RU2776850C2 - Methods for treatment of eye diseases - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: patient is administered with five separate doses of VEGF antagonist at intervals of 6 weeks for the treatment of diabetic macular edema. VEGF antagonist is then additionally administered once every 8 weeks or once every 12 weeks. VEGF antagonist contains sequences SEQ ID NO:1 and SEQ ID NO:2.

EFFECT: group of inventions provides for an effective method for the treatment of diabetic macular edema and the use of less frequent administration of doses of a drug than it is provided in treatment schemes approved nowadays.

48 cl, 1 tbl, 1 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The present invention relates to methods for treating an ocular disease with a VEGF antagonist. In particular, the present invention relates to the treatment of diabetic macular edema using less frequent dosing than currently approved regimens.

BACKGROUND OF THE INVENTION

Diabetes mellitus (DM) is the most common endocrine disease in developed countries, with prevalence estimates ranging from 2% to 5% of the world's population. Diabetic retinopathy (DR) and diabetic macular edema (DME) are common microvascular complications in patients with diabetes and can have a debilitating effect on visual acuity (VA), eventually leading to blindness. DME is a common manifestation of DR (Riordan-Eva, 2004, Eye (Lond). 2004, 18:1161-8) and is the main cause of vision loss in DR patients.

Anti-VEGF agents such as ranibizumab or aflibercept demonstrated a favorable benefit/risk ratio with superior efficacy compared to the previous standard of care (laser photocoagulation) in large Phase 3 study programs that subsequently led to their approval for the treatment of DME. The use of anti-VEGF therapies resulted in clinically meaningful improvements in BCVA, reduced fluid accumulation, and decreased severity of diabetic retinopathy.

Current treatment options for patients with DME are: laser photocoagulation, intravitreal (IVT) corticosteroids, IVT corticosteroid implants, or anti-VEGF IVT therapeutics. The efficacy and safety profile of anti-VEGF therapy has made it a first-line treatment. Corticosteroids are used as a second-line treatment, and focal/sectoral laser photocoagulation remains a therapeutic option, but with a lower expected benefit compared to steroid and anti-VEGF therapy.

Despite the success of treatment with existing anti-VEGF agents, there remains a need for additional treatment options to improve response rates and/or reduce resource utilization and injection frequency in patients with DME (Mitchell et al., 2011, Ophthalmology 118(4) :615-25; Smiddy, 2011, Ophthalmology 118(9):1827-33; Lang et al., 2013, Ophthalmology 120(10):2004-12; Virgili et al., 2014, Br J Ophthalmol 98(4) :421-2; Agarwal et al., 2015, Curr Diab Rep. 15(10):75).

SHORT DESCRIPTION

The present invention provides an improved method of administering a therapeutic VEGF antagonist for the treatment of ocular diseases, in particular diabetic macular edema (DME). In certain aspects, the present invention provides methods for treating DME comprising administering to a mammal five separate doses of a VEGF antagonist at 6 week intervals, followed by additional doses every 12 weeks (q12) and/or every 8 weeks (q8) depending on the results. procedures for assessing disease activity using predefined visual and anatomical criteria. In one aspect, the frequency of dosing may be increased by an additional four weeks if disease activity is not detected at certain scheduled visits during the treatment period.

The present invention also provides a VEGF antagonist for use in a method treatment of ocular diseases, in particular ocular neovascular diseases, more specifically diabetic macular edema (DME), in a patient, where the VEGF antagonist is first provided in a loading phase during which the patient receives five separate doses of the VEGF antagonist at intervals of 6 weeks, and the VEGF antagonist is then given in a maintenance phase during which the patient receives an additional dose of the VEGF antagonist once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen).

In some aspects, the VEGF antagonist used in the method of the present invention is an antibody to VEGF. In a specific aspect, the anti-VEGF antibody is a single chain antibody (scFv) or a Fab fragment. In particular, the anti-VEGF antibody is RTH258.

Specific preferred embodiments of the present invention will become apparent from the following more detailed description of some preferred embodiments and the claims.

DETAILED DESCRIPTION

Definitions

It is implied and provided that the following definitions and explanations take precedence in any following construction, unless they are expressly and unambiguously modified in the following examples or when considered in the context of semantic meaning makes any construction meaningless or essentially meaningless. Where the construction of a term makes it meaningless or essentially meaningless, reference should be made to the 3rd edition of Webster's Dictionary or to a dictionary known to those skilled in the art, such as the Oxford Dictionary of Biochemistry and Molecular Biology (Ed. Anthony Smith, Oxford) for a definition. University Press, Oxford, 2004).

All percentages used in this document are percentages by weight unless otherwise noted.

As used herein and unless otherwise indicated, terms in the singular mean "one", "at least one", or "one or more". Unless the context otherwise requires, singular terms used herein should include the plural, and plural terms should include the singular.

The contents of any patents, patent applications, and references cited throughout this specification are hereby incorporated by reference in their entirety.

The term "VEGF" refers to 165-amino acid vascular endothelial growth factor and related 121-, 189- and 206-amino acid vascular endothelial growth factors as described by Leung et al. , Science 246:1306 (1989) and Houck et al. , Mol. Endocrin. 5:1806 (1991), together with the naturally occurring allelic and processed forms of these growth factors.

The term "VEGF receptor" or "VEGFr" refers to the cellular VEGF receptor, typically the cell surface receptor, found on vascular endothelial cells, as well as variants thereof that retain the ability to bind hVEGF. One example of a VEGF receptor is fms-like tyrosine kinase (flt), which is a transmembrane receptor from the tyrosine kinase family. DeVries et al. , Science 255:989 (1992); Shibuya et al. , Oncogene 5:519 (1990). The Flt receptor contains an extracellular domain, a transmembrane domain, and an intracellular domain with tyrosine kinase activity. The extracellular domain is involved in VEGF binding, while the intracellular domain is involved in signal transduction. Another example of a VEGF receptor is the flk-1 receptor (also referred to as KDR). Matthews et al. , Proc. Nat. Acad. sci. 88:9026 (1991); Terman et al. , Oncogene 6:1677 (1991); Terman et al. , Biochem. Biophys. Res. commun. 187:1579 (1992). Binding of VEGF to the flt receptor results in the formation of at least two high molecular weight complexes having an apparent molecular weight of 205,000 and 300,000 daltons. The 300,000 dalton complex is believed to be a dimer containing two receptor molecules bound to one VEGF molecule.

