Extended, high dose VEGF antagonist regimens for treatment of angiogenic eye disorders

Abstract

To provide a method for treating or preventing a neovascular age-related macular degeneration (nAMD).SOLUTION: A method comprises administering one or more doses of aflibercept at an interval and quantity. Here, the clearance of free aflibercept from the ocular compartment is about 0.3, 0.4, 0.41 or 0.37 to 0.46 mL / day after an intravitreal injection of aflibercept; the time for the amount for free aflibercept to reach a lower limit of quantitation (LLOQ) in the ocular compartment of a subject after the intravitreal injection of aflibercept is about 15 weeks; and / or the time for free aflibercept to reach the lower limit of quantitation (LLOQ) in the plasma of the subject after the intravitreal injection of aflibercept is about 3.8, 3.5 or 3.5 to 3.8 weeks.SELECTED DRAWING: None

Description

Technical field

[0001] This application is filed in U.S. Provisional Patent Application No. 63 / 319,869, filed on March 15, 2022, and U.S. Provisional Patent Application No. 63 / 404,512, filed on September 7, 2022. U.S. Provisional Patent Application No. 63 / 404,893 filed on September 29, 2022, U.S. Provisional Patent Application No. 63 / 411,594 filed on September 30, 2022 / 412,165, U.S. Provisional Patent Application No. 63 / 421,298, filed November 1, 2022, and U.S. Provisional Patent Application No. 63 / 434,920, filed December 22, 2022, February 9, 2023. U.S. Provisional Patent Application No. 63 / 444480, filed on February 22, 2023, and Canadian Patent Application No. 3190733, filed on February 22, 2023. No. 1, No. 1, No. 1, No. 1, No. 1, No. 1, No. 1, December 1999, 1999, each of which is incorporated herein by reference in its entirety.

[0002] Sequence listing reference This application incorporates by reference a computer-readable sequence listing in ST.26XML format entitled 11193WO01_Sequence, created on March 13, 2023, and containing 5,464 bytes.

[0003] The field of the invention relates to methods of treating or preventing neovascular eye disorders by administering VEGF antagonists. [Background technology]

[0004] Neovascular (wet) AMD (nAMD) is a significant health problem in aging populations worldwide. Vision loss in nAMD is due to abnormal blood vessel growth and leakage in the macula. In older subjects with nAMD, visual loss often has an even greater impact as it substantially reduces visual compensation for functional impairment due to other age-related comorbidities such as arthritis and osteoporosis.

[0005] Intravitreal (IVT) administered anti-vascular endothelial growth factor (VEGF) treatments such as EYLEA® inhibit neovascular growth and leakage in the retina, and they are currently the standard of care for subjects with nAMD. be. Those treatments not only preserve visual function but also result in clinically meaningful visual improvements. Treatment of nAMD is chronic and lifelong in most subjects to suppress retinal edema and choroidal neovascularization (CNV) recurrence. Although currently approved IVT anti-VEGF treatments are effective and well tolerated, the need for IVT injections every 4 to 8 weeks, especially during the initial phase and maintenance of treatment, is important for physicians and subjects. , and place a heavy burden on caregivers. Although the procedure is simple and relatively easy to perform, there are capacity issues to ensure adequate injection frequency to achieve results in subjects similar to those seen in the pivotal trial. Represents a growing challenge to individual practices and the health care system as a whole. Furthermore, frequent administration leads to an increased burden on subjects, such as having to find transportation and being absent from work. A secondary effect of this burden is that non-compliance with prescribed treatment regimens is less likely.

[0006] The efficacy and safety of currently approved VEGF antagonist therapies have been established for the treatment of nAMD, but the efficacy and safety of currently approved VEGF antagonist therapies have been established for the treatment of nAMD, with at least similar or even improved visual outcomes relative to currently available standard treatments. There continues to be an unmet medical need for the development of treatments that have the potential to reduce the burden of treatment while providing a therapeutic benefit.

[0007] Increasing the molar concentration of VEGF antagonist therapeutic proteins in the dosage formulation is a potential method of providing additional benefit to subjects with chorioretinal vascular disease, including nAMD. IVT administration of higher doses of aflibercept may prolong the therapeutic effect of the drug. Extending the treatment interval to every 12 or 16 weeks early after treatment initiation results in a reduction in the number of injections in the first treatment year. The potential reduction in injection-related procedural burden and safety events due to fewer injections could significantly contribute to patient / subject care and healthcare services. EYLEA (2 mg dose, administered at a concentration of 40 mg / mL, also referred to as intravitreal aflibercept injection [IAI]) is currently approved in the United States (US) for the treatment of nAMD and retinal vein occlusion ( It is also approved for the treatment of post-RVO macular edema, diabetic macular edema (DME), and diabetic retinopathy (DR). [Summary of the invention]

[0008] The present invention provides a method for treating or preventing neovascular age-related macular degeneration, the method providing a method for treating or preventing neovascular age-related macular degeneration, wherein the clearance of free aflibercept from the ocular compartment after intravitreal injection of aflibercept is approximately 0.367 to 0.458 mL / day (e.g., 0.41 mL / day), and the time required for the amount of free aflibercept to reach the lower limit of quantification (LLOQ) in the subject's ocular compartment after intravitreal injection of aflibercept is approximately 15 The time required for free aflibercept in a subject's plasma to reach the lower limit of quantification (LLOQ) (e.g., approximately 0.0156 mg / L) after intravitreal injection of aflibercept is approximately 3.5 weeks. including administering one or more doses (e.g., 8 mg or more) of aflibercept to the patient, for example, the aflibercept is in an aqueous pharmaceutical formulation, and the aflibercept is administered immediately after manufacturing and purification to about less than 3.5% high molecular weight species and / or less than about 6% high molecular weight species after storage at about 2-8°C for about 24 months. In one embodiment of the invention, the aqueous pharmaceutical formulation comprises at least about 100 mg / ml of two polypeptides each comprising immunoglobulin-like (Ig) domain 2 of VEGFR1, Ig domain 3 of VEGFR2, and a multimerizing component. An aqueous pharmaceutical formulation comprising a VEGF receptor fusion protein, about 10 to 100 mM L-arginine, sucrose, a histidine-based buffer, and a surfactant, the formulation having a pH of about 5.0 to about 6.8. However, the VEGF receptor fusion protein has less than about 3.5% high molecular weight species immediately after manufacture and purification and / or less than about 6% high molecular weight species after storage for about 24 months at about 2-8°C. In one embodiment of the invention, the method comprises administering a single initial dose of aflibercept of about 8 mg or more, followed by one or more secondary doses of aflibercept of about 8 mg or more, administering one or more tertiary doses of aflibercept of 8 mg or more, each secondary dose being administered about 2 to 4 weeks (preferably 4 weeks) after the immediately preceding dose; Each is administered about 12 to 20 weeks (preferably 12, 16, or 20 weeks) after the immediately preceding dose.

[0009] The present invention provides a method for slowing the clearance of free aflibercept from the ocular compartment after intravitreal injection compared to the clearance rate of aflibercept from the ocular compartment after intravitreal injection of 4 mg or less of aflibercept. Provided are methods, comprising administering to the eye of a subject in need thereof a single initial dose of aflibercept of about 8 mg or more, followed by one or more secondary doses of aflibercept of about 8 mg or more. , followed by intravitreal injection of one or more third doses of aflibercept of about 8 mg or more, each of the second doses being administered about 2 to 4 weeks after the immediately preceding dose, and the third dose Each dose is administered approximately 12 to 20 weeks after the previous dose. In one embodiment of the invention, the clearance of free aflibercept from the ocular compartment is approximately 34% slower than the clearance from the ocular compartment following intravitreal injection of 4 mg or less of aflibercept, e.g. The clearance of free aflibercept is approximately 0.367-0.458 mL / day or 0.41 mL / day after intravitreal injection of 8 mg or more of aflibercept.

[0010] The present invention also determines the time for the amount of free aflibercept in the ocular compartment of a subject to reach the lower limit of quantitation (LLOQ) after an intravitreal injection of approximately 2 mg of aflibercept in a subject after an intravitreal injection of aflibercept. The method provides a method for increasing the amount of free aflibercept in the ocular compartment of the eye by more than 1.3 weeks, such as from about 6 weeks to more than 10 weeks, such as about 15 weeks, for the time to reach the LLOQ of the amount of free aflibercept in the ocular compartment of a single initial dose of aflibercept of about 8 mg or more, followed by one or more secondary doses of aflibercept of about 8 mg or more, followed by a single initial dose of aflibercept of about 8 mg or more, involves intravitreal injection of one or more tertiary doses of Sept, with each secondary dose being administered about 2 to 4 weeks after the immediately preceding dose, and each tertiary dose being administered about 12 to 4 weeks after the immediately preceding dose. Administered after 20 weeks.

[0011] The present invention also determines the time for free aflibercept in a subject's plasma to reach the lower limit of quantification (LLOQ) (e.g., about 0.0156 mg / L) after intravitreal injection of aflibercept, at a dose of about 2 mg aflibercept. Provides a method for increasing the time to LLOQ of free aflibercept in plasma by more than 1.5 weeks, e.g., from about 2 weeks to about 3.5 weeks, after intravitreal injection of sept; a single initial dose of aflibercept of about 8 mg or more, followed by one or more secondary doses of aflibercept of about 8 mg or more, followed by a single initial dose of aflibercept of about 8 mg or more, involves intravitreal injection of one or more tertiary doses of Sept, with each secondary dose being administered about 2 to 4 weeks after the immediately preceding dose, and each tertiary dose being administered about 12 to 4 weeks after the immediately preceding dose. Administered after 20 weeks. In one embodiment of the invention, 8 mg or more of aflibercept is present in one or more of a histidine-based buffer, arginine (e.g., L-arginine, such as L-arginine HCl), a sugar or a polyol such as sucrose. Aflibercept is administered in an aqueous pharmaceutical formulation containing aflibercept and having a pH of about 5.8. In one embodiment of the invention, aflibercept has less than about 3.5% high molecular weight species immediately after manufacture and purification and / or no more than about 6% high molecular weight species after storage at about 2-8°C for about 24 months. for example, 8 mg or more of aflibercept is in an aqueous pharmaceutical formulation, the formulation each comprising immunoglobulin-like (Ig) domain 2 of VEGFR1, Ig domain 3 of VEGFR2, and multimerizing component 2. a VEGF receptor fusion protein containing at least about 100 mg / ml of a polypeptide, about 10 to 100 mM L-arginine, sucrose, a histidine-based buffer, and a surfactant; Having a pH of about 6.8, the VEGF receptor fusion protein contains less than about 3.5% high molecular weight species immediately after manufacture and purification and / or less than about 6% high molecular weight species after storage for about 24 months at about 2-8°C. It has molecular weight species.

[0012] The present invention provides a method for improving best-corrected visual acuity in a needy subject with neovascular age-related macular degeneration (nAMD), or for promoting retinal dryness in a needy subject having nAMD. 12, 13, 14, 15, 16, 17, 18, 19, or 20, or 12-20, or comprising administering one or more doses of about 8 mg or more of the VEGF receptor fusion protein once every 12 to 16, or 16 to 20 weeks.

[0013] The present invention provides a method of treating or preventing neovascular age-related macular degeneration (nAMD) in a subject in need thereof, the method comprising administering to the eye of the subject about 8 mg or more of a VEGF receptor fusion protein, preferably is a single initial dose of aflibercept, followed by one or more secondary doses of about 8 mg or more of VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of VEGF receptor fusion protein. each tertiary dose is administered about 2 to 4 weeks (preferably 4 weeks) after the immediately preceding dose, and each tertiary dose is administered about 12 to 20 weeks after the immediately preceding dose. administered later.

[0014] The present invention provides a method of treating or preventing neovascular age-related macular degeneration (nAMD) in a subject in need thereof, the method comprising administering to the eye of the subject about 8 mg or more of a VEGF receptor fusion protein, preferably is a single initial dose of aflibercept, followed by one or more secondary doses of about 8 mg or more of VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of VEGF receptor fusion protein. tertiary doses, each secondary dose being administered about 2 to 4 weeks (preferably 4 weeks) after the immediately preceding dose, and each tertiary dose being administered about 12 weeks after the immediately preceding dose. be done.

[0015] The present invention provides a method of treating or preventing neovascular age-related macular degeneration (nAMD) in a subject in need thereof, the method comprising administering to the eye of the subject about 8 mg or more of a VEGF receptor fusion protein, preferably is a single initial dose of aflibercept, followed by one or more secondary doses of about 8 mg or more of VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of VEGF receptor fusion protein. tertiary doses, each secondary dose being administered about 2 to 4 weeks (preferably 4 weeks) after the immediately preceding dose, and each tertiary dose being administered about 16 weeks after the immediately preceding dose. be done.

[0016] The present invention provides a method of treating or preventing neovascular age-related macular degeneration (nAMD) in a subject in need thereof, the method comprising administering to the eye of the subject about 8 mg or more of a VEGF receptor fusion protein, preferably is a single initial dose of aflibercept, followed by one or more secondary doses of about 8 mg or more of VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of VEGF receptor fusion protein. tertiary doses, each secondary dose being administered about 2 to 4 weeks after the immediately preceding dose, and each tertiary dose being administered about 20 weeks after the immediately preceding dose.

[0017] The present invention provides a method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject in need thereof, which method comprises administering 8 mg of a VEGF receptor fusion protein, preferably aflibercept ( 0.07 mL or 70 microliters) administered by intravitreal injection every 4 weeks (approximately every 28 days + / - 7 days, monthly) for the first 3 doses, followed by 8 mg aflibercept (0.07 mL) It involves administration by intravitreal injection once every 8 to 16 weeks (2 to 4 months + / -7 days).

[0018] The present invention provides a method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject in need thereof, which method comprises administering 8 mg of a VEGF receptor fusion protein, preferably aflibercept ( 0.07 mL or 70 microliters) was administered by intravitreal injection every 4 weeks (approximately every 28 days + / - 7 days, monthly) for the first 3 doses, followed by 8 mg of VEGF receptor fusion protein (0.07 mL) administered by intravitreal injection once every 12 weeks (2-4 months + / -7 days).

[0019] The present invention provides a method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject in need thereof, which method comprises administering 8 mg of a VEGF receptor fusion protein, preferably aflibercept ( 0.07 mL or 70 microliters) was administered by intravitreal injection every 4 weeks (approximately every 28 days + / - 7 days, monthly) for the first 3 doses, followed by 8 mg of VEGF receptor fusion protein (0.07 mL) administered by intravitreal injection once every 16 weeks (2-4 months + / -7 days).

[0020] The present invention provides a method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject in need thereof, which method comprises administering 8 mg of a VEGF receptor fusion protein, preferably aflibercept ( 0.07 mL or 70 microliters) was administered by intravitreal injection every 4 weeks (approximately every 28 days + / - 7 days, monthly) for the first 3 doses, followed by 8 mg of VEGF receptor fusion protein (0.07 mL) administered by intravitreal injection once every 20 weeks (+ / -7 days).

[0021] The present invention provides a method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject in need thereof, wherein: (1) the subject is administered an initial dose of 2 mg of a VEGF receptor fusion protein; and the method then administers to the subject, one month later, an initial dose of 8 mg of VEGF receptor fusion protein, and one month later, a second dose of 8 mg of VEGF receptor fusion protein. one month later, a second 8 mg VEGF receptor fusion protein sub-dose, followed by 8 mg VEGF every 12 or 16 or 20 weeks thereafter according to the HDq12 or HDq16 or HDq20 dosing regimen. administering one or more maintenance doses of the receptor fusion protein; (2) the subject has been administered an initial dose of 2 mg of the VEGF receptor fusion protein; One month later, the first 8 mg secondary dose of VEGF receptor fusion protein was administered, and one month later, the second 8 mg secondary dose of VEGF receptor fusion protein was administered, followed by 12 or (3) administering one or more maintenance doses of 8 mg VEGF receptor fusion protein every 16 or 20 weeks according to a HDq12 or HDq16 or HDq20 dosing regimen; an initial dose of the protein, the method then administers to the subject a second 8 mg secondary dose of the VEGF receptor fusion protein one month later, and then for 12 or 16 or 20 weeks thereafter. (4) administering one or more maintenance doses of 8 mg VEGF receptor fusion protein according to an HDq12 or HDq16 or HDq20 dosing regimen; and the method then administers to the subject, one month later, a first maintenance dose of 8 mg of VEGF receptor fusion protein, and then every 12 or 16 or 20 weeks, HDq12 or HDq16 or (5) Subjects receive an initial dose of 2 mg VEGF receptor fusion protein and, one month later, a first 2 mg of the VEGF receptor fusion protein, and the method then administers to the subject, one month later, an initial dose of 8 mg of the VEGF receptor fusion protein; Administer the first 8 mg secondary dose of VEGF receptor fusion protein, then one month later, administer the second 8 mg secondary dose of VEGF receptor fusion protein, then for 12 or 16 or 20 weeks thereafter. (6) administering one or more maintenance doses of 8 mg VEGF receptor fusion protein according to an HDq12 or HDq16 or HDq20 dosing regimen; and, one month later, a first 2 mg second dose of the VEGF receptor fusion protein; A second dose of protein is administered, followed one month later by a second dose of 8 mg of VEGF receptor fusion protein, followed by HDq12 or HDq16 or HDq20 administration every 12 or 16 or 20 weeks thereafter. (7) Subjects receive an initial dose of 2 mg VEGF receptor fusion protein and, 1 month later, one or more maintenance doses of 8 mg VEGF receptor fusion protein. a second dose of 2 mg of VEGF receptor fusion protein; the method then administers to the subject, one month later, a second second dose of 8 mg of VEGF receptor fusion protein; then, every 12 or 16 or 20 weeks thereafter, administering one or more maintenance doses of 8 mg VEGF receptor fusion protein according to an HDq12 or HDq16 or HDq20 dosing regimen, (8) in which the subject receives 2 mg of VEGF receptor fusion protein and, one month later, a second dose of 2 mg of VEGF receptor fusion protein; Administer the first 8 mg VEGF receptor fusion protein maintenance dose, then every 12 or 16 or 20 weeks, all additional 8 mg VEGF receptor fusion protein maintenance doses according to the HDq12 or HDq16 or HDq20 dosing regimen. (9) in which the subject receives an initial dose of 2 mg of VEGF receptor fusion protein, one month later, a second dose of 2 mg of VEGF receptor fusion protein, and one month later, a second dose of VEGF receptor fusion protein; and a second dose of 2 mg of VEGF receptor fusion protein; the method then administers to the subject, one month later, an initial dose of 8 mg of VEGF receptor fusion protein; followed by administration of the first 8 mg secondary dose of VEGF receptor fusion protein, followed one month later by administration of the second 8 mg secondary dose of VEGF receptor fusion protein, then subsequent 12 or 16 or every 20 weeks, including administering one or more maintenance doses of 8 mg of VEGF receptor fusion protein according to HDq12 or HDq16 or HDq20 dosing regimens, including (10) subject receiving 2 mg of VEGF receptor fusion protein; an initial dose and, one month later, a first secondary dose of 2 mg of VEGF receptor fusion protein, and one month later, a second secondary dose of 2 mg of VEGF receptor fusion protein; The method then administers to the subject, one month later, a first 8 mg secondary dose of VEGF receptor fusion protein, and one month later, a second 8 mg secondary dose of VEGF receptor fusion protein. and then every 12 or 16 or 20 weeks thereafter one or more maintenance doses of 8 mg of VEGF receptor fusion protein according to a HDq12 or HDq16 or HDq20 dosing regimen; (11) Subjects received an initial dose of 2 mg of VEGF receptor fusion protein, 1 month later a first secondary dose of 2 mg of VEGF receptor fusion protein, and 1 month later a second dose of 2 mg of VEGF receptor fusion protein. the subject receives a second dose of 8 mg of the VEGF receptor fusion protein one month later, and then 12 or 16 days thereafter. or every 20 weeks, administering one or more maintenance doses of 8 mg of VEGF receptor fusion protein according to a HDq12 or HDq16 or HDq20 dosing regimen, and (12) the subject receives 2 mg of VEGF receptor fusion protein. 1 month later, a second dose of 2 mg of VEGF receptor fusion protein, and 1 month later, a second dose of 2 mg of VEGF receptor fusion protein. , the method then administers to the subject a first maintenance dose of 8 mg of VEGF receptor fusion protein two months later, and then every 12 or 16 or 20 weeks according to an HDq12 or HDq16 or HDq20 dosing regimen. (13) Subjects received an initial dose of 2 mg VEGF receptor fusion protein and, 1 month later, a first dose of 2 mg VEGF receptor fusion protein. A second dose of fusion protein followed one month later by a second 2 mg VEGF receptor fusion protein followed 8 weeks later by a first 2 mg maintenance dose of VEGF receptor fusion protein. and the method then administers to the subject an initial dose of 8 mg of VEGF receptor fusion protein up to 2 months after the last dose of VEGF receptor fusion protein, and 1 month later, the first dose of VEGF receptor fusion protein. a second dose of 8 mg of VEGF receptor fusion protein, followed one month later by a second dose of 8 mg of VEGF receptor fusion protein, then every 12 or 16 or 20 weeks thereafter. , administering one or more maintenance doses of 8 mg VEGF receptor fusion protein according to a HDq12 or HDq16 or HDq20 dosing regimen, (14) in which the subject receives an initial dose of 2 mg VEGF receptor fusion protein; One month later, a second dose of 2 mg of VEGF receptor fusion protein, followed by a second dose of 2 mg of VEGF receptor fusion protein one month later, and 8 weeks later, a second dose of 2 mg of VEGF receptor fusion protein. and one or more maintenance doses of the VEGF receptor fusion protein, and the method then administers to the subject a first 8 mg VEGF dose up to 2 months after the last dose of the VEGF receptor fusion protein. A second dose of receptor fusion protein is administered, followed one month later by a second 8 mg second dose of VEGF receptor fusion protein, and then every 12 or 16 or 20 weeks thereafter, HDq12 or HDq16 or administering one or more maintenance doses of 8 mg VEGF receptor fusion protein according to an HDq20 dosing regimen (15) in which the subject receives an initial dose of 2 mg VEGF receptor fusion protein and 1 month later One second dose of 2 mg VEGF receptor fusion protein, followed one month later by a second second dose of 2 mg VEGF receptor fusion protein, followed 8 weeks later by 2 mg VEGF receptor fusion protein. and one or more maintenance doses, and the method then administers to the subject a second 8 mg dose of VEGF receptor fusion protein up to 2 months after the last dose of VEGF receptor fusion protein. administering a secondary dose and then administering one or more maintenance doses of 8 mg VEGF receptor fusion protein every 12 or 16 or 20 weeks thereafter according to a HDq12 or HDq16 or HDq20 dosing regimen. , (16) in which subjects received an initial dose of 2 mg of VEGF receptor fusion protein, followed 1 month later by a second dose of 2 mg VEGF receptor fusion protein, and 1 month later received a second dose of 2 mg VEGF receptor fusion protein. the subject has been administered a second dose of the VEGF receptor fusion protein followed 8 weeks later by one or more maintenance doses of 2 mg of the VEGF receptor fusion protein; Administer a first maintenance dose of 8 mg of VEGF receptor fusion protein up to 2 months after the last dose of protein, then every 12 or 16 or 20 weeks thereafter according to the HDq12 or HDq16 or HDq20 dosing regimen. (i) the HDq12 dosing regimen includes administering a single initial dose of about 8 mg or more of VEGF receptor fusion protein, followed by a single initial dose of about 8 mg or more of VEGF receptor fusion protein; of the VEGF receptor fusion protein, followed by one or more third doses of the VEGF receptor fusion protein of about 8 mg or more, each of the secondary doses is administered approximately 2 to 4 weeks after the immediately preceding dose, and each tertiary dose is administered approximately 12 weeks after the immediately preceding dose; administration of one initial dose, followed by one or more secondary doses of VEGF receptor fusion protein of about 8 mg or more, followed by one or more third doses of VEGF receptor fusion protein of about 8 mg or more each of the secondary doses being administered about 2 to 4 weeks after the immediately preceding dose, and each of the tertiary doses being administered about 16 weeks after the immediately preceding dose; A single initial dose of 8 mg or more of VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of VEGF receptor fusion protein, followed by about 8 mg or more of VEGF receptor fusion protein. comprising one or more tertiary doses, each secondary dose being administered about 2 to 4 weeks after the immediately preceding dose, and each tertiary dose being administered about 20 weeks after the immediately preceding dose; The fusion protein is aflibercept and the period is 2 to 4 weeks, preferably 4 weeks.

[0022] The invention also provides a method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject in need thereof, wherein: (a) the subject receives an initial dose of 8 mg of a VEGF receptor fusion protein; and the method then administers to the subject, one month later, a second dose of 8 mg of VEGF receptor fusion protein, and one month later, a second dose of 8 mg of VEGF receptor fusion protein. administering a second dose of protein and then administering one or more maintenance doses of 8 mg VEGF receptor fusion protein every 12 or 16 or 20 weeks thereafter according to a HDq12 or HDq16 or HDq20 dosing regimen. (b) the subject has been administered an initial dose of 8 mg of VEGF receptor fusion protein and, one month later, a second dose of 8 mg of VEGF receptor fusion protein; , subjects received a second 8 mg secondary dose of VEGF receptor fusion protein one month later, and then every 12 or 16 or 20 weeks thereafter, 8 mg of VEGF receptor fusion protein, according to the HDq12 or HDq16 or HDq20 dosing regimen. (c) the subject receives an initial dose of 8 mg VEGF receptor fusion protein and, one month later, a first dose of 8 mg VEGF receptor fusion protein; a second dose of the fusion protein and, one month later, a second 8 mg second dose of the VEGF receptor fusion protein; , administer the first 8 mg VEGF receptor fusion protein maintenance dose, then every 12 or 16 or 20 weeks, all additional 8 mg VEGF receptor fusion protein maintenance doses according to the HDq12 or HDq16 or HDq20 dosing regimen. or (d) the subject receives an initial dose of 8 mg of VEGF receptor fusion protein and, one month later, a second dose of 8 mg of VEGF receptor fusion protein, and one month later, a second secondary dose of 8 mg VEGF receptor fusion protein, and then every 12 or 16 or 20 weeks thereafter, the subject receives one or more maintenance doses of 8 mg VEGF receptor fusion protein. and the method then administers to the subject one or more maintenance doses of 8 mg of VEGF receptor fusion protein 12 or 16 or 20 weeks after the last maintenance dose of VEGF receptor fusion protein. administration of a maintenance dose of VEGF receptor fusion protein, and then every 12 or 16 or 20 weeks, each additional 8 mg maintenance dose of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen, comprising: (i) administering HDq12 as described above; If the regimen is a single initial dose of about 8 mg or more of VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of VEGF receptor fusion protein, followed by about 8 mg or more of VEGF receptor fusion protein. administering one or more tertiary doses of the body fusion protein, each of the secondary doses being administered about 2 to 4 weeks after the immediately preceding dose, and each of the tertiary doses being administered about 12 weeks after the immediately preceding dose. (ii) said HDq16 dosing regimen comprises a single initial dose of about 8 mg or more of VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of VEGF receptor fusion protein; , followed by administering one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein, each of the secondary doses being administered about 2 to 4 weeks after the immediately preceding dose, and the tertiary dose (iii) said HDq20 dosing regimen comprises a single initial dose of about 8 mg or more of VEGF receptor fusion protein, followed by a single initial dose of about 8 mg or more of VEGF receptor fusion protein; one or more secondary doses of VEGF receptor fusion protein, followed by one or more third doses of about 8 mg or more of VEGF receptor fusion protein, each secondary dose about 2 to 4 weeks after the previous dose. and each third dose is administered about 20 weeks after the previous dose, preferably the VEGF receptor fusion protein is aflibercept, and 2 to 4 weeks, preferably 4 weeks.

[0023] The invention also provides a method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject in need thereof, wherein the subject receives about 2 mg of a VEGF receptor fusion protein, preferably aflibercept. a single initial dose of VEGF receptor fusion protein, followed by one or more secondary doses of about 2 mg of VEGF receptor fusion protein, followed by one or more third doses of about 2 mg of VEGF receptor fusion protein. in a dosing regimen for treating or preventing nAMD, wherein each secondary dose is administered about 4 weeks after the immediately preceding dose and each tertiary dose is administered about 8 weeks after the immediately preceding dose. and the subject is at any stage on a 2 mg VEGF receptor fusion protein dosing regimen, the method includes administering to the subject's eye an 8 mg dose of the VEGF receptor fusion protein and administering about 8 or 8 mg of VEGF receptor fusion protein every 12 weeks or every 16 weeks if, in the judgment of the treating physician, dosing every 12 weeks or every 16 weeks is appropriate. Continue to administer the subject, or assess the subject after approximately 8 or 10 or 12 weeks of administration, and if, in the judgment of the treating physician, dosing every 12 weeks is appropriate, an additional 8 mg of VEGF receptor fusion protein dose, re-evaluate the subject approximately 12 weeks later, and continue to administer 8 mg of VEGF receptor fusion protein every 16 weeks to the subject if dosing every 16 weeks is appropriate in the judgment of the treating physician. ,including.

[0024] In one embodiment of the invention, the subject receives a single initial dose of about 2 mg of VEGF receptor fusion protein, preferably aflibercept, followed by two secondary doses of about 2 mg of VEGF receptor fusion protein, Subsequently, in a dosing regimen for treating or preventing neovascular age-related macular degeneration of one or more tertiary doses of about 2 mg of VEGF receptor fusion protein, each secondary dose being The dose is administered approximately 4 weeks after the first dose, with each tertiary dose being administered approximately 8 weeks after the previous dose.

[0025] The present invention provides a method of treating or preventing neovascular age-related macular degeneration (nAMD) in a subject in need thereof, the method comprising administering to the eye of the subject about 8 mg or more of a VEGF receptor fusion protein, preferably is a single initial dose of aflibercept, followed by one or more secondary doses of about 8 mg or more of VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of VEGF receptor fusion protein. tertiary doses, each of the secondary doses being administered about 2 to 4 weeks (preferably 4 weeks) after the immediately preceding dose, and each of the tertiary doses being administered about 12 or 16 weeks after the immediately preceding dose. After one or more of the above tertiary doses are administered approximately 12 or 16 weeks after the immediately preceding dose, the tertiary dose interval is increased from 12 weeks to 16 weeks after the immediately preceding dose, from 12 weeks to 20 weeks after the immediately preceding dose. weeks, or extending from 16 weeks to 20 weeks, eg, the tertiary dose interval is adjusted about 48 or 60 weeks after initiation of treatment. In one embodiment of the invention, prior to said prolongation, the subject exhibits (a) a BCVA loss of less than 5 letters, and / or (b) a CRT of less than 300 or 320 μm. In one embodiment of the invention, the method comprises assessing the BVCA and / or CRT of a subject and determining whether the subject has (a) a BCVA loss of less than 5 letters, and / or (b) a CRT of less than 300 or 320 μm. further including extending the tertiary dose interval if present.

[0026] The present invention provides a method of treating or preventing nAMD in a subject in need thereof, comprising administering to the eye of the subject a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, preferably aflibercept; followed by administering one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more third doses of about 8 mg or more of the VEGF receptor fusion protein. , each of the secondary doses is administered about 2 to 4 weeks (preferably 4 weeks) after the immediately preceding dose, and each of the tertiary doses is administered about 12 or 16 or 20 weeks after the immediately preceding dose; After administering one or more of the above tertiary doses after about 12 or 16 or 20 weeks, increasing the tertiary dose interval from 12 weeks to 8 weeks, from 16 weeks to 12 weeks, from 16 weeks to 8 weeks, from 20 Further including shortening from 1 week to 8 weeks, from 20 weeks to 12 weeks, or from 20 weeks to 16 weeks. In one embodiment of the invention, prior to said shortening, the subject has (a) a BCVA loss of more than 10 letters compared to baseline, and / or (b) 50 μm of CRT compared to baseline. shows a super increase. In one embodiment of the invention, the method assesses a subject's BVCA and / or CRT and determines whether the subject has (a) a BCVA loss of more than 10 letters compared to baseline, and / or (b) Further including shortening the tertiary dose interval if the comparison shows a CRT increase of more than 50 μm.

[0027] In one embodiment of the invention, (a) more than 5 characters are missing in the BCVA (ETDRS) compared to the BCVA observed at about 12 weeks after initiation of treatment; (c) a CRT increase of greater than 25 micrometers is observed compared to the CRT observed at approximately 12 weeks after initiation; and / or (c) a new The interval between tertiary doses is reduced from 12 or 16 weeks to 8 weeks if there is foveal neovascularization or foveal hemorrhage that has developed in or (a) observed approximately 12 weeks after the start of treatment; >5 letters lost in BCVA(ETDRS) compared to BCVA; (b) CRT increase of >25 micrometers compared to CRT observed approximately 12 weeks after initiation of treatment; is observed, and / or (c) there is new-onset foveal neovascularization or foveal hemorrhage, for example, at 24 weeks after the start of treatment, the interval between tertiary doses is from 16 weeks to 12 weeks. be shortened.

[0028] The present invention provides a method for treating or preventing neovascular age-related macular degeneration in a subject in need thereof, the method comprising administering about 114.3 mg / ml of a VEGF receptor fusion protein, preferably aflibercept. administering three doses of approximately 8 mg of VEGF receptor fusion protein to the subject's eyes at four-week intervals, and after the three doses, one dose of VEGF receptor fusion protein or including administering multiple doses at extended intervals of up to 12, 16, or 20 weeks.

[0029] The present invention provides a method for treating or preventing nAMD in a subject in need thereof, the method comprising administering a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, preferably aflibercept, to the eye of the subject. followed by administering two secondary doses of about 8 mg or more of the VEGF receptor fusion protein, each secondary dose being administered about 2 to 4 (preferably 4) weeks after the previous dose. , after the dose, (a) the subject shortens or lengthens (lengthens) one or more intervals of 2 weeks, 3 weeks, 4 weeks, or 2-4 weeks between doses of the VEGF receptor fusion protein; and (b) if the determination is made, administering an additional dose of the VEGF receptor fusion protein at a shortened or extended inter-dose interval. , provides a method in which the criteria for shortening the interval includes: BCVA loss of more than 5 characters, 2. increase in central retinal thickness (CRT) of more than 25 micrometers, 3. new foveal hemorrhage, and / or 4. new foveal vessels with interval lengthening criteria including: Newborn. BCVA loss of less than 1.5 letters, 2. no fluid in the central subfield of OCT, 3. no development of new foveal hemorrhage, and / or 4. no foveal neovascularization. In one embodiment of the invention, criteria for extending the interval include: 1. less than 5 letters of BCVA loss from week 12, 2. no fluid in the central subfield of OCT, and 3. new onset central No foveal hemorrhage or foveal neovascularization, and / or criteria for shortening the interval include both of the following: 1. BCVA loss >5 letters from week 12, and 2. Central retina >25 micrometers from week 12 increased thickness (CRT) or new foveal hemorrhage or new foveal neovascularization. In one embodiment of the invention, if the above criteria are met, the interval is extended to 12, 16, or 20 weeks.

[0030] The present invention provides for the treatment or prevention of neovascular age-related macular degeneration (nAMD) in a subject in need thereof pretreated with one or more 2 mg doses of a VEGF receptor fusion protein, preferably aflibercept. The method provides a method of administering to the eye of a subject a single initial dose of about 8 mg or more of VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of VEGF receptor fusion protein. the next dose, followed by one or more third doses of about 8 mg or more of the VEGF receptor fusion protein, each sub-dose being administered for about 2 to 4 weeks (preferably 4 to 4 weeks) of the immediately preceding dose. weeks) later, with each tertiary dose being administered about 12 to 20 weeks (eg, 12, 16, or 20 weeks) after the previous dose.

[0031] The present invention provides a method of treating or preventing a neovascular eye disorder (preferably nAMD) in a subject in need thereof, the method comprising administering to the subject's eye: (1) about 8 mg or more of a VEGF receptor fusion protein; Preferably a single initial dose of aflibercept followed by one or more (e.g., 2, 3, or 4) secondary doses of VEGF receptor fusion protein of about 8 mg or more, followed by about 8 mg or more. administering one or more tertiary doses of the above VEGF receptor fusion protein, each of the secondary doses being administered about 2 to 4 weeks (preferably 4 weeks) after the immediately preceding dose; each dose is administered about 8 weeks after the immediately preceding dose, or (2) administering one or more doses of 8 mg or more of the VEGF receptor fusion protein about every 4 weeks.

[0032] In one embodiment of the invention, subjects with one or more of ocular or periocular infection, active intraocular inflammation, and / or hypersensitivity are excluded from treatment or prophylaxis. There is no need to exclude subjects who lack such criteria. In one embodiment of the invention, the methods herein include any one or more of the steps of: assessing the subject for ocular or periocular infection, active intraocular inflammation, and / or hypersensitivity; and excluding treatment or prophylaxis in the subject if the method is found in the subject.

[0033] In one embodiment of the invention, the subject is monitored for adverse events such as conjunctival hemorrhage, opacification, vitreous detachment, vitreous floaters, corneal epithelial defects, and / or increased intraocular pressure. If such AEs are identified, the identified AEs may be treated and / or such treatment or prophylaxis may be discontinued.

[0034] In one embodiment of the invention, the method comprises the preparation of a VEGF receptor fusion protein, preferably aflibercept, prior to administration. For example, the method may include one single-dose glass vial with a protective plastic cap and stopper containing an aqueous formulation containing 8 mg of VEGF receptor fusion protein in approximately 70 microliters and a distal tip prior to each administration. and a bevel, e.g., one 18 gauge x 1.5 inch, 5 micron filter needle, a needle of the invention, e.g., one 30 gauge x 1 / 2 inch injection needle, and a syringe, e.g., a 70 microliter providing or making available packaged together with one 1 mL Luer-lock syringe having graduation markings for volume, and then (1) visually inspecting the aqueous formulation in the vial; but if particulates, cloudiness, or discoloration are visible, use another vial of the aqueous formulation containing the VEGF receptor fusion protein, (2) remove the protective plastic cap from the vial, and (3) remove the vial. cleaning the top with an alcohol wipe, then using aseptic technique, (4) removing the 18 gauge x 1.5 inch, 5 micron filter needle and 1 mL syringe from their packaging, and (5) using the Luer lock. Attach the filter needle to the syringe by twisting the filter needle over the syringe tip and (6) insert the filter needle into the vial stop until the needle is fully inserted into the vial and the tip contacts the bottom or bottom rim of the vial. (7) Withdraw all of the VEGF receptor fusion protein vial contents into the syringe, holding the vial in an upright position while ensuring that the bevel of the filter needle is immersed in the liquid; (8) keep the vial tilted during withdrawal to keep the bevel of the filter needle submerged in the formulation; and (9) tilt the vial to completely empty the filter needle. (10) remove the filter needle from the syringe and discard the filter needle, and (11) remove the 30 gauge x 1 / 2 inch needle from its packaging. Attach the needle to the syringe by removing and twisting the needle tightly with the Luer lock syringe tip; (12) Hold the syringe with the needle facing up and check the syringe for air bubbles; If present, tap the syringe with your finger until air bubbles rise to the top; (13) slowly press down on the plunger so that the plunger tip lines up with the graduation line marking 70 microliters on the syringe; ,including. In one embodiment of the invention, the injection of the VEGF receptor fusion protein is performed under controlled aseptic conditions, and the aseptic conditions include surgical hand disinfection and sterile gloves, sterile drapes, and sterile eyelid openers (or equivalent). including the use of anesthesia and topical broad-spectrum microbicides are administered prior to injection.

[0035] In one embodiment of the invention, the subject receives a single initial dose of about 2 mg of VEGF receptor fusion protein, preferably aflibercept, followed by two secondary doses of about 2 mg of VEGF receptor fusion protein, Subsequently, in a dosing regimen for treating or preventing nAMD that requires one or more third doses of a VEGF receptor fusion protein of about 2 mg, each secondary dose being about 2 mg of the immediately preceding dose. administered 4 weeks later, with each tertiary dose administered approximately 8 weeks after the previous dose, and subjects receiving 2 mg of VEGF receptor fusion protein at any stage of the dosing regimen (initial dose, secondary dose, or tertiary dose). be.

[0036] In one embodiment of the invention, the one or more secondary doses are two secondary doses, 2-4 weeks is about 4 weeks, 12-20 weeks is about 12 weeks, 12 ~20 weeks is about 16 weeks, 12-20 weeks is about 20 weeks, 12-20 weeks is about 12-16 weeks, 8-16 weeks is about 12 weeks, 8-16 weeks is about 16 weeks about 16 weeks, 8-16 weeks is about 12-16 weeks, 2-4 weeks is about 4 weeks, one or more secondary doses is two secondary doses, 12 ~20 weeks is about 12 weeks and one or more secondary doses is 2 secondary doses, 12-20 weeks is about 16 weeks and one or more secondary doses are 2 secondary doses, 12-20 weeks is about 20 weeks, and one or more secondary doses are 2 secondary doses, 12-20 weeks is about 12-16 weeks. Yes, one or more secondary doses are two secondary doses, 2 to 4 weeks is about 4 weeks, one or more secondary doses are two secondary doses. , VEGF receptor fusion protein is aflibercept, 12-20 weeks is about 12 weeks, one or more secondary doses are two secondary doses, VEGF receptor fusion protein is aflibercept Bercept, 12-20 weeks is approximately 16 weeks, the one or more secondary doses are two secondary doses, and the VEGF receptor fusion protein is aflibercept, 12-20 week is approximately 20 weeks, one or more secondary doses are two secondary doses, the VEGF receptor fusion protein is aflibercept, and / or 12 to 20 weeks is approximately 12 to 16 weeks, the one or more secondary doses are two secondary doses, and the VEGF receptor fusion protein is aflibercept.

