of the needle is disposed within at least one of a suprachoroidal space or a lower portion of the sclera, the force being insufficient to convey the substance from the medicament container via the needle when the distal tip of the needle is disposed within an upper portion of the sclera of the eye.
  • a method of treating wet age-related macular degeneration (AMD) or choroidal neovascularization (CNV) in a human subject in need thereof includes, in a dosing session, non-surgically administering an effective amount of an aflibercept drug formulation comprising a first drug to the suprachoroidal space (SCS) of the eye of the human subject in need of treatment of the wet AMD or the CNV.
  • the method includes non-surgically administering an effective amount of an anti-inflammatory, an anti-VEGF, an anti-PDGF, or an anti-angiopoetin to the SCS of the eye of the human subject in need of treatment of the wet AMD or the CNV.
  • the method further comprises intravitreal administration of a biologic.
  • the biologic is an anti-VEGF, an anti-PDGF, or an anti-angiopoetin.
  • the biologic is aflibercept.
  • a method of treating wet age-related macular degeneration (AMD) in a human subject in need thereof includes, in a dosing session, non-surgically administering an effective amount of an aflibercept drug formulation comprising a first drug to the suprachoroidal space (SCS) of the eye of the human subject in need of treatment of the wet AMD.
  • SCS suprachoroidal space
  • the aflibercept drug formulation flows away from the insertion site and is substantially localized to the posterior segment of the eye.
  • the wet AMD is associated with choroidal neovascularization (CNV) in the human subject.
  • CNV choroidal neovascularization
  • a VEGF inhibitor is administered to the patient intravitreally.
  • a method of improving the effectiveness of a biologic in the treatment of an ocular disease in a human subject wherein the administration of the biologic is coupled with SCS administration of an anti-inflammatory, anti-VEGF, anti-PDGF, or anti-angiopoetin agent.
  • the biologic and the agent administered SCS act synergistically to improve effectiveness of treatment of the ocular disease.
  • the biologic is a VEGF modulator such as aflibercept.
  • the administration of the anti-inflammatory drug reduces the number of VEGF modulator drug treatments necessary to treat the ocular disease.
  • a method of treating macular edema associated with retinal vein occlusion (RVO) in a human subject in need thereof comprises administering to the human subject an effective amount of a VEGF modulator, and non- surgically administering an effective amount of an anti-inflammatory drug to the suprachoroidal space (SCS) of the eye of the human subject.
  • the combination therapy acts synergistically relative to administration of either drug alone.
  • the anti-inflammatory drug is selected from the group consisting of a steroid and a non-steroid inflammatory drug (NSAID).
  • the steroid is triamcinolone acetonide (TA).
  • the TA is administered to the SCS of the human subject at a dose level of about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg.
  • the TA is administered to the SCS of the human subject at a dose level of about 4 mg.
  • the VEGF modulator is administered to the subject intravitreally.
  • the VEGF modulator is a VEGF antagonist selected from a VEGF-receptor kinase antagonist, an anti-VEGF antibody or fragment thereof, an anti-VEGF receptor antibody, an anti-VEGF aptamer, a small molecule VEGF antagonist, a thiazolidinedione, a quinoline or a designed ankyrin repeat protein (DARPin).
  • the VEGF antagonist is aflibercept, ziv-aflibercept, bevacizumab, sonepcizumab, VEGF sticky trap, cabozantinib, foretinib, vandetanib, nintedanib, regorafenib, cediranib, ranibizumab, lapatinib, sunitinib, sorafenib, plitidepsin, regorafenib, verteporfin, bucillamine, axitinib, pazopanib, fluocinolone acetonide, nintedanib, AL8326, 2C3 antibody, AT001 antibody, XtendVEGF antibody, HuMax-VEGF antibody, R3 antibody, AT001/r84 antibody, HyBEV, ANG3070, APX003 antibody, APX004 antibody, ponatinib, BDM-E, VGX100 antibody, VG
  • the VEGF modulator is aflibercept
  • the aflibercept is administered intravitreally to the human subject at a dose level of about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg.
  • the aflibercept is administered intravitreally to the human subject at a dose level of about 2 mg.
  • the VEGF modulator is administered intravitreally to the subject concomitantly with the SCS administration of the anti-inflammatory drug. In other embodiments, the VEGF modulator and anti-inflammatory drug are administered sequentially.
  • the methods provided herein decrease retina thickness and/or macula thickness relative to a baseline measurement prior to treatment of the subject with the VEGF modulator or anti-inflammatory drug. In other embodiments, the methods provided herein decrease retina thickness and/or macula thickness relative to a subject that received the VEGF modulator but did not receive the anti-inflammatory drug administered to the SCS.
  • the retinal thickness is central subfield thickness (CST). In further embodiments, the CST is measured by spectral domain optical coherence tomography (SD-OCT). In some embodiments, the CST is decreased by at least about 20 ⁇ , at least about 40 ⁇ , at least about 50 ⁇ , at least about 100 ⁇ , at least about 150 ⁇ , or at least about 200 ⁇ .
  • the methods provided herein increase a Best Corrected Visual Acuity (BCVA) of the subject relative to a baseline measurement prior to treatment of the subject with the VEGF modulator or anti-inflammatory drug.
  • the methods provided herein increase the BCVA of the subject relative to a subject that received the VEGF modulator but did not receive the anti-inflammatory drug administered to the SCS.
  • the BCVA is assessed using an Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity charts protocol.
  • EDRS Early Treatment of Diabetic Retinopathy Study
  • the increase in the BVCA is a gain of about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, or more letters.
  • the present disclosure provides methods for improving anti-VEGF therapy (e.g., aflibercept therapy) in subjects suffering from RVO by administering a steroid formulation to the SCS of the eye of the subject.
  • the present disclosure provides methods for treating subjects suffering from RVO comprising administering an effective amount of a VEGF modulator and an antiinflammatory drug to the eye of the subject.
  • the administration is surgical, and comprises, for example, insertion of a stent, shunt, or cannula.
  • the administration is non-surgical, for example, via injection.
  • the RVO is BRVO or CRVO.
  • the RVO is ischemic or non-ischemic RVO. In some embodiments the RVO is ischemic CRVO. In some embodiments, the present disclosure provides surprisingly effective treatments for ischemic CRVO patients. In some embodiments, the present disclosure provides methods of treatment for ischemic CRVO patients that result in an increase in BVCA of 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, or more letters.
  • the steroid formulation is administered to the SCS of the eye of the subject. In some embodiments, the steroid formulation is non-surgically administered to the SCS of the eye of the subject. In some embodiments, the steroid formuation is administered non-surgically to the SCS of the eye of the subject and the VEGF modulator is administered by intravitreal injection.
  • the present disclosure provides methods for treating a subject suffering from ischemic CRVO, the method comprising administering aflibercept and TA.
  • the aflibercept and/or TA is administered surgically.
  • the aflibercept and/or TA is administered non-surgically.
  • the aflibercept is administered intravitreally in one or more doses; and the TA is nonsurgically administered to the SCS in one or more doses.
  • the method for treating RVO provided herein comprising administration of a VEGF modulator (e.g., aflibercept) in combination with administration of the anti-inflammatory drug, reduces the need to retreat the subject with additional doses of the VEGF modulator.
  • a VEGF modulator e.g., aflibercept
  • the assessment for the need for retreatment with the VEGF modulator is assessed by the CST, BVCA, or a combination thereof.
  • the VEGF modulator is aflibercept, and the aflibercept is administered intravitreally; and the antiinflammatory drug is TA.
  • FIG. 1 is a cross-sectional view of an illustration of the human eye.
  • FIG. 2 is a cross-sectional view of a portion of the human eye of FIG. 1 taken along the line 2-2.
  • FIGS. 3 and 4 are cross-sectional views of a portion of the human eye of FIG. 1 taken along the line 3-3, illustrating the suprachoroidal space without and with, respectively, the presence of a fluid.
  • FIG. 5 is a perspective view of a medical injector according to an embodiment.
  • FIG. 6 is a partially exploded view of the medical injector of FIG. 5.
  • FIG. 7 is an exploded view of the medical injector of FIG. 5, shown without a needle cap.
  • FIG. 8 is a front view of a handle included in the medical injector of FIG. 5.
  • FIG. 9 is a cross-sectional view of the handle of FIG. 8 taken along the line 9-9.
  • FIG 10 is a perspective view of a barrel included in the medical injector of FIG. 5.
  • FIG. 11 is an exploded view of a needle hub included in the medical injector of FIG. 5.
  • FIG. 12 is a front view of the needle hub of FIG. 9.
  • FIG. 13 is an enlarged view of a portion of the needle hub of FIG. 12, identified by the region Z ⁇ .
  • FIG. 14 is a rear perspective view of a needle cap included in the medical injector of FIG. 5.
  • FIG. 15 is a front view of the medical injector of FIG. 5.
  • FIG. 16 is a cross-sectional view of the medical injector of FIG. 5, taken along the like 16-16 in FIG. 15.
  • FIG. 17 is a view of the medical injector of FIG. 5 in use during an injection procedure into the human eye.
  • FIG. 18 is an enlarged view of a portion of the medical injector of FIG. 5 and the human eye, identified in FIG. 17 by the region Z 2 .
  • FIG. 19 is an exploded view of a needle hub configured for use with the medical injector of FIG. 5, according to an embodiment.
  • FIG. 20 is a front view of the needle hub of FIG. 19.
  • FIG. 21 is a flowchart illustrating a method of using a medical injector to inject a medicament into an eye.
  • FIG. 22 is a graph of mean change in intraocular pressure vs. hours or weeks post- treatment.
  • FIG. 24 is a plot of mean reduction in retinal thickness vs. weeks post-treatment.
  • FIG. 25 are optical coherence tomography images of the eyes of a bilateral chronic uveitis patient with macular edema, prior to (top images) and subsequent to (bottom images) SCS TA injection (left 2 images) or sub-tenon TA injection (right 2 images).
  • FIG. 26 are optical coherence tomography images of the eyes of a bilateral chronic uveitis patient with macular edema, prior to (top images) and subsequent to (bottom images) SCS TA injection (right 2 images, right eye) or Ozurdex (dexamethasone 0.7 mg intravitreal implant) (left 2 images, left eye).
  • FIG. 27 illustrates distribution in various parts of the eye following intravitreal and SCS injection of Triesence in rabbits.
  • FIGS 28A-F illustrate distribution of TA in various parts of the eye (28A: sclera- choroid-outer retina; FIG. 28B: inner retina; FIG. 28C: vitreous; FIG. 28D: aqueous humour; FIG. 28E: lens; FIG. 28F: iris-ciliary body) following intravitreal and SCS injection of Triesence.
  • FIGS. 29 and 30 illustrate TA concentration for Trisence and CLS-TA over a 90- day period in either the sclera-choroid-outer retina (FIG. 29) or the inner retina (FIG. 30).
  • FIG. 31 is a bar graph showing the cumulative ophthalmoscopy inflammation scores (mean ⁇ SD) for each treatment group.
  • FIG. 32 is a bar graph showing the intraocular pressure (mmHg; mean ⁇ SD) for each treatment group over the study period.
  • Group 1 Negative control (LPS / BSS SCS);
  • Group 2 Oral high dose prednisone (LPS / Prednisonel mg/kg/day PO);
  • Group 3 CLS-TA (LPS / 2 mg CLS-TA);
  • Group 4 Oral low dose prednisone (LPS / Prednisone 0.1 mg/kg/day PO);
  • FIG. 33 are graphs showing the mean histologic score for various treatment groups for the anterior segment (left) and posterior segment (right).
  • FIG. 34A is a bar graph showing mean lesion area 3 weeks post-laser induced choroidal neovascularization in a rat model, with rats treated, via the suprachoroidal space, either with saline or Eylea.
  • FIG. 34B is a bar graph showing mean lesion area 22 days post- laser induced choroidal neovascularization in a rat model, with rats treated, via the intravitreal space, either with saline.
  • Anti-VEGF antibodies, or Eylea is a bar graph showing mean lesion area 3 weeks post-laser induced choroidal neovascularization in a rat model, with rats treated, via the suprachoroidal space, either with saline or Eylea.
  • FIG. 35 is a chart showing an experimental protocol for laser induced choroidal neovascularization in a rat model.
  • FIG. 36 is a timeline for the experimental protocol of FIG. 35.
  • FIG. 37A is a bar graph showing mean lesion area 3 weeks post-laser induced choroidal neovascularization in a rat model, including the bar graphs of FIG. 34A as single- injection treated animals, and further including additional plots to show data for double- injection treated animals.
  • FIG. 37B illustrates the bar graph of FIG. 34B, repeated herein for direct comparison with FIG. 37A. [1055] FIG.
  • 38 is a bar graph showing mean lesion area 3 weeks post-laser induced choroidal neovascularization in a rat model, for rats treated with saline or Eylea, including single-injection animals treated via the suprachoroidal space, double-injection animals treated via the suprachoroidal space, and single-injection animals treated via the intravitreal space.
  • FIG. 39 is a bar graph showing some of the plots of FIG. 38 for direct comparsion, including single-injection animals treated via the suprachoroidal space with Eylea, and single-injection animals treated via the intravitreal space with saline or Eylea..
  • FIG. 40 is a bar graph showing some of the plots of FIG. 38 for direct comparison, including single-injection animals treated via the suprachoroidal space and double-injection animals treated via the suprachoroidal space.
  • FIG. 41 is a bar graph showing the number of additional IVT injections of aflibercept (EYLEA®) that were required in the Control Arm (IVT aflibercept alone) versus the Active Arm (aflibercept + SCS CLS-TA) of the study provided in Example 4.
  • EYLEA® aflibercept
  • SCS CLS-TA Active Arm
  • FIG. 42 is a bar graph showing the improvement in BCVA at Month 3 in the Active Arm (aflibercept + SCS CLS-TA) compared to the Control Arm (aflibercept only) in the study provided in Example 4.
  • FIG. 43 is a bar graph showing improvement in BCVA (the y axis represents the BCVA letters read, change from baseline) at months 1, 2, and 3 in the Active Arm (aflibercept + SCS CLS-TA) compared to the Control Arm (aflibercept only) in the study provided in Example 4.
  • the Control group exhibited an 11.4 increase in BCVA letters, and the Active group exhibited an increase in 16.1 letters; thus, at month 1, the Active arm provided a 4.7 letter increase relative to control.
  • the Control group exhibited an 11.9 increase in BCVA letters, and the Active group exhibited an increase in 20.4 letters; thus, at month 2, the Active arm provided an 8.5 letter increase relative to control.
  • the Control group exhibited an 11.3 increase in BCVA letters, and the Active group exhibited an increase in 18.9 letters; thus, at month 3, the Active arm provided a 7.6 letter increase relative to control.
  • FIG. 44 is a bar graph showing that the Active arm (SCS-CLS-TA with IVT aflibercept (EYLEA®)) exhibited an improvement in macular edema relative to the control arm (IVT aflibercept (EYLEA®) only) at month 3.
  • Subjects in the Active group exhibited reduced central subfield thickness (CST) by 446 microns, while subjects in the Control group exhibited reduced CST by 343 microns, showing an increased reduction in retinal thickness of 103 microns for the Active group over the Control group.
  • CST central subfield thickness
  • FIG. 45 is a bar graph showing that the improvement in macular edema was also present at months 1 and 2.
  • subjects in the Active group exhibited a CST reduced by 446 compared to a CST reduction of 405 in the Control group.
  • subjects in the Active group exhibited a CST reduced by 459 compared to a CST reduction of 344 in the Control group.
  • FIG. 46 shows the patient number and percentage qualified for additional Eylea treatment (aflibercept) for branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO) patients in both the Active and the Control groups.
  • aflibercept branch retinal vein occlusion
  • CRVO central retinal vein occlusion
  • FIG. 47 shows the mean of central subfoveal thickness (CST) in subjects with branch retinal vein occlusion (BRVO) treated either by aflibercept + Zuprata (Active group) or aflibercept + sham (control group).
  • CST central subfoveal thickness
  • BRVO branch retinal vein occlusion
  • FIG. 48 shows the mean changes in central subfoveal thickness (CST) in subjects with branch retinal vein occlusion (BRVO) treated either by aflibercept + Zuprata (Active group) or aflibercept + sham (Control group).
  • CST central subfoveal thickness
  • BRVO branch retinal vein occlusion
  • FIG. 49 shows the mean best corrected visual acuity (BCVA) in subjects with branch retinal vein occlusion (BRVO) treated either by aflibercept + Zuprata (Active group) or aflibercept + sham (Control group). Subjects in both treatment groups exhibited increased BCVA from baseline to month 3. At month 2, subjects in the Active group exhibited higher mean BCVA compared to the mean BCVA in control group (71 vs. 67, respectively). IVT: Intravitreal.
  • FIG. 50 shows the mean changes in best corrected visual acuity (BCVA) in subjects with branch retinal vein occlusion (BRVO) treated either by aflibercept + Zuprata (Active group) or aflibercept + sham (Control group).
  • BCVA visual acuity
  • BRVO branch retinal vein occlusion
  • subjects in Active group exhibited an increased mean BCVA by score of 16 compared to an increased mean BCVA by score of 12 in the Control group (4 scores differences between the groups).
  • subjects in Active group exhibited an increased mean BCVA by score of 17 compared to an increased mean BCVA by score of 18 in the Control group (1 score difference between the groups)
  • FIG. 51 the mean of central subfoveal thickness (CST) in subjects with central retinal vein occlusion (CRVO) treated either by aflibercept + Zuprata (Active group) or aflibercept + sham (Control group).
  • CST central subfoveal thickness
  • CRVO central retinal vein occlusion
  • subjects in both treatment groups exhibited reduced mean CST (268 ⁇ vs. 326 ⁇ ) compared to the mean CST at baseline (876 ⁇ vs. 778 ⁇ ).
  • subjects in Active group consistently exhibited lower mean CST compared to the mean CST of the control group.
  • IVT Intravitreal.
  • FIG. 52 shows the mean changes in central subfoveal thickness (CST) in subjects with central retinal vein occlusion (CRVO) treated either by aflibercept + Zuprata (Active group) or aflibercept + sham (Control group).
  • CST central subfoveal thickness
  • CRVO central retinal vein occlusion
  • FIG. 53 shows the mean best corrected visual acuity (BVCA) in subjects with central retinal vein occlusion (CRVO) treated either by aflibercept + Zuprata (Active group) or aflibercept + sham (Control group).
  • BVCA central retinal vein occlusion
  • Subject in both treatment groups exhibited increased BCVA from baseline to month 1 (40 vs. 47 to 61 vs. 57).
  • subjects in Active group exhibited a further higher mean BCVA compared to decreased mean BCVA in control group (67 vs. 55, respectively).
  • subjects in Active group exhibited the mean BCVA of score of 62 compared to mean BCVA of score of 52 in control group.
  • IVT Intravitreal.
  • FIG. 54 shows the mean changes in best corrected visual acuity (BCVA) in subjects with central retinal vein occlusion (CRVO) treated either by aflibercept + Zuprata (Active group) or aflibercept + sham (Control group).
  • BCVA visual acuity
  • CRVO central retinal vein occlusion
  • At month 1 subjects in Active group exhibited an increase of mean BCVA by score of 21 compared to an increase of mean BCVA by score of 10 in the control group (11 scores differences between the groups).
  • subjects in Active group exhibited an increase of mean BCVA by scrore of 27 compared to an increase of mean BCVA by score of 9 (18 scores differences between the groups) in control group.
  • subjects in Active group exhibited an increase of mean BCVA by score of 22 compared to an increase of mean BCVA by score of 6 in the Control group (16 scores differences between the groups).
  • IVT Intravitreal.
  • FIG. 55 shows the total number of patients that qualified for aflibercept retreatment at any time in the study (independent of treatment), stratified by non-ischemic (left panel) and ischemic (right panel) perfusion type.
  • FIG. 56 shows the number of ischemic patients that qualified for aflibercept retreatment during the study, in Control (left panel) vs. Active (right panel) arm subjects.
  • FIG. 57 shows the number of nonischemic patients that qualified for aflibercept retreatment during the study, in Control (left panel) vs. Active (right panel) arm subjects.
  • FIG. 58A-D shows the BVCA and CST data for ischemic versus non-ischemic patients independent of treatment, at months 1, 2, and 3 of the study.
  • FIG. 58A shows BVCA in ischemic versus non-ischemic patients.
  • FIG. 58B shows the change in BVCA in ischemic versus non-ischemic patients.
  • FIG. 58C shows CST in ischemic versus non-ischemic patients.
  • FIG. 58D shows the change in CST in ischemic versus non-ischemic patients.
  • FIG. 59A-D shows the BVCA and CST data for non-ischemic patients in each treatment group, at months 1, 2, and 3 of the study.
  • FIG. 59A shows BVCA in non-ischemic patients in the control arm (aflibercept + sham) versus the active arm (aflibercept + Zuprata).
  • FIG. 59B shows the change in BVCA in non-ischemic patients in the control arm (aflibercept + sham) versus the active arm (aflibercept + Zuprata).
  • FIG. 59C shows CST in non-ischemic patients in the control arm (aflibercept + sham) versus the active arm (aflibercept + Zuprata).
  • FIG. 59D shows the change in CST in non-ischemic patients in the control arm (aflibercept + sham) versus the active arm (aflibercept + Zuprata).
  • FIG. 60A-D shows the BVCA and CST data for ischemic patients in each treatment group, at months 1, 2, and 3 of the study.
  • FIG. 60 A shows BVCA in ischemic patients in the control arm (aflibercept + sham) versus the active arm (aflibercept + Zuprata).
  • FIG. 60B shows the change in BVCA in ischemic patients in the control arm (aflibercept + sham) versus the active arm (aflibercept + Zuprata).
  • FIG. 60C shows CST in ischemic patients in the control arm (aflibercept + sham) versus the active arm (aflibercept + Zuprata).
  • FIG. 60D shows the change in CST in ischemic patients in the control arm (aflibercept + sham) versus the active arm (aflibercept + Zuprata).
  • FIG. 61A-D shows the BVCA data for each treatment group, stratified into ischemic or non-ischemic and BRVO or CRVO groups, at months 1, 2, and 3 of the study.
  • FIG. 61A shows BVCA in ischemic BRVO patients in the control arm (aflibercept + sham) versus the active arm (aflibercept + Zuprata).
  • FIG. 61B shows BVCA in non-ischemic BRVO patients in the control arm (aflibercept + sham) versus the active arm (aflibercept + Zuprata).
  • FIG. 61C shows BVCA in ischemic patients in the control arm (aflibercept + sham) versus the active arm (aflibercept + Zuprata).
  • FIG. 61D shows BVCA in non-ischemic patients in the control arm (aflibercept + sham) versus the active arm (aflibercept + Zuprata).
  • FIG. 62 provides a summary of the data shown graphically in FIG 61A-D.
  • Methods, devices and drug formulations are provided herein for treating posterior ocular disorders, for example wet AMD, CNV, wet AMD associated with CNV, macular edema associated with uveitis (e.g., infectious or non-infectious uveitis) and macular edema associated with retinal vein occlusion (RVO) in a human subject in need thereof.
  • the RVO is branch retinal vein occlusion (BRVO), hemiretinal vein occlusion (HRVO) or central retinal vein occlusion (CRVO).
  • the uveitis is intermediate, posterior or pan uveitis, and can be infectious or non-infectious uveitis.
  • the drug formulation includes aflibercept.
  • Intravitreal injections result in drugs diffusing throughout the eye, including into the lens, iris and ciliary body at the front of the eye, which for some drugs, has been associated with safety issues, such as cataracts and elevated intraocular pressure (IOP) levels.
  • IOP intraocular pressure
  • TA triamcinolone
  • SCS injection of drugs appears to result in drug remaining localized in the retina and choroid without substantial diffusion to the vitreous or the front portion of the eye, without wishing to be bound by theory, it is thought that SCS injection has the potential to reduce the incidence of these side effects.
  • the methods and devices provided herein for example, for the treatment of macular edema associated with uveitis, macular edema associated with RVO, wet AMD and/or diabetic macular edema (DME), choroidal neovascularization (CNV), wet AMD associated with CNV, in one embodiment, are used to restore or improve visual function primarily by reducing the macular edema affecting the retina, the tissue that lines the inside of the eye and is the part of the eye primarily responsible for vision, and the choroid, the layer adjacent to the retina that supplies the retina with blood, oxygen and nourishment.