As used herein, the term "VEGF antagonist" refers to a compound that can reduce or inhibit the activity of VEGF in vivo . The VEGF antagonist may bind to the VEGF receptor(s) or block the binding of the VEGF protein(s) to the VEGF receptor(s). The VEGF antagonist can be, for example, a small molecule, an anti-VEGF antibody or antigen-binding fragments thereof, a fusion protein (such as aflibercept or another such soluble decoy receptor), an aptamer, an antisense nucleic acid molecule, interfering RNA, receptor proteins, and the like. that can specifically bind to one or more VEGF proteins or one or more VEGF receptors. Several VEGF antagonists are described in WO 2006/047325.

In a preferred embodiment, the VEGF antagonist is an anti-VEGF antibody (such as RTH258 or ranibizumab) or a soluble VEGF receptor (such as aflibercept).

The term "antibody" as used herein includes full length antibodies and any antigen binding fragment (i.e. "antigen-binding portion", "antigen-binding polypeptide" or "immunobinding agent") or one chain thereof. An "antibody" includes a glycoprotein containing at least two heavy (H) chains and two light (L) chains linked by disulfide bonds, or an antigen-binding portion thereof. Each heavy chain is composed of a heavy chain variable region (abbreviated herein as V_H) and the heavy chain constant region. The heavy chain constant region consists of three domains: CH1, CH2, and CH3. Each light chain is composed of a light chain variable region (abbreviated herein as V_L) and the light chain constant region. The light chain constant region consists of a single domain, referred to as CL. V_H- and V_LThe α-regions can be further subdivided into regions of hypervariability called complementarity determining regions (CDRs) that alternate with more conserved regions called framework regions (FRs). Each of the V_H and V_L formed by three CDRs and four FRs arranged from amino to carboxy in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with the antigen. Antibody constant regions can mediate immunoglobulin binding to host tissues or factors, including various cells of the immune system (eg, effector cells) and the first component (Clq) of the classical complement system.

The terms "single chain antibody", "single chain Fv", or "scFv" are intended to refer to a molecule comprising an antibody heavy chain variable domain (or region; V _H ) and an antibody light chain variable domain (or region; V _L ) connected by a linker. Such scFv molecules may have the general structure: NH ₂ -V _L -linker-V _H -COOH or NH ₂ -V _H -linker-V _L -COOH.

The term "antigen-binding portion" of an antibody (or simply "antibody portion") refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., VEGF). It has been shown that the antigen-binding function of an antibody can be carried out by fragments of a full-length antibody. Examples of binding fragments encompassed by the term "antigen-binding portion" of an antibody include (i) Fab fragment, a monovalent fragment consisting of V_L-, V_H-, CL- and CH1-domain; (ii) F(ab')₂-fragment, a bivalent fragment containing two Fab fragments connected by a disulfide bridge in the hinge region; (iii) Fd-fragment consisting of V_H- and CH1-domain; (iv) Fv-fragment consisting of V_L- and V_H-domain of one arm of the antibody, (v) single-domain antibody or dAb fragment (Wardet al., (1989)Nature 341:544-546), which consists of V_H-domain; and (vi) an isolated complementarity determining region (CDR), or (vii) a combination of two or more isolated CDRs, which may optionally be joined by a synthetic linker. In addition, although the two domains of the Fv fragment V_L and V_H are encoded by separate genes, they can be combined using recombinant methods with the help of a synthetic linker, which makes it possible to convert them into a single protein chain in which the V_L and V_H pair up to form monovalent molecules (known as single-stranded Fvs (scFvs); see, for example, birdet al., 1988Science 242:423-426 and Hustonet al., 1988Proc. Natl. Acad. sci. USA85:5879-5883). It is contemplated that such single chain antibodies are also encompassed by the term "antigen-binding portion" of an antibody. Such antibody fragments are prepared using conventional techniques known to those skilled in the art and the fragments are screened for suitability in the same manner as intact antibodies. Antigen-binding portions can be obtained by recombinant DNA techniques or by enzymatic or chemical cleavage of intact immunoglobulins. Antibodies can be of different isotypes, for example an IgG isotype antibody (for example, subtype IgG1, IgG2, IgG3 or IgG4), IgA1, IgA2, IgD, IgE or IgM.

The term "mammal" as used herein includes any animal classified as a mammal, including, without limitation, humans, domestic animals, farm and companion animals, and the like.

As used herein, the term "subject" or "patient" refers to humans and non-human mammals, including, without limitation, primates, pigs, horses, dogs, cats, sheep, and cows. Preferably the subject or patient is a human.

An "ocular disease" or "neovascular ocular disease" that can be treated using the method of the present invention includes a condition, disease, or disorder associated with ocular neovascularization, including, but not limited to, abnormal angiogenesis, choroidal neovascularization (CNV), retinal vascular permeability , retinal edema, diabetic retinopathy (particularly proliferative diabetic retinopathy), diabetic macular edema (DME), neovascular (exudative) age-related macular degeneration (AMD), including nAMD-associated CNV (neovascular AMD), complications, associated with retinal ischemia, central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), and posterior segment neovascularization. In a preferred embodiment, the disease is DME. In some embodiments, the disease is macular edema secondary to CRVO or BRVO.

Treatment regimen

The present invention provides methods for determining whether patients being treated for an ocular disease with a VEGF antagonist are eligible for treatments every eight weeks, every twelve weeks, or every 16 weeks.

The present invention provides methods for treating ocular neovascular diseases, including DME, in a mammal, the methods comprising administering multiple doses of a VEGF antagonist to the mammal at various intervals for at least two years. In some embodiments, doses are administered at intervals of five to 6 weeks during a "loading phase" followed by further doses at intervals of 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks (i.e. q12w) during the "maintenance phase". Disease activity assessment procedures are performed at least at each additional scheduled administration during the maintenance phase. When disease activity is identified as described herein, the treatment regimen is changed from administration every 12 weeks to administration every 8 weeks (ie q8w). The present invention provides specific criteria, established by the present inventors based on disease activity assessment procedures, to determine when to use the 8 week interval and when to continue using the 12 week interval. In some cases, the patient may be on a 12 week interval regimen for a while and then switch to an 8 week interval and then back to a 12 week interval. Thus, patients may not adhere to only one interval regimen, but may switch from one regimen to another depending on the results of the evaluation procedures in accordance with the criteria set forth in this document.

In one embodiment, when disease activity is not detected during several consecutive visits during a treatment period, the attending physician may extend treatment for an additional one to four weeks. For example, if a patient is treated every 12 weeks, the attending physician may extend the treatments to every 13, 14, 15, or 16 weeks; or if the patient is treated every 8 weeks, the attending physician may extend the treatments to every 9, 10, 11 or 12 weeks. If disease activity is detected at any visit during the treatment period, the treatment regimen is adjusted back to a treatment regimen of 12 weeks or 8 weeks. As used herein, the term "disease activity" refers to the worsening of an eye disease based on the criteria presented herein.