[0037] In one embodiment of the invention, the VEGF receptor fusion protein comprises (i) (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 comprising amino acids 232-457 of SEQ ID NO: 2, (ii) immunoglobulin-like (lg) domain 2 of VEGFR1, lg domain 3 of VEGFR2, and multiple (iii) two polypeptides comprising the immunoglobulin-like (lg) domain 2 of VEGFR1, the lg domain 3 of VEGFR2, the lg domain 4 of VEGFR2, and the multimerization component; (iv) two VEGFR1R2-FcΔC1(a) polypeptides encoded by the nucleic acid sequence of SEQ ID NO: 1, or (v) selected from the group consisting of aflibercept and conbercept. In an embodiment of the invention, the VEGF receptor fusion protein comprises amino acids 27-457 of the amino acid sequence shown in SEQ ID NO:2.

[0038] In an embodiment of the invention, 8 mg of VEGF receptor fusion protein, preferably aflibercept, is in an aqueous pharmaceutical formulation selected from the group consisting of A-KKKK.

[0039] In an embodiment of the invention, 8 mg of VEGF receptor fusion protein, preferably aflibercept, is administered in an aqueous pharmaceutical formulation containing about 114.3 mg / ml of VEGF receptor fusion protein.

[0040] In one embodiment of the invention, the VEGF receptor fusion protein, preferably aflibercept, is administered intravitreally from a syringe or prefilled syringe that is, for example, glass or plastic and / or sterile. In one embodiment of the invention, the VEGF receptor fusion protein is injected intravitreally using a 30 gauge x 1 / 2 inch sterile needle.

[0041] In one embodiment of the invention, the subject has received one or more previous doses of 2 mg of a VEGF receptor fusion protein, preferably aflibercept, eg Eylea.

[0042] In one embodiment of the invention, the methods described herein further include one or more additional doses administered.

[0043] In one embodiment of the invention, 2 mg of VEGF receptor fusion protein, preferably aflibercept, is added to an aqueous pharmaceutical formulation comprising 40 mg / ml of VEGF receptor fusion protein, e.g. It is in an aqueous pharmaceutical formulation containing 10mM sodium phosphate, 40mM NaCl, 0.03% polysorbate 20, and 5% sucrose, with a pH of 6.2.

[0044] In one embodiment of the invention, 8 mg of VEGF receptor fusion protein is prepared in an aqueous solution containing 100 mg / ml or more of VEGF receptor fusion protein, preferably aflibercept, a histidine-based buffer, and arginine (e.g., L-arginine). Found in pharmaceutical preparations. In one embodiment of the invention, 8 mg of VEGF receptor fusion protein is in an aqueous pharmaceutical formulation containing a sugar or polyol, such as sucrose. In one embodiment of the invention, 8 mg of VEGF receptor fusion protein is in an aqueous pharmaceutical formulation having a pH of about 5.8. In one embodiment of the invention, 8 mg of VEGF receptor fusion protein is added to an aqueous pharmaceutical formulation comprising about 103-126 mg / ml of VEGF receptor fusion protein, a histidine-based buffer, and arginine, e.g., about 114.3 mg / ml. VEGF receptor fusion protein, a histidine-based buffer, and arginine.

[0045] In one embodiment of the invention, 8 mg of VEGF receptor fusion protein is about 100 μl or less, about 75 μl or less, about 70 μl or less, or about 50 μl, 51 μl, 52 μl, 53 μl, 54 μl, 55 μl, 56 μl, 57 μl, 58 μl, 59 μl , 60μl, 61μl, 62μl, 63μl, 64μl, 65μl, 66μl, 67μl, 68μl, 69μl, 70μl, 71μl, 72μl, 73μl, 74μl, 75μl, 76μl, 77μl, 78μl, 79μl, 80μl, 81μl, 82μl, 83μl, 84μl , 85 μl, 86 μl, 87 μl, 88 μl, 89 μl, 90 μl, 91 μl, 92 μl, 93 μl, 94 μl, 95 μl, 96 μl, 97 μl, 98 μl, 99 μl, or 100 μl, eg, about 70 ± 4 or 5 microliters.

[0046] In one embodiment of the invention, the methods herein include administering a VEGF receptor fusion protein, preferably aflibercept, to both eyes of the subject, eg, intravitreally.

[0047] In one embodiment of the invention, the subject achieves and / or maintains one or more of the following: a best-corrected visual acuity (BCVA) of 5 or more letters, 10 or more letters, 15 or more letters, or 20 or more letters. improvement, no decrease in best-corrected visual acuity (BCVA), loss of retinal fluid, loss of intraretinal fluid (IRF) and / or subretinal fluid, reduction in total lesional choroidal neovascularization (CNV) area, loss of intraretinal fluid. loss or decrease in subretinal fluid, decrease in central subfield retinal thickness (CST), improvement in vision-related quality of life, treatment-emergent adverse events (AEs) and / or severe AEs (SAEs). ), an ETDRS letter score of at least 69 (approximately 20 / 40 Snellen equivalent table), a BCVA of 5 or more, 10 or more, 15 or more as measured by the Early Treatment Diabetic Retinopathy Screening (ETDRS) visual acuity chart, or improvement of 20 or more letters or lack of decline in BCVA during the course of treatment, improvement in mean BCVA over a 12-week period, absence of intraretinal fluid (IRF) and subretinal fluid, reduction in choroidal neovascularization (CNV) size, Decrease in total lesion CNV area from baseline, loss of IRF and / or SRF, decrease in central subfield retinal thickness (CST), as measured by National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) Improved vision-related quality of life, absence of treatment-emergent adverse events (AEs) and / or serious AEs (SAEs), approximately every 4 weeks for the first 3 months in subjects with nAMD. 2 mg, followed by aflibercept administered intravitreally once every 8 weeks or once every 2 months, with efficacy and / or safety similar to that of aflibercept administered intravitreally, with efficacy associated with improved BCVA and / or Measured as a decrease in retinal thickness, safety is measured as the incidence of adverse events such as increased blood pressure, increased intraocular pressure, visual impairment, vitreous disease, vitreous detachment, iris neovascularization, and / or vitreous hemorrhage. undetected anti-drug antibodies while undergoing treatment, at 4, 8, 12, 16, 20, 24, and 28 weeks from the start of treatment (baseline) Improvement in best-corrected visual acuity (BVCA) by week 32, week 36, week 40, week 44, week 48, week 52, week 56, or week 60, early treatment diabetic retina BCVA improvement of 2 or more, 3 or 4, 5 or 6, or 7 or more letters as measured by ETDRS visual acuity chart or Snellen equivalent chart, 4 or more after initiation of treatment. By week 1, approximately 2 or 3 letters of BCVA (ETDRS or Snellen Equivalent Table) for HDq12 regimens or approximately 3 letters of BCVA (ETDRS or Snellen Equivalent Tables) for HDq16 regimens, improvement of treatment. By week 8 after initiation, an improvement in BCVA (ETDRS or Snellen equivalent table) of approximately 5 letters for HDq12 regimens or approximately 4 or 5 letters for HDq16 regimens (ETDRS or Snellen equivalent table); By week 12 after the start of treatment, approximately 5 or 6 letters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 5 or 6 letters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens. ), by week 16 after the start of treatment, approximately 6 letters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 6 or 7 letters of BCVA (ETDRS or Snellen equivalent tables) for HDq16 regimens. By week 20 after the start of treatment, approximately 6 letters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 6 letters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens. By week 24 after the start of treatment, approximately 5 or 6 letters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 5 or 6 letters of BCVA for HDq16 regimens (ETDRS or Snellen Equivalent Table), approximately 7 letters of BCVA (ETDRS or Snellen Equivalent Table) for HDq12 regimens or approximately 6 letters of BCVA for HDq16 regimens by week 28 after treatment initiation Improvement in BCVA (ETDRS or Snellen Equivalent Table) by approximately 6 or 7 letters for HDq12 regimens (ETDRS or Snellen Equivalent Table) or approximately 7 letters for HDq16 regimens by week 32 after treatment initiation improvement in BCVA (ETDRS or Snellen equivalent table) of approximately 6 or 7 letters for the HDq12 regimen or approximately 6 or 7 letters of BCVA (ETDRS or Snellen equivalent table) for the HDq16 regimen by week 36 after treatment initiation. Improvement in 6-letter BCVA (ETDRS or Snellen Equivalent Table) by week 40 after initiation of treatment, approximately 6 or 7 letter BCVA (ETDRS or Snellen Equivalent Table) for HDq12 regimens or approximately 6 or 7 letter BCVA (ETDRS or Snellen Equivalent Tables) for HDq16 regimens is approximately a 5 or 6 letter BCVA (ETDRS or Snellen Equivalent Table) improvement, by week 44 after the start of treatment, and approximately 7 letter BCVA (ETDRS or Snellen Equivalent Table) improvement for HDq12 regimens or approximately 7 letter BCVA (ETDRS or Snellen Equivalent Table) for HDq16 regimens. BCVA (ETDRS or Snellen Equivalent Table) improvement of approximately 5 or 6 letters in BCVA (ETDRS or Snellen Equivalent Table) for HDq12 regimens by week 48 after initiation of treatment; or an improvement in BCVA (ETDRS or Snellen equivalent table) of approximately 6 letters for HDq16 regimens and approximately 7 or 8 letters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens by week 52 after treatment initiation. (table) or approximately 6 or 7 letters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens, and approximately 6 or 7 letters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens by week 56 after treatment initiation; ETDRS or Snellen Equivalent Table) or BCVA (ETDRS or Snellen Equivalent Table) of approximately 6 or 7 letters for HDq16 regimens, by week 60 after initiation of treatment and approximately 6 or 7 for HDq12 regimens. Improvement in BCVA (ETDRS or Snellen Equivalent Table) of letters (ETDRS or Snellen Equivalent Table) or approximately 6 or 7 letters of BCVA (ETDRS or Snellen Equivalent Table) for HDq16 regimens, by approximately 48 to 60 weeks after initiation of treatment, for HDq12 regimens. BCVA (ETDRS or Snellen Equivalent Table) of approximately 6 or 7 letters for HDq16 regimens or approximately 6 or 7 letters of BCVA (ETDRS or Snellen Equivalent Table) for HDq16 regimens by week 60 after initiation of treatment. , BCVA (ETDRS or Snellen equivalent table) improvement of approximately 5, 10, or 15 letters for HDq12 or HDq16 regimens; BCVA by approximately 8, 9, 10, 11, or 12 weeks after initiation of treatment BCVA of approximately 63 letters for HDq12 regimens by week 4 after initiation of treatment, where an improvement of approximately ±1 or ±2 ETDRS letters or within the Snellen equivalent table is achieved and maintained during subsequent treatment regimens. (ETDRS or Snellen Equivalent Table) or approximately 63 characters of BCVA for HDq16 regimens (ETDRS or Snellen Equivalent Table); By week 8 after the start of treatment, the BCVA of approximately 65 characters (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 65 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens, of treatment. Approximately 66 characters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens by week 12 after initiation of treatment By week 16, approximately 66 characters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens, 20 weeks after initiation of treatment BCVA of approximately 66 characters (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens by 24 weeks after initiation of treatment approximately 66 characters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens by week 28 after initiation of treatment; Approximately 67 characters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens, no later than 32 weeks after the start of treatment. BCVA of approximately 67 characters (ETDRS or Snellen Equivalent Table) for HDq16 regimens or BCVA of approximately 67 characters (ETDRS or Snellen Equivalent Tables) for HDq16 regimens by week 36 after initiation of treatment for HDq12 regimens BCVA of approximately 67 characters (ETDRS or Snellen Equivalent Table) for HDq16 regimens or approximately 66 characters of BCVA (ETDRS or Snellen Equivalent Tables) for HDq16 regimens by week 40 after initiation of treatment for HDq12 regimens. BCVA of approximately 67 characters (ETDRS or Snellen equivalent table) or approximately 66 characters BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens, approximately 68 for HDq12 regimens by week 44 after treatment initiation BCVA of letters (ETDRS or Snellen Equivalent Table) or approximately 66 letters (ETDRS or Snellen Equivalent Table) for HDq16 regimens, approximately 67 letters for HDq12 regimens by week 48 after treatment initiation. BCVA (ETDRS or Snellen Equivalent Table) or approximately 66 characters of BCVA (ETDRS or Snellen Equivalent Table) for HDq16 regimens, approximately 67 or 68 characters for HDq12 regimens by week 52 after treatment initiation. BCVA (ETDRS or Snellen Equivalent Table) or BCVA (ETDRS or Snellen Equivalent Table) of approximately 66 or 67 characters for HDq16 regimens, approximately 66 or 67 for HDq12 regimens by week 56 after treatment initiation BCVA of letters (ETDRS or Snellen Equivalent Table) or approximately 66 or 67 letters BCVA (ETDRS or Snellen Equivalent Table) for HDq16 regimens, approximately 66 for HDq12 regimens by week 60 after initiation of treatment or 67 character BCVA (ETDRS or Snellen equivalent table) or approximately 66 or 67 character BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens, by 48 to approximately 60 weeks after initiation of treatment, for HDq12 regimens. BCVA (ETDRS or Snellen Equivalent Table) of approximately 66 to approximately 72 characters for HDq16 regimens (ETDRS or Snellen Equivalent Table) or BCVA of approximately 66 to approximately 70 characters (ETDRS or Snellen Equivalent Table) for HDq16 regimens, with fluid in the central subfield (total fluid, Retina without intraretinal fluid [IRF] and / or subretinal fluid [SRF]), absence of non-subretinal pigment epithelial fluid, absence of fluid leak on fluorescein angiography (FA), central retinal thickness (CRT) A decrease of at least about 100, 125, 130, 135, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, or 150 micrometers in the HDq12 regimen by 4 weeks after the start of treatment about -120 or -121 or -122 or -122.4 or -120.2 micrometers (± about 10, 11, or 12 micrometers) or about -126 or -127 or -126.6 or Change in central retinal thickness of -126.3 micrometers (± approximately 10, 11, or 12 micrometers) by week 8 after treatment initiation, approximately -132, -133, -134, - for HDq12 regimens 135 or -136 or -136.2 or -132.8 micrometers (± about 10, 11, or 12 micrometers) or about -139 or -140 or -139.5 or -139.6 micrometers (± about 10, 11, or 12 micrometers) in central retinal thickness, approximately -136, -137, -138, -139, -140 or -141 for HDq12 regimens by week 12 after initiation of treatment. Central retina at 140.9 or -136.6 micrometers (± about 10, 11, or 12 micrometers) or about -144 or -143 or -143.5 micrometers (± about 10, 11, or 12 micrometers) for HDq16 Change in thickness, by week 16 after treatment initiation, approximately -120 or -121 or -122 or -123 or -124 or -123.4 or -120.1 micrometers (± about 10, 11, or 12 micrometers) or a change in central retinal thickness of about -132 or -133 or -132.1 or -133.1 micrometers (± about 10, 11, or 12 micrometers) for HDq16 regimens, 20 days after initiation of treatment. By week 1, about -110 or -111 or -112 or -113 or -114 or -113.6 or -110.9 micrometers - micrometers (± about 10, 11, or 12 micrometers) or Change in central retinal thickness of approximately -115 or -116 or -117 or -118 or -115.8 or -117.7 micrometers (± approximately 10, 11, or 12 micrometers) for HDq16 regimens after initiation of treatment 24 By week 1, approximately -134, -135, -136 or -137 or -138 or -137.6 or -134.9 micrometers (± about 10, 11, or 12 micrometers) for HDq12 regimens or change in central retinal thickness of about -105 or -106 or -107 or -108 or -105.3 or -107.8 micrometers (± about 10, 11, or 12 micrometers) up to 28 weeks after initiation of treatment approximately -130, -131 or -132 or -133 or -134 or -133.7 or -130.7 micrometers (± approximately 10, 11, or 12 micrometers) for an HDq12 regimen or for an HDq16 regimen. Change in central retinal thickness of about -144 or -145 or -146 or -147 or -148 or -144.7 or -147.2 micrometers (± about 10, 11, or 12 micrometers) up to 32 weeks after initiation of treatment about -118 or -19 or -120 or -121 or -120.4 or -118.1 micrometers (± about 10, 11, or 12 micrometers) for HDq12 regimens or about -141 for HDq16 regimens. or -142 or -143 or -144 or -141.5 or -144 micrometers (± approximately 10, 11, or 12 micrometers) change in central retinal thickness, up to 36 weeks after initiation of treatment, for HDq12 regimens. about -142 or -143 or -144 or -144.2 or -142.2 micrometers (± about 10, 11, or 12 micrometers), or about -126 or -127, -128 or - for HDq16 regimens. Change in central retinal thickness of 129 or -130 or -131 or -126.4 or -130.5 micrometers (± approximately 10, 11, or 12 micrometers) by week 40 after initiation of treatment for HDq12 regimens about -131, -132, -133 or -134 or -133.8 or -131.2 micrometers (± about 10, 11, or 12 micrometers) or about -127, -128 or 127.5 micrometers for HDq16 regimens ( ± about 10, 11, or 12 micrometers) change in central retinal thickness by week 44 after initiation of treatment, about −120 or −121 or −122 or −123 or −124 or -125 or -124.7 or 120.3 micrometers (± about 10, 11, or 12 micrometers) or about -143, -144 or -145 or -144.8 micrometers (± about 10, 11, or -142 or -143 or -144 or -144.4 or -142.3 micrometers (± about 10, 11 , or 12 micrometers), or about -143 or -144 or -145 or -146 or -147 or -148 or -143.8 or -147.1 micrometers (± about 10, 11, or 12 micrometers) for HDq16 regimens. change in central retinal thickness in meters), By week 52 after the start of treatment, approximately -143.2 micrometers (± about 10, 11, or 12 micrometers) for the HDq12 regimen or about -139.6 micrometers (± about 10, 11, or 12 micrometers), by week 56 after treatment initiation, by approximately -136.3 micrometers (± approximately 10, 11, or 12 micrometers) for HDq12 regimens or approximately -136.3 micrometers for HDq16 regimens. Central retinal thickness change of approximately -137.5 micrometers (± approximately 10, 11, or 12 micrometers) for HDq12 regimens and approximately -151.8 micrometers (± approximately 10, 11, or 12 micrometers) for HDq12 regimens by week 60 after initiation of treatment. change in central retinal thickness of ± approximately 10, 11, or 12 micrometers) or approximately −148.8 micrometers (± approximately 10, 11, or 12 micrometers) for HDq16 regimens, 4 weeks after initiation of treatment By week 8 of treatment, central retinal thickness of approximately 248.2 micrometers for HDq12 regimens or approximately 244.1 micrometers for HDq16 regimens; by week 8 after initiation of treatment, approximately 234.4 micrometers for HDq12 regimens or A central retinal thickness of approximately 231.2 micrometers for HDq16 regimens and a central retinal thickness of approximately 229.7 micrometers for HDq12 regimens or approximately 226.7 micrometers for HDq16 regimens by week 12 after treatment initiation. , by week 16 after the start of treatment, central retinal thickness of approximately 247.2 micrometers for the HDq12 regimen or approximately 238.6 micrometers for the HDq16 regimen, by week 20 after the start of treatment, for the HDq12 regimen central retinal thickness of approximately 257 micrometers for HDq16 regimens or approximately 254.9 micrometers for HDq16 regimens, by week 24 after treatment initiation, approximately 233 micrometers for HDq12 regimens or approximately 233 micrometers for HDq16 regimens. Central retinal thickness of approximately 265.4 micrometers by week 28 after the start of treatment; central retinal thickness of approximately 236.9 micrometers for the HDq12 regimen or approximately 226 micrometers for the HDq16 regimen by week 28 after the start of treatment; By week 36, central retinal thickness is approximately 250.2 micrometers for HDq12 regimens or approximately 229.2 micrometers for HDq16 regimens; by week 36 after treatment initiation, approximately 226.4 micrometers for HDq12 regimens. By week 40 after the start of treatment, central retinal thickness of approximately 244.3 micrometers for the HDq16 regimen or approximately 236.8 micrometers for the HDq12 regimen or approximately 243.7 micrometers for the HDq16 regimen. Retinal thickness, by week 44 after the start of treatment, central retinal thickness of approximately 245.9 micrometers for the HDq12 regimen or approximately 227.7 micrometers for the HDq16 regimen; by week 48 after the start of treatment, the HDq12 Central retinal thickness of approximately 226.2 micrometers for the HDq16 regimen or approximately 226.9 micrometers for the HDq16 regimen, by week 52 after treatment initiation, approximately 227.4 micrometers for the HDq12 regimen or approximately 227.4 micrometers for the HDq16 regimen Central retinal thickness of approximately 231.1 micrometers by week 56 after initiation of treatment; central retinal thickness of approximately 234.3 micrometers for HDq12 regimens or approximately 233.2 micrometers for HDq16 regimens by week 56 after initiation of treatment; Central retinal thickness of approximately 218.8 micrometers for HDq12 regimens or approximately 221.9 micrometers for HDq16 regimens by week 60 after initiation of treatment at approximately 4, 5, 6, 7, or 8 weeks CRT up to or by 4, 5, 6, 7, or 8 weeks after initiation of treatment (within approximately ±10, ±11, or ±12 micrometers) achieved and maintained during subsequent treatment regimens. free aflibercept concentration in plasma of approximately 0.0409 (±0.0605) or 0 mg / L (or less than 0.0156 mg / L) approximately 4 hours after initiation of HDq12 or HDq16 treatment, Free aflibercept concentrations in plasma of about 0.05 (±3.78), 0.0973 (±0.102), or 0.0672 mg / L, about 8 hours after initiation, about 2 days after initiation of treatment on HDq12 or HDq16, about Plasma free aflibercept concentrations of 0.11(±2.21), 0.146(±0.110), or 0.0903 mg / L, approximately 0.11(±2.06), 0.137( ±0.0947), or 0.112 mg / L plasma free aflibercept concentration, approximately 5 days after initiation of treatment for HDq12 or HDq16; Free aflibercept concentration in plasma, HDq12 or HDq16 At about day 8 after initiation of treatment, free aflibercept concentration in plasma of about 0.07 (±1.75), 0.0794 (±0.0413), or 0.0682 mg / L , about 15 days after the start of HDq12 or HDq16 treatment, a plasma free aflibercept concentration of about 0.04 (±1.76, 0.0435 (±0.0199) or 0.0385 mg / L, about 15 days after the start of HDq12 or HDq16 treatment) On day 22, plasma free aflibercept concentrations of approximately 0.02 (± 1.76, 0.0213 (± 0.0148), or 0.0232 mg / L; approximately 0.00766 (± Free aflibercept concentration in plasma of 0.00958) or 0 mg / L (or less than 0.0156 mg / L), adjusted to approximately 0.00 mg / L in plasma approximately 4 hours after administration after initiation of HDq12 or HDq16 treatment. Adjusted bound aflibercept concentration in plasma of approximately 0.00 mg / L approximately 8 hours after administration after initiation of treatment for HDq12 or HDq16; approximately 2 days after initiation of treatment for HDq12 or HDq16 On about 3 days after initiation of treatment, about 0.06 (±3.50) or 0.124 (±0.186) mg / L of adjusted binding aflibercept, HDq12 or HDq16 in plasma, about 0.13 (±2.07) or 0.173 ( Adjusted conjugated aflibercept concentrations in plasma of ±0.155) mg / L, approximately 5 days after initiation of treatment for HDq12 or HDq16, approximately 0.18 (±1.88) or 0.223 (±0.157) mg / L in plasma. Adjusted bound aflibercept concentration, HDq12 or HDq16 At about day 8 after initiation of treatment, adjusted bound aflibercept concentration in plasma of about 0.31 (±1.56) or 0.334 (±0.135) mg / L, HDq12 or HDq16 Adjusted conjugated aflibercept concentration in plasma of about 0.37 (± 1.50) or 0.393 (± 0.130) mg / L, about 22 days after the start of treatment for HDq12 or HDq16, on about 15 days after the start of treatment for , about 0.25 (± 3.00) or 0.335 (± 0.155) mg / L adjusted bound aflibercept concentration in plasma, about 29 days after initiation of treatment for HDq12 or HDq16, about 0.32 (± 1.39) or 0.331 ( Adjusted combined aflibercept concentration in plasma of ±0.0953) mg / L, 2 mg approximately every 4 weeks for the first 5 injections, then 2 mg approximately once every 8 weeks or once every 2 months Non-inferior BVCA compared to aflibercept administered intravitreally, 2 mg approximately every 4 weeks for the first 3 or 4 or 5 injections, followed by 1 mg approximately every 8 weeks. Ocular and non-ocular safety or mortality in subjects suffering from DME, similar to that of aflibercept administered intravitreally at 2 mg once every 2 months or every 2 months, after initiation of treatment, 4; Improvement in best-corrected visual acuity by weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 after initiation of treatment, 4, 8, 12, 16, 20, 24, 28 , 2 or more letters, 3 or more letters as measured by the Early Treatment Diabetic Retinopathy Screening (ETDRS) visual acuity chart or Snellen equivalent chart by week 32, 36, 40, 44, 48, 52, 56, or 60 , 4 or more letters, 5 or more letters, 6 or more letters, or 7 or more letters of best-corrected visual acuity improvement after treatment initiation, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 , retina without central subfield fluid (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF]) by week 48, 52, 56 or 60, and / or after initiation of treatment. , at least 100, 125, 130, 135, 140, 141, 142 by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, or 60 central retinal thickness (CRT) decrease of , 143, 144, 145, 146, 147, 148, 149, or 150 micrometers. In one embodiment of the invention, a dry retina is characterized by a lack of intraretinal fluid and / or subretinal fluid, or by a lack of intraretinal fluid (IRF) and subretinal fluid (SRF) in the subject's eye. characterized. In one embodiment of the invention, dry retina is characterized by the absence of intraretinal fluid (IRF) and subretinal fluid (SRF) in the subject's eyes after the subject receives the VEGF receptor fusion protein three times per month. Can be attached.

[0048] In one embodiment of the invention, one initial dose, two secondary doses, and three tertiary doses are administered to a subject in year 1. one initial dose, two secondary doses, and three tertiary doses are administered to the subject in year 1, or one initial dose, two secondary doses, and three tertiary doses are administered to the subject in year 1. , followed by 2-4 tertiary doses in the second year.

[0049] In one embodiment of the invention, the interval between doses is adjusted based on visual and / or anatomical results (increase / maintain / ).

[0050] In one embodiment of the invention, 12-20 weeks is 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks, and 2-4 weeks is 2, 3, 4, or 5 weeks. It's a week.

[0051] Preferably, the VEGF receptor fusion protein herein is aflibercept.

[0052] The present invention provides a kit comprising a container containing a VEGF receptor fusion protein, preferably aflibercept, and instructions for use of the VEGF receptor fusion protein, the container being a vial or a prefilled syringe; contains 100 mg / mL or more of VEGF receptor fusion protein, the container contains 114.3 mg / mL or more of VEGF receptor fusion protein, and the instructions are for administration of VEGF receptor fusion protein to DME / AMD patients. The instructions include instructions that the VEGF receptor fusion protein 8mg treatment is to be started with monthly injections (every 4 weeks) in 3 consecutive doses, and the instructions include instructions that the VEGF receptor fusion protein 8 mg treatment is to be initiated with monthly injections (every 4 weeks) after the first 3 consecutive doses. including instructions that the interval may be extended up to every 16 weeks or every 20 weeks; the instructions include instructions that the treatment interval may be adjusted based on the physician's judgment regarding visual and / or anatomical results; .

[0053] The present invention provides aflibercept for use in the treatment or prevention of neovascular age-related macular degeneration (nAMD) in a subject in need thereof, comprising administering one or more doses of aflibercept at intervals and amounts. , the clearance of free aflibercept from the ocular compartment is approximately 0.37-0.46 mL / day after intravitreal injection of aflibercept, and The time for the amount of free aflibercept in the compartment to reach the lower limit of quantification (LLOQ) is approximately 15 weeks, and / or the amount of free aflibercept in the subject's plasma after intravitreal injection of aflibercept is below the lower limit of quantification (LLOQ). ) is approximately 3.5 weeks.

[0054] The present invention delays the clearance of free aflibercept from the ocular compartment after intravitreal injection compared to the clearance rate of aflibercept from the ocular compartment after intravitreal injection of less than 4 mg of aflibercept. provides aflibercept for use in the method of administering a single initial dose of about 8 mg or more of aflibercept to the eye of a subject in need thereof, followed by administering a single initial dose of about 8 mg or more of aflibercept to the eye of a subject in need thereof. comprising intravitreal injection of one or more secondary doses followed by one or more tertiary doses of aflibercept of about 8 mg or more, each secondary dose about 2 times the previous dose. ~4 weeks later, with each tertiary dose being administered approximately 12-20 weeks after the previous dose.

[0055] The present invention shows that after an intravitreal injection of aflibercept, the amount of free aflibercept reaches the lower limit of quantification (LLOQ) in the ocular compartment of a subject after an intravitreal injection of approximately 2 mg of aflibercept. provides aflibercept for use in a method of increasing the time for the amount of free aflibercept in the ocular compartment of a subject to reach the LLOQ, the method comprising administering approximately 8 mg or more to the eye of a subject in need thereof; A single initial dose of aflibercept, followed by one or more secondary doses of aflibercept of about 8 mg or more, followed by one or more third doses of aflibercept of about 8 mg or more. Involves intravitreal injection. each secondary dose is administered approximately 2 to 4 weeks after the immediately preceding dose; Each tertiary dose is administered approximately 12-20 weeks after the previous dose.

[0056] The present invention shows that the time for free aflibercept in the plasma of a subject to reach the lower limit of quantitation (LLOQ) after an intravitreal injection of approximately 2 mg of aflibercept in a subject after an intravitreal injection of aflibercept provides aflibercept for use in a method for increasing the time for free aflibercept to reach the LLOQ in the plasma of This method applies to the eyes of a subject in need of A single initial dose of aflibercept of approximately 8 mg or more, followed by one or more secondary doses of aflibercept of about 8 mg or more, followed by comprising intravitreal injection of one or more tertiary doses of aflibercept of about 8 mg or more; Each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose, and each tertiary dose is administered about 12 to 20 weeks after the immediately preceding dose.

[0057] The present invention - for the treatment or prevention of neovascular age-related macular degeneration (nAMD) in subjects in need thereof; - to improve best-corrected visual acuity in subjects with nAMD in need, or - providing a VEGF receptor fusion protein for use in a method for promoting retinal dryness in a subject with nAMD in need thereof; The method comprises administering approximately 8 mg to the subject's eye once every 12, 13, 14, 15, 16, 17, 18, 19, or 20, or 12-20, or 12-16, or 16-20 weeks. the administration of one or more doses of the VEGF receptor fusion protein.

[0058] The present invention provides aflibercept for use in the treatment or prevention of neovascular age-related macular degeneration (nAMD) in a subject in need thereof, wherein the treatment or prevention is administered in three consecutive doses per month. Initiating treatment with one injection of 8 mg aflibercept (every 4 weeks) followed by one or more injections once every 8 to 16 weeks or 8 to 20 weeks, each of the above. The concentration of aflibercept in the dose is 114.3 mg / mL, or the application volume of each said dose is 70 μL. In one embodiment of the invention, the treatment interval between two consecutive administrations of 8 mg or more of aflibercept is determined by BCVA letter gain or letter loss, CRT increase or decrease, presence or absence of subretinal fluid, or presence or absence of hemorrhage. , etc., are adjusted (increased / maintained / decreased) based on visual and / or anatomical results, including but not limited to. In one embodiment of the invention, the subject has at least one of the following criteria for shortening the treatment interval: BCVA loss of more than 5 letters, increase in central retinal thickness (CRT) of more than 25 micrometers, new If significant foveal hemorrhage, or new foveal neovascularization, is identified, the treatment interval will be shortened by 2 to 4 weeks, 2 weeks, 3 weeks, or 4 weeks compared to the previous treatment interval. . In one embodiment of the invention, the subject meets at least one of the following criteria for reduced treatment interval: less than 5 letters of BCVA loss, no fluid in the central subfield, no new onset foveal hemorrhage. , or no new foveal neovascularization, the treatment interval is extended by 2-4 weeks, 2 weeks, 3 weeks, or 4 weeks compared to the previous treatment interval.

[0059] The present invention provides a VEGF receptor fusion protein for use in the treatment or prevention of neovascular age-related macular degeneration (nAMD) in a subject in need thereof, the method comprising: 8 mg of VEGF receptor fusion protein (0.07 mL or 70 microliters) administered by intravitreal injection weekly (approximately every 28 days + / - 7 days, monthly), followed by every 8 to 16 weeks (2 Administer 8 mg of VEGF receptor fusion protein (0.07 mL) by intravitreal injection once every 8 to 20 weeks (~4 months, + / -7 days) or every 8 to 20 weeks (2 to 5 months, + / -7 days) including.

[0060] The present invention provides a VEGF receptor fusion protein for use in the treatment or prevention of neovascular age-related macular degeneration (nAMD) in a subject in need thereof, the method comprising: Administer 8 mg of VEGF receptor fusion protein (0.07 mL or 70 microliters) administered by intravitreal injection weekly (approximately every 28 days + / - 7 days, monthly), followed by every 12 weeks (approximately every 2-4 days). This involves administering 8 mg of VEGF receptor fusion protein (0.07 mL) by intravitreal injection once every month, + / -7 days).

[0061] The present invention provides a VEGF receptor fusion protein for use in the treatment or prevention of neovascular age-related macular degeneration (nAMD) in a subject in need thereof, the method comprising: Administer 8 mg of VEGF receptor fusion protein (0.07 mL or 70 microliters) administered by intravitreal injection weekly (approximately every 28 days + / - 7 days, monthly), followed by every 16 weeks (approximately every 2-4 days). This involves administering 8 mg of VEGF receptor fusion protein (0.07 mL) by intravitreal injection once every month, + / -7 days).

[0062] The present invention provides a VEGF receptor fusion protein for use in the treatment or prevention of neovascular age-related macular degeneration (nAMD) in a subject in need thereof, the method comprising: Administer 8 mg of VEGF receptor fusion protein (0.07 mL or 70 microliters) administered by intravitreal injection weekly (approximately every 28 days + / - 7 days, monthly), followed by every 20 weeks (approximately every 2-4 days). This involves administering 8 mg of VEGF receptor fusion protein (0.07 mL) by intravitreal injection once every month, + / -7 days).

[0063] The present invention provides VEGF receptor fusion proteins for use in the treatment or prevention of neovascular age-related macular degeneration (nAMD) in a subject in need thereof; (1) the subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein; the method then administers to the subject, one month later, an initial dose of 8 mg or more of VEGF receptor fusion protein; One month later, a first secondary dose of 8 mg or more of VEGF receptor fusion protein is administered, and one month later, a second secondary dose of 8 mg or more of VEGF receptor fusion protein is administered, and then administering one or more maintenance doses of 8 mg or more of a VEGF receptor fusion protein every 12 or 16 or 20 weeks according to a HDq12 or HDq16 or HDq20 dosing regimen; (2) the subject has received an initial dose of 2 mg of VEGF receptor fusion protein; the method then administers to the subject a second dose of 8 mg or more of VEGF receptor fusion protein one month later; 8 mg or more every 12 or 16 or 20 weeks thereafter according to the HDq12 or HDq16 or HDq20 dosing regimen. administering one or more maintenance doses of a VEGF receptor fusion protein of (3) the subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein; the method then administers to the subject a second secondary dose of 8 mg or more of VEGF receptor fusion protein one month later; and then administering one or more maintenance doses of 8 mg or more of the VEGF receptor fusion protein according to an HDq12 or HDq16 or HDq20 dosing regimen every 12 or 16 or 20 weeks thereafter; (4) the subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein; the method then administers to the subject a first maintenance dose of 8 mg or more of VEGF receptor fusion protein one month later; and then every 12 or 16 or 20 weeks, administering a maintenance dose of 8 mg or more of any additional VEGF receptor fusion protein according to an HDq12 or HDq16 or HDq20 dosing regimen, (5) the subject has received an initial dose of 2 mg of VEGF receptor fusion protein and, one month later, a second dose of 2 mg of VEGF receptor fusion protein; , 1 month later, an initial dose of 8 mg or more of VEGF receptor fusion protein is administered, 1 month later, a second dose of 8 mg or more of VEGF receptor fusion protein is administered, and 1 month later, Administer a second secondary dose of 8 mg or more of VEGF receptor fusion protein, then every 12 or 16 or 20 weeks thereafter, one dose of 8 mg or more of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen. comprising administering one or more maintenance doses; (6) the subject has received an initial dose of 2 mg of VEGF receptor fusion protein and, one month later, a second dose of 2 mg of VEGF receptor fusion protein; , one month later, a first secondary dose of 8 mg or more of VEGF receptor fusion protein is administered, one month later a second secondary dose of 8 mg or more of VEGF receptor fusion protein is administered, and then , administering one or more maintenance doses of VEGF receptor fusion protein of 8 mg or more according to an HDq12 or HDq16 or HDq20 dosing regimen every 12 or 16 or 20 weeks thereafter; (7) the subject has received an initial dose of 2 mg of VEGF receptor fusion protein and, one month later, a second dose of 2 mg of VEGF receptor fusion protein; , 1 month later, administer a second secondary dose of 8 mg or more of VEGF receptor fusion protein, then every 12 or 16 or 20 weeks thereafter, 8 mg or more of VEGF according to the HDq12 or HDq16 or HDq20 dosing regimen. administering one or more maintenance doses of the receptor fusion protein; (8) the subject has received an initial dose of 2 mg of VEGF receptor fusion protein and, one month later, a second dose of 2 mg of VEGF receptor fusion protein; , followed by a first maintenance dose of 8 mg or more of VEGF receptor fusion protein 1 month later, followed by all additional 8 mg or more of VEGF every 12 or 16 or 20 weeks following HDq12 or HDq16 or HDq20 dosing regimens. administering a maintenance dose of the receptor fusion protein; (9) Subjects received an initial dose of 2 mg VEGF receptor fusion protein, 1 month later a first secondary dose of 2 mg VEGF receptor fusion protein, and 1 month later a second dose of 2 mg VEGF receptor fusion protein. The method then administers to the subject, one month later, an initial dose of 8 mg or more of the VEGF receptor fusion protein, and one month later, the subject receives a second dose of the VEGF receptor fusion protein. A second dose of 8 mg or more of VEGF receptor fusion protein is administered, followed one month later by a second secondary dose of 8 mg or more of VEGF receptor fusion protein, then every 12 or 16 or 20 weeks thereafter. administering one or more maintenance doses of 8 mg or more of a VEGF receptor fusion protein according to an HDq12 or HDq16 or HDq20 dosing regimen, (10) Subjects received an initial dose of 2 mg VEGF receptor fusion protein, 1 month later a first secondary dose of 2 mg VEGF receptor fusion protein, and 1 month later a second dose of 2 mg VEGF receptor fusion protein. The method then administers to the subject, one month later, a second dose of 8 mg or more of the VEGF receptor fusion protein; , administer a second secondary dose of 8 mg or more of VEGF receptor fusion protein, and then every 12 or 16 or 20 weeks thereafter, according to the HDq12 or HDq16 or HDq20 dosing regimen, of 8 mg or more of VEGF receptor fusion protein. comprising administering one or more maintenance doses; (11) Subjects received an initial dose of 2 mg of VEGF receptor fusion protein, 1 month later a first secondary dose of 2 mg of VEGF receptor fusion protein, and 1 month later a second dose of 2 mg of VEGF receptor fusion protein. a second dose of VEGF receptor fusion protein, the method then administers to the subject a second 8 mg or more second dose of VEGF receptor fusion protein one month later; or every 16 or 20 weeks, administering one or more maintenance doses of 8 mg or more of a VEGF receptor fusion protein according to a HDq12 or HDq16 or HDq20 dosing regimen; (12) Subjects received an initial dose of 2 mg VEGF receptor fusion protein, 1 month later a first secondary dose of 2 mg VEGF receptor fusion protein, and 1 month later a second dose of 2 mg VEGF receptor fusion protein. and a second dose of the fusion protein, the method then administers to the subject, two months later, a first maintenance dose of 8 mg or more of the VEGF receptor fusion protein, followed by 12 or 16 or every 20 weeks, administering every additional maintenance dose of VEGF receptor fusion protein of 8 mg or more according to a HDq12 or HDq16 or HDq20 dosing regimen; (13) Subjects received an initial dose of 2 mg VEGF receptor fusion protein, 1 month later a first secondary dose of 2 mg VEGF receptor fusion protein, and 1 month later a second dose of 2 mg VEGF receptor fusion protein. The subject has received a second dose of the fusion protein and, eight weeks later, a first maintenance dose of 2 mg of the VEGF receptor fusion protein; Up to 2 months after the initial dose of 8 mg or more of VEGF receptor fusion protein, followed 1 month later by the first secondary dose of 8 mg or more of VEGF receptor fusion protein, and 1 month after that. followed by a second secondary dose of VEGF receptor fusion protein of 8 mg or more, and then every 12 or 16 or 20 weeks thereafter, 8 mg or more of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen. administering one or more maintenance doses of (14) Subjects received an initial dose of 2 mg VEGF receptor fusion protein, 1 month later a first secondary dose of 2 mg VEGF receptor fusion protein, and 1 month later a second dose of 2 mg VEGF receptor fusion protein. a second dose of the fusion protein followed eight weeks later by one or more maintenance doses of 2 mg of the VEGF receptor fusion protein; up to 2 months after the last dose of VEGF receptor fusion protein, and 1 month later, a second 8 mg or more secondary dose of VEGF receptor fusion protein. and then every 12 or 16 or 20 weeks thereafter, administering one or more maintenance doses of 8 mg or more of the VEGF receptor fusion protein according to a HDq12 or HDq16 or HDq20 dosing regimen; (15) Subjects received an initial dose of 2 mg VEGF receptor fusion protein, 1 month later a first secondary dose of 2 mg VEGF receptor fusion protein, and 1 month later a second dose of 2 mg VEGF receptor fusion protein. a second dose of the fusion protein followed eight weeks later by one or more maintenance doses of 2 mg of the VEGF receptor fusion protein; Administer a second secondary dose of 8 mg or more of VEGF receptor fusion protein up to 2 months after the last dose of , administering one or more maintenance doses of 8 mg or more of the VEGF receptor fusion protein; (16) Subjects received an initial dose of 2 mg of VEGF receptor fusion protein, 1 month later a first secondary dose of 2 mg of VEGF receptor fusion protein, and 1 month later a second dose of 2 mg of VEGF receptor fusion protein. a second dose of the fusion protein followed eight weeks later by one or more maintenance doses of 2 mg of the VEGF receptor fusion protein; Administer a first maintenance dose of 8 mg or more of VEGF receptor fusion protein up to 2 months after the last dose of and then every 12 or 16 or 20 weeks thereafter according to an HDq12 or HDq16 or HDq20 dosing regimen; administering every additional maintenance dose of 8 mg or more of the VEGF receptor fusion protein; (i) HDq12 administration regimen is a single initial dose of about 8 mg or more of VEGF receptor fusion protein, followed by one or more secondary doses of VEGF receptor fusion protein of about 8 mg or more, followed by administering one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; each secondary dose is administered approximately 2 to 4 weeks after the immediately preceding dose; each tertiary dose is administered about 12 weeks after the immediately preceding dose; (ii) the HDq16 administration regimen is a single initial dose of about 8 mg or more of VEGF receptor fusion protein, followed by one or more secondary doses of VEGF receptor fusion protein of about 8 mg or more, followed by administering one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; each secondary dose is administered approximately 2 to 4 weeks after the immediately preceding dose; each tertiary dose is administered about 16 weeks after the immediately preceding dose; and (iii) the HDq20 administration regimen is a single initial dose of about 8 mg or more of VEGF receptor fusion protein, followed by one or more secondary doses of VEGF receptor fusion protein of about 8 mg or more, followed by administering one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; each secondary dose is administered approximately 2 to 4 weeks after the immediately preceding dose; Each tertiary dose is administered approximately 20 weeks after the previous dose.