  • Macular edema is the build-up of fluid that can cause abnormal swelling of the macula, the portion of the retina responsible for central vision and color perception. This swelling can rapidly result in deterioration of vision and can eventually lead to blindness.
  • RVO retinal vein occlusion
  • BRVO Branch retinal vein occlusion
  • CRVO central retinal vein occlusion
  • BRVO is the most common form, and is characterized by venous occlusion at any smaller branch of the central retinal vein.
  • CRVO is characterized by blockage of the main vein in the retina.
  • Occlusion occurring at a main branch from the central retinal vein can be characterized as hemispheric retinal or hemi-retinal vein occlusion (HRVO).
  • HRVO hemispheric retinal or hemi-retinal vein occlusion
  • RVO can be further classified into perfused (nonischemic) or nonperfused (ischemic).
  • Non-ischemic RVO of any classification is more common and less severe than ischemic RVO.
  • Ischemic CRVO is characterized by a rapid onset of venous obstruction, resulting in reduced retinal perfusion, capillary closure, and retinal hypoxia; this type of CRVO can cause severe vision loss.
  • non-surgical ocular drug delivery devices and methods refer to methods and devices for drug delivery that do not require general anesthesia and/or retrobulbar anesthesia (also referred to as a retrobulbar block). Alternatively or additionally, a “non-surgical" ocular drug delivery method is performed with an instrument having a diameter of 28 gauge or smaller. Alternatively or additionally, “non-surgical" ocular drug delivery methods do not require a guidance mechanism that is typically required for ocular drug delivery via a shunt or cannula.
  • surgical ocular drug delivery includes insertion of devices or administration of drugs by surgical means, for example, via incision to expose and provide access to regions of the eye including the posterior region, and/or via insertion of a stent, shunt, or cannula.
  • the surgical and non-surgical posterior ocular disorder treatment methods and devices described herein are particularly useful for the local delivery of drugs to the posterior region of the eye, for example the retinochoroidal tissue, macula, retinal pigment epithelium (RPE) and optic nerve in the posterior segment of the eye.
  • the nonsurgical methods and microneedles provided herein can be used to target drug delivery to specific posterior ocular tissues or regions within the eye or in neighboring tissue.
  • the methods described herein deliver drug specifically to the sclera, the choroid, the Brach's membrane, the retinal pigment epithelium, the subretinal space, the retina, the macula, the optic disk, the optic nerve, the ciliary body, the trabecular meshwork, the aqueous humor, the vitreous humor, and/or other ocular tissue or neighboring tissue in the eye of a human subject in need of treatment.
  • the methods and microneedles provided herein in one embodiment, can be used to target drug delivery to specific posterior ocular tissues or regions within the eye or in neighboring tissue.
  • a patient in need of treatment is administered a drug, e.g., aflibercept or triamcinolone acetonide, to the suprachoroidal space of one or both eyes for at least one dosing session.
  • a drug e.g., aflibercept or triamcinolone acetonide
  • Non-surgical administration is achieved by inserting a microneedle into one or both eyes of the patient, for example the sclera, and injecting or infusing a drug formulation through the inserted microneedle and into the suprachoroidal space of the eye.
  • Surgical administration in another embodiment, is achieved by making a conjunctival peritomy in the eye to expose and provide access to a posterior region of the eye; or by any other traditional surgical means of accessing the posterior region of the eye, known in the art.
  • the treatment is administered via a shunt, stent, or cannula that is surgically placed into the eye of the subject.
  • the effective amount of the drug administered to the SCS provides higher thereapeutic efficacy of the drug, compared to the therapeutic efficacy of the drug when the identical dosage is administered intravitreally, topically, intracamerally, parenterally or orally.
  • the microneedle drug delivery methods described herein precisely deliver the drug into the SCS for subsequent local delivery to nearby posterior ocular tissues (e.g., the retina and choroid) in need of treatment.
  • the drug may be released into the ocular tissues from the infused volume (or, e.g., from microparticles or nanoparticles in the drug formulation) for an extended period, e.g., several hours or days or weeks or months, after the non-surgical drug administration has been completed.
  • the drug formulation includes aflibercept.
  • the drug formulation includes triamcinolone acetonide.
  • the SCS drug delivery methods advantageously include precise control of the depth of insertion into the ocular tissue, so that the microneedle tip can be placed into the eye so that the drug formulation flows into the suprachoroidal space and into one or more posterior ocular tissues surrounding the SCS, e.g., the choroid and retina.
  • insertion of the microneedle is in the sclera of the eye.
  • drug flow into the SCS is accomplished without contacting underlying tissues with the microneedle, such as choroid and retina tissues.
  • the methods provided herein achieve delivery of drug to the suprachoroidal space, thereby allowing drug access to posterior ocular tissues (e.g., the choroid and retina) not obtainable via topical, parenteral, intracameral or intravitreal drug delivery. Because the methods provided herein deliver drug to the posterior ocular tissue for the treatment of a posterior ocular disorder, the suprachoroidal drug dose sufficient to achieve a therapeutic response and/or the frequency of dosing in a human subject treated with the methods provided herein is less than the intravitreal, topical, parenteral or oral drug dose or dosing schedule sufficient to elicit the same or substantially the same therapeutic response.
  • the SCS delivery methods described herein allow for decreased drug dose of the posterior ocular disorder treating drug, compared to the intravitreal, topical, intracameral parenteral or oral drug dose sufficient to elicit the same or substantially the same therapeutic response.
  • the suprachoroidal drug dose sufficient to elicit a therapeutic response is 75% or less, or 50% or less, or 25% or less than the intravitreal, topical parenteral or oral drug dose sufficient to elicit a therapeutic response.
  • the therapeutic response in one embodiment, is a reduction in severity of a symptom/clinical manifestation of the posterior ocular disorder (macular edema associated with uveitis, macular edema associated with RVO, wet AMD, choroidal neovascularization (CNV), wet AMD associated with CNV) for which the patient is undergoing treatment, or a reduction in number of symptom(s)/clinical manifestation(s) of the posterior ocular disorder for which the patient is undergoing treatment.
  • a symptom/clinical manifestation of the posterior ocular disorder macular edema associated with uveitis, macular edema associated with RVO, wet AMD, choroidal neovascularization (CNV), wet AMD associated with CNV
  • CNV choroidal neovascularization
  • suprachoroidal space is used interchangeably with suprachoroidal, SCS, suprachoroid and suprachoroidia, and describes the potential space in the region of the eye disposed between the sclera and choroid. This region primarily is composed of closely packed layers of long pigmented processes derived from each of the two adjacent tissues; however, a space can develop in this region as a result of fluid or other material buildup in the suprachoroidal space and the adjacent tissues. Those skilled in the art will appreciate that the suprachoroidal space frequently is expanded by fluid buildup because of some disease state in the eye or as a result of some trauma or surgical intervention.
  • the fluid buildup is intentionally created by infusion of a drug formulation into the suprachoroid to create the suprachoroidal space (which is filled with drug formulation).
  • the SCS region serves as a pathway for uveoscleral outflow (i.e., a natural process of the eye moving fluid from one region of the eye to the other through) and becomes a real space in instances of choroidal detachment from the sclera.
  • FIGS. 1-4 are a various views of a human eye 10 (with FIGS. 2-4 being cross-sectional views). While specific regions are identified, those skilled in the art will recognize that the proceeding identified regions do not constitute the entirety of the eye 10, rather the identified regions are presented as a simplified example suitable for the discussion of the embodiments herein.
  • the eye 10 includes both an anterior segment 12 (the portion of the eye in front of and including the lens) and a posterior segment 14 (the portion of the eye behind the lens).
  • the anterior segment 12 is bounded by the comea 16 and the lens 18, while the posterior segment 14 is bounded by the sclera 20 and the lens 18.
  • the anterior segment 12 is further subdivided into the anterior chamber 22, between the iris 24 and the comea 16, and the posterior chamber 26, between the lens 18 and the iris 24.
  • the comea 16 and the sclera 20 collectively form a limbus 38 at the point at which they meet.
  • the exposed portion of the sclera 20 on the anterior segment 12 of the eye is protected by a clear membrane referred to as the conjunctiva 45 (see e.g., FIGS. 2 and 3).
  • Underlying the sclera 20 is the choroid 28 and the retina 27, collectively referred to as retinachoroidal tissue.
  • a vitreous humour 30 (also referred to as the "vitreous") is disposed between a ciliary body 32 (including a ciliary muscle and a ciliary process) and the retina 27.
  • the anterior portion of the retina 27 forms an ora serrata 34.
  • the loose connective tissue, or potential space, between the choroid 28 and the sclera 20 is referred to as the suprachoroid.
  • FIG. 2 illustrates the cornea 16, which is composed of the epithelium 40, the Bowman's layer 41, the stroma 42, the Descemet's membrane 43, and the endothelium 44.
  • FIG. 3 illustrates the sclera 20 with surrounding Tenon's Capsule 46 or conjunctiva 45, suprachoroidal space 36, choroid 28, and retina 27, substantially without fluid and/or tissue separation in the suprachoroidal space 36 (i.e., the in this configuration, the space is "potential" suprachoroidal space).
  • the sclera 20 has a thickness between about 500 ⁇ and 700 ⁇ .
  • FIG. 4 illustrates the sclera 20 with the surrounding Tenon's Capsule 46 or the conjunctiva 45, suprachoroidal space 36, choroid 28, and retina 27, with fluid 50 in the suprachoroidal space 36.
  • the dashed line in FIG. 1 represents the equator of the eye 10.
  • the insertion site of any of the microneedles and/or methods described herein is between the equator and the limbus 38 (i.e., in the anterior portion 12 of the eye 10)
  • the insertion site is between about two millimeters and 10 millimeters (mm) posterior to the limbus 38.
  • the insertion site of the microneedle is at about the equator of the eye 10.
  • the insertion site is posterior the equator of the eye 10.
  • a drug formulation can be introduced (e.g., via the microneedle) into the suprachoroidal space 36 at the site of the insertion and can flow through the suprachoroidal space 36 away from the site of insertion during an infusion event (e.g., during injection).
  • the drug formulation includes aflibercept or triamcinolone acetonide.
  • the microneedle may extend from the base of the microneedle device at any angle suitable for insertion into the eye 10.
  • the microneedle extends from the base at an angle of about 90 degrees to provide approximately perpendicular insertion of the microneedle into the surface of the eye.
  • the microneedle extends from the base at an angle from about 60 to about 110 degrees, from about 70 degrees to about 100 degrees, from about 80 degrees to about 90 degrees, or from about 85 degrees to about 95 degrees.
  • the microneedle device may comprise a means for controllably inserting, and optionally retracting, the microneedle into the ocular tissue.
  • the microneedle device may include means of controlling the angle at which the at least one microneedle is inserted into the ocular tissue (e.g., by inserting the at least one microneedle into the surface of the ocular tissue at an angle of about 90 degrees).
  • the depth of microneedle insertion into the ocular tissue can be controlled by the length of the microneedle, as well as other geometric features of the microneedle. For example, a flange or other a sudden change in microneedle width can be used to limit the depth of microneedle insertion.
  • the microneedle insertion can also be controlled using a mechanical micropositioning system involving gears or other mechanical components that move the microneedle into the ocular tissue a controlled distance and, likewise, can be operated, for example, in reverse, to retract the microneedle a controlled distance.
  • the depth of insertion can also be controlled by the velocity at which the microneedle is inserted into the ocular tissue.
  • the retraction distance can be controlled by elastic recoil of the ocular tissue into which the microneedle is inserted or by including an elastic element within the microneedle device that pulls the microneedle back a specified distance after the force of insertion is released.
  • the angle of insertion can be directed by positioning the microneedle at a first angle relative to the microneedle base and positioning the base at a second angle relative to the ocular surface.
  • the first angle can be about 90° and the second angle can be about 0°.
  • the angle of insertion can also be directed by having the microneedle protrude from a device housing through a channel in that housing that is oriented at a specified angle.
  • microneedle refers to a conduit body having a base, a shaft, and a tip end suitable for insertion into the sclera and other ocular tissue and has dimensions suitable for minimally invasive insertion and drug formulation infusion as described herein. That is, the microneedle has a length or effective length that does not exceed about 2000 microns and a diameter that does not exceed about 600 microns. Both the "length” and “effective length” of the microneedle encompass the length of the shaft of the microneedle and the bevel height of the microneedle.
  • the microneedle used to carry out the methods described herein comprises one of the devices disclosed in International Patent Application Publication No. WO2014/179698 (Application No. PCT/US2014/036590), filed May 2, 2014 and entitled “Apparatus and Method for Ocular Injection,” incorporated by reference herein in its entirety for all purposes.
  • the microneedle used to carry out the methods described herein comprises one of the devices disclosed in International Patent Application Publication No. WO2014/036009 (Application No. PCT/US2013/056863), filed August 27, 2013 and entitled "Apparatus and Method for Drug Delivery Using Microneedles," incorporated by reference herein in its entirety for all purposes.
  • the microneedle is designed to have a length longer than the desired penetration depth, but the microneedle is controllably inserted only part way into the tissue. Partial insertion may be controlled by the mechanical properties of the tissue, which bends and dimples during the microneedle insertion process. In this way, as a microneedle is inserted into the tissue, its movement partially elastically deforms the tissue and partially penetrates into the tissue. By controlling the degree to which the tissue deforms, the depth of microneedle insertion into the tissue can be controlled.
  • the device used to carry out one of the methods described herein comprises the device described in U.S. Design Patent Application Serial No. 29/506,275 entitled, “Medical Injector for Ocular Injection,” filed October 14, 2014, the disclosure of which is incorporated herein by reference in its entirety for all purposes.
  • the microneedle is inserted into the eye of the human patient using a rotational/drilling technique and/or a vibrating action.
  • the microneedle can be inserted to a desired depth by, for example, drilling the microneedles a desired number of rotations, which corresponds to a desired depth into the tissue. See, e.g., U.S. Patent Application Publication No. 2005/0137525, which is incorporated herein by reference, for a description of drilling microneedles.
  • the rotational/drilling technique and/or a vibrating action may be applied during the insertion step, retraction step, or both.
  • proximal and distal refer to the direction closer to and away from, respectively, an operator (e.g., surgeon, physician, nurse, technician, etc.) who would insert the medical device into the patient, with the tip-end (i.e., distal end) of the device inserted inside a patient's body first.
  • an operator e.g., surgeon, physician, nurse, technician, etc.
  • the tip-end i.e., distal end
  • the end of a microneedle described herein first inserted inside the patient's body would be the distal end, while the opposite end of the microneedle (e.g., the end of the medical device being manipulated by the operator) would be the proximal end of the microneedle.
  • the terms "about” and “approximately” generally mean plus or minus 10% of the value stated. For example, about 0.5 would include 0.45 and 0.55, about 10 would include 9 to 11, about 1000 would include 900 to 1100.
  • fluid-tight is understood to encompass both a hermetic seal (i.e., a seal that is gas-impervious) as well as a seal that is only liquid-impervious.
  • the term “substantially” when used in connection with “fluid-tight,” “gas-impervious,” and/or “liquid- impervious” is intended to convey that, while total fluid imperviousness is desirable, some minimal leakage due to manufacturing tolerances, or other practical considerations (such as, for example, the pressure applied to the seal and/or within the fluid), can occur even in a “substantially fluid-tight" seal.
  • a "substantially fluid-tight" seal includes a seal that prevents the passage of a fluid (including gases, liquids and/or slurries) therethrough when the seal is maintained at a constant position and at fluid pressures of less than about 5 pounds per square inch gage (psig), less than about 10 psig, less than about 20 psig, less than about 30 psig, less than about 50 psig, less than about 75 psig, less than about 100 psig and all values in between.
  • psig pounds per square inch gage
  • a "substantially liquid-tight" seal includes a seal that prevents the passage of a liquid (e.g., a liquid medicament) therethrough when the seal is maintained at a constant position and is exposed to liquid pressures of less than about 5 psig, less than about 10 psig, less than about 20 psig, less than about 30 psig, less than about 50 psig, less than about 75 psig, less than about 100 psig and all values in between.
  • a liquid e.g., a liquid medicament
  • a hollow microneedle has a structure that includes one or more continuous pathways from the base of the microneedle to an exit point (opening) in the shaft and/or tip portion of the microneedle distal to the base.
  • the microneedle device in one embodiment, comprises a fluid reservoir for containing the therapeutic formulation (e.g., drug or cell formulation), e.g., as a solution or suspension, and the drug reservoir (which can include any therapeutic formulation) being in operable communication with the bore of the microneedle at a location distal to the tip end of the microneedle.
  • the fluid reservoir may be integral with the microneedle, integral with the elongated body, or separate from both the microneedle and elongated body.
  • microneedle and/or any of the components included in the embodiments described herein is/are formed and/or constructed of any suitbale biocompatible material or combination of materials, including metals, glasses, semi-conductor materials, ceramics, or polymers.
  • suitable metals include pharmaceutical grade stainless steel, gold, titanium, nickel, iron, gold, tin, chromium, copper, and alloys thereof.
  • the polymer can be biodegradable or non-biodegradable.
  • suitable biocompatible, biodegradable polymers include polylactides, polyglycolides, polylactide-co-glycolides (PLGA), polyanhydrides, polyorthoesters, polyetheresters, polycaprolactones, polyesteramides, poly(butyric acid), poly(valeric acid), polyurethanes and copolymers and blends thereof.
  • Representative non-biodegradable polymers include various thermoplastics or other polymeric structural materials known in the fabrication of medical devices.
  • Biodegradable microneedles can provide an increased level of safety compared to non-biodegradable ones, such that they are essentially harmless even if inadvertently broken off into the ocular tissue.
  • the hollow microneedle provided herein is fabricated using a laser or similar optical energy source.
  • a microcannula may be cut using a laser to represent the desired microneedle length.
  • the laser may also be use to shape single or multiple tip openings. Single or multiple cuts may be performed on a single microncannula to shape the desired microneedle structure.
  • the microcannula may be made of metal such as stainless steel and cut using a laser with a wavelength in the infrared region of the light spectrum (e.g., from about 0.7 to about 300 ⁇ ). Further refinement may be performed using metal electropolishing techniques familiar to those in the field.
  • the microneedle length and optional bevel is formed by a physical grinding process, which for example may include grinding a metal cannula against a moving abrasive surface.
  • the fabrication process may further include precision grinding, micro-bead jet blasting and ultrasonic cleaning to form the shape of the desired precise tip of the microneedle.
  • an apparatus in some embodiments, includes a medicament container, a piston assembly and a handle.
  • the medicament container defines a lumen configured to contain a medicament.
  • a distal end portion of the medicament container includes a coupling portion configured to be removably coupled to a needle assembly.
  • a proximal end portion of the medicament container includes a flange and a longitudinal shoulder.
  • a distal end portion of the piston assembly includes an elastomeric member movably disposed within the lumen of the medicament container.
  • the handle is coupled to a proximal end portion of the piston assembly such movement of the handle produces movement of the elastomeric member within the medicament container.
  • the proximal end portion of the medicament container is movably disposed within the handle.
  • a portion of the handle is configured to contact the flange to limit proximal movement of the handle relative to the medicament container.
  • the handle includes a protrusion configured to engage the longitudinal shoulder of the medicament container to limit rotation of the handle relative to the medicament container.
  • an apparatus includes a medicament container, a needle assembly, and a piston assembly.
  • the medicament container contains a dose of a medicament, such as, for example a drug or cellular therapeutic, e.g., a steroid formulation or a cell suspension (e.g., a stem cell suspension).
  • the dose has a delivered volume of at least about 20 ⁇ , at least about 50 uL, at least about 100 ⁇ , at least about 200 or at least about 500 ⁇ .
  • the amount of therapeutic formulation delivered into the suprachoroidal space from the devices described herein is from about 10 ⁇ to about 200 ⁇ , e.g., from about 50 ⁇ to about 150 ⁇ .
  • from about 10 ⁇ to about 500 ⁇ , e.g., from about 50 ⁇ to about 250 ⁇ is non-surgically administered to the suprachoroidal space.
  • the needle assembly is coupled to a distal end portion of the medicament container, and includesss a contact surface and a needle.
  • the contact surface is configured to contact a target surface of an eye, and can include a convex surface and/or a sealing portion, as described herein.
  • the needle is coupled to the base.
  • a distal end portion of the piston assembly includes an elastomeric member movably disposed within the medicament container.
  • a proximal end portion of the piston assembly is configured to receive a force to move the elastomeric within the medicament container to deliver the dose of the medicament via the needle assembly.
  • an apparatus includes a medicament container, a needle assembly, and a piston assembly.
  • the medicament container contains a dose of a medicament, such as, for example a steroidal composition such as a triamcinolone composition.
  • the needle assembly is coupled to a distal end portion of the medicament container, and includesss a contact surface and a needle.
  • the contact surface is configured to contact a target surface of an eye, and can include a convex surface and/or a sealing portion, as described herein.
  • the needle is coupled to the base.
  • a distal end portion of the piston assembly includes an elastomeric member movably disposed within the medicament container.
  • a proximal end portion of the piston assembly is configured to receive a force to move the elastomeric within the medicament container to deliver the dose of the medicament via the needle assembly.
  • the needle assembly and the piston assembly being collectively configured to deliver the dose of the medicament into a suprachoroidal space of the eye such that a therapeutic response resulting from the dose is substantially equivalent to a therapeutic response resulting from the delivery of a corresponding dose of the medicament via any one of an intravitreal delivery method, a topical delivery method, a parenteral delivery method or an oral delivery method.
  • An amount of the dose is less than about 75 percent of an amount of the corresponding dose.
  • an apparatus includes a medicament container, a needle assembly, and a piston assembly.
  • the medicament container contains a dose of a medicament, such as, for example a steroidal composition such as a triamcinolone composition.
  • the needle assembly is coupled to a distal end portion of the medicament container, and includesss a contact surface and a needle.
  • the contact surface is configured to contact a target surface of an eye, and can include a convex surface and/or a sealing portion, as described herein.
  • the needle is coupled to the base.
  • a distal end portion of the piston assembly includes an elastomeric member movably disposed within the medicament container.
  • a proximal end portion of the piston assembly is configured to receive a force to move the elastomeric within the medicament container to deliver the dose of the medicament via the needle assembly.
  • the needle assembly and the piston assembly being collectively configured to deliver the dose of the medicament into a suprachoroidal space of the eye such that an intraocular Cmax resulting from the dose is greater, for example at least about 1.25 x, 1.5 x or 2x greater than an intraocular Cmax resulting from the delivery of a corresponding dose of the medicament via any one of an intravitreal delivery method, a topical delivery method, a parenteral delivery method or an oral delivery method.
  • the needle assembly and the piston assembly being collectively configured to deliver the dose of the medicament into a suprachoroidal space of the eye such that an intraocular AUC resulting from the dose is greater, for example at least about 1.25x, 1.5* or 2x greater than an intraocular AUC resulting from the delivery of a corresponding dose of the medicament via any one of an intravitreal delivery method, a topical delivery method, a parenteral delivery method or an oral delivery method.
  • FIGS. 5-18 illustrate a medical injector 100 configured to deliver a medicament to, for example, ocular tissue, according to an embodiment.
  • the medical injector 100 can be used in conjunction with any of the methods and therapeutic formulations described herein. More specifically, the medical injector 100 (also referred to herein as "injector”) can have a size, shape, and/or configuration that is based at least in part on constraints and/or challenges associated with delivering a drug formulation into ocular tissue. For example, as described in further detail herein, medicament delivery into ocular tissue using conventional devices and/or needles can lead to incomplete delivery of a dose, reduction in efficacy of an injected medicament, seeding of undersirable cells, trauma, etc. Thus, the medical injector 100 can have a size and/or configuration that effectively deliver a medicament to a portion of the eye such as a posterior region thereof.
  • the medical injector 100 includes a handle 110, a barrel 130, a piston 150, a needle hub 160, and a cap 170.
  • the handle 110 can be any suitable shape, size, and/or configuration.
  • the handle 110 can have an ergonomic shape and/or size, which can enable to manipulate the injector 100 with one hand or with two hands.