In one embodiment, the invention relates to a method of treating ocular diseases, in particular ocular neovascular diseases, more specifically DME, comprising administering a VEGF antagonist to a mammal in need according to the following schedule:

a "loading phase" of 5 doses administered at 6 week intervals (i.e. "q6" or "q6w") (e.g. day 0, week 6, week 12, week 18, week 24), and

"maintenance phase" of additional doses administered at intervals of 12 weeks (ie "q12" or "q12w").

In some embodiments, the "maintenance phase" may be additional doses at intervals of 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks and may be adjusted as described herein based on results. disease activity assessment procedures as described herein.

In some embodiments, the "loading phase" may include 5 doses administered at intervals of 4 weeks (q4w) or q6w, or 4 doses administered at intervals of q4w or q6w. In some embodiments, where the ocular disease being treated is BRVO or CRVO (e.g., macular edema secondary to BRVO or CRVO), the loading phase is 4 doses or 5 doses at intervals of q4w followed by maintenance phase as described above and herein.

In some embodiments, a disease activity assessment ("DAA") is performed at all scheduled visits during the treatment period. In one embodiment, the patient is re-assigned to the q8 dose regimen based on the presence of a certain level of disease activity as determined by the attending physician.

During evaluation weeks, patients may follow their current regimen at intervals of 8 weeks or 12 weeks. Thus, the evaluation can determine whether the patient should continue with the current interval or should move to a different interval.

The assessment described herein preferably includes one or more of the following tests to assess RTH258 activity in relation to visual function, retinal structure, and fluid leakage.

Maximum corrected visual acuity obtained using a similar ETDRS chart at a distance of 4 meters.

Anatomical markers according to optical coherence tomography.

DRSS ETDRS score based on 7-site stereo color fundus photography.

Evaluation of fluid leakage through the vessels using fluorescein angiography.

Visual acuity can be assessed using the best correction score determined by the refraction protocol (BCVA). BCVA measurements can be made in a seated position using visual acuity charts like ETDRS.

Optical coherence tomography (OCT), color fundus photography, and fluorescein angiography can be evaluated according to methods known to those skilled in the art.

Additional criteria for assessing disease activity include, but are not limited to, changes in central subfield thickness (CST). CST is the average thickness of a 1 mm rounded area centered in the foveal region measured from the retinal pigment epithelium (RPE) to the inner limiting membrane (ILM) inclusive. CST can be measured, for example, using optical coherence tomography in the spectral domain (SD-OCT).

Methods for performing the above tests are well known and widely used by those skilled in the art.

Disease activity is assessed by clinically significant improvements in BCVA score, reduction in central subfield thickness (CST), reduction in fluid accumulation (eg, retinal fluid), and/or reduction in severity of diabetic retinopathy. As disease activity worsens (eg, omission of letters as measured by BCVA, increased CST, increased fluid accumulation, or increased severity of diabetic retinopathy), more frequent dosing intervals are established thereafter. If there is an improvement in disease activity, a less frequent dosing interval is established. If there is neither deterioration nor improvement in disease activity, the interval between doses is maintained or increased (less often). The fluid measured in the eye may be intraretinal and/or subretinal fluid.

An assessment of disease activity status may be based, for example, on dynamic changes in BCVA score, central subfield thickness (CST), and/or intraretinal fluid status, as assessed, for example, by optical coherence tomography in the spectral domain. Subsequently, you can be guided, for example, by a decrease in BCVA due to disease activity compared to the results of a previous assessment. It should be understood that the attending physician may make a decision based on clinical judgment, which may include more than just visual acuity criteria. Disease activity assessment procedures may include both visual acuity and anatomical criteria.

In one embodiment, DME disease activity assessment procedures to establish a patient's disease status occur at week 28 (exercise phase treatment outcome). The disease activity assessment (DAA) during treatment regimens is performed at the discretion of the assessor (e.g., treating physician) and is based on changes in vision and anatomical parameters with reference to the patient's disease status at week 28. The outcome of this assessment is reported as:

'need for q8w': identified disease activity that, in the opinion of the treating physician, requires more frequent use of anti-VEGF therapies, such as missing ≥5 letters in BCVA (compared to week 28), which, based on anatomical parameters, is associated with presence of DME disease activity;

'no need for q8w': otherwise, if the DAA determines a need for additional q8w treatment, the subject is subsequently given q8w injections. If the disease status improves, the attending physician may re-initiate the q12w regimen for the patient.

If the DAA indicates a need for more frequent treatment, the patient is subsequently given q8w injections or an extension of the interval between treatments based on a stability assessment up to week 72, as described herein.

In some embodiments, the patient may be treated with brolucizumab once every four weeks (q4w) or once every six weeks (q6w), and the attending physician may evaluate disease activity at each treatment or before the scheduled treatment to determine if the less frequent dosing (eg, q8w, or q12w, or q16w) as appropriate, using, for example, DAA as described herein. For example, a patient may be treated with q4w for several months and then switched to a less frequent dosing regimen (eg, q8w, q12w, or q16w) based on favorable DAA.

Antibodies to VEGF

In some embodiments, the VEGF antagonist used in the method of the present invention is an anti-VEGF antibody, in particular an anti-VEGF antibody described in WO 2009/155724, the entire content of which is incorporated herein by reference.

In one embodiment, an anti-VEGF antibody of the present invention comprises a heavy chain variable region having the sequence set forth in SEQ ID NO: 1 and a light chain variable region having the sequence set forth in SEQ ID NO: 2.

VH: SEQ ID NO: 1

EVQLVESGGGLVQPGGSLRLSCTASGFSLTDYYYMTWVRQAPGKGLEWVGFIDPDDDPYYATWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGGDHNSGWGLDIWGQGTLVTVSS

VL: SEQ ID NO: 2

EIVMTQSPSTLSASVGDRVIITCQASEIIHSWLAWYQQKPGKAPKLLIYLASTLASGVPSRFSGSGSGAEFTLTISSLQPDDFATYYCQNVYLASTNGANFGQGTKLTVLG

In another embodiment, the anti-VEGF antibody used in the method of the present invention contains the sequence shown under SEQ ID NO: 3.

EIVMTQSPSTLSASVGDRVIITCQASEIIHSWLAWYQQKPGKAPKLLIYLASTLASGVPSRFSGSGSGAEFTLTISSLQPDDFATYYCQNVYLASTNGANFGQGTKLTVLGGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCTASGFSLTDYYYMTWVRQAPGKGLEWVGFIDPDDDPYYATWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGGDHNSGWGLDIWGQGTLVTVSS

In a preferred embodiment, the anti-VEGF antibody used in the method of the present invention is RTH258 (which contains SEQ ID NO: 3). Methionine derived from the start codon in the expression vector is present in the final protein in cases where it has not been post-translationally cleaved, as shown below.

