Use of VEGF Antagonists to Treat Neovascular Ocular Diseases

Abstract

To provide methods for treating angiogenic eye disorders by sequentially administering repeated doses of a VEGF antagonist to a patient.SOLUTION: The methods of the present invention include the administration of repeated doses of a VEGF antagonist to a patient with a frequency of once every 8 or more weeks. The methods of the present invention are useful for the treatment of angiogenic eye disorders such as age-related macular degeneration, diabetic retinopathy, diabetic macular edema, central retinal vein occlusion, and corneal neovascularization.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the field of therapeutic treatment of ocular diseases. More particularly, the present invention relates to the administration of VEGF antagonists to treat ocular diseases caused by or associated with neovascularization. [Background technology]

[0002] Several eye diseases are associated with pathological angiogenesis. For example, the development of age-related macular degeneration (AMD) is associated with a process called choroidal neovascularization (CNV). Leakage from CNV causes macular edema and fluid accumulation under the macula, leading to vision loss. Diabetic macular edema (DME) is another eye disease with a neovascular component. DME is the most common cause of moderate vision loss in diabetic patients and a common complication of diabetic retinopathy, a disease affecting the blood vessels of the retina. Clinically significant DME occurs when fluid leaks into the center of the macula, the light-sensitive part of the retina responsible for sharp, direct vision. Fluid in the macula can cause severe vision loss or even blindness. Yet another eye disease associated with abnormal angiogenesis is central retinal vein occlusion (CRVO). CRVO is caused by a blockage of the central vein, leading to a backup of blood and fluid in the retina. The retina may also become ischemic, leading to inappropriate new blood vessel growth, which can lead to further vision loss and more serious complications. The release of vascular endothelial growth factor (VEGF) contributes to increased vascular permeability in the eye and inappropriate new blood vessel growth. Therefore, inhibiting the pro-angiogenic properties of VEGF may be an effective strategy for treating neovascular eye diseases.

[0003] FDA-approved treatments for neovascular eye disorders such as AMD and CRVO include ranibizumab (Lucentis) administered intravitreously on a monthly basis. (R) (Lucentis (R) Examples of treatments include the administration of an anti-VEGF antibody called an anti-VEGF antibody (Genentech, Inc.).

[0004] Methods for treating eye diseases with VEGF antagonists are described, for example, in US Pat. Nos. 5,629,999; 5,729,999; 5,8 ... and 5,929,999. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] U.S. Patent No. 7,303,746 [Patent Document 2] U.S. Patent No. 7,306,799 [Patent Document 3] U.S. Patent No. 7,300,563 [Patent Document 4] U.S. Patent No. 7,303,748 [Patent Document 5] U.S. Patent Application 2007 / 0190058 Summary of the Invention [Problem to be solved by the invention]

[0006] Nevertheless, there remains a need in the art for dosing regimens for neovascular eye diseases, particularly those that allow for less frequent dosing while maintaining a high level of efficacy. [Means for solving the problem]

[0007] The present invention provides methods for treating neovascular eye diseases. The methods of the present invention comprise sequentially administering to a patient multiple doses of a VEGF antagonist over an extended period of time. In particular, the methods of the present invention include a single initial dose of a VEGF antagonist, followed by one or more secondary doses ... The present invention also provides a method for treating neovascular eye disease, comprising sequentially administering a VEGF antagonist to a patient with a VEGF antagonist at a frequency of once per week for eight weeks or more, particularly when the patient has previously been administered about three doses of the VEGF antagonist at a frequency of about two to four weeks. Thus, according to the method of the present invention, each secondary dose of the VEGF antagonist is administered two to four weeks after the immediately preceding dose, and each tertiary dose is administered at least eight weeks after the immediately preceding dose. An example of the dosing regimen of the present invention is shown in Figure 1. One advantage of such a dosing regimen is that it is superior to prior art dosing regimens for neovascular eye disease (e.g., Lucentis) that require monthly administration throughout the entire course of treatment. (R) Compared with ranibizumab (see prescribing information for Genentech), The goal is to allow for less frequent dosing (e.g., once every 8 weeks) over the majority of the treatment course (i.e., the 3rd dose).

[0008] The methods of the present invention can be used to treat any neovascular eye disease, including, for example, age-related macular degeneration, diabetic retinopathy, diabetic macular edema, central retinal vein occlusion, corneal neovascularization, and the like.

[0009] The method of the present invention comprises administering any VEGF antagonist to patient.In one embodiment, the VEGF antagonist comprises one or more VEGF receptor-based chimeric molecules (also referred to herein as "VEGF-Trap" or "VEGFT").The exemplary VEGF antagonist that can be used in the context of the present invention is a multimeric VEGF binding protein that comprises two or more VEGF receptor-based chimeric molecules, referred to herein as "VEGFR1R2-FcΔC1(a)" or "aflibercept".

[0010] A variety of routes of administration are contemplated for use in the methods of the present invention, including, for example, topical administration or intraocular administration (eg, intravitreal administration).

[0011] Aflibercept [Eylea TM (EYLEA TM ), Regeneron Pharmaceuticals, Inc., was approved by the FDA in November 2011 for the treatment of patients with neovascular (wet) age-related macular degeneration at a recommended dose of 2 mg administered by intravitreal injection every four weeks for the first three months, followed by 2 mg administered by intravitreal injection once every eight weeks thereafter.