  • the handle 110 has a proximal end portion 111 and a distal end portion 112, and defines an inner volume 113 (see e.g., FIG. 9).
  • the inner volume 113 of the handle 110 receives and/or is configured to house at least a portion of the barrel 130 and the piston 150, as described in further detail herein.
  • the handle 110 is formed by coupling a first handle member 115A to a second handle member 115B.
  • the handle member 115A and the handle member 115B can be relatively thin shelled or the like and can be formed from any suitable material such as the biocompatible materials described above.
  • the handle members 115A and 1158B can be substantially hollow and/or can define an inner volume (e.g., the inner volume 113).
  • the first handle member 115A has a proximal end portion 116A and a distal end portion 117A.
  • the first handle member 115A has an inner surface 118A that can include any suitable feature, cutout, coupler, wall, etc., any of which can be used to facilitate the coupling of the first handle member 115 A to the second handle member 115B and/or to engage a portion of the piston 150 and/or the barrel 130.
  • the inner surface 118A of the first handle member 115 A can form a rib 120A, a retention member 119A, and at least one coupler 121A, which can be used, iner alia, to engage the barrel 130, the piston 150, and/or the second handle member 115B, respectively, as described in further detail herein.
  • the second handle member 115B has a proximal end portion 116B and a distal end portion 117B.
  • the second handle member 115B also has an inner surface 118B that forms a rib 120B, a retention member 119B, and at least one coupled 121B, which can be used to engage the barrel 130, the piston 150, and the first handle member 115A, respectively, as described in further detail herein.
  • the first handle member 115 A and the second handle member 115B are coupled together to collectively form the handle 100.
  • the first handle member 115A and the second handle member 115B can be coupled in any suitable member.
  • the retention member 119B of the second handle member 115B can define an opening or the like configured to matingly receive a portion of the retention member 119A of the first handle member 115A.
  • the at least one coupler 121B of the second handle member 119B can define an opening configured to matingly receive a portion of an associated coupler 121 A of the first handle member 115 A.
  • the retention member 119A and the coupler(s) 121B of the first handle member 115A can be configured to form a press or friction fit with an inner surface of the retention member 119B and the coupler(s) 12 IB of the second handle member 115B, which can be operable in coupling the first handle member 115A to the second handle member 115B.
  • the first handle member 115A and the second handle member 115B can be coupled via any suitable method such as, for example, an adhesive, an ultrasonic weld, a mechanical fastener, and/or the like.
  • the inner surfaces 118A and 118B of the handle members 115 A and 115B, respectively, collectively define the inner volume 113 of the handle 110, as shown in FIG. 9.
  • the barrel 130 of the injector 100 can be any suitable shape, size, or configuration. As shown in FIG. 10, the barrel 130 has a proximal end portion 131 and a distal end portion 132 and defines a lumen 133 therethrough. In addition, the barrel 130 has an outer surface that defines a set of slots 136 (only one is shown in FIG. 10) and a grip portion 137.
  • the grip portion 137 can be configured to facilitate the use of the device by providing a user with a predetermined location to engage the injector 100.
  • the grip portion 137 can have any suitable surface finish or the like, which can, in some instances, increase a friction between the grip portion 137 and a user's fingers and/or hand. In other embodiments, the barrel 130 does not include a grip portion.
  • the lumen 133 of the barrel 130 movably receives at least a portion of the piston 150, as described in further detail herein.
  • at least a portion of the lumen 133 can define a medicament volume configured to receive, store, house, and/or otherwise contain a medicament (e.g., a corticosteroid such as triamcinolone acetonide, or any other medicament described herein).
  • at least a portion of the barrel 130 can be substantially transparent and/or can include an indicator or the like configured to allow a user to visually inspect a volume of fluid (e.g., medicament/therapeutic formulation) within the lumen 133.
  • such an indicator can be, for example, any number of lines and/or markings associated with a volume of fluid disposed within the barrel 130.
  • the barrel 130 can be substantially opaque and/or does not include an indicator or the like.
  • the distal end portion 132 includes and/or forms a coupler 138 configured to be physically and fluidically coupled to the needle hub 160, as described in further detail herein.
  • the proximal end portion 131 of the barrel 130 includes a flanged end 135 and defines a set of slots 136 (only one slot is shown in FIG. 10).
  • at least a portion of the barrel 130 is disposed within the inner volume 113 of the handle 110 (see, e.g., FIG. 16). Specifically, at least the proximal end portion 131 of the barrel 130 can be inserted into the handle 110 in such a manner that the handle 110 can be moved relative to the barrel 130.
  • proximal end portion 131 of the barrel 130 can be movably disposed within the inner volume 113 defined by the handle 110.
  • the ribs 120A and 120B of the handle members 115A and 115B, respectively are movably disposed in its associated slot 136 defined by the barrel 130.
  • Such an arrangement can, for example, define a range of motion of the handle 110 relative to the barrel 130.
  • Such an arrangement can also limit a rotational motion of the handle 110 about the barrel 130 while allowing a translational motion of the handle 110 relative to the barrel 130 in a proximal or a distal direction.
  • the arrangement of the flanged end 135 of the barrel 130 and the inner surfaces 1 18A and 118B of the handle members 115A and 1 15B, respectively, can define a translational range of motion of the handle 1 10 relative to the barrel 130 in the proximal or the distal direction (see e.g., FIG. 16).
  • the piston 150 of the injector 100 can be any suitable shape, size, and/or configuration.
  • the pison 150 can have a size and shape that are each associated with the handle 1 10 and/or the barrel 130, which in turn, can allow at least a portion of the piston 150 to be disposed within the handle 1 10 and/or the barrel 130.
  • the piston 150 has a proximal end portion 151 and a distal end portion 152.
  • the proximal end portion 151 of the piston 150 is configured to be disposed within the inner volume 1 13 of the handle 1 10. As shown in FIG.
  • the proximal end portion 151 of the piston 150 includes a tab 153 or the like that defines an opening 154, which in turn, can receive at least a portion of the retention members 119A and 1 19B of the handle members 115A and 1 15B, respectively.
  • the proximal end portion 151 of the piston 150 can be positioned relative to the retention member 119B of the second handle member 1 15B such that at least a portion of the retention member 119B is disposed within the opening 154 defined by the piston 150.
  • the tab 153 at or near the proximal end portion 151 of the piston 150 can be disposed about a portion of the retention member 119B prior to coupling the first handle member 115 A to the second handle member 115B.
  • the piston 150 can be fixedly coupled to the handle 1 10.
  • the distal end portion 152 of the piston 150 is configured to be movably disposed in the lumen 133 of the barrel 130.
  • the distal end portion 152 of the piston 150 includes and/or is coupled to an elastomeric member 155.
  • the elastomeric member 155 can be monolithically formed with the piston 150 (e.g., overmolded or the like).
  • the elastomeric member 155 can be formed independently of the piston 150 and coupled thereto.
  • the elastomeric member 155 can be made of an inert and/or biocompatible material, which can have any suitable hardness and/or durometer.
  • the elastomeric member 155 can be formed from and/or constructed out of a rubber, silicone, plastic, nylon, polymers, any other suitable material or combination thereof.
  • at least a portion of the elastomeric member 155 can be configured to deform or the like while substantially maintaining its original shape. That is to say, the elastomeric member 155 can have a durometer that is sufficiently low to allow at least some deformation thereof, while preventing the elastomeric member 155 from being substantially reconfigured and/or the like.
  • the elastomeric member 155 can be disposed in the lumen 1 13 such that an outer surface of the elastomeric member 155 is in contact with an inner surface of the barrel 130 defining the lumen 133.
  • the elastomeric member 155 and the inner surface of the barrel 130 collectively form a substantially fluid-tight seal and/or a hermetic seal, which can, for example, prevent leakage, out gassing, contamination, and/or the like of a substance (e.g., a medicament) disposed within the barrel 130.
  • the elastomeric member 155 can have a size, shape and/or can be constructed from a material such that movement of the piston 150 and/or elastomeric member 155 within the barrel 130 is limited when a force applied is below a predetermined threshold. In this manner, the piston 150 can be maintained in a substantially fixed position relative to the barrel 130 until a force exerted, for example, on the handle 1 10 is sufficient to inject a medicament into a target tissue, as described in further detail herein.
  • the size, shape, and/or configuration of the elastomeric member 155 can be changed to, for example, increase or decrease an amount of force used to move the piston 150 within the barrel 130, which in some instances, can be based on one or more characteristics associated with a target tissue and/or the like, as described in further detail herein.
  • the needle hub 160 of the injector 100 can be any suitable shape, size, and/or configuration. As shown in FIGS. 11-13, 15, and 16, the needle hub 160 has a proximal end portion 161, a distal end portion 162, an indicator portion 168, and a pair of tabs 164, and defines a lumen 167 (see e.g., FIG. 16).
  • the proximal end portion 161 of the needle hub 160 is configured to be coupled to the distal end portion 132 of the barrel 130.
  • the needle hub 160 can include a coupler 163 (see e.g., FIG.
  • the coupler 163 of the needle hub 160 and the coupler 138 of the barrel 130 can form a threaded coupling or the like.
  • a user can, for example, engage the tabs 164 to rotate the needle hub 160 relative to the barrel 130, thereby threading the coupler 163 of the needle hub 160 onto the coupler 138 of the barrel 130.
  • the coupler 163 of the needle hub 160 can be a locking mechanism and/or the like such as, for example, a Luer-Lok® (or other locking mechanism) configured to form a fluid tight seal with the distal end portion 132 of the barrel 130 when coupled thereto.
  • the distal end portion 162 of the needle hub 160 includes and/or is coupled to a base 165, which in turn, is coupled to and/or forms a microneedle 166, as described below.
  • the indicator portion 168 of the needle hub 160 is configured to provide a visual indication associated with one or more characteristics of the microneedle 166.
  • the indicator portion 168 can be configured to provide a visual indication associated with an effective length of the microneedle 166 (e.g., "900" micrometers, as shown in FIG. 12).
  • the base 165 can be any suitable shape, size, and/or configuration and can be configured to contact a portion of the ocular tissue during an injection event.
  • the base 165 has a convex distal end surface, which is configured to contact a target surface of a target tissue when a substance is conveyed through the needle into the target tissue (see, e.g., FIG. 18).
  • the distal end surface includes a sealing portion (not identified in the FIGS.) configured to define a substantially fluid-tight seal with the target surface when the distal end surface is in contact with the target surface.
  • the distal end surface of the base 165 can deform the target surface such that the sealing portion is contiguous with the target surface and forms the substantially fluid-tight seal.
  • the sealing portion can be symmetrical about the microneedle 166.
  • the base 165 can be formed from a material or combination of materials that is/are relatively flexible and/or that has/have a relatively low durometer.
  • the base 165 can be formed from a material with a durometer that is sufficiently low to limit and/or prevent damage to the ocular tissue when placed in contact therewith.
  • the base 165 can be configured to deform (e.g., elastically or plastically) when placed in contact with the ocular tissue.
  • the base 165 can be formed from a material of sufficient hardness such that the target tissue (and not the base) is deformed when the base 165 is placed in contact with and/or pressed against the target tissue.
  • the base 165 is constructed from a medical grade stainless steel, and has a surface finish of less than about 1.6 ⁇ Ra. In this manner, the surface finish can facilitate the formation of a substantially fluid-tight seal between the base 165 and the target tissue.
  • a lumen 169 defined by the microneedle 166 is in fluid communication with the lumen 167 of the needle hub 160 (see, e.g., FIG. 16).
  • a substance can flow through the lumen 167 of the needle hub 160 and the lumen 169 of the microneedle 166 to be injected into a target tissue, as described in further detail herein.
  • the microneedle 166 can be any suitable device or structure that is configured to puncture a target tissue of a patient.
  • the microneedle 166 can be any of the microneedles described herein configured to puncture ocular tissue.
  • the microneedle 166 can be a 30 gauge microneedle, a 32 gauge microneedle or a 34 gauge microneedle. As shown in FIG. 13, the microneedle 166 extends from a distal surface of the base 165 by a distance Di (also referred to herein as an "effective length").
  • Di also referred to herein as an "effective length"
  • the shape and/or size of the microneedle 166 can correspond with at least a portion of a target tissue.
  • the effective length of the microneedle 166 (e.g., the portion of the microneedle 166 that is outside or distal to the base 165) can correspond with a portion of ocular tissue such that when the microneedle 166 is inserted into the ocular tissue, a portion of the microneedle 166 is disposed within the sclera or suprachoroidal space of the eye.
  • the effective length and/or the distance Di is about 900 micrometers ( ⁇ ).
  • the indicator portion 168 of the needle hub 160 can be configured to provide a user with a visual indication associated the effective length and/or distance Di.
  • the microneedle 166 can have a bevel geometry (e.g., bevel angle, bevel height, bevel aspect ratio or the like), which can facilitate the piercing and/or insertion of a tip of the microneedle 166 into the target tissue and the opening (not shown) of the microneedle 166 can be maintained within a desired region during an injection event.
  • the microneedle 166 or any of the microneedles described herein can include a bevel or other characteristics of the types shown and described in International Patent Application Publication No. WO2014/036009 (Application No.
  • the base 165 can be coupled to the needle hub 160, which in turn, is coupled to the barrel 130 such that the lumen 133 of the barrel, the lumen 167 of the needle hub 160, and the lumen 169 of the microneedle 166 define a fluid flow path through which a medicament and/or substance contained within the barrel 130 can flow, for example, to be injected into a target tissue.
  • the cap 170 of the injector 100 is removably disposed adjacent to a distal end portion 132 of the barrel 130 and is configured to substantially house, cover, enclose, protect, isolate, etc. at least a portion of the needle hub 160. More specifically, the cap 170 can be moved relative to the remaining portions of the medical injector 100 to position at least a portion of the needle hub 160 within an inner volume 174 (see, e.g., FIG. 14) of the cap 170. As such, the cap 170 can have a size and/or shape that is associated with and/or at least partially based on a size and/or shape of the needle hub 160.
  • the cap 170 and a portion of the needle hub 160 can collectively define a friction fit or the like, which can be operable in maintaining the cap 170 in a substantially fixed position relative to the needle hub 160.
  • the cap 170 and the portion of the needle hub 160 can collectively form a substantially fluid tight and/or substantially hermetic seal, which in turn, can maintain the sterility of a microneedle 166 prior to use of the medicament delivery device 100.
  • the cap 170 can include a plug, a seal, a sterilization member (e.g., wipe, pad, etc.), and/or the like configured to maintain the sterility of the microneedle 166 prior to use.
  • a sterilization member e.g., wipe, pad, etc.
  • the cap 170 includes an indicator portion 173 that can provide a visual indication to a user associated with a size and/or effective length of the microneedle 166.
  • the indicator portion 173 can be substantially similar in form and function to the indicator portion 168 of the needle hub 160 and can be configured to provide substantially the same visual indication.
  • a user can manipulate the injector 100 to deliver a drug formulation to the suprachoroidal space of an eye according to an embodiment.
  • the drug formulation includes aflibercept and is used to treat a patient for wet AMD, CNV, wet AMD associated with CNV or wet AMD associated with RVO.
  • the drug formulation includes triamcinolone acetonide and is used in conjunction with aflibercept to treat a patient for wet AMD, CNV, wet AMD associated with CNV or wet AMD associated with RVO; or is used to improve any VEGF therapy in ocular disease.
  • the user can, for example, couple the distal end portion 132 of the barrel 130 to a fluid reservoir or the like and/or any suitable transfer device (not shown) to transfer a volume of a medicament and/or drug formulation into the lumen of the barrel 130.
  • the distal end portion 132 of the barrel 130 can be physically and fluidically coupled to a transfer adapter and/or the like having a puncture member configured to puncture a fluid reservoir containing a drug formulation such as those described herein.
  • transfer adapters can be similar to the adapter 21280 shown and described in International Patent Application Publication No. WO2014/179698 (Application No.
  • the puncture member places the transfer adapter in fluid communication with the fluid reservoir.
  • the transfer adapter With the transfer adapter physically and fluidically coupled to the barrel 130, the transfer adapter similarly places the lumen 133 of the barrel 130 in fluid communication with the fluid reservoir.
  • the user can manipulate the injector 100 by moving the handle 110 relative to the barrel 130 in the proximal direction, which in turn, moves the piston 150 disposed within the lumen 133 of the barrel 130 in the proximal direction.
  • a volume associated with a portion of the lumen 133 defined by the barrel 130 distal to the elastomeric member 155 of the piston 150 increases and a volume associated with a portion of the lumen 133 proximal to the elastomeric member 155 decreases.
  • the friction fit and/or fluidic seal defined between the elastomeric member 155 and the inner surface of the barrel 130 can be such that the proximal movement of the piston 150 (e.g., the increase in volume of the portion of the lumen 133 distal to the elastomeric member 155) produces a negative pressure differential within the portion of the lumen 133, which can be operable in drawing a volume of the medicament and/or the drug formulation from the fluid reservoir and into the portion of the lumen 133 distal to the elastomeric member 155 (e.g., a medicament volume).
  • a predetermined volume of the drug formulation can be drawn into the lumen 133 of the barrel 130.
  • the volume of the drug formulation drawn into the lumen 133 is not predetermined.
  • the user can, for example, decouple the barrel 130 from the transfer adapter (not shown).
  • the coupler 138 and/or the distal end portion 132 of the barrel 130 can include a self-sealing port and/or any other suitable port configured to fluidically isolate the lumen 133 of the barrel 130 from a volume outside of the barrel 130.
  • the injector 100 can be prefilled during, for example, a manufacturing process and/or any other time prior to use.
  • the user can manipulate the injector 100 to couple the needle hub 160 (e.g., disposed within the cap 170 or not disposed within the cap 170) to the distal end portion 132 of the barrel 130, thereby placing the lumen 169 of the microneedle 166 in fluid communication with the lumen 133 of the barrel 130.
  • the user can remove the cap 170 from the needle hub 160 if it is disposed thereabout. In other instances, the cap 170 can already be removed.
  • the user can position the injector 100 relative to the ocular tissue such that the microneedle 166 disposed at or near a desired injection site.
  • the injection site can be a predetermined distance from, for example, the limbus 32.
  • the injection site can be a distance D 2 from the limbus 32 that is about 1 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 7 mm, about 8 mm, about 9 mm, about 10 mm, or more.
  • an injection site can be relative to any suitable portion of the eye.
  • the base 165 of the needle hub 160 can be pressed against a target surface of the eye 10 as the microneedle 166 is inserted into the target surface.
  • the base 165 of the needle hub 160 can deform, define an indent, and/or otherwise form a "dimple" in the target surface (e.g., the conjunctiva 45 of the eye 10, as shown in FIG. 18).
  • the "dimple” can facilitate a desired transfer of the medicament from the barrel 130 to the target region via the microneedle 166.
  • the base 165 of the needle hub 160 can be maintained in such a position throughout the procedure (e.g., the injection of medicament into a SCS 36).
  • the "dimple" e.g., the interface between the distal surface of the base 165 and the surface of the target location
  • the target region e.g., the SCS 36.
  • the microneedle 166 is inserted substantially perpendicular or at an angle from about 80° to about 100°, into the eye 10, reaching the suprachoroidal space in a short penetration distance (e.g., about 1.1 mm, about 1 mm, about 0.9 mm, or less).
  • a short penetration distance e.g., about 1.1 mm, about 1 mm, about 0.9 mm, or less.
  • long conventional microneedles 166 or a cannula which approach the suprachoroidal space at a steep angle, taking a longer penetration path through the sclera 20 and other ocular tissues, increasing the invasiveness of the method, the size of the microneedle track and consequently increasing the risk of infection and/or vascular rupture.
  • the ability to precisely control insertion depth is diminished relative to the micromicroneedle 166 approach described herein.
  • the medicament can be conveyed from the barrel 130. More specifically, while maintaining the dimple at the conjunctiva 45, a user can exert a force on the handle 110 to begin an infusion event.
  • the force exerted by a user on the handle 110 can be insufficient to move the piston 150 within the barrel 130 when the distal tip of the microneedle 166 is not disposed within the desired position (e.g., when the microneedle 166 is in the sclera 20 and not the SCS 36 of the eye 10).
  • the injector 100 can be configured to assist a user in delivering at least a portion of the drug formulation to the region, while be configured or "calibrated" to limit and/or prevent delivery to another, different region.
  • the injector 100 can be configured to inform the user when the distal tip of the microneedle 166 is in the target region, for example, such that the drug formulation can be delivered to the target region with high confidence.
  • the injector 100 can be configured to limit movement of the piston 150 within the lumen 133 of the barrel 130 when the distal tip of the microneedle 166 is disposed within a region of the eye 10, which has a greater density, such as the sclera 20.
  • the injector 100 can limit movement of the piston 150 within the lumen 133 when the applied force is below a predetermined threshold such as about 6 Newtons (N).
  • the injector 100 can allow movement of the piston 150 within the barrel 130 when the distal tip of the microneedle 166 is disposed within the target location (e.g., a region having a lower density, such as the SCS 36) and when the force having the magnitude of less than about 6 N is exerted on the piston 150 and/or the handle 110.
  • the system can be configured or "calibrated" to provide feedback (e.g., tactile feedback) to a user to allow the user to deliver the drug formulation to a target region with high confidence.
  • the user can observe movement, or lack of movement, of the piston 150 within the barrel 130 to determine whether medicament has been conveyed to the eye. If the medicament has not been conveyed, the user can respond accordingly. For example, the user can re-align the system, relocate to a different injection site, and/or use a different sized microneedle 166 (e.g., a different microneedle 166 length).
  • a user can manipulate the injector 100 to insert the microneedle 166 into the eye 10 at a desired injection site.
  • a force exerted by the user on the handle 110 can be insufficient to move the piston 150 within the barrel 130.
  • the sclera 20 can produce a backpressure that, in conjunction with the friction between the elastomeric member 155 and the inner surface of the barrel 130 and resistance to flow caused by the characteristics of the drug (e.g., viscosity, density or the like), overcomes the force exerted by the user, thereby preventing and/or limiting delivery of the drug formulation to the sclera 20.
  • the injector 100 is specifically configured or "calibrated" such that the force is insufficient to convey the drug formulation to the sclera 20.
  • the same force exerted by the user can be sufficient to move the piston 150 within the barrel, based at least in part on anatomical differences and/or the differences in material properties between the sclera 20 and the SCS 36 (e.g., densities or the like). In other words, the force can be sufficient to overcome a backpressure produced by the SCS 36.
  • the injector 100 can be configured to ensure that the injection is initiated only when the distal tip of the microneedle 166 is in and/or near the SCS 36 such that the drug formulation (e.g., a medicament such as, for example, a corticosteroid (e.g., triamcinolone) VEGF inhibitor, a combination thereof, or any other medicament described herein) can be delivered only to that region.
  • the SCS 36 produces a first pressure that resists and/or opposes flow from the distal tip of the microneedle 166
  • the sclera 20 produces a second pressure that resists and/or opposes flow from the distal tip of the microneedle 166, which is higher than the first pressure.
  • a user can be informed by a loss of resistance felt at the handle 110 when the distal tip of the microneedle 166 is transitioned from the sclera 20 to or near the SCS 36.
  • the force exerted can be about 2 N, about 3 N, about 4 N, about 5 N, about 6 N or more and inclusive of all ranges therebetween.
  • the piston 150 and the barrel 130 can be collectively configured such that the force produces an injection pressure within the barrel 130 of between about 100 kPa and about 500 kPa.
  • the injection pressure can be about 100 kPa, 110 kPa, 120 kPa, 130 kPa, 140 kPa, 150 kPa, 160 kPa, 170 kPa, 180 kPa, 190 kPa, 200 kPa, 220 kPa, 240 kPa, 260 kPa, 280 kPa, 300 kPa, 320 kPa, 340 kPa, 360 kPa, 380 kPa, 400 kPa, 420 kPa, 440 kPa, 460 kPa, or about 480 kPa, inclusive of all ranges and values therebetween.
  • the injection pressure can be sufficient to overcome the backpressure produced by SCS 36, but insufficient to overcome the backpressure produced by the sclera 20.