MEIVMTQSPS TLSASVGDRV IITCQASEII HSWLAWYQQK PGKAPKLLIY LASTLASGVP SRFSGSGSGA EFTLTISSLQ PDDFATYYCQ NVYLASTNGA NFGQGTKLTV LGGGGGSGGG GSGGGGSGGG GSEVQLVESG GGLVQPGGSL RLSCTASGFS LTDYYYMTWV RQAPGKGLEW VGFIDPDDDP YYATWAKGRF TISRDNSKNT LYLQMNSLRA EDTAVYYCAG GDHNSGWGLD IWGQGTLVTV SS (SEQ ID NO: 4)

RTH258, also known as brolucizumab, is a single chain Fv fragment (scFv) of a humanized VEGF inhibitory antibody with a molecular weight of ~26 kDa. It is an inhibitor of VEGF-A and functions by binding to the receptor binding site of the VEGF-A molecule, thereby preventing VEGF-A from interacting with its VEGFR1 and VEGFR2 receptors on the surface of endothelial cells. Increased levels of signaling through the VEGF signaling pathway are associated with abnormal angiogenesis in the eye and retinal edema. Suppression of the VEGF signaling pathway has been shown to inhibit the growth of neovascular lesions and reverse retinal edema in nAMD patients.

Pharmaceuticals

In one aspect, the methods of the present invention include the use of pharmaceutical formulations containing anti-VEGF antibodies. The term "pharmaceutical formulation" refers to preparations that are in such a form as to provide unambiguous efficacy of the biological activity of the antibody or antibody derivative, and which do not contain additional components that are toxic to subjects to whom the formulation will be administered. "Pharmaceutical" excipients (carrier media, additives) are those which are acceptable for administration to a mammalian subject to provide an effective dose of the active ingredient used.

A "stable" formulation is one in which the antibody or antibody derivative therein substantially retains its physical stability and/or chemical stability and/or biological activity upon storage. Various analytical procedures for measuring protein stability are available in the art and are discussed in Peptide and Protein Drug Delivery, 247-301, Vincent Lee Ed., Marcel Dekker, Inc., New York, N.Y., Pubs. (1991) and Jones, A. Adv. Drug Delivery Rev. 10:29-90 (1993), e.g. Stability can be measured at a selected temperature for a selected period of time. Preferably the composition is stable at room temperature (about 30°C) or at 40°C for at least 1 week and/or stable at about 2-8°C for at least 3 months to 2 years. In addition, the composition is preferably stable after freezing (before, eg -70°C) and thawing the formulation.

An antibody or antibody derivative "retains its physical stability" in a pharmaceutical formulation if it meets certain release requirements for aggregation, degradation, precipitation and/or denaturation as measured by visual assessment of color and/or clarity, or measured by UV light scattering, or size exclusion chromatography, or other suitable methods known in the art.

An antibody or antibody derivative "retains its physical stability" in a pharmaceutical formulation if the chemical stability at a given point in time is such that the protein is considered to still retain its biological activity, as defined below. Chemical stability can be assessed by detecting and quantifying chemically altered forms of a protein. The chemical change may include size modification (for example, cut-off) that can be assessed using size exclusion chromatography, SDS-PAGE and/or matrix-assisted laser desorption ionization/time-of-flight mass spectrometry (MALDI/TOF MS), for example. Other types of chemical change include charge change (for example, occurring as a result of deamidation), which can be assessed, for example, using ion exchange chromatography.

An antibody or antibody derivative "retains its biological activity" in a pharmaceutical formulation if the biological activity of the antibody at a given point in time is within approximately 10% (within assay error) of the biological activity exhibited immediately after preparation of the pharmaceutical formulation, e.g., as determined in the assay antigen binding. Other assays for the "biological activity" of antibodies are described in detail herein below.

By "isotonic" is meant that the composition of interest has substantially the same osmotic pressure as human blood. Isotonic formulations typically have an osmotic pressure of about 250 to 350 mOsm. Isotonicity can be measured, for example, with a vapor pressure osmometer or an osmometer that measures the drop in freezing point.

"Polyol" is a substance with multiple hydroxyl groups and includes sugars (reducing and non-reducing sugars), sugar alcohols and sugar acids. Preferred polyols herein have a molecular weight that is less than about 600 kDa (e.g., in the range from about 120 to about 400 kDa). A "reducing sugar" is a sugar that contains a hemiacetal group that can reduce metal ions or covalently react with lysine and other amino groups in proteins, and a "non-reducing sugar" is a sugar that does not have these reducing sugar properties. Examples of reducing sugars are fructose, mannose, maltose, lactose, arabinose, xylose, ribose, rhamnose, galactose and glucose. Non-reducing sugars include sucrose, trehalose, sorbose, melicitose and raffinose. Mannitol, xylitol, erythritol, threitol, sorbitol and glycerin are examples of sugar alcohols. With regard to sugar acids, these include L-gluconate and its metal salts. If it is desired that the formulation be freeze-thaw stable, the polyol is preferably a polyol that does not crystallize at freezing temperatures (e.g. -20°C) so that it does not destabilize the antibody in the formulation. Non-reducing sugars such as sucrose and trehalose are the polyols preferred herein, with trehalose being preferred over sucrose due to the excellent stability of trehalose solution.

As used herein, the term "buffer" refers to a buffered solution that prevents pH change through the action of its acid-base conjugate components. The buffer of this invention is characterized by a pH in the range from about 4.5 to about 8.0; preferably from about 5.5 to about 7. Examples of buffers that will control the pH in this range include acetate (e.g., sodium acetate), succinate (such as sodium succinate), gluconate, histidine, citrate, and other organic acid buffers. If a freeze-thaw resistant formulation is desired, the buffer is preferably non-phosphate.

In a pharmacological sense, in the context of the present invention, a "therapeutically effective amount" of an antibody or antibody derivative refers to an amount effective in preventing or treating the disorder for which the antibody or antibody derivative is effective. A "disease/disorder" is any condition in which treatment with an antibody or antibody derivative can have a beneficial effect. This includes chronic and acute disorders or diseases, including those pathological conditions which predispose the mammal to the disorder in question.

A "preservative" is a compound that can be included in a formulation to substantially reduce bacterial activity therein, thereby facilitating, for example, a formulation for repeated use. Examples of potential preservatives include octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride (a mixture of alkylbenzyldimethylammonium chlorides in which the alkyl groups are long chain compounds) and benzethonium chloride. Other types of preservatives include aromatic alcohols such as phenol, butyl and benzyl alcohols, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol and m-cresol. The most preferred preservative herein is benzyl alcohol.