[0064] The present invention provides aflibercept for use in the treatment or prevention of neovascular age-related macular degeneration (nAMD) in a subject in need thereof, wherein a single dose of 8 mg or more of aflibercept is administered to the eye of the subject. administering an initial dose, followed by one or more third doses of aflibercept of about 8 mg or more, each third dose about 8, 12, 16, or 20 weeks after the immediately preceding dose. administered. In one embodiment of the invention, the subject is not a treatment-naïve subject, or the subject has been pretreated with a VEGF antagonist, or preferably, the subject has been pretreated with 8 mg aflibercept or 2 mg aflibercept. ing.

[0065] The present invention provides aflibercept for use in the treatment or prevention of neovascular age-related macular degeneration (nAMD) in a subject pretreated with 2 mg of aflibercept, and about 8 mg of aflibercept in the eye of the subject. A single initial dose of aflibercept of about 8 mg or more, followed by one or more secondary doses of aflibercept of about 8 mg or more, followed by one or more tertiary doses of aflibercept of about 8 mg or more. each of the secondary doses being administered about 4 weeks after the immediately preceding dose and each of the tertiary doses being administered about 8, 10, 12, 14, 16, 18 or 20 weeks after the immediately preceding dose. be done. In one embodiment of the invention, administration of one or more doses of 8 mg aflibercept to the subject's eye follows an HDq12, HDq16, HDq20, or treatment and degree dosing regimen.

[0066] The present invention provides VEGF receptor fusion proteins for use in the treatment or prevention of neovascular age-related macular degeneration (nAMD) in a subject in need thereof, wherein the subject is provided with a dosing regimen for treating or preventing nAMD. inside, (a) the subject has been administered an initial dose of VEGF receptor fusion protein of 8 mg or more; the method then administers to the subject a second dose of VEGF receptor fusion protein of 8 mg or more one month later; one month later, a second secondary dose of 8 mg or more of VEGF receptor fusion protein, then every 12 or 16 or 20 weeks thereafter according to the HDq12 or HDq16 or HDq20 dosing regimen. , administering one or more maintenance doses of 8 mg or more of the VEGF receptor fusion protein; or (b) the subject has received an initial dose of VEGF receptor fusion protein of 8 mg or more and, one month later, a second dose of VEGF receptor fusion protein of 8 mg or more; Subjects will receive a second secondary dose of VEGF receptor fusion protein of 8 mg or more one month later and then 8 mg or more every 12 or 16 or 20 weeks thereafter according to the HDq12 or HDq16 or HDq20 dosing regimen. administering one or more maintenance doses of a VEGF receptor fusion protein of or (c) Subjects receive an initial dose of VEGF receptor fusion protein of 8 mg or more, 1 month later a first secondary dose of VEGF receptor fusion protein of 8 mg or more, and 1 month later a second dose of 8 mg or more of VEGF receptor fusion protein. and a second dose of VEGF receptor fusion protein, the method then administers to the subject, 12 or 16 or 20 weeks later, a maintenance dose of 8 mg or more of VEGF receptor fusion protein. and then every 12 or 16 or 20 weeks, administering every additional maintenance dose of 8 mg or more of the VEGF receptor fusion protein according to an HDq12 or HDq16 or HDq20 dosing regimen; or (d) Subject receives an initial dose of VEGF receptor fusion protein of 8 mg or more, 1 month later a first secondary dose of VEGF receptor fusion protein of 8 mg or more, and 1 month later a second dose of 8 mg or more of VEGF receptor fusion protein; has been administered a second dose of the VEGF receptor fusion protein and 12 or 16 or 20 weeks later one or more maintenance doses of 8 mg or more of the VEGF receptor fusion protein, and the method then comprises: Subjects will be administered one or more maintenance doses of 8 mg or more of VEGF receptor fusion protein 12 or 16 or 20 weeks after the last dose of VEGF receptor fusion protein, and then 12 or 16 or 20 weeks thereafter. administering every additional weekly maintenance dose of 8 mg or more of the VEGF receptor fusion protein according to a HDq12 or HDq16 or HDq20 dosing regimen; (i) The above HDq12 administration regimen is a single initial dose of about 8 mg or more of VEGF receptor fusion protein, followed by one or more secondary doses of VEGF receptor fusion protein of about 8 mg or more, followed by comprising one or more tertiary doses of about 8 mg or more of a VEGF receptor fusion protein; each secondary dose is administered approximately 2 to 4 weeks after the immediately preceding dose; each tertiary dose is administered about 12 weeks after the immediately preceding dose; (ii) The above HDq16 administration regimen is a single initial dose of about 8 mg or more of VEGF receptor fusion protein, followed by one or more secondary doses of VEGF receptor fusion protein of about 8 mg or more, followed by comprising one or more tertiary doses of about 8 mg or more of a VEGF receptor fusion protein; each secondary dose is administered approximately 2 to 4 weeks after the immediately preceding dose; each tertiary dose is administered about 16 weeks after the immediately preceding dose; and (iii) The above HDq20 administration regimen is a single initial dose of about 8 mg or more of VEGF receptor fusion protein, followed by one or more secondary doses of VEGF receptor fusion protein of about 8 mg or more, followed by comprising one or more tertiary doses of about 8 mg or more of a VEGF receptor fusion protein; each secondary dose is administered approximately 2 to 4 weeks after the immediately preceding dose; Each tertiary dose is administered approximately 20 weeks after the previous dose.

[0067] The present invention also provides the use of a VEGF receptor fusion protein for use in the treatment or prevention of neovascular age-related macular degeneration (nAMD) in a subject in need thereof, wherein the subject receives approximately 2 mg of VEGF receptor fusion protein. A single initial dose of fusion protein, followed by one or more secondary doses of about 2 mg of VEGF receptor fusion protein, followed by one or more third doses of about 2 mg of VEGF receptor fusion protein. is in a dosing regimen for treating or preventing nAMD, requiring that each secondary dose be administered approximately 4 weeks after the immediately preceding dose and each tertiary dose administered approximately 8 weeks after the immediately preceding dose. administered and the subject is at any stage on a 2 mg VEGF receptor fusion protein dosing regimen, the method comprises administering to the subject's eye a dose of 8 mg or more of the VEGF receptor fusion protein; 8 mg or more of VEGF receptor fusion protein every 12 weeks or every 16 weeks if, in the judgment of the treating physician, dosing every 12 weeks or every 16 weeks is appropriate. Continue dosing the subject every 16 weeks, or evaluate the subject after approximately 8 or 10 or 12 weeks of dosing and if, in the judgment of the treating physician, dosing every 12 weeks is appropriate, administer an additional 8 mg of VEGF receptor. dose of VEGF receptor fusion protein and re-evaluate the subject approximately 12 weeks later, and if in the judgment of the treating physician, dosing every 16 weeks is appropriate, administer 8 mg or more of VEGF receptor fusion protein to the subject every 16 weeks. and continuing to administer the drug.

[0068] The present invention provides VEGF receptor fusion proteins for use in the treatment and prevention of neovascular age-related macular degeneration (nAMD) in a subject in need thereof, the treatment or prevention comprising: administering a single initial dose of 8 mg or more of VEGF receptor fusion protein, followed by one or more secondary doses, preferably 2 doses, of about 8 mg or more of VEGF receptor fusion protein, followed by administration of about 8 mg or more of VEGF receptor fusion protein, administering one or more tertiary doses of VEGF receptor fusion protein of 8 mg or more. each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose, and each tertiary dose is administered about 12 or 16 weeks after the immediately preceding dose; After one or more tertiary doses have been administered approximately 12 or 16 weeks after the previous dose, the tertiary dose interval is · From 12 weeks to 16 weeks, · From 12 weeks to 20 weeks, or · Further includes an extension from 16 weeks to 20 weeks.

[0069] The present invention provides VEGF receptor fusion proteins for use in the treatment and prevention of neovascular age-related macular degeneration (nAMD) in a subject in need thereof. providing the subject's eye with a single initial dose of about 8 mg or more of VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of VEGF receptor fusion protein; administering one or more tertiary doses of VEGF receptor fusion protein of about 8 mg or more, each of the secondary doses being administered about 2 to 4 weeks after the immediately preceding dose, and each of the tertiary doses being administered about 2 to 4 weeks after the immediately preceding dose; administered approximately 12 or 16 or 20 weeks after the dose of a tertiary dose interval after one or more tertiary doses have been administered approximately 12 or 16 or 20 weeks after the immediately preceding dose; · From 12 weeks to 8 weeks, · From 16 weeks to 12 weeks, · From 16 weeks to 8 weeks, · From 20 weeks to 8 weeks, · From 20 weeks to 12 weeks, or · Further including shortening from 20 weeks to 16 weeks.

[0070] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of neovascular age-related macular degeneration (nAMD) in a subject in need thereof, comprising approximately 114.3 mg / ml of a VEGF receptor fusion protein. administering to the subject's eye three doses of about 8 mg or more of a VEGF receptor fusion protein in a formulation containing at four-weekly intervals, and after said three doses, up to 12, 16, or comprising administering one or more doses of the VEGF receptor fusion protein at extended intervals of 20 weeks.

[0071] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of neovascular age-related macular degeneration (nAMD) in a subject in need thereof, wherein the subject's eye receives approximately 8 mg or more of VEGF receptor fusion protein. comprising administering a single initial dose of the fusion protein followed by two secondary doses of about 8 mg or more of the VEGF receptor fusion protein; each of the secondary doses is administered about 2 to 4 weeks after the immediately preceding dose, and after said dose; a) whether the subject meets at least one criterion for reducing or extending the interval between administration of the VEGF receptor fusion protein by 2 weeks, 3 weeks, 4 weeks, or 2-4 weeks; to judge and b) if said determination is made, administering an additional dose of the VEGF receptor fusion protein at said reduced or extended dose interval; Criteria for extending the interval include: BCVA reduction of more than 1.5 characters, 2. Increase in central retinal thickness (CRT) of more than 25 micrometers, 3. New foveal hemorrhage, and / or 4. New foveal angiogenesis, Criteria for reducing the interval include: BCVA reduction of less than 1.5 characters, 2.No fluid in the central subfield of OCT, 3. No development of new foveal hemorrhage, and / or 4. No foveal vascularization.

[0072] The present invention provides a method for treating VEGF receptor fusion protein for use in the treatment and prevention of neovascular age-related macular degeneration (nAMD) in a subject in need thereof, pretreated with one or more 2 mg doses of a VEGF receptor fusion protein. providing a receptor fusion protein and administering to the subject's eye a single initial dose of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein; , followed by administering one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; Each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose, and each tertiary dose is administered about 12 to 20 weeks after the immediately preceding dose.

[0073] The present invention provides VEGF receptor fusion proteins for use in the treatment and prevention of neovascular eye diseases in a subject in need thereof; (1) a single initial dose of about 8 mg or more of VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of VEGF receptor fusion protein, followed by about 8 mg or more of VEGF receptor fusion protein; administering one or more tertiary doses of the body fusion protein, each of the secondary doses being administered about 2 to 4 weeks after the immediately preceding dose, and each of the tertiary doses being about 8 weeks after the immediately preceding dose. administered after a week, or (2) administering one or more doses of 8 mg or more of the VEGF receptor fusion protein about every 4 weeks;

[0074] A VEGF receptor fusion protein for use in the treatment and prevention of neovascular eye disorders, wherein the treatment or prevention comprises: · One single-dose glass vial with a protective plastic cap and stopper, containing an aqueous formulation containing 8 mg of VEGF receptor fusion protein in approximately 70 microliters; · One 18-gauge x 1.5-inch, 5-micron filter needle, including tip and bevel; providing all of them together, and then, (1) Visually inspect the aqueous formulation in the vial and if particulates, cloudiness, or discoloration are visible, use a separate vial of the aqueous formulation containing the VEGF receptor fusion protein; (2) removing the protective plastic cap from the vial; (3) cleaning the top of the vial with an alcohol wipe, and then Using aseptic technique, (4) removing the 18 gauge x 1.5 inch, 5 micron filter needle and 1 mL syringe from their packaging; (5) attaching the filter needle to the syringe by twisting the filter needle over the Luer Lock syringe tip; (6) pushing the filter needle into the center of the vial stopper until the needle is fully inserted into the vial and the tip contacts the bottom or bottom edge of the vial; (7) withdrawing all of the VEGF receptor fusion protein vial contents into a syringe, holding the vial in an upright position and tilting it slightly while ensuring that the bevel of the filter needle is immersed in the liquid; (8) continuing to tilt the vial during withdrawal to keep the bevel of the filter needle submerged in the formulation; (9) pulling back the plunger rod sufficiently when emptying the vial to completely empty the filter needle; (10) removing the filter needle from the syringe and discarding the filter needle; (11) removing the 30 gauge x 1 / 2 inch needle from its packaging and attaching the needle to the syringe by twisting the needle tightly with the Luer lock syringe tip; (12) Hold the syringe with the needle facing up, check for air bubbles in the syringe, and if there are air bubbles, tap the syringe with your finger until the air bubbles rise to the top. (13) slowly depressing the plunger so that the plunger tip is aligned with the line marking 70 microliters on the syringe;

[0075] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of neovascular age-related macular degeneration (nAMD) in a subject in need thereof, wherein 8 mg or more of the VEGF receptor fusion protein comprises about 103 in an aqueous pharmaceutical formulation containing ~126 mg / ml of VEGF receptor fusion protein, histidine-based buffer, and arginine.

[0076] The present invention provides VEGF receptor fusion proteins for use in the treatment and prevention of neovascular age-related macular degeneration (nAMD) in a subject in need thereof, wherein 8 mg or more of VEGF receptor fusion protein comprises approximately 114.3 mg / ml of VEGF receptor fusion protein, a histidine-based buffer, and arginine in an aqueous pharmaceutical formulation.

[0077] The present invention provides aflibercept for use in the treatment and prevention of neovascular age-related macular degeneration (nAMD) in a subject in need thereof, wherein 8 mg or more of aflibercept is in an aqueous pharmaceutical formulation; Aflibercept has less than about 3.5% high molecular weight species immediately after manufacture and purification, and / or has less than about 6% high molecular weight species after storage for about 24 months at about 2-8°C.

[0078] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of neovascular age-related macular degeneration (nAMD) in a subject in need thereof, wherein 8 mg or more of the VEGF receptor fusion protein comprises: at least about 100 mg / ml of a VEGF receptor fusion protein; Approximately 10-100mM L-arginine and Sucrose and a histidine-based buffer; in an aqueous pharmaceutical formulation containing a surfactant and: If the formulation has a pH of about 5.0 to about 6.8, the VEGF receptor fusion protein contains less than about 3.5% high molecular weight species immediately after manufacture and purification and / or after storage for about 24 months at about 2-8°C. Contains about 6% or less high molecular weight species.

[0079] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of neovascular age-related macular degeneration (nAMD) in a subject in need thereof, wherein 8 mg or more of the VEGF receptor fusion protein comprises: Found in aqueous pharmaceutical formulations containing: · >100 mg / ml of VEGF receptor fusion protein, histidine-based buffer, and L-arginine; · 140mg / ml aflibercept, 20mM histidine-based buffer, 5% sucrose, 0.03% (w / v) polysorbate 20, 10mM arginine, pH 5.8, · 150+15mg / ml aflibercept, 10mM phosphate buffer, 8+0.8% (w / v) sucrose, 0.02-0.04% (w / v) polysorbate 20, 50mM L-arginine , pH5.9~6.5, · 103-126mg / ml aflibercept, 10+1mM histidine-based buffer, 5+0.5% (w / v) sucrose, 0.02-0.04% (w / v) polysorbate 20, 50+5mM L -Arginine, pH5.5~6.1, · 140mg / ml aflibercept, 10mM histidine-based buffer, 2.5% (w / v) sucrose, 2.0% (w / v) proline, 0.03% (w / v) polysorbate 20, and 50mM L-arginine, pH5.8, · 114.3mg / ml aflibercept, 10mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, 50mM L-arginine, pH 5.8, · >100 mg / ml of aflibercept, histidine-based buffers, and L-arginine; · Aflibercept greater than 100 mg / ml, pH approximately 5.8, where the formulation forms less than 3% HMW aggregates after 2 months incubation at 5°C; · Approximately 114.3mg / mL aflibercept, 10mM~50mM histidine-based buffer, sugar, nonionic surfactant, L-arginine, pH5.8, · Approximately 114.3 mg / mL aflibercept, 10 mM His / His-HCl buffer, 5% sucrose, 0.03% polysorbate-20, 50 mM L-arginine, pH 5.8, or · Approximately 114.3 mg / mL of aflibercept, arginine monohydrochloride, histidine, histidine hydrochloride monohydrate, polysorbate 20, sucrose, and water for injection. · Improving best corrected visual acuity (BCVA), · An increase in best-corrected visual acuity (BCVA) of 5 or more, 10 or 15, or 20 or more characters; · No decline in best corrected visual acuity (BCVA); · Disappearance of retinal fluid, · No retinal fluid leak by fluorescein angiography; · Decrease in choroidal neovascularization size, · No intraretinal fluid (IRF) and / or subretinal fluid in the central subfield; · Reduction in total lesional choroidal neovascularization (CNV) area; · Loss or reduction of intraretinal fluid; · Loss or reduction of subretinal fluid; · Decreased central subfield retinal thickness (CST), · Improved vision-related quality of life (e.g., as measured by NEI-VFQ-25 total score); · Absence of treatment-emergent adverse events (AEs) and / or serious AEs (SAEs); · ETDRS letter score of at least 69 (approximately 20 / 40 Snellen equivalent table); · An increase in BCVA of more than 5, 10, 15, or 20 characters as measured by the Early Treatment Diabetic Retinopathy Screening (ETDRS) visual chart, or no decrease in BCVA during the course of treatment; · Average BCVA improvement over a 12-week period, · Absence of intraretinal fluid (IRF) and subretinal fluid; · Decrease in choroidal neovascularization (CNV) size, · Reduction in total lesion CNV area from baseline, · Loss of IRF and / or SRF, · Decreased central subfield retinal thickness (CST), · Improved vision-related quality of life as measured by the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25); · Absence of treatment-emergent adverse events (AEs) and / or serious AEs (SAEs); · Aflibercept administered intravitreally at 2 mg approximately every 4 weeks for the first 3 months, followed by 2 mg approximately once every 8 weeks or once every 2 months in subjects with nAMD. Efficacy and / or safety is similar to that of 100%, with efficacy measured as improved BCVA and / or decreased central retinal thickness, and safety measured as increased blood pressure, increased intraocular pressure, visual impairment, vitreous disease, and vitreous detachment. , measured as the incidence of adverse events such as iris neovascularization, and / or vitreous hemorrhage; · Undetected anti-drug antibodies while undergoing treatment; · Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 from the start of treatment (baseline) improvement in best-corrected visual acuity (BVCA) by week 48, week 52, week 56, or week 60; · BCVA improvement of 2 or more, 3 or more, 4 or more, 5 or more, 6 or 7 characters as measured by the Early Treatment Diabetic Retinopathy Screening (ETDRS) visual acuity chart or Snellen equivalent chart. , BCVA of approximately 2 or 3 letters (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 3 letters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens by week 4 after initiation of treatment improvement, BCVA of approximately 5 letters (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 4 or 5 letters (ETDRS or Snellen equivalent table) for HDq16 regimens by week 8 after initiation of treatment improvement, · By week 12 after starting treatment, approximately 5 or 6 letters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 5 or 6 letters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens. Table) improvement, · By week 16 after initiation of treatment, approximately 6 letters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 6 or 7 letters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens improvement, · Improvement in BCVA (ETDRS or Snellen Equivalent Table) by approximately 6 letters for the HDq12 regimen or approximately 6 letters for the HDq16 regimen (ETDRS or Snellen Equivalent Table) by week 20 after initiation of treatment , · By week 24 after starting treatment, approximately 5 or 6 letters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 5 or 6 letters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens. Table) improvement, · Improvement in BCVA (ETDRS or Snellen Equivalent Table) by approximately 7 letters for HDq12 regimens or approximately 6 letters for HDq16 regimens (ETDRS or Snellen Equivalent Tables) by week 28 after initiation of treatment , BCVA of approximately 6 or 7 characters (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 7 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens by week 32 after initiation of treatment improvement, · By week 36 after initiation of treatment, approximately 6 or 7 letters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 6 letters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens improvement, · By week 40 after the start of treatment, approximately 6 or 7 letters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 5 or 6 letters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens. Table) improvement, · By week 44 after initiation of treatment, BCVA of approximately 7 characters (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 5 or 6 characters (ETDRS or Snellen equivalent table) for HDq16 regimens improvement, BCVA of approximately 6 or 7 letters (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 6 letters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens by week 48 after initiation of treatment improvement, · By week 52 after the start of treatment, approximately 7 or 8 letters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 6 or 7 letters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens. Table) improvement, · By week 56 after the start of treatment, approximately 6 or 7 letters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 6 or 7 letters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens. Table) improvement, · By week 60 after the start of treatment, approximately 6 or 7 letters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 6 or 7 letters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens. Table) improvement, · By approximately 48 to 60 weeks after the start of treatment, approximately 6 or 7 letters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 6 or 7 letters of BCVA (ETDRS) for HDq16 regimens. or Snellen equivalent table) improvement, · Improvement in BCVA (ETDRS or Snellen equivalent table) by approximately 5, 10, or 15 letters for HDq12 or HDq16 regimens by week 60 after initiation of treatment; · Improvement in BCVA (within approximately +1 or +2 ETDRS letters or Snellen equivalent tables) is achieved by approximately 8, 9, 10, 11, or 12 weeks after initiation of treatment and maintained during subsequent treatment regimens; · By week 4 after initiation of treatment, BCVA of approximately 63 characters (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 63 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens; · By week 8 after starting treatment, approximately 65 characters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 65 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens; · By week 12 after initiation of treatment, BCVA of approximately 66 characters (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens; · By week 16 after initiation of treatment, BCVA of approximately 66 characters (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens; · By week 20 after initiation of treatment, BCVA of approximately 66 characters (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens; · By week 24 after initiation of treatment, BCVA of approximately 66 characters (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens; · By week 28 after initiation of treatment, approximately 67 characters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens; · By week 32 after initiation of treatment, approximately 67 characters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 67 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens; · By week 36 after initiation of treatment, approximately 67 characters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens; · By week 40 after initiation of treatment, approximately 67 characters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens; · By week 44 after initiation of treatment, BCVA of approximately 68 characters (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens; · By week 48 after initiation of treatment, approximately 67 characters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens; · By week 52 after the start of treatment, approximately 67 or 68 characters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 or 67 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens. table), · By week 56 after the start of treatment, approximately 66 or 67 characters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 or 67 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens. table), · By week 60 after the start of treatment, approximately 66 or 67 characters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 or 67 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens. table), · By 48 to about 60 weeks after initiation of treatment, a BCVA of about 66 to about 72 letters (ETDRS or Snellen equivalent table) for HDq12 regimens or about 66 to about 70 letters for HDq16 regimens (ETDRS or Snellen equivalent table), · Retina without fluid (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF]) in the central subfield, · Absence of non-subretinal pigment epithelial fluid; · Absence of fluid leakage on fluorescein angiography (FA); · a decrease in central retinal thickness (CRT) of at least about 100, 125, 130, 135, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, or 150 micrometers; · By the fourth week after starting treatment, approximately -120 or -121 or -122 or -122.4 or -120.2 micrometers (± approximately 10, 11, or 12 micrometers) for HDq12 regimens or a change in central retinal thickness of about -126 or -127 or -126.6 or -126.3 micrometers (± about 10, 11, or 12 micrometers); · By week 8 after starting treatment, approximately -132, -133, -134, -135, or -136, or -136.2, or -132.8 micrometers (± approximately 10, 11, or 12 micrometers) or a change in central retinal thickness of about -139 or -140 or -139.5 or -139.6 micrometers (± about 10, 11, or 12 micrometers) for HDq16 regimens; · By week 12 after starting treatment, approximately -136, -137, -138, -139, -140, or -141 or -140.9 or -136.6 micrometers (± approximately 10, 11 or 12 micrometers) or a change in central retinal thickness of about -144 or -143 or -143.5 micrometers (± about 10, 11, or 12 micrometers) for HDq16 regimens; · By week 16 after starting treatment, approximately -120 or -121 or -122 or -123 or -124 or -123.4 or -120.1 micrometers (± about 10, 11, or 12 micrometers) for HDq12 regimens. a change in central retinal thickness of about -132 or -133 or -132.1 or -133.1 micrometers (± about 10, 11, or 12 micrometers) for HDq16 regimens; · By week 20 after the start of treatment, approximately -110 or -111 or -112 or -113 or -114 or -113.6 or -110.9 micrometers (± about 10, 11, or 12 micrometers) for HDq12 regimens. a change in central retinal thickness of about -115 or -116 or -117 or -118 or -115.8 or -117.7 micrometers (± about 10, 11, or 12 micrometers) for HDq16 regimens; · By week 24 after starting treatment, approximately -134, -135, -136 or -137 or -138 or -137.6 or -134.9 micrometers (± about 10, 11, or 12 micrometers) for HDq12 regimens. a change in central retinal thickness of about -105 or -106 or -107 or -108 or -105.3 or -107.8 micrometers (± about 10, 11, or 12 micrometers) for HDq16 regimens; · By week 28 after starting treatment, approximately -130, -131 or -132 or -133 or -134 or -133.7 or -130.7 micrometers (± about 10, 11, or 12 micrometers) for HDq12 regimens. m) or a change in central retinal thickness of about -144 or -145 or -146 or -147 or -148 or -144.7 or -147.2 micrometers (± about 10, 11, or 12 micrometers) for HDq16 regimens. , · By week 32 after the start of treatment, approximately -118 or -19 or -120 or -121 or -120.4 or -118.1 micrometers (± about 10, 11, or 12 micrometers) or a change in central retinal thickness of about -141 or -142 or -143 or -144 or -141.5 or -144 micrometers (± about 10, 11, or 12 micrometers) for HDq16 regimens; · By week 36 after the start of treatment, approximately -142 or -143 or -144 or -144.2 or -142.2 micrometers (± approximately 10, 11, or 12 micrometers) for HDq12 regimens or a change in central retinal thickness of about -126 or -127, -128 or -129 or -130 or -131 or -126.4 or -130.5 micrometers (± about 10, 11, or 12 micrometers); · By week 40 after the start of treatment, approximately -131, -132, -133 or -134 or -133.8 or -131.2 micrometers (± approximately 10, 11, or 12 micrometers) or Changes in central retinal thickness of approximately -127, -128, or 127.5 micrometers (± approximately 10, 11, or 12 micrometers) for HDq16 regimens; · By week 44 after the start of treatment, approximately -120 or -121 or -122 or -123 or -124 or -125 or -124.7 or -120.3 micrometers (± about 10, 11, or 12 micrometers) or a change in central retinal thickness of about -143, -144 or -145 or -144.8 micrometers (± about 10, 11, or 12 micrometers) for HDq16 regimens; · By week 48 after the start of treatment, approximately -142 or -143 or -144 or -144.4 or -142.3 micrometers (± approximately 10, 11, or 12 micrometers) for HDq12 regimens or a change in central retinal thickness of about -143 or -144 or -145 or -146 or -147 or -148 or -143.8 or -147.1 micrometers (± about 10, 11, or 12 micrometers), if · By week 52 after the start of treatment, approximately -143.2 micrometers (± approximately 10, 11, or 12 micrometers) for the HDq12 regimen or approximately -139.6 micrometers (± approximately 10 micrometers) for the HDq16 regimen. , 11, or 12 micrometers) change in central retinal thickness; · By week 56 after the start of treatment, approximately -136.3 micrometers (± approximately 10, 11, or 12 micrometers) for an HDq12 regimen or approximately -137.5 micrometers (± approximately 10 micrometers) for an HDq16 regimen. , 11, or 12 micrometers) change in central retinal thickness; · By week 60 after the start of treatment, approximately -151.8 micrometers (± approximately 10, 11, or 12 micrometers) for an HDq12 regimen or approximately -148.8 micrometers (± approximately 10 micrometers) for an HDq16 regimen. , 11, or 12 micrometers) change in central retinal thickness; Central retinal thickness of approximately 248.2 micrometers for HDq12 regimens or approximately 244.1 micrometers for HDq16 regimens by week 4 after initiation of treatment; Central retinal thickness of approximately 234.4 micrometers for HDq12 regimens or approximately 231.2 micrometers for HDq16 regimens by week 8 after initiation of treatment; Central retinal thickness of approximately 229.7 micrometers for the HDq12 regimen or approximately 226.7 micrometers for the HDq16 regimen by week 12 after the start of treatment; Central retinal thickness of approximately 247.2 micrometers for HDq12 regimens or approximately 238.6 micrometers for HDq16 regimens by week 16 after the start of treatment; · Central retinal thickness of approximately 257 micrometers for HDq12 regimens or approximately 254.9 micrometers for HDq16 regimens by week 20 after initiation of treatment; Central retinal thickness of approximately 233 micrometers for HDq12 regimens or approximately 265.4 micrometers for HDq16 regimens by week 24 after the start of treatment; Central retinal thickness of approximately 236.9 micrometers for the HDq12 regimen or approximately 226 micrometers for the HDq16 regimen by week 28 after the start of treatment; · Central retinal thickness of approximately 250.2 micrometers for HDq12 regimens or approximately 229.2 micrometers for HDq16 regimens by week 32 after initiation of treatment; Central retinal thickness of approximately 226.4 micrometers for the HDq12 regimen or approximately 244.3 micrometers for the HDq16 regimen by week 36 after the start of treatment; Central retinal thickness of approximately 236.8 micrometers for HDq12 regimens or approximately 243.7 micrometers for HDq16 regimens by week 40 after the start of treatment; Central retinal thickness of approximately 245.9 micrometers for HDq12 regimens or approximately 227.7 micrometers for HDq16 regimens by week 44 after initiation of treatment; Central retinal thickness of approximately 226.2 micrometers for the HDq12 regimen or approximately 226.9 micrometers for the HDq16 regimen by week 48 after the start of treatment; Central retinal thickness of approximately 227.4 micrometers for the HDq12 regimen or approximately 231.1 micrometers for the HDq16 regimen by week 52 after the start of treatment; Central retinal thickness of approximately 234.3 micrometers for the HDq12 regimen or approximately 233.2 micrometers for the HDq16 regimen by week 56 after the start of treatment; Central retinal thickness of approximately 218.8 micrometers for the HDq12 regimen or approximately 221.9 micrometers for the HDq16 regimen by week 60 after the start of treatment; · CRT by approximately 4, 5, 6, 7, or 8 weeks after initiation of treatment, or decrease in CRT (approximately ±10, ± 11, or within ±12 micrometers) is achieved and maintained during subsequent treatment regimens, A free aflibercept concentration in the plasma of approximately 0.0409 (±0.0605) or 0 mg / L (or less than 0.0156 mg / L) approximately 4 hours after initiation of HDq12 or HDq16 treatment; · A free aflibercept concentration in the plasma of approximately 0.05 (±3.78), 0.0973 (±0.102), or 0.0672 mg / L approximately 8 hours after initiation of HDq12 or HDq16 treatment; A free aflibercept concentration in the plasma of approximately 0.11 (±2.21), or 0.146 (±0.110), or 0.0903 mg / L approximately 2 days after initiation of HDq12 or HDq16 treatment; Free aflibercept concentrations in plasma of approximately 0.11 (±2.06), 0.137 (±0.0947) or 0.112 mg / L approximately 3 days after initiation of HDq12 or HDq16 treatment; Free aflibercept concentrations in plasma of approximately 0.08 (±1.86), 0.0933 (±0.0481) or 0.0854 mg / L approximately 5 days after initiation of HDq12 or HDq16 treatment; Free aflibercept concentrations in the plasma of approximately 0.07 (±1.75), 0.0794 (±0.0413) or 0.0682 mg / L approximately 8 days after initiation of HDq12 or HDq16 treatment; Free aflibercept concentrations in plasma of approximately 0.04 (±1.76), 0.0435 (±0.0199) or 0.0385 mg / L approximately 15 days after initiation of HDq12 or HDq16 treatment; Free aflibercept concentrations in plasma of approximately 0.02 (± 1.76), 0.0213 (± 0.0148) or 0.0232 mg / L approximately 22 days after initiation of HDq12 or HDq16 treatment; A free aflibercept concentration in the plasma of approximately 0.00766 (±0.00958) or 0 mg / L (or less than 0.0156 mg / L) approximately 29 days after initiation of HDq12 or HDq16 treatment; Adjusted conjugated aflibercept concentration in plasma of approximately 0.00 mg / L approximately 4 hours after administration after initiation of HDq12 or HDq16 treatment; Adjusted conjugated aflibercept concentration in plasma of approximately 0.00 mg / L approximately 8 hours after administration after initiation of HDq12 or HDq16 treatment; Coordinating binding aflibercept in plasma at approximately 0.06 (± 3.50) or 0.124 (± 0.186) mg / L approximately 2 days after initiation of HDq12 or HDq16 treatment; Adjusted bound aflibercept concentration in plasma of approximately 0.13 (±2.07) or 0.173 (±0.155) mg / L approximately 3 days after initiation of HDq12 or HDq16 treatment; Adjusted bound aflibercept concentration in plasma of approximately 0.18 (± 1.88) or 0.223 (± 0.157) mg / L approximately 5 days after initiation of HDq12 or HDq16 treatment; Adjusted bound aflibercept concentration in plasma of approximately 0.31 (±1.56) or 0.334 (±0.135) mg / L approximately 8 days after initiation of HDq12 or HDq16 treatment; Adjusted conjugated aflibercept concentration in plasma of approximately 0.37 (± 1.50) or 0.393 (± 0.130) mg / L approximately 15 days after initiation of HDq12 or HDq16 treatment; Adjusted bound aflibercept concentration in plasma of about 0.25 (±3.00) or 0.335 (±0.155) mg / L at about 22 days after initiation of HDq12 or HDq16 treatment; Adjusted bound aflibercept concentration in plasma of about 0.32 (±1.39) or 0.331 (±0.0953) mg / L at about day 29 after initiation of HDq12 or HDq16 treatment; · Non-inferior BVCA compared to aflibercept administered intravitreally at 2 mg approximately every 4 weeks for the first 5 injections, followed by 2 mg approximately once every 8 weeks or once every 2 months. , · Aflibercept administered intravitreally at 2 mg approximately every 4 weeks for the first 3 or 4 or 5 injections, followed by 2 mg approximately once every 8 weeks or once every 2 months. ocular and non-ocular safety or mortality in subjects suffering from DME, as in · Improvement in best-corrected visual acuity by 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 weeks after initiation of treatment; · Early Treatment Diabetic Retinopathy Test (ETDRS) by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56 or 60 after the start of treatment an improvement in best-corrected visual acuity of 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, or more than 7 letters as measured by an eye chart or Snellen equivalent chart; · Fluid (total fluid, retina free of retinal fluid [IRF] and / or subretinal fluid [SRF]); · At least 100, 125, 130, 135, by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, or 60 after the start of treatment. Central retinal thickness (CRT) decrease of 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, or 150 micrometers.

[0080] The present invention provides VEGF receptor fusion proteins for use in the treatment and prevention of neovascular age-related macular degeneration (nAMD) in a subject in need thereof; one initial dose, two secondary doses, and three tertiary doses of VEGF receptor fusion protein of 8 mg or more are administered to the subject in Year 1; one initial dose, two secondary doses, and two tertiary doses of VEGF receptor fusion protein of 8 mg or more are administered to the subject in year 1, or · One initial dose, two secondary doses, and three tertiary doses of 8 mg or more of VEGF receptor fusion protein are administered to subjects in year 1, followed by 2 to 4 tertiary doses. is administered in the second year.

[0081] The present invention provides VEGF receptor fusion proteins for use in the treatment and prevention of neovascular age-related macular degeneration (nAMD) in a subject in need thereof, and between administration of 8 mg or more of VEGF receptor fusion protein. The interval is adjusted (increased / maintained / decreased) based on visual and / or anatomical results.

[0082] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of neovascular age-related macular degeneration (nAMD) in a subject in need thereof, wherein a dose of 8 mg or more of the VEGF receptor fusion protein is Administered according to pro re nata (PRN), capped PRN, or treat and extend (T&E) dosing regimens.

[0083] The invention also provides a kit comprising: i) a container containing a VEGF receptor fusion protein, preferably aflibercept; and ii) instructions for use of the VEGF fusion protein. In one embodiment of the invention, the container is a vial or a prefilled syringe. The vial is a type I glass vial containing a nominal fill volume of approximately 0.26 mL solution for intravitreal injection. In one embodiment of the invention, the container contains a VEGF receptor fusion protein at a concentration of 100 mg / mL or more, or the container contains aflibercept at a concentration of about 114.3 mg / mL. In one embodiment of the invention, the instructions for use include instructions for the use of VEGF fusion protein or aflibercept for the treatment of DME and / or AMD. In one embodiment of the invention, the instructions for use include: i) the container contains 8 mg or more (114.3 mg / mL) of aflibercept intravitreal injection solution; ii) each single-dose vial is provide a volume that can be used to deliver a single 70 microliter dose containing 8 mg of aflibercept to a patient; iii) a recommended dose of 8 mg or more of aflibercept (equivalent to a 70 microliter solution for injection); iv) Aflibercept treatment of 8 mg or more is initiated with monthly injections (every 4 weeks) in 3 consecutive doses; v) injection intervals are then extended up to every 16 weeks or every 20 weeks. vi) treatment intervals may be adjusted based on the physician's judgment regarding visual and / or anatomical results, and / or vii) 8 mg or more of aflibercept / 0.07 mL is arginine monohydrochloride, Contains the information that it is provided as a sterile aqueous solution containing histidine, histidine hydrochloride monohydrate, polysorbate 20 sucrose, and water for injection. [Brief explanation of drawings]

[0084]

Figure 1

Figure 2

table 1

[0085] The present invention provides, in part, a safe and effective high-dose aflibercept IVT that extends maintenance dosing intervals beyond 8 weeks, with at least similar functional outcomes and potentially improved anatomical outcomes. Provide injections. The regimen demonstrated an unexpectedly higher level of tolerance in the subjects than would be expected simply based on the higher dose of aflibercept.

[0086] EYLEA has become the standard treatment nAMD. Eylea is prescribed for nAMD at a dose of 2 mg once a month for 3 doses, followed by maintenance dosing every 8 weeks. The dosing regimen of the invention has demonstrated that a significantly higher proportion of subjects can be maintained at 12- and 16-week dosing intervals. In clinical trials testing these dosing regimens, approximately 90% of subjects with diabetic macular edema were able to maintain the dosing regimen for 16 weeks. These tolerability data, coupled with a safety profile consistent with that of EYLEA, support high-dose aflibercept as a potential new standard of care in neovascular eye disorders such as nAMD. The data presented herein demonstrate that 12- and 16-week dosing regimens of aflibercept 8 mg achieve a high bar of maintaining improvements in visual acuity and retinal fluid anatomical measures over 48 weeks in subjects with nAMD. I have proven that I did it. All of these results were achieved in subjects who were started rapidly with extended dosing intervals, and the majority did not require changes in regimen. In summary, pivotal data support that aflibercept 8mg offers a longer duration of action while maintaining a similar safety profile to EYLEA.