  • the force can be varied depending on the diameter of the barrel 130 and/or the piston 150, the viscosity of the drug formulation, and/or the material of the barrel 130 and/or the piston 150. In this manner, regardless of the variations in the piston 150, the barrel 130, and/or the drug formulation, the injector 100 produces an injection pressure within the barrel 130 of between about 100 kPa and about 500 kPa.
  • the drug formulation includes aflibercept and is used to treat a patient for wet AMD, CNV, wet AMD associated with CNV or wet AMD associated with RVO.
  • the drug formulation includes triamcinolone acetonide and is used in conjunction with aflibercept to treat a patient for wet AMD, CNV, wet AMD associated with CNV or wet AMD associated with RVO; or is used to improve any VEGF therapy in ocular disease.
  • the injector 100 can be configured such that injection distance traversed by the piston 150 is sufficient to deliver substantially the entire desired dose of the drug formulation into the SCS 36. In other embodiments, the injector 100 can be configured such that the injection distance traversed by the piston 150 is sufficient to deliver only a portion of the desired dose of the drug formulation into the SCS 36. In such embodiments, the injector 100 can be configured to initiate delivery of the drug formulation into the SCS 36, for example, to inform the user that the distal tip of the microneedle 166 is disposed within the SCS 36 (e.g., the user would see or otherwise detect that the piston 150 has moved, thus indicating the desired positioning of the microneedle 166).
  • the injector 100 can assist the user in determining whether the distal tip of the microneedle 166 is within the SCS 36 or not by initiating delivery of the drug formulation.
  • the injection distance can be a first injection distance.
  • the user can then move the distal end portion of the piston 150 a second injection distance, for example, by applying a manual force on the piston 150 (e.g., by moving the handle 110 relative to the barrel 130, as described herein).
  • the hub 160 can be maintained in contact with the target surface for a time to allow for a desired medicament absorption by the eye.
  • the medicament can spread through tissues of the back of the eye without the medicament seeping from the injection site (e.g., where the microneedle 166 pierced the conjunctiva).
  • the distal end surface of the base 165 can include a sealing portion configured to form a substantially fluid-tight seal with the conjunctiva to limit movement of the medicament out of the eye along the needle track. In this manner, the injector 100 and the methods described herein can facilitate delivery of the desired dose to the desired regions of the eye.
  • FIGS. 19 and 20 illustrate a needle hub 260 according to another embodiment.
  • the needle hub 260 has a proximal end portion 261, a distal end portion 262, and an indicator portion 268.
  • the needle hub 260 can be substantially similar in form and function as the needle hub 160 described in detail above with reference to FIGS. 11-13. Thus, portions of the needle hub 260 are not described in further detail herein.
  • the needle hub 260 can differ, however, by being coupled to a base 265 including a microneedle 266 with an effective length greater than the effective length of the microneedle 160.
  • the microneedle 266 extends from the base 265 by a distance D 3 of about 1100 ⁇ .
  • the indicator portion 268 of the needle hub 260 is configured to present a visual indication associated with the effective length and/or distance D 3 (e.g., represented in FIGS. 19 and 20 with the text "1100").
  • an injector can include a microneedle having an effective length of between about 200 ⁇ and about 1500 ⁇ .
  • a short effective length microneedle e.g., a length of between about 200 ⁇ and about 400 ⁇
  • injectors with a longer effective length microneedle e.g., a length of between about 1200 ⁇ and about 1500 ⁇
  • the drug formulation includes aflibercept and is used to treat a patient for wet AMD, CNV, wet AMD associated with CNV or wet AMD associated with RVO.
  • the drug formulation includes triamcinolone acetonide and is used in conjunction with aflibercept to treat a patient for wet AMD, CNV, wet AMD associated with CNV or wet AMD associated with RVO; or is used to improve any VEGF therapy in ocular disease.
  • the method 1000 includes placing a needle hub of an injector in contact with a surface of an eye at a target location, at 1001.
  • the medical injector can be any suitable injector.
  • the injector can be substantially similar to or the same as the injector 100 described above.
  • the injector can include at least a handle, a barrel, a piston, and the needle hub.
  • the piston can be at least partially disposed in the handle and fixedly coupled thereto.
  • a portion of the barrel can be movably disposed in the handle to allow for relative movement, for example, in a proximal or distal direction.
  • the barrel can define a lumen configured to movably receive a portion of the piston and that can receive, store, and/or contain a volume of a drug formulation.
  • the needle hub can be coupled to the barrel to place a lumen of a microneedle coupled thereto, in fluid communication with the lumen of the microneedle.
  • a first force is exerted on a portion of the injector to deform a portion of the surface of the eye associated with the target location, at 1002.
  • a user can align the injector with a target location along the surface of the eye and can move the injector to insert the microneedle into the eye and to place the needle hub in contact with a surface of the eye.
  • the user can then exert the first force on the handle, and in response, at least a portion of the first force is transferred from the needle hub to the surface of the eye.
  • the needle hub can exert on the conjunctiva, which can result in a dimple being formed in the conjunctiva.
  • the needle hub can remain in contact with the eye and can continue to deform the portion of the eye until after an injection event, which in turn, can prevent seepage and/or the like.
  • a second force is exerted on the portion of the injector to move a needle (e.g., the microneedle) of the injector through the sclera of the eye until a distal surface of the needle is disposed at a predetermined depth within the eye, at 1003.
  • the arrangement of the injector can be such that prior to the distal surface of the needle being disposed at the predetermined depth, the second force exerted on the portion of the injector is sufficient to move the needle through the ocular tissue, but insufficient to move the piston within the barrel.
  • the piston can include an elastomeric member (e.g., a plunger or the like) that can form a friction fit with an inner surface of the barrel, which in turn, can define a reaction force that resists the movement of the piston within the barrel.
  • the ocular tissue exerts a backpressure or the like in response to the insertion of the needle.
  • the amount of force exerted to move the needle through the ocular tissue can be less than an amount of force to move the piston within the barrel and/or otherwise inject the drug formulation.
  • a volume of a drug formulation is expelled through the needle and into a region of the eye associated with a suprachoroidal space, at 1004.
  • the region of the eye can be disposed at the predetermined depth within the eye. More specifically, while the injector is described above as moving the needle through the eye substantially without expelling the drug formulation in response to the second force, the second force exerted on the portion of the injector (e.g., the handle) can be sufficient to expel the drug formulation through the needle and into the suprachoroidal space when the needle is disposed at a predetermined depth.
  • the density of the sclera and the friction force between the piston and the inner surface of the barrel are sufficient to resist a distal movement of the piston in response to the second force.
  • the density of that portion of the eye can be less than the density of the sclera.
  • the collective force exerted by the friction force and the anatomy of the eye in response to the second force is reduced.
  • the second force can become sufficient to move the piston in the distal direction within the barrel to expel the drug formulation into the suprachoroidal space.
  • the user exerting the second force on the portion of the injector can feel a loss of resistance and/or the like, which can be an indication that the distal surface of the needle is disposed at a desired depth.
  • the method 1000 can include any number of optional steps and/or pre-procedural or post-procedural steps.
  • a method of delivering a drug formulation to ocular tissue in a clinical study can be similar to the method 1000 and can include at least some of the following steps:
  • the injector can be any of the injectors shown and described herein, such as the inj ector 100.
  • the microneedle can include the hub 160 shown and described above.
  • the drug formulation should be injected without delay to prevent settling of the drug in the syringe.
  • microneedle Once the microneedle is inserted into the sclera, ensure that the hub of the microneedle is in firm contact with the conjunctiva. Firm contact of the microneedle injection system with the conjunctiva will be observed as a slight, localized dimple of the globe around the microneedle hub.
  • microneedle 14 If there is resistance to flow through the microneedle, remove the microneedle from the eye and examine the eye for any issues. If subject safety is not at risk, investigator may choose to verify patency of the microneedle and use best medical judgment to restart the injection procedure at a new site adjacent to the original injection site or use a longer microneedle length (1 100 ⁇ ). Ensure there is enough the drug formulation remaining in the microinjector to prime the replacement microneedle and deliver a 100 ⁇ dose.
  • the drug formulation includes aflibercept and is used to treat a patient for wet AMD, CNV, wet AMD associated with CNV or wet AMD associated with RVO.
  • the drug formulation includes triamcinolone acetonide and is used in conjunction with aflibercept to treat a patient for wet AMD, CNV, wet AMD associated with CNV or wet AMD associated with RVO; or is used to improve any VEGF therapy in ocular disease.
  • the triamcinolone acetonide is administered to the SCS using the methods provided herein, and aflibercept is administered intravitreally.
  • preparing an injector which can be any of the injectors shown and described herein, suhb as the injector 100 (e.g., step 8 above) can include:
  • a medical device or kit can include a simulated medicament injector.
  • the simulated medicament injector can correspond to an actual medicament injector (e.g., the medical injector 100 described above) and can be used, for example, to train a user in the operation of the corresponding actual medical injector, to perform a "sham" injection as part of a clinical trial protocol, or the like.
  • a simulated medical injector can simulate the actual medical injector in any number of ways.
  • the simulated medical injector can have a shape corresponding to a shape of the actual medical injector (e.g., injector 100), a size corresponding to a size of the actual medical injector (e.g., injector 100) and/or a weight corresponding to a weight of the actual medical injector (e.g., injector 100).
  • the simulated medical injector can include components that correspond to the components of the actual medical injector. In this manner, the simulated medical injector can simulate the look, feel and sounds of the actual medical injector.
  • the simulated medical injector can include external components (e.g., a base, a handle, or the like) that correspond to external components of the actual medical injector.
  • the simulated medical injector can include internal components (e.g., a plunger) that correspond to internal components of the actual medical injector.
  • the simulated medical injector can be devoid of a medicament and/or those components that cause the medicament to be delivered (e.g., a microneedle). In this manner, the simulated medical injector can be used to train a user in the use of the actual medical injector without exposing the user to a needle and/or a medicament. Moreover, the simulated medical injector can have features to identify it as a training device to prevent a user from mistakenly believing that the simulated medical injector can be used to deliver a medicament. [1158] In some embodiments, a method of delivering a drug formulation to ocular tissue in a clinical study can be similar to the method 1000 and can include at least some of the following steps:
  • microinjector can be any of the injectors shown and described herein, such as the injector 100. Moreover, the microinjector can be a simulated microinjector, including a needless hub. This preparation includes:
  • the microneedle devices described herein also may be adapted to use the one or more microneedles as a sensor to detect analytes, electrical activity, and optical or other signals.
  • the sensor may include sensors of pressure, temperature, chemicals, and/or electromagnetic fields (e.g., light).
  • Biosensors can be located on or within the microneedle, or inside a device in communication with the body tissue via the microneedle.
  • the microneedle biosensor can be any of the four classes of principal transducers: potentiometric, amperometric, optical, and physiochemical.
  • a hollow microneedle is filled with a substance, such as a gel, that has a sensing functionality associated with it.
  • a substance such as a gel
  • the substrate or enzyme can be immobilized in the needle interior.
  • a wave guide can be incorporated into the microneedle device to direct light to a specific location, or for detection, for example, using means such as a pH dye for color evaluation.
  • heat, electricity, light, ultrasound or other energy forms may be precisely transmitted to directly stimulate, damage, or heal a specific tissue or for diagnostic purposes.
  • the microneedle device for non-surgically delivering drug to the suprachoroidal space of the eye of a human subject comprises a hollow microneedle.
  • the device may include an elongated housing for holding the proximal end of the microneedle.
  • the device may further include a means for conducting a drug formulation through the microneedle.
  • the means may be a flexible or rigid conduit in fluid connection with the base or proximal end of the microneedle.
  • the means may also include a pump or other devices for creating a pressure gradient for inducing fluid flow through the device.
  • the conduit may in operable connection with a source of the drug formulation.
  • the source may be any suitable container.
  • the source may be in the form of a conventional syringe.
  • the source may be a disposable unit dose container.
  • the drug formulation includes aflibercept and is used to treat a patient for wet AMD, CNV, wet AMD associated with CNV or wet AMD associated with RVO.
  • the drug formulation includes triamcinolone acetonide and is used in conjunction with aflibercept to treat a patient for wet AMD, CNV, wet AMD associated with CNV or wet AMD associated with RVO; or is used to improve any VEGF therapy in ocular disease.
  • the transport of drug formulation or biological fluid through a hollow microneedle can be controlled or monitored using, for example, one or more valves, pumps, sensors, actuators, and microprocessors.
  • the microneedle device may include a micropump, microvalve, and positioner, with a microprocessor programmed to control a pump or valve to control the rate of delivery of a drug formulation through the microneedle and into the ocular tissue.
  • the flow through a microneedle may be driven by diffusion, capillary action, a mechanical pump, electroosmosis, electrophoresis, convection or other driving forces. Devices and microneedle designs can be tailored using known pumps and other devices to utilize these drivers.
  • the microneedle device may further include an iontophoretic apparatus, similar to that described in U.S. Patent 6,319,240 to Beck, for enhancing the delivery of the drug formulation to the ocular tissue.
  • the microneedle devices can further include a flowmeter or other means to monitor flow through the microneedles and to coordinate use of the pumps and valves.
  • the flow of drug formulation or biological fluid can be regulated using various valves or gates known in the art.
  • the valve may be one which can be selectively and repeatedly opened and closed, or it may be a single-use type, such as a fracturable barrier.
  • Other valves or gates used in the microneedle devices can be activated thermally, electrochemically, mechanically, or magnetically to selectively initiate, modulate, or stop the flow of material through the microneedles.
  • the flow is controlled with a rate-limiting membrane acting as the valve.
  • the flow of drug formulation or biological fluid can be regulated by the internal friction of various components, the characteristics of the medicament to be injected (e.g., the viscosity) and/or the characteristics of the desired injection site.
  • a drug product can be configured for delivery of a specific formulation to a specific location.
  • a drug product can include a microinjector (e.g., microinjector 100) and a medicament (e.g., triamcinolone or any other formulations described herein) that is configured to deliver the medicament to a specific target region (e.g., the SCS).
  • the drug product can be configured such that the flow of the medicament is limited when injection is attempted into a different target region having a higher density (e.g., the sclera).
  • the drug product is configured to regulate the flow by allowing flow when the injection is attempted into the desired target region.
  • the microneedle in one embodiment, is part of an array of two or more microneedles such that the method further includes inserting at least a second microneedle into the sclera without penetrating across the sclera.
  • the drug formulation of each of the two or more microneedles may be identical to or different from one another, in drug, formulation, volume/quantity of drug formulation, or a combination of these parameters.
  • different types of drug formulations may be injected via the one or more microneedles. For example, inserting a second hollow microneedle comprising a second drug formulation into the ocular tissue will result in delivery of the second drug formulation into the ocular tissue.
  • the device includes an array of two or more microneedles.
  • the device may include an array of from 2 to 1000 (e.g., from 2 to 100 or from 2 to 10) microneedles.
  • a device includes between 1 and 10 microneedles.
  • An array of microneedles may include a mixture of different microneedles.
  • an array may include microneedles having various lengths, base portion diameters, tip portion shapes, spacings between microneedles, drug coatings, etc.
  • the angle at which a single microneedle extends from the base may be independent from the angle at which another microneedle in the array extends from the base.
  • the SCS drug delivery methods provided herein allow for the delivery of drug formulation over a larger tissue area and to more difficult to target tissue in a single administration as compared to previously known needle devices. Not wishing to be bound by theory, it is believed that upon entering the SCS the drug formulation flows circumferentially from the insertion site toward the retinochoroidal tissue, macula, and optic nerve in the posterior segment of the eye as well as anteriorly toward the uvea and ciliary body.
  • a portion of the infused drug formulation may remain in the SCS as a depot, or remain in tissue overlying the SCS, for example the sclera, near the microneedle insertion site, serving as additional depot of the drug formulation that subsequently can diffuse into the SCS and into other adjacent posterior tissues.
  • the human subject treated with the methods and devices provided herein may be an adult or a child.
  • the patient presents with a retinal thickness of greater than 300 ⁇ (e.g., central subfield thickness as measured by optical coherence tomography).
  • the patient in need of treatment has a BCVA score of > 20 letters read in each eye (e.g. , 20/400 Snellen approximate).
  • the patient in need of treatment has a BCVA score of > 20 letters read in each eye (e.g. , 20/400 Snellen approximate) , but ⁇ 70 letters read in the eye in need of treatment.
  • the patient in one embodiment has macular edema (ME) that involves the fovea.
  • the ME in a method for treating ME associated with uveitis, the ME is due to the uveits and not due to any other cause.
  • the ME in an embodiment for treating ME following RVO, the ME is due to RVO and not due to any other cause of ME.
  • the RVO is branch retinal vein occlusion (BRVO), hemiretinal vein occlusion (HRVO) or central retinal vein occlusion (CRVO).
  • BRVO branch retinal vein occlusion
  • HRVO hemiretinal vein occlusion
  • CRVO central retinal vein occlusion
  • the patient in need of treatment experiences a decrease in visual acuity due to the ME.
  • microneedle devices and non-surgical methods described herein may be used to deliver drug formulations to the eye of a human subject, particularly for the treatment, diagnosis, or prevention of a posterior ocular disorder, such as uveitis (e.g., non-infectious, infectious, intermediate, posterior or pan uveitis), macular edema associated with uveitis, e.g., non-infectious, intermediate, posterior or pan uveitis and macular edema associated with RVO.
  • uveitis e.g., non-infectious, infectious, intermediate, posterior or pan uveitis
  • macular edema associated with uveitis e.g., non-infectious, intermediate, posterior or pan uveitis
  • macular edema associated with RVO macular edema associated with RVO.
  • the drug formulation comprises an effective amount of an antiinflammatory drug.
  • the patient is in need of treatment of macular edema associated with uveitis or macular edema associated with RVO and the drug formulation comprises an anti-inflammatory drug selected from a steroid compound and a non-steroidal anti-inflammatory drug (NSAID).
  • the drug formulation is a triamcinolone formulation, e.g., a triamcinolone acetonide formulation.
  • Posterior ocular disorders amenable for treatment by the methods, devices and drug formulations described herein can include, but are not limited to, uveitis (e.g., infectious uveitis, non-infectious uveitis, chronic uveitis, and/or acute uveitis), macular edema, diabetic macular edema (DME), macular edema associated with uveitis (encompassing macular edema associated with infectious uveitis and macular edema associated with non-infectious uveitis), macular edema following retinal vein occlusion (RVO), macular edema associated with RVO,.
  • the posterior ocular disorder is macular edema associated with uveitis.
  • the uveitis is a non-infectious uveitis.
  • the uveitis can be either acute or chronic uveitis.
  • Uveitis, and macular edema associated with uveitis can be caused by infectious causes leading to infectious uveitis, such as infection with viruses, fungi, parasites, and/or the like.
  • Uveitis can also be caused by noninfectious causes, such as the presence of noninfectious foreign substances in the eye, autoimmune diseases, surgical and/or traumatic injury, and/or the like.
  • disorders caused by pathogenic organisms that can lead to infectious uveitis, and to macular edema associated with infectious uveitis include, but are not limited to, toxoplasmosis, toxocariasis, histoplasmosis, herpes simplex or herpes zoster infection, tuberculosis, syphilis, sarcoidosis, Vogt-Koyanagi-Harada syndrome, Behcet's disease, idiopathic retinal vasculitis, Vogt- Koyanagi-Harada Syndrome, acute posterior multifocal placoid pigment epitheliopathy (APMPPE), presumed ocular histoplasmosis syndrome (POHS), birdshot chroidopathy, Multiple Sclerosis, sympathetic opthalmia, punctate inner choroidopathy, pars planitis, or iridocyclitis.
  • toxoplasmosis toxocariasis
  • histoplasmosis histoplasmos
  • Acute uveitis and/or macular edema associated with acute uveitis occurs suddenly and may last for up to about six weeks.
  • chronic uveitis and/or macular edema associated with chronic uveitis the onset of signs and/or symptoms is gradual, and symptoms last longer than about six weeks.
  • Signs of uveitis include ciliary injection, aqueous flare, the accumulation of cells visible on ophthalmic examination, such as aqueous cells, retrolental cells, and vitreouscells, keratic precipitates, and hypema.
  • Symptoms of uveitis include pain (such as ciliary spasm), redness, photophobia, increased lacrimation, and decreased vision.
  • Posterior uveitis affects the posterior or choroid part of the eye. Inflammation of the choroid part of the eye is also often referred to as choroiditis.
  • Posterior uveitis is may also be associated with inflammation that occurs in the retina (retinitis) or in the blood vessels in the posterior segment of the eye (vasculitis).
  • the methods provided herein comprise non-surgically administering to a uveitis patient suffering from macular edema associated with uveitis (e.g., non-infectious uveitis) in need thereof, an effective amount of an anti-inflammatory drug formulation to the SCS of the eye of the patient.
  • the patient experiences a reduction in the severity of the symptoms of with macular edema associated with uveitis, after administration of the drug formulation.
  • the drug is a steroidal compound.
  • the drug is triamcinolone.
  • the drug formulation includes aflibercept and is used to treat a patient for wet AMD, CNV, wet AMD associated with CNV or wet AMD associated with RVO.
  • the drug formulation includes triamcinolone acetonide and is used in conjunction with aflibercept to treat a patient for wet AMD, CNV, wet AMD associated with CNV or wet AMD associated with RVO; or is used to improve any VEGF therapy in ocular disease.
  • the patient undergoing one of the treatment methods provided herein experiences a reduction in fluid accumulation, inflammation, neuroprotection, complement inhibition, drusen formation, scar formation, and/or a reduction in choriocapillaris or choroidal neocasvularization.
  • the drug upon non-surgical SCS administration, the drug remains localized in the posterior segment of the eye, specifically, the choroid and retina. Limiting drug exposure to other eye tissues, in one embodiment, reduces the incidences of side effects associated with the prior art methods.
  • from about 2 to about 24 dosing sessions are employed, for example, from about 2 to about 24 intraocular dosing sessions (e.g., intravitreal or suprachoroidal injection).
  • from about 3 to about 30, or from about 5 to about 30, or from about 7 to about 30, or from about 9 to about 30, or from about 10 to about 30, or from about 12 to about 30 or from about 12 to about 24 dosing sessions are employed.
  • Treatment regimens will vary based on the therapeutic formulation being delivered and/or the indication being treated.
  • a single dosing session is effective in treating one of the indications described herein.
  • multiple dosing sessions are employed.
  • the dosing sessions are spaced apart by from about 10 days to about 70 days, or from about 10 days to about 60 days, or from about 10 days to about 50 days, or from about 10 days to about 40 days, or from about 10 days to about 30 days, or from about 10 days to about 20 days.
  • the dosing sessions are spaced apart by from about 20 days to about 60 days, or from about 20 days to about 50 days, or from about 20 days to about 40 days, or from about 20 days to about 30 days.
  • the multiple dosing sessions are weekly (about every 7 days), bi-weekly (e.g. , about every 14 days), about every 21 days, monthly (e.g., about every 30 days), or bi-monthly (e.g., about every 60 days).
  • the dosing sessions are monthly dosing sessions (e.g., from about 28 days to about 31 days) and at least three dosing sessions are employed.
  • the non-surgical SCS delivery methods are used to treat a patient in need of treatment of macular edema associated with uveitis (e.g., non-infectious uveitis).
  • SCS administration of a drug e.g., an anti-inflammatory compound such as a steroid or NSAID
  • vitreous haze will is assessed via indirect ophthalmoscopy using a standardized photographic scale ranging from 0 to 4, with 0 - 4 defined below in Table 1 (Nussenblatt 1985 as modified in Lowder 2011, incorporated by reference herein in their entireties). Vitreous haze in another embodiment, is graded from color fundus photographs according to a similar scale.
  • the non-surgical SCS delivery methods provided herein reduce the macular edema experienced by a patient suffering from macular edema associated with RVO.
  • a method for treating a human patient for wet AMD, CNV, wet AMD associated with CNV or wet AMD associated with RVO.
  • the method comprises surgically or non-surgically administering aflibercept to the SCS of one or both of the patient's eyes, wherein upon administration, the drug is substantially retained in the SCS and/or another posterior region of the eye.
  • the drug upon administration, the drug is substantially localized to one or more of the SCS, choroid and/or retina.
  • the efficacy of the method in one embodiment, is measured by measuring the patient's mean change from baseline in macula thickness at one or more time points after the patient is treated.
