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

Abstract

To provide a method for treating or preventing diabetic retinopathy and / or diabetic macular edema.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 US Provisional Patent Application No. 63 / 319,865 filed on March 15, 2022, US Provisional Patent Application No. 63 / 404,511 filed on September 7, 2022, and filed on September 8, 2022. U.S. Provisional Patent Application No. 63 / 404,889 filed on September 29, 2022, U.S. Provisional Patent Application No. 63 / 411,589 filed on September 30, 2022 / 412,158, U.S. Provisional Patent Application No. 63 / 421,296, filed November 1, 2022, U.S. Provisional Patent Application No. 63 / 434,918, filed December 22, 2022, February 9, 2023 U.S. Provisional Patent Application No. 63 / 444,470 filed on February 22, 2023, and Canadian Provisional Patent Application No. 3,190,726 filed on February 22, 2023. No. 1, 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 11192WO01_Sequence, created on March 13, 2023, and containing 5,464 bytes.

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

[0004] Diabetic retinopathy (DR) is the most common microvascular diabetic complication. Diabetic macular edema (DME), a manifestation of diabetic retinopathy, is a major cause of vision loss and blindness in subjects with diabetes and is the most common cause of blindness in young and middle-aged adults. If left untreated, approximately half of subjects with DME lose two or more lines of visual acuity (VA) within two years. Among subjects with diabetes, the prevalence of clinically significant macular edema (CSME) ranges from 2.77% to 7.6%.

[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 DME. be. Those treatments not only preserve visual function but also result in clinically meaningful visual improvements. Treatment of DME is chronic and lifelong in most subjects to control retinal edema and recurrence of choroidal neovascularization (CNV). 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 DME, but the efficacy and safety of currently approved VEGF antagonist therapies have been established for the treatment of DME, 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 DME. 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 targeted care and healthcare services.

[0008] 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]

[0009] The present invention provides a method for treating or preventing diabetic retinopathy and / or diabetic macular edema, the method providing a method for treating or preventing diabetic retinopathy and / or diabetic macular edema, wherein the clearance of free aflibercept from the ocular compartment after intravitreal injection of aflibercept is approximately 0.367-0.458 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 as described above. is about 15 weeks, and the time it takes for free aflibercept in the subject's plasma to reach the lower limit of quantification (LLOQ) (e.g., about 0.0156 mg / L) after the above intravitreal injection of aflibercept is about 3.5 weeks. including administering one or more doses (e.g., 8 mg or more) of aflibercept, such that the aflibercept is in an aqueous pharmaceutical formulation; have less than about 3.5% high molecular weight species immediately 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 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.

[0010] 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.

[0011] 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 patient 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, each of the secondary doses being administered approximately 2 to 4 weeks after the immediately preceding dose, and each of the tertiary doses being approximately 12 to 4 weeks after the immediately preceding dose. Administered after 20 weeks.

[0012] 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, each of the secondary doses being administered approximately 2 to 4 weeks after the immediately preceding dose, and each of the tertiary doses being approximately 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. The drug is administered in an aqueous pharmaceutical formulation containing aflibercept, 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 aqueous pharmaceutical formulation comprising immunoglobulin-like (Ig) domain 2 of VEGFR1, Ig domain 3 of VEGFR2, and the multimerizing component, respectively. the formulation comprises at least about 100 mg / ml of a VEGF receptor fusion protein containing two polypeptides containing at least about 100 mg / ml of a VEGF receptor fusion protein, about 10 to 100 mM of L-arginine, sucrose, a histidine-based buffer, and a surfactant; With a pH of 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 less than about 6% after storage for about 24 months at about 2-8°C. It has high molecular weight species.

[0013] The present invention is used to improve best-corrected visual acuity (BCVA) in subjects in need with diabetic retinopathy (DR) and / or diabetic macular edema (DMA), or in need with DR and / or DME. Provided are methods for treating or preventing DR and / or DME in a subject in need thereof to promote retinal dryness in a subject in need thereof; , 16, 17, 18, 19, or 20, or 12 to 20, or 12 to 16, or 16 to 20 weeks, one time of about 8 mg or more of a VEGF receptor fusion protein, preferably aflibercept. or including administering multiple doses. In one embodiment of the invention, the method comprises administering to the subject's eye a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, preferably aflibercept, followed by administering a single initial dose of about 8 mg or more of a VEGF receptor fusion protein to the subject's eye. 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 secondary dose being about 8 mg or more of the immediately preceding dose. It is administered 2 to 4 weeks (preferably 4 weeks) later, with each tertiary dose being administered about 12 to 20 weeks after the previous dose.

[0014] The present invention also provides a method of treating or preventing diabetic retinopathy (DR) and / or diabetic macular edema (DME) in a subject in need thereof, the method comprising administering about 8 mg or more of blood to the eye of the subject. of a VEGF receptor fusion protein, preferably aflibercept, followed by one or more secondary doses of a VEGF receptor fusion protein of about 8 mg or more, followed by about 8 mg or more of a VEGF receptor fusion protein, preferably aflibercept. administering one or more tertiary doses of the body fusion protein, 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 2 to 4 weeks (preferably 4 weeks) after the immediately preceding dose; is administered approximately 12 weeks after the first dose.