[0012] Other embodiments of the present invention will become apparent from consideration of the following detailed description. [Brief explanation of the drawings]

[0013] [Figure 1] 1 shows an exemplary dosing regimen of the present invention, in which a single "initial dose" of a VEGF antagonist ("VEGFT") is administered at the beginning of the treatment regimen (i.e., at "week 0"), two "secondary doses" are administered at week 4 and week 8, respectively, and at least six "tertiary doses" are administered once every eight weeks thereafter (i.e., at weeks 16, 24, 32, 40, 48, 56, etc.). DETAILED DESCRIPTION OF THE INVENTION

[0014] Before describing the present invention in detail, it is of course to be understood that this invention is not limited to the particular methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0015] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. As used herein, the term "about," when used in connection with a specific specified numerical value, means that the value may vary by 1% or less from the recited value. For example, the expression "about 100" used herein includes 99 and 101, and all values ​​therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0016] Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described.

[0017] Dosage regimen The present invention provides a method for treating neovascular eye diseases. The method of the present invention comprises sequentially administering repeated doses of a VEGF antagonist to a patient. As used herein, "sequential administration" means that each dose of a VEGF antagonist is administered to a patient at different times (e.g., different days) separated by a predetermined interval (e.g., several hours, several days, several weeks, or several months). The present invention comprises sequentially administering to a patient a single initial dose of a VEGF antagonist, followed by one or more secondary doses of a VEGF antagonist, followed by one or more tertiary doses of a VEGF antagonist.

[0018] The terms "initial dose," "secondary dose," and "tertiary dose" refer to the time sequence of VEGF antagonist administration. Thus, an "initial dose" is a dose administered at the beginning of a treatment regimen (also referred to as a "baseline dose"); a "secondary dose" is a dose administered after the initial dose; and a "tertiary dose" is a dose administered after the secondary dose. The initial, secondary, and tertiary doses may all contain the same amount of VEGF antagonist, but generally differ from one another in terms of frequency of administration. However, in certain embodiments, the amount of VEGF antagonist contained in the initial, secondary, and / or tertiary doses will vary from one another (e.g., adjusted up or down as needed) during the course of treatment.

[0019] In an exemplary embodiment of the invention, each secondary dose is administered 2 to 4 weeks (e.g., 2, 2 1 / 2, 3, 3 1 / 2, or 4 weeks later), with each tertiary dose being administered at least 8 weeks (e.g., 8, 8 1 / 2, 9, 9 1 / 2, 10, 10 1 / 2, 11, 11 1 / 2, 12, 12 1 / 2, 13, 13 1 / 2, 14, 14 1 / 2 weeks later or more As used herein, the phrase "the immediately preceding dose" refers to the dose of a VEGF antagonist administered to a patient in a repeat administration sequence prior to the administration of the next dose in the sequence, without any intervening doses.

[0020] In one exemplary embodiment of the invention, a single initial dose of a VEGF antagonist is administered to a patient on the first day of the treatment regimen (i.e., at week 0), followed by two secondary doses each administered four weeks after the immediately preceding dose (i.e., at week 4 and week 8), followed by at least five tertiary doses each administered eight weeks after the immediately preceding dose (i.e., at weeks 16, 24, 32, 40, and 48). The tertiary doses can continue indefinitely (at intervals of 8 or more weeks) during the course of the treatment regimen. This exemplary dosing regimen is graphically depicted in FIG. 1.

[0021] The methods of the invention can include administering any number of secondary and / or tertiary doses of a VEGF antagonist to the patient. For example, in certain embodiments, only a single secondary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient. Similarly, in certain embodiments, only a single tertiary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.

[0022] In embodiments comprising multiple secondary doses, each secondary dose can be administered at the same frequency as the other secondary doses. For example, each secondary dose can be administered to a patient 4 weeks after the immediately preceding dose. Similarly, in embodiments comprising multiple tertiary doses, each tertiary dose can be administered at the same frequency as the other tertiary doses. For example, each tertiary dose can be administered to a patient 8 weeks after the immediately preceding dose. Alternatively, the frequency with which the secondary and / or tertiary doses are administered to a patient can vary over the course of a treatment regimen. For example, the present invention comprises administering to a patient a single initial dose of a VEGF antagonist, followed by administering to the patient one or more secondary doses of a VEGF antagonist, and administering to the patient at least five tertiary doses of a VEGF antagonist, wherein the first through fourth tertiary doses are administered 8 weeks after the immediately preceding dose, and each subsequent tertiary dose is administered 8 to 12 (e.g., 8, 8 1 / 2, 9, 9 1 / 2, 10, 10 1 / 2, 11, 11 1 The frequency of administration can be adjusted by the physician during the course of treatment according to the needs of the individual patient after clinical examination.

[0023] VEGF antagonists The methods of the present invention comprise administering to a patient a VEGF antagonist according to a particular dosing regimen. As used herein, the phrase "VEGF antagonist" refers to any molecule that blocks, reduces, or interferes with the normal biological activity of VEGF.

[0024] VEGF antagonists include molecules that interfere with the interaction between VEGF and a VEGF receptor, e.g., molecules that bind to VEGF or a VEGF receptor and inhibit or otherwise prevent the interaction between VEGF and a VEGF receptor. Specific exemplary VEGF antagonists include anti-VEGF antibodies, anti-VEGF receptor antibodies, and VEGF receptor-based chimeric molecules (hereinafter referred to as VEGF-traps). .

[0025] VEGF receptor-based chimeric molecules include chimeric polypeptides that contain two or more immunoglobulin (Ig)-like domains of a VEGF receptor, such as VEGFR1 (also referred to herein as Flt1) and / or VEGFR2 (also referred to herein as Flk1 or KDR), and may also contain a multimerization domain (e.g., an Fc domain that promotes multimerization (e.g., dimerization) of two or more chimeric polypeptides). An exemplary VEGF receptor-based chimeric molecule is a molecule designated VEGFR1R2-FcΔC1(a), encoded by the nucleic acid sequence of SEQ ID NO: 1. VEGFR1R2-FcΔC1(a) contains three components: (1) a VEGFR1 component comprising amino acids 27-129 of SEQ ID NO: 2; (2) a VEGFR2 component comprising amino acids 130-231 of SEQ ID NO: 2; and (3) a multimerization component ("FcΔC1(a)") comprising amino acids 232-457 of SEQ ID NO: 2 [the C-terminus of SEQ ID NO: 2]. The amino acid (i.e., K458) may or may not be present in the VEGF antagonist used in the methods of the present invention; see, for example, U.S. Patent No. 7,396,664. Amino acids 1 to 26 in column 2 are the signal sequence.