The pharmaceutical compositions used in the present invention comprise a VEGF antagonist, preferably an anti-VEGF antibody (e.g., an anti-VEGF antibody comprising a light chain variable region sequence of SEQ ID NO: 1 and a heavy chain variable region sequence of SEQ ID NO: 2, such as brolucizumab), together with at least one physiologically acceptable carrier or excipient. Pharmaceutical compositions may contain, for example, one or more of water, buffers (for example, neutral buffered saline or phosphate buffered saline), ethanol, mineral oil, vegetable oil, dimethyl sulfoxide, carbohydrates (eg. glucose, mannose, sucrose or dextrans), mannitol, proteins, adjuvants, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione and/or preservatives. As noted above, other active ingredients may (but need not) be included in the pharmaceutical compositions provided herein.

A carrier is a substance that can be associated with an antibody or antibody derivative prior to administration to a patient, often to control the stability or bioavailability of the compound. Carriers for use in such formulations are generally biocompatible and may also be biodegradable. Carriers include, for example, monovalent or polyvalent molecules such as serum albumin (for example, human or bovine), ovalbumin, peptides, polylysine and polysaccharides such as aminodextran and polyamidoamines. Carriers also include solid auxiliary materials such as microgranules and microparticles containing, for example, polylactate-polyglycolate, lactide-glycolide copolymer, polyacrylate, latex, starch, cellulose or dextran. The carrier may carry the compounds in a variety of ways, including covalent bonding (either directly or via a linker group), non-covalent interaction, or admixture.

Pharmaceutical compositions may be formulated for any suitable route of administration, including, for example, topical, intraocular, oral, nasal, rectal, or parenteral administration. In some embodiments, compositions in a form suitable for intraocular injection, such as intravitreal injection, are preferred. Other forms include, for example, pills, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules or syrups or tinctures. In still other embodiments, the compositions provided herein may be formulated as a lyophilisate. The term parenteral as used herein includes subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal and intraperitoneal injection, as well as any similar injection or infusion technique.

The pharmaceutical composition can be prepared as a sterile injectable aqueous or oily suspension in which the active agent (ie the VEGF antagonist), depending on the carrier and concentration used, is either suspended or dissolved in the carrier medium. Such a composition can be formulated according to a method known in the art using suitable dispersing, wetting and/or suspending agents, such as those mentioned above. Acceptable vehicles and solvents that may be used include water, 1,3-butanediol, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils can be used as a solvent or suspending medium. For this purpose, any non-volatile fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectable compositions, and adjuvants such as local anesthetics, preservatives and/or buffering agents may be dissolved in the carrier medium.

Dosage

The dose used in the method of the present invention depends on the particular disease or condition being treated. The term "therapeutically effective dose" is defined as an amount sufficient to achieve or at least partially achieve the desired effect. A therapeutically effective dose is sufficient if it can cause even a gradual change in the symptoms or conditions associated with the disease. A therapeutically effective dose need not completely cure the disease or completely eliminate the symptoms. Preferably, a therapeutically effective dose can at least partially arrest the disease and its complications in a patient already suffering from the disease. Amounts effective for a given use will depend on the severity of the disorder being treated and the general condition of the patient's own immune system.

The dose size can be readily determined using known dose adjustment techniques by a physician skilled in the treatment of the disease or condition. A therapeutically effective amount of a VEGF antagonist used in the method of the present invention is determined, for example, in terms of the required dose volumes and mode(s) of administration. Typically, therapeutically effective compositions are administered at dosages ranging from 0.001 mg/mL to about 200 mg/mL per dose. Preferably, the dosage used in the method of the present invention is from about 60 mg/ml to about 120 mg/ml (for example, the dosage is 60, 70, 80, 90, 100, 110, or 120 mg/ml). In a preferred embodiment, the dosage of the anti-VEGF antibody used in the method of the present invention is 60 mg/ml or 120 mg/ml.

In some embodiments, the dose is administered directly to the patient's eye. In one embodiment, the dose per eye is at least about 0.5 mg to about 6 mg. Preferred doses per eye include approximately 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg and 6.0 mg. Doses can be administered in various volumes suitable for ophthalmic administration, such as 50 μl or 100 μl, including, for example, 3 mg/50 μl or 6 mg/50 μl. Smaller volumes can also be used, including 20 µl or less, such as about 20 µl, about 10 µl, or about 8.0 µl. In some embodiments, a dose of 2.4 mg/20 μl, 1.2 mg/10 μl, or 1 mg/8.0 μl (e.g., 1 mg/8.3 μl) is administered to a patient's eye to treat or reduce the intensity of one or several diseases and disorders described above. Administration may be by, for example, intravitreal injection.

As used herein, the term "about" includes and describes a value or parameter as such. For example, "about x" includes and describes "x" as such. As used herein, the term "approximately" when used in connection with a measurement or when used to modify a value, unit, constant, or range of values, refers to variations of ±1-10% in addition to the included value or parameter as such. In some embodiments, the term "about" when used in connection with a measurement or when used to modify a value, unit, constant, or range of values, refers to variations of ±1, ±2, ±3, ±4, ±5, ±6, ±7, ±8, ±9 or ±10%.

The aqueous anti-VEGF antibody formulation used in the method of the present invention is prepared in a pH buffered solution. Preferably, the buffer of this aqueous formulation has a pH in the range of about 4.5 to about 8.0, preferably about 5.5 to about 7.0, most preferably about 6.75. In one embodiment, the pH of the aqueous pharmaceutical composition of the present invention is about 7.0-7.5, or about 7.0-7.4, about 7.0-7.3, about 7.0-7.2, about 7.1-7.6, about 7.2-7.6, about 7.3-7.6, or about 7.4-7.6. In one embodiment, the aqueous pharmaceutical composition of the present invention has a pH of about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 7.6. In a preferred embodiment, the aqueous pharmaceutical composition has a pH ≥7.0. In a preferred embodiment, the aqueous pharmaceutical composition has a pH of about 7.2. In another preferred embodiment, the aqueous pharmaceutical composition has a pH of about 7.4. In another preferred embodiment, the aqueous pharmaceutical composition has a pH of about 7.6. Examples of buffers that will control the pH within this range include acetate (e.g. sodium acetate), succinate (such as sodium succinate), gluconate, histidine, citrate, and other organic acid buffers. The buffer concentration may be from about 1 mM to about 50 mM, preferably from about 5 mM to about 30 mM, depending, for example, on the buffer and the desired isotonicity of the formulation.