  • a second drug formulation comprising a VEGF modulator (e.g., a VEGF antagonist) is administered to the eye of the patient via an intravitreal injection.
  • the VEGF modulator is ranibizumab, aflibercept or bevacizumab.
  • a decrease in retina thickness and/or macula thickness is one measurement of treatment efficacy of the methods provided herein.
  • a patient treated by one of the methods provided herein for example with one of the devices described herein experiences a decrease in retinal thickness from baseline (e.g. , retinal thickness such as central subfield thickness (CST) prior to treatment), at any given time point after at least one dosing session (single session or multiple dosing sessions, of at least about 20 ⁇ , or at least about 40 ⁇ , or at least about 50 ⁇ , or at least about 100 ⁇ , or at least about 150 ⁇ or at least about 200 ⁇ , or from about 50-100 ⁇ , and all values in between.
  • the patient experiences a > 5% > 10%, ⁇ 15%, ⁇ 20%, ⁇ 25% decrease in retinal thickness (e.g., CST) subsequent to at least one dosing session.
  • the decrease in retinal thickness is measured about 2 weeks, about 1 month, about 2 months, about 3 months or about 6 months after the at least one dosing session. In another embodiment, the decrease in retinal thickness is measured at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 months or at least about 6 months after the at least one dosing session. In one embodiment, where multiple dosing sessions are employed, a decrease in retinal thickness is sustained by the patient for at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 months or at least about 6 months after each dosing session.
  • a macular edema associated with uveitis (e.g., non-infectious uveitis) patient treated by the methods provided herein experiences a decrease in retinal thickness from baseline (i.e., retinal thickness prior to treatment), at any given time point, of from about 20 ⁇ to about 200 ⁇ , at from about 40 ⁇ to about 200 ⁇ , of from about 50 ⁇ to about 200 ⁇ , of from about 100 ⁇ to about 200 ⁇ , or from about 150 ⁇ to about 200 ⁇ .
  • change in retinal thickness from baseline is measured as a change in CST, for example, by spectral domain optical coherence tomography (SD-OCT).
  • SD-OCT spectral domain optical coherence tomography
  • the therapeutic response is a change from baseline in macula thickness at one or more time points after the patient is treated. For example, at one week, two weeks, three weeks, one month, two months, three months, four months or more, including all durations in between, after a dosing session, e.g., with an anti-inflammatory drug such as triamcinolone delivered non-surgically to the SCS, change from baseline in macula thickness is measured.
  • a decrease in macula thickness is one measurement of therapeutic response (e.g., by about 10%, or about 20%, or about 30%, or about 40%, or about 50%, or about 60% and more, including all values in between).
  • Efficacy in another embodiment, is assessed via a visual acuity measurement at one and/or two months post treatment (e.g., by measuring the mean change in best corrected visual acuity (BCVA) from baseline, i.e., prior to treatment).
  • BCVA best corrected visual acuity
  • a patient treated by one or more of the methods provided herein experiences an improvement in BCVA from baseline, at any given time point (e.g., 2 weeks after administration, 4 weeks after administration, 2 months after at least one dosing session, 3 months after administration), of at least 2 letters, at least 3 letters, at least 5 letters, at least 8 letters, at least 12 letters, at least 13 letters, at least 15 letters, at least 20 letters, and all values in between, as compared to the patient's BVCA prior to the at least one dosing session.
  • any given time point e.g., 2 weeks after administration, 4 weeks after administration, 2 months after at least one dosing session, 3 months after administration
  • the patient for example a macular edema associated with uveitis patient or a macular edema associated with RVO patient gains about 5 letters or more, about 10 letters or more, 15 letters or more, about 20 letters or more, about 25 letters or more in a BCVA measurement after a dosing regimen is complete, for example a monthly dosing regimen, compared to the patient's BCVA measurement prior to undergoing treatment.
  • the patient gains from about 5 to about 30 letters, 10 to about 30 letters, from about 15 letters to about 25 letters or from about 15 letters to about 20 letters in a BCVA measurement upon completion of at least one dosing session, compared to the patient's BCVA measurement prior to the at least one dosing session.
  • the BCVA gain is about 2 weeks, about 1 month, about 2 months, about 3 months or about 6 months after the at least one dosing session.
  • the BCVA is measured at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 months or at least about 6 months after the at least one dosing session.
  • the BCVA is based on the Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity charts and is assessed at a starting distance of 4 meters.
  • EDRS Early Treatment of Diabetic Retinopathy Study
  • the patient subjected to a treatment method substantially maintains his or her vision subsequent to the treatment (e.g., a single dosing session or multiple dosing sessions), as measured by losing fewer than 15 letters in a best-corrected visual acuity (BCVA) measurement, compared to the patient's BCVA measurement prior to undergoing treatment.
  • BCVA visual acuity
  • the patient loses fewer than 10 letters, fewer than 8 letters, fewer than 6 letters or fewer than 5 letters in a BCVA measurement, compared to the patient's BCVA measurement prior to undergoing treatment.
  • Decrease in vitreous haze can also be used as a measure of the method's efficacy. Decreases in vitreous haze can be qualitatively and/or quantitatively determined by techniques such as, but not limited to, photographic grading, a scoring system, a multi-point scale, a multi-step scale (e.g. a multi-step logarithmic scale, manual screening by one or more examiners, and/or the like).
  • the decrease in vitreous haze is present about 2 weeks, about 1 month, about 2 months, about 3 months or about 6 months after the at least one dosing session.
  • the decrease in retinal thickness is present at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 months or at least about 6 months after the at least one dosing session.
  • a decrease in vitreous haze is experienced by the patient and is present at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 months or at least about 6 months after each dosing session.
  • the methods provided herein provide for effective treatment of a patient who had previously undergone treatment for wet AMD, CNV, wet AMD associated with CNV or wet AMD associated with RVO but was unresponsive, or not properly responsive to the prior treatment for the respective posterior ocular disorder.
  • a patient unresponsive or not properly responsive to treatment does not exhibit an improvement in a symptom or improvement in a clinical manifestation of macular edema associated with the disorder.
  • the symptom or clinical manifestation is lesion size, inflammation, edema, visual acuity and/or vitreous haze.
  • the intraocular pressure (IOP) of the patient's eye undergoing treatment for macular edema associated with uveitis e.g., noninfectious uveitis
  • macular edema associated with RVO 2 minutes, 10 minutes, 15 minutes, 30 minutes or 1 hour after suprachoroidal drug administration according to the devices (e.g., the device 100) and/or the methods disclosed herein, is substantially the same IOP, compared to the IOP of the patient's eye prior to administration of the drug for treating macular edema associated with uveitis.
  • the IOP of the patient's eye undergoing treatment for macular edema associated with uveitis e.g., non-infectious uveitis
  • macular edema associated with RVO or wet AMD e.g., choroidal neovascularization (CNV), wet AMD associated with CNV, 2 minutes, 10 minutes, 15 minutes, 30 minutes or 1 hour after suprachoroidal drug administration
  • choroidal neovascularization CNV
  • wet AMD associated with CNV
  • 2 minutes, 10 minutes, 15 minutes, 30 minutes or 1 hour after suprachoroidal drug administration varies by no more than 10%, compared to the IOP of the patient's eye prior to administration of the drug for treating macular edema associated with uveitis (e.g., non-infectious uveitis), macular edema associated with RVO or wet AMD.
  • the IOP of the patient's eye undergoing treatment for the macular edema associated with uveitis e.g., non-infectious uveitis
  • macular edema associated with RVO or wet AMD 2 minutes, 10 minutes, 15 minutes or 30 minutes after suprachoroidal drug administration
  • the IOP of the patient's eye undergoing treatment for macular edema associated with uveitis e.g., noninfectious uveitis
  • macular edema associated with RVO or wet AMD e.g., choroidal neovascularization (CNV), wet AMD associated with CNV
  • wet AMD associated with RVO 2 minutes, 10 minutes, 15 minutes or 30 minutes after suprachoroidal drug administration
  • varies by no more than 10%-30% compared to the IOP of the patient's eye prior to administration of the drug for treating macular edema associated with uveitis (e.g., noninfectious uveitis), macular edema associated with RVO, wet AMD, choroidal neovascularization (CNV), or wet AMD associated with CNV.
  • macular edema associated with uveitis e.g., noninfectious uveitis
  • macular edema associated with RVO e.g.,
  • the effective amount of the drug for treating macular edema associated with uveitis comprises an effective amount of an anti-inflammatory drug (e.g., triamcinolone).
  • the drug formulation includes aflibercept.
  • the methods described herein relate to the administration of a drug formulation for the treatment of uveitis (infectious or non-infectious), macular edema, macular edema associated with non-infectious uveitis, macular edema associated with infectious uveitis, macular edema associated with RVO, wherein the majority of the drug formulation is retained in the SCS and/or other posterior ocular tissue, in one or both eyes of a patient in need of treatment of the posterior ocular disorder, for a period of time after the treatment method is completed.
  • drug formulation retention in the SCS contributes to the sustained release profile of the drug formulations described herein.
  • a VEGF modulator intravitreally in addition to non-surgical or surgical administration of an anti-inflammatory compound (e.g., a steroid such as triamcinolone).
  • an anti-inflammatory compound e.g., a steroid such as triamcinolone
  • the method of treating uveitis comprises, in one embodiment, surgically or non-surgically administering a drug formulation to the suprachoroidal space of the affected eye of the human subject, wherein upon administration, the drug formulation flows away from the insertion site and is substantially localized to the posterior segment of the eye, for example to the posterior ocular tissue such as the retina and/or choroid.
  • the methods provided herein allow for longer retention of the drug in the eye, e.g., the posterior segment of the eye, as compared to intravitreal, topical, parenteral, intracameral or oral administration of the same drug dose.
  • the suprachoroidal drug dose sufficient to achieve a therapeutic response in a human subject treated with the non-surgical SCS drug delivery method is less than the intravitreal, parenteral, intracameral, topical, or oral drug dose sufficient to elicit the identical or substantially identical therapeutic response.
  • the suprachoroidal drug dose is at least 10 percent less than the oral, parenteral or intravitreal dose sufficient to achieve the identical or substantially identical therapeutic response.
  • the suprachoroidal dose is about 10 percent to about 25 percent less, or about 10 percent to about 50 percent less than the oral, parenteral, intracameral, topical, or intravitreal dose sufficient to achieve the identical or substantially identical therapeutic response.
  • the non-surgical SCS administration method of treating macular edema associated with uveitis, macular edema associated with RVO achieves a greater therapeutic efficacy than other routes of administration.
  • the non-surgical method provided herein comprises inserting a hollow microneedle into the sclera of the eye of the human subject and infusing a drug formulation through the hollow microneedle and into the suprachoroidal space of the eye.
  • the drug formulation in one embodiment, is a solution or suspension of the drug.
  • the drug formulation includes aflibercept.
  • the amount of therapeutic formulation delivered into the suprachoroidal space from the devices described herein is from about 10 to about 200 ⁇ , e.g., from about 50 to about 150 ⁇ . In another embodiment, from about 10 ⁇ to about 500 ⁇ , e.g., from about 50 ⁇ to about 250 ⁇ , is non-surgically administered to the suprachoroidal space.
  • the amount of drug delivered within the SCS also may be controlled, in part, by the type of microneedle used and how it is used.
  • a hollow microneedle is inserted into the ocular tissue and progressively retracted from the ocular tissue after insertion to deliver a fluid drug, where after achieving a certain dosage, the delivery could be stopped by deactivating the fluid driving force, such as pressure (e.g., from a mechanical device such as a syringe) or an electric field, to avoid leakage/uncontrolled deliver of drug.
  • the amount of drug being delivered is controlled by driving the fluid drug formulation at a suitable infusion pressure.
  • the infusion pressure may be at least 150 kPa, at least 250 kPa, or at least 300 kPa. In another embodiment, the infusion pressure is about 150 kPa to about 300 kPa. Suitable infusion pressures may vary with the particular patient or species. In another embodiment, the methods provided herein are carried out with one of the devices described above (e.g, the injector 100) or in PCT/US2014/36590, filed May 2, 2014 and entitled "Apparatus and Method for Ocular Injection,” incorporated by reference herein in its entirety for all purposes.
  • the desired infusion pressure to deliver a suitable amount of drug formulation might be influenced by the depth of insertion of the microneedle and the composition of the drug formulation.
  • a greater infusion pressure may be required in embodiments wherein the drug formulation for delivery into the eye is in the form of or includes nanoparticles or microparticles encapsulating the active agent or microbubbles. Nanoparticle or microparticle encapsulation techniques are well known in the art.
  • the drug formulation is comprised of drug particles in suspension with a D 99 of 10 ⁇ or less. In one embodiment, the drug formulation is comprised of drug particles in suspension with a D 99 of 7 ⁇ or less.
  • the drug formulation is comprised of drug particles in suspension with a D 99 of 3 ⁇ or less. In another embodiment, the drug formulation is comprised of drug particles in suspension with a D 50 of 5 ⁇ or less. In one embodiment, the drug formulation is comprised of drug particles in suspension with a D 50 1 ⁇ or less. In some embodiments, the drug formulation includes aflibercept.
  • the non-surgical method of administering a drug to the SCS further includes partially retracting the hollow microneedle after insertion of the microneedle into the eye, and before and/or during the infusion of the drug formulation into the suprachoroidal space.
  • the partial retraction of the microneedle occurs prior to the step of infusing the drug formulation into the ocular tissue. This insertion/retraction step may form a pocket and beneficially permits the drug formulation to flow out of the microneedle unimpeded or less impeded by ocular tissue at the opening at the tip portion of the microneedle.
  • This pocket may be filled with drug formulation, but also serves as a conduit through with drug formulation can flow from the microneedle, through the pocket and into the suprachoroidal space.
  • the drug formulation includes aflibercept and is used to treat a human patient for wet AMD, CNV, wet AMD associated with CNV or wet AMD associated with RVO via suprachoroidal administration.
  • the drug formulation includes triamcinolone acetonide and is administered via suprachoroidal administration, and is used in conjunction with aflibercept to treat a human patient for wet AMD, CNV, wet AMD associated with CNV or wet AMD associated with RVO.
  • the methods provided herein allow for greater drug retention in the eye compared to other drug delivery methods, for example, a greater amount of drug is retained in the eye when delivered via the methods provided herein as compared to the same dose delivered via intracameral, sub-tenon, intravitreal, topical, parenteral or oral drug delivery methods.
  • the intraocular elimination half life (tm) of the drug when delivered via the methods described herein is greater than the intraocular tm of the drug when the same drug dose is administered intravitreally, intracamerally, topically, parenterally or orally.
  • the intraocular Cmax of the drug when delivered via the methods described herein, is greater than the intraocular Cmax of the drug when the same drug dose is administered intravitreally, intracamerally, sub-tenonally, topically, parenterally or orally.
  • the mean intraocular area under the curve (AUCO-t) of the drug when administered to the SCS via the methods described herein, is greater than the intraocular AUCO-t of the drug, when administered intravitreally, intracamerally, sub-tenonally, topically, parenterally or orally.
  • the intraocular time to peak concentration (tmax) of the drug when administered to the SCS via the methods described herein, is greater than the intraocular tmax of the drug, when the same drug dose is administered intravitreally, intracamerally, topically, parenterally or orally.
  • the drug is aflibercept.
  • the intraocular tm of the drug when administered via the nonsurgical SCS drug delivery methods provided herein is longer than the intraocular t of the drug when the identical dose is administered topically, intracamerally, intravitreally, orally or parenterally.
  • the intraocular t of the drug when administered via the non-surgical SCS drug delivery methods provided herein is from about 1.1 times to about 10 times longer, or from about 1.25 times to about 10 times longer, or from about 1.5 times to about 10 times longer, or about 2 times to about 5 times longer, than the intraocular tl/2 of the drug when the identical dosage is administered topically, intracamerally, sub-tenonally, intravitreally, orally or parenterally.
  • the drug is aflibercept.
  • the intraocular Cmax of the drug when delivered via the methods described herein, is greater than the intraocular Cmax of the drug when the same drug dose is administered intravitreally, intracamerally, topically, parenterally or orally.
  • the intraocular Cmax of the drug when administered via the non-surgical SCS drug delivery methods provided herein is at least 1.1 times greater, or at least 1.25 times greater, or at least 1.5 times greater, or at least 2 times greater, or at least 5 times greater, than the intraocular Cmax of the drug when the identical dose is administered topically, intracamerally, intravitreally, orally or parenterally.
  • the intraocular Cmax of the drug when administered via the non-surgical SCS drug delivery methods provided herein is about 1 to about 2 times greater, or about 1.25 to about 2 times greater, or about 1 to about 5 times greater, or about 1 to about 10 times greater, or about 2 to about 5 times greater, or about 2 to about 10 times greater, than the intraocular Cmax of the drug when the identical dose is administered topically, intracamerally, sub-tenonally, intravitreally, orally or parenterally.
  • the drug is aflibercept.
  • the mean intraocular area under the curve (AUCo-t) of the drug when administered to the SCS via the methods described herein, is greater than the intraocular AUCo-t of the drug, when administered intravitreally, intracamerally, sub- tenonally, topically, parenterally or orally.
  • the intraocular AUCo-t of the drug when administered via the non-surgical SCS drug delivery methods provided herein is at least 1.1 times greater, or at least 1.25 times greater, or at least 1.5 times greater, or at least 2 times greater, or at least 5 times greater, than the intraocular AUCO-t of the drug when the identical dose is administered topically, intracamerally, sub-tenonally, intravitreally, orally or parenterally.
  • the intraocular AUCo-t of the drug when administered via the non-surgical SCS drug delivery methods provided herein is about 1 to about 2 times greater, or about 1.25 to about 2 times greater, or about 1 to about 5 times greater, or about 1 to about 10 times greater, or about 2 to about 5 times greater, or about 2 to about 10 times greater, than the intraocular AUCO-t of the drug when the identical dose is administered topically, intracamerally, sub-tenonally, intravitreally, orally or parenterally.
  • the drug is aflibercept.
  • the drug formulation comprising the effective amount of the drug (e.g., an anti-inflammatory drug (e.g., a steroid such as triamcinolone or NSAID), once delivered to the SCS, is substantially retained in the SCS over a period of time.
  • an anti-inflammatory drug e.g., a steroid such as triamcinolone or NSAID
  • the drug is aflibercept.
  • the suprachoroidal drug delivery methods provided herein result in an increased therapeutic efficacy and/or improved therapeutic response, as compared to oral, parenteral, sub-tenon, and/or intravitreal drug delivery methods of the identical or similar drug dose.
  • the SCS drug dose sufficient to provide a therapeutic response is about 90%, or about 75%, or about one-half (e.g., about one half or less) the intravitreal, intracameral, topical, oral or parenteral drug dose sufficient to provide the same or substantially the same therapeutic response.
  • the SCS dose sufficient to provide a therapeutic response is about one-fourth the intravitreal, intracameral, sub-tenon, topical, oral or parenteral drug dose sufficient to provide the same or substantially the same therapeutic response.
  • the SCS dose sufficient to provide a therapeutic response is one-tenth the intravitreal, intracameral, sub-tenon, topical, oral or parenteral drug dose sufficient to provide the same or substantially the same therapeutic response.
  • the therapeutic response is a decrease in inflammation, as measured by methods known to those of skill in the art.
  • the therapeutic response is a decrease in number of ocular lesions, or decrease in ocular lesion size.
  • the therapeutic response is a decrease in fluid accumulation and/or intraocular pressure.
  • Therapeutic response is measured at a time point post-treatment, for example 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 1 1 weeks or 12 weeks post -treatment, and all values in between.
  • the therapeutic efficacy of the drug formulations delivered by the methods described herein and therapeutic response of the human subject can be assayed by standard means in the art, as known to those of skill in the art.
  • the therapeutic efficacy of any particular drug can be assessed by measuring the response of the human subj ect after administration of the drug; a drug with a high therapeutic efficacy will show a greater amelioration and/or discontinuation of symptoms than a drug with a lower therapeutic efficacy.
  • the efficacy of the drug formulations provided herein can be measured, for example, by observing changes in pain intensity, changes in ocular lesions (size or number), intraocular pressure, fluid accumulation, inflammation (e.g., by measuring changes in the hackett/McDonald ocular score), ocular hypertension, and/or visual acuity.
  • the efficacy of the therapeutic formulation is measured by observing changes in the measurements according to the Hackett/McDonald ocular scores, inflammation, visual acuity, and/or edema. In another embodiment, the efficacy of the therapeutic formulation is measured, for example, by observing changes in the measurements according to the Hackett/McDonald ocular scores, inflammation, visual acuity, and/or edema.
  • the non-surgical administration of an effective amount of a drug formulation to the SCS results to treat uveitis (e.g., non-infectious uveitis), macular edema associated with uveitis, macular edema associated with RVO, wet AMD, CNV, wet AMD associated with RVO, or wet AMD associated with CNV results in a decreased number of deleterious side effects or clinical manifestations in the treated patient as compared to the number of side effects or clinical manifestations caused by the same drug dose administered intravitreally, intracamerally, orally or parenterally.
  • uveitis e.g., non-infectious uveitis
  • macular edema associated with uveitis e.g., macular edema associated with RVO
  • wet AMD e.g., wet AMD
  • wet AMD associated with RVO e.g., wet AMD associated with RVO
  • wet AMD associated with CNV results in a decreased number of
  • the non-surgical administration of an effective amount of a drug formulation to the SCS results in a decreased number of one or more deleterious side effects or clinical manifestations, as compared to the deleterious side effects or clinical manifestations caused by the same drug dose administered intravitreally, intracamerally, sub-tenonally, orally or parenterally.
  • side effects and clinical manifestations that can be reduced or ameliorated include, but are not limited to, inflammation, gastrointestinal side effects (e.g., diarrhea, nausea, gastroenteritis, vomiting, gastrointestinal, rectal, and duodenal hemorrhage, hemorrhagic pancreatitis, large intestine perforation black or bloody stools, and/or coughing up blood); hematologic side effects (e.g., leucopenia, anemia, pancytopenia and agranulocytosis, thrombocytopenia, neutropenia, pure red cell aplasia (PRCA), deep venous thrombosis easy bruising, and /or unusual bleeding from the nose, mouth, vagina, or rectum); immunologic side effects/clinical manifestations (e.g., immunosuppression, immunosuppression resulting in sepsis, opportunistic infections (herpes simplex virus ,herpes zoster, and invasive candidal infections
  • dysuria urgency, urinary tract infections, hematuria, kidney tubular necrosis, and/or BK virus-associated nephropathy
  • metabolic side effects/clinical manifestations e.g. edema, hyperphosphatemia, hypokalemia, hyperglycemia, hyperkalemia, swelling, rapid weight gain, and/or enlarged thyroid
  • respiratory side effects/clinical manifestations e.g., respiratory infection, dyspnea, increased cough, primary tuberculosis dry cough, wheezing, and/or stuffy nose
  • dermatologic side effects/clinical manifestations e.g., acne, rash, dyshidrotic eczema, papulosquamous psoriatic-like skin eruption rash, blisters, oozing, mouth sores, and/or hair loss
  • muscoskeletal side effects/clinical manifestations e.g.
  • myopathy and/or muscle pain myopathy and/or muscle pain
  • hepatic side effects/clinical manifestations e.g. hepatoxicity and/or jaundice
  • abdominal pain increased incidence of first trimester pregnancy loss, missed menstrual periods, severe headache, confusion, change in mental status, vision loss, seizure (convulsions), increased sensitivity to light, dry eye, red eye, itchy eye, and/or high blood pressure.
  • the reduction or amelioration of the side effect or clinical manifestation is a reduction or amelioration, as compared to the severity of the side effect or clinical manifestation prior to administration of the drug formulation to the SCS of the eye of the patient, or a reduction or amelioration of the side effect or clinical manifestation in the patient, as compared to the reduction or amelioration experienced upon intravitreal, intracameral, parenteral or oral administration of the same drug.
  • a wide range of therapeutic formulations for example those that include one or more drugs and/or cellular therapies may be formulated for delivery to the suprachoroidal space and posterior ocular tissues with the present microneedle devices and methods.
  • drug refers to any prophylactic, therapeutic, or diagnostic agent, i.e., an ingredient useful for medical applications.