[0026] The VEGF antagonist used in the examples presented herein below is a dimeric molecule comprising two VEGFR1R2-FcΔC1(a) molecules, herein referred to as "VEGFT." Further VEGF receptor-based chimeric molecules that can be used in this context of the present invention are described in U.S. Patent Nos. 7,396,664, 7,303,746, and International Patent Application Publication (WO) No. 00 / 075319.

[0027] Angiogenic eye disease The method of the present invention can be used to treat any neovascular eye disease. As used herein, the expression "neovascular eye disease" refers to any eye disease caused by or associated with the growth or proliferation of blood vessels, or by vascular leakage. Non-limiting examples of neovascular eye diseases that can be treated using the method of the present invention include choroidal neovascularization, age-related macular degeneration (AMD), diabetic retinopathy, diabetic macular edema (DME), central retinal vein occlusion (CRVO), corneal neovascularization, and retinal neovascularization.

[0028] Pharmaceutical preparations The present invention includes methods in which the VEGF antagonist administered to a patient is contained in a pharmaceutical formulation. The pharmaceutical formulation may include the VEGF antagonist along with at least one inactive ingredient, such as a pharmaceutically acceptable carrier. Other agents may be incorporated into the pharmaceutical composition to provide improved transport, delivery, tolerability, etc. The term "pharmaceutically acceptable" means approved by a federal or United States government regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, particularly humans. The term "carrier" refers to an excipient, adjuvant, additive, or vehicle with which the antibody is administered. A formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences (15th Edition, 1975, Mack Publishing Company, Penn State, NY, USA). Easton, Pennsylvania (15 th Numerous suitable formulations can be found in "The Infectious Diseases of the Present," ed., Mack Publishing Company, Easton, Pa., 1975), particularly Chapter 87 by Blaug and Seymour. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic)-containing vesicles [e.g., lipofectin], and the like. TM (LIPOFECTIN TM)], DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, carbowax emulsions Examples of suitable excipients and carriers include emulsions of carbowax (polyethylene glycol of various molecular weights), semi-solid gels, and semi-solid mixture formulations containing carbowax. Any of the aforementioned mixture formulations may be suitable in the context of the methods of the present invention, provided that the VEGF antagonist is not inactivated by the formulation and that the formulation is physiologically compatible and acceptable for the route of administration. For further information regarding excipients and carriers familiar to pharmaceutical chemists, see Powell et al. PDA (1998), J. Pharm. Sci. Technol. 52:238-311 and references therein.

[0029] In the context of the present invention, pharmaceutical preparations useful for administration by injection can be prepared by dissolving, suspending, or emulsifying the VEGF antagonist in a sterile aqueous or oily medium commonly used for injections.Aqueous media for injections include, for example, physiological saline, isotonic solutions containing glucose and other auxiliary agents, which can be used in combination with suitable solubilizers such as alcohol (e.g., ethanol), polyhydric alcohols (e.g., propylene glycol, polyethylene glycol), nonionic surfactants (e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 moles) adduct of hydrogenated castor oil)).Oil media can include, for example, sesame oil, soybean oil, etc., which can be used in combination with solubilizers such as benzyl benzoate, benzyl alcohol, etc.

[0030] Mode of administration The VEGF antagonist (or pharmaceutical formulation comprising the VEGF antagonist) can be administered to a patient by any known delivery system and / or method of administration. In certain embodiments, the VEGF antagonist is administered ocularly, intraocularly, intravitreally, or subconjunctivally. In other embodiments, the VEGF antagonist can be administered by topical administration, such as via eye drops or other liquids, gels, ointments, or fluids containing the VEGF antagonist, which can be applied directly to the eye. Other possible routes of administration include, for example, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral.

[0031] Amount of VEGF antagonist administered Each dose of VEGF antagonist administered to a patient over the course of a treatment regimen may contain the same or substantially the same amount of VEGF antagonist. Alternatively, the amount of VEGF antagonist contained within each dose may vary over the course of a treatment regimen. For example, in certain embodiments, a first amount of VEGF antagonist is administered in an initial dose, a second amount of VEGF antagonist is administered in a secondary dose, and a third amount of VEGF antagonist is administered in a tertiary dose. The present invention also contemplates possible dosing schemes in which the amount of VEGF antagonist contained within each dose increases over time (e.g., each subsequent dose contains more VEGF antagonist than the previous one), decreases over time (e.g., each subsequent dose contains less VEGF antagonist than the previous one), increases initially and then decreases, decreases initially and then increases, or remains the same throughout the course of a dosing regimen.