A polyol that functions as a tonicity modifying agent can be used to stabilize the antibody in an aqueous formulation. In preferred embodiments, the polyol is a non-reducing sugar such as sucrose or trehalose. If necessary, the polyol is added to the composition in an amount that may vary depending on the required isotonicity of the composition. Preferably, the aqueous formulation is isotonic, in which case suitable concentrations of the polyol in the formulation are in the range of about 1% to about 15% w/v, preferably in the range of about 2% to about 10% w/v, for example. However, hypertonic or hypotonic formulations may also be suitable. The amount of added polyol may also vary depending on the molecular weight of the polyol. For example, a lower amount of a monosaccharide may be added (for example, mannitol) compared to a disaccharide (such as trehalose).

A surfactant is also added to the aqueous antibody formulation. Exemplary surfactants include nonionic surfactants such as polysorbates (e.g., polysorbates 20, 80, etc.) or poloxamers (for example, poloxamer 188). The amount of surfactant added is such that it reduces aggregation of the formulated antibody/antibody derivative and/or minimizes particulate formation in the formulation and/or reduces adsorption. For example, the surfactant may be present in the formulation in an amount of from about 0.001% to about 0.5%, preferably from about 0.005% to about 0.2%, and most preferably from about 0.01% to about 0.1%.

In one embodiment, the aqueous antibody formulation used in the method of the present invention is substantially free of one or more preservatives such as benzyl alcohol, phenol, m-cresol, chlorobutanol, and benzethonium Cl. In another embodiment, a preservative may be included in the formulation, particularly if the formulation is a multi-dose formulation. The concentration of the preservative may range from about 0.1% to about 2%, most preferably from about 0.5% to about 1%. One or more other pharmaceutically acceptable carriers, excipients, or stabilizers, such as those described in Remington's Pharmaceutical Sciences 21st edition, Osol, A. Ed. (2006) may be included provided that they do not adversely affect the required characteristics of the formulation. Acceptable carriers, excipients or stabilizers are non-toxic to recipients at the dosages and concentrations used and include additional buffering agents, co-solvents, antioxidants including ascorbic acid and methionine, chelating agents such as EDTA, metal complexes (e.g. Zn-protein complexes), biodegradable polymers such as polyesters and/or salt-forming counterions such as sodium.

Formulations to be used for in vivo administration must be sterile. This is easily achieved by filtration through sterile filtration membranes before or after formulation.

In one embodiment, the VEGF antagonist is administered to the eye of a mammal in need of treatment according to known ocular delivery methods. Preferably the mammal is a human, the VEGF antagonist is an anti-VEGF antibody, and the antibody is administered directly to the eye. Administration to a patient may be by, for example, intravitreal injection.

The VEGF antagonist in the method of the present invention may be administered as the sole treatment or in combination with other drugs or therapies useful in treating the condition in question.

A preferred RTH258 formulation for intravitreal injection contains about 4.5% to 11% (w/v) sucrose, 5-20 mM sodium citrate, and 0.001% to 0.05% (w/v) polysorbate 80, where pH composition is from about 7.0 to about 7.4. One such composition is shown in the table below. Another such formulation contains 5.9% (w/v) sucrose, 10 mM sodium citrate, 0.02% (w/v) polysorbate 80 at pH 7.2, and 6 mg RTH258. Another such formulation contains 6.4% (w/v) or 5.8% sucrose, 12 mM or 10 mM sodium citrate, 0.02% (w/v) polysorbate 80 at pH 7.2, and 3 mg RTH258 . Preferred concentrations of RTH258 are about 120 mg/ml and about 60 mg/ml. Doses can be administered, for example, at concentrations of 6 mg/50 μl and 3 mg/50 μl.

Table 1
Preferred Water Composition Component Concentration (% w/v) Concentration range (% w/v) RTH258 12 6-12 Citric acid, anhydrous 0.009 0.006-0.012 Trisodium citrate (dihydrate) 0.4 0.2-0.6 sucrose 6.75 4.5-11% Polysorbate 80 0.02% 0.01-0.05% hydrochloric acid or
sodium hydroxide pH 7.0 pH 6.0-7.5 Water for injections qs to bring up to 100 qs to bring up to 100

The following examples are provided to demonstrate preferred embodiments of the present invention. It will be appreciated by those skilled in the art that the techniques disclosed in the examples below are those that the present inventor has found to work reliably in the practice of the present invention, and thus may be considered to be preferred. ways of its practical application. However, those skilled in the art should, in light of the present invention, appreciate that many changes can be made to the specific embodiments that are disclosed and still a similar or analogous result can be obtained without departing from the spirit and scope of the invention. .

EXAMPLES

In the loading phase, the RTH258 treatment is administered every 6 weeks for five (5) consecutive injections (Day 0, Weeks 6, 12, 18 and 24).

The interval between treatments during the maintenance phase is shown below.

From week 24 onwards, patients receive one injection of RTH258 every 12 weeks. The patient's disease activity is assessed at week 32 and every 12 weeks (eg, weeks 32, 36, 48, 60, 72, and 84) before or after receiving a scheduled injection. If disease activity is determined during any of the assessment procedures, the patient is treated every 8 weeks (see "Assessment of disease activity" below).

At week 72, based on the evaluation of the stability of the disease (see "Evaluation of the stability of the disease" below), the attending physician has the opportunity to extend the interval between treatments by 4 weeks, i.e. q12w patients at week 72 may be given q16w and q8w patients may be given q12w. If the attending physician determines the presence of disease activity during the scheduled visit during the treatment period (in accordance with the treatment regimen for a particular patient, which includes q12w or q16w), the patient is assigned to the q8w treatment regimen.

Assessment of disease activity

The concept of the q12w/q8w regimen is to administer to patients, according to their individual treatment needs, either a q12w or q8w treatment regimen. The initial regimen is q12w and the patient will remain on the q12w regimen until the attending physician determines the presence of DME disease activity requiring more frequent use of anti-VEGF therapies. Disease Activity Assessment (DAA) procedures, and the resulting potential adjustment in treatment frequency, are limited to pre-defined DAA-enabled visits:

more careful monitoring of patients for individual treatment needs is carried out during the first treatment interval corresponding to q12w with DAA at weeks 32 and 36 (i.e. for patients 8 and 12 weeks after the last injection during the loading phase) to ensure that patients with a high need for treatment are identified at an early stage;

after the first treatment interval corresponding to q12w, DAA is performed in conjunction with a scheduled visit during the q12w treatment period, for example, at week 48, week 60, week 72, week 84, etc.