  • the drug may be selected from cellular therapeutics, small molecules, biologies such as proteins, peptides and fragments thereof, nucleic acids including vectors encoding nucleic acid gene therapeutics, which can be naturally occurring, synthesized or recombinantly produced.
  • the drug delivered to the suprachoroidal space with the non-surgical methods described herein is an antibody or a fragment thereof (e.g., a Fab, Fv or Fc fragment).
  • the drug is a sub-immunoglobulin antigen-binding molecule, such as Fv immunoglobulin fragment, minibody, diabody, and the like, as described in U.S. Patent No. 6,773,916, incorporated herein by reference in its entirety for all purposes.
  • the drug is a humanized antibody or a fragment thereof.
  • the non-surgical treatment methods and devices described herein may be used in gene-based therapy applications.
  • the method comprises administering a drug formulation into the suprachoroidal space to deliver select DNA, RNA, or oligonucleotides to targeted ocular tissues.
  • the drug is selected from a suitable oligonucleotide (e.g., antisense oligonucleotide agents), polynucleotide (e.g., therapeutic DNA), ribozyme, dsRNA, siRNA, RNAi, gene therapy vectors, and/or vaccine.
  • the drug is an aptamer (e.g., an oligonucleotide or peptide molecule that binds to a specific target molecule).
  • a nucleic acid therapeutic is delivered by one of the devices and/or methods provided herein.
  • the nucleic acid therapeutic is delivered via a viral particle (viral vector).
  • the virus particle in one embodiment, is an adenovirus, (Ad), adenoassociated virus (AAV), or lentivirus.
  • the viral vector is a self-complementary AAV (scAAV) or helper-dependent adenovirus (HD- Ad).
  • a plasmid vector expressing siRNA or other nucleic acid therapeutic is delivered via one of the devices and/or methods described herein.
  • a nucleic acid therapeutic is delivered via a (1) polymeric, (2) lipid (e.g., liposomal), (3) protein or (4) dendrimeric nanocarrier delivery system.
  • the drug formulation delivered via the methods provided herein comprises a small molecule drug, an endogenous protein or fragment thereof, or an endogenous peptide or fragment thereof.
  • uveitis e.g., non-infectious uveitis
  • macular edema associated with uveitis e.g., non-infectious uveitis
  • macular edema associated with RVO wet AMD
  • CNV wet AMD associated with RVO
  • wet AMD associated with RVO or wet AMD associated with CNV
  • anti-inflammatory drugs including, but not limited to steroids (e.g., triamcinolone), immunosuppressives, antimetabolites, T-cell inhibitors, alkylating agents, biologies, TNF antagonists (e.g., TNF-a antagonists), vascular endothelial growth factor (VEGF) modulators (e.g., VEGF antagonists), and/or non-steroidal anti-inflammatory drugs (NSAIDs).
  • steroids e.g., triamcinolone
  • immunosuppressives e.g., antimetabolites, T-cell inhibitors, alkylating agents, biologies
  • Non-limiting examples of specific drugs and classes of drugs that can be delivered to the suprachoroidal space to treat macular edema associated with uveitis include miotics (e.g., pilocarpine, carbachol, physostigmine), sympathomimetics (e.g., adrenaline, dipivefrine), carbonic anhydrase inhibitors (e.g., acetazolamide, dorzolamide), VEGF antagonists, platelet derived growth factor (PDGF) modulators (e.g., PDGF antagonists), NSAIDs, steroids, prostaglandins, anti-microbial compounds, including anti-bacterials and anti-fungals (e.g., chloramphenicol, chlortetracycline, ciprofloxacin, framycetin, fusidic acid, gentamicin, neomycin, norfloxacin, ofloxacin, polymyxin, propamidine, tetracycline, tobramycin, quinolines),
  • an angiogenesis inhibitor is administered to the SCS of a patient in need thereof.
  • the angiogenesis inhibitor delivered via the methods and devices described herein is interferon gamma 1 ⁇ , interferon gamma 1 ⁇ (Actimmune®) with pirfenidone, ACUHTR028, ⁇ 5, aminobenzoate potassium, amyloid P, ANG1122, ANG1170, ANG3062, ANG3281, ANG3298, ANG4011, anti-CTGF RNAi, Aplidin, astragalus membranaceus extract with salvia and schisandra chinensis, atherosclerotic plaque blocker, Azol, AZX100, BB3, connective tissue growth factor antibody, CT140, danazol, Esbriet, EXCOOl, EXC002, EXC003, EXC004, EXC005, F647, FG3019, Fibrocorin, Follistatin, FT
  • the drug delivered to the suprachoroidal space is sirolimus (Rapamycin®, Rapamune®).
  • the non-surgical drug delivery methods disclosed herein are used in conjunction with rapamycin to treat, prevent and/or ameliorate macular edema associated with uveitis or macular edema associated with RVO.
  • delivery of rapamycin using the microneedle devices and methods disclosed herein may be combined with one or more agents listed herein or with other agents known in the art.
  • the macular edema associated with uveitis is macular edema associated with non-infectious uveitis.
  • the drug delivered to the suprachoroidal space using the nonsurgical methods e.g., microneedle devices and methods
  • surgical methods e.g., via a shunt, stent, or cannula
  • macular edema associated with uveitis or macular edema associated with RVO is triamcinolone (e.g., triamcinolone acetonide).
  • the non-surgical and surgical drug delivery methods disclosed herein are used in conjunction with triamcinolone to treat, prevent and/or ameliorate macular edema associated with uveitis (e.g., non-infectious uveitis or infectious uveitis).
  • the macular edema associated with uveitis is macular edema associated with non-infectious uveitis.
  • the drug formulation includes aflibercept.
  • a VEGF modulator is delivered via one of the devices described herein.
  • the VEGF modulator is a VEGF antagonist.
  • the VEGF modulator is a VEGF-receptor kinase antagonist, an anti-VEGF antibody or fragment thereof, an anti-VEGF receptor antibody, an anti-VEGF aptamer, a small molecule VEGF antagonist, a thiazolidinedione, a quinoline or a designed ankyrin repeat protein (DARPin).
  • DARPin ankyrin repeat protein
  • an anti-inflammatory drug is delivered to the SCS of the eye of a patient in need thereof, in combination with intravitreal delivery of a VEGF modulator (e.g., VEGF antagonist) to the same eye.
  • a VEGF modulator e.g., VEGF antagonist
  • the VEGF antagonist is an antagonist of a VEGF receptor (VEGFR), i.e., a drug that inhibits, reduces, or modulates the signaling and/or activity of a VEGFR.
  • the VEGFR may be a membrane-bound or soluble VEGFR.
  • the VEGFR is VEGFR- 1, VEGFR-2 or VEGFR-3.
  • the VEGF antagonist targets the VEGF-C protein.
  • the VEGF modulator is an antagonist of a tyrosine kinase or a tyrosine kinase receptor.
  • the VEGF modulator is a modulator of the VEGF-A protein.
  • the VEGF antagonist is a monoclonal antibody.
  • the monoclonal antibody is a humanized monoclonal antibody.
  • the drug formulation includes aflibercept.
  • the VEGF modulator is one or more of the following: AL8326, 2C3 antibody, AT001 antibody, HyBEV, bevacizumab (Avastin®), ANG3070, APX003 antibody, APX004 antibody, ponatinib (AP24534), BDM-E, VGX100 antibody (VGX100 ORCADIAN), VGX200 (c-fos induced growth factor monoclonal antibody), VGX300, COSMIX, DLX903/1008 antibody, ENMD2076, sunitinib malate (Sutent®), INDUS815C, R84 antibody, KD019, NM3, allogenic mesenchymal precursor cells combined with an anti-VEGF antagonist (e.g., anti-VEGF antibody), MGCD265, MG516, VEGF- Receptor kinase inhibitor, MP0260, NT503, anti-DLL4/VEGF bispecific antibody, PAN90806, Pal
  • an immunosuppressive agent is delivered via one of the devices described herein.
  • the immunosuppressive agent is a glucocorticoid, cytokine inhibitor, cytostatic, alkylating agent, anti-metabolite, folic acid analogue, cytotoxic antibiotic, interferon, opioid, T-cell receptor directed antibody or an IL-2 receptor directed antibody.
  • the immunosuppressive agent is an antimetabolite and the anti-metabolite is a purine analog, pyrimidine analogue, folic acid analogue or a protein synthesis inhibitor.
  • the immunosuppressive agent is an interleukin-2 inhibitor (e.g., basiliximab or daclizumab).
  • interleukin-2 inhibitor e.g., basiliximab or daclizumab.
  • Other immunosuppressive agents amenable for use with the methods and formulations described herein include, but are not limited to cyclophosphamide, nitrosourea, methotrexate, azathioprine, mercaptopurine, fluorouracil, dactinomycin, anthracycline, mitomycin C, bleomycin, mithramycin, muromonab-CD3, cyclosporine, tacrolimus, sirolimus or mycophenolate.
  • the drug formulation comprises an effective amount mycophenolate.
  • the drug formulation delivered to the SCS of an eye of a patient in need thereof via the methods described herein comprises an effective amount of vascular permeability inhibitor.
  • the vascular permeability inhibitor is a vascular endothelial growth factor (VEGF) antagonist or an angiotensin converting enzyme (ACE) inhibitor.
  • the vascular permeability inhibitor is an angiotensin converting enzyme (ACE) inhibitor and the ACE inhibitor is captopril.
  • the drug is a steroid or a non-steroid anti-inflammatory drug (NSAID).
  • the anti-inflammatory drug is an antibody or fragment thereof, an anti-inflammatory peptide(s) or an anti-inflammatory aptamer(s).
  • the delivery of the anti-inflammatory drug to the suprachoroidal space results in benefits over administration of the same drug delivered via oral, intravitreal, intracameral, topical and/or a parenteral route of administration.
  • the therapeutic effect of the drug delivered to the suprachoroidal space is greater than the therapeutic effect of the same drug, delivered at the same dosage, when the drug is delivered via oral, intravitreal, topical or parenteral route.
  • the intraocular elimination half life (tl/2) of the anti-inflammatory drug administered to the SCS is greater than the intraocular tl/2 of the anti-inflammatory drug, when the identical dosage of the anti-inflammatory drug is administered intravitreally, intracamerally, topically, parenterally or orally.
  • the mean intraocular maximum concentration (Cmax) of the anti-inflammatory drug, when administered to the SCS via the methods described herein is greater than the intraocular Cmax of the anti-inflammatory drug, when administered intravitreally, intracamerally, topically, parenterally or orally.
  • the mean intraocular area under the curve (AUCO-t) of the anti-inflammatory drug when administered to the SCS via the methods described herein, is greater than the intraocular AUCO-t of the anti-inflammatory drug, when the identical dosage of the antiinflammatory drug is administered intravitreally, intracamerally, topically, parenterally or orally.
  • Steroidal compounds that can be administered via the methods provided herein include hydrocortisone, hydrocortisone-17-butyrate, hydrocortisone- 17-aceponate, hydrocortisone-17-buteprate, cortisone, tixocortol pivalate, prednisolone, methylprednisolone, prednisone, triamcinolone, triamcinolone acetonide, mometasone, amcinonide, budesonide, desonide, fluocinonide, halcinonide, bethamethasone, bethamethasone dipropionate, dexamethasone, fluocortolone, hydrocortisone-17-valerate, halometasone, alclometasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortol
  • NSAIDs that can be administered via the methods provided herein include salicylates, propionic acid derivatives, acetic acid derivatives, enolic acid derivatives, fenamic acid derivatives and cyclooxygenase-2 (COX-2) inhibitors.
  • the methods provided herein are used to deliver one or more of the following NSAIDs to the SCS of an eye of a patient in need thereof: acetylsalicylic acid, diflunisal, salsalate, ibuprofen, dexibuprofen, naproxen, fenoprofen, keotoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxaprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac or nabumetone, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam or isoxicam, mefanamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib, refecoxib, valdecoxib, parecoxib, lumiracoxib, e
  • anti-inflammatory drugs that can be used in the methods provided herein for treating macular edema associated with uveitis (infectious or noninfectious uveitis) include, but are not limited to: mycophenolate, remicase, nepafenac, 19AV agonist(s), 19GJ agonists, 2MD analogs, 4SC101, 4SC102, 57-57, 5-HT2 receptor antagonist, 64G12, A804598, A967079, AAD2004, AB1010, AB224050, abatacept, etaracizumab (AbegrinTM), Abevac®, AbGnl34, AbGnl68, Abki, ABN912, ABR215062, ABR224050, cyclosporine (Abrammune®), docosanol (behenyl alcohol, Abreva®), ABS15, ABS4, ABS6, ABT122, ABT325, ABT494, ABT874, A
  • the drug is a drug that inhibits, reduces or modulates the signaling and/or activity of PDGF-receptors (PDGFR).
  • the PDGF antagonist delivered to the suprachoroidal space for the treatment of one or more posterior ocular disorders such as macular edema associated with uveitis (e.g., non-infectious uveitis), macular edema associated with RVO or wet AMD, in one embodiment, is an anti-PDGF aptamer, an anti-PDGF antibody or fragment thereof, an anti-PDGFR antibody or fragment thereof, or a small molecule antagonist.
  • the PDGF antagonist is an antagonist of the PDGFRa or PDGFR .
  • the PDGF antagonist is the anti-PDGF- ⁇ aptamer El 0030, dasatinib, sunitinib, axitinib, sorefenib, imatinib, imatinib mesylate, nintedanib, pazopanib HC1, ponatinib , MK-2461, pazopanib, crenolanib, PP-121, telatinib, imatinib, KRN 633, CP 673451, TSU-68 (orantinib), ⁇ 8751, amuvatinib, tivozanib, masitinib, motesanib diphosphate, dovitinib, dovitinib dilactic acid, FOVISTA, or linifanib (ABT-869).
  • the PDGF antagonist for example, one of the PDGF antagonists described above, can be used in the methods for treating macular edema associated with uveitis, macular edema associated with RVO, wet AMD, CNV, wet AMD associated with RVO, or wet AMD associated with CNV via SCS administration.
  • the PDGF antagonist is administered intravitreally in conjunction with SCS administration aflibercept, in a method of treating one of the aforementioned indications.
  • the PDGF antagonist also has VEGF antagonist activity.
  • VEGF antagonist activity for example, an anti-VEGF/PDGF-B darpin, dasatinib, dovitinib, Ki8751, telatinib, TSU-68 (orantinib) or motesanib diphosphate are known inhibitors of both VEGF and PDGF, and can be used in the methods described herein.
  • the dual PDGF/VEGF antagonist can also be administered intravitreally in conjunction with non-surgical delivery of aflibercept to the SCS.
  • Examples of other suitable drugs for use with the devices and methods described herein include, but are not limited to: A0003, A36 peptide, AAV2-sFLT01, ACE041, ACU02, ACU3223, ACU4429, AdPEDF, aflibercept, AG13958, aganirsen, AGN150998, AGN745, AL39324, AL78898A, AL8309B, ALN-VEG01, alprostadil, AMI 101, amyloid beta antibody, anecortave acetate, Anti-VEGFR-2 Alterase, Aptocine, APX003, ARC 1905, ARC 1905 with Lucentis, ATG3, ATP -binding cassette, sub-family A, member 4 gene, ATXS10, Avastin with Visudyne, AVT101, AVT2, bertilimumab, bevacizumab with verteporfin, bevasiranib sodium, bevasiranib sodium, bevas
  • the drug is interferon gamma lb (Actimmune®) with pirfenidone, ACUHTR028, AlphaVBeta5, aminobenzoate potassium, amyloid P, ANG1122, ANG1170, ANG3062, ANG3281, ANG3298, ANG4011, Anti-CTGF RNAi, Aplidin, astragalus membranaceus extract with salvia and schisandra chinensis, atherosclerotic plaque blocker, Azol, AZX100, BB3, connective tissue growth factor antibody, CT140, danazol, Esbriet, EXCOOl, EXC002, EXC003, EXC004, EXC005, F647, FG3019, Fibrocorin, Foil-statin, FT011, Galectin-3 inhibitors
  • a drug that treats, prevents and/or ameliorates diabetic macular edema is used in conjunction with the devices and methods described herein and is delivered to the suprachoroidal space of the eye.
  • the drug is AKB9778, bevasiranib sodium, Cand5, choline fenofibrate, Cortiject, c-raf 2-methoxy ethyl phosphorothioate oligonucleotide, DEI 09, dexamethasone, DNA damage inducible transcript 4 oligonucleotide, FOV2304, iCo007, KH902, MP0112, NCX434, Optina, Ozurdex, PF4523655, SARI 118, sirolimus, SK0503 or TriLipix.
  • one or more of the diabetic macular edema treating drugs described above is combined with one or more agents listed above or herein or with other agents known in the art.
  • the methods and devices provided herein are used to deliver triamcinolone or triamcinolone acetonide to the suprachoroidal space of an eye of a human subject in need of treatment for treating uveitis (e.g., non-infectious uveitis), macular edema associated with uveitis, wet AMD, CNV, wet AMD associated with RVO, or wet AMD associated with CNV.
  • triamcinolone or triamcinolone acetonide is delivered via one of the methods described herein.
  • the therapeutic formulation comprises a suspension of cells, for example, a suspension of rentinal stem cells.
  • a suspension of neural stem cells is administered to the SCS via one of the devices and/or methods provided herien.
  • NSCs are self-renewing, multipotent cells that can differentiate into the main cell phenotypes of the nervous system. They have been isolated from the adult mammalian brain tissue, including humans.
  • a suspension of retinal stem cells is administered to the SCS via one of the devices and/or methods provided herien.
  • retinal stem cells are a possible donor source that give rise to all retinal cell types. These cells can be isolated, expanded, and differentiated into retinal neurons by culturing them in the presence of growth factors, such as epidermal growth factor and fibroblast growth factor.
  • a suspension of adult stem cells or mesenchymal stem cells is administered to the SCS of a patient in need thereof via one of the devices and/or methods provided herein.
  • Other cell types amenable for administration via the devices and methods provided herein include but are not limited to hematopoietic stem cells (HSCs), human embryonic stem cells (hESCs), retinal progenitor cells, endothelial progenitor cells or a combination thereof.
  • one or more of the stem cells described in Arch Ophthalmol. 2004;122(4):621-627, incorporated by reference herein in its entirety for all purposes, is delivered to a patient via a device or method described herein.
  • the "therapeutic formulation” delivered via the methods and devices provided herein in one embodiment is an aqueous solution or suspension, and comprises an effective amount of the drug or therapeutic agent, for example, a cellular suspension.
  • the therapeutic formulation is a fluid drug formulation.
  • the "drug formulation” is a formulation of a drug, which typically includes one or more pharmaceutically acceptable excipient materials known in the art.
  • excipient refers to any non-active ingredient of the formulation intended to facilitate handling, stability, dispersibility, wettability, release kinetics, and/or injection of the drug.
  • the excipient may include or consist of water or saline.
  • the therapeutic formulation delivered to the suprachoroidal space of the eye of a human subject for the treatment of uveitis may be in the form of a liquid drug, a liquid solution that includes a drug or therapy in a suitable solvent, or liquid suspension.
  • the liquid suspension may include microparticles or nanoparticles dispersed in a suitable liquid vehicle for infusion.
  • the drug is included in a liquid vehicle, in microparticles or nanoparticles, or in both the vehicle and particles.
  • the drug formulation is sufficiently fluid to flow into and within the suprachoroidal space, as well as into the surrounding posterior ocular tissues.
  • the viscosity of the fluid drug formulation is about 1 cP at 37 °C.
  • the drug formulation (e.g., fluid drug formulation) includes microparticles or nanoparticles, either of which includes at least one drug.
  • the microparticles or nanoparticles provide for the controlled release of drug into the suprachoroidal space and surrounding posterior ocular tissue.
  • the term "microparticle” encompasses microspheres, microcapsules, microparticles, and beads, having a number average diameter of from about 1 ⁇ to about 100 ⁇ , for example from about 1 to about 25 ⁇ , or from about 1 ⁇ to about 7 ⁇ .
  • Nanoparticles are particles having an average diameter of from about 1 nm to about 1000 nm.
  • the microparticles in one embodiment, have a D 50 of about 3 ⁇ or less. In a further embodiment, the D 50 is about 2 ⁇ . In another embodiment, the D 50 of the particles in the drug formulation is about 2 ⁇ or less. In another embodiment, the D 50 of the particles in the drug formulation is about 1000 nm or less. In one embodiment, the drug formulation comprises microparticles having a D 99 of about 10 ⁇ or less. The microparticles, in one embodiment, have a D 50 of about 3 ⁇ or less. In a further embodiment, the D 50 is about 2 ⁇ . In another embodiment, the D 50 of the particles in the drug formulation is about 2 ⁇ or less. In another embodiment, the D50 of the particles in the drug formulation is about 1000 nm or less.
  • the drug formulation comprises microparticles having a D 99 of about 10 ⁇ or less.
  • the microparticles in one embodiment, have a D 50 of about 3 ⁇ or less. In a further embodiment, the D 50 is about 2 ⁇ . In another embodiment, the D 50 of the particles in the drug formulation is about 2 ⁇ or less. In another embodiment, the D50 of the particles in the drug formulation is about 100 nm to about 1000 nm.
  • the drug formulation comprises microparticles having a D 99 of about 1000 nm to about 10 ⁇ .
  • the microparticles in one embodiment, have a D 50 of about 1 ⁇ to about 5 ⁇ or less. In another embodiment, the drug formulation comprises particles having a D 99 of about 10 ⁇ .
  • the D 99 of the particles in the formulation is less than about 10 ⁇ , or less than about 9 ⁇ , or less than about 7 ⁇ or less than about 3 ⁇ .
  • the microparticles or nanoparticles comprise an anti-inflammatory drug.
  • the anti-inflammatory drug is triamcinolone.
  • Microparticles and nanoparticles may or may not be spherical in shape.
  • "Microcapsules” and “nanocapsules” are defined as microparticles and nanoparticles having an outer shell surrounding a core of another material.
  • the core can be liquid, gel, solid, gas, or a combination thereof.
  • the microcapsule or nanocapsule may be a "microbubble” or “nanobubble” having an outer shell surrounding a core of gas, wherein the drug is disposed on the surface of the outer shell, in the outer shell itself, or in the core.
  • Microbubbles and nanobubles may be respond to accoustic vibrations as known in the art for diagnosis or to burst the microbubble to release its payload at/into a select ocular tissue site.
  • "Microspheres" and “nanospheres” can be solid spheres, can be porous and include a spongelike or honeycomb structure formed by pores or voids in a matrix material or shell, or can include multiple discrete voids in a matrix material or shell.
  • the microparticles or nanoparticles may further include a matrix material.
  • the shell or matrix material may be a polymer, amino acid, saccharide, or other material known in the art of microencapsulation.
  • the drug-containing microparticles or nanoparticles may be suspended in an aqueous or non-aqueous liquid vehicle.
  • the liquid vehicle may be a pharmaceutically acceptable aqueous solution, and optionally may further include a surfactant.
  • the microparticles or nanoparticles of drug themselves may include an excipient material, such as a polymer, a polysaccharide, a surfactant, etc., which are known in the art to control the kinetics of drug release from particles.
  • the drug formulation further includes an agent effective to degrade collagen or GAG fibers in the sclera, which may enhance penetration/release of the drug into the ocular tissues.
  • This agent may be, for example, an enzyme, such a hyaluronidase, a collagenase, or a combination thereof.
  • the enzyme is administered to the ocular tissue in a separate step from— preceding or following— infusion of the drug. The enzyme and drug are administered at the same site.
  • the drug formulation is one which undergoes a phase change upon administration.
  • a liquid drug formulation may be injected through hollow microneedles into the suprachoroidal space, where it then gels and the drug diffuses out from the gel for controlled release.
  • the therapeutic substance in one embodiment is formulated with one or more polymeric excipients to limit therapeutic substance migration and/or to increase viscosity of the formulation.
  • a polymeric excipient may be selected and formulated to act as a viscous gel-like material in-situ and thereby spread into a region of the suprachoroidal space and uniformly distribute and retain the drug.
  • the polymer excipient in one embodiment is selected and formulated to provide the appropriate viscosity, flow and dissolution properties.