[0032] The amount of VEGF antagonist administered to a patient in each dose is most often a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" refers to a dose of a VEGF antagonist that results in a detectable improvement in one or more symptoms or signs of a neovascular ocular disease, or a dose of a VEGF antagonist that inhibits, prevents, reduces, or slows the progression of a neovascular ocular disease. In the case of an anti-VEGF antibody or a VEGF receptor-based chimeric molecule such as VEGFR1R2-FcΔC1(a), a therapeutically effective amount is about 0. 0.05 mg to about 5 mg, for example, about 0.05 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 1.0 mg, about 1.05 mg, about 1.1 mg, about 1.15 mg, about 1.2 mg, about 1.25 mg, about 1.3 mg, about 1.35 mg, about 1.4 mg, about 1.45 mg, about 1.5 mg, about 1.55 mg, about 1.6 mg, about The amount of the antibody or receptor-based chimeric molecule may be 1.65 mg, about 1.7 mg, about 1.75 mg, about 1.8 mg, about 1.85 mg, about 1.9 mg, about 2.0 mg, about 2.05 mg, about 2.1 mg, about 2.15 mg, about 2.2 mg, about 2.25 mg, about 2.3 mg, about 2.35 mg, about 2.4 mg, about 2.45 mg, about 2.5 mg, about 2.55 mg, about 2.6 mg, about 2.65 mg, about 2.7 mg, about 2.75 mg, about 2.8 mg, about 2.85 mg, about 2.9 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, or about 5.0 mg.

[0033] The amount of VEGF antagonist contained in each dose can be expressed in mg antibody per kg of patient body weight (i.e., mg / kg). For example, the VEGF antagonist can be administered to a patient at a dose of about 0.0001 to 10 mg / kg of patient body weight.

[0034] Treatment population and efficacy The method of the present invention is useful for treating neovascular eye diseases in patients who have been diagnosed with or are at risk of developing such diseases. Generally, the method of the present invention shows efficacy within 104 weeks of the start of the treatment regimen (with the initial dose administered at "week 0"), for example, by the end of week 16, by the end of week 24, by the end of week 32, by the end of week 40, by the end of week 48, by the end of week 56, etc. In the context of methods for treating neovascular eye diseases such as AMD, CRVO, and DME, "efficacy" refers to the treatment of neovascular eye diseases. means that the patient shows a loss of 15 or fewer letters on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart from the start of treatment. In certain embodiments, "efficacy" means an improvement of one or more letters (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or more) on the ETDRDS chart from the start of treatment. [Example]

[0035] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions of the present invention, and are not intended to limit the scope of what the inventors consider to be their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric.

[0036] The exemplary VEGF antagonist used in all examples below is a dimeric molecule with two functional VEGF-binding units. Each functional binding unit is composed of Ig domain 2 from VEGFR1 fused to Ig domain 3 from VEGFR2, which is further fused to the hinge region of a human IgG1 Fc domain [VEGFR1R2-FcΔC1(a): encoded by SEQ ID NO: 1]. This VEGF antagonist is described in the following examples. In the examples below, "monthly" administration is equivalent to administration once every four weeks.

[0037] [Example 1] Phase I clinical trial of intravitreally administered VEGF receptor-based chimeric molecule (VEGFT) in subjects with neovascular AMD In this Phase I study, 21 subjects with neovascular AMD received a single intravitreal (IVT) dose of VEGFT. Five subjects (3 subjects per group) received either 0.05, 0.15, 0.5, 2, or 4 mg of VEGFT, while six subjects (6 subjects per group) received 1 mg. There were no serious adverse events related to the study drug, and no discernible intraocular inflammation was reported. Preliminary results showed that after VEGFT injection, a rapid decrease in central retinal thickness and macular volume was observed, which was maintained through 6 weeks. On day 43, across all dose groups, the mean increase in retinal thickness on optical coherence tomography (OCT) [retinal thickness increase = (retinal thickness - 179 μm)], as assessed by Fast Macular Scan, decreased from 119 μm to 27 μm, a decrease from a single dose. As assessed by a single posterior pole scan, visual acuity decreased from 194 μ to 60 μ. The mean improvement in best-corrected visual acuity (BCVA) was 4.75 letters, with BCVA remaining stable or improving in 95% of subjects. In the two highest dose groups (2 and 4 mg), the mean improvement in BCVA was 13.5 letters, with 3 of 6 subjects showing an improvement of 3 or more lines.

[0038] [Example 2] Phase II clinical trial of repeated doses of intravitreal VEGF receptor-based chimeric molecule (VEGFT) in subjects with neovascular AMD This study was a double-blind, randomized trial of three doses (0.5, 2, and 4 mg) of VEGFT tested at 4-week and / or 12-week dosing intervals. There were five treatment arms in the study: 1) 0.5 mg every 4 weeks, 2) 0.5 mg every 12 weeks, 3) 2 mg every 4 weeks, 4) 2 mg every 12 weeks, and 5) 4 mg every 12 weeks. Subjects were dosed at fixed intervals for the first 12 weeks, after which they were evaluated every 4 weeks for 9 months, during which time additional doses were administered based on pre-specified criteria. All subjects were then followed for 1 year after receiving their final dose of VEGFT. Predictions from a pre-planned interim analysis were not included. Preliminary data showed that VEGFT met its primary endpoint of a statistically significant reduction in retinal thickness at 12 weeks compared to baseline (a 135μ reduction across all groups, p<0.01). The mean change from baseline in visual acuity, a key secondary outcome of the study, was 0.0001. The clinical endpoint also showed statistically significant improvements (5.9 letter improvement across all groups combined, p<0.0001). Furthermore, patients in the single-dose group showed, on average, a reduction in retinal thickness increase (p<0.0001) and improved visual acuity (p=0.012) at 12 weeks. There were no drug-related serious adverse events, and treatment with the VEGF antagonist was generally well tolerated. The most frequent adverse events were those typically associated with intravitreal injections.