[0015] The present invention also provides a method of treating or preventing diabetic retinopathy (DR) or diabetic macular edema (DME) in a subject in need thereof, the method comprising administering to the eye of the subject about 8 mg or more of VEGF receptor. a single initial dose of body fusion protein, preferably aflibercept, 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. 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 about 2 to 4 weeks (preferably 4 weeks) after the immediately preceding dose. It will be administered approximately 16 weeks later.

[0016] The present invention provides a method of treating or preventing diabetic retinopathy (DR) or diabetic macular edema (DME) in a subject in need thereof, the method comprising administering about 8 mg or more of VEGF receptor to the subject's eye. A single initial dose of the fusion protein, preferably aflibercept, followed by one or more secondary doses of about 8 mg or more of the VEGF receptor fusion protein, followed by about 8 mg or more of the VEGF receptor fusion protein. administering one or more 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 2 to 4 weeks (preferably 4 weeks) after the immediately preceding dose; administered after 20 weeks; In one embodiment of the invention, a method for treating or preventing DR and / or DME in a subject in need thereof 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 of VEGF receptor fusion protein (0.07 mL) for 8 to 16 weeks (approximately every 28 days + / - 7 days, monthly). It involves administration by intravitreal injection once every 2 to 4 months + / -7 days). In one embodiment of the invention, the method comprises administering 8 mg of a VEGF receptor fusion protein, preferably aflibercept (0.07 mL or 70 microliters) every 4 weeks (approximately 28 days + / - - every 7 days, monthly) by intravitreal injection, followed by 8 mg of VEGF receptor fusion protein (0.07 mL) by intravitreal injection once every 12 weeks (2-4 months + / - 7 days). including administering. In one embodiment of the invention, the method comprises administering 8 mg of a VEGF receptor fusion protein, preferably aflibercept (0.07 mL or 70 microliters) every 4 weeks (approximately 28 days + / - - every 7 days, monthly) by intravitreal injection, followed by 8 mg of VEGF receptor fusion protein (0.07 mL) by intravitreal injection once every 16 weeks (2-4 months + / - 7 days). including administering. In one embodiment of the invention, the method comprises administering 8 mg of a VEGF receptor fusion protein, preferably aflibercept (0.07 mL or 70 microliters) every 4 weeks (approximately 28 days + / - - every 7 days, monthly) by intravitreal injection, followed by 8 mg of VEGF receptor fusion protein (0.07 mL) once every 20 weeks (+ / -7 days) by intravitreal injection. include.