[0087] Before initiating the HD aflibercept clinical development program, pharmacokinetic simulations of free aflibercept concentration-time profiles in the human vitreous using a one-compartment eye model showed that aflibercept at an IVT dose of 8 mg It was anticipated that the dosing interval could be extended by approximately 20 days (2 half-lives) compared to the IVT dose. Aflibercept HDq12 and HDq16 regimens demonstrated longer duration of efficacy in HD trials than expected. A subsequent population PK analysis combining data from the CANDELA PHOTON and PULSAR Phase 3 trials showed that the ocular clearance of free aflibercept was significantly lower than that of HD aflibercept compared to 2 mg of IVT aflibercept administered as the Eylea formulation. Slower ocular clearance for HD aflibercept, 34% slower for sept formulations, results in both longer persistence of free aflibercept in the eye and approximately 6 weeks longer duration of efficacy compared to 2mg It was predicted. The magnitude of the decrease in ocular clearance for the HD aflibercept formulation compared to the 2 mg Eylea formulation is greater than expected and highly statistically significant in the population PK model that cannot be explained solely by the dose increase from 2 mg to 8 mg. This was due to the ``HD aflibercept formulation effect,'' which is a significant effect.

[0088] The predicted population PK median time for plasma free aflibercept concentrations to reach the lower limit of quantitation (LLOQ) after 2 mg aflibercept IVT is 1.5 weeks compared to 3.5 weeks for 8 mg HD aflibercept It was estimated that For HD aflibercept regimens, the longer duration of systemic exposure to free aflibercept, which represents the transfer of free aflibercept from the eye, results in higher doses and nonlinear systemic target-mediated elimination as well as free aflibercept. Bercept was also attributable to a 34% slower ocular clearance. The slower ocular clearance of HD aflibercept formulations reflects the estimated population PK time to achieve a free aflibercept amount in the ocular compartment for the 2q8 regimen at the end of the 8-week dosing interval of 6 weeks for HD aflibercept formulations. was predicted to provide a 6-week longer duration of efficacy compared to that of the 2 mg aflibercept formulation. Exposure-response analysis showed a 20.6% slower ocular clearance for 8 mg aflibercept due to the effect of the HD formulation than would be expected if the HD formulation had the same ocular clearance as 2 mg aflibercept. It was estimated that this resulted in a lower dosing regimen modification rate (DRM).

[0089] General methods for protein purification are described, including immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization (Coliganet al. (2000) J. Current Protocols in Protein Science, Vol. 1, John Wiley and Sons, Inc., New York). Chemical analysis, chemical modification, post-translational modification, production of fusion proteins, and protein glycosylation are described (e.g., Colligan et al. (2000) Current Protocols in Protein Science, Vol. 2, John Wiley and Sons, Inc. .,New York, Ausubel et al.(2001)Current Protocols in Molecular Biology,Vol.3,John Wiley and Sons,Inc.,NY,N.Y.,pp.16.0.5-16.22.17;Sigma-Aldrich,Co. (2001) Products for Life Science Research, St. Louis, Mo., pp. 45-89; see Amersham Pharmacia Biotech (2001) BioDirectory, Piscataway, N.J., pp. 384-391). Production, purification, and fragmentation of polyclonal and monoclonal antibodies are described (Coligan et al. (2001) J. Current Protcols in Immunology, Vol. 1, John Wiley and Sons, Inc., New York, Harlow and Lane (1999) Using Antibodies, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., Harlow and Lane, supra). Standard techniques are available to characterize ligand / receptor interactions (see, e.g., Colligan et al. (2001) J. Current Protocols in Immunology, Vol. 4, John Wiley, Inc., New York). I want to be).

[0090] Flow cytometry methods including fluorescence-activated cell sorting (FACS) are available (e.g., Owens et al. (1994) Flow Cytometry Principles for Clinical Laboratory Practice, John Wiley and Sons, Hoboken, N.J., Givan (2001). )Flow Cytometry, 2nd edition, Wiley-Liss, Hoboken, N.J., see Shapiro (2003) Practical Flow Cytometry, John Wiley and Sons, Hoboken, NJ). For example, fluorescent reagents suitable for modifying nucleic acids, polypeptides, and antibodies, including nucleic acid primers and probes, are available for use as diagnostic reagents. Molecular Probes (2003) J. Catalog, Molecular Probes, Inc. .,Eugene,Oreg. Sigma-Aldrich (2003) Catalog, St. Louis, Missouri).

[0091] Standard methods for immune system histology have been described (e.g. Muller-Harmelink (ed.) (1986) Human Thymus: Histopathology and Pathology, Springer Verlag, New York, N.Y., Hiatt et al. (2000) Color Atlas of Histology, Lippincott, Williams, and Wilkins, Philadelphia, PA; see Louis et al. (2002) Basic Histology: Text and Atlas, McGraw-Hill, New York, NY).

[0092] "Isolated" VEGF antagonists and VEGF receptor fusion proteins (e.g., aflibercept), polypeptides, polynucleotides, and vectors refer to other biological molecules from the cells or cell cultures in which they are produced. at least partially free. Such biological molecules include nucleic acids, proteins, other VEGF antagonists and VEGF receptor fusion proteins, lipids, carbohydrates, or other materials such as cell debris and growth media. An isolated VEGF antagonist or VEGF receptor fusion protein may further be at least partially free of expression system components such as biological molecules from the host cell or its growth medium. Generally, the term "isolated" refers to the complete absence of such biological molecules (e.g., trace or negligible amounts of impurities may be present) or the presence of water, buffers, is not intended to imply the absence of salts or components of pharmaceutical formulations containing VEGF antagonists or VEGF receptor fusion proteins.

[0093] "Isolated" VEGF antagonists and VEGF receptor fusion proteins (e.g., aflibercept), polypeptides, polynucleotides, and vectors refer to other biological molecules from the cells or cell cultures in which they are produced. at least partially free. Such biological molecules include nucleic acids, proteins, other VEGF antagonists and VEGF receptor fusion proteins, lipids, carbohydrates, or other materials such as cell debris and growth media. An isolated VEGF antagonist or VEGF receptor fusion protein may further be at least partially free of expression system components such as biological molecules from the host cell or its growth medium. Generally, the term "isolated" refers to the complete absence of such biological molecules (e.g., trace or negligible amounts of impurities may be present) or the presence of water, buffers, is not intended to imply the absence of salts or components of pharmaceutical formulations containing VEGF antagonists or VEGF receptor fusion proteins.

[0094] A dose referred to herein, eg, 8 mg, encompasses embodiments comprising ±10% of the specified amount, eg, 8 mg (±0.8 mg). For example, concentrations or amounts mentioned herein of formulation excipients also encompass embodiments that include ±10% of the specified amount.

[0095] Subject and patient are used interchangeably herein. The subject or patient is a mammal, such as a human, mouse, rabbit, monkey, or non-human primate, preferably a human. A subject or patient can be said to "suffer" from a neovascular eye disorder such as nAMD. Such subjects or patients have a disorder in one or both eyes. In one embodiment of the invention, the subject or patient (preferably human) has (currently or in the past) one or more of the following characteristics: 1. Over 50 years old, for example 61, 62, 63, 74 or 75 years old. 2. Have active subfoveal CNV secondary to nAMD, with a total area greater than 50% of the total lesion area, including, for example, parafoveal lesions affecting the fovea of ​​the eye. 3. For example, about 78-24, 73-78, less than 73, 58, 59, 60, 61, or 62 (20 / 40, 20 / 63, 20 / 50, 20 / 32, or 20 / have a Best Corrected Visual Acuity (BCVA) Early Treatment Diabetic Retinopathy Test (ETDRS) letter score) of 320 (Snellen Equivalent Table); 4. Central retinal thickness greater than or equal to 300 micrometers or greater than or equal to 320 micrometers, or approximately 367, 368, 369, 370, 450, 451, 452, 453, 454, or 455 micrometers, and / or CRT greater than or equal to 300 micrometers (or Spectralis DME, which mainly involves the eye (over 320 micrometers), 5. For example, the lesion type is occult, predominantly classic, or minimally classic, approximately 6 or 7 mm. 2 total lesion area of 6. DRSS score of level 43 or higher and level 47 or lower, 7. Type 1 or type 2 diabetes mellitus, and / or 8. Presence of intraretinal and / or subretinal fluid in the central subfield on OCT in the eye; 9. Body mass index of approximately 27 or 28 or higher, and / or 10. Hypertension and / or 11. Cataract, dry age-related macular degeneration, vitreous detachment, dry eye, cataract nucleus, glaucoma, astigmatism, presbyopia, choroidal neovascularization, open-angle glaucoma, hyperopia, macular degeneration, myopia, posterior capsule opacification , premacular membrane, retinal degeneration, cutis laxa, retinopathy hypertension, retinal drusen, desquamation syndrome, vitreous floaters, cortical cataract, ptosis, retinal tear, vitreous disorder, pterygium, vitreous degeneration, ocular fatigue, cataract surgery, intraocular lens insertion, capsulotomy, blepharoplasty, keratoplasty, laser therapy, neoplasms (benign, malignant, and unspecified (including cysts and polyps)), or bulbar history of any one or more of the plaques; and / or Having or lacking any one or more of the following characteristics: 1. Subretinal hemorrhage in the eye that is 50% or more of the total lesion area; Intraocular pressure of 2.25 mmHg or higher, 3. Evidence of infectious blepharitis, keratitis, scleritis or conjunctivitis in the eye; 4. Any intraocular inflammation and / or eye infection, 5. Any history of stage 2 or higher macular hole in the eye, 6. Visible, current iris neovascularization, vitreous hemorrhage, or tractional retinal detachment 7. Uncontrolled BP (defined as systolic >140 mmHg or diastolic >90 mmHg); 8. More than 10% variation in three BP measurements; 9. Cerebrovascular accident / transient ischemic attack or myocardial infarction / history of acute coronary syndrome, 10.History of renal failure, dialysis, or renal transplant; 11. Known susceptibility to aflibercept, 12. Women who are pregnant or breastfeeding 13. Women of childbearing potential who do not wish to use highly effective contraception; 14. Intraocular surgery within 12 weeks (84 days) and / or 15. History of corneal transplant surgery or corneal dystrophy in the eye.

[0096] Accordingly, the present invention includes methods of treating or preventing neovascular age-related macular degeneration (nAMD) in a subject in need thereof. 1. Age is 50 years or older, 2. Active subfoveal CNV secondary to nAMD, 3. Best corrected visual acuity (BCVA) of approximately 78~24 early treatment diabetic retinopathy examination (ETDRS) with character score, 4. Having a central retinal thickness of 300 micrometers or more or 320 micrometers or more, 5. About 6 or 7mm 2 with a lesion area of 6. Have a DRSS score of level 43 or higher and level 47 or lower, and / or 7.Have type 1 or type 2 diabetes mellitus, and / or 1.The eye does not have subretinal hemorrhage that accounts for 50% or more of the total lesion area; 2.Does not have intraocular pressure of 25mmHg or more in the eyes, 3. No evidence of infectious blepharitis, keratitis, scleritis, or conjunctivitis in the eye; 4. Does not have intraocular inflammation and / or eye infection in the eye; 5. No history of stage 2 or higher macular hole in the eye; 6. Does not have visible current iris neovascularization, vitreous hemorrhage, or tractional retinal detachment; 7. Does not have uncontrolled BP, 8. No variation of more than 10% in the three BP measurements; 9. No history of cerebrovascular accident / transient ischemic attack or myocardial infarction / acute coronary syndrome; 10. No history of renal failure, dialysis, and / or renal transplantation; 11. Does not have a known susceptibility to aflibercept; 12. Not pregnant or breastfeeding; 13. Not a woman of childbearing potential who does not wish to have a high contraceptive effect; 14. Have not undergone intraocular surgery within 12 weeks (84 days) and / or 15. No history of corneal transplant surgery or corneal dystrophy in the eye; administering a single initial dose of a VEGF receptor fusion protein, preferably aflibercept, of about 8 mg or more to the subject's eye, followed by one or more secondary doses of a VEGF receptor fusion protein of about 8 mg or more; administering one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein, each of the secondary doses being administered about 2 to 4 weeks after the immediately preceding dose, and each of the tertiary doses is administered approximately 12 to 20 weeks after the previous dose.

[0097] VEGF antagonist The invention includes methods for using VEGF antagonists to treat or prevent neovascular eye disorders. VEGF antagonists include molecules that interfere with the interaction between VEGF and the natural VEGF receptor, such as by binding to VEGF or a VEGF receptor and preventing or interfering with the interaction between VEGF and the VEGF receptor. do. Certain exemplary VEGF antagonists include anti-VEGF antibodies, anti-VEGF receptor antibodies, and VEGF receptor fusion proteins. Although VEGF receptor fusion proteins, such as aflibercept, are preferred for use in connection with the methods described herein, the scope of the invention includes the VEGF antagonists described herein (e.g., scFv , DARPin, anti-VEGF antibodies) are used in place of such fusion proteins.

[0098] For purposes herein, a "VEGF receptor fusion protein" refers to one or more VEGF receptors fused to another polypeptide that disrupts the interaction between VEGF and the native VEGF receptor. or a molecule containing domains thereof, eg, two such fusion polypeptides join together, thereby forming a homodimer or other multimer. Such VEGF receptor fusion proteins are sometimes referred to as "VEGF traps" or "VEGF traps." VEGF receptor fusion proteins within the context of this disclosure included within this definition include two or more of the VEGF receptors, such as VEGFR1 (also known as Flt1) and / or VEGFR2 (also known as Flk1 or KDR). Included are chimeric polypeptides that include an immunoglobulin (Ig)-like domain, and may also include a multimerization domain (eg, an Fc domain).

[0099] An exemplary VEGF receptor fusion protein is a molecule called VEGF1R2-FcΔC1(a) encoded by the nucleic acid sequence of SEQ ID NO: 1 or nucleotides 79-1374 or 79-1371 thereof.

[0100] VEGF1R2-FcΔC1(a) has three components, namely: (1) VEGFR1 component containing amino acids 27 to 129 of SEQ ID NO: 2, (2) VEGFR2 component containing amino acids 130 to 231 of SEQ ID NO: 2, and (3) Multimerization component (“FcΔC1(a)”) containing amino acids 232 to 457 of SEQ ID NO: 2 (the C-terminal amino acid of SEQ ID NO: 2, that is, K458, may or may not be included in the VEGF receptor fusion protein) (see US Pat. No. 7,396,664 or US Pat. No. 7,354,579), which are incorporated herein for all purposes. Note that amino acids 1-26 of SEQ ID NO: 2 are the signal sequence.

[0101] When the multimerization component (MC) of the VEGF receptor fusion protein is derived from an IgG (eg, IgG1) Fc domain, the MC has fewer amino acids than amino acids 232-457 of SEQ ID NO:2. Therefore, MC IgG cannot be cleaved to shorter than 226 amino acids.

[0102] In embodiments of the invention, the VEGF receptor fusion protein comprises amino acids 27-458 or 27-457 (eg, in homodimeric form) of SEQ ID NO:2.

[0103] [Table 4]

[0104] [Table 5]

[0105] In an embodiment of the invention, the VEGF receptor fusion protein is (1) immunoglobulin-like (Ig) domain 2 of the first VEGF receptor (e.g., VEGFR1), and (2) Ig domain 3 of a second VEGF receptor (e.g., VEGFR2); (3) and, optionally, Ig domain 4 of a second VEGF receptor (e.g., VEGFR2), and (4) further comprising a multimerization component (eg, the Fc domain of IgG, including the hinge, CH2, and CH3 domains).

[0106] For example, in an embodiment of the invention, the VEGF receptor fusion protein has the following arrangement of said domains: · [VEGFR1 Ig domain 2]-[VEGFR2 Ig domain 3]-[MC] (e.g., its homodimer) or · [VEGFR1 Ig domain 2]-[VEGFR2 Ig domain 3]-[VEGFR2 Ig domain 4]-[MC] (eg, its homodimer).

[0107] The present disclosure also includes within its scope, in place of VEGF receptor fusion proteins, VEGF binding molecules and anti-VEGF antibodies and antigen-binding fragments thereof or biopolymer conjugates thereof (e.g., KSI-301), e.g. · Bevacizumab (e.g., at a concentration of about 80-90 or 88 mg / ml), ranibizumab (e.g., at a concentration of about 20-40 mg / ml, e.g. 21-35, 21 or 35 mg / ml), Anti-VEGF aptamers such as pegaptanib (e.g. pegaptanib sodium), · Single chain such as brolucizumab (e.g. V L -V H ) anti-VEGF antibodies (e.g., at a concentration of about 200-400 or 200, 210, 400 or 420 mg / ml), anti-VEGF darpin, such as abiciperpegol DARPin (e.g., at a concentration of about 70-140, 70 or 140 mg / ml), or · Note that this includes highly concentrated formulations containing bispecific anti-VEGF antibodies that also bind ANG2 (e.g., at concentrations of approximately 100-400, 100, 105, 400, or 420 mg / ml), such as RG7716 (faricimab). I want to be

[0108] To minimize the repetitiveness of the embodiments discussed herein, any of the formulations discussed herein may be substituted for the anti-VEGF antibody or antibody fragment or antibody described herein in place of the VEGF receptor fusion protein. It is contemplated that the scope of the invention includes embodiments that include other VEGF binding molecules discussed herein (eg, substituted with an anti-VEGF DARPin) at any of the concentrations discussed in . For example, the invention includes formulations with 35 or 80 mg / ml ranibizumab, buffers, heat stabilizers, viscosity reducers and surfactants.

[0109] DARPin is an engineered ankyrin repeat protein. DARPins generally contain three to four closely packed repeats of approximately 33 amino acid residues, each repeat containing a β-turn and two antiparallel α-helices. This rigid framework provides protein stability while allowing presentation of variable regions, typically containing six amino acid residues per repeat, for target recognition.

[0110] An "anti-VEGF" antibody or antigen-binding fragment of an antibody refers to an antibody or fragment that specifically binds to VEGF.

[0111] Exemplary VEGF receptor fusion proteins include aflibercept (EYLEA®, Regeneron Pharmaceuticals, Inc.) or conbercept (sold commercially by Chengdu Kanghong Biotechnology Co., Ltd.) . See International Patent Application Publication No. WO2005 / 121176 or WO2007 / 112675. The terms "aflibercept" and "conbercept" include biosimilar versions thereof. A biosimilar version of a reference product (e.g., aflibercept) generally refers to a product that contains the same amino acid sequence, but under the U.S. Biologics Price Competition and Innovation Act, a biosimilar version of a reference product (e.g., aflibercept) generally refers to a product that contains the same amino acid sequence; include.

[0112] The present invention also contemplates administering one or more additional therapeutic agents in addition to the VEGF antagonist, such as (one or more doses of) a second VEGF antagonist, antibiotics, anesthetics (e.g., non- steroidal anti-inflammatory drugs (NSAIDs), steroids (e.g., corticosteroids, dexamethasone), triamcinolone acetonide (TA), methotrexate, rapamycin, anti-tumor necrosis factor alpha drugs (e.g., infliximab), daclizumab, and / or complement (e.g., a C3 or C5) inhibitor).

[0113] pharmaceutical formulations The invention includes a method in which a VEGF antagonist is included within a pharmaceutical formulation that is administered to the eye of a subject. The pharmaceutical formulation includes a VEGF antagonist along with a pharmaceutically acceptable carrier. Other agents may be incorporated into the pharmaceutical formulation to provide improved migration, delivery, tolerance, etc. The term "pharmaceutically acceptable" means one that has been approved by a federal or state regulatory agency for use in animals, and more specifically humans, or that has been approved by the United States Pharmacopoeia or other generally accepted means that it is listed in the pharmacopoeia of The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which a VEGF antagonist is administered. Many suitable formulations can be found in a formulary known to all pharmacists: Remington's Pharmaceutical Sciences (15th ed., Mack Publishing Company, Easton, Pa., 1975), eg, chapter 87 by Blaug, Seymour.

[0114] Pharmaceutical formulations used in the methods of the invention can be "highly concentrated." Highly concentrated pharmaceutical formulations of the invention include at least 41 mg / ml, at least 80 mg / ml, at least 100 mg / ml, at least 125 mg / ml, at least 140 mg / ml, at least 150 mg / ml, at least 175 mg / ml, at least 200 mg / ml, at least A VEGF antagonist, such as a VEGF receptor fusion protein, at a concentration of 225 mg / ml, at least 250 mg / ml, or at least 275 mg / ml. "High concentration" means about 140 mg / ml to about 160 mg / ml, at least about 140 mg / ml but less than 160 mg / ml, 41 mg / ml to about 275 mg / ml, about 70 mg / ml to about 75 mg / ml, or about 80 mg may refer to a formulation containing a concentration of VEGF antagonist from 250 mg / ml to about 250 mg / ml. In some embodiments, the VEGF antagonist concentration in the formulation is approximately any of the following concentrations: 41 mg / ml, 42 mg / ml, 43 mg / ml, 44 mg / ml, 45 mg / ml, 46 mg / ml, 47 mg / ml. ml, 48mg / ml, 49mg / ml, 50mg / ml, 51mg / ml, 52mg / ml, 53mg / ml, 54mg / ml, 55mg / ml, 56mg / ml, 57mg / ml, 58mg / ml, 59mg / ml, 60mg / ml, 61mg / ml, 62mg / ml, 63mg / ml, 64mg / ml, 65mg / ml, 66mg / ml, 67mg / ml, 68mg / ml, 69mg / ml, 70mg / ml, 71mg / ml, 72mg / ml, 73mg / ml, 74mg / ml, 75mg / ml, 76mg / ml, 77mg / ml, 78mg / ml, 79mg / ml, 80mg / ml, 81mg / ml, 82mg / ml, 83mg / ml, 84mg / ml, 85mg / ml, 86mg / ml, 87mg / ml, 88mg / ml, 89mg / ml, 90mg / ml, 91mg / ml, 92mg / ml, 93mg / ml, 94mg / ml, 95mg / ml, 96mg / ml, 97mg / ml ml, 98mg / ml, 99mg / ml, 100mg / ml, 101mg / ml, 102mg / ml, 103mg / ml, 104mg / ml, 105mg / ml, 106mg / ml, 107mg / ml, 108mg / ml, 109mg / ml, 110mg / ml, 111mg / ml, 112mg / ml, 113mg / ml, 113.3mg / ml, 114mg / ml, 114.1mg / ml, 114.2mg / ml, 114.3mg / ml, 114.4mg / ml, 114.5mg / ml, 114.6mg / ml, 114.7mg / ml, 114.8mg / ml, 114.9mg / ml, 115mg / ml, 116mg / ml, 117mg / ml, 118mg / ml, 119mg / ml, 120mg / ml, 121mg / ml, 122mg / ml, 123mg / ml, 124mg / ml, 125mg / ml, 126mg / ml, 127mg / ml, 128mg / ml, 129mg / ml, 130mg / ml, 131mg / ml, 132mg / ml, 133mg / ml, 133.3mg / ml , 133.4mg / ml,134mg / ml, 135mg / ml, 136mg / ml, 137mg / ml, 138mg / ml, 139mg / ml, 140mg / ml, 141mg / ml, 142mg / ml, 143mg / ml, 144mg / ml, 145mg / ml, 146mg / ml, 147mg / ml, 148mg / ml, 149mg / ml, 150mg / ml, 151mg / ml, 152mg / ml, 153mg / ml, 154mg / ml, 155mg / ml, 156mg / ml, 157mg / ml, 158mg / ml, 159mg / ml, 160mg / ml, 161mg / ml, 162mg / ml, 163mg / ml, 164mg / ml, 165mg / ml, 166mg / ml, 167mg / ml, 168mg / ml, 169mg / ml, 170mg / ml, 171mg / ml, 172mg / ml, 173mg / ml, 174mg / ml, 175mg / ml, 176mg / ml, 177mg / ml, 178mg / ml, 179mg / ml, 180mg / ml, 181mg / ml, 182mg / ml, 183mg / ml, 184mg / ml, 185mg / ml, 186mg / ml, 187mg / ml, 188mg / ml, 189mg / ml, 190mg / ml, 191mg / ml, 192mg / ml, 193mg / ml, 194mg / ml, 195mg / ml, 196mg / ml, 197mg / ml, 198mg / ml, 199mg / ml, 200mg / ml, 201mg / ml, 202mg / ml, 203mg / ml, 204mg / ml, 205mg / ml, 206mg / ml, 207mg / ml, 208mg / ml, 209mg / ml, 210mg / ml, 211mg / ml, 212mg / ml, 213mg / ml, 214mg / ml, 215mg / ml, 216mg / ml, 217mg / ml, 218mg / ml, 219mg / ml, 220mg / ml, 221mg / ml, 222mg / ml, 223mg / ml, 224mg / ml, 225mg / ml, 226mg / ml, 227mg / ml, 228mg / ml, 229mg / ml, 230mg / ml, 231mg / ml, 232mg / ml, 233mg / ml, 234mg / ml, 235mg / ml, 236mg / ml, 237mg / ml, 238mg / ml, 239mg / ml, 240mg / ml, 241mg / ml, 242mg / ml, 243mg / ml, 244mg / ml, 245mg / ml, 246mg / ml, 247mg / ml, 248mg / ml, 249mg / ml, 250mg / ml, 251mg / ml, 252mg / ml, 253mg / ml, 254mg / ml, 255mg / ml, 256mg / ml, 257mg / ml, 258mg / ml, 259mg / ml, 260mg / ml, 261mg / ml, 262mg / ml, 263mg / ml, 264mg / ml, 265mg / ml, 266mg / ml, 267mg / ml, 268mg / ml, 269mg / ml, 270mg / ml, 271mg / ml, 272mg / ml, 273mg / ml, 274mg / ml, or 275mg / ml. Other VEGF antagonist concentrations are contemplated herein, so long as the concentrations function in accordance with the embodiments herein.

[0115] In one embodiment of the invention, the pharmaceutical formulation used in the methods of the invention comprises about 4, 6, 8, 10, 12, 14, 16, 18, or 20 mg of VEGF receptor fusion protein (e.g., afliber sept), or at any of their acceptable doses as contemplated herein, less than or equal to about 100 μl, less than or equal to about 75 μl, or less than or equal to about 70 μl, e.g., about 50 μl , 51μl, 52μl, 53μl, 54μl, 55μl, 56μl, 57μl, 58μl, 59μl, 60μl, 61μl, 62μl, 63μl, 64μl, 65μl, 66μl, 67μl, 68μl, 69μl, 70μl, 71μl, 72μl, 73μl, 74μl, 75μl , 76μl, 77μl, 78μl, 79μl, 80μl, 81μl, 82μl, 83μl, 84μl, 85μl, 86μl, 87μl, 88μl, 89μl, 90μl, 91μl, 92μl, 93μl, 94μl, 95μl, 96μl, 97μl, 98μl, 99μl, or Pharmaceutical formulation in a volume of 100 μl.

[0116] The present invention includes methods of using any of the formulations described herein under "Exemplary Formulations" (as described herein), except for VEGF receptor fusion proteins (e.g., Vercept) is replaced with the concentrations listed in this section ("VEGF Receptor Fusion Proteins and Other VEGF Inhibitors").

[0117] Buffers for use in pharmaceutical formulations herein that may be used in the methods of the invention refer to solutions that resist pH changes due to the use of acid-base conjugates. The buffer can maintain a pH in the range of about 5.0 to about 6.8, more typically about 5.8 to about 6.5, most typically about 6.0 to about 6.5. In some cases, the pH of the formulations of the invention is about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2 , about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, or about 6.8. Exemplary buffers for inclusion in the formulations herein include histidine-based buffers, such as histidine, including histidine hydrochloride and histidine acetate. Buffers for inclusion in the formulations herein may alternatively be phosphate-based buffers, including e.g. sodium phosphate, acetate-based buffers, e.g. sodium acetate or acetic acid, or e.g. sodium citrate or It can be a citric acid-based buffer containing citric acid. It is also recognized that the buffer can be a mixture of the above, so long as the buffer functions to buffer the formulation at the pH range described above. In some cases, the buffer is about 5mM to about 25mM, or more typically about 5mM to about 15mM. The buffer can be about 5mM, about 6mM, about 7mM, about 8mM, about 9mM, about 10mM, about 11mM, about 12mM, about 13mM, about 14mM, about 15mM, about 16mM. , about 17mM, about 18mM, about 19mM, about 20mM, about 21mM, about 22mM, about 23mM, about 24mM, or about 25mM.

[0118] In one embodiment of the invention, a histidine-based buffer is prepared using histidine and histidine monohydrochloride.

[0119] Surfactant, as used herein, refers to a component that protects VEGF antagonists, such as high concentration VEGF receptor fusion proteins, from stress induced by various surfaces and interfaces. As such, detergents can be used to limit or minimize aggregation of the VEGF receptor fusion protein and promote protein solubility. Suitable surfactants herein are shown to be nonionic and may include surfactants having polyoxyethylene moieties. Exemplary surfactants in this category include polysorbate 20, polysorbate 80, poloxamer 188, polyethylene glycol 3350, and mixtures thereof. Surfactants in the formulation may be present at about 0.02% to about 0.1% weight per volume (w / v), more typically about 0.02% to about 0.04% (w / v). In some cases, the surfactant is about 0.02% (w / v), about 0.03% (w / v), about 0.04% (w / v), about 0.05% (w / v), about 0.06% (w / v), about 0.07% (w / v), about 0.08% (w / v), about 0.09% (w / v), or about 0.1% (w / v).

[0120] Thermostabilizers for use in pharmaceutical formulations that may be used in the methods described herein provide thermostability against thermal denaturation of VEGF receptor fusion proteins, as well as VEGF antagonists, e.g. Refers to a component that protects the fusion protein from loss of potency or activity. Suitable heat stabilizers include sugars, which may be sucrose, trehalose, sorbitol or mannitol, or amino acids, such as L-proline, L-arginine (e.g. L-arginine monohydrochloride), or taurine. could be. Additionally, heat stabilizers may also include substituted acrylamides or propane sulfonic acids, or may be compounds such as glycerol.

[0121] In some cases, pharmaceutical formulations for use in the methods herein include sugars and taurine, sugars and amino acids, sugars and propanesulfonic acid, sugars and taurine, glycerol and taurine, glycerol and propanesulfonic acid, amino acids and taurine, or contains both amino acids and propane sulfonic acid. Additionally, the formulation may include sugars, taurine and propane sulfonic acid, glycerol, taurine and propane sulfonic acid, and L-proline, taurine and propane sulfonic acid.

[0122] Embodiments herein have thermal stabilizers present alone, each independently ranging from about 2% (w / v) to about 10% (w / v) or 4% (w / v) Present at ~10% (w / v), or about 4% (w / v) to about 9% (w / v), or about 5% (w / v) to about 8% (w / v) obtain. Thermal stabilizers in the formulation are approximately 2% (w / v), approximately 2.5% (w / v), approximately 3% (w / v), approximately 4% (w / v), and approximately 5% (w / v). v), about 6% (w / v), about 7% (w / v), about 8% (w / v), about 9% (w / v), about 10% (w / v), or about It can be at a concentration of 20% (w / v).

[0123] Regarding taurine and propane sulfonic acid, in one embodiment of the invention these heat stabilizers may be present in the formulation from about 25 mM to about 100 mM, more typically from about 50 mM to about 75 mM (other heat stabilizers (compared to agents).

[0124] Viscosity-lowering agents are typically used to reduce or prevent protein aggregation. Viscosity-lowering agents for inclusion herein include sodium chloride, magnesium chloride, D- or L-arginine (eg, L-arginine monohydrochloride), lysine, or mixtures thereof. When present herein, the viscosity reducing agent may be present from about 10 mM to about 100 mM, more typically from about 30 mM to about 75 mM, even more typically from about 40 mM to about 70 mM. In some cases, the viscosity reducing agent is about 10mM, about 15mM, about 20mM, about 25mM, about 30mM, about 35mM, about 40mM, about 45mM, about 50mM, about 55mM, about 60mM, about 65mM, about 70mM, about 75mM , about 80mM, about 85mM, about 90mM, about 95mM, or about 100mM.

[0125] Pharmaceutical formulations for use in the methods described herein can also have a pharmaceutically acceptable viscosity for ocular administration, such as intravitreal injection. Viscosity is generally a measure of the resistance of a fluid to be deformed by either shear or tensile stress (typically measured by techniques known in the art, e.g., by a viscometer or a rheometer). ). Typical viscosities of formulations for use in the methods described herein are from about 5.0 cP (centipoise) to about 15 cP, from about 11 cP to about 14 cP, from about 12 cP to about 15 cP, or from about 11 cP to about 12 cP. be. Accordingly, the viscosities of the formulations herein are about 5.0 cP, about 6.0, about 7.1 cP, about 7.2 cP, about 7.3 cP, about 7.4 cP, about 7.5 cP, about 7.6 cP, about 10 cP, about 10.5 cP, about 11.0 cP, about 11.5 cP, about 12.0, about 12.5 cP, about 13.0 cP, about 13.5 cP, about 14.0 cP, about 14.5 cP, or about 15.0 cP (eg, when measured at 20° C.).

[0126] Various embodiments herein do not require the inclusion of inorganic salts or other viscosity reducing agents to maintain these very useful viscosities. Typically, highly concentrated protein solutions require viscosity-lowering agents to avoid protein aggregation and high viscosity, making intravitreal injection difficult and reducing the efficacy of VEGF receptor fusion proteins. Thus, embodiments herein include sodium chloride (NaCl), magnesium chloride (MgCl 2 ), D- or L-arginine (eg, D- or L-arginine hydrochloride), lysine, or other viscosity-lowering agents.

[0127] Osmolality is an important attribute for injectable pharmaceutical formulations for use in the methods of the invention. It is desirable that the product match physiological osmotic conditions. Additionally, osmolarity provides confirmation of soluble content in solution. In embodiments of the invention, the osmolality of the formulation for use in the methods of the invention is less than or equal to about 506 mmol / Kg, or from about 250 to about 506 mmol / Kg, such as about 250, 260, 270, 280, 290, 299 , 300, 310, 314, 315, 316, 324, 343, 346, 349, 369, 384, 403, 426, 430, or 506 mmol / Kg. In one embodiment of the invention, the osmolality is less than about 250 mmol / Kg.