[0039] [Example 3] Phase I clinical trial of systemically administered VEGF receptor-based chimeric molecule (VEGFT) in subjects with neovascular AMD This study was a placebo-controlled, sequential-group, dose-escalation safety, tolerability, and bioefficacy study of intravenous VEGFT in subjects with neovascular AMD. Eight subjects meeting eligibility criteria for subfoveal choroidal neovascularization (CNV) associated with AMD were assigned to receive four intravenous infusions of VEGFT or placebo at dose levels of 0.3, 1, or 3 mg / kg over an 8-week period. The most common adverse events attributed to VEGFT were mild to moderate in severity, although two of five subjects treated at 3 mg / kg experienced dose-limiting toxicity (DLT) (one severe). Grade 4 hypertension and one case of Grade 2 proteinuria; therefore, all patients in the 3 mg / kg group All subjects were excluded from the study. The mean percent changes in retinal thickness increase were: -12%, -10%, -66%, and -60% (ANOVA p<0.02) for the placebo, 0.3, 1, and 3 mg / kg dose groups at day 15, and -5.6%, +47.1%, and -63.3% (ANOVA p<0.02) for the placebo, 0.3, and 1 mg / kg dose groups at day 71. There was a numerical improvement in BCVA in subjects treated with VEGFT. As expected in such a small study, the results were not statistically significant.

[0040] [Example 4] A phase III clinical trial of the efficacy, safety, and tolerability of intravitreal repeated-administration VEGF receptor-based chimeric molecule (VEGFT) in subjects with neovascular age-related macular degeneration A. Objectives, Hypotheses, and Endpoints Two parallel-group, comparative Phase III clinical trials were conducted to investigate the use of VEGFT to treat patients with neovascular age-related macular degeneration (Study 1 and Study 2). The primary objective of the study is to evaluate the efficacy of ranibizumab (Lucentis) in preventing moderate visual acuity loss in subjects with all subtypes of neovascular AMD. (R) , Genentech) The objective of this study was to evaluate the efficacy of IVT-administered VEGFT in a recessive paradigm.

[0041] Secondary objectives were (a) to evaluate the safety and tolerability of VEGFT administered via repeated IVT for up to 2 years in subjects with all subtypes of neovascular AMD, and (b) to evaluate the effect of VEGFT administered via repeated IVT on vision-related quality of life (QOL) in subjects with all subtypes of neovascular AMD.

[0042] The primary hypothesis of these trials was that the proportion of VEGFT-treated subjects with stable or improved BCVA (<15 letters of visual acuity loss) would be similar to the proportion of ranibizumab-treated subjects with stable or improved BCVA, thereby demonstrating non-inferiority.

[0043] The primary endpoint of these trials was the prevention of visual acuity loss of 15 or more letters on the ETDRS chart at 52 weeks compared with baseline. Secondary endpoints were: These were: (a) change in ETDRS chart letter score from baseline to week 52; (b) improvement of 15 or more letters on the ETDRS chart from baseline to week 52; (c) change in total NEI VFQ-25 score from baseline to week 52; and (d) change in CNV area from baseline to week 52.

[0044] B. Study Design For each study, subjects were randomly assigned to one of four dosing regimens: (1) 2 mg VEGFT every 4 weeks (2Q4); (2) 0.5 mg VEGFT every 4 weeks (0.5Q4); 2 mg VEGFT every 4 to 8 weeks, then every 8 weeks (sham injections at interim 4 weeks visits where no study drug was administered) (2Q8); and (4) 0.5 mg VEGFT every 4 weeks. Subjects were randomly assigned 1:1:1:1 to one of two treatments: ranibizumab (R0.5Q4); ranibizumab (R0.5Q4); and ranibizumab (R0.5Q8). Subjects assigned to treatment (R0.5Q8) received a 2 mg injection every 4 to 8 weeks, followed by a sham injection at the interim 4-week visit (when no study drug administration was scheduled) during the first 52 weeks of the study (sham injections were not given at week 52).

[0045] The study duration for each subject was scheduled to be 96 weeks plus the recruitment period. During the first 52 weeks (year 1), subjects received IV CT scans in the study eye every 4 weeks. Subjects received either IVT or sham injections (no sham injections were given at week 52). During the second year of the study, subjects were evaluated every 4 weeks and received IVT administration of the investigational drug at intervals determined by established dosing criteria, but at least every 12 weeks (no sham injections were given during the second year of the study). During this period, injections may be given as frequently as every 4 weeks, but not more frequently than every 12 weeks, according to the following criteria: (i) an increase in central retinal thickness of ≥ 100 μm compared to the lowest pre-treatment value, as measured by optical coherence tomography (OCT); or (ii) a loss of vision of at least 5 ETDRS letters from the highest pre-treatment letter score associated with recurrent fluid as shown by OCT. or (iii) new or recurring persistent fluid as shown by OCT; or (iv) new onset of classic neovascularization or new or recurring leakage on fluorescein angiography (FA); or (v) new macular hemorrhage; or (vi) 12 weeks have passed since the previous injection. According to this protocol, subjects are required to receive an injection at least every 12 weeks.

[0046] Subjects were evaluated for safety and best-corrected visual acuity (BCVA) every 4 weeks using a 4-meter ETDRS protocol. Quality of life (QOL) was assessed using the NEI VFQ-25 questionnaire. OCT and FA examinations were performed periodically.

[0047] Approximately 1200 subjects were enrolled, with a target enrollment of 300 subjects per treatment group.

[0048] To be eligible for this study, subjects were required to have subfoveal choroidal neovascularization (CNV) due to AMD. "Subfoveal" CNV was defined as the presence of subfoveal neovascularization as demonstrated by FA or angiographically located lesions affecting the fovea. Study eligibility was confirmed based on angiographic criteria prior to randomization.

[0049] Only one eye was designated as the study eye. For subjects with both eyes meeting the eligibility criteria, the eye with the poorest VA was selected as the study eye. If both eyes had comparable VA, the eye with the clearest lens and optic corpus and the least amount of subfoveal scarring or geographic atrophy was selected.