The attending physician evaluates DME disease activity to establish the patient's disease status at week 28 (treatment outcome in the exercise phase). Assessment of disease activity is at the discretion of the treating physician and should be made based on changes in vision and anatomical parameters with reference to the patient's disease status at week 28. The outcome of this assessment is recorded as:

'need for q8w': identified disease activity that, in the opinion of the treating physician, requires more frequent use of anti-VEGF therapies, such as missing ≥5 letters in BCVA (compared to week 28), which, based on anatomical parameters, is associated with presence of DME disease activity;

'no need for q8w': otherwise, if the DAA determines a need for additional q8w treatment, the subject is subsequently given q8w injections. If the disease status improves, the attending physician may re-initiate the q12w regimen for the patient.

If the DAA indicates a need for more frequent treatment, the patient is subsequently given q8w injections or an extension of the interval between treatments, based on a stability assessment, up to week 72, as described herein.

Assessment of disease stability

At week 72, the attending physician evaluates the patient for the possibility of extending the current interval between treatments by 4 weeks, that is, extending the treatment regimen from q12w to q16w and from q8w to q12w.

Based on the general concept that an extension of the treatment interval should only be considered for patients who have shown an adequate level of disease stability on the current treatment regimen, the treating physician will assess at week 72 whether a 4-week extension of the treatment interval is sufficient. The result of this assessment is recorded as:

'Treatment Interval Extension': In the judgment of the treating physician, there is sufficient disease stability to justify an increase in the treatment interval of 4 weeks, e.g. the patient did not show any disease activity during the previous two DAAs, i.e. . at week 60 and week 72.

'No Treatment Interval Extension': Otherwise, patients for whom a treatment interval extension has not been set by the treating physician continue treatment at the last scheduled treatment frequency, adjusted for future DAA procedures, at each scheduled visit to treatment period.

Activity score

To evaluate the activity of RTH258 in relation to visual function, retinal structure and fluid leakage, the following tests are performed:

Maximum corrected visual acuity obtained using a similar ETDRS chart at a distance of 4 meters.

Anatomical markers according to optical coherence tomography.

DRSS ETDRS score based on 7-site stereo color fundus photography.

Evaluation of fluid leakage through the vessels using fluorescein angiography.

Visual acuity will be assessed at each visit during the treatment period using the best correction score determined by the refraction protocol (BCVA). BCVA measurements are made in a seated position using visual acuity charts like the ETDRS. Details of the procedure and training materials are provided in the respective manuals.

Evaluation by optical coherence tomography (OCT) is done at screening (eg, day 0) and periodically during treatment visits. The attending physicians will evaluate the OCT results to assess disease activity status. The OCT machine used for an individual patient should not be changed during treatment. In addition to the standard OCT assessment as an optional assessments in facilities where appropriate equipment is available, OCT angiography should be performed at baseline, at week 28, at week 52, at week 76, etc. If OCT angiography is performed, it should be done for this patient starting from baseline. If OCT angiography was not performed at baseline, it should not be used at subsequent visits.

Color fundus photography and fluorescein angiography will be taken at screening at weeks 28, 52 and 76 etc. In institutions where appropriate equipment is available, optional wide-field angiography and fundus photography (at least 100 degrees) of the eye being examined should be performed at the same visit as the standard assessment procedures (screening, weeks 28, 52, 76 and final/abort visit). Wide field fundus photography replaces images acquired with a 7-field color fundus photograph, therefore both types of images must be acquired. Wide-field images should be obtained at screening. If wide-field angiography and fundus photography were not performed at screening, they should not be performed at subsequent visits.

The Diabetic Retinopathy Severity Scale (DRSS) will be scored by the attending physician or technician using criteria known to those of skill in the art.

BCVA as a measure of retinal function and OCT-derived images for analysis of anatomical changes are standard scoring criteria for monitoring DME and potential treatment effects in routine practice and clinical trials. Similarly, FA has been found to help classify the type of macular edema and is used to assess fluid leakage through vessels. The Diabetic Retinopathy Early Treatment Study (DRSS ETDRS) is a recent addition to clinical trials. This grading provides information regarding the severity of diabetic retinopathy underlying macular edema.

The present invention and its embodiments have been described in detail. However, specific embodiments of any process, manufacturing procedure, mixture of substances, compounds, means, methods and/or steps described herein are not intended to limit the scope of the present invention. Various modifications, substitutions and variations may be made to the disclosed material without departing from the spirit and/or essential features of the present invention. Accordingly, one of ordinary skill in the art will readily appreciate upon reading the present disclosure that further modifications, substitutions, and/or variations that perform essentially the same function or achieve essentially the same result as the embodiments disclosed herein may be used in accordance with such related embodiments of the present invention. Thus, the following claims are intended to cover modifications, substitutions, and variations of the processes, manufacturing procedures, mixtures of substances, compounds, agents, methods, and/or steps disclosed herein. The claims are not to be construed as being limited to the order or elements described, unless specifically indicated. It should be appreciated that various changes in form and detail may be made without departing from the scope of the appended claims.

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SEQUENCE LIST

<110> Novartis AG

WEICHSELBERGER, Andreas

WARBURTON, James

RACINE, Amy

<120> METHODS OF TREATMENT OF EYE DISEASES

<130> PAT058094

<150> US 62/643,887

<151> 2018-03-16

<150> US 62/805,344

<151> 2019-02-14

<160> 4

<170> PatentIn version 3.5

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<---

Claims (54)