[0128] Exemplary pharmaceutical formulations for use in the methods of the invention include: Formulation A: 80mg / ml aflibercept, 10mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 40mM with pH 5.8-6.2. sodium chloride, Formulation B: 80 mg / ml aflibercept, 10 mM phosphate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, and pH 5.8-6.2. 40mM sodium chloride, Formulation C: 80mg / ml aflibercept, 10mM citrate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 40mM with pH 5.8-6.2. of sodium chloride, Formulation D: 80mg / ml aflibercept, 10mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80, and 40mM sodium chloride with pH 6.2. , Formulation E: 80 mg / ml aflibercept, 10 mM phosphate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80, with pH 5.8-6.2. 40mM sodium chloride, Formulation F: 80mg / ml aflibercept, 10mM citrate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80, and 40mM with pH 5.8-6.2. of sodium chloride; Formulation G: 80 mg / ml aflibercept, 10 mM histidine-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 20, with pH 5.8-6.2; If necessary, especially without viscosity reducing agents, Formulation H: 80 mg / ml aflibercept, 10 mM phosphate buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 20 with pH 5.8-6.2. Yes, if necessary, especially without viscosity reducing agents, Formulation I: 80 mg / ml aflibercept, 10 mM citrate-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 20, with pH 5.8-6.2. , optionally specifically free of viscosity reducing agents, Formulation J: 80 mg / ml aflibercept, 10 mM histidine-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 80, with pH 5.8-6.2; If necessary, especially without viscosity reducing agents, Formulation K: 80 mg / ml aflibercept, 10 mM phosphate buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 80 with pH 5.8-6.2. Yes, if necessary, especially without viscosity reducing agents, Formulation L: 80 mg / ml aflibercept, 10 mM citrate-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 80, with pH 5.8-6.2. , optionally specifically free of viscosity reducing agents, Formulation M: 150mg / ml aflibercept, 10mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 40mM with pH 5.8-6.2. sodium chloride, Formulation N: 150 mg / ml aflibercept, 10 mM phosphate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, and pH 5.8-6.2. 40mM sodium chloride, Formulation O: 150mg / ml aflibercept, 10mM citrate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 40mM with pH 5.8-6.2 of sodium chloride, Formulation P: 150mg / ml aflibercept, 10mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80, and 40mM sodium chloride with pH 6.2. , Formulation Q: 150 mg / ml aflibercept, 10 mM phosphate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80, with pH 5.8-6.2, and 40mM sodium chloride, Formulation R: 150mg / ml aflibercept, 10mM citrate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80, and 40mM with pH 5.8-6.2 of sodium chloride, Formulation S: 150 mg / ml aflibercept, 10 mM histidine-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 20, with pH 5.8-6.2; If necessary, especially without viscosity reducing agents, Formulation T: 150 mg / ml aflibercept, 10 mM phosphate buffer, 8% (w / v) sucrose, and 0.03% (w / v) with pH 5.8-6.2 (e.g. 6.2). ) polysorbate 20, optionally without any viscosity reducing agent, Formulation U: 150 mg / ml aflibercept, 10 mM citrate-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 20, with pH 5.8-6.2. , optionally specifically free of viscosity reducing agents, Formulation V: 150 mg / ml aflibercept, 10 mM histidine-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 80, with pH 5.8-6.2; If necessary, especially without viscosity reducing agents, Formulation W: 150 mg / ml aflibercept, 10 mM phosphate buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 80 with pH 5.8-6.2. Yes, if necessary, especially without viscosity reducing agents, Formulation X: 150 mg / ml aflibercept, 10 mM citrate-based buffer, 8% (w / v) sucrose, 0.03% (w / v) polysorbate 80, with pH 5.8-6.2; If necessary, especially without viscosity reducing agents, Formulation Y: 80mg / ml conbercept, 10mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 40mM sodium chloride with pH 5.8-6.2. , Formulation Z: 80mg / ml Conbercept, 10mM phosphate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 40mM with pH 5.8-6.2. sodium chloride, Formulation AA: 80mg / ml Conbercept, 10mM citrate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 40mM chloride with pH 5.8-6.2. sodium, Formulation BB: 80 mg / ml Conbercept, 10 mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80, and 40 mM sodium chloride, with pH 6.2. Formulation CC: 80mg / ml Conbercept, 10mM phosphate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80, and 40mM with pH 5.8-6.2. sodium chloride, Formulation DD: 80mg / ml Conbercept, 10mM citrate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80, and 40mM chloride with pH 5.8-6.2. sodium, Formulation EE: 80 mg / ml Conbercept, 10 mM histidine-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 20 with pH 5.8-6.2, as required. Accordingly, especially without viscosity reducing agents, Formulation FF: 80 mg / ml Conbercept, 10 mM phosphate buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 20, with pH 5.8-6.2; If necessary, especially without viscosity reducing agents, Formulation GG: 80 mg / ml Conbercept, 10 mM citrate-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 20 with pH 5.8-6.2; Depending on the product, especially without viscosity reducing agents, Formulation HH: 80 mg / ml conbercept, 10 mM histidine-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 80 with pH 5.8-6.2, as required. Accordingly, especially without viscosity reducing agents, Formulation II: 80 mg / ml Conbercept, 10 mM phosphate buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 80, with pH 5.8-6.2; If necessary, especially without viscosity reducing agents, Formulation JJ: 80 mg / ml Conbercept, 10 mM citrate-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 80 with pH 5.8-6.2; Depending on the product, especially without viscosity reducing agents, Formulation KK: 150mg / ml conbercept, 10mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 40mM sodium chloride with pH 5.8-6.2. , Formulation LL: 150mg / ml Conbercept, 10mM phosphate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 40mM with pH 5.8-6.2. sodium chloride, Formulation MM: 150mg / ml Conbercept, 10mM citrate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 40mM chloride with pH 5.8-6.2. sodium, Formulation NN: 150 mg / ml Conbercept, 10 mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80, and 40 mM sodium chloride, with pH 6.2. Formulation OO: 150mg / ml Conbercept, 10mM phosphate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80, and 40mM with pH 5.8-6.2. sodium chloride, Formulation PP: 150mg / ml Conbercept, 10mM citrate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80, and 40mM chloride with pH 5.8-6.2. sodium, Formulation QQ: 150 mg / ml Conbercept, 10 mM histidine-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 20 with pH 5.8-6.2, as required. Accordingly, especially without viscosity reducing agents, Formulation RR: 150 mg / ml Conbercept, 10 mM phosphate buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 20, with pH 5.8-6.2; If necessary, especially without viscosity reducing agents, Formulation SS: 150 mg / ml Conbercept, 10 mM citrate-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 20 with pH 5.8-6.2, as required Depending on the product, especially without viscosity reducing agents, Formulation TT: 150 mg / ml Conbercept, 10 mM histidine-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 80 with pH 5.8-6.2, as required. Accordingly, especially without viscosity reducing agents, Formulation UU: 150 mg / ml Conbercept, 10 mM phosphate buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 80, with pH 5.8-6.2; If necessary, especially without viscosity reducing agents, Formulation VV: 150 mg / ml Conbercept, 10 mM citrate buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 80 with pH 5.8-6.2, as required Depending on the product, especially without viscosity reducing agents, Formulation WW: 140 mg / ml VEGF receptor fusion protein (e.g. aflibercept), 10 mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) with pH 5.8. of polysorbate 20, and 50mM taurine, Formulation XX: 140 mg / ml VEGF receptor fusion protein (e.g. aflibercept), 20 mM histidine-based buffer, 4% (w / v) proline, 0.03% (w / v) with pH 5.8. of polysorbate 20, and 50mM arginine (e.g., arginine hydrochloride), Formulation YY: 140 mg / ml VEGF receptor fusion protein (e.g. aflibercept), 20 mM histidine-based buffer, 2.5% (w / v) sucrose, 2.0% (w / v) with pH 5.8. of proline, 0.03% (w / v) polysorbate 20, and 50mM taurine, Formulation ZZ: 140 mg / ml VEGF receptor fusion protein (e.g. aflibercept), 10 mM histidine-based buffer, 2.5% (w / v) sucrose, 2.0% (w / v) with pH 5.8. of proline, 0.03% (w / v) polysorbate 20, and 50mM arginine hydrochloride, Formulation AAA: 140 mg / ml VEGF receptor fusion protein (e.g. aflibercept), 20 mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) with pH 5.8. polysorbate 20, and 50mM PSA, Formulation BBB: 140 mg / ml VEGF receptor fusion protein (e.g. aflibercept), 20 mM histidine-based buffer, 2.5% (w / v) sucrose, 2.0% (w / v) with pH 5.8. of proline, 0.03% (w / v) polysorbate 20, and 50mM PSA, Formulation CCC: 80, 100, 120, or 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine-based buffer, 5% (w / v) sucrose, with pH 5.8. 0.03% (w / v) polysorbate 20 and 50mM arginine (e.g. arginine hydrochloride), Formulation DDD: 140 mg / ml VEGF receptor fusion protein (e.g. aflibercept), 10 mM histidine-based buffer, 4% (w / v) proline, 0.03% (w / v) with pH 5.8. polysorbate 20, and 50mM PSA, Formulation EEE: 140 mg / ml VEGF receptor fusion protein (e.g. aflibercept), 20 mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) with pH 5.8. of polysorbate 20, without heat stabilizers, if necessary. Formulation FFF: 140 mg / ml VEGF receptor fusion protein (e.g. aflibercept), 10 mM sodium phosphate, 5% (w / v) sucrose, and 0.03% polysorbate 20, with pH 6.2. Formulation GGG: 140mg / ml VEGF receptor fusion protein (e.g. aflibercept), 20mM histidine, pH 5.8, 5% sucrose, 0.03% polysorbate 20, 50mM sodium sulfate. Formulation HHH: 140mg / ml VEGF receptor fusion protein (e.g. aflibercept), 20mM histidine, pH 5.8, 5% sucrose, 0.03% polysorbate 20, 50mM sodium thiocyanate. Formulation III: 140mg / ml VEGF receptor fusion protein (e.g. aflibercept), 20mM histidine, pH 5.8, 5% sucrose, 0.03% polysorbate 20, 40mM sodium citrate. Formulation JJJ: 140mg / ml VEGF receptor fusion protein (e.g. aflibercept), 20mM histidine, pH 5.8, 5% sucrose, 0.03% polysorbate 20, 50mM glycine. Formulation KKK: 140mg / ml VEGF receptor fusion protein (e.g. aflibercept), 20mM histidine, pH 5.8, 5% sucrose, 0.03% polysorbate 20, 50mM sodium chloride. Formulation LLL: 140mg / ml VEGF receptor fusion protein (e.g. aflibercept), 20mM histidine, pH 5.8, 5% sucrose, 0.03% polysorbate 20, 50mM lysine. Formulation MMM: 140mg / ml VEGF receptor fusion protein (e.g. aflibercept), 20mM histidine, pH 5.8, 5% sucrose, 0.03% polysorbate 20, 50mM sodium aspartate. Formulation NNN: 140mg / ml VEGF receptor fusion protein (e.g. aflibercept), 20mM histidine, pH 5.8, 5% sucrose, 0.03% polysorbate 20, 50mM monosodium glutamate. Formulation OOO: 140 mg / ml VEGF receptor fusion protein (e.g. aflibercept), 20mM histidine, pH 5.8, 5% sucrose, 0.03% polysorbate 20, 50mM sodium citrate, 50mM arginine (e.g. , arginine hydrochloride) Formulation PPP: 140 mg / ml VEGF receptor fusion protein (e.g. aflibercept), 20 mM histidine, pH 5.8, 5% sucrose, 0.03% polysorbate 20, 50 mM glycine, 50 mM arginine (e.g. hydrochloride) Formulation QQQ: 140mg / ml VEGF receptor fusion protein (e.g. aflibercept), 20mM histidine, pH5.8, 5% sucrose, 0.03% polysorbate 20, 50mM sodium aspartate, 50mM arginine (e.g. , arginine hydrochloride) Formulation RRR: 140mg / ml VEGF receptor fusion protein (e.g. aflibercept), 20mM histidine, pH 5.8, 5% sucrose, 0.03% polysorbate 20, 50mM sodium glutamate, 50mM arginine (e.g. arginine hydrochloride) Formulation SSS: 140mg / ml VEGF receptor fusion protein (e.g. aflibercept), 20mM histidine, pH 5.8, 5% sucrose, 0.03% polysorbate 20, 10mM L-arginine (e.g. L-arginine hydrochloride) Formulation TTT: 140 mg / ml VEGF receptor fusion protein (e.g. aflibercept), 20 mM histidine, pH 5.8, 5% sucrose, 0.03% polysorbate 20, 100 L-arginine (L-arginine hydrochloride) Formulation UUU: 30 mg / ml VEGF receptor fusion protein (e.g. aflibercept), 10% sucrose, 10 mM phosphate, 0.03% polysorbate 20, at pH 6.2. Formulation VVV: 30 mg / ml VEGF receptor fusion protein (e.g. aflibercept), 20% sucrose, 10 mM phosphate, 0.03% polysorbate 20, at pH 6.2. Formulation WWW: 60 mg / ml VEGF receptor fusion protein (e.g. aflibercept), 10% sucrose, 10 mM phosphate, 0.03% polysorbate 20, at pH 6.2. Formulation XXX: 60 mg / ml VEGF receptor fusion protein (e.g. aflibercept), 20% sucrose, 10 mM phosphate, 0.03% polysorbate 20, at pH 6.2. Formulation YYY: 120 mg / ml VEGF receptor fusion protein (e.g. aflibercept), 10% sucrose, 10 mM phosphate, 0.03% polysorbate 20, at pH 6.2. Formulation ZZZ: 120 mg / ml VEGF receptor fusion protein (e.g. aflibercept), 20% sucrose, 10 mM phosphate, 0.03% polysorbate 20, at pH 6.2. Formulation AAAA: 120 mg / ml VEGF receptor fusion protein (e.g. aflibercept), 10% sucrose, 10 mM phosphate, 0.03% polysorbate 20, 50 mM NaCl, at pH 6.2. Formulation BBBB: 120 mg / ml VEGF receptor fusion protein (e.g. aflibercept), 20% sucrose, 10 mM phosphate, 0.03% polysorbate 20, 50 mM NaCl, at pH 6.2. Formulation CCCC: 140 mg / ml VEGF receptor fusion protein (e.g. aflibercept), 10 mM sodium phosphate, 5% sucrose, 40 mM sodium chloride, 0.03% PS20, at pH 6.2. Formulation DDDD: 80 mg / ml VEGF receptor fusion protein (e.g. aflibercept), 20 mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) with pH 5.8. of polysorbate 20, and 50mM L-arginine monohydrochloride, Formulation EEEE: 120.0 mg / ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., ±12 mg / ml), 20 mM histidine, with pH 5.8 (e.g., 5.6-6.0 or 5.5-6.1) buffer (e.g. ±2mM), 5% (w / v) sucrose (e.g. ±0.5%), 0.03% (w / v) polysorbate 20 (e.g. 0.02-0.04%), and 50mM L- arginine monohydrochloride (e.g. ±5mM), Formulation FFFF: 113.3 mg / ml VEGF receptor fusion protein (e.g. aflibercept) (e.g. 102-125 mg / ml) with pH 5.8 (e.g. 5.6-6.0 or 5.5-6.1), 20 mM histidine. system buffer (e.g. ±2mM), 5% (w / v) sucrose (e.g. ±0.5%), 0.03% (w / v) polysorbate 20 (e.g. 0.02-0.04%), and 50mM L - arginine (L-arginine monohydrochloride) (e.g. ±5mM), Formulation GGGG: 114.3 mg / ml VEGF receptor fusion protein (e.g. aflibercept) (e.g. 103-126 mg / ml), e.g. histidine, with pH 5.8 (e.g. 5.6-6.0 or 5.5-6.1) and histine-HCl in 10mM histidine-based buffer (e.g., ±1mM), 5% (w / v) sucrose (e.g., ±0.5%), 0.03% (w / v) polysorbate 20 (e.g., 0.02 ~0.04%), and 50mM L-arginine (L-arginine monohydrochloride) (e.g., ±5mM), Formulation HHHH: 100.0 mg / ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., ±10 mg / ml), 20 mM histidine, with pH 5.8 (e.g., 5.6-6.0 or 5.5-6.1) buffer (e.g. ±2mM), 5% (w / v) sucrose (e.g. ±0.5%), 0.03% (w / v) polysorbate 20 (e.g. 0.02-0.04%), and 50mM L- arginine (L-arginine monohydrochloride) (e.g. ±5mM), Formulation III: 133.3 mg / ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., ±13 mg / ml), 20 mM histidine, with pH 5.8 (e.g., 5.6-6.0 or 5.5-6.1) buffer (e.g. ±2mM), 5% (w / v) sucrose (e.g. ±0.5%), 0.03% (w / v) polysorbate 20 (e.g. 0.02-0.04%), and 50mM L- arginine (L-arginine monohydrochloride) (e.g. ±5mM), Formulation JJJJ: 150 mg / ml aflibercept (e.g., aflibercept) (e.g., ±15 mg / ml), 10 mM sodium phosphate, 8 % (w / v) sucrose (e.g. ±0.8%), 0.03% (w / v) polysorbate 20 (e.g. 0.02-0.04%), and 50 mM L-arginine (L-arginine hydrochloride), Formulation KKKK: 114.3 mg / ml VEGF receptor fusion protein (e.g. aflibercept) (e.g. ±14 mg / ml), 20 mM histidine, with pH 5.8 (e.g. 5.6-6.0 or 5.5-6.1) buffer (e.g. ±2mM), 5% (w / v) sucrose (e.g. ±0.5%), 0.03% (w / v) polysorbate 20 (e.g. 0.02-0.04%), and 50mM L- arginine monohydrochloride (e.g. ±5mM), See International Patent Application Publication No. WO2019 / 217927.

[0129] In one embodiment of the invention, 8 mg or more of a VEGF receptor fusion protein, preferably aflibercept, when administered, is administered at a concentration of at least about 100 mg / ml, immunoglobulin-like (Ig) domain 2 of VEGFR1, VEGFR2 A VEGF receptor fusion protein comprising two polypeptides each comprising an Ig domain 3 of 3 and a multimerization component (e.g., comprising amino acids 27-457 of SEQ ID NO: 2), approximately 5% sucrose, and L-arginine. (e.g., L-arginine monohydrochloride), a histidine-based buffer (e.g., containing histidine HCl), and about 0.03% surfactant, the formulation comprising about 5.0% to It has a pH of about 6.8 (eg, 5.8-6.5, eg, 5.8). Preferably, the formulation is suitable for intravitreal administration. Other ingredients that may be included are sodium sulfate, sodium thiocyanate, glycine, NaCl, sodium aspartate, and / or sodium glutamate. In one embodiment of the invention, the VEGF receptor fusion protein is about 100 mg / ml, about 111.5 mg / ml, about 112.0 mg / ml, about 113.3 mg / ml, about 114.3 mg / ml, about 115.6 mg / ml, at a concentration of about 116.3 mg / ml, about 120 mg / ml, about 133 mg / ml, about 140 mg / ml, about 150 mg / ml, about 200 mg / ml, or about 250 mg / ml. The formulation may be characterized by (i) an osmolality of about 299 to about 506 mmol / Kg, and / or (ii) a viscosity of about 6 to 15 cP at 20°C. The surfactant may be a nonionic surfactant such as polysorbate 20, polysorbate 80, poloxamer 188, polyethylene glycol 3350, or mixtures thereof. The histidine-based buffer may have a concentration of about 10mM to 20mM. In one embodiment of the invention, the VEGF receptor fusion protein contains less than about 3.5% high molecular weight species immediately after manufacture and purification and / or about 6% or less high molecular weight species after storage at about 2-8°C for about 24 months. It has molecular weight species.

[0130] In one embodiment of the invention, 8 mg or more of the VEGF receptor fusion protein is administered in an aqueous pharmaceutical formulation, the aqueous pharmaceutical formulation comprising immunoglobulin-like (Ig) domain 2 of VEGFR1, Ig domain 3 of VEGFR2, and multimeric the formulation comprises at least about 100 mg / ml of a VEGF receptor fusion protein comprising two polypeptides each containing a compound, about 10 to 100 mM L-arginine, sucrose, a histidine-based buffer, and a surfactant; With a pH of ~6.8, the VEGF receptor fusion protein contains less than about 3.5% high molecular weight species immediately after manufacture and purification and / or less than about 6% high molecular weight species after storage for about 24 months at about 2-8°C. It has high molecular weight species.

[0131] In one embodiment of the invention, the aqueous formulation comprises: · VEGF receptor fusion protein (e.g., aflibercept), histidine-based buffer, and L-arginine at about 100 mg / ml or more; · Approximately 140mg / ml aflibercept, 20mM histidine-based buffer, 5% sucrose, 0.03% polysorbate 2010mM arginine, pH 5.8, · Approximately 150±15mg / ml aflibercept, 10mM phosphate buffer, 8±0.8% (w / v) sucrose, 0.02-0.04% (w / v) polysorbate 20, and 50mM L -Arginine, pH5.9~6.5, · Approximately 103-126mg / ml aflibercept, 10±1mM histidine-based buffer, 5±0.5% (w / v) sucrose, 0.02-0.04% (w / v) polysorbate 20, and 50±5mM L-arginine, pH5.5~6.1, · Approximately 140mg / ml aflibercept, 10mM histidine-based buffer, 2.5% (w / v) sucrose, 2.0% (w / v) proline, 0.03% (w / v) polysorbate 20, and 50mM L-arginine, pH5.8, · Approximately 114.3mg / ml aflibercept, 10mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, 50mM L-arginine, pH 5.8, · Approximately 100 mg / ml or more of aflibercept, histidine-based buffer, and L-arginine, · aflibercept of about 100 mg / ml or more, pH about 5.8, where the formulation forms less than 3% HMW aggregates after 2 months incubation at 5°C; · Approximately 114.3mg / mL aflibercept, 10mM~50mM histidine-based buffer, sugar, nonionic surfactant, L-arginine, pH5.8, or · Contains approximately 114.3mg / mL aflibercept, 10mM His / His-HCl based buffer, 5% sucrose, 0.03% polysorbate-20, 50mM L-arginine, pH 5.8.

[0132] In one embodiment of the invention, when 8 mg or more of the VEGF receptor fusion protein is administered in an aqueous pharmaceutical formulation, the aqueous pharmaceutical formulation is aflibercept at a concentration of at least about 100 mg / ml (e.g., about 111.5 mg / ml, 112.0 mg / ml, 113.3 mg / ml, about 114.3 mg / ml, about 115.6 mg / ml, or about 116.3 mg / ml); sugar, amino acid, sucrose, mannitol, sorbitol, trehalose, L-proline, glycine, glycerol, taurine, or propane sulfonic acid (e.g., about 2% (w / v) to about 10% (w / v), e.g., 5 %(w / v)), Buffers that are histidine-based buffers, phosphate-based buffers, acetate-based buffers (e.g., at a concentration of about 5-25mM, e.g., 10mM or 20mM), or citrate-based buffers; For example, nonionic surfactants such as polyoxyethylene, polysorbate 20, polysorbate 80, poloxamer 188, or polyethylene glycol 3350 (e.g., about 0.02% to about 0.1% (w / v), e.g., about 0.03% ( w / v) concentration), and NaCl, MgCl 2 , a viscosity reducing agent that is D-arginine, L-arginine or lysine (e.g. at a concentration of about 10-100mM, e.g. 50mM); The formulation has a pH of about 5.0 to about 6.8 (eg, 5.0 to 6.0 or 5.8).

[0133] In one embodiment of the invention, aflibercept is in an aqueous pharmaceutical formulation of about 100 mg / ml, 101 mg / ml, 102 mg / ml, 103 mg / ml, 104 mg / ml, 105 mg / ml, 106 mg / ml, 107 mg / ml. , 108mg / ml, 109mg / ml, 110mg / ml, 111mg / ml, 112mg / ml, 113mg / ml, 113.3mg / ml, 114mg / ml, 114.1mg / ml, 114.2mg / ml, 114.3mg / ml, 114.4 mg / ml, 114.5mg / ml, 114.6mg / ml, 114.7mg / ml, 114.8mg / ml, 114.9mg / ml, 115mg / ml, 116mg / ml, 117mg / ml, 118mg / ml, 119mg / ml, 120mg / ml, 121mg / ml, 122mg / ml, 123mg / ml, 124mg / ml, 125mg / ml, 126mg / ml, 127mg / ml, 128mg / ml, 129mg / ml, 130mg / ml, 131mg / ml, 132mg / ml , 133mg / ml, 133.3mg / ml, 133.4mg / ml, 134mg / ml, 135mg / ml, 136mg / ml, 137mg / ml, 138mg / ml, 139mg / ml, 140mg / ml, 141mg / ml, 142mg / ml , 143mg / ml, 144mg / ml, 145mg / ml, 146mg / ml, 147mg / ml, 148mg / ml, 149mg / ml, 150mg / ml, 151mg / ml, 152mg / ml, 153mg / ml, 154mg / ml, 155mg / ml, 156mg / ml, 157mg / ml, 158mg / ml, 159mg / ml, 160mg / ml, 161mg / ml, 162mg / ml, 163mg / ml, 164mg / ml, 165mg / ml, 166mg / ml, 167mg / ml , 168mg / ml, 169mg / ml, 170mg / ml, 171mg / ml, 172mg / ml, 173mg / ml, 174mg / ml, 175mg / ml, 176mg / ml, 177mg / ml, 178mg / ml, 179mg / ml, 180mg / ml, 181mg / ml, 182mg / ml, 183mg / ml, 184mg / ml, 185mg / ml, 186mg / ml, 187mg / ml, 188mg / ml, 189mg / ml, 190mg / ml, 191mg / ml, 192mg / ml , 193mg / ml, 194mg / ml, 195mg / ml, 196mg / ml, 197mg / ml, 198mg / ml, 199mg / ml, 200mg / ml, 201mg / ml, 202mg / ml, 203mg / ml, 204mg / ml, 205mg / ml, 206mg / ml, 207mg / ml, 208mg / ml, 209mg / ml, 210mg / ml, 211mg / ml, 212mg / ml, 213mg / ml, 214mg / ml, 215mg / ml, 216mg / ml, 217mg / ml , 218mg / ml, 219mg / ml, 220mg / ml, 221mg / ml, 222mg / ml, 223mg / ml, 224mg / ml, 225mg / ml, 226mg / ml, 227mg / ml, 228mg / ml, 229mg / ml, 230mg / ml, 231mg / ml, 232mg / ml, 233mg / ml, 234mg / ml, 235mg / ml, 236mg / ml, 237mg / ml, 238mg / ml, 239mg / ml, 240mg / ml, 241mg / ml, 242mg / ml , 243mg / ml, 244mg / ml, 245mg / ml, 246mg / ml, 247mg / ml, 248mg / ml, 249mg / ml, 250mg / ml, 251mg / ml, 252mg / ml, 253mg / ml, 254mg / ml, 255mg / ml, 256mg / ml, 257mg / ml, 258mg / ml, 259mg / ml, 260mg / ml, 261mg / ml, 262mg / ml, 263mg / ml, 264mg / ml, 265mg / ml, 266mg / ml, 267mg / ml , 268 mg / ml, 269 mg / ml, 270 mg / ml, 271 mg / ml, 272 mg / ml, 273 mg / ml, 274 mg / ml, or 275 mg / ml.

[0134] In one embodiment of the invention, the aqueous pharmaceutical formulation comprises aflibercept at a concentration of at least about 100 mg / ml, sucrose, mannitol, sorbitol, trehalose, a histidine-based buffer, polysorbate 20 or polysorbate 80, L- arginine at a pH of about 5.0 to about 6.8, and aflibercept contains less than about 3.5% high molecular weight species immediately after manufacture and purification and / or about 6% after storage at about 2 to 8°C for about 24 months. % or less of high molecular weight species.

[0135] In one embodiment of the invention, sucrose, mannitol, sorbitol, or trehalose is at a concentration of about 2-10% (w / v), L-arginine is at a concentration of about 10-100 mM, and polysorbate 20 or Polysorbate 80 has a concentration of about 0.02 to 0.1% (w / v), and the histidine-based buffer has a concentration of about 5 to 25 mM, and a pH of about 5.0 to about 6.8.

[0136] Treatment and administration The present invention provides an initial loading dose (e.g., 2 mg or more, 4 mg or more, or preferably 8 mg or more of a VEGF antagonist or inhibitor, e.g., a VEGF receptor fusion protein such as aflibercept) (e.g., about 2 to 4 mg or more). Angiogenic eye disorders ( For example, methods of treating neovascular age-related macular degeneration (nAMD) are provided. For example, the present invention provides methods of treating neovascular age-related macular degeneration (nAMD). a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) at a dose of about 8 mg or more every 5 days, or about every 4 weeks) in one or more consecutive (e.g., 3 or 4 or 5 doses) administration, followed by one or more doses of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) of about 8 mg or more every 12 weeks (or about 3 months or about 1 / 4 year) or about every 84 days) or every 16 weeks (or about every 4 months, or about 1 / 3 year, or about 112 days), or every 20 weeks. A dosing regimen comprising a tertiary dose interval of 12 weeks may be referred to herein as a 12 week dosing regimen or 8q12 or HDq12. Dosing regimens comprising tertiary dose intervals of 20 weeks may be referred to herein as 16 week dosing regimens or 8q16 or HDq16, and dosing regimens comprising 20 week tertiary dose intervals may be referred to herein as 20 week dosing regimens or 8q20 or HDq20. A dosing regimen that includes a tertiary dose interval of 12 to 20 weeks may be referred to herein as a 12 to 20 week dosing regimen or 8q12-20 or HDq12-20.

[0137] In addition, the present invention provides for administering 8 mg or more of a VEGF receptor fusion protein, preferably aflibercept, every 4 weeks, 8 weeks, 12-20 weeks, 12-16 weeks, 12 weeks, or 16 weeks, as well as initially every 4 weeks for 3, 4, or 5 doses, followed by one or more doses about every 8 weeks to treat neovascular eye disorders (e.g. Includes methods of treating macular degeneration (nAMD).

[0138] In one embodiment of the invention, the subject begins receiving a monthly loading dose of 8 mg or more followed by a maintenance dose of 8 mg or more every 12 or 16 or 20 weeks without an intervention dose. Subjects will enter a maintenance dose phase immediately following the loading dose phase. In one embodiment of the invention, the subject continues to receive doses of 8 mg or more every 12-20, 12 or 16 or 20 weeks without any intervention doses.

[0139] In one embodiment of the invention, the subject does not undergo a dosing regimen modification (DRM) or complete treatment for at least 1, 2, 3, 4, or 5 years.

[0140] The terms "initial dose," "secondary dose," and "tertiary dose" refer to the time sequence of administration of a VEGF antagonist (eg, a VEGF receptor fusion protein such as aflibercept). Accordingly, an "initial dose" is the dose administered at the beginning of a treatment regimen (also referred to as the "baseline dose"). A "secondary dose" is a dose administered after the initial dose, and a "tertiary dose" is a dose administered after the second dose. The primary, secondary, and tertiary doses may all contain the same amount of VEGF antagonist (eg, a VEGF receptor fusion protein such as aflibercept), but generally may differ from each other in terms of frequency of administration. However, in certain embodiments, the amount of VEGF antagonist (e.g., VEGF receptor fusion protein, such as aflibercept) included in the initial dose, secondary dose, and / or tertiary dose differs from each other during the course of treatment. (e.g. adjusted up or down as needed).

[0141] Therefore, the dosing regimen of the present invention can be expressed as follows.

[0142] Method (I) for treating a neovascular eye disorder (e.g., nAMD) in a subject in need thereof comprises: A single initial dose of about 8 mg or more (about 100 μl or less, about 75 μl or less, or about 70 μl or less, such as about 50 μl, 51 μl, 52 μl, 53 μl, 54 μl, 55 μl, 56 μl, 57 μl, 58 μl, 59 μl, 60 μl, 61 μl, 62 μl, 63μl, 64μl, 65μl, 66μl, 67μl, 68μl, 69μl, 70μl, 71μl, 72μl, 73μl, 74μl, 75μl, 76μl, 77μl, 78μl, 79μl, 80μl, 81μl, 82μl, 83μl, 84μl, 85μl, 86μl, 8 7μl, VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), followed by one or more (e.g. two, or three or four, preferably two) secondary doses of a VEGF antagonist (e.g. a VEGF receptor fusion protein such as aflibercept), followed by comprising administering (e.g., intravitreally) one or more tertiary doses of a VEGF receptor fusion protein such as a VEGF antagonist (e.g., aflibercept); each secondary dose is administered about 2 to 4 weeks (preferably 4 weeks) after the immediately preceding dose; Each of the tertiary doses is administered at least 12 or 16 or 20 weeks (preferably 12-20, 12-16, 12, or 16 weeks) after the immediately preceding dose.

[0143] The invention provides that in addition to any of the scheduled initial, secondary, and / or tertiary doses of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), one or more additional scheduled including methods in which a dose that is not administered to a subject is administered to a subject. Such doses are typically administered at the discretion of the treating physician, depending on the particular needs of the subject. The present invention also provides a subject in need thereof with a dose of about 8 mg or more (e.g., about 100 μl or less, about 75 μl or less, or about 70 μl or less, such as about 50 μl, 51 μl, 52 μl, 53 μl, 54 μl, 55 μl, 56 μl, 57 μl, 58 μl) , 59μl, 60μl, 61μl, 62μl, 63μl, 64μl, 65μl, 66μl, 67μl, 68μl, 69μl, 70μl, 71μl, 72μl, 73μl, 74μl, 75μl, 76μl, 77μl, 78μl, 79μl, 80μl, 81μl, 82μl, 83μl , 84μl, 85μl, 86μl, 87μl, 88μl, 89μl, 90μl, 91μl, 92μl, 93μl, 94μl, 95μl, 96μl, 97μl, 98μl, 99μl, or 100μl) of VEGF antagonists (e.g. VEGF receptors such as aflibercept) fusion proteins), thereby providing methods for treating neovascular eye disorders based on PRN.

[0144] pro re nata (PRN) treatment protocols are based on a fixed interval between physician visits (e.g., once every 2, 3, 4, 8, 12, 16, or 20 weeks) and an anatomical Requires a decision to perform an injection of the VEGF receptor fusion protein based on the findings. A capped PRN dosing regimen is a PRN in which the subject must be treated with a certain minimum frequency, for example, at least once every 2 or 3 or 4 months.

[0145] Treat & Extend (T&E) regimens require adjusting the time interval between physician visits based on the patient's clinical course, e.g., if the subject does not show signs of active disease (e.g., the macula remains dry). (and there are no leaks), the next one or more intervals can be extended. If there is fluid accumulation, the next interval will be shortened. At each post-T&E visit, an injection of VEGF receptor fusion protein is given, and only the current clinical condition influences the duration of the next injection interval.

[0146] The invention includes embodiments in which a patient can be switched to a PRN, capped PRN, or T&E regimen at any point during the HDq12-20, HDq12, HDq16, or HDq20 treatment regimen. PRN, capped PRN, and / or T&E may be continued indefinitely or stopped at any time and the HDq12, HDq16, or HDq20 regimen then resumed at any stage. . There may be a period of PRN, capped PRN, and / or T&E before or after any HDq12-20, HDq12, HDq16 or HDq20 regimen.

[0147] The present invention provides a method comprising administering the required doses of an HDq12-20 or HDq12 or HDq16 or HDq20 regimen, wherein each tertiary dose is administered 12 to 20 or 12 or 16 or 20 weeks after the immediately preceding dose. , the treatment interval between two tertiary doses increases until signs of disease activity or visual impairment worsen or recur (e.g., from 12 weeks to 13, 14, 15, 16, or 20 weeks, or from 16 weeks to 17 weeks). , 18, 19, or 20 weeks) and then continuing dosing at the last tertiary interval used or the penultimate tertiary interval used. In one embodiment of the invention, the subject undergoes an initial, secondary, and then tertiary interval of 12 or 16 weeks, and then extends the tertiary interval to about 20 weeks after about 1 year.

[0148] The invention includes a method comprising administering a required dose of an HDq12-20 or HDq12 or HDq16 or HDq20 regimen, wherein the treatment interval between any two tertiary doses is such that signs of disease activity or visual impairment improve. (e.g., until BCVA stabilizes or improves and / or CRT stabilizes or decreases) (e.g., from 20 weeks to 8, 12, or 16 weeks, or from 16 weeks to 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 weeks, or from 12 weeks to 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 weeks ), then optionally the interval between doses may be extended, eg, back to a longer interval length.

[0149] For example, in one embodiment of the invention, during administration phases of, for example, 12 to 20, 12 weeks or 16 weeks or 20 weeks, the dose interval is · For example, persistent or worsening AMD may result in a loss of >5 letters of BCVA (ETDRS or Snellen equivalent table) (e.g., compared to the BCVA observed approximately 12 weeks after initiation of treatment). and / or · A CRT increase of >25 micrometers is observed (e.g., compared to CRT observed approximately 12 weeks after initiation of treatment) and / or new-onset foveal neovascularization or fovea Can be shortened (eg, to 8 weeks) if bleeding is observed.

[0150] In one embodiment of the invention, the interval between doses is shortened to 8 weeks if the criteria for shortening the interval between doses are met in subjects receiving the HDq12 regimen at week 16 or week 20.

[0151] In one embodiment of the invention, if the criteria for shortening the interval between doses is met in subjects receiving the HDq16 regimen at week 16 or week 20, the interval between doses is shortened to 8 weeks and at week 24. If the criteria for shortening the interdose interval are met in subjects receiving an HDq16 regimen in the eyes, the interval between doses will be shortened to 12 weeks.

[0152] In one embodiment of the invention, the interval is not reduced to less than 8 weeks.

[0153] For example, in one embodiment of the invention, the interval between doses during the administration phase, e.g. It can be extended to 16 weeks or from 16 weeks to 20 weeks. · BCVA decrease of less than 5 letters (e.g. from week 12), · No fluid in the central subfield, e.g. OCT and / or · No new onset foveal hemorrhage or foveal neovascularization (e.g. if all three criteria are met).

[0154] Please refer to Figure 3 or Figure 4.

[0155] The present invention also provides A dose of about 8 mg or more (e.g., about 100 μl or less, about 75 μl or less, or about 70 μl or less, such as about 50 μl, 51 μl, 52 μl, 53 μl, 54 μl, 55 μl, 56 μl, 57 μl, 58 μl, 59 μl, 60 μl, 61 μl, 62 μl, 63μl, 64μl, 65μl, 66μl, 67μl, 68μl, 69μl, 70μl, 71μl, 72μl, 73μl, 74μl, 75μl, 76μl, 77μl, 78μl, 79μl, 80μl, 81μl, 82μl, 83μl, 84μl, 85μl, 86μl, 8 7μl, 88μl, 89μl, 90μl, 91μl, 92μl, 93μl, 94μl, 95μl, 96μl, 97μl, 98μl, 99μl, or 100μl) about 1 every 4, 5, 6, 7, 8, 12, 16, or 20 weeks. to be administered twice; or A single initial dose (e.g., about 8 mg or more, such as about 100 μl or less, about 75 μl or less, or about 70 μl or less, such as about 50 μl, 51 μl, 52 μl, 53 μl, 54 μl, 55 μl, 56 μl, 57 μl, 58 μl, 59 μl, 60 μl) , 61μl, 62μl, 63μl, 64μl, 65μl, 66μl, 67μl, 68μl, 69μl, 70μl, 71μl, 72μl, 73μl, 74μl, 75μl, 76μl, 77μl, 78μl, 79μl, 80μl, 81μl, 82μl, 83μl, 84μl, 85μl , 86 μl, 87 μl, 88 μl, 89 μl, 90 μl, 91 μl, 92 μl, 93 μl, 94 μl, 95 μl, 96 μl, 97 μl, 98 μl, 99 μl, or 100 μl) of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept); continue, one or more (e.g. two or three or four, preferably two or four) secondary doses of a VEGF antagonist (e.g. a VEGF receptor fusion protein such as aflibercept), followed by administering one or more tertiary doses of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), comprising: each secondary dose is administered about 2 to 4 weeks (preferably 4 weeks) after the immediately preceding dose; each of the tertiary doses is administered about 4, 5, 6, 7, or 8 (e.g., 8) weeks after the immediately preceding dose; or about 8 mg or more (e.g., about 100 μl or less, about 75 μl or less, or about 70 μl or less, (e.g., about 50 μl, 51 μl, 52 μl, 53 μl, 54 μl, 55 μl, 56 μl, 57 μl, 58 μl, 59 μl, 60 μl, 61 μl, 62 μl, 63 μl) , 64μl, 65μl, 66μl, 67μl, 68μl, 69μl, 70μl, 71μl, 72μl, 73μl, 74μl, 75μl, 76μl, 77μl, 78μl, 79μl, 80μl, 81μl, 82μl, 83μl, 84μl, 85μl, 86μl, 87μl, 88μl , 89 μl, 90 μl, 91 μl, 92 μl, 93 μl, 94 μl, 95 μl, 96 μl, 97 μl, 98 μl, 99 μl, or 100 μl) of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) approximately every 4 weeks. administering times (q4w); or less than about 8 doses (e.g., about 5 doses or 6 doses), about 8 mg or more (e.g., less than or equal to about 100 μl, less than or equal to about 75 μl, or less than or equal to about 70 μl, such as about 50 μl, 51 μl, 52 μl, 53 μl, 54 μl, 55 μl, 56 μl) , 57μl, 58μl, 59μl, 60μl, 61μl, 62μl, 63μl, 64μl, 65μl, 66μl, 67μl, 68μl, 69μl, 70μl, 71μl, 72μl, 73μl, 74μl, 75μl, 76μl, 77μl, 78μl, 79μl, 80μl, 81μl , 82 μl, 83 μl, 84 μl, 85 μl, 86 μl, 87 μl, 88 μl, 89 μl, 90 μl, 91 μl, 92 μl, 93 μl, 94 μl, 95 μl, 96 μl, 97 μl, 98 μl, 99 μl, or 100 μl) of a VEGF antagonist (e.g., aflibercept) VEGF receptor fusion protein) for about 48 weeks.

[0156] Administration every "month" or after "months" refers to administration after about 28 days, about 4 weeks, or about 28 (±5 days), and can include up to 5 weeks (±5 days).

[0157] Administration “every 4 weeks” or after “4 weeks” refers to administration approximately 28 days (± 5 days), approximately 1 month or approximately 28 days (± 5 days), up to a maximum of 5 weeks (± 5 days) It can include up to every time.

[0158] Administration “every 2 to 4 weeks” or after “2 to 4 weeks” refers to administration after about 2 weeks (±5 days), 3 weeks (±5 days), or 4 weeks (±5 days).

[0159] Administration “every 8 weeks” or after “8 weeks” refers to administration after about 2 months (±5 days) or about 56 days (±5 days).

[0160] Administration “every 12 weeks” or after “12 weeks” means administration after about 3 months, about 84 days (±5 days), about 90 days (±5 days), or about 84 days (±5 days). Point.

[0161] Administration “every 16 weeks” or after “16 weeks” refers to administration after about 4 months or about 112 days (±5 days).

[0162] Administration “every 12 to 20 weeks” or after “12 to 20 weeks” means about 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks (±5 days), preferably about 12 to 20 weeks. Refers to administration after 16 weeks (±5 days), about 12 weeks (±5 days), about 16 weeks (±5 days), or about 20 weeks (±5 days).

[0163] Administration “every 12 to 20 weeks” means about 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks (±5 days), preferably about 12 to 16 weeks (±5 days) , refers to administration after about 12 weeks (±5 days), about 16 weeks (±5 days), or about 20 weeks (±5 days).

[0164] Doses of 8 mg or more include doses of about 8 mg or more than 8 mg, such as about 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg.

[0165] Any dosing frequency specified herein may be expressed as a dosing frequency of "±5 days" in one embodiment of the invention. (For example, if "4 weeks" is stated, the invention also includes embodiments such as 4 weeks ± 5 days). The phrase ±5 days includes ±1, ±2, ±3, ±4, and / or ±5 days.

[0166] As used in the present invention, "sequentially administered" means that each dose of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) is administered at different times, e.g., at predetermined intervals (e.g., several hours). , days, weeks, or months). The present invention provides a method of administering a single initial dose of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) to the eye of a subject, followed by administering a single initial dose of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) to the eye of a subject. Methods comprising sequentially administering one or more secondary doses followed by one or more tertiary doses of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) .

[0167] An effective or therapeutically effective dose of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) to treat or prevent neovascular eye disorders is determined to reduce or eliminate such signs and / or symptoms. alleviating one or more signs and / or symptoms of the disease or condition in the subject being treated, whether by inducing or inhibiting the progression of such signs and / or symptoms; refers to the amount of a VEGF antagonist (eg, a VEGF receptor fusion protein such as aflibercept) sufficient to In one embodiment of the invention, an effective or therapeutically effective dose of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) is about 8 mg or more three times monthly for 12 to 20 weeks. Once every time. In one embodiment of the invention, alleviation of signs and / or symptoms is, for example, a gain in BCVA of 5 or more, 10, or 15 characters (relative to baseline) by 1 year (e.g., in patients with nAMD). Achievement of BCVA of 69 or more letters, Achievement of no central foveal fluid, Central Retinal Thickness (CRT) of about 150 micrometers or more (e.g., less than 300 micrometers reduction in nAMD subjects / patients and / or at least about 200 micrometers reduction in DR or RVO patients / subjects) or achieving normal CRT (e.g., reduction of approximately 300 micrometers or less) and / or the achievement of no leakage in fluorescein angiography.

[0168] In one embodiment of the invention, for example, by week 60 after initiation of treatment, subjects receiving HDq12-20, HDq16, or HDq16 receive one month or one quarter more Receive fewer injections each month. For example, subjects receiving HDq12 will receive about 7 injections over 60 weeks, and / or subjects receiving HDq16 regimen will receive about 6 injections over 60 weeks.

[0169] "Angiogenic eye disorder" means any disease of the eye caused by or associated with the growth or proliferation of blood vessels and / or by vascular leakage. Non-limiting examples of neovascular eye disorders treatable or preventable using the formulations and methods herein include: · Age-related macular degeneration (neovascular (nAMD)), · Macular edema (ME), · Macular edema after retinal vein occlusion (ME-RVO), · Retinal vein occlusion (RVO), · Central retinal vein occlusion (CRVO), · Branch retinal vein occlusion (BRVO), · Diabetic macular edema (DME), · Choroidal neovascularization (CNV), · Iris neovascularization, · Neovascular glaucoma, · Postoperative fibrosis of glaucoma, · Proliferative vitreoretinopathy (PVR), · Optic disc neovascularization, · Corneal neovascularization, · Retinal neovascularization, · Vitreous neovascularization, · pannus, · Optionally, polypoidal choroidal vasculopathy (PCV), where the subject also has nAMD; · Pterygium, · Vascular retinopathy, Diabetic retinopathy (e.g., non-proliferative diabetic retinopathy (e.g., characterized by a Diabetic Retinopathy Severity Scale (DRSS) level of about 47 or 53) or proliferative diabetic retinopathy, e.g., DME subjects not affected by ), and · Diabetic retinopathy in subjects with diabetic macular edema (DME).