[0050] Inclusion criteria for both studies were: (i) signed informed consent; (ii) age of at least 50 years; (iii) foveal occlusion in the study eye, as confirmed by FA. (iv) active subfoveal CNV lesions due to AMD, including juxtafoveal lesions affecting the eye; (iv) CNV occupying at least 50% of the total lesion size; (v) diabetic plexus in the study eye Early Treatment of Diabetes Mellitus Study (ETDRS) best corrected visual acuity of 20 / 40 to 20 / 320 (letter score 73 to 25); (vi) willingly admitted and returned for all clinical visits and completed all (vii) able to read, understand, and voluntarily sign the informed consent form (or have it read to them by a person administering the informed consent or a family member if they are unable to read due to visual impairment).

[0051] Exclusion criteria for both studies were as follows: 1. Previous ocular (in the study eye) or systemic treatment, or surgery, for neovascular AMD, with the exception of dietary supplements or vitamins; 2. Previous treatment with other investigational drugs or concomitant therapy to treat neovascular AMD in the study eye, with the exception of dietary supplements or vitamins; 3. Previous treatment with the following anti-VEGF agents: (a) Previous treatment with anti-VEGF therapy in the study eye was not permitted; (b) Anti-VEGF therapy with an investigational drug (not FDA approved, e.g., bevacizumab) in the fellow eye within 3 months prior to the first dose of this study. (c) Previous treatment with an investigational or FDA / Health Canada approved anti-VEGF therapy was allowed only up to 3 months prior to the first dose of the study, but not during the study; (d) total lesion size in the study eye was >12 disc areas (including blood, scar, and neovascularization) as assessed by FA >30.5 mm 2 5. Subretinal hemorrhage that is 50% or more of the total lesion area, or or hemorrhage subfoveal and ≥1 papilla area in the study eye (if the hemorrhage is subfoveal, the fovea must be surrounded by 270° visible CNV); 6. Scar, fibrosis in the study eye comprising >50% of the total lesion; 7. Scar, fibrosis, or atrophy involving the center of the fovea; 8. Presence of a break or tear in the retinal pigment epithelium involving the globe in the study eye; 9. History of vitreous hemorrhage in the study eye within 4 weeks prior to Visit 1; 10 11. Presence of other causes of CNV, including pathological myopia (spherical equivalent of -8 diopters or less, or axial length of 25 mm or more), ocular histoplasmosis, angioid streaks, choroidal rupture, and multifocal choroiditis; 12. Presence or history of clinically significant diabetic retinopathy, diabetic macular edema, or other vascular disease affecting the retina other than AMD in either eye; 13. Previous vitrectomy in the target eye; 14. History of retinal detachment, or treatment or surgery for retinal detachment in the target eye; 15. Stage 2 or greater macular circle in the target eye 15. Intraocular or periocular surgery in the study eye within 3 months prior to Day 1, excluding eyelid surgery not performed within 1 month prior to Day 1, as long as it would not interfere with the injection; 16. Previous trabeculectomy or other filtration surgery in the study eye; 17. Uncontrolled glaucoma in the study eye (defined as intraocular pressure of 25 mmHg or greater despite treatment with antiglaucoma medications); 18. Active ophthalmia in either eye; 19. Active ocular or periocular infection in either eye; 20. Previous screening in either eye ocular or periocular infection within the immediately preceding 2 weeks; 21. History of uveitis in either eye; 22. Active scleritis or episcleritis in either eye; 23. Presence or history of scleral softening in either eye; 24. Aphakia or pseudoaphakia with no posterior capsule [other than as a result of yttrium aluminum garnet (YAG) laser posterior capsulotomy] in either eye; 25. Previous radiation therapy to an area in the study eye; 26. History of corneal transplant or corneal dysfunction in the study eye; 27. Significant medial opacity in the study eye, including cataract, that may interfere with visual acuity, safety assessments, or fundus photography; 28. Concurrent intraocular conditions (e.g., cataract) in the study eye that, in the investigator's opinion, may require either medical or surgical intervention during the 96-week study period; 29. ​​In the investigator's opinion, 30. Any other medical history, metabolic dysfunction, physical examination finding, or laboratory test result that contraindicates the use of the investigational drug or that gives reasonable suspicion of a disease or condition that may affect the interpretation of the results of the study or confer a high risk of procedural complications; 31. Participation as a subject in any clinical trial within 12 weeks prior to Day 1; 32. Systemic or ocular treatment with an investigational drug within the past 3 months prior to Day 1; 33. Use of systemic or intraocular long-acting steroids within 6 months prior to Day 1; 34. History of allergy to povidone-iodine; 35. Known severe allergy to sodium fluorescein for angiographic injection; 36. Ranibizumab (Lucentis) (R) ) FDA 37. Presence of contraindications as indicated in the approved label; 37. Women of childbearing potential who are pregnant, breastfeeding, or who do not intend to use adequate contraception throughout the study. Adequate methods of contraception include oral contraceptives (stable use for 2 or more cycles prior to screening); IUD; Depo-Provera. (R) (Depo-Provera (R) );Norplant (R) (Norplant (R) ) system implant; tubal ligation; vasectomy; condom or diaphragm plus either a contraceptive sponge, foam, or jelly.

[0052] Subjects were not permitted to receive any standard or investigational medications for treating AMD in the study eye other than the subject's VEGFT or ranibizumab study treatment assigned as specified in the protocol until they completed the Completion / Early Discontinuation Visit evaluation. This included locally administered medications (e.g., IVT, topical, juxtascleral, or periorbital routes) and systemically administered medications for the purpose of treating the study eye and / or fellow eye.