  • carboxymethylcellulose is used in one embodiment to form a gel-like material in the suprachoroidal space.
  • the viscosity of the polymer in one embodiment is enhanced by appropriate chemical modification to the polymer to increase associative properties such as the addition of hydrophobic moieties, the selection of higher molecular weight polymer or by formulation with appropriate surfactants.
  • the dissolution properties of the therapeutic formulation in one embodiment is adjusted by tailoring of the water solubility, molecular weight, and concentration of the polymeric excipient in the range of appropriate thixotropic properties to allow both delivery through a small gauge needle and localization in the suprachoroidal space.
  • the polymeric excipient may be formulated to increase in viscosity or to cross-link after delivery to further limit migration or dissolution of the material and incorporated drug.
  • Water soluble polymers that are physiologically compatible are suitable for use as polymeric excipients in the therapeutic formulations described herein, and for delivery via the methods and devices described herein include but are not limited to synthetic polymers such as polyvinylalcohol, polyvinylpyrollidone, polyethylene glycol, polyethylene oxide, polyhydroxyethylmethacrylate, polypropylene glycol and propylene oxide, and biological polymers such as cellulose derivatives, chitin derivatives, alginate, gelatin, starch derivatives, hyaluronic acid, chondroiten sulfate, dermatin sulfate, and other glycosoaminoglycans, and mixtures or copolymers of such polymers.
  • the polymeric excipient is selected in one embodiment to allow dissolution over time, with the rate controlled by the concentration, molecular weight, water solubility, crosslinking, enzyme lability and tissue adhesive properties of the polymer.
  • a viscosity modifying agent is present in a therapeutic formulation delivered by one of the methods and/or devices described herein.
  • the viscosity modifying agent is polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose or hydroxypropyl cellulose.
  • the formulation comprises a gelling agent such as po3y(hydroxymethylmetliacr date), poly(N-vinylpyrrolidone), polyvinyl alcohol or an acrylic acid polymer such as Carbopol.
  • the therapeutic formulation is delivered via one of the methods and or devices described herein as a liposomal formulation.
  • Liposomes can be produced by a variety of methods. Bangham's procedure (J. Mol. Biol, J Mol Biol. 13(l):238-52, 1965) produces ordinary multilamellar vesicles (MLVs).
  • MUVs multilamellar vesicles
  • Lenk et al. U.S. Pat. Nos. 4,522,803, 5,030,453 and 5,169,637)
  • Fountain et al. U.S. Pat. No. 4,588,578
  • Cullis et al. U.S. Pat. No. 4,975,282 disclose methods for producing multilamellar liposomes having substantially equal interlamellar solute distribution in each of their aqueous compartments.
  • the liposomal formulation comprises a phosolipid. In a further embodiment, the liposomal formulation comprises a sterol such as cholesterol.
  • the liposomal formulation comprises unilamellar vesiscles.
  • Unilamellar vesicles can be produced from MLVs by a number of techniques, for example, the extrusion of Cullis et al. (U.S. Pat. No. 5,008,050) and Loughrey et al. (U.S. Pat. No. 5,059,421). Sonication and homogenization can be used to produce smaller unilamellar liposomes from larger liposomes (see, for example, Paphadjopoulos et al., Biochim. Biophys. Acta., 135:624-638, 1967; Deamer, U.S. Pat. No.
  • the drug formulation delivered to the suprachoroidal space via the methods described herein can be administered with one or more additional drugs.
  • the one or more additional drugs in one embodiment, are present in the same formulation as the initial drug formulation. In another embodiment, the one or more additional drugs are present in a second formulation. In even a further embodiment, the second drug formulation is delivered to the patient in need thereof via a non-surgical SCS delivery method described herein.
  • the second drug formulation is delivered intravitreally, intracamerally, sub-tenonally, orally, topically or parenterally to the human subject in need of treatment of macular edema associated with uveitis or macular edema associated with RVO.
  • a VEGF antagonist is delivered to the suprachoroidal space of the eye of a human subject in need of treatment of macular edema associated with uveitis or macular edema associated with RVO via one of the methods and/or devices disclosed herein, in conjunction with an anti-inflammatory compound.
  • the drug formulation includes aflibercept.
  • the one or more additional drugs delivered to the human subject can be delivered via intravitreal (IVT) administration (e.g., intravitreal injection, intravitreal implant or eye drops).
  • IVT intravitreal
  • Methods of IVT administration are well known in the art. Examples of classes of drugs that can be administered via IVT include, but are not limited to: VEGF modulators, PDGF modulators, anti-inflammatory drugs.
  • the methods provided herein comprise administering one or more drugs via IVT and one or more drugs via SCS.
  • SCS administration of a drug formulation improves the effectiveness of a drug administered IVT to treat one or more of the ocular disorders disclosed herein.
  • SCS administration of an anti-inflammatory drug concomitantly with IVT administration of a biologic vastly improves the effectiveness of the biologic treatment.
  • the drug administered via IVT and the drug administered to the SCS act synergistically. Two or more compounds that act synergistically interact such that the combined effect of the two compounds is greater than the sum of the individual effects of each compound when administered alone.
  • the a biologic (e.g. , aflibercept) administered IVT combined with a drug (e.g. , TA) administered by SCS administration act synergistically to treat an ocular disorder (e.g. , macular edema).
  • a drug e.g. , TA
  • Triamcinolone is delivered to the suprachoroidal space using the methods and devices provided herein.
  • the triamcinolone formulation in one embodiment, is selected from one of the following seven formulations in Table 2.
  • Example 2 Phase 1/2 open-label, safety and tolerability study of triamcinolone acetonide administered to the suprachoroidal space in patients with non-infectious uveitis.
  • a clinical trial was designed to evaluate the safety and tolerability of a single injection of TA (triamcinolone acetonide administered as TRIESCENCETM) into the SCS in patients diagnosed with non-infectious uveitis.
  • TA triamcinolone acetonide administered as TRIESCENCETM
  • TRIESENCETM Each mL of the sterile, aqueous suspension of TRIESENCETM provides 4 mg of triamcinolone acetonide, with sodium chloride for isotonicity, 0.5% (w/v) carboxymethylcellulose sodium and 0.015% polysorbate 80. It also contains potassium chloride, calcium chloride (dihydrate), magnesium chloride (hexahydrate), sodium acetate (trihydrate), sodium citrate (dihydrate) and water for injection. Sodium hydroxide and hydrochloric acid may be present to adjust pH to a target value 6 - 7.5.
  • the primary purpose of this trial was to evaluate the overall safety and tolerability of treating uveitis patients (non-infectious uveitis - intermediate, posterior or pan-uveitis) by administering a triamcinolone into the SCS via a single suprachoroidal injection.
  • Eligibility criteria include adult patients with non-infectious uveitis experiencing either macular edema or vitreous haze, a common complication of uveitis. This was in order to determine whether SCS administration of TA could improve patient vision through reducing the effects of either condition.
  • IOP intra-ocular pressure
  • Patients may receive other treatment at any time during the trial with any accepted therapy based on their physician's best medical judgment, if their condition deteriorates or if the physician otherwise determines it to be advisable. In the event a patient received other treatment, the patient was followed for the duration of the trial for safety purposes, but efficacy measures were no longer considered thereafter.
  • Endpoints The main safety endpoint was changes from baseline in intraocular pressure (IOP). Also assessed was an efficacy endpoint relating to changes in best-corrected visual acuity, or BCVA, as well as changes in excess retinal thickness.
  • IOP intraocular pressure
  • BCVA best-corrected visual acuity
  • the graph in FIG. 22 shows the mean change in IOP for patients in the trial, as measured at different time points post-treatment.
  • the number of patients included in the results for the various measurement time points below varies because the four patients were treated on different dates and only two patients have currently completed the full 26-week observation period.
  • BCVA (best corrected visual acuity) was measured for all eight patients. BCVA is a common measurement of a patient's ability to see at distances and changes are measured as the difference in number of letters read on a standard eye chart.
  • FIG. 23 summarizes the mean improvement in BCVA observed. Four of the eight patients showed meaningful improvements in BCVA (a gain of about 3 lines) at 26 weeks following a single suprachoroidal injection of TA on Day 1.
  • the graph in FIG. 24 summarizes the mean change in retinal thickness observed to date in the trial.
  • the mean reduction in macular edema at week 26 was over 100 microns with a range from 76 to 154 microns reduction over the 26-week post treatment observation period following the single TA injection into the SCS.
  • An average reduction of about 20 percent in CME was observed for the seven patients.
  • FIG. 25 provides OCT images of the eyes of this patient prior to and subsequent to the dosing session, results for this patient (FIG. 25).
  • the eye treated with TA via suprachoroidal injection provides a greater decrease in retinal thickness as compared to the subtenon injection (FIG. 25).
  • the trial described in this Example is a Phase 2, randomized, masked, multicenter study to assess the safety and efficacy of CLS-TA in the treatment of subjects with ME following non-infectious uveitis.
  • the purpose of this study is to evaluate the safety and efficacy of CLS-TA in subjects with ME following non-infectious uveitis.
  • Two different doses, 4 mg and 0.8 mg, of CLS-TA will each be evaluated for safety and efficacy.
  • Oral corticosteroids remain the main initial choice in treating patients with uveitis not responding to topical treatment, however their chronic use can be toxic, especially for bones, including osteoporosis or growth retardation.
  • Non-steroidal immunosuppressive agents can either be used to treat uveitis directly, or they are used as corticosteroid sparing therapy or they are used as agents to control refractory uveitis when the condition is sight threatening.
  • Agents commonly used are cyclosporine A, methotrexate, azathioprine, cyclophosphamide and chlorambucil. Cyclosporine is efficacious but is nephrotoxic, particularly in elderly patients.
  • Methotrexate is well tolerated, and has been the usual first line steroid sparing agent for many years. Although it is quite effective in many patients, its onset of action is very delayed (months), and it carries with it the risks of liver toxicity and decreased white blood cell counts (Kalinina 2011). As well, it causes significant fatigue and nausea, making it difficult for some patients to tolerate. It is also absolutely contraindicated in pregnancy (pregnancy category X). Azathioprine is another drug in the same class as methotrexate. It also has a delayed onset of action, and may not be very well tolerated. Mycophenolate mofetil is another steroid sparing agent.
  • the subjects enrolled in this study will be chosen from subjects with ME in the study eye with a retinal thickness of at least 310 microns in the central subfield (average retinal thickness in the central 1 mm) as measured by SD-OCT, using a Heidelberg SPECTRALIS®, and confirmed by the Central Reading Center.
  • CLS-TA triamcinolone acetonide injectable suspension
  • aqueous suspension formulated for administration into the SCS as a single injection of up to 4 mg in 100 microliters ( ⁇ ), or up to 0.8 mg in 100 microliters ( ⁇ ) using a microinjector.
  • the drug product is intended for single use.
  • CLS-TA is supplied as a 1.3 mL fill of a 40 mg/mL or 8
  • the study has 2 arms randomized 4: 1. See Table below. Subjects are randomized in a 4: 1 ratio to receive a single injection of CLS-TA, 4 mg in a volume of 100 or CLS-TA, 0.8 mg in a volume of 100 ⁇ .. Study personnel, study patients, the sponsor, and project teams at the Contract Research Organizations (CROs) involved in the study will be masked to treatment assignments. Approximately 20 total subjects at approximately 11 U.S. sites will be enrolled. The study design includes 5 clinic visits over roughly two (2) months. Subjects will be in the study for no more than 70 days. Subjects will receive treatment at Day 1 (Visit 2), approximately 1-10 days after the initial screening visit (Visit 1). They will continue to be monitored for safety and efficacy for 2 months following their injection.
  • CROs Contract Research Organizations
  • Eligibility will be established at Visit 1 (Screening Visit). Subjects must qualify on SD-OCT readings confirmed by a Central Reading Center prior to being treated. Depending on the treatment arm to which subjects are assigned, subjects will either receive a single suprachoroidal injection of CLS-TA, up to 4 mg in 100 ⁇ ., or a single suprachoroidal injection of CLS-TA, up to 0.8 mg in 100 in a single eye. Injection is carried out as described in FIG. 21.
  • both eyes are eligible (see below for inclusion and exclusion criteria), the eye with worse edema (that with the greater degree of macular thickening per SD-OCT) will be selected. If ME is equivalent in both eyes, the right eye will be chosen.
  • the primary objective of this study is to determine the safety and efficacy of CLS- TA, with doses up to 4 mg and 0.8 mg, each in a volume of up to 100 ⁇ , by determining change in retinal thickness from baseline in central subfield thickness (CST) as measured by spectral domain optical coherence tomography (SD-OCT) in subjects with ME following non-infectious uveitis.
  • CST central subfield thickness
  • SD-OCT spectral domain optical coherence tomography
  • TEAEs treatment-emergent adverse events
  • SAEs serious adverse events
  • ⁇ If female, the subject must be non-pregnant, non-lactating and not planning a pregnancy.
  • Females of childbearing potential must agree to use an acceptable method of contraception throughout participation in the study.
  • Acceptable methods of contraception include double barrier methods (condom with spermicide or diaphragm with spermicide), hormonal methods (oral contraceptives, implantable, transdermal, or injectable contraceptives), or an intrauterine contraceptive device (IUCD) with a documented failure rate of less than 1% per year. Abstinence may be considered an acceptable method of contraception at the discretion of the investigator, but the subject must agree to use one of the acceptable birth control methods if she becomes sexually active.
  • a retinal thickness of > 310 microns in the central subfield average retinal thickness in the central 1 mm ring, as measured by SD-OCT (using the Heidelberg
  • I l l History of any serious or active psychiatric illness that, in the opinion of the investigator, would interfere with subject treatment, assessment or compliance with the protocol.
  • Has a history of any vitreoretinal surgery (scleral buckle, pars plana vitrectomy, retrieval of a dropped nucleus or intraocular lens, etc. ; prior photocoagulation and IVT injections are acceptable) in the study eye.
  • Prior cataract extraction or Yttrium- Aluminum-Garnet (YAG) laser capsulotomy is allowed, but must have been performed at least 3 months prior to treatment.
  • Has eye diseases other than uveitis that could compromise central visual acuity e.g. clinically significant diabetic retinopathy, scleritis, ischemic optic neuropathy or retinitis pigmentosa
  • central visual acuity e.g. clinically significant diabetic retinopathy, scleritis, ischemic optic neuropathy or retinitis pigmentosa
  • IluvienTM implant in the study eye in the past 1 year prior to study treatment is provided.
  • Randomization Criteria Subjects are eligible for randomization at Visit 2 if the following criteria are met:
  • Visit 3 occurs 7 to 10 days post Visit 2 (Randomization/Treatment). During Visit 3, the following procedures will be performed:
  • Visit 4 occurs approximately 1 month post injection. The visit should be 28 ⁇ 3 days from Visit 2. During Visit 4, the following procedures will be performed:
  • Visit 5 will be the final evaluation visit and exit from the study. Visit 5 occurs within 56 ⁇ 4 days from Visit 2. The following procedures will be performed:
  • Central Subfield Thickness as measured by SD-OCT will be assessed as a measure of efficacy.
  • Each site will be provided an imaging protocol and submission procedures from the Central Reading Center.
  • the SD-OCT instrument and technician must be certified prior to submission of study data. They will be trained on imaging and uploading images to EyeKor's Excelsior system for this specific protocol.
  • Retinal thickness and disease characterization will be assessed via SD-OCT (Heidelberg SPECTRALIS®) at every visit. OCT will be performed on both eyes at Visits 1 and 5, and in the study eye only at Visits 2, 3 and 4.
  • the Central Reading Center will evaluate study images in a masked, independent manner. At Screening (Visit 1), the Central Reading Center will confirm subject eligibility on the basis of retinal thickness criteria prior to subject enrollment. Upon confirmation from the Central Reading Center via email, the site may proceed with qualifying the subject for Randomization/Treatment which will occur at Visit 2.
  • SD-OCT submissions will include a volume (cube) scan consisting of 49 B-scans of 6 mm length centered on the fovea.
  • An additional Enhanced Depth Imaging (EDI) scan will be obtained horizontally through the fovea.
  • SD-OCT scans will be evaluated for quality and any segmentation errors affecting the measurement of central subfield retina thickness will be corrected. Additional evaluation outputs will include macular grid volume and assessment of retinal and choroidal anatomy.
  • BCVA assessed using the ETDRS protocol will also be assessed. Each site will have at least one certified exam lane that includes all required equipment to assess BCVA by one or more certified visual acuity examiner. Training/certifi cation on the ETDRS protocol will be completed prior to subject enrollment. In addition, ETDRS training/certification documentation will be kept on site and with the sponsor. Site staff will be masked to treatment. BCVA will be assessed at every visit. BCVA will be measured on both eyes at Visits 1 and 5, and in the study eye only at Visits 2, 3 and 4.
  • Slit-lamp biomicroscopy Slit-lamp biomicroscopy. Slit-lamp biomicroscopy will be performed using the investigator's standard slit lamp equipment and procedure. This procedure should be the same for all subjects observed at the investigator's site. Observations for each eye should be made for the following variables (including but not limited to): conjunctiva, cornea, lens, anterior chamber, iris, and pupil. Slit-lamp biomicroscopy will be assessed at every visit. It will be measured on both eyes at Visits 1 and 5 and the study eye only at Visits 2, 3 and 4.
  • Indirect ophthalmoscopy Dilated ophthalmoscopy should be performed according to the investigator's standard dilation procedure. This procedure should be the same for all subjects observed at the investigator's site. The fundus will be examined thoroughly and the following variables (including but not limited to): vitreous haze, vitreous, retina, choroid, and optic nerve/disc. Dilated indirect ophthalmoscopy will be assessed at every visit. It will be measured on both eyes at Visits 1 and 5 and the study eye only at Visits 2, 3 and 4.
  • Fluorescein Angiogram It is recommended that when both fundus photos and FA are conducted in the same visit that the Fundus Photos be taken first. Digital equipment will be registered and photographers certified for the imaging procedures. The same equipment should be used throughout the study. All testing should be carried out by the same operator, whenever possible, on all subjects per research site. The designated person must be on the site delegation log. It is recommended that a backup also be named. All data/images will be uploaded to EyeKor's Excelsior system. As a reminder all images should be de- identified before uploading. FA will be performed at Visits 1 and 5 on the study eye only.
  • Anatomic assessments will include the area of fluorescein leakage, area of capillary nonperfusion, the presence of retinal vascular and optic nerve head staining, and retinal pigment epithelium abnormalities.
  • Fundus Photographs. FP-4W fields (4 standard Wide Angle Fields). The same camera should be used throughout the study. All photos should be taken by the same photographer, whenever possible, on all subjects per research site. De-identified images will be uploaded to EyeKor's Excelsior system. Fundus photographs will be taken at Visits 1 and 5 on both eyes and the study eye only at Visit 3. Characteristics graded from fundus photographs includes vitreous haze score, lesions consistent with posterior uveitis, optic disc swelling, and vascular abnormalities.
  • Vitreous Haze Photographic vitreous haze will be assessed clinically at every visit via indirect ophthalmoscopy using a standardized photographic scale ranging from 0 to 4, with 0 - 4 defined below in Table 4 (Nussenblatt 1985 as modified in Lowder 2011). Vitreous haze will also be graded from the color fundus photographs according to a similar scale. It will be assessed on both eyes at Visits 1 and 5, and in the study eye only at Visits 2, 3 and 4.
  • This Phase 2, multicenter, randomized, active-controlled, masked, parallel arm study seeks to evaluate the safety and efficacy of a single suprachoroidal injection of CLS- TA given concomitantly with an intravitreal (IVT) injection of aflibercept compared to IVT aflibercept alone in subjects with macular edema (ME) following retinal vein occlusion (RVO).
  • IVTT intravitreal
  • ME macular edema
  • RVO retinal vein occlusion
  • RVO is a condition that affects vision, resulting from a blockage in one of the veins returning blood flow from the retina.
  • RVO is the second most common cause of vision loss due to retinal vascular disease.
  • This study assesses the safety and efficacy of a suprachoroidal injection of CLS- TA plus IVT aflibercept compared to subjects administered a sham suprachoroidal procedure plus IVT aflibercept in the treatment of subjects with ME following retinal vein occlusion (RVO).
  • RVO retinal vein occlusion
  • Each subject will receive at least one IVT aflibercept injection and approximately half of the subjects will receive a single suprachoroidal injection of CLS-TA.
  • the subjects enrolled in this study will be treatment naive RVO subjects (HRVO, CRVO and BRVO) with ME in the study eye.
  • All qualifying subjects will be randomized (Day 1) to receive an IVT injection of an anti-VEGF treatment (aflibercept) plus a suprachoroidal injection of CLS-TA or an IVT injection of aflibercept plus a sham suprachoroidal procedure. Subjects will be followed for approximately 3 months following randomization. The subject, sponsor, visual acuity technician and the optical coherence tomography (OCT) reading center will be masked to treatment.
  • OCT optical coherence tomography
  • Approximately 40 subjects at approximately 10 U.S. sites will be enrolled.
  • the study design includes 5 clinic visits and one safety phone call over approximately three (3) months.
  • Subject eligibility will be established at Visit 1 during the screening process (Day - 14 to -1) where subjects must qualify on spectral-domain optical coherence tomography (SD- OCT) readings confirmed by a Central Reading Center (CRC) prior to being treated.
  • SD- OCT spectral-domain optical coherence tomography
  • CRC Central Reading Center
  • Eligible subjects will return to the clinic for Visit 2 - Randomization (Day 1) where subjects will be randomized via the interactive web response system (IWRS).
  • Subjects will be randomized to receive either an IVT aflibercept injection followed by a suprachoroidal CLS-TA injection or an IVT aflibercept injection followed by a suprachoroidal sham procedure.
  • Subjects remain at the clinic after the suprachoroidal CLS-TA injection or sham for about 30 minutes for evaluation. A follow-up safety phone call will be required on Day 2 (24-48 hours following treatment). Subjects will then receive an IVT aflibercept injection at Visits 3 (Month 1) and 4 (Month 2) only if criteria for additional therapy are met. If subjects do not qualify for the IVT injection of aflibercept, they will be given a sham IVT aflibercept procedure. Subjects will have their final evaluation conducted at Visit 5 - End of Study (Month 3). No study injections will occur at Visit 5.
  • the primary endpoint is the total number of times subjects qualify to be administered IVT aflibercept in each arm through Month 3.
  • CLS-TA triamcinolone acetonide injectable suspension
  • CLS-TA is a sterile aqueous suspension formulated for administration into the eye.
  • the drug product is terminally sterilized and is intended for single use.
  • CLS-TA is supplied as a 1.3 mL fill of 40 mg/mL sterile CLS-TA suspension in a 2 mL/13 mm TopLyo® single use vial, with a rubber stopper and an aluminum seal.
  • CLS-TA must be stored under ambient temperature conditions at ca. 20° - 25° C (68° - 77° F); do not freeze. Protect from light by storing in the kit.
  • the 4 mg dose of CLS-TA contains 40 mg/mL of TA.
  • Subjects will be randomized 1 : 1 to receive a single suprachoroidal injection of 40 mg/mL (4 mg in 100 ⁇ ) CLS-TA (Active arm) or a sham suprachoroidal procedure (Control arm). This will be based on the randomization code and what is assigned via the IWRS.
  • EYLEA® (afiibercept) Injection is an FDA approved prescription medicine for the treatment of RVO.
  • the dosage for EYLEA® is 2 mg (0.05 mL) administered by intravitreal injection.
  • Aflibercept will be acquired commercially by the clinical sites.
  • ACTIVE ARM an IVT injection of aflibercept [2 mg (0.05 mL)] plus a suprachoroidal injection of CLS-TA [4 mg (100 ⁇ )] or
  • CONTROL ARM an IVT injection of aflibercept [2 mg (0.05 mL)] plus a sham suprachoroidal procedure.
  • Ophthalmic Inclusion Criteria Individuals are eligible for participation in this study if he/she meet the following criteria: (1) Clinical diagnosis of ME following RVO in the study eye; (2) CST of > 310 microns (average retinal thickness in the central 1mm ring) in the study eye as measured by SD-OCT (using the Heidelberg SPECTRALIS®) with or without subretinal fluid and confirmed by the CRC; (3) ETDRS BCVA score of > 20 letters read (20/400 Snellen equivalent) in each eye, and ⁇ 70 letters read (20/40 Snellen equivalent) in the study eye; (4) Macular Edema with the following characteristics: a. Involving the fovea, b. Due to any RVO and not due to other causes of ME, c. History of ME ⁇ 12 months, d. Visual acuity decrease due to edema.