[0170] The present invention provides a method for treating a neovascular eye disorder (e.g., nAMD) in a subject in need thereof, the method comprising an initial loading dose (e.g., 2 mg or more, 4 mg or more, or preferably about 8 mg or more). or more VEGF antagonist or inhibitor, e.g., a VEGF receptor fusion protein such as aflibercept) (e.g., about every 2 to 4 or 3 to 5 weeks, preferably every 4 weeks, preferably 3 initial doses) dosage), followed by consecutive administrations every 12 to 20 weeks, preferably every 12 to 16 weeks, 12 weeks, 16 weeks, or 20 weeks, and the subject receives, for example, 4, 8, Until week 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, or 96: achieve and / or maintain; · as measured by the Early Treatment Diabetic Retinopathy Screening (ETDRS) visual acuity chart (e.g., 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60 , 64, 68, 72, 76, 80, 84, 88, 92, or 96 weeks) 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 characters, or 5 or more characters , BCVA increase of 10 or more, 15 or 20 characters, or lack of BCVA loss during the course of the procedure; · Dosage regimens are not subject to modification, e.g., intervals between doses (e.g., tertiary doses) once initiated, e.g., for at least 48, 60, or 96 weeks, HDq12-20 or HDq12 or HDq16 or HDq20 treatment regimens. will be reduced from · For example, 100% of all scheduled doses are administered for at least 48, 60 or 96 weeks; · Increase in BCVA averaged over a 12-week period, e.g. by week 36 or week 48; · If the subject has nAMD and PCV (e.g., 4th, 8th, 12th, 16th, 20th, 24th, 28th, 32nd, 36th, 40th, 44th, 48th, 52th, 56th, 60th, 64th, 68th, 72th, by week 76, 80, 84, 88, 92, or 96) no intraretinal fluid (IRF) and / or no subretinal fluid and / or no subretinal epithelial fluid; For example, if the subject has nAMD and PCV (e.g., after the start of treatment, e.g. By weeks 60, 64, 68, 72, 76, 80, 84, 88, 92 or 96) fluid (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF] and / or or retina without subretinal epithelial fluid), · (For example, approximately 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, by week 84, 88, 92 or 96) no subretinal pigment epithelial fluid; · (For example, approximately 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, by week 84, 88, 92, or 96) absence of fluid leak by fluorescein angiography (FA); · For example, the baseline size is approximately 6 or 6.5mm 2 (e.g., 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, by week 80, 84, 88, 92, or 96) approximately 2.9, 3, 3.5, 3.65, or 4 mm 2 reduction in choroid neovascularization (CNV) size, · (e.g. 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84 , by weeks 88, 92, or 96) reduction in total lesion CNV area from baseline; · (e.g. 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84 , by week 88, 92 or 96), e.g. loss of central subfield IRF and / or SRF, · (e.g. 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84 , by weeks 88, 92, or 96), e.g., a decrease in central subfield retinal thickness (CST) of approximately 125, 150, 175, or 200 micrometers; · (e.g. 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84 , by weeks 88, 92, or 96) of approximately 3 or 4 points of vision-related quality of life, as measured by the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25). improvement (e.g., baseline score is about 76 or 77), · (e.g. 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84 , up to week 88, 92, or 96) of treatment-induced adverse effects such as increased blood pressure, increased intraocular pressure, blurred vision, vitreous floaters, vitreous detachment, iris neovascularization, and / or vitreous hemorrhage. Absence of treatment-induced adverse events (AEs) and / or serious AEs (SAEs), e.g., treatment-induced adverse events occurring at any time within 30 days after injection; · (e.g. 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84 , by week 88, 92, or 96) of at least 69 (approximately 20 / 40 Snellen equivalent table), and / or · Aflibercept administered intravitreally at 2 mg approximately every 4 weeks for the first 3 months, followed by 2 mg approximately once every 8 weeks or once every 2 months in subjects with nAMD. For example, efficacy is measured as an improvement in BCVA and / or reduction in central retinal thickness, and safety is measured as an increase in blood pressure, increased intraocular pressure, visual impairment, vitreous disease, vitreous measured as the incidence of adverse events (treatment-emergent events occurring any time within 30 days after injection) such as corporal detachment, iris neovascularization, and / or vitreous hemorrhage;

[0171] The present invention provides a method for treating a neovascular eye disorder (e.g., nAMD) in a subject in need thereof, the method comprising an initial loading dose (e.g., 2 mg or more, 4 mg or more, or preferably about 8 mg or more). or more VEGF antagonist or inhibitor, e.g., a VEGF receptor fusion protein such as aflibercept) (e.g., about every 2 to 4 or 3 to 5 weeks, preferably every 4 weeks, preferably 3 initial doses) dosage), followed by consecutive administrations every 12 to 20 weeks, preferably every 12 to 16 weeks, 12 weeks, 16 weeks, or 20 weeks, and the subject receives, for example, 4, 8, By week 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, or 96: achieve and / or maintain · Undetected anti-drug antibodies (e.g. anti-aflibercept) while undergoing treatment; · After the start of treatment 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92 , or improvement in best-corrected visual acuity (BVCA) by week 96, (e.g. 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, (by week 88, 92, or 96) e.g., 2 or more letters, 3 or more letters, 4 or more letters, 5 or more letters, as measured by the Early Treatment Diabetic Retinopathy Screen (ETDRS) eye chart or Snellen equivalent, Improved BCVA of 6 or more characters or 7 or more characters, BCVA of approximately 2 or 3 letters (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 3 letters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens by week 4 after initiation of treatment improvement, BCVA of approximately 5 letters (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 4 or 5 letters (ETDRS or Snellen equivalent table) for HDq16 regimens by week 8 after initiation of treatment improvement, · By week 12 after starting treatment, approximately 5 or 6 letters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 5 or 6 letters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens. Table) improvement, · By week 16 after initiation of treatment, approximately 6 letters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 6 or 7 letters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens improvement, · Improvement in BCVA (ETDRS or Snellen Equivalent Table) by approximately 6 letters for the HDq12 regimen or approximately 6 letters for the HDq16 regimen (ETDRS or Snellen Equivalent Table) by week 20 after initiation of treatment , · By week 24 after starting treatment, approximately 5 or 6 letters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 5 or 6 letters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens. Table) improvement, · Improvement in BCVA (ETDRS or Snellen Equivalent Table) by approximately 7 letters for HDq12 regimens or approximately 6 letters for HDq16 regimens (ETDRS or Snellen Equivalent Tables) by week 28 after initiation of treatment , BCVA of approximately 6 or 7 characters (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 7 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens by week 32 after initiation of treatment improvement, · By week 36 after initiation of treatment, approximately 6 or 7 letters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 6 letters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens improvement, · By week 40 after the start of treatment, approximately 6 or 7 letters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 5 or 6 letters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens. Table) improvement, · By week 44 after initiation of treatment, BCVA of approximately 7 characters (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 5 or 6 characters (ETDRS or Snellen equivalent table) for HDq16 regimens improvement, BCVA of approximately 6 or 7 letters (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 6 letters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens by week 48 after initiation of treatment improvement, · By week 52 after the start of treatment, approximately 7 or 8 letters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 6 or 7 letters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens. Table) improvement, · By week 56 after the start of treatment, approximately 6 or 7 letters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 6 or 7 letters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens. Table) improvement, · By week 60 after the start of treatment, approximately 6 or 7 letters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 6 or 7 letters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens. Table) improvement, · By approximately 36 to 48 weeks after initiation of treatment, an improvement in BCVA of approximately 6 or 7 letters for HDq12 regimens or up to 46 letters of BCVA (ETDRS or Snellen equivalent table) or for HDq16 regimens. Improved BCVA of approximately 6 or 7 characters or up to 40 characters (ETDRS or Snellen equivalent table); · By 48 to approximately 60 weeks after initiation of treatment, an improvement in BCVA of approximately 6 or 7 letters for HDq12 regimens or up to 46 letters of BCVA (ETDRS or Snellen equivalent table) or for HDq16 regimens. Improved BCVA of approximately 6 or 7 characters or up to 40 characters (ETDRS or Snellen equivalent table); · Improvement in BCVA (ETDRS or Snellen equivalent table) of at least approximately 5, 10, or 15 letters for HDq12 or HDq16 regimens by week 48 or 60 after initiation of treatment; · No loss of 5, 10 or 15 letters of BCVA (ETDRS letters or Snellen equivalent table) for HDq12 or HDq16 regimens by 48 or 60 or 96 weeks after initiation of treatment; · An improvement in BCVA (within approximately ±1 or ±2 ETDRS letters or Snellen equivalent tables) is achieved by approximately 8, 9, 10, 11, or 12 weeks after initiation of treatment and during subsequent treatment regimens, e.g. maintained until 48 weeks, · By approximately week 48 or week 60, BCVA (ETDRS letters or Snellen equivalent table) of at least 69 letters if receiving HDq12 or HDq16 regimens; · By week 4 after initiation of treatment, BCVA of approximately 63 characters (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 63 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens; · By week 8 after starting treatment, approximately 65 characters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 65 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens; · By week 12 after initiation of treatment, BCVA of approximately 66 characters (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens; · By week 16 after initiation of treatment, BCVA of approximately 66 characters (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens; · By week 20 after initiation of treatment, BCVA of approximately 66 characters (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens; · By week 24 after initiation of treatment, BCVA of approximately 66 characters (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens; · By week 28 after initiation of treatment, approximately 67 characters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens; · By week 32 after initiation of treatment, approximately 67 characters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 67 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens; · By week 36 after initiation of treatment, approximately 67 characters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens; · By week 40 after initiation of treatment, approximately 67 characters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens; · By week 44 after initiation of treatment, BCVA of approximately 68 characters (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens; · By week 48 after initiation of treatment, approximately 67 characters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens; · BCVA (ETDRS or Snellen equivalent table) of approximately 66, 67, 68, 69, 70, 71, or 72 characters or up to 91 characters for HDq12 regimens from 36 to 48 weeks after initiation of treatment; · BCVA (ETDRS or Snellen equivalent table) of approximately 66, 67, 68, 69, or 70 characters or up to 94 characters for HDq16 regimens from 36 to 48 weeks after initiation of treatment; BCVA (ETDRS or Snellen equivalent table) of approximately 66, 67, 68, 69, 70, 71, or 72 characters or up to 91 characters for HDq12 regimens from 48 to 60 weeks after initiation of treatment; BCVA (ETDRS or Snellen equivalent table) of approximately 66, 67, 68, 69, or 70 characters or up to 94 characters for HDq16 regimens from 48 to 60 weeks after initiation of treatment; · By approximately 48 weeks, for example, if the baseline BCVA is 54 characters or less, an improvement in BCVA of approximately 7, 8, 9, 10, or 11 characters (ETDRS or Snellen equivalent table); · By approximately 48 weeks, for example, an improvement in BCVA of approximately 5, 6, or 7 characters (ETDRS or Snellen equivalent table) if baseline BCVA is 55-73 characters or less; · By approximately 48 weeks, for example, if the baseline BCVA is approximately 74 characters or greater, an improvement in BCVA of approximately 1, 2, or 3 characters (ETDRS or Snellen equivalent table); · By approximately 48 weeks, for example, if baseline BCVA is approximately 63 characters or less and baseline CRT is less than 400 micrometers, BCVA improvement of approximately 4, 5, or 6 characters (ETDRS or Snellen equivalent) table), · By approximately 48 weeks, for example, if the baseline BCVA is approximately 52-53 letters or less and the baseline CRT is 400 micrometers or greater, a BCVA of approximately 5, 6, 7, 8, or 9 letters. Improvement (ETDRS or Snellen equivalent table), · By about 48 weeks, for example, if the baseline BCVA is about 56, 57, or 58 letters and the subject has minimal classical CNV, the BCVA of about 2, 3, 4, 5, or 6 letters ( ETDRS or Snellen equivalent table) improvements, · By about 48 weeks, for example, if the baseline BCVA is about 62, 63, or 64 letters and the subject has subclinical CNV, an improvement in BCVA (ETDRS or Snellen equivalent table) of about 5 letters; · By approximately 48 weeks, for example, if the baseline BCVA is approximately 53 or 54 characters and the subject has a predominant classical CNV, the BCVA of approximately 6, 7, 8, 9, or 10 characters (ETDRS or Snellen equivalent table) improvement, · By week 52 after the start of treatment, approximately 67 or 68 characters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 or 67 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens. table), · By week 56 after the start of treatment, approximately 66 or 67 characters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 or 67 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens. table), · By week 60 after the start of treatment, approximately 66 or 67 characters of BCVA (ETDRS or Snellen equivalent table) for HDq12 regimens or approximately 66 or 67 characters of BCVA (ETDRS or Snellen equivalent table) for HDq16 regimens. table), · By 48 to about 60 weeks after initiation of treatment, a BCVA of about 66 to about 72 letters (ETDRS or Snellen equivalent table) for HDq12 regimens or about 66 to about 70 letters for HDq16 regimens (ETDRS or Snellen equivalent table), · In subjects with polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (nAMD), approximately 59 letter BCVA (ETDRS ) (e.g., baseline BCVA is approximately 57 characters) and / or BCVA (ETDRS) of approximately 64 characters when receiving HDq16 regimen (e.g., baseline BCVA is approximately 60 characters); · In subjects with polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (nAMD), approximately 63 letters of BCVA ( ETDRS) (e.g., baseline BCVA is approximately 57 characters) and / or BCVA (ETDRS) of approximately 65 characters when receiving HDq16 regimen (e.g., baseline BCVA is approximately 60 characters); · In subjects with polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (nAMD), approximately 63 letters of BCVA ( ETDRS) (e.g., baseline BCVA is approximately 57 characters) and / or BCVA (ETDRS) of approximately 66 characters when receiving HDq16 regimen (e.g., baseline BCVA is approximately 60 characters); · In subjects with polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (nAMD), approximately 64-letter BCVA (ETDRS ) (e.g., baseline BCVA is approximately 57 characters) and / or BCVA (ETDRS) of approximately 67 characters when receiving HDq16 regimen (e.g., baseline BCVA is approximately 60 characters); · In subjects with polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (nAMD), approximately 64-letter BCVA ( ETDRS) (e.g., baseline BCVA is approximately 57 characters) and / or BCVA (ETDRS) of approximately 68 characters when receiving HDq16 regimen (e.g., baseline BCVA is approximately 60 characters); · In subjects with polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (nAMD), approximately 64-letter BCVA ( ETDRS) (e.g., baseline BCVA is approximately 57 characters) and / or BCVA (ETDRS) of approximately 67 characters when receiving HDq16 regimen (e.g., baseline BCVA is approximately 60 characters); · In subjects with polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (nAMD), approximately 65 letter BCVA ( ETDRS) (e.g., baseline BCVA is approximately 57 characters) and / or BCVA (ETDRS) of approximately 68 characters when receiving HDq16 regimen (e.g., baseline BCVA is approximately 60 characters); · In subjects with polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (nAMD), approximately 64 letters of BCVA ( ETDRS) (e.g., baseline BCVA is approximately 57 characters) and / or BCVA (ETDRS) of approximately 71 characters when receiving HDq16 regimen (e.g., baseline BCVA is approximately 60 characters); · In subjects with polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (nAMD), approximately 64 letters of BCVA ( ETDRS) (e.g., where baseline BCVA is approximately 57 characters) and / or BCVA of approximately 71 characters when receiving HDq16 regimen (ETDRS) (e.g., where baseline BCVA is approximately 60 characters) be), · In subjects with polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (nAMD), approximately 65 letters of BCVA ( ETDRS) (e.g., baseline BCVA is approximately 57 characters) and / or BCVA (ETDRS) of approximately 69 characters when receiving HDq16 regimen (e.g., baseline BCVA is approximately 60 characters); · In subjects with polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (nAMD), approximately 65-letter BCVA (ETDRS ) (e.g., baseline BCVA is approximately 57 characters) and / or BCVA (ETDRS) of approximately 68 characters when receiving HDq16 regimen (e.g., baseline BCVA is approximately 60 characters); · In subjects with PCV and nAMD, by approximately 4 weeks after initiation of treatment, BCVA increases by approximately 3.0 letters (ETDRS) if receiving HDq12 regimen and / or approximately 3.0 letters if receiving HDq16 regimen , · In subjects with PCV and nAMD, by approximately 8 weeks after initiation of treatment, BCVA (ETDRS) of approximately 6.0 characters when receiving an HDq12 regimen and / or approximately 5.0 characters when receiving an HDq16 regimen. BCVA increase, · In subjects with PCV and nAMD, by approximately 12 weeks after initiation of treatment, BCVA (ETDRS) of approximately 7.0 characters when receiving an HDq12 regimen and / or approximately 6.0 characters when receiving an HDq16 regimen. BCVA increase, · In subjects with PCV and nAMD, by approximately 16 weeks after initiation of treatment, BCVA (ETDRS) of approximately 7.0 characters when receiving an HDq12 regimen and / or approximately 7.0 characters when receiving an HDq16 regimen. BCVA increase, · In subjects with PCV and nAMD, by approximately 20 weeks after initiation of treatment, an increase in BCVA of approximately 7.0 letters BCVA (ETDRS) when receiving an HDq12 regimen and / or when receiving an HDq16 regimen. Approximately 7.0 characters increase, · In subjects with PCV and nAMD, by approximately 24 weeks after initiation of treatment, BCVA (ETDRS) of approximately 7.0 characters when receiving an HDq12 regimen and / or approximately 5.0 characters when receiving an HDq16 regimen. BCVA increase, In subjects with PCV and nAMD, by approximately 28 weeks after initiation of treatment, BCVA (ETDRS) of approximately 9.0 characters when receiving an HDq12 regimen and / or approximately 7.0 characters when receiving an HDq16 regimen. BCVA increase, In subjects with PCV and nAMD, by approximately 32 weeks after initiation of treatment, BCVA (ETDRS) of approximately 8.0 characters when receiving an HDq12 regimen and / or approximately 10.0 characters when receiving an HDq16 regimen. BCVA increase, In subjects with PCV and nAMD, by approximately 36 weeks after initiation of treatment, BCVA (ETDRS) of approximately 8.0 characters when receiving an HDq12 regimen and / or approximately 10.0 characters when receiving an HDq16 regimen. BCVA increase, · In subjects with PCV and nAMD, by approximately 40 weeks after initiation of treatment, BCVA (ETDRS) of approximately 9.0 characters when receiving an HDq12 regimen and / or approximately 8.0 characters when receiving an HDq16 regimen. BCVA increase, · In subjects with PCV and nAMD, by approximately 44 weeks after initiation of treatment, BCVA (ETDRS) of approximately 9.0 characters when receiving an HDq12 regimen and / or approximately 8.0 characters when receiving an HDq16 regimen. BCVA increase, · In subjects with PCV and nAMD, by approximately 48 weeks after initiation of treatment, BCVA (ETDRS) of approximately 9.0 characters when receiving an HDq12 regimen and / or approximately 9.0 characters when receiving an HDq16 regimen. BCVA increase, · In subjects with polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (nAMD), approximately 65-letter BCVA (ETDRS ) (e.g., baseline BCVA is approximately 57 characters) and / or BCVA (ETDRS) of approximately 69 characters when receiving HDq16 regimen (e.g., baseline BCVA is approximately 60 characters); · By approximately 12 weeks after initiation of treatment, approximately 0.45 (±2.3) or 0.5 (±2.3) or 0.23 mm if receiving HDq12 regimen 2 or up to 11mm 2 or approximately 0.40 (±2.6) or 0.13 mm if receiving HDq16 regimen 2 or up to 17mm 2 reduction in total lesion size (e.g., baseline total lesion area approximately 5 or 6 or 7 mm) 2 ), · By approximately 48 weeks after initiation of treatment, approximately 0.36 or 0.4 or 0.46 or 0.26 (±2.9 or ±0.19) mm if receiving HDq12 regimen 2 ) or approximately 0.2, 0.2856, 0.3, or 0.04 (±3.2 or ±0.2) mm if receiving HDq16 regimen 2 or up to 16mm 2 reduction in total lesion size (e.g., baseline total lesion area approximately 5 or 6 or 7 mm) 2 ), · By approximately 60 weeks after initiation of treatment, approximately 0.52 or 0.6 or 0.32 (±2.8) mm if receiving HDq12 regimen 2 or up to 14mm 2 or approximately 0.35 or 0.4 or 0.14 (±3.2) mm if receiving HDq16 regimen 2 or up to 17mm 2 reduction in total lesion size (e.g., baseline total lesion area approximately 5 or 6 or 7 mm) 2 ), · By week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 after the start of treatment, e.g., at least about 100, 125, 130, 135, 140, 141 , 142, 143, 144, 145, 146, 147, 148, 149, or 150 micrometer central retinal thickness (CRT) decrease; · By the fourth week after the start of treatment, approximately -120 or -121 or -122 or -122.4 or -120.2 micrometers for HDq12 regimens or about -126 or -127 or -126.6 for HDq16 regimens or a change in central retinal thickness of -126.3 micrometers; · By week 8 after the start of treatment, approximately -132, -133, -134, -135 or -136 or -136.2 or -132.8 micrometers for HDq12 regimens or -139 for HDq16 regimens or a change in central retinal thickness of -140 or -139.5 or -139.6 micrometers; · By week 12 after the start of treatment, approximately -136, -137, -138, -139, -140, or -141 or -140.9 or -136.6 micrometers for HDq12 regimens or -136.6 micrometers for HDq16 regimens. is a change in central retinal thickness of approximately -144 or -143 or -143.5 micrometers, · By week 16 after the start of treatment, about -120 or -121 or -122 or -123 or -124 or -123.4 or -120.1 micrometers for HDq12 regimens or about -132 for HDq16 regimens or a change in central retinal thickness of -133 or -132.1 or -133.1 micrometers; · By week 20 after the start of treatment, approximately -110 or -111 or -112 or -113 or -114 or -113.6 or -110.9 micrometers for HDq12 regimens or about -115 for HDq16 regimens or a change in central retinal thickness of -116 or -117 or -118 or -115.8 or -117.7 micrometers; · By week 24 after the start of treatment, approximately -134, -135, -136, or -137, or -138, or -137.6, or -134.9 micrometers for HDq12 regimens or -134.9 micrometers for HDq16 regimens. is a change in central retinal thickness of approximately -105 or -106 or -107 or -108 or -105.3 or -107.8 micrometers, · By week 28 after the start of treatment, approximately -130, -131, or -132 or -133 or -134 or -133.7 or -130.7 micrometers for HDq12 regimens or -130.7 micrometers for HDq16 regimens. central retinal thickness change of 144 or -145 or -146 or -147 or -148 or -144.7 or -147.2 micrometers; · By week 32 after the start of treatment, approximately -118 or -19 or -120 or -121 or -120.4 or -118.1 micrometers for HDq12 regimens or about -141 or -142 for HDq16 regimens or a change in central retinal thickness of -143 or -144 or -141.5 or -144 micrometers; · By week 36 after the start of treatment, approximately -142 or -143 or -144 or -144.2 or -142.2 micrometers for HDq12 regimens or -126 or -127, -128 for HDq16 regimens or a change in central retinal thickness of -129 or -130 or -131 or -126.4 or -130.5 micrometers, · By week 40 after the start of treatment, approximately -131, -132, -133, or -134, or -133.8, or -131.2 micrometers for an HDq12 regimen or about -127 for an HDq16 regimen , a change in central retinal thickness of -128 or -127.5 micrometers, · By week 44 after the start of treatment, approximately -120 or -121 or -122 or -123 or -124 or -125 or -124.7 or -120.3 micrometers for HDq12 regimens or -120.3 micrometers for HDq16 regimens. a change in central retinal thickness of approximately -143, -144 or -145 or -144.8 micrometers; · By week 48 after initiation of treatment, approximately -141, -141.9, -142, -142.3, -143, -144, -144.4, -145, -146, -147, -147.37 for HDq12 regimens , or -148 micrometers (e.g., baseline CRT is about 370 micrometers) or about -143, -144, -145, -146, -146.76, -147, -147.1, - for HDq16 regimens. a change in central retinal thickness of 148, -143.8, or -147.1 micrometers (e.g., baseline CRT is approximately 370 micrometers); · By week 60 after initiation of treatment, central retinal thickness change of approximately -153 micrometers for HDq16 regimens; Central retinal thickness of approximately 248.2 micrometers for HDq12 regimens or 244.1 micrometers for HDq16 regimens (e.g., initial CRT is approximately 370 micrometers) by week 4 after initiation of treatment; Central retinal thickness of approximately 234.4 micrometers for HDq12 regimens or 231.2 micrometers for HDq16 regimens (e.g., initial CRT is approximately 370 micrometers) by week 8 after initiation of treatment; Central retinal thickness of approximately 229.7 micrometers for HDq12 regimens or approximately 226.7 micrometers for HDq16 regimens (e.g. initial CRT is approximately 370 micrometers) by week 12 after the start of treatment; Central retinal thickness of approximately 247.2 micrometers for HDq12 regimens or approximately 238.6 micrometers for HDq16 regimens (e.g., initial CRT is approximately 370 micrometers) by week 16 after initiation of treatment; Central retinal thickness of approximately 257 micrometers for HDq12 regimens or approximately 254.9 micrometers for HDq16 regimens (e.g., initial CRT is approximately 370 micrometers) by week 20 after initiation of treatment; Central retinal thickness of approximately 233 micrometers for HDq12 regimens or approximately 265.4 micrometers for HDq16 regimens (e.g., initial CRT is approximately 370 micrometers) by week 24 after initiation of treatment; Central retinal thickness of approximately 236.9 micrometers for HDq12 regimens or approximately 226 micrometers for HDq16 regimens (e.g., initial CRT is approximately 370 micrometers) by week 28 after initiation of treatment; Central retinal thickness of approximately 250.2 micrometers for HDq12 regimens or approximately 229.2 micrometers for HDq16 regimens (e.g., initial CRT is approximately 370 micrometers) by week 32 after initiation of treatment; Central retinal thickness of approximately 226.4 micrometers for HDq12 regimens or approximately 244.3 micrometers for HDq16 regimens (e.g., initial CRT is approximately 370 micrometers) by week 36 after initiation of treatment; Central retinal thickness of approximately 236.8 micrometers for HDq12 regimens or approximately 243.7 micrometers for HDq16 regimens (e.g., initial CRT is approximately 370 micrometers) by week 40 after initiation of treatment; Central retinal thickness of approximately 245.9 micrometers for HDq12 regimens or approximately 227.7 micrometers for HDq16 regimens (e.g. initial CRT is approximately 370 micrometers) by week 44 after initiation of treatment; Central retinal thickness of approximately 226 micrometers for HDq12 regimens or approximately 226.9 micrometers for HDq16 regimens (e.g., initial CRT is approximately 370 micrometers) by week 48 after initiation of treatment; Central retinal thickness of approximately 227.4 micrometers for HDq12 regimens or approximately 231.1 micrometers for HDq16 regimens (e.g., initial CRT is approximately 370 micrometers) by week 52 after initiation of treatment; Central retinal thickness of approximately 234.3 micrometers for HDq12 regimens or approximately 233.2 micrometers for HDq16 regimens (e.g., initial CRT is approximately 370 micrometers) by week 56 after initiation of treatment; Central retinal thickness of approximately 218.8 micrometers for HDq12 regimens or approximately 221.9 micrometers for HDq16 regimens (e.g., initial CRT is approximately 370 micrometers) by week 60 after initiation of treatment; · Change in central retinal thickness between week 0 (start of treatment) and week 4 of approximately -112 or -113 or -112.4 micrometers for HDq12 regimens; · Change in central retinal thickness between weeks 4 and 8 of approximately -13 or -14 or -13.8 micrometers for HDq12 regimens; · Change in central retinal thickness between weeks 8 and 12 of approximately -4 or -5 or -4.7 micrometers for HDq12 regimens; · Change in central retinal thickness between weeks 20 and 24 of approximately -24 or -25 micrometers for HDq12 regimens; · Change in central retinal thickness between weeks 32 and 36 of approximately -23 or -24 or -23.8 micrometers for HDq12 regimens; · Change in central retinal thickness between weeks 44 and 48 of approximately -19 or -20 or -19.7 micrometers for HDq12 regimens; · Change in central retinal thickness between weeks 0 and 4 of approximately -126, -127, or -126.6 micrometers for HDq16 regimens; · Change in central retinal thickness between weeks 4 and 8 of approximately -12, -13, or -12.9 micrometers for HDq16 regimens; · Change in central retinal thickness between weeks 8 and 12 of approximately -4 or -5 or -4.5 micrometers for HDq16 regimens; · Change in central retinal thickness between weeks 24 and 28 of approximately -39, -40, or -39.4 micrometers for HDq16 regimens; · Central retinal thickness change of approximately 0 or -1 or -0.6 micrometers for HDq16 regimens between weeks 36 and 40; Change in central retinal thickness between weeks H40 and 44 of approximately -15 or -16 micrometers for HDq16 regimens; · Change in central retinal thickness between weeks 44 and 48 of approximately 0 or -1 or -0.8 micrometers for HDq16 regimens; · Central retinal thickness change of approximately -11, -12, or -11.3 micrometers for HDq16 regimens between weeks 56 and 60; · CRT up to about 4, 5, 6, 7, or 8 weeks after the start of treatment, or a CRT reduction up to about 4, 5, 6, 7, or 8 weeks after the start of treatment, after said treatment regimen. for example, maintained (within about ±10, ±11, or ±12 micrometers) for at least 48 weeks; · In subjects with PCV and nAMD, by approximately 4 weeks after initiation of treatment, change in central retinal thickness (CRT) of approximately -130.2 micrometers when receiving an HDq12 regimen and / or when receiving an HDq16 regimen CRT variation of approximately -111.6 micrometers, · In subjects with PCV and nAMD, by approximately 8 weeks after initiation of treatment, change in central retinal thickness (CRT) of approximately -152.5 micrometers when receiving an HDq12 regimen and / or when receiving an HDq16 regimen CRT variation of approximately -134.5 micrometers, · In subjects with PCV and nAMD, by approximately 12 weeks after initiation of treatment, change in central retinal thickness (CRT) of approximately -160.9 micrometers when receiving an HDq12 regimen and / or when receiving an HDq16 regimen CRT variation of approximately -147.7 micrometers, · In subjects with PCV and nAMD, by approximately 16 weeks after initiation of treatment, central retinal thickness (CRT) change of approximately -150 micrometers if receiving HDq12 regimen and / or if receiving HDq16 regimen CRT variation of approximately -141.1 micrometers, · In subjects with PCV and nAMD, by approximately week 20 after initiation of treatment, change in central retinal thickness (CRT) of approximately -135.9 micrometers when receiving an HDq12 regimen and / or when receiving an HDq16 regimen CRT variation of approximately -128 micrometers, · In subjects with PCV and nAMD, by approximately 24 weeks after initiation of treatment, change in central retinal thickness (CRT) of approximately -162.7 micrometers when receiving an HDq12 regimen and / or when receiving an HDq16 regimen CRT variation of approximately -115.7 micrometers, · In subjects with PCV and nAMD, by approximately 28 weeks after initiation of treatment, change in central retinal thickness (CRT) of approximately -163.4 micrometers when receiving an HDq12 regimen and / or when receiving an HDq16 regimen CRT variation of approximately -147.9 micrometers, · In subjects with PCV and nAMD, by approximately 32 weeks after initiation of treatment, change in central retinal thickness (CRT) of approximately -148.2 micrometers when receiving an HDq12 regimen and / or when receiving an HDq16 regimen CRT variation of approximately -142.3 micrometers, · In subjects with PCV and nAMD, by approximately 36 weeks after initiation of treatment, change in central retinal thickness (CRT) of approximately -167.4 micrometers when receiving an HDq12 regimen and / or when receiving an HDq16 regimen CRT variation of approximately -132.6 micrometers, · In subjects with PCV and nAMD, by approximately 40 weeks after initiation of treatment, central retinal thickness (CRT) change of approximately -159.2 micrometers when receiving HDq12 regimen and / or when receiving HDq16 regimen CRT variation of approximately -121.1 micrometers, Central retinal thickness (CRT) change of approximately -146.7 micrometers if receiving an HDq12 regimen and / or receiving an HDq16 regimen by approximately 44 weeks after initiation of treatment in subjects with PCV and nAMD CRT change of approximately -143.9 micrometers in case, · In subjects with PCV and nAMD, by approximately 48 weeks after initiation of treatment, change in central retinal thickness (CRT) of approximately -170.6 micrometers when receiving an HDq12 regimen and / or when receiving an HDq16 regimen CRT variation of approximately -146.1 micrometers, In subjects with PCV and nAMD, by approximately 4 weeks after initiation of treatment, central retinal thickness (e.g., baseline CRT is approximately 390.4 micrometers) of approximately 260.2 micrometers (e.g., baseline CRT is approximately 390.4 micrometers) when receiving an HDq12 regimen CRT) and / or approximately 263.6 micrometers (e.g., baseline CRT is approximately 375.2 micrometers) when receiving an HDq16 regimen; In subjects with PCV and nAMD, central retinal thickness of approximately 237.9 micrometers (e.g., baseline CRT is approximately 390.4 micrometers) when receiving HDq12 regimens by approximately 8 weeks after initiation of treatment (e.g., baseline CRT is approximately 390.4 micrometers) CRT) and / or approximately 240.7 micrometers (e.g., baseline CRT is approximately 375.2 micrometers) when receiving an HDq16 regimen; In subjects with PCV and nAMD, by approximately 12 weeks after initiation of treatment, central retinal thickness of approximately 229.5 micrometers (e.g., baseline CRT is approximately 390.4 micrometers) when receiving HDq12 regimens ( CRT) and / or approximately 227.5 micrometers (e.g., baseline CRT is approximately 375.2 micrometers) when receiving an HDq16 regimen; In subjects with PCV and nAMD, by approximately 16 weeks after initiation of treatment, central retinal thickness of approximately 240.4 micrometers (e.g., baseline CRT is approximately 390.4 micrometers) when receiving an HDq12 regimen ( CRT) and / or approximately 234.1 micrometers (e.g., baseline CRT is approximately 375.2 micrometers) when receiving an HDq16 regimen; In subjects with PCV and nAMD, by approximately 20 weeks after initiation of treatment, central retinal thickness of approximately 254.5 micrometers (e.g., baseline CRT is approximately 390.4 micrometers) when receiving an HDq12 regimen ( CRT) and / or approximately 247.2 micrometers (e.g., baseline CRT is approximately 375.2 micrometers) when receiving an HDq16 regimen; In subjects with PCV and nAMD, by approximately 24 weeks after initiation of treatment, central retinal thickness of approximately 227.7 micrometers (e.g., baseline CRT is approximately 390.4 micrometers) when receiving an HDq12 regimen ( CRT) and / or a CRT of approximately 259.5 micrometers (e.g., baseline CRT is approximately 375.2 micrometers) when receiving an HDq16 regimen; In subjects with PCV and nAMD, by approximately 28 weeks after initiation of treatment, central retinal thickness of approximately 227 micrometers (e.g., baseline CRT is approximately 390.4 micrometers) when receiving an HDq12 regimen ( CRT) and / or approximately 227.3 micrometers (e.g., baseline CRT is approximately 375.2 micrometers) when receiving an HDq16 regimen; In subjects with PCV and nAMD, by approximately 32 weeks after initiation of treatment, central retinal thickness of approximately 242.2 micrometers (e.g., baseline CRT is approximately 390.4 micrometers) when receiving an HDq12 regimen ( CRT) and / or approximately 232.9 micrometers (e.g., baseline CRT is approximately 375.2 micrometers) when receiving an HDq16 regimen; In subjects with PCV and nAMD, by approximately 36 weeks after initiation of treatment, central retinal thickness of approximately 223 micrometers (e.g., baseline CRT is approximately 390.4 micrometers) when receiving HDq12 regimens ( CRT) and / or approximately 242.6 micrometers (e.g., baseline CRT is approximately 375.2 micrometers) when receiving an HDq16 regimen; In subjects with PCV and nAMD, by approximately 40 weeks after initiation of treatment, central retinal thickness (e.g., baseline CRT is approximately 390.4 micrometers) of approximately 231.2 micrometers (e.g., baseline CRT is approximately 390.4 micrometers) when receiving an HDq12 regimen CRT) and / or approximately 254.1 micrometers (e.g., baseline CRT is approximately 375.2 micrometers) when receiving an HDq16 regimen; In subjects with PCV and nAMD, by approximately 44 weeks after initiation of treatment, central retinal thickness of approximately 243.7 micrometers (e.g., baseline CRT is approximately 390.4 micrometers) when receiving HDq12 regimens ( CRT) and / or approximately 231.3 micrometers (e.g., baseline CRT is approximately 375.2 micrometers) when receiving an HDq16 regimen; In subjects with PCV and nAMD, by approximately 48 weeks after initiation of treatment, central retinal thickness (e.g., baseline CRT is approximately 390.4 micrometers) of approximately 219.8 micrometers (e.g., baseline CRT is approximately 390.4 micrometers) when receiving HDq12 regimens. CRT) and / or approximately 229.1 micrometers (e.g., baseline CRT is approximately 375.2 micrometers) when receiving an HDq16 regimen; · By week 12 if receiving an HDq12 regimen (e.g., baseline size at the start of treatment of approximately 4, 5, or 6 mm) 2 ) approx. 0.6, 1.5, 1, or 2mm 2 (±3.7mm 2 ), or up to about 11 or 12mm 2 reduction in choroidal neovascular size, · By week 48 if receiving an HDq12 regimen (e.g., baseline size at the start of treatment of approximately 4, 5, or 6 mm) 2 ) approx. 2, 3, 4, 3.5, or 2.5mm 2 (±5mm 2 ), or up to about 15 or 16mm 2 reduction in choroidal neovascular size, · By week 60 if receiving an HDq12 regimen (e.g., baseline size at the start of treatment of approximately 4, 5, or 6 mm) 2 ) approx. 2, 3, 4, 3.8, 2.8mm 2 (±5mm 2 ), or up to 13mm 2 reduction in choroidal neovascular size, · By week 12 if receiving an HDq16 regimen (e.g., baseline size at the start of treatment of approximately 4, 4.5, 5, 6, 6.5, or 7 mm) 2 ) approx. 1, 2, 0.5, or 1.5mm 2 (±4.2mm 2 ), or up to 17mm 2 reduction in choroidal neovascular size. · By week 48 if receiving an HDq16 regimen (e.g., baseline size at the start of treatment of approximately 4, 4.5, 5, 6, 6.5, or 7 mm) 2 ) approx. 1, 2, 1.4, or 3mm 2 (±5mm 2 ), or up to 16mm 2 Choroidal neovascularization size (mm 2 ) decrease, · By week 60 if receiving an HDq16 regimen (e.g., baseline size at the start of treatment of approximately 4, 4.5, 5, 6, 6.5, or 7 mm) 2 ) approx. 2, 3, 4, or 3.7mm 2 (±5.7mm 2 ), or up to 17mm 2 reduction in choroidal neovascular size, · At baseline, the free aflibercept concentration in plasma is approximately 0 mg / L (or less than 0.0156 mg / L); · A free aflibercept concentration in the plasma of approximately 0.04 (±0.06) or 0 mg / L (or less than 0.0156 mg / L) approximately 4 hours after initiation of HDq12 or HDq16 treatment; · A free aflibercept concentration in the plasma of approximately 0.05 (±3.8), 0.1 (±0.102), or 0.067 mg / L approximately 8 hours after initiation of HDq12 or HDq16 treatment; Free aflibercept concentrations in plasma of approximately 0.11 (±2.21), 0.146 (±0.110), or 0.0903 mg / L approximately 2 days after initiation of HDq12 or HDq16 treatment; Free aflibercept concentrations in plasma of approximately 0.11 (±2.06), 0.137 (±0.0947), or 0.112 mg / L approximately 3 days after initiation of HDq12 or HDq16 treatment; Free aflibercept concentrations in plasma of 0.08 (±1.86), 0.09 (±0.048), or 0.085 mg / L approximately 5 days after initiation of HDq12 or HDq16 treatment; Free aflibercept concentrations in plasma of approximately 0.07 (±1.75), 0.0794 (±0.041), or 0.068 mg / L approximately 8 days after initiation of treatment for HDq12 or HDq16; Free aflibercept concentrations in plasma of approximately 0.04 (±1.76), 0.044 (±0.0199), or 0.039 mg / L approximately 15 days after initiation of HDq12 or HDq16 treatment; Free aflibercept concentrations in the plasma of approximately 0.02 (±1.76), 0.021 (±0.0148), or 0.023 mg / L approximately 22 days after initiation of HDq12 or HDq16 treatment; A free aflibercept concentration in the plasma of approximately 0.0077 (±0.0096) or 0 mg / L (or less than 0.0156 mg / L) approximately 29 days after initiation of HDq12 or HDq16 treatment; · At approximately 48 weeks after initiation of HDq12 treatment, plasma free aflibercept concentrations of approximately 0.014 mg / L (±0.018); · At approximately 48 weeks after initiation of HDq16 treatment, plasma free aflibercept concentrations of approximately 0.00056 mg / L (±0.0038); · At approximately 28 weeks after initiation of HDq12 treatment, plasma free aflibercept concentrations of approximately 0.00088 mg / L (±0.0053); · At approximately 28 weeks after initiation of HDq16 treatment, plasma free aflibercept concentrations of approximately 0.015 mg / L (±0.016); · Free aflibercept concentrations in the plasma of about 0.02 mg / L (±2) or about 0.028 mg / L (±0.023) at about 12 weeks after initiation of HDq12 treatment; · At about 12 weeks after initiation of treatment for HDq16, a free aflibercept concentration in the plasma of about 0.02 mg / L (±2) or about 0.029 mg / L (±0.023); · At approximately 4 weeks after initiation of HDq12 treatment, plasma free aflibercept concentrations of approximately 0.017 mg / L (±0.016); · Approximately 4 weeks after initiation of HDq16 treatment, plasma free aflibercept concentrations of approximately 0.017 mg / L (±0.016); Adjusted conjugated aflibercept concentration in plasma of approximately 0.00 mg / L approximately 4 hours after administration from the start of HDq12 or HDq16 treatment; Adjusted conjugated aflibercept concentration in plasma of approximately 0.00 mg / L approximately 8 hours after administration from the start of HDq12 or HDq16 treatment; Adjusted bound aflibercept concentration in plasma of approximately 0.06 (±3.50) or 0.12 (±0.19) mg / L approximately 2 days after initiation of HDq12 or HDq16 treatment; Adjusted bound aflibercept concentration in plasma of approximately 0.13 (±2.07) or 0.17 (±0.155) mg / L approximately 3 days after initiation of HDq12 or HDq16 treatment; Adjusted bound aflibercept concentration in plasma of about 0.18 (± 1.9) or 0.22 (± 0.157) mg / L approximately 5 days after initiation of HDq12 or HDq16 treatment; Adjusted bound aflibercept concentration in plasma of about 0.31 (± 1.56) or 0.33 (± 0.135) mg / L at about 8 days after initiation of HDq12 or HDq16 treatment; Adjusted bound aflibercept concentration in plasma of approximately 0.37 (± 1.50) or 0.39 (± 0.130) mg / L approximately 15 days after initiation of HDq12 or HDq16 treatment; Adjusted bound aflibercept concentration in plasma of about 0.25 (± 3.00) or 0.34 (± 0.155) mg / L at about 22 days after initiation of HDq12 or HDq16 treatment; Adjusted bound aflibercept concentration in plasma of about 0.32 (±1.39) or 0.33 (±0.0953) mg / L at about day 29 after initiation of HDq12 or HDq16 treatment; Adjusted bound aflibercept concentration in plasma of approximately 0.3 or 0.38 mg / l (±2.4 or 0.18) at approximately 48 weeks after initiation of HDq12 treatment; Adjusted bound aflibercept concentration in plasma of approximately 0.17 or 0.2 mg / l (±2 or 0.11) at approximately 48 weeks after initiation of HDq16 treatment; Adjusted bound aflibercept concentration in plasma of approximately 0.2 or 0.22 mg / l (±1.8 or 0.12) at approximately 28 weeks after initiation of HDq12 treatment; Adjusted bound aflibercept concentration in plasma of approximately 0.32 or 0.37 mg / l (±2 or 0.15) approximately 28 weeks after initiation of HDq16 treatment; Adjusted conjugated aflibercept concentration in plasma of approximately 0.6 mg / l (±1.5 or 0.22) approximately 12 weeks after initiation of HDq12 treatment; Adjusted conjugated aflibercept concentration in plasma of approximately 0.6 mg / l (±1.6 or 0.22) approximately 12 weeks after initiation of treatment for HDq16; Adjusted bound aflibercept concentration in plasma of approximately 0.34 or 0.38 mg / l (±1.7 or 0.13) approximately 4 weeks after initiation of HDq12 treatment; Adjusted bound aflibercept concentration in plasma of approximately 0.33 or 0.36 mg / l (±1.7 or 0.14) approximately 4 weeks after initiation of HDq16 treatment · Non-inferior BVCA compared to aflibercept administered intravitreally at 2 mg approximately every 4 weeks for the first 5 injections, followed by 2 mg approximately once every 8 weeks or once every 2 months. , · Aflibercept administered intravitreally at 2 mg approximately every 4 weeks for the first 3 or 4 or 5 injections, followed by 2 mg approximately every 8 weeks or once every 2 months. Intraocular safety (e.g., intraocular pressure) and non-intraocular safety (e.g., hypertensive events or APTC events) or mortality in subjects suffering from DME, as well as · In subjects with pterygium, nAMD, the first three injections are 2 mg approximately every 4 weeks, followed by 2 mg intravitreally administered approximately once every 8 weeks or once every 2 months. Efficacy and / or safety similar to that of aflibercept, e.g., efficacy is measured as an increase in BCVA and / or decrease in central retinal thickness; measured as the incidence of adverse events (treatment-emergent events occurring any time within 30 days after injection) such as vitreous disease, vitreous detachment, iris neovascularization, and / or vitreous hemorrhage; Peak free aflibercept concentration in plasma approximately 1, 1.5, 2, or 3 days after initiation of treatment, · Maximum free aflibercept concentration in plasma of approximately 0.1, 0.12, 0.13, 0.14, or 0.2 mg / l, · Plasma half-life of free aflibercept of approximately 10, 11, 12 or 13 days; · Peak adjusted bound aflibercept concentration in plasma approximately 14 days after initiation of treatment; · Maximum free aflibercept concentration in plasma of approximately 0.4 mg / l, and / or · Plasma half-life of free aflibercept at approximately 281 days.