[0053] The test method is summarized below:

[0054] best corrected visual acuity Visual function in the study eye and fellow eye was assessed using the ETDRS protocol (Early Treatment of Diabetic Retinopathy Study Group) at 4 meters. A visual acuity examiner was certified to ensure consistent measurements of BCVA. The VA examiner was required to remain masked to treatment allocation.

[0055] Optical coherence tomography Retinal and lesion characteristics were assessed using optical coherence tomography (OCT) in the study eye. Images were captured and transmitted for both eyes at the Screen Visit (Visit 1). All OCT images were acquired using a Zeiss-Strauss OCT system. TM (Zeiss Stratus OCT TM ) and OCT images were captured using version 3 or later software. OCT images were sent to an independent reading center, where they were read by a masked reader at visits where OCT images were needed. All OCT images were archived on-site as part of the source documentation. A subset of OCT images was read. OCT technicians were required to be certified by the reading center to ensure consistency and quality of image acquisition. Substantial efforts were made to ensure that the on-site OCT technicians remained masked to treatment assignment.

[0056] Fundus photography and fluorescein angiography (FA)The anatomical status of the retinal vasculature of the study eyes was assessed by fundus examination, fundus photography, and FA. At the screening visit (Visit 1), images were captured and transmitted for both eyes by fundus examination, fundus photography, and FA. Fundus and angiographic images were sent to an independent reading center, where they were read by a masked reader. The reading center confirmed subject eligibility based on angiographic criteria before randomization. All FA and fundus photographs were archived on-site as part of the source documentation. Photographers were required to be certified by the reading center to ensure consistency and quality of image acquisition. The on-site Great efforts were made to ensure that all photographers remained masked to treatment allocation.

[0057] Vision-related quality of life Vision-related quality of life was assessed using the interviewer-administered format of the National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25). The NEI VFQ-25 was administered by qualified personnel at a contracted call center. At the screening visit, the site assisted subjects, initiated the initial call to the call center, collected all subject contact information, and completed the first NEI VFQ-25 over the phone prior to randomization and IVT injection. During all subsequent visits, the call center called subjects and completed the questionnaires.

[0058] intraocular pressure Intraocular pressure (IOP) in the target eye was measured using applanation tonometry or Tonopen. The same method of IOP measurement was used for each subject in the study.

[0059] C. Summary of results (52-week data) In this study, all three VEGFT groups (2Q4, 0.5Q4, and 2Q8) met the primary endpoint (prevention of moderate or severe vision loss as previously defined). The results of both studies are summarized in Table 1.

[0060] [Table 1]

[0061] In Study 1, patients receiving monthly VEGFT 2 mg (2Q4) achieved a statistically significant greater mean improvement in visual acuity (secondary endpoint) versus baseline at 52 weeks compared with monthly ranibizumab 0.5 mg (RQ4); patients receiving monthly VEGFT 2 mg (2Q4) improved by a mean of 10.9 letters compared with a mean improvement of 8.1 letters with monthly ranibizumab 0.5 mg (RQ4) (p<0.01). All other doses of VEGFT in Study 1 and all doses in Study 2 were not statistically different from ranibizumab on this secondary endpoint.

[0062] An overall favorable safety profile was observed for both VEGFT and ranibizumab. The incidence of ocular treatment-emergent adverse events was balanced across all four treatment arms in both studies, with the most common events related to the injection technique, underlying disease, and / or aging. The most common ocular adverse events were conjunctival hemorrhage, macular degeneration, eye pain, retinal hemorrhage, and vitreous floaters. The most common serious nonocular adverse events were typical of those reported in elderly populations receiving intravitreal treatment for wet AMD; the most frequently reported events were falls, pneumonia, myocardial infarction, atrial fibrillation, breast cancer, and acute coronary syndrome. There were no notable differences between treatment arms.

[0063] [Example 5] A Phase II Clinical Trial of VEGFT in Subjects with Diabetic Macular Edema (DME) In this study, 221 patients with clinically significant DME involving the central macula were randomized, with 219 patients treated in a balanced distribution across five groups. The control group received macular laser treatment at baseline, and patients were eligible for repeat laser treatments, but as frequently as every 16 weeks. The remaining four groups received intravitreal VEGFT as follows: two groups received 0.5 mg or 2 mg VEGFT every four weeks (0.5Q4 and 2Q4, respectively) throughout the 12-month treatment period. Two groups received three initial doses of 2 mg VEGFT every four weeks (i.e., baseline, week 4, week 8), followed by either every eight weeks (2Q8) for 52 weeks or as needed (PRN) with a very strict repeat dosing criteria. The mean improvement in visual acuity relative to baseline is shown in Table 2:

[0064] [Table 2]

[0065] In this study, in all VEGFT study arms, including the 2 mg every other month dose, the visual acuity improvements achieved with VEGFT administered at week 24 were maintained or numerically improved through the completion of the week 52 study.

[0066] As demonstrated in the previous examples, administration of VEGFT once every 8 weeks to individuals with neovascular eye diseases (e.g., AMD and DME) after a single initial dose and two secondary doses spaced 4 weeks apart resulted in significant prevention of moderate or severe vision loss or improvement in vision.

[0067] [Example 6] A randomized, multicenter, double-blind clinical trial of previously treatment-naive patients with macular edema secondary to CRVO. In this randomized, double-blind, phase 3 study, patients received either 2 mg VEGFT intravitreal injections (114 patients) or sham injections (73 patients) every 6 months. From Week 24 to Week 52, all patients received 2 mg VEGFT (PRN) as needed, according to the retreatment criteria. Thus, "sham-treated patients" refer to patients who received sham injections every 4 weeks from Week 0 to Week 20, followed by intravitreal VEGFT injections as needed from Week 24 to Week 52. "VEGFT-treated patients" refer to patients who received intravitreal VEGFT injections every 4 weeks from Week 0 to Week 20, followed by intravitreal VEGFT injections as needed from Week 24 to Week 52. The primary endpoint was the proportion of patients who improved by ≥ 15 letters from baseline at Week 24. Secondary outcomes of visual acuity, anatomical vision, and quality of life (NEI VFQ-25) at Week 24 and Week 52 were also assessed.