  • Ophthalmic Exclusion Criteria An individual is ineligible for participation in this study if he/she meets the following criteria: (1) Has had any IVT injection of anti-VEGF (bevacizumab, aflibercept, pegaptanib or ranibizumab) for RVO in the study eye; (2) In the study eye, any intraocular and periocular corticosteroid injection in the 3 months prior to treatment, OZURDEX® implant in the 6 months prior to treatment, RETISERTTM implant in the 1 year prior to treatment or ILUVEIN® implant in the 3 years prior to treatment; (3) Evidence of or history of any ophthalmic condition in the study eye, other than RVO, that, in the investigator's opinion, might compromise visual acuity (e.g., AMD, diabetic retinopathy, retinal detachment, central serious chorioretinopathy, scleritis, optic neuropathy or retinitis pigmentosa); (4) History of any vitreoretinal
  • History of IVT injections are allowed; (5) History of an ocular procedure or condition, within the 3 months prior to randomization, or condition that, in the investigator's opinion, could compromise globe or retinal integrity (e.g., staphyloma, cryotherapy, high myopia [defined as a spherical equivalent > -8 diopters], predisposition to scleral thinning, etc.) in the study eye; (6) An ocular condition that in the opinion of the Investigator would put the subject at risk due to study treatment or procedures in the study eye (e.g., active ocular infection, history of a suprachoroidal hemorrhage, chalazion, significant blepharitis); (7) In the study eye, > 3 treatments of macular laser photocoagulation.
  • Randomization Criteria Subjects are eligible for randomization at Visit 2 if the following criteria are met: (1) CRC confirmation of ME by SD-OCT (from Visit 1 OCT data), with or without subretinal fluid, caused by RVO in the study eye; (2) CRC confirmation of a retinal thickness of > 310 microns in the central subfield from the Visit 1 SD-OCT data; (3) The study eye gained no more than 10 letters of vision between the Screening visit and Randomization (Visit 2) in the study eye; (4) Subject continues to meet all of the inclusion and none of the exclusion criteria.
  • subjects will receive a single IVT injection of aflibercept (per package insert) into the study eye, followed by a single, unilateral, suprachoroidal injection of CLS-TA or a suprachoroidal sham procedure in the study eye, depending on the randomization code assigned. Subjects will remain in the clinic for approximately 30 minutes following the suprachoroidal injection or sham and be assessed for safety. Subjects will receive a Safety Phone Call from the site 24-48 hours post injection and then return 1 month post injection for evaluation (Visit 3). Additional follow-up visits will occur at Months 2 and 3 (Visits 4 and 5).
  • Visit 1 - Screening Day -14 to -1). At Visit 1, subjects will be screened for eligibility. Before any study-specific assessments are performed, written informed consent will be obtained for each subject. During Visit 1, the following assessments will be performed:
  • Visit 2 - Randomization/Treatment (Day 1). Visit 2 must occur within 14 days of Visit 1 (Screening) and may only occur once subject is eligible for treatment which includes central lab results being received and reviewed, and confirmation of eligibility by the CRC. No subject may be treated without CRC confirmation of qualifying disease and CST > 310 microns. Once qualification is confirmed, subjects will be randomized via the IWRS. All qualifying subjects will be randomized (Day 1) to receive either:
  • ACTIVE an IVT injection of aflibercept [2 mg (0.05 mL)] plus a suprachoroidal injection of CLS-TA [4 mg (100 L)] or CONTROL: an IVT injection of aflibercept [2 mg (0.05 mL)] plus a sham suprachoroidal procedure.
  • IVT Injection of aflibercept Prepare study eye for IVT injection of aflibercept. Administer aflibercept IVT injection per package insert. It is recommended that the intravitreal injection and the suprachoroidal injection are approximately 2 clock hours apart. The superior temporal quadrant is the recommended location for suprachoroidal injections.
  • Suprachoroidal Injection of CLS-TA (ACTIVE KIT): Suprachoroidal injection should be administered following the IVT injection of aflibercept when the study eye IOP is ⁇ 30 mmHg, either spontaneously or by treatment, as determined by the Investigator.
  • the injection of 100 of CLS-TA is administered into the SCS of the study eye using the Clearside microinjector approximately 2 clock hours from where the IVT aflibercept was administered, preferably in the superior temporal quadrant. See FIG. 21 for method.
  • Suprachoroidal sham procedure (CONTROL KIT): Sham procedure is administered following the IVT injection of aflibercept when the study eye IOP is ⁇ 30 mmHg, either spontaneously or by treatment, as determined by the Investigator. The eye is prepared as it would for a suprachoroidal CLS-TA injection. A mock suprachoroidal injection to the study eye is performed.
  • Post-Injection Procedures The subjects remain on site for observation for approximately 30 minutes after injection. The following assessments occur following the IVT injection and suprachoroidal injection or sham procedure: (1) Assess retinal artery for perfusion; (2) Assess for AEs; (3) Review changes to concomitant medications; (4) Measure seated, resting heart rate and blood pressure; (5) Perform ophthalmic assessments on the study eye only (a. slit-lamp biomicroscopy; b. Evaluate IOP 10 - 30 minutes post injection; c. Perform indirect ophthalmoscopy). If IOP remains elevated, subject must remain on site until IOP is under control per investigator's best medical judgment. If IOP is ⁇ 30 mmHg, the subject may leave the clinic.
  • Visits 3 (Month 1 Post Injection Follow-Up (Day 28 ⁇ 3)) Visit 4 (2 Month Post Injection Follow-Up (Day 56 ⁇ 3)). Visit 3 occurs approximately 1 month post Visit 2 (Randomization/Treatment). The visit is 28 ⁇ 3 days from Visit 2. Visit 4 occurs approximately 2 months post Visit 2 (Randomization/Treatment). Visit 4 is 56 ⁇ 3 days from Visit 2. During Visits 3 and 4, the following procedures are performed:
  • o OPTIONAL Perform FA with the early series of the study eye and upload to the CRC only if the investigator feels it is necessary for medical judgment.
  • Visit 5 is the final evaluation visit and exit from the study. Visit 5 occurs within 84 ⁇ 4 days from Visit 2. During Visit 5, the following procedures are performed:
  • o OPTIONAL Perform FA with the early series of the study eye and upload to the CRC only if the investigator feels it is necessary for medical judgment.
  • An additional Enhanced Depth Imaging scan will be obtained horizontally through the fovea. SD-OCT scans will be evaluated for quality and any segmentation errors affecting the measurement of central subfield retina thickness will be corrected. Additional evaluation outputs will include macular grid volume and assessment of retinal and choroidal anatomy.
  • BCVA assessed using the ETDRS protocol. BCVA is assessed at every visit. BCVA will be measured on both eyes at Visits 1 and 5, and in the study eye only at Visits 2, 3 and 4.
  • Slit-lamp biomicroscopy Slit-lamp biomicroscopy. Slit-lamp biomicroscopy is performed using the investigator's standard slit lamp equipment and procedure. Observations for each eye are made for the following variables (including but not limited to): conjunctiva, cornea, lens, anterior chamber, iris, and pupil. Slit-lamp biomicroscopy is assessed at every visit. It will be measured on both eyes at Visits 1 and 5 and the study eye only at Visits 2, 3 and 4.
  • Indirect ophthalmoscopy The fundus is examined thoroughly and the following variables (including but not limited to): vitreous, retina, choroid, and optic nerve/disc. Dilated indirect ophthalmoscopy will be assessed at every visit. It will be measured on both eyes at Visits 1 and 5 and the study eye only at Visits 2, 3 and 4.
  • Fluorescein Angiogram FA
  • All data/images are uploaded to EyeKor's Excelsior system. As a reminder all images should be de-identified before uploading.
  • FA will be performed at Visits 1 and 5 on the study eye only.
  • FA may be performed (it is optional) at Visits 3 and 4 if the investigator feels it is necessary for medical judgment only.
  • Anatomic assessments include the area of fluorescein leakage, area of capillary nonperfusion, the presence of retinal vascular and optic nerve head staining, and retinal pigment epithelium abnormalities.
  • Fundus Photographs are taken at Visits 1 and 5 on both eyes. Characteristics graded from fundus photographs includes optic disc swelling, and vascular abnormalities.
  • Macular edema was also improved in the Active compared to the Control group. Subjects in the Active group exhibited reduced central subfield thickness (CST) by 446 microns, while subjects in the Control group exhibited reduced CST by 343 microns, showing an increased reduction in retinal thickness of 103 microns for the Active group over the Control group at month 3 ( Figure 44). Macular edema was improved as early as months 1 and 2 as well. At month 1, subjects in the Active group exhibited CST reduced by 446 compared to a CST reduction of 405 ( Figure 45). At month 2, subjects in the Active group exhibited a CST reduced by 459 compared to a CST reduction of 344 in the Control group ( Figure 45).
  • CST central subfield thickness
  • each rabbit received a single dose of 4.0 mg of Triesence on day 1 of the study injected either intravitreally or into the SCS. The rabbits were then observed for periods of up to 90 days and the concentration of Triesence in various parts of the eye was measured at days 14, 28, 56 and 91.
  • FIGS. 27, 28A-28F illustrate the results of this study.
  • the values shown in FIG. 28 for various parts of the eye represent ratios of total drug over the 91 -day time frame of the study, when comparing the two routes of injection.
  • the measures in FIGS. 28A-28F represent the amount of drug found in a specific tissue or area following SCS injection expressed as a proportion of the amount found in the same tissue or area following intravitreal injection. For example, a ratio of 1.0 indicates that there is an equal amount of drug found in the specific tissue following both routes of injection, whereas a ratio of 10 indicates that there is ten times more drug present in the tissue following SCS administration as compared to intravitreal administration. A ratio of 0.03 indicates that there is approximately thirty three times more drug in the specific area following intravitreal injection as compared to SCS injection.
  • CCS-TA triamcinolone acetonide formulation
  • a pharmacokinetic study in rabbits was conducted comparing the pharmacokinetic profile of CLS-TA with the profile of Triesence, each administered into the SCS.
  • Pharmacokinetics refers to the process by which a drug is distributed and metabolized in the body, which provides information on drug levels in specific tissues and how these levels change over time.
  • Each rabbit received a single dose of 4.0 mg of either CLS-TA or Triesence administered through the SCS on day 1 of the study. The rabbits were then observed for periods of up to 90 days and the resulting concentration of each of the two TA formulations in various parts of the eye was measured at days 15, 29, 58, 63 and 91.
  • Example 8 Evaluatoion of Suprachoroidal Triamcinolone Injection and Oral Prednisone in a Porcine Model of Uveitis
  • the eye Prior to all ocular injections, the eye was prepped with sterile 5% betadine solution then followed by irrigation with sterile eyewash. Immediately following the injections, 1 drop of moxifloxacin ophthalmic solution (Vigamox®, Alcon Laboratories, Fort Worth, TX) was applied topically, and the pigs were allowed to recover from anesthesia.
  • moxifloxacin ophthalmic solution Vigamox®, Alcon Laboratories, Fort Worth, TX
  • Ocular Inflammation Score A modified Fishett-McDonald microscopic ocular inflammation scoring system was used to evaluate the ocular anterior segment, lens, and anterior vitreous. Specifically, both eyes of each animal were examined by a board-certified veterinary ophthalmologist using a handheld slit lamp and indirect ophthalmoscope as follows. Lenticular Examination: Approximately one drop of a short-acting mydriatic solution was instilled onto each eye in order to dilate the pupil. After acceptable dilation has occurred, the lens of each eye was examined using a slit-lamp biomicroscope.
  • Intraocular Pressure Intraocular pressure (IOP) was measured with the pigs awake and hand restrained at -144, -96, -24, 0, 24, 48, and 72 hours (see Figure 1) using a TonoVet Tonometer (iCare, Finland). The measurements were performed with the pigs awake and without use of topical anesthetic. The tip of the probe was directed to contact the central cornea and 6 measurements were made consecutively. After the six measurements, the mean IOP was shown on the display providing the IOP that was recorded.
  • ERG Scotopic Electroretinography
  • ERGs were elicited by brief flashes at 0.33 Hz delivered with a mini- ganzfeld photostimulator (Roland Instruments, Wiesbaden, Germany) at maximal intensity. Twenty responses were amplified, filtered, and averaged (Retiport Electrophysiologic Diagnostic Systems, Roland Instruments, Wiesbaden, Germany). B wave amplitudes were recorded from each pig at the designated times.
  • grading scale used was modified from Tilton, et al (IOVS 1994): [1370] Anterior chamber tissues including the iris, ciliary body, ciliary process, corneal endothelium, and the anterior chamber, were scored for severity of inflammation as follows:
  • Injection Procedure Observations. Injections of CLS-TA or BSS into the SCS (Groups 1 and 3) were accomplished using microneedles without difficulty or adverse effect. Eyes were examined via slit lamp biomicroscopy and indirect ophthalmoscopy following each injection. No evidence of backleakage of treatment materials through the microneedle scleral perforation or leakage of drug into the vitreous was observed. Furthermore, there was no evidence of injection site or vitreal hemorrhage following any injections (SCS).
  • Groups 2 high dose of prednisone
  • Group 3 Group 3
  • Group 4 low dose oral prednisone mean cumulative inflammation scores were not significantly different than saline treated eyes at any treatment time.
  • Intraocular Pressure Mean intraocular pressure ranged from 14.24 to 17 mmHg during acclimation and increased slightly as pigs became accustomed to being handled. On induction of uveitis, the mean IOP decreased by Time 0 to between 11.5 and 14.25 mmHg in all groups, which were not significantly different. Following treatment, IOP returned to baseline by Day 1 in all groups. On Day 3, Group 4 eyes (low dose oral prednisone) had significantly lower IOP than all other groups (P ⁇ 0.0065) suggesting that these eyes had more inflammation compared to the other groups. IOP in Group 3 eyes stayed substantially constantthroughout the study period (FIG. 32).
  • Wide-field Ocular Fundus Digital Photography Wide-field ocular fundus images revealed substantial cloudiness of the ocular posterior segment 24 hours after LPS injection. The cloudiness observed in eyes on Day 0 was a result of predominantly cellular infiltrate into the vitreous humor and some changes to the retina. In BSS treated eyes (Group 1), the cloudiness appeared to worsen from 24 to 72 hours. Treatment with high dose prednisone (Group 2) and CLS-TA (Group 3) resulted in fundus images near pre-treatment appearance at 72 hours. However, treatment with low dose prednisone (Group 4) resulted in images only slightly improved over vehicle treated eyes.
  • Treatment of chronic retinal diseases such as neovascular (wet) age related macular degeneration (AMD)
  • AMD age related macular degeneration
  • a biological drug such as Lucentis, Eylea (aflibercept) or Avastin
  • Lucentis Lucentis
  • Eylea aflibercept
  • Avastin Avastin
  • the disease shows new blood vessel formation from the choroid.
  • the disease affects the choroid and retina and specific targeting of these tissues might be more beneficial in modulating disease progression.
  • Specific tissues can be targeted by directly administering the drug to the choroid rather than the current method of injecting into the vitreous.
  • methods of targeting the choroid and the retina via a suprachoroidal injection technique are methods of targeting the choroid and the retina via a suprachoroidal injection technique.
  • This example demonstrates that a suprachoroidal injection of Eylea can lead to a reduction in neovascular area in a validated animal disease model.
  • This experiment shows that this anti-VEGF agent can provide the potential for a useful alternative treatment approach. Further, there is potential to access the new blood vessels in the choroid, which could reduce the necessary frequency of treatment. If this experimental result can be translated into clinical practice, this may offer unique options for the treatment of this and other vision threatening diseases.
  • microneedle was inserted 1-2 mm posterior to the limbus and 5 microliters of test article was injected into the suprachoroidal space. Rats were treated with either saline or aflibercept (Eylea 40 mg/mL, Regeneron Pharmaceuticals).
  • FIGS. 37A-37B which also includes the results of single-injection saline and Eylea treated animals from Example 8, the double-injection saline treated animals exhibited approximately 4898 ⁇ 254 pixels 2 while the double-injection aflibercept treated animals showed approximately 3485 ⁇ 280 pixels 2 based on evaluation of neovascular leak area. The difference between these measurements represents a statistically significant (pO.001) reduction in neovascularization on comparing the double-injection aflibercept treated group to the double-injection saline treated group.
  • FIGS. 38-40 illustrates that there is little statistically significant differences in the lesion area between the single-injection saline treated animals and the double-injection saline treated animals.
  • FIGS. 38-40 also illustrates the difference in the lesion area between the single-injection Eylea (aflibercept) treated animals (200 ⁇ g) and the double-injection Eylea (aflibercept) treated animals (400 ⁇ g).
  • the lesion area values for saline (intravitreal administration) and Eylea (200 ⁇ g, intravitreal administration) are also shown for comparison.
  • FIG. 39 better illustrates the comparison between the single-injection Eylea treatment (200 ⁇ g, suprachoroidal space administration), saline treatment (intravitreal administration) and Eylea (aflibercept) (200 ⁇ g, intravitreal administration).
  • Example 10 Efficacy of Suprachoroidal CLS-TA in Combination with Intravitreal Aflibercept in Subjects with BRVO or CRVO
  • All qualifying subjects were randomized (Day 1) to receive an IVT injection of an anti- VEGF treatment (aflibercept) plus a suprachoroidal injection of CLS-TA or an IVT injection of aflibercept plus a sham suprachoroidal procedure. Subjects were followed for approximately 3 months following randomization. The subject, sponsor, visual acuity technician and the optical coherence tomography (OCT) reading center were masked to treatment.
  • OCT optical coherence tomography
  • Example 4 The design of scheduled visits for the 46 total enrolled subjects was described in Example 4. The following assessments were made: the total number of times subjects qualified to be administered IVT aflibercept in each arm through month 3; mean central subfoveal thickness (CST) at 1, 2, and 3 months; mean change in central subfoveal thickness (CST) at 1, 2, and 3 months; mean best corrected visual acity (BCVA) at 1, 2, and 3 months; and mean change in best corrected visual acity (BCVA) at 1, 2, and 3 months.
  • CST central subfoveal thickness
  • BCVA best corrected visual acity
  • BCVA mean change in best corrected visual acity
  • FIG. 46 shows the qualification for retreatment with aflibercept of the enrolled patients from both arms.
  • the mean central subfoveal thickness (CST) was 638 ⁇ in the BRVO subjects treated with aflibercept + Zuprata (Active group) and was 586 ⁇ in the BRVO subjects in the Control group at baseline.
  • the mean CST was reduced to approximately 300 ⁇ in both treatment groups at month 1.
  • the mean CST in the subjects treated with Active group remained at 295 ⁇ .
  • the mean CST was approximately 300 ⁇ for the subjects in both groups.
  • the Active group was more consistently effective in reducing CST.
  • aflibercept + Zuprata also improved the mean score of BCVA more compared to subjects in the Control group from baseline to month 3 in CRVO patients.
  • subjects in the Active group gained 21 socres while subjects in the Control group gained 10 scores, showing an additional increase in BCVA of 11 scores for the Active group over the Control group at month 1 (FIG. 54).
  • BCVA was also improved at month 2 and month 3, with 18 scores increase in the Active group compared to the Control group at month 2, and a 16 scores increase in the Active group compared to the Control group at month 3.
  • FIG. 55 A greater proportion of non-ischemic patients qualified for aflibercept retreatment, independent of Control vs. Active group (FIG. 55). Within the ischemic group (independent of RVO type), no active arm patients qualified for aflibercept retreatment, while 40% of Control group patients qualified for aflibercpet retreatment (FIG. 56). Within the nonischemic group (independent of RVO type), far more patients in the control arm required aflibercept retreatment relative to active arm (13 (72%) vs. 5 (29%) of total patients in each group; FIG. 57).
  • FIG. 58A-D shows the BVCA and CST data for ischemic versus non-ischemic patients independent of treatment, at months 1, 2, and 3 of the study.
  • FIG. 58A shows BVCA in ischemic versus non-ischemic patients. There was little difference in BVCA between non- schemic and ischemic groups.
  • FIG. 58B shows that the change in BVCA remained the same (13 or 14) in the non-ischemic group but increased (to 16, 21, and 20 at months 1, 2, and 3, respectively) in the ischemic group.
  • FIG. 58C shows that CST in non-ischemic patients was reduced from 715 ⁇ at baseline to 352 ⁇ at month 3; and CST in ischemic patients was reduced from 773 ⁇ at baseline to 280 ⁇ at month 3.
  • FIG. 58D shows the change in CST, and indicates that ischemic patients consistenly exhibited more of a reduction in CST over the 3 month study period.
  • FIG. 59A-D shows the BVCA and CST data for non-ischemic patients in each treatment group, at months 1, 2, and 3 of the study.
  • FIG. 59A shows that for non-ischemic patients, BVCA increased from about 52 at baseline to about 69 at month 3 in the Active treatment group, whereas BVCA increased from about 48 at baseline to only about 58 in the control group.
  • the change in BVCA over time in these patients was about 3 letters better in the the Active group versus the control group at month 1, and about 8 letters better in the Active group versus the control group at months 2 and 3 (FIG. 59B).
  • FIG. 59C shows that CST was reduced in the Active arm relative to the control arm by month 2 and remained reduced compared to control at month 3.
  • FIG. 59D shows that at months 2 and 3, the active arm exhibited more of a reduction in CST relative to the control arm.
  • FIG. 60A-D shows the BVCA and CST data for ischemic patients in each treatment group, at months 1, 2, and 3 of the study.
  • FIG. 60A shows that for ischemic patients, BVCA for the group was similar at each month of the study in both groups.
  • FIG. 60B shows the change in BVCA in ischemic patients in the control arm was reduced compared to the change in BVCA in the active arm; active arm patients gained about 9 more letters at months 1 and 2, and about 7 more letters at month 3, relative to control patients.
  • FIG. 60C shows that CST was reduced in the Active arm relative to the control arm by month 1.
  • FIG. 60D shows the change in CST, and indicates that active arm patients consistenly exhibited more of a reduction in CST over the 3 month study period.
  • FIG. 61A-D shows the BVCA data for each treatment group, stratified into ischemic or non-ischemic and BRVO or CRVO groups, at months 1, 2, and 3 of the study.
  • FIG. 61A shows BVCA in ischemic BRVO patients in the control arm (aflibercept + sham) versus the active arm, and indicates that the patients in the active arm exhibited an increase in BVCE at each month of the study.
  • FIG. 61B shows that while patients in the active arm exhibited a consistent increase in BVCA, patients in the control arm exhibited higher BVCA than active arm patients at both month 1 and month 3.
  • FIG. 62 provides a summary of the data provided in FIGS. 61 A-D.

Abstract

La présente invention concerne des méthodes et des dispositifs pour le traitement de la dégénérescence maculaire liée à l'âge (DMLA) humide, la néovascularisation choroïdienne (CNV), la DMLA humide associée à la CNV et/ou la DMLA humide associée à l'occlusion veineuse rétinienne (RVO) chez un sujet humain qui en a besoin. Selon certains aspects, les dispositifs décrits dans la présente description comprennent un récipient de médicament délimitant une lumière conçue pour contenir un médicament, une partie terminale distale du récipient de médicament comprenant une partie d'accouplement conçue pour être accouplée amovible à un ensemble aiguille, une partie terminale proximale du récipient de médicament comprenant un rebord et un épaulement longitudinal ; un ensemble piston comprenant une partie terminale distale disposée mobile à l'intérieur de la lumière du récipient de médicament ; et une poignée accouplée à une partie terminale proximale de l'ensemble piston.
EP17736528.5A 2016-01-08 2017-01-09 Méthodes et dispositifs pour le traitement de troubles oculaires postérieurs avec l'aflibercept et d'autres substances biologiques Withdrawn EP3400014A1 (fr)

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KR20180101488A (ko) 2018-09-12
AU2017206114A1 (en) 2018-08-02
CA3010862A1 (fr) 2017-07-13
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