[0172] That is, the present invention provides the following. · In eligible subjects with PCV and nAMD, by approximately 4 weeks after initiation of treatment, central retinal thickness (CRT) change of approximately -130.2 micrometers when receiving HDq12 regimen and / or HDq16 regimen. A change in CRT of approximately -111.6 micrometers when receiving an HDq12 regimen, and a change in central retinal thickness (CRT) of approximately -152.5 micrometers when receiving an HDq12 regimen and / or HDq16 by approximately 8 weeks after the start of treatment. CRT change of approximately -134.5 micrometers when receiving the regimen; by approximately 12 weeks after initiation of treatment, central retinal thickness (CRT) change of approximately -160.9 micrometers when receiving the HDq12 regimen and / or or a change in CRT of approximately -147.7 micrometers when receiving an HDq16 regimen, and a change in central retinal thickness (CRT) of approximately -150 micrometers when receiving an HDq12 regimen by approximately 16 weeks after the start of treatment. and / or a change in CRT of approximately −141.1 micrometers when receiving an HDq16 regimen, and a change in central retinal thickness (CRT) of approximately −135.9 micrometers when receiving an HDq12 regimen by approximately week 20 after the start of treatment. and / or CRT change of approximately −128 micrometers when receiving an HDq16 regimen, and by approximately 24 weeks after the start of treatment, a change in central retinal thickness of approximately −162.7 micrometers when receiving an HDq12 regimen ( CRT) change and / or CRT change of approximately -115.7 micrometers when receiving an HDq16 regimen, and central retinal change of approximately -163.4 micrometers when receiving an HDq12 regimen by approximately 28 weeks after the start of treatment. Change in thickness (CRT) and / or CRT change of approximately -147.9 micrometers when receiving an HDq16 regimen and of approximately -148.2 micrometers when receiving an HDq12 regimen by approximately 32 weeks after initiation of treatment. Changes in central retinal thickness (CRT) and / or CRT changes of approximately -142.3 micrometers when receiving an HDq16 regimen and approximately -167.4 micrometers when receiving an HDq12 regimen by approximately 36 weeks after initiation of treatment Central retinal thickness (CRT) change of approximately -132.6 micrometers if receiving HDq16 regimen and / or CRT change of approximately -132.6 micrometers if receiving HDq12 regimen by approximately 40 weeks after initiation of treatment; Central retinal thickness (CRT) change of 159.2 micrometers and / or CRT change of approximately -121.1 micrometers if receiving HDq16 regimen, by approximately 44 weeks after initiation of treatment, if receiving HDq12 regimen Central retinal thickness (CRT) change of approximately -146.7 micrometers and / or CRT change of approximately -143.9 micrometers if receiving HDq16 regimen, by approximately 48 weeks after initiation of treatment, if receiving HDq12 regimen Central retinal thickness (CRT) change of approximately -170.6 micrometers if receiving HDq16 regimen and / or CRT change of approximately -146.1 micrometers if receiving HDq12 regimen by approximately 4 weeks after initiation of treatment. Central retinal thickness (CRT) of approximately 260.2 micrometers (e.g., baseline CRT is approximately 390.4 micrometers) when receiving a HDq16 regimen and / or approximately 263.6 micrometers (e.g., baseline CRT is approximately 390.4 micrometers) when receiving an HDq16 regimen. CRT of approximately 375.2 micrometers), central retinal thickness of approximately 237.9 micrometers (e.g., baseline CRT is approximately 390.4 micrometers) when receiving an HDq12 regimen by approximately 8 weeks after the start of treatment (CRT) and / or approximately 240.7 micrometers (e.g., baseline CRT is approximately 375.2 micrometers) if receiving an HDq12 regimen by approximately 12 weeks after initiation of treatment Central retinal thickness (CRT) of approximately 229.5 micrometers when receiving an HDq16 regimen (e.g., baseline CRT is approximately 390.4 micrometers) and / or approximately 227.5...

Claims

1. A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method for treating or preventing neovascular age-related macular degeneration (nAMD) in subjects requiring it, wherein the method comprises administering one or more doses of the VEGF receptor fusion protein at certain intervals and in certain amounts. - The clearance of free VEGF receptor fusion protein from the ocular compartment is approximately 0.3, 0.4, 0.41, or 0.37–0.46 mL / day after intravitreal injection of VEGF receptor fusion protein. - The time it takes for the amount of free VEGF receptor fusion protein in the subject's ocular compartment to reach the limit of quantification (LLOQ) after intravitreous injection of the VEGF receptor fusion protein is approximately 15 weeks, and / or A pharmaceutical composition wherein, after intravitreal injection of the VEGF receptor fusion protein, the time it takes for the free VEGF receptor fusion protein in the subject's plasma to reach the lower limit of quantification (LLOQ) is approximately 3.8, 3.5, or 3.5 to 3.8 weeks.

2. A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method for slowing the clearance of free VEGF receptor fusion protein from the ocular compartment after intravitreous injection compared to the clearance rate of VEGF receptor fusion protein from the ocular compartment after intravitreous injection of 2 mg or 4 mg or less of VEGF receptor fusion protein, wherein the method is To the eyes of the subjects who need it, A single initial dose of approximately 8 mg or more of VEGF receptor fusion protein, followed by... One or more secondary doses of approximately 8 mg or more of the VEGF receptor fusion protein, followed by, This includes intravitreal injection of one or more tertiary doses of approximately 8 mg or more of the VEGF receptor fusion protein. Each secondary dose is administered approximately 2 to 4 weeks after the previous dose. A pharmaceutical composition in which each of the tertiary doses is administered approximately 12 to 20 weeks after the immediately preceding dose.

3. The pharmaceutical composition according to claim 1, wherein the clearance of the VEGF receptor fusion protein released from the ocular compartment is about 34% slower than the clearance from the ocular compartment after intravitreal injection of VEGF receptor fusion protein at a dose of 2 mg or 4 mg or less.

4. The pharmaceutical composition according to claim 1, wherein the clearance of free VEGF receptor fusion protein from the ocular compartment is approximately 0.37 to 0.46 mL / day or 0.41 mL / day after intravitreal injection of 8 mg or more of VEGF receptor fusion protein.

5. A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method to increase the duration of efficacy and / or the time it takes for the amount of free VEGF receptor fusion protein in the subject's ocular compartment to reach the lower limit of quantification (LLOQ) after intravitreal injection of the VEGF receptor fusion protein, compared to the time it takes for the amount of free VEGF receptor fusion protein in the subject's ocular compartment to reach LLOQ after intravitreal injection of approximately 2 mg or 4 mg or less of the VEGF receptor fusion protein, wherein the method involves, in the eye of the subject as needed, A single initial dose of approximately 8 mg or more of VEGF receptor fusion protein, followed by... One or more secondary doses of approximately 8 mg or more of the VEGF receptor fusion protein, followed by, This includes intravitreal injection of one or more tertiary doses of approximately 8 mg or more of the VEGF receptor fusion protein, Each secondary dose is administered approximately 2 to 4 weeks after the previous dose. A pharmaceutical composition in which each of the tertiary doses is administered approximately 12 to 20 weeks after the immediately preceding dose.

6. The pharmaceutical composition according to claim 5, wherein the duration of efficacy and / or the time it takes for the amount of free VEGF receptor fusion protein in the subject's ocular compartment to reach the limit of quantification (LLOQ) after intravitreous injection of the VEGF receptor fusion protein is increased by about 5 or 6 weeks compared to the time it takes for the amount of free VEGF receptor fusion protein in the subject's ocular compartment to reach LLOQ after intravitreous injection of about 2 mg or 4 mg or less of the VEGF receptor fusion protein.

7. The pharmaceutical composition according to claim 5, wherein the time it takes for the amount of free VEGF receptor fusion protein in the subject's ocular compartment to reach the lower limit of quantification (LLOQ) after intravitreous injection of the VEGF receptor fusion protein is increased by approximately 1, 2, 1.2, or 1.3 weeks compared to the time it takes for the amount of free VEGF receptor fusion protein in the subject's ocular compartment to reach LLOQ after intravitreous injection of approximately 2 mg or 4 mg or less of VEGF receptor fusion protein.

8. The pharmaceutical composition according to claim 5, wherein the time it takes for the amount of free VEGF receptor fusion protein in the subject's ocular compartment to reach the lower limit of quantification (LLOQ) after intravitreous injection of 8 mg or more of the VEGF receptor fusion protein is approximately 15 weeks.

9. The pharmaceutical composition according to claim 5, wherein the time it takes for the amount of free VEGF receptor fusion protein in the subject's ocular compartment to reach the lower limit of quantification (LLOQ) after intravitreal injection of 8 mg or more of the VEGF receptor fusion protein is approximately 8, 8.7, 8.71, 9, 9.2, 9.21, or more than 10 weeks.

10. Free VEGF receptors in the plasma of subjects after intravitreal injection of VEGF receptor fusion protein. A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method to increase the time it takes for the amount of VEGF receptor fusion protein to reach the lower limit of quantification (LLOQ) compared to the time it takes for the amount of free VEGF receptor fusion protein in a subject's plasma to reach LLOQ after intravitreal injection of approximately 2 mg or 4 mg or less of VEGF receptor fusion protein, wherein the method involves the required amount being delivered to the eye of the subject. A single initial dose of approximately 8 mg or more of VEGF receptor fusion protein, followed by... One or more secondary doses of approximately 8 mg or more of the VEGF receptor fusion protein, followed by, This includes intravitreal injection of one or more tertiary doses of approximately 8 mg or more of the VEGF receptor fusion protein, Each secondary dose is administered approximately 2 to 4 weeks after the previous dose. A pharmaceutical composition in which each of the tertiary doses is administered approximately 12 to 20 weeks after the immediately preceding dose.

11. The pharmaceutical composition according to claim 10, wherein the LLOQ of the free VEGF receptor fusion protein measured in plasma is approximately 0.0156 mg / L.

12. The pharmaceutical composition according to claim 10, wherein the time it takes for the amount of free VEGF receptor fusion protein in the subject's plasma to reach the lower limit of quantification (LLOQ) after intravitreous injection of the VEGF receptor fusion protein is increased by about two weeks compared to the time it takes for the amount of free VEGF receptor fusion protein in the subject's plasma to reach LLOQ after intravitreous injection of about 2 mg of VEGF receptor fusion protein.

13. The pharmaceutical composition according to claim 10, wherein the time it takes for the free VEGF receptor fusion protein in the subject's plasma to reach the lower limit of quantification (LLOQ) after intravitreous injection of 8 mg or more of the VEGF receptor fusion protein is approximately 3, 3.5, 3.8, or 4 weeks.

14. The pharmaceutical composition according to claim 10, wherein the time it takes for the free VEGF receptor fusion protein in the subject's plasma to reach the lower limit of quantification (LLOQ) after intravitreous injection of 8 mg or more of the VEGF receptor fusion protein is approximately 1.5 or 1.6 weeks or longer.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein 4 mg or less is approximately 2 mg or 2 to 4 mg.

16. The pharmaceutical composition according to any one of claims 1 to 14, wherein the subject suffers from neovascular age-related macular degeneration (nAMD).

17. The pharmaceutical composition according to any one of claims 1 to 14, wherein the VEGF receptor fusion protein of 8 mg or more is present in an aqueous pharmaceutical formulation containing a histidine-based buffer.

18. The pharmaceutical composition according to any one of claims 1 to 14, wherein 8 mg or more of the VEGF receptor fusion protein is present in an aqueous pharmaceutical formulation containing arginine.

19. The pharmaceutical composition according to any one of claims 1 to 14, wherein the VEGF receptor fusion protein of 8 mg or more is present in an aqueous pharmaceutical formulation having a pH of about 5.

8.

20. The pharmaceutical composition according to any one of claims 1 to 14, wherein 8 mg or more of the VEGF receptor fusion protein is present in an aqueous pharmaceutical formulation containing a sugar or a polyol.

21. The pharmaceutical composition according to any one of claims 1 to 14, wherein 8 mg or more of the VEGF receptor fusion protein is present in an aqueous pharmaceutical formulation containing sucrose.

22. The pharmaceutical composition according to any one of claims 1 to 14, wherein the VEGF receptor fusion protein is present in an aqueous pharmaceutical formulation in an amount of 8 mg or more, and the VEGF receptor fusion protein has a high molecular weight species of less than about 3.5% immediately after production and purification and / or a high molecular weight species of less than 6% after being stored at about 2 to 8°C for about 24 months.

23. The pharmaceutical composition according to any one of claims 1 to 14, wherein the VEGF receptor fusion protein is present in an aqueous pharmaceutical formulation, and the formulation comprises at least about 100 mg / ml of VEGF receptor fusion protein, each comprising two polypeptides containing the immunoglobulin-like (Ig) domain 2 of VEGFR1, the Ig domain 3 of VEGFR2, and a polymerizing component, respectively, about 10 to 100 mM of L-arginine, sucrose, a histidine-based buffer, and a surfactant, the formulation having a pH of about 5.0 to about 6.8, and the VEGF receptor fusion protein having less than about 3.5% high molecular weight species immediately after production and purification and / or about 6% or less high molecular weight species after storage at about 2 to 8°C for about 24 months.

24. - Methods for treating or preventing neovascular age-related macular degeneration (nAMD) in subjects who require it. - A method for improving the best corrected visual acuity in subjects who require it and have nAMD, or A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method for promoting retinal dryness in a subject having -nAMD, wherein the method is A pharmaceutical composition comprising administering to the eyes of the subject one or more doses of approximately 8 mg or more of a VEGF receptor fusion protein once every 12, 13, 14, 15, 16, 17, 18, 19, or 20, or 12 to 20, or 12 to 16, or 16 to 20 weeks.

25. The above method involves the subject's eyes, A single initial dose of approximately 8 mg or more of VEGF receptor fusion protein, followed by... One or more secondary doses of approximately 8 mg or more of the VEGF receptor fusion protein, followed by, This includes administering one or more tertiary doses of approximately 8 mg or more of the VEGF receptor fusion protein, Each secondary dose is administered approximately 2 to 4 weeks after the previous dose. A pharmaceutical composition according to any one of claims 1 to 14 and 24, for treating or preventing neovascular age-related macular degeneration (nAMD) in subjects in need, each of which is administered approximately 12 to 20 weeks after the preceding dose.

26. The above method involves the subject's eyes, A single initial dose of approximately 8 mg or more of VEGF receptor fusion protein, followed by... One or more secondary doses of approximately 8 mg or more of the VEGF receptor fusion protein, followed by, This includes administering one or more tertiary doses of approximately 8 mg or more of the VEGF receptor fusion protein, Each secondary dose is administered approximately 2 to 4 weeks after the previous dose. A pharmaceutical composition according to any one of claims 1 to 14 and 24, for treating or preventing neovascular age-related macular degeneration (nAMD) in subjects in need, each of which is administered approximately 12 weeks after the preceding dose.

27. The method involves administering a single initial dose of approximately 8 mg or more of VEGF receptor fusion protein to the subject's eye, followed by... One or more secondary doses of approximately 8 mg or more of the VEGF receptor fusion protein, followed by, This includes administering one or more tertiary doses of approximately 8 mg or more of the VEGF receptor fusion protein, Each secondary dose is administered approximately 2 to 4 weeks after the previous dose. A pharmaceutical composition according to any one of claims 1 to 14 and 24, for treating or preventing neovascular age-related macular degeneration (nAMD) in subjects in need, each of which is administered approximately 16 weeks after the preceding dose.

28. The above method involves the subject's eyes, A single initial dose of approximately 8 mg or more of VEGF receptor fusion protein, followed by... One or more secondary doses of approximately 8 mg or more of the VEGF receptor fusion protein, followed by, This includes administering one or more tertiary doses of approximately 8 mg or more of the VEGF receptor fusion protein, Each secondary dose is administered approximately 2 to 4 weeks after the previous dose. A pharmaceutical composition according to any one of claims 1 to 14 and 24, for treating or preventing neovascular age-related macular degeneration (nAMD) in subjects in need, each of which is administered approximately 20 weeks after the preceding dose.

29. A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method for treating or preventing neovascular age-related macular degeneration (nAMD) in subjects requiring it, the method comprising administering 8 mg of VEGF receptor fusion protein (0.07 mL or 70 microliters) by intravitreal injection every four weeks (approximately every 28 days + / - 7 days, monthly) for the first three doses, followed by administering 8 mg of aflibercept (0.07 mL) once by intravitreal injection every 8 to 16 weeks (2 to 4 months + / - 7 days).

30. A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method for treating or preventing neovascular age-related macular degeneration (nAMD) in subjects requiring it, the method comprising administering 8 mg of VEGF receptor fusion protein (0.07 mL or 70 microliters) by intravitreal injection every four weeks (approximately every 28 days + / - 7 days, monthly) for the first three doses, and subsequently administering 8 mg of VEGF receptor fusion protein (0.07 mL) once every 12 weeks (2 to 4 months + / - 7 days) by intravitreal injection.

31. A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method for treating or preventing neovascular age-related macular degeneration (nAMD) in subjects requiring it, the method comprising administering 8 mg of VEGF receptor fusion protein (0.07 mL or 70 microliters) by intravitreal injection every four weeks (approximately every 28 days + / - 7 days, monthly) for the first three doses, and subsequently administering 8 mg of VEGF receptor fusion protein (0.07 mL) once every 16 weeks (2 to 4 months + / - 7 days) by intravitreal injection.

32. A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method for treating or preventing neovascular age-related macular degeneration (nAMD) in subjects requiring it, the method comprising administering 8 mg of VEGF receptor fusion protein (0.07 mL or 70 microliters) by intravitreal injection every four weeks (approximately every 28 days + / - 7 days, monthly) for the first three doses, and subsequently administering 8 mg of VEGF receptor fusion protein (0.07 mL) once every 20 weeks (+ / - 7 days) by intravitreal injection. , pharmaceutical composition.

33. A pharmaceutical composition comprising a VEGF receptor fusion protein in a dose of 8 mg (equivalent to 70 microliters of injectable solution) for use in a method to treat or prevent neovascular age-related macular degeneration (nAMD) in subjects requiring treatment, wherein the method comprises administering three consecutive doses of the 8 mg VEGF receptor fusion protein by injection once a month (every four weeks), the injection interval may be extended up to every 16 weeks based on the physician's judgment regarding visual and / or anatomical results.

34. A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method for treating or preventing neovascular age-related macular degeneration (nAMD) in subjects requiring it, (1) The subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein, and the method then administers to the subject an initial dose of 8 mg of VEGF receptor fusion protein one month later, a first secondary dose of 8 mg of VEGF receptor fusion protein one month later, a second secondary dose of 8 mg of VEGF receptor fusion protein one month later, and thereafter administers one or more maintenance doses of 8 mg of VEGF receptor fusion protein every 12, 16, or 20 weeks according to an HDq12, HDq16, or HDq20 administration regimen. (2) The subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein, and the method then comprises administering to the subject a first secondary dose of 8 mg of VEGF receptor fusion protein one month later, a second secondary dose of 8 mg of VEGF receptor fusion protein one month thereafter, and then administering one or more maintenance doses of 8 mg of VEGF receptor fusion protein every 12, 16, or 20 weeks thereafter, according to an HDq12, HDq16, or HDq20 administration regimen. (3) The subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein, and the method then administers to the subject a second dose of 8 mg of VEGF receptor fusion protein one month later, and thereafter administers one or more maintenance doses of 8 mg of VEGF receptor fusion protein every 12, 16, or 20 weeks according to an HDq12, HDq16, or HDq20 administration regimen. (4) The subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein, and the method then comprises administering to the subject a first maintenance dose of 8 mg of VEGF receptor fusion protein one month later, and thereafter administering all further 8 mg of VEGF receptor fusion protein maintenance doses every 12, 16, or 20 weeks according to an HDq12, HDq16, or HDq20 administration regimen. (5) The subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein and a first secondary dose of 2 mg of VEGF receptor fusion protein one month later, and the method then administers to the subject an initial dose of 8 mg of VEGF receptor fusion protein one month later, a first secondary dose of 8 mg of VEGF receptor fusion protein one month later, a second secondary dose of 8 mg of VEGF receptor fusion protein one month later, and thereafter administers one or more maintenance doses of 8 mg of VEGF receptor fusion protein every 12, 16, or 20 weeks according to an HDq12, HDq16, or HDq20 administration regimen. (6) The subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein and a first secondary dose of 2 mg of VEGF receptor fusion protein one month later, and the method then administers to the subject a first secondary dose of 8 mg of VEGF receptor fusion protein one month later, and a second secondary dose of 8 mg of VEGF receptor fusion protein one month later, and thereafter every 12, 16, or 20 weeks, according to the HDq12, HDq16, or HDq20 administration regimen, 8 mg of VEGF receptor This includes administering one or more maintenance doses of a fusion protein. (7) The subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein and a first secondary dose of 2 mg of VEGF receptor fusion protein one month later, and the method then comprises administering to the subject a second secondary dose of 8 mg of VEGF receptor fusion protein one month later, and thereafter administering one or more maintenance doses of 8 mg of VEGF receptor fusion protein every 12, 16, or 20 weeks thereafter, according to an HDq12, HDq16, or HDq20 administration regimen. (8) The subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein and a first secondary dose of 2 mg of VEGF receptor fusion protein one month later, and the method then comprises administering to the subject a first maintenance dose of 8 mg of VEGF receptor fusion protein one month later, and thereafter administering all further 8 mg of VEGF receptor fusion protein maintenance doses every 12, 16, or 20 weeks according to an HDq12, HDq16, or HDq20 administration regimen. (9) The subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein, a first secondary dose of 2 mg of VEGF receptor fusion protein one month later, and a second secondary dose of 2 mg of VEGF receptor fusion protein one month later, and the method then administers to the subject an initial dose of 8 mg of VEGF receptor fusion protein one month later, a first secondary dose of 8 mg of VEGF receptor fusion protein one month later, a second secondary dose of 8 mg of VEGF receptor fusion protein one month later, and thereafter administers one or more maintenance doses of 8 mg of VEGF receptor fusion protein every 12, 16, or 20 weeks according to an HDq12, HDq16, or HDq20 administration regimen. (10) The subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein, a first secondary dose of 2 mg of VEGF receptor fusion protein one month later, and a second secondary dose of 2 mg of VEGF receptor fusion protein one month later, and the method then administers to the subject a first secondary dose of 8 mg of VEGF receptor fusion protein one month later, a second secondary dose of 8 mg of VEGF receptor fusion protein one month later, and thereafter administers one or more maintenance doses of 8 mg of VEGF receptor fusion protein every 12, 16, or 20 weeks according to an HDq12, HDq16, or HDq20 administration regimen. (11) The subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein, a first secondary dose of 2 mg of VEGF receptor fusion protein one month later, and a second secondary dose of 2 mg of VEGF receptor fusion protein one month later, and the method then administers to the subject a second secondary dose of 8 mg of VEGF receptor fusion protein one month later, and thereafter administers one or more maintenance doses of 8 mg of VEGF receptor fusion protein every 12, 16, or 20 weeks according to an HDq12, HDq16, or HDq20 administration regimen. (12) The subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein, a first secondary dose of 2 mg of VEGF receptor fusion protein one month later, and a second secondary dose of 2 mg of VEGF receptor fusion protein one month later, and the method then comprises administering to the subject a first maintenance dose of 8 mg of VEGF receptor fusion protein two months later, and thereafter administering all further 8 mg of VEGF receptor fusion protein maintenance doses every 12, 16, or 20 weeks according to an HDq12, HDq16, or HDq20 administration regimen. (13) The subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein, a first secondary dose of 2 mg of VEGF receptor fusion protein one month later, a second secondary dose of 2 mg of VEGF receptor fusion protein one month later, and a first maintenance dose of 2 mg of VEGF receptor fusion protein eight weeks later, and the method then administers to the subject an initial dose of 8 mg of VEGF receptor fusion protein up to two months after the last dose of VEGF receptor fusion protein, and one month later, the first 8 The regimen includes administering a secondary dose of 8 mg of VEGF receptor fusion protein, followed one month later by a second secondary dose of 8 mg of VEGF receptor fusion protein, and then, every 12, 16, or 20 weeks thereafter, administering one or more maintenance doses of 8 mg of VEGF receptor fusion protein according to an HDq12, HDq16, or HDq20 administration regimen. (14) The subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein, a first secondary dose of 2 mg of VEGF receptor fusion protein one month later, a second secondary dose of 2 mg of VEGF receptor fusion protein one month later, and one or more maintenance doses of 2 mg of VEGF receptor fusion protein eight weeks later, and the method then administers to the subject a first secondary dose of 8 mg of VEGF receptor fusion protein up to two months after the last dose of VEGF receptor fusion protein, a second secondary dose of 8 mg of VEGF receptor fusion protein one month later, and then one or more maintenance doses of 8 mg of VEGF receptor fusion protein every 12, 16, or 20 weeks thereafter, according to an HDq12, HDq16, or HDq20 administration regimen. (15) The subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein, a first secondary dose of 2 mg of VEGF receptor fusion protein one month later, a second secondary dose of 2 mg of VEGF receptor fusion protein one month later, and one or more maintenance doses of 2 mg of VEGF receptor fusion protein eight weeks later, the method then administers to the subject a second secondary dose of 8 mg of VEGF receptor fusion protein up to two months after the last dose of VEGF receptor fusion protein, and thereafter administers one or more maintenance doses of 8 mg of VEGF receptor fusion protein every 12, 16, or 20 weeks according to an HDq12, HDq16, or HDq20 administration regimen. (16) The subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein, a first secondary dose of 2 mg of VEGF receptor fusion protein one month later, a second secondary dose of 2 mg of VEGF receptor fusion protein one month later, and one or more maintenance doses of 2 mg of VEGF receptor fusion protein eight weeks later, and the method then administers the subject a first maintenance dose of 8 mg of VEGF receptor fusion protein up to two months after the last dose of VEGF receptor fusion protein, and thereafter administers all further maintenance doses of 8 mg of VEGF receptor fusion protein every 12, 16, or 20 weeks thereafter, according to an HDq12, HDq16, or HDq20 administration regimen. (i) The HDq12 administration regimen is A single initial dose of approximately 8 mg or more of VEGF receptor fusion protein, followed by... One or more secondary doses of approximately 8 mg or more of the VEGF receptor fusion protein, followed by, The VEGF receptor fusion protein comprises one or more tertiary doses of approximately 8 mg or more, Each secondary dose is administered approximately 2 to 4 weeks after the previous dose. Each of the tertiary doses is administered approximately 12 weeks after the previous dose. (ii) The HDq16 administration regimen is A single initial dose of approximately 8 mg or more of VEGF receptor fusion protein, followed by... One or more secondary doses of approximately 8 mg or more of the VEGF receptor fusion protein, followed by, The VEGF receptor fusion protein comprises one or more tertiary doses of approximately 8 mg or more, Each secondary dose is administered approximately 2 to 4 weeks after the previous dose. Each of the tertiary doses is administered approximately 16 weeks after the previous dose. and (iii) The HDq20 administration regimen is, A single initial dose of approximately 8 mg or more of VEGF receptor fusion protein, followed by... One or more secondary doses of approximately 8 mg or more of the VEGF receptor fusion protein, followed by, The VEGF receptor fusion protein comprises one or more tertiary doses of approximately 8 mg or more, Each of the aforementioned secondary doses is administered approximately 2 to 4 weeks after the immediately preceding dose. A pharmaceutical composition in which each of the aforementioned tertiary doses is administered approximately 20 weeks after the immediately preceding dose.

35. A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method for treating or preventing neovascular age-related macular degeneration (nAMD) in subjects requiring it, (a) The subject is administered an initial dose of 8 mg of VEGF receptor fusion protein, and the method then administers to the subject a first secondary dose of 8 mg of VEGF receptor fusion protein one month later, a second secondary dose of 8 mg of VEGF receptor fusion protein one month thereafter, and then administers one or more maintenance doses of 8 mg of VEGF receptor fusion protein every 12, 16, or 20 weeks thereafter, according to an HDq12, HDq16, or HDq20 administration regimen. (b) The subject has been administered an initial dose of 8 mg of VEGF receptor fusion protein and a first secondary dose of 8 mg of VEGF receptor fusion protein one month later, and the method then administers to the subject a second secondary dose of 8 mg of VEGF receptor fusion protein one month later, and thereafter administers one or more maintenance doses of 8 mg of VEGF receptor fusion protein every 12, 16, or 20 weeks according to an HDq12, HDq16, or HDq20 administration regimen. (c) The subject has been administered an initial dose of 8 mg of VEGF receptor fusion protein, a first secondary dose of 8 mg of VEGF receptor fusion protein one month later, and a second secondary dose of 8 mg of VEGF receptor fusion protein one month later, and the method then comprises administering to the subject a first maintenance dose of 8 mg of VEGF receptor fusion protein 12, 16, or 20 weeks later, and thereafter administering all further maintenance doses of 8 mg of VEGF receptor fusion protein every 12, 16, or 20 weeks according to the HDq12, HDq16, or HDq20 administration regimen. or (d) The subject has been administered an initial dose of 8 mg of VEGF receptor fusion protein, a first secondary dose of 8 mg of VEGF receptor fusion protein one month later, a second secondary dose of 8 mg of VEGF receptor fusion protein one month later, and thereafter the subject has been administered one or more maintenance doses of 8 mg of VEGF receptor fusion protein every 12, 16, or 20 weeks, and the method then comprises administering to the subject one or more maintenance doses of 8 mg of VEGF receptor fusion protein 12, 16, or 20 weeks after the last maintenance dose of VEGF receptor fusion protein, and thereafter every 12, 16, or 20 weeks, all further maintenance doses of 8 mg of VEGF receptor fusion protein according to an HDq12, HDq16, or HDq20 dosing regimen. (i) The HDq12 administration regimen is A single initial dose of approximately 8 mg or more of VEGF receptor fusion protein, followed by... One or more secondary doses of approximately 8 mg or more of the VEGF receptor fusion protein, followed by, The VEGF receptor fusion protein comprises one or more tertiary doses of approximately 8 mg or more, Each of the aforementioned secondary doses is administered approximately 2 to 4 weeks after the immediately preceding dose. Each of the aforementioned tertiary doses is administered approximately 12 weeks after the immediately preceding dose. (ii) The HDq16 administration regimen is A single initial dose of approximately 8 mg or more of VEGF receptor fusion protein, followed by... One or more secondary doses of approximately 8 mg or more of the VEGF receptor fusion protein, followed by, The VEGF receptor fusion protein comprises one or more tertiary doses of approximately 8 mg or more, Each of the aforementioned secondary doses is administered approximately 2 to 4 weeks after the immediately preceding dose. Each of the aforementioned tertiary doses is administered approximately 16 weeks after the previous dose. and (iii) The HDq20 administration regimen is, A single initial dose of approximately 8 mg or more of VEGF receptor fusion protein, followed by... One or more secondary doses of approximately 8 mg or more of the VEGF receptor fusion protein, followed by, The VEGF receptor fusion protein comprises one or more tertiary doses of approximately 8 mg or more, Each of the aforementioned secondary doses is administered approximately 2 to 4 weeks after the immediately preceding dose. A pharmaceutical composition in which each of the aforementioned tertiary doses is administered approximately 20 weeks after the immediately preceding dose.

36. A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method for treating or preventing neovascular age-related macular degeneration (nAMD) in subjects requiring it, The subject is in an administration regimen for treating or preventing nAMD, which requires a single initial dose of approximately 2 mg of VEGF receptor fusion protein, followed by one or more secondary doses of approximately 2 mg of VEGF receptor fusion protein, followed by one or more tertiary doses of approximately 2 mg of VEGF receptor fusion protein, each of which is administered approximately 4 weeks after the previous dose, and each of which is administered approximately 8 weeks after the previous dose, and the subject is in any stage of the 2 mg VEGF receptor fusion protein administration regimen, and the method is In the eyes of the aforementioned subject, Administer a dose of 8 mg of VEGF receptor fusion protein, Approximately 8, 10, or 12 weeks after the administration, the subject will be evaluated, and if the treating physician determines that administration every 12 or 16 weeks is appropriate, the subject will continue to be administered 8 mg of VEGF receptor fusion protein every 12 or 16 weeks, or A pharmaceutical composition comprising: evaluating the subject approximately 8, 10, or 12 weeks after the administration described above; administering a further dose of 8 mg of VEGF receptor fusion protein if the treating physician determines that administration every 12 weeks is appropriate; re-evaluating the subject approximately 12 weeks later; and continuing to administer 8 mg of VEGF receptor fusion protein to the subject every 16 weeks if the treating physician determines that administration every 16 weeks is appropriate.

37. The aforementioned subject, In a regimen for treating or preventing neovascular age-related macular degeneration, the administration regimen for treating or preventing angiogenic age-related macular degeneration consists of a single initial dose of approximately 2 mg of VEGF receptor fusion protein, followed by two secondary doses of approximately 2 mg of VEGF receptor fusion protein, followed by one or more tertiary doses of approximately 2 mg of VEGF receptor fusion protein. Each secondary dose is administered approximately four weeks after the previous dose. The pharmaceutical composition according to any one of claims 1 to 14, 24, and 29 to 36, wherein each of the tertiary doses is administered approximately eight weeks after the immediately preceding dose.

38. The above method involves the subject's eyes, A single initial dose of approximately 8 mg or more of VEGF receptor fusion protein, followed by... One or more secondary doses of approximately 8 mg or more of the VEGF receptor fusion protein, followed by, This includes administering one or more tertiary doses of approximately 8 mg or more of the VEGF receptor fusion protein, Each secondary dose is administered approximately 2 to 4 weeks after the preceding dose, and each tertiary dose is administered approximately 12 or 16 weeks after the preceding dose. After one or more tertiary doses are administered approximately 12 or 16 weeks after the previous dose, the tertiary dose interval is set after the previous dose. ・ Between 12 and 16 weeks, ・ Between 12 and 20 weeks, or A pharmaceutical composition according to any one of claims 1 to 14, 24, and 29 to 36, for use in a method for treating or preventing neovascular age-related macular degeneration (nAMD) in subjects requiring treatment, further comprising extending the treatment period from 16 to 20 weeks.

39. The pharmaceutical composition according to claim 38, wherein the tertiary dose interval is adjusted to occur approximately 48 or 60 weeks after the start of treatment.

40. Prior to the extension, the subject (a) Loss of BCVA of less than 5 characters, and / or (b) The pharmaceutical composition according to claim 38, which exhibits a CRT of less than 300 or 320 μm.

41. To evaluate BVCA and / or CRT in the subject, (a) Loss of BCVA of less than 5 characters, and / or (b) If a CRT of less than 300 or 320 μm is present, The pharmaceutical composition according to claim 38, further comprising extending the tertiary dose interval.

42. The above method involves the subject's eyes, A single initial dose of approximately 8 mg or more of VEGF receptor fusion protein, followed by... One or more secondary doses of approximately 8 mg or more of the VEGF receptor fusion protein, followed by, This includes administering one or more tertiary doses of approximately 8 mg or more of the VEGF receptor fusion protein, Each of the aforementioned secondary doses is administered approximately 2 to 4 weeks after the immediately preceding dose. Each of the aforementioned tertiary doses is administered approximately 12, 16, or 20 weeks after the immediately preceding dose. After administering one or more tertiary doses approximately 12, 16, or 20 weeks after the preceding dose, the tertiary dose interval is as follows: From 12 weeks to 8 weeks, From 16 weeks to 12 weeks, From 16 weeks to 8 weeks, From 20 weeks to 8 weeks, - From 20 weeks to 12 weeks, or A pharmaceutical composition according to any one of claims 1 to 14, 24, and 29 to 36 for treating or preventing nAMD in subjects in need, further comprising shortening the treatment period from 20 weeks to 16 weeks.

43. Before the aforementioned shortening, the subject, (a) Loss of more than 10 BCVA characters compared to baseline, and / or (b) The present invention according to claim 42, exhibiting an increase of more than 50 μm in CRT compared to baseline. A pharmaceutical composition.

44. To evaluate the BVCA and / or CRT of the subject, (a) Loss of more than 10 BCVA characters compared to baseline, and / or (b) If the CRT shows an increase of more than 50 μm compared to baseline, The pharmaceutical composition according to claim 42, further comprising shortening the tertiary dose interval.

45. 16 or 20 weeks after the start of treatment, (a) Compared to the BCVA observed approximately 12 weeks after the start of treatment, more than 5 letters are lost in the BCVA (ETDRS). (b) A CRT increase of more than 25 micrometers is observed compared to the CRT observed approximately 12 weeks after the start of treatment, and / or (c) If there is newly developed foveal neovascularization or foveal hemorrhage, The interval between the aforementioned tertiary doses is shortened from 12 weeks or 16 weeks to 8 weeks, or 24 weeks after the start of treatment, (a) Compared to the BCVA observed approximately 12 weeks after the start of treatment, the BCVA (ETDRS) shows a decrease of more than 5 letters. (b) An increase in CRT of more than 25 micrometers is observed compared to the CRT observed approximately 12 weeks after the start of treatment, and / or (c) If there is newly developed foveal neovascularization or foveal hemorrhage, The pharmaceutical composition according to any one of claims 1 to 14, 24, and 29 to 36, wherein the interval between the tertiary doses is shortened from 16 weeks to 12 weeks.

46. The method comprises administering three doses of about 8 mg of VEGF receptor fusion protein in a formulation containing about 114.3 mg / ml of VEGF receptor fusion protein to the eyes of a subject at intervals of four weeks, and administering one or more doses of VEGF receptor fusion protein thereafter at intervals extended to up to 12, 16, or 20 weeks, for treating or preventing neovascular age-related macular degeneration in a subject in need, according to any one of claims 1 to 14, 24, and 29 to 36.