[0068] At week 24, 56.1% of VEGFT-treated patients improved by ≥15 ETDRS letters compared with 12.3% of sham-treated patients (p<0.0001). Similarly, at week 52, 55.3% of VEGFT-treated patients improved by ≥15 ETDRS letters compared with 30.1% of sham-treated patients (p<0.01). At week 52, VEGFT-treated patients improved by a mean of 16.2 letters compared with 3.8 letters for sham-treated patients (p<0.001). The mean number of injections was ≥15 for sham-treated patients. The mean change in central retinal thickness was 3.9 for VEGFT-treated patients and 2.7 for VEGFT-treated patients. The mean change in central retinal thickness was -413.0 μm for VEGFT-treated patients compared with -381.8 μm for sham-treated patients. At week 24, the proportion of patients with ocular neovascularization was 0% for VEGFT-treated patients and 6.8% for sham-treated patients, respectively; at week 52 after receiving VEGFT PRN, the proportions were 0% and 6.8% for VEGFT-treated and sham-treated patients, respectively. At week 24, the mean change from baseline in VFQ-25 total score was 7.2 vs. 0.7 for VEGFT-treated and sham-treated groups; at week 52, the scores were 7.5 vs. 5.1 for VEGFT-treated and sham-treated groups.

[0069] This example confirms that monthly administration of 2 mg VEGFT intravitreal injections resulted in a statistically significant improvement in visual acuity at week 24, which was maintained with PRN through week 52, compared to sham PRN injections.

[0070] [Sequence table] SEQ ID NO: 1 (DNA sequence with 1377 nucleotides): ATGGTCAGCTACTGGGACACCGGGGTCCTGCTGTGCGCGCTGCTCAGCTGTCTGCTTCTCACAGGATCTAGTTCCGGAAGTGATACCGGTAGACCTTTCGTAGAGATGTACAGTGAAATCCCCGAAATTATACACATGACTGAAGGAAGGGAGCTCGTCATTCCCTGCCGGGTTACGTCA CCTAACATCACTGTTACTTTAAAAAAGTTTCCACTTGACACTTTGATCCCTGATGGAAAACGCATAATCTGGGACAGTAGAAAGGGCTTCATCATATCAAATGCAACGTACAAAGAAATAGGGCTTCTGACCTGTGAAGCAACAGTCAATGGGCATTTGTATAAGACAAACTATCTCACA CATCGACAAACCAATACAATCATAGATGTGGTTCTGAGTCCGTCTCATGGAATTGAACTATCTGTTGGAGAAAAGCTTGTCTTAAATTGTACAGCAAGAACTGAACTAAATGTGGGGATTGACTTCAACTGGGAATACCCTTCTTCGAAGCATCAGCATAAGAAAACTTGTAAACCGAGAC CTAAAAACCCAGTCTGGGAGTGAGATGAAGAAATTTTGAGCACCTTAACTATAGATGGTGTAACCCGGAGTGACCAAGGATTGTACACCTGTGCAGCATCCAGTGGGCTGATGACCAAGAAACAGCACATTTGTCAGGGTCCATGAAAAGGACAAAACTCACACATGCCCACCGTGC CCAGCACCTGAACTCCTGGGGGGACCGTCAGTTCTCCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGT GCATAATGCCAAGACAAAGCCGCGGGAGGACAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCCATCGAGAAAACCATCTCCAAAG CCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAAACAACTACAAGACC ACGCCTCCCGTGCTGGACTCCGACGCTCCTTCTCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA

[0071] SEQ ID NO: 2 (Polypeptide with 458 amino acids): MVSYWDTGVLLCALLSCLLLTGSSSGSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLY KTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVH EKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0072] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing disclosure and the accompanying figures. Such modifications are also intended to be within the scope of the appended claims.

Claims

1. 1. A pharmaceutical formulation for use in treating a neovascular ocular disease in a patient, said pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a VEGF antagonist, wherein said formulation is used by sequentially administering to the patient a single initial dose of the formulation, followed by four or more secondary doses of the formulation, followed by one or more tertiary doses of the formulation; wherein each secondary dose is administered 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered 8 weeks after the immediately preceding dose; wherein the VEGF antagonist is: SDTGRPFVEMYSEIPEIIHMTEGRELVI PCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGI ELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (amino acids 27-457 of SEQ ID NO: 2) a VEGF receptor-based chimeric molecule comprising the amino acid sequence The pharmaceutical preparation described above, wherein the preparation is administered to a patient by intravitreal administration.

2. 10. The formulation of claim 1, wherein four secondary doses of the formulation are administered to the patient.

3. The formulation of claim 1, wherein the neovascular eye disease is age-related macular degeneration.

4. The formulation according to claim 1, wherein the neovascular eye disease is diabetic retinopathy.

5. The formulation of claim 1, wherein the neovascular eye disease is diabetic macular edema.

6. The formulation according to claim 1, wherein the neovascular eye disease is central retinal vein occlusion.

7. The formulation of claim 1, wherein the neovascular eye disease is corneal neovascularization.

8. 10. The formulation of claim 1, wherein all doses of the formulation comprise from about 0.5 mg to about 2 mg of the VEGF antagonist.

9. 9. The formulation of claim 8, wherein all doses of the formulation comprise 0.5 mg of the VEGF antagonist.

10. 9. The formulation of claim 8, wherein all doses of the formulation comprise 2 mg of the VEGF antagonist.

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