1. A method of treating diabetic macular edema (DME) in a patient, the method comprising: a) administering to the patient five separate doses of the VEGF antagonist at intervals of 6 weeks; and b) subsequently administering to the patient an additional dose of the VEGF antagonist once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen), where the VEGF antagonist contains the sequences of SEQ ID NO: 1 and SEQ ID NO: 2. 2. The method of claim 1 further comprising evaluating the patient for DME disease activity before or after each dose of the q8w or q12w regimen. 3. The method of claim 2, wherein in the event that deterioration in DME disease activity is detected after dosing on the q12w regimen, the patient is switched to the q8w regimen, with additional doses administered once every 8 weeks instead of once every 12 weeks. 4. The method of claim 3, wherein the deterioration in DME disease activity is represented by letter omission at maximum corrected visual acuity (BCVA), increased central subfield thickness (CST), and/or increased fluid accumulation compared to any previous assessment. 5. The method of claim 2, wherein at week 72 after the first dose, the treatment interval corresponding to q12w is extended by 4 weeks if the patient's DME disease activity is stable when compared to the previous two assessments. 6. The method of claim 2 or 3, wherein at week 72 after the first dose, the treatment interval corresponding to q8w is extended by 4 weeks if the patient's DME disease activity is stable compared to the previous two evaluations. 7. The method according to any one of paragraphs. 3-6, where disease activity is assessed based on the determination of dynamic changes in maximum corrected visual acuity (BCVA), central subfield thickness (CST), and/or intraretinal fluid status. 8. The method according to any one of paragraphs. 1-7, where the patient is a human. 9. The method according to any one of paragraphs. 1-8, where the antagonist directed against VEGF contains the sequence of SEQ ID NO: 3 or SEQ ID NO: 4. 10. The method of claim 8 wherein the VEGF antagonist is brolucizumab. 11. The method according to any one of paragraphs. 1-10 wherein the VEGF antagonist is administered by intravitreal injection. 12. The method according to any one of paragraphs. 1-11 wherein the concentration of the VEGF antagonist is approximately 60, 70, 80, 90, 100, 110, or 120 mg/mL. 13. The method according to any one of paragraphs. 1-12 wherein each dose of the VEGF antagonist is 3 mg to 6 mg. 14. The method of claim 13 wherein each dose of the VEGF antagonist is 3 mg. 15. The method of claim 13 wherein each dose of the VEGF antagonist is 6 mg. 16. The method according to any one of paragraphs. 11-15, wherein each dose of the VEGF antagonist is administered as a 50 μl intravitreal injection. 17. A method of treating DME comprising administering to a patient five separate doses of a VEGF antagonist at intervals of 6 weeks, followed by additional doses every 8 weeks (q8w regimen), wherein the VEGF antagonist is an anti-VEGF antibody that contains a light chain variable region sequence under SEQ ID NO: 1 and heavy chain variable region sequence under SEQ ID NO: 2. 18. The method of claim 17, further comprising assessing the patient's DME disease activity before or after administration of each q8w dose. 19. The method of claim 18, wherein if there is an improvement in DME disease activity compared to the previous assessment, the patient is switched to the q12w regimen, with additional doses administered once every 12 weeks instead of once every 8 weeks. 20. The method of claim 19, wherein at week 72 after the first dose, the treatment interval corresponding to q12w is extended by 4 weeks if the patient's DME disease activity is stable when compared to the previous two evaluations. 21. The method of claim 20, wherein at week 72 after the first dose, the treatment interval corresponding to q8w is extended by 4 weeks if the patient's DME disease activity is stable compared to the previous two assessments. 22. The method according to any one of paragraphs. 17-21, where disease activity is assessed based on the determination of dynamic changes in maximum corrected visual acuity (BCVA), central subfield thickness (CST), and/or intraretinal fluid status. 23. The method according to any one of paragraphs. 17-22, where the patient is a human. 24. The method according to any one of paragraphs. 17-23, where the antagonist directed against VEGF is an antibody that contains the sequence under SEQ ID NO: 3 or SEQ ID NO: 4. 25. The method of claim 24 wherein the VEGF antagonist is brolucizumab. 26. The method according to any one of paragraphs. 17-25 wherein the VEGF antagonist is administered by intravitreal injection. 27. The method according to any one of paragraphs. 17-26, where the concentration of the VEGF antagonist is approximately 60, 70, 80, 90, 100, 110, or 120 mg/mL. 28. The method according to any one of paragraphs. 17-27 wherein each dose of the VEGF antagonist is 3 mg to 6 mg. 29. The method of claim 28 wherein each dose of the VEGF antagonist is 3 mg. 30. The method of claim 28 wherein each dose of the VEGF antagonist is 6 mg. 31. The method according to any one of paragraphs. 26-30, wherein each dose of the VEGF antagonist is administered as a 50 μl intravitreal injection. 32. Use of a VEGF antagonist for treatment diabetic macular edema (DME) in a patient, wherein the VEGF antagonist is administered to the patient: a) as five separate doses at intervals of 6 weeks; and b) subsequently as an additional dose every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen), where the VEGF antagonist contains the sequences of SEQ ID NO: 1 and SEQ ID NO: 2. 33. Use of a VEGF antagonist for the treatment of diabetic macular edema (DME) in a patient, wherein the VEGF antagonist comprises the sequences of SEQ ID NO: 1 and SEQ ID NO: 2, wherein the VEGF antagonist is first provided in a loading phase during which the patient receives five separate doses of the VEGF antagonist at intervals of 6 weeks, and then the VEGF antagonist is given in a maintenance phase during which the patient receives an additional dose of the VEGF antagonist once every 8 weeks (q8w regimen) or once every 12 weeks (q12w regimen). 34. The use of claim 32 or 33, which further comprises evaluating the patient for DME disease activity before or after each dose of the q8w or q12w regimen. 35. The use of claim 34, wherein if deterioration in DME disease activity is detected after dosing on the q12w regimen, the patient is switched to the q8w regimen, with additional doses administered once every 8 weeks instead of once every 12 weeks. 36. The use of claim 35, wherein the deterioration in DME disease activity is represented by letter omission at maximum corrected visual acuity (BCVA), increased central subfield thickness (CST), and/or increased fluid accumulation compared to any previous assessment. 37. The use of claim 35, wherein at week 72 after the first dose of the VEGF antagonist, the treatment interval corresponding to q12w is extended by 4 weeks if the patient's DME disease activity is stable when compared to the results of the previous two assessments. 38. Use according to claim 34 or 35, wherein at week 72 after administration of the first dose of the VEGF antagonist, the treatment interval corresponding to q8w is extended by 4 weeks if the patient's DME disease activity is stable when compared to the previous two assessments. 39. Application according to any one of paragraphs. 34-38, where disease activity is assessed based on the determination of dynamic changes in maximally corrected visual acuity (BCVA), central subfield thickness (CST), and/or intraretinal fluid status. 40. Application according to any one of paragraphs. 32-39, where the patient is a human. 41. Application according to any one of paragraphs. 32-40, where the antagonist directed against VEGF is an antibody that contains the sequence of SEQ ID NO: 3 or SEQ ID NO: 4. 42. Use according to claim 41, wherein the anti-VEGF antagonist is brolucizumab. 43. Application according to any one of paragraphs. 32-42, where the VEGF antagonist is administered by intravitreal injection. 44. Application according to any one of paragraphs. 32-43, where the concentration of the VEGF antagonist is approximately 60, 70, 80, 90, 100, 110, or 120 mg/mL. 45. Application according to any one of paragraphs. 32-44 wherein each dose of the VEGF antagonist is 3 mg to 6 mg. 46. The use of claim 45 wherein each dose of the VEGF antagonist is 3 mg. 47. The use of claim 46 wherein each dose of the VEGF antagonist is 6 mg. 48. Application according to any one of paragraphs. 43-47, wherein each dose of the VEGF antagonist is administered as a 50 μl intravitreal injection.