47. A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method for treating or preventing nAMD in a subject in need, wherein the method involves the subject's eyes, A single initial dose of approximately 8 mg or more of VEGF receptor fusion protein, followed by... Administering two secondary doses of approximately 8 mg or more of the VEGF receptor fusion protein, Each secondary dose is administered approximately 2 to 4 weeks after the preceding dose, and after the aforementioned dose, a) Determining whether the subject meets at least one criterion for reducing or extending one or more intervals between administrations of the VEGF receptor fusion protein by two weeks, three weeks, four weeks, or two to four weeks, b) If the determination is made, administer a further dose of the VEGF receptor fusion protein at the reduced or extended dose interval, The criteria for reducing the aforementioned interval are, 1. Loss of BCVA exceeding 1.5 characters, 2. Central retinal thickness (CRT) increase of more than 2.25 micrometers, 3. New foveal hemorrhage, and / or 4. Including new foveal angiogenesis, The criteria for extending the aforementioned interval are, 1. Loss of BCVA with less than 1.5 characters, 2. No fluid in the central subfield.

3. No new foveal hemorrhage, and / or 4. A pharmaceutical composition containing a substance without foveal neovascularization.

48. The criteria for extending the aforementioned interval are, 1. Loss of BCVA with fewer than 5 letters from week 12, 2. No fluid in the central subfield of the OCT, and 3. No new onset of foveal hemorrhage or foveal neovascularization, including, and / or, the criteria for shortening the interval are 1. Loss of BCVA of more than 5 letters from week 12, and 2. The pharmaceutical composition according to claim 47, comprising both an increase of more than 25 micrometers in central retinal thickness (CRT) from week 12, or new foveal hemorrhage or new foveal neovascularization.

49. The pharmaceutical composition according to claim 48, wherein the interval is extended to 12, 16, or 20 weeks if the aforementioned criteria are met.

50. The method described above involves pre-treating a subject who requires a VEGF receptor fusion protein with one or more doses, and then applying the protein to the subject's eye. A single initial dose of approximately 8 mg or more of VEGF receptor fusion protein, followed by... One or more secondary doses of approximately 8 mg or more of the VEGF receptor fusion protein, followed by, This includes administering one or more tertiary doses of approximately 8 mg or more of the VEGF receptor fusion protein, Each secondary dose is administered approximately 2 to 4 weeks after the previous dose. A pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, and 47 to 49, wherein each of the tertiary doses is administered approximately 12 to 20 weeks after the immediately preceding dose, for the treatment or prevention of neovascular age-related macular degeneration (nAMD).

51. A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method for treating or preventing neovascular ophthalmic disorders in a subject requiring such treatment, wherein the method involves applying the protein to the eye of the subject. (1) Administering a single initial dose of approximately 8 mg or more of VEGF receptor fusion protein, followed by one or more secondary doses of approximately 8 mg or more of VEGF receptor fusion protein, followed by one or more tertiary doses of approximately 8 mg or more of VEGF receptor fusion protein, wherein each secondary dose is administered approximately 2 to 4 weeks after the preceding dose, and each tertiary dose is administered approximately 8 weeks after the preceding dose, or (2) A pharmaceutical composition comprising administering one or more doses of VEGF receptor fusion protein of 8 mg or more approximately every four weeks.

52. The pharmaceutical composition according to claim 51, wherein the neovascular eye disorder is nAMD.

53. The pharmaceutical composition according to claim 51, wherein one or more secondary doses are two, three, or four secondary doses, and / or about two to four weeks is about four weeks.

54. Infection of the eye or around the eye, Active intraocular inflammation, and / or Subjects with one or more hypersensitivity reactions, A pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49, and 51 to 53, which is excluded from treatment or prevention.

55. The above method is for treating infections of the eye or around the eye. Active intraocular inflammation, and / or A step of evaluating the subject for hypersensitivity, A pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49, and 51 to 53, further comprising the step of excluding treatment or prevention of the subject if any one or more is found in the subject.

56. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49 and 51 to 53, further comprising monitoring the subject for conjunctival hemorrhage, cataracts, vitreous detachment, vitreous floaters, corneal epithelial defects, and / or elevated intraocular pressure during the treatment or prevention.

57. The above method, before any administration, - A single-dose glass vial with a protective plastic cap and stopper, containing an aqueous formulation containing 8 mg of VEGF receptor fusion protein in approximately 70 microliters. - One 18-gauge x 1.5-inch, 5-micron filter stylus including bevel, - One 30 gauge x 1 / 2 inch hypodermic needle, and - One 1 mL Luer lock syringe with graduation markings for a 70 microliter capacity. To package and provide them together, and then, (1) Visually inspect the aqueous formulation containing the VEGF receptor fusion protein, and if any particulate matter, cloudiness, or discoloration is observed, use a different vial of the aqueous formulation. (2) Remove the protective plastic cap from the vial, (3) Clean the top of the vial with an alcohol wipe, and then, Using sterile techniques, (4) Remove the 18 gauge x 1.5 inch, 5 micron filter needle and the 1 mL syringe from their packaging, (5) Attaching the filter needle to the syringe by twisting it on the tip of the Luer lock syringe, (6) Pushing the filter needle towards the center of the vial stopper until the needle is fully inserted into the vial and its tip contacts the bottom or bottom edge of the vial, (7) Withdraw all of the contents of the VEGF receptor fusion protein vial into the syringe, and while ensuring that the bevel of the filter needle is immersed in the liquid, hold the vial in an upright position and tilt it slightly, (8) Keeping the vial tilted during withdrawal so that the bevel of the filter needle remains submerged in the formulation, (9) In order to completely empty the filter needle, fully retract the plunger rod when emptying the vial, (10) Remove the filter needle from the syringe and discard the filter needle, (11) Remove the 30 gauge × 1 / 2 inch injection needle from its packaging and attach the injection needle to the syringe by twisting it firmly at the tip of the Luer lock syringe, (12) Hold the syringe with the needle pointing upwards, check the syringe for air bubbles, and if there are air bubbles, gently tap the syringe with your finger until the air bubbles rise to the top, (13) The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49 and 51 to 53, comprising: (13) slowly pushing down the plunger so that the tip of the plunger aligns with the line marking 70 microliters on the syringe. thing.

58. A pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49 and 51 to 53, wherein the VEGF inhibitor is a VEGF receptor fusion protein, the injection of the VEGF receptor fusion protein is performed under controlled sterile conditions, the sterile conditions include surgical hand disinfection and the use of sterile gloves, sterile drapes and sterile eyelid retractors (or equivalents), and an anesthetic and a local broad-spectrum microbial agent are administered before the injection.

59. The aforementioned subject, In a dosing regimen for treating or preventing nAMD, a single initial dose of approximately 2 mg of VEGF receptor fusion protein is required, followed by two secondary doses of approximately 2 mg of VEGF receptor fusion protein, followed by one or more tertiary doses of approximately 2 mg of VEGF receptor fusion protein, with each secondary dose administered approximately 4 weeks after the preceding dose, and each tertiary dose administered approximately 8 weeks after the preceding dose. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49, and 51 to 53, wherein the subject is in any stage (initial dose, secondary dose, or tertiary dose) of the 2 mg VEGF receptor fusion protein administration regimen.

60. - One or more secondary doses are two secondary doses. - 2 to 4 weeks is approximately 4 weeks. -12 to 20 weeks is approximately 12 weeks. - 12 to 20 weeks is approximately 16 weeks. -12 to 20 weeks is approximately 20 weeks. - 12 to 20 weeks is approximately 12 to 16 weeks. - 8 to 16 weeks is approximately 12 weeks. - 8 to 16 weeks is approximately 16 weeks. - 8 to 16 weeks is approximately 12 to 16 weeks. - 2 to 4 weeks is approximately 4 weeks, and one or more secondary doses are two secondary doses. -12 to 20 weeks is approximately 12 weeks, and one or more secondary doses are two secondary doses. -12 to 20 weeks is approximately 16 weeks, and one or more secondary doses are two secondary doses. -12 to 20 weeks is approximately 20 weeks, and one or more secondary doses are two secondary doses. - 12 to 20 weeks is approximately 12 to 16 weeks, and one or more secondary doses are two secondary doses. - 2 to 4 weeks is approximately 4 weeks, one or more secondary doses is two secondary doses, and the VEGF receptor fusion protein is aflibercept. -12 to 20 weeks is approximately 12 weeks, one or more secondary doses is two secondary doses, and the VEGF receptor fusion protein is aflibercept. -12 to 20 weeks is approximately 16 weeks, one or more secondary doses are two secondary doses, and the VEGF receptor fusion protein is aflibercept. -12 to 20 weeks is approximately 20 weeks, one or more secondary doses is two secondary doses, the VEGF receptor fusion protein is aflibercept, and / or - The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49 and 51 to 53, wherein 12 to 20 weeks is approximately 12 to 16 weeks, one or more secondary doses is two secondary doses, and the VEGF receptor fusion protein is aflibercept.

61. The aforementioned VEGF receptor fusion protein, (i) (1) VEGFR1 component containing amino acids 27-129 of SEQ ID NO: 2, (2) sequence (3) A polypeptide comprising two polypeptides: a VEGFR2 component containing amino acids 130-231 of number 2, and a polymerized component containing amino acids 232-457 of SEQ ID NO:

2. (ii) A polypeptide comprising the immunoglobulin-like (lg) domain 2 of VEGFR1, the lg domain 3 of VEGFR2, and two polymerizing components, (iii) Containing two polypeptides, including the immunoglobulin-like (lg) domain 2 of VEGFR1, the lg domain 3 of VEGFR2, the lg domain 4 of VEGFR2, and a polymerizing component, (vi) comprising two VEGFR1R2-FcΔC1(a) polypeptides encoded by the nucleic acid sequence of SEQ ID NO: 1, or (v) A pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49 and 51 to 53, selected from the group consisting of aflibercept and convercept.

62. The pharmaceutical composition according to claim 61, wherein the VEGF receptor fusion protein comprises amino acids 27 to 457 of the amino acid sequence shown in SEQ ID NO:

2.

63. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49, and 51 to 53, wherein the 8 mg of VEGF receptor fusion protein is present in an aqueous pharmaceutical formulation selected from the group consisting of A to KKKK.

64. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49, and 51 to 53, wherein 8 mg of VEGF receptor fusion protein is administered in an aqueous pharmaceutical formulation containing approximately 114.3 mg / ml of VEGF receptor fusion protein.

65. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49, and 51 to 53, wherein the VEGF receptor fusion protein is administered intravitreously from a syringe or a pre-filled syringe.

66. The pharmaceutical composition according to claim 65, wherein the syringe or pre-filled syringe is made of glass or plastic and / or is sterile.

67. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49, and 51 to 53, wherein the VEGF receptor fusion protein is injected intravitreously using a 30 gauge × 1 / 2 inch injection needle.

68. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49, and 51 to 53, wherein the subject has previously been administered one or more doses of 2 mg of VEGF receptor fusion protein.

69. A pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49 and 51 to 53, wherein one or more additional doses are administered.

70. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49, and 51 to 53, wherein 2 mg of VEGF receptor fusion protein is present in an aqueous pharmaceutical formulation containing 40 mg / ml of VEGF receptor fusion protein.

71. 2 mg of VEGF receptor fusion protein, The pharmaceutical composition according to claim 70, which is contained in a pharmaceutical formulation comprising 40 mg / ml of VEGF receptor fusion protein, 10 mM sodium phosphate, 40 mM NaCl, 0.03% polysorbate 20, and 5% sucrose at pH 6.

2.

72. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49, and 51 to 53, wherein 8 mg of VEGF receptor fusion protein is present in an aqueous pharmaceutical formulation containing a sugar or a polyol.

73. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49, and 51 to 53, wherein 8 mg of VEGF receptor fusion protein is present in an aqueous pharmaceutical formulation containing sucrose.

74. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49, and 51 to 53, wherein 8 mg of VEGF receptor fusion protein is present in an aqueous pharmaceutical formulation having a pH of approximately 5.

8.

75. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49, and 51 to 53, wherein 8 mg of VEGF receptor fusion protein is present in an aqueous pharmaceutical formulation containing approximately 103 to 126 mg / ml of VEGF receptor fusion protein, a histidine-based buffer, and arginine.

76. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49, and 51 to 53, wherein 8 mg of VEGF receptor fusion protein is present in an aqueous pharmaceutical formulation containing approximately 114.3 mg / ml of VEGF receptor fusion protein, a histidine-based buffer, and arginine.

77. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49, and 51 to 53, wherein the VEGF receptor fusion protein is present in an aqueous pharmaceutical formulation in an aqueous form, and the VEGF receptor fusion protein has a high molecular weight species of less than about 3.5% immediately after production and purification and / or a high molecular weight species of less than 6% after being stored at about 2 to 8°C for about 24 months.

78. The aforementioned 8 mg or more of VEGF receptor fusion protein, At least approximately 100 mg / ml of VEGF receptor fusion protein, Approximately 10-100 mM L-arginine, Sucrose and, Histidine-based buffer and It is present in an aqueous pharmaceutical formulation containing a surfactant, The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49, and 51 to 53, wherein the formulation has a pH of about 5.0 to about 6.8, and the VEGF receptor fusion protein has high molecular weight species of less than about 3.5% immediately after production and purification and / or high molecular weight species of less than 6% after being stored at about 2 to 8°C for about 24 months.

79. 8 mg of VEGF receptor fusion protein, VEGF receptor fusion protein at a concentration of 100 mg / ml or higher, histidine-based buffer, and L-arginine. - 140 mg / ml aflibercept, 20 mM histidine buffer, 5% sucrose, 0.03% polysorbate 20, 10 mM arginine, pH 5.

8. - 150 ± 15 mg / ml aflibercept, 10 mM phosphate buffer, 8 ± 0.8% (w / v) sucrose, 0.02–0.04% (w / v) polysorbate 20, 50 mM L-arginine, pH 5.9–6.

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

8. - 114.3 mg / ml aflibercept, 10 mM histidine buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, 50 mM L-arginine, pH 5.

8. - Aflibercept in concentrations exceeding 100 mg / ml, histidine-based buffer, and L-arginine. - The formulation forms less than 3% HMW aggregates after incubation at 5°C for 2 months, with aflibercept at a concentration of over 100 mg / ml and a pH of approximately 5.

8. - Approximately 114.3 mg / mL of aflibercept, 10 mM to 50 mM histidine-based buffer, sugar, nonionic surfactant, L-arginine, pH 5.8, or A pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49, and 51 to 53, comprising in an aqueous pharmaceutical formulation containing approximately 114.3 mg / mL of aflibercept, 10 mM His / His-HCl-based buffer, 5% sucrose, 0.03% polysorbate 20, 50 mM L-arginine, and pH 5.

8.

80. 8 mg of VEGF receptor fusion protein in approximately 100 μl or less, approximately 75 μl or less, approximately 70 μl or less, or approximately 50 μl, 51 μl, 52 μl, 53 μl, 54 μl, 55 μl, 56 μl, 57 μl, 58 μl, 59 μl, 60 μl, 61 μl, 62 μl, 63 μl, 64 μl, 65 μl, 66 μl, 67 μl, 68 μl, 69 μl, 70 μl, 71 μl, 72 μl, 73 μl, 74 μl, 75 μl, 7 A pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49 and 51 to 53, administered in amounts of 6 μl, 77 μl, 78 μl, 79 μl, 80 μl, 81 μl, 82 μl, 83 μl, 84 μl, 85 μl, 86 μl, 87 μl, 88 μl, 89 μl, 90 μl, 91 μl, 92 μl, 93 μl, 94 μl, 95 μl, 96 μl, 97 μl, 98 μl, 99 μl, or 100 μl.

81. The pharmaceutical composition according to claim 80, wherein the VEGF receptor fusion protein is administered in an amount of approximately 70 ± 4 or 5 microliters.

82. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49 and 51 to 53, wherein the method comprises administering the VEGF receptor fusion protein to both eyes of the subject.

83. The aforementioned subject, - An increase of 5 or more letters, 10 or more letters, 15 or more letters, or 20 or more letters in best corrected visual acuity (BCVA). - No decrease in best corrected visual acuity (BCVA) - Disappearance of retinal fluid, - Disappearance of intraretinal fluid (IRF) and / or subretinal fluid, - Reduction in the total area of ​​lesional choroidal neovascularization (CNV), - Loss or decrease of intraretinal fluid, - Loss or reduction of subretinal fluid, - Decrease in central subfield retinal thickness (CST), - Improving the quality of life related to vision, - Absence of treatment-induced adverse events (AEs) and / or serious AEs (SAEs), - At least 69 ETDRS character scores (approximately 20 / 40 Snellen equivalent tables), - Early treatment diabetic retinopathy screening (ETDRS) is measured using a visual acuity chart, with a maximum of 5 letters. Above, an improvement of BCVA of 10 or more characters, 15 or more characters, or 20 or more characters, or the absence of BCVA loss during the treatment process. - Average BCVA improvement over a 12-week period, - No intraretinal fluid (IRF) or subretinal fluid present. - Decrease in choroidal neovascularization (CNV) size, - Reduction in total lesion CNV area from baseline, Loss of IRF and / or SRF, - Decrease in central subfield retinal thickness (CST), - Improvement in vision-related quality of life as measured by the National Ophthalmological Institute Visual Function Questionnaire-25 (NEI-VFQ-25), - Absence of treatment-induced adverse events (AEs) and / or serious AEs (SAEs), In subjects with nAMD, the efficacy and / or safety of aflibercept administered intravitreally at a dose of 2 mg approximately every 4 weeks for the first 3 months, followed by a dose of 2 mg approximately every 8 weeks or every 2 months, with efficacy measured as an improvement in BCVA and / or a reduction in central retinal thickness, and safety measured as the incidence of adverse events such as elevated blood pressure, elevated intraocular pressure, visual impairment, vitreous disease, vitreous detachment, iris neovascularization, and / or vitreous hemorrhage. - No detection of anti-drug antibodies during treatment. - Improvement in best corrected visual acuity (BVCA) by the 4th, 8th, 12th, 16th, 20th, 24th, 28th, 32nd, 36th, 40th, 44th, 48th, 52nd, 56th, or 60th week from the start of treatment (baseline). - Improvement in BCVA of 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, or 7 or more characters, as measured by the Early Treatment Diabetic Retinopathy Screening (ETDRS) visual acuity chart or Snellen equivalent chart. - Within four weeks of the start of treatment, an improvement of approximately two or three letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq12 regimen, or approximately three letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq16 regimen, - Within 8 weeks of the start of treatment, an improvement of approximately 5 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq12 regimen, or approximately 4 or 5 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq16 regimen. - Within 12 weeks of the start of treatment, an improvement of approximately 5 or 6 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq12 regimen, or approximately 5 or 6 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq16 regimen, - Within 16 weeks after the start of treatment, an improvement of approximately 6 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq12 regimen, or approximately 6 or 7 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq16 regimen. - Within 20 weeks after the start of treatment, an improvement of approximately 6 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq12 regimen or approximately 6 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq16 regimen. - By the 24th week after the start of treatment, an improvement of approximately 5 or 6 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq12 regimen, or approximately 5 or 6 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq16 regimen, - Within 28 weeks after the start of treatment, an improvement of approximately 7 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq12 regimen, or approximately 6 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq16 regimen. - By the 32nd week after the start of treatment, an improvement of approximately 6 or 7 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq12 regimen, or approximately 7 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq16 regimen, - By week 36 after the start of treatment, approximately 6 or 7 letters of BCVA (ETDRS or Snellen equivalent table) for the HDq12 regimen, or approximately 6 letters for the HDq16 regimen. Improvement of the BCVA (ETDRS or Snellen equivalent table) for characters. - By 40 weeks after the start of treatment, an improvement of approximately 6 or 7 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq12 regimen, or approximately 5 or 6 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq16 regimen, - By 44 weeks after the start of treatment, an improvement of approximately 7 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq12 regimen, or approximately 5 or 6 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq16 regimen. - By 48 weeks after the start of treatment, an improvement of approximately 6 or 7 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq12 regimen, or approximately 6 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq16 regimen, - By the 52nd week after the start of treatment, an improvement of approximately 7 or 8 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq12 regimen, or approximately 6 or 7 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq16 regimen, - By week 56 after the start of treatment, an improvement of approximately 6 or 7 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq12 regimen, or approximately 6 or 7 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq16 regimen, - By 60 weeks after the start of treatment, an improvement of approximately 6 or 7 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq12 regimen, or approximately 6 or 7 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq16 regimen, - Within 48 to approximately 60 weeks after the start of treatment, improvement of approximately 6 or 7 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq12 regimen, or approximately 6 or 7 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq16 regimen. - By 60 weeks after the start of treatment, an improvement of approximately 5, 10, or 15 letters in the BCVA (ETDRS or Snellen equivalent table) for the HDq12 or HDq16 regimen, - Improvement in BCVA is achieved (approximately ±1 or ±2 ETDRS letters or Snellen equivalents) by approximately 8, 9, 10, 11, or 12 weeks after the start of treatment, and is maintained throughout the subsequent treatment regimen. • Within four weeks of the start of treatment, for the HDq12 regimen, a BCVA of approximately 63 characters (ETDRS or Snellen equivalent table) or for the HDq16 regimen, a BCVA of approximately 63 characters (ETDRS or Snellen equivalent table) • Within 8 weeks of the start of treatment, a BCVA of approximately 65 characters (ETDRS or Snellen equivalent table) for the HDq12 regimen or a BCVA of approximately 65 characters (ETDRS or Snellen equivalent table) for the HDq16 regimen. - By the 12th week after the start of treatment, a BCVA of approximately 66 characters (ETDRS or Snellen equivalent table) for the HDq12 regimen or a BCVA of approximately 66 characters (ETDRS or Snellen equivalent table) for the HDq16 regimen. - By the 16th week after the start of treatment, a BCVA of approximately 66 characters (ETDRS or Snellen equivalent table) for the HDq12 regimen or a BCVA of approximately 66 characters (ETDRS or Snellen equivalent table) for the HDq16 regimen. - Within 20 weeks of the start of treatment, a BCVA of approximately 66 characters (ETDRS or Snellen equivalent table) for the HDq12 regimen or a BCVA of approximately 66 characters (ETDRS or Snellen equivalent table) for the HDq16 regimen. - By the 24th week after the start of treatment, a BCVA of approximately 66 characters (ETDRS or Snellen equivalent table) for the HDq12 regimen or a BCVA of approximately 66 characters (ETDRS or Snellen equivalent table) for the HDq16 regimen, - By the 28th week after the start of treatment, a BCVA of approximately 67 characters (ETDRS or Snellen equivalent table) for the HDq12 regimen or a BCVA of approximately 66 characters (ETDRS or Snellen equivalent table) for the HDq16 regimen. - By week 32 after the start of treatment, the BCV should be approximately 67 characters long in the case of the HDq12 regimen. For regimens A (ETDRS or Snellen equivalent table) or HDq16, the BCVA (ETDRS or Snellen equivalent table) is approximately 67 characters long. - By the 36th week after the start of treatment, a BCVA of approximately 67 characters (ETDRS or Snellen equivalent table) for the HDq12 regimen or a BCVA of approximately 66 characters (ETDRS or Snellen equivalent table) for the HDq16 regimen. - By the 40th week after the start of treatment, a BCVA of approximately 67 characters (ETDRS or Snellen equivalent table) for the HDq12 regimen or a BCVA of approximately 66 characters (ETDRS or Snellen equivalent table) for the HDq16 regimen. - By the 44th week after the start of treatment, a BCVA of approximately 68 characters (ETDRS or Snellen equivalent table) for the HDq12 regimen or a BCVA of approximately 66 characters (ETDRS or Snellen equivalent table) for the HDq16 regimen. - By 48 weeks after the start of treatment, a BCVA of approximately 67 characters (ETDRS or Snellen equivalent table) for the HDq12 regimen or a BCVA of approximately 66 characters (ETDRS or Snellen equivalent table) for the HDq16 regimen. - By week 52 after the start of treatment, a BCVA of approximately 67 or 68 characters (ETDRS or Snellen equivalent table) for the HDq12 regimen, or a BCVA of approximately 66 or 67 characters (ETDRS or Snellen equivalent table) for the HDq16 regimen. - By week 56 after the start of treatment, a BCVA of approximately 66 or 67 characters (ETDRS or Snellen equivalent table) for the HDq12 regimen, or a BCVA of approximately 66 or 67 characters (ETDRS or Snellen equivalent table) for the HDq16 regimen, - By the 60th week after the start of treatment, a BCVA of approximately 66 or 67 characters (ETDRS or Snellen equivalent table) for the HDq12 regimen, or a BCVA of approximately 66 or 67 characters (ETDRS or Snellen equivalent table) for the HDq16 regimen, - Between 48 and approximately 60 weeks after the start of treatment, a BCVA of approximately 66 to 72 characters (ETDRS or Snellen equivalent table) for the HDq12 regimen, or a BCVA of approximately 66 to 70 characters (ETDRS or Snellen equivalent table) for the HDq16 regimen. - Retina without fluid (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF]) in the central subfield, - Absence of non-subretinal pigment epithelial fluid, - Absence of fluid leakage in fluorescein angiography (FA), - A decrease in central retinal thickness (CRT) of at least approximately 100, 125, 130, 135, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, or 150 micrometers. - Within four weeks of the start of treatment, a change in central retinal thickness of approximately -120, -121, -122, -122.4, or -120.2 micrometers (±10, 11, or 12 micrometers) is observed for the HDq12 regimen, or approximately -126, -127, -126.6, or -126.3 micrometers (±10, 11, or 12 micrometers) is observed for the HDq16 regimen. - Within 8 weeks after the start of treatment, a change in central retinal thickness of approximately -132, -133, -134, -135, -136, -136.2, or -132.8 micrometers (±10, 11, or 12 micrometers) is observed for the HDq12 regimen, or approximately -139, -140, -139.5, or -139.6 micrometers (±10, 11, or 12 micrometers) is observed for the HDq16 regimen. - Within 12 weeks after the start of treatment, a change in central retinal thickness of approximately -136, -137, -138, -139, -140, or -141, -140.9, or -136.6 micrometers (±10, 11, or 12 micrometers) for the HDq12 regimen, or approximately -144, -143, or -143.5 micrometers (±10, 11, or 12 micrometers) for the HDq16 regimen. - By the 16th week after the start of treatment, in the case of the HDq12 regimen, approximately -120 or A change in central retinal thickness of -121, -122, -123, -124, -123.4, or -120.1 micrometers (±approximately 10, 11, or 12 micrometers) or, in the case of the HDq16 regimen, approximately -132, -133, -132.1, or -133.1 micrometers (±approximately 10, 11, or 12 micrometers). - Within 20 weeks after the start of treatment, a change in central retinal thickness of approximately -110, -111, -112, -113, -114, -113.6, or -110.9 micrometers (±10, 11, or 12 micrometers) is observed for the HDq12 regimen, or approximately -115, -116, -117, -118, -115.8, or -117.7 micrometers (±10, 11, or 12 micrometers) is observed for the HDq16 regimen. - Within 24 weeks after the start of treatment, a change in central retinal thickness of approximately -134, -135, -136, -137, -138, -137.6, or -134.9 micrometers (±10, 11, or 12 micrometers) for the HDq12 regimen, or approximately -105, -106, -107, -108, -105.3, or -107.8 micrometers (±10, 11, or 12 micrometers) for the HDq16 regimen. - By 28 weeks after the start of treatment, a change in central retinal thickness of approximately -130, -131, -132, -133, -134, -133.7, or -130.7 micrometers (±10, 11, or 12 micrometers) is observed for the HDq12 regimen, or approximately -144, -145, -146, -147, -148, -144.7, or -147.2 micrometers (±10, 11, or 12 micrometers) is observed for the HDq16 regimen. - By 32 weeks after the start of treatment, a change in central retinal thickness of approximately -118 or -19 or -120 or -121 or -120.4 or -118.1 micrometers (±10, 11 or 12 micrometers) for the HDq12 regimen, or approximately -141 or -142 or -143 or -144 or -141.5 or -144 micrometers (±10, 11 or 12 micrometers) for the HDq16 regimen. - By 36 weeks after the start of treatment, a change in central retinal thickness of approximately -142, -143, -144, -144.2, or -142.2 micrometers (±10, 11, or 12 micrometers) is observed for the HDq12 regimen, or approximately -126, -127, -128, -129, -130, -131, -126.4, or -130.5 micrometers (±10, 11, or 12 micrometers) is observed for the HDq16 regimen. - Within 40 weeks after the start of treatment, a change in central retinal thickness of approximately -131, -132, -133, -134, -133.8, or -131.2 micrometers (±10, 11, or 12 micrometers) is observed for the HDq12 regimen, or approximately -127, -128, or 127.5 micrometers (±10, 11, or 12 micrometers) is observed for the HDq16 regimen. - By 44 weeks after the start of treatment, a change in central retinal thickness of approximately -120, -121, -122, -123, -124, -125, -124.7, or -120.3 micrometers (±10, 11, or 12 micrometers) is observed for the HDq12 regimen, or approximately -143, -144, -145, or -144.8 micrometers (±10, 11, or 12 micrometers) is observed for the HDq16 regimen. • By 48 weeks after the start of treatment, the diaphragm should be approximately -142, -143, -144, -144.4, or -142.3 micrometers (±10, 11, or 12 micrometers) for the HDq12 regimen, or approximately -143, -144, -145, -146, or -147 micrometers for the HDq16 regimen. The change in central retinal thickness is -148, -143.8, or -147.1 micrometers (± approximately 10, 11, or 12 micrometers). - By week 52 after the start of treatment, a change in central retinal thickness of approximately -143.2 micrometers (±10, 11, or 12 micrometers) for the HDq12 regimen or approximately -139.6 micrometers (±10, 11, or 12 micrometers) for the HDq16 regimen. - By week 56 after the start of treatment, a change in central retinal thickness of approximately -136.3 micrometers (±10, 11, or 12 micrometers) for the HDq12 regimen or approximately -137.5 micrometers (±10, 11, or 12 micrometers) for the HDq16 regimen. - By 60 weeks after the start of treatment, a change in central retinal thickness of approximately -151.8 micrometers (±10, 11, or 12 micrometers) for the HDq12 regimen or approximately -148.8 micrometers (±10, 11, or 12 micrometers) for the HDq16 regimen. • Within four weeks of the start of treatment, the central retinal thickness should be approximately 248.2 micrometers for the HDq12 regimen or approximately 244.1 micrometers for the HDq16 regimen. • By the 8th week after the start of treatment, the central retinal thickness should be approximately 234.4 micrometers for the HDq12 regimen or approximately 231.2 micrometers for the HDq16 regimen. • By the 12th week after the start of treatment, the central retinal thickness should be approximately 229.7 micrometers for the HDq12 regimen or approximately 226.7 micrometers for the HDq16 regimen. • By the 16th week after the start of treatment, the central retinal thickness should be approximately 247.2 micrometers for the HDq12 regimen or approximately 238.6 micrometers for the HDq16 regimen. • By the 20th week after the start of treatment, the central retinal thickness should be approximately 257 micrometers for the HDq12 regimen or approximately 254.9 micrometers for the HDq16 regimen. • By 24 weeks after the start of treatment, the central retinal thickness should be approximately 233 micrometers for the HDq12 regimen or approximately 265.4 micrometers for the HDq16 regimen. • By 28 weeks after the start of treatment, the central retinal thickness should be approximately 236.9 micrometers for the HDq12 regimen or approximately 226 micrometers for the HDq16 regimen. • By 32 weeks after the start of treatment, the central retinal thickness should be approximately 250.2 micrometers for the HDq12 regimen or approximately 229.2 micrometers for the HDq16 regimen. • By 36 weeks after the start of treatment, the central retinal thickness should be approximately 226.4 micrometers for the HDq12 regimen or approximately 244.3 micrometers for the HDq16 regimen. - By 40 weeks after the start of treatment, the central retinal thickness should be approximately 236.8 micrometers for the HDq12 regimen or approximately 243.7 micrometers for the HDq16 regimen. • By 44 weeks after the start of treatment, the central retinal thickness should be approximately 245.9 micrometers for the HDq12 regimen or approximately 227.7 micrometers for the HDq16 regimen. • By 48 weeks after the start of treatment, the central retinal thickness should be approximately 226.2 micrometers for the HDq12 regimen or approximately 226.9 micrometers for the HDq16 regimen. • By 52 weeks after the start of treatment, the central retinal thickness should be approximately 227.4 micrometers for the HDq12 regimen or approximately 231.1 micrometers for the HDq16 regimen. • By 56 weeks after the start of treatment, the central retinal thickness should be approximately 234.3 micrometers for the HDq12 regimen or approximately 233.2 micrometers for the HDq16 regimen. • By 60 weeks after the start of treatment, the central retinal thickness should be approximately 218.8 micrometers for the HDq12 regimen or approximately 221.9 micrometers for the HDq16 regimen. - The CRT (Critical Rate of Throat Radiation) up to approximately 4, 5, 6, 7, or 8 weeks after the start of treatment, or the decrease in CRT up to approximately 4, 5, 6, 7, or 8 weeks after the start of treatment, is maintained within approximately ±10, ±11, or ±12 micrometers during the subsequent treatment regimen. - Approximately 4 hours after the start of HDq12 or HDq16 treatment, the plasma free aflibercept concentration was approximately 0.0409 (±0.0605) or 0 mg / L (or less than 0.0156 mg / L). - Approximately 8 hours after the start of HDq12 or HDq16 treatment, the plasma free aflibercept concentration was approximately 0.05 (±3.78), 0.0973 (±0.102), or 0.0672 mg / L. - Approximately two days after the start of HDq12 or HDq16 treatment, the plasma free aflibercept concentration was approximately 0.11 (±2.21), 0.146 (±0.110), or 0.0903 mg / L. - Approximately 3 days after the start of HDq12 or HDq16 treatment, the plasma free aflibercept concentration was approximately 0.11 (±2.06), 0.137 (±0.0947), or 0.112 mg / L. - Approximately 5 days after the start of HDq12 or HDq16 treatment, the plasma free aflibercept concentration was approximately 0.08 (±1.86), 0.0933 (±0.0481), or 0.0854 mg / L. - Approximately 8 days after the start of HDq12 or HDq16 treatment, the free aflibercept concentration in plasma was approximately 0.07 (±1.75), 0.0794 (±0.0413), or 0.0682 mg / L. - Approximately 15 days after the start of HDq12 or HDq16 treatment, the plasma free aflibercept concentration was approximately 0.04 (±1.76), 0.0435 (±0.0199), or 0.0385 mg / L. - Approximately 22 days after the start of HDq12 or HDq16 treatment, the plasma free aflibercept concentration was approximately 0.02 (±1.76), 0.0213 (±0.0148), or 0.0232 mg / L. - Approximately 29 days after the start of HDq12 or HDq16 treatment, the plasma free aflibercept concentration was approximately 0.00766 (±0.00958) or 0 mg / L (or less than 0.0156 mg / L). - Approximately 4 hours after administration following the start of HDq12 or HDq16 treatment, the plasma concentration of modified conjugated aflibercept was approximately 0.00 mg / L. - Approximately 8 hours after administration following the start of HDq12 or HDq16 treatment, the plasma concentration of modified conjugated aflibercept was approximately 0.00 mg / L. - Approximately two days after the start of HDq12 or HDq16 treatment, the plasma concentration of adjusted conjugated aflibercept was approximately 0.06 (±3.50) or 0.124 (±0.186) mg / L. - Approximately 3 days after the start of HDq12 or HDq16 treatment, the plasma concentration of adjusted conjugated aflibercept was approximately 0.13 (±2.07) or 0.173 (±0.155) mg / L. Approximately 5 days after the start of HDq12 or HDq16 treatment, approximately 0.18 (±1.88) ) or a plasma concentration of 0.223 (±0.157) mg / L of adjusted conjugated aflibercept, - Approximately 8 days after the start of HDq12 or HDq16 treatment, the plasma concentration of adjusted conjugated aflibercept was approximately 0.31 (±1.56) or 0.334 (±0.135) mg / L. - Approximately 15 days after the start of HDq12 or HDq16 treatment, the plasma concentration of adjusted conjugated aflibercept was approximately 0.37 (±1.50) or 0.393 (±0.130) mg / L. - Approximately 22 days after the start of HDq12 or HDq16 treatment, the plasma concentration of adjusted conjugated aflibercept was approximately 0.25 (±3.00) or 0.335 (±0.155) mg / L. - Approximately 29 days after the start of HDq12 or HDq16 treatment, the plasma concentration of adjusted conjugated aflibercept was approximately 0.32 (±1.39) or 0.331 (±0.0953) mg / L. Compared to aflibercept, which is administered intravitreally at a dose of 2 mg approximately every 4 weeks for the first 5 injections, and then once every 8 weeks or once every 2 months at a dose of 2 mg, BVCA is non-inferior. - Similar to aflibercept administered intravitreally as 2 mg approximately every 4 weeks for the first 3, 4, or 5 injections, followed by 2 mg once every 8 weeks or once every 2 months, ocular and non-ocular safety or mortality in subjects suffering from DME. - Improvement in best corrected visual acuity within 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 weeks after the start of treatment. - An improvement in best corrected visual acuity of 2 or more letters, 3 or more letters, 4 or more letters, 5 or more letters, 6 or more letters, or 7 or more letters, as measured by the Early Treatment Diabetic Retinopathy Screening (ETDRS) visual acuity chart or Snellen equivalent chart, within 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, or 60 weeks after the start of treatment. - Within 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, or 60 weeks after the start of treatment, the central subfield of the retina is free of fluid (total fluid, retinal fluid [IRF], and / or subretinal fluid [SRF]). A pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49 and 51 to 53, which achieves and / or maintains one or more of the following reductions in central retinal thickness (CRT) of at least 100, 125, 130, 135, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, or 150 micrometers by 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, or 60 weeks after the start of treatment.

84. The pharmaceutical composition according to claim 83, wherein the dry retina lacks intraretinal fluid and / or subretinal fluid.

85. The pharmaceutical composition according to claim 83, wherein the dry retina is characterized by the absence of intraretinal fluid (IRF) and subretinal fluid (SRF) in the eye of the subject.

86. The pharmaceutical composition according to claim 83, wherein the dry retina is characterized by the absence of intraretinal fluid (IRF) and subretinal fluid (SRF) in the eye of the subject after the subject has been administered three monthly doses of VEGF receptor fusion protein.

87. - The subject is administered a single initial dose, two secondary doses, and three tertiary doses of 8 mg or more of the VEGF receptor fusion protein during the first year. - One initial dose of 8 mg or more of the VEGF receptor fusion protein, and two secondary doses. The amount, and two tertiary doses, are administered to the subject in the second year, or - The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49, and 51 to 53, wherein one initial dose, two secondary doses, and three tertiary doses of 8 mg or more of the VEGF receptor fusion protein are administered to the subject in the first year, and thereafter, two to four tertiary doses are administered in the second year.

88. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49 and 51 to 53, wherein the interval between doses is adjusted (increased / maintained / decreased) based on visual and / or anatomical results.

89. A pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49 and 51 to 53, wherein 12 to 20 weeks is 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks, and 2 to 4 weeks is 2, 3, 4, or 5 weeks.

90. A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method for treating or preventing neovascular age-related macular degeneration (nAMD) in subjects requiring it, wherein the method In the eyes of the aforementioned subjects, a single initial dose of approximately 8 mg or more of VEGF receptor fusion protein was administered. Next, one or more secondary doses of approximately 8 mg or more of VEGF receptor fusion protein, Next, the treatment includes administering one or more tertiary doses of approximately 8 mg or more of VEGF receptor fusion protein. Each secondary dose is administered approximately 2 to 4 weeks after the previous dose. Each of the tertiary doses is administered approximately 12 to 16 weeks after the previous dose. The VEGF receptor fusion protein is aflibercept, A pharmaceutical composition in which the intravitreous half-life of aflibercept is increased compared to the intravitreous half-life of aflibercept after intravitreous administration in a solution of 40 mg / mL aflibercept, 10 mM phosphate buffer, 5% sucrose, 0.03% polysorbate 20, 40 mM NaCl, and pH 6.2–6.

3.

91. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49, 51 to 53, and 90, wherein the VEGF receptor fusion protein of 8 mg or more is present in the aqueous pharmaceutical formulation, and after incubation at 37°C for 28 days, it forms 3 to 20% high molecular weight (HMW) aggregates, and after incubation at 5°C for 2 months, it forms HMW aggregates of less than 3%.

92. pro re nata (PRN), capped PRN or treat and A pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49, 51 to 53 and 90, further comprising one or more periods of extended (T&E) administration.

93. A pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 36, 47 to 49, 51 to 53 and 90, wherein the VEGF receptor fusion protein is aflibercept.

94. It's a kit, - A container for containing the VEGF receptor fusion protein, - Includes instructions for the use of the VEGF receptor fusion protein, The container is a vial or a pre-filled syringe. The container contains VEGF receptor fusion protein at a concentration of 100 mg / mL or more, or the container contains VEGF receptor fusion protein at a concentration of 114.3 mg / mL or more. The aforementioned instruction document is an instruction document for the administration of VEGF receptor fusion protein to nAMD patients. Includes, The aforementioned instruction includes instructions that treatment with 8 mg of VEGF receptor fusion protein should be initiated with three consecutive doses administered by monthly (every four weeks) injections. The instruction includes a statement that after the initial three consecutive doses, the injection interval may be extended up to every 16 weeks or every 20 weeks. A kit comprising instructions that allow the treatment interval to be adjusted based on the physician's judgment regarding visual and / or anatomical results.

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