[0017] The invention also provides a method for treating or preventing diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, comprising: (1) administering an initial dose of 2 mg of VEGF receptor fusion protein to a subject; 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 secondary dose of VEGF receptor fusion protein, then every 12 or 16 or 20 weeks thereafter, according to the HDq12 or HDq16 or HDq20 dosing regimen. (2) the subject has been administered an initial dose of 2 mg of the VEGF receptor fusion protein; , one month later, a first 8 mg secondary dose of VEGF receptor fusion protein was administered, one month later a second 8 mg VEGF receptor fusion protein secondary dose was administered, and then 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, and (3) the subject receives 2 mg VEGF receptor fusion protein. the subject has been administered an initial dose of fusion protein, and then the method administers to the subject, one month later, a second 8 mg secondary dose of VEGF receptor fusion protein, and then 12 or 16 or 20 mg thereafter. (4) administering one or more maintenance doses of 8 mg VEGF receptor fusion protein weekly according to HDq12 or HDq16 or HDq20 dosing regimens; dose, 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 thereafter, the subject receives HDq12 or HDq16. or HDq20 dosing regimen, including administering every additional 8 mg VEGF receptor fusion protein maintenance dose; (5) subject receives an initial dose of 2 mg 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, one month later, an initial dose of 8 mg of 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 12 or 16 or 20 (6) administering one or more maintenance doses of 8 mg VEGF receptor fusion protein weekly according to HDq12 or HDq16 or HDq20 dosing regimens; dose and, one month later, a second dose of 2 mg of VEGF receptor fusion protein; Administer a second dose of fusion protein, then one month later administer a second 8 mg second dose of VEGF receptor fusion protein, then every 12 or 16 or 20 weeks thereafter HDq12 or HDq16 or HDq20 (7) Subjects receive an initial dose of 2 mg VEGF receptor fusion protein and, one month later, a first 2 mg of VEGF receptor fusion protein, and the method then administers to the subject a second 8 mg VEGF receptor fusion protein one month later. and then administering one or more maintenance doses of 8 mg of VEGF receptor fusion protein according to an HDq12 or HDq16 or HDq20 dosing regimen every 12 or 16 or 20 weeks thereafter, (8) the subject The subject has been administered 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; , 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 and, 1 month later, a second dose of 2 mg of 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, an initial dose of 8 mg of VEGF receptor fusion protein; After 1 month, administer the first 8 mg secondary dose of VEGF receptor fusion protein, and 1 month later, administer the second 8 mg VEGF receptor fusion protein secondary dose, then 12 or 16 days later. or every 20 weeks, administering one or more maintenance doses of 8 mg VEGF receptor fusion protein according to a HDq12 or HDq16 or HDq20 dosing regimen, and (10) the subject receives 2 mg 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 secondary dose of 8 mg VEGF receptor fusion protein one month later, and a second secondary dose of 8 mg VEGF receptor fusion protein one month later. 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. a second dose of VEGF receptor fusion protein, the method then administers to the subject a second second dose of 8 mg of VEGF receptor fusion protein one month later, and then 12 or (12) 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 protein was administered, followed one month later by a second dose of 2 mg of VEGF receptor fusion protein, and one 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, followed by a HDq12 or HDq16 or HDq20 dosing regimen every 12 or 16 or 20 weeks thereafter. (13) in which subjects received an initial dose of 2 mg VEGF receptor fusion protein and, one month later, a first dose of 2 mg VEGF receptor fusion protein. a second dose of body fusion protein, followed one month later by a second secondary dose of 2 mg VEGF receptor fusion protein, and one month later a third maintenance dose of 2 mg 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 a second dose of VEGF receptor fusion protein; Administer a second 8 mg VEGF receptor fusion protein sub-dose, then one month later, administer a second 8 mg VEGF receptor fusion protein sub-dose, then every 12 or 16 or 20 weeks thereafter. (14) in which the subject receives an initial dose of 2 mg VEGF receptor fusion protein and , 1 month later, a first 2 mg secondary dose of VEGF receptor fusion protein, 1 month later a second 2 mg VEGF receptor fusion protein secondary dose, and 1 month later a third dose of 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 dose of 8 mg of VEGF receptor fusion protein; Administer a second 8 mg VEGF receptor fusion protein secondary dose one month later, then every 12 or 16 or 20 weeks thereafter, 8 mg VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen. (15) in which the subject receives an initial dose of 2 mg VEGF receptor fusion protein and, 1 month later, a second dose of 2 mg VEGF receptor fusion protein. dose, and one month later, a second 2 mg secondary dose of VEGF receptor fusion protein, and one month later, a third 2 mg secondary dose of VEGF receptor fusion protein, and then , the method involves administering to the subject a second 8 mg secondary dose of VEGF receptor fusion protein one month later, and then administering a HDq12 or HDq16 or HDq20 dosing regimen every 12 or 16 or 20 weeks thereafter. (16) in which subjects receive an initial dose of 2 mg VEGF receptor fusion protein and, 1 month later, a first dose of 2 mg VEGF receptor fusion protein. of VEGF receptor fusion protein, followed one month later by a second second dose of 2 mg VEGF receptor fusion protein, and one month later, a third dose of 2 mg VEGF receptor fusion protein. VEGF receptor fusion protein, the method then administers to the subject, two months later, a first maintenance dose of 8 mg of VEGF receptor fusion protein, and then every 12 or 16 or 20 weeks thereafter, or administering all additional maintenance doses of 8 mg VEGF receptor fusion protein according to HDq16 or HDq20 dosing regimens (17) in which subjects receive an initial dose of 2 mg VEGF receptor fusion protein and 1 month later, A second dose of 2 mg of VEGF receptor fusion protein, followed one month later by a second dose of 2 mg of VEGF receptor fusion protein, and one month later, a third dose of 2 mg of VEGF receptor fusion protein. a second dose of protein, one month later a fourth second dose of 2 mg of VEGF receptor fusion protein, and then the method administers a second dose of 8 mg of VEGF receptor fusion protein two months later Initial dose administered, 1 month later, first 8 mg secondary dose of VEGF receptor fusion protein, followed 1 month later by second 8 mg VEGF receptor fusion protein secondary dose (18) the subject an initial dose of 2 mg of VEGF receptor fusion protein, followed by a second dose of 2 mg of VEGF receptor fusion protein after 1 month, and a second dose of 2 mg of VEGF receptor fusion protein after 1 month. one month later, a third 2 mg secondary dose of VEGF receptor fusion protein; one month later, a fourth 2 mg secondary dose of VEGF receptor fusion protein; , the method involves administering to a subject, two months 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 administering one or more maintenance doses of 8 mg of VEGF receptor fusion protein according to a HDq12 or HDq16 or HDq20 dosing regimen every 12 or 16 or 20 weeks thereafter, (19) Subjects received an initial dose of 2 mg VEGF receptor fusion protein, 1 month later a second 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 VEGF receptor fusion protein, followed one month later by a third dose of 2 mg of VEGF receptor fusion protein, and one month later a fourth dose of 2 mg of VEGF receptor fusion protein; The method then administers to the subject a second 8 mg secondary dose of VEGF receptor fusion protein two months later, and then 12 or 16 or 20 weeks later according to the HDq12 or HDq16 or HDq20 dosing regimen. , including administering one or more maintenance doses of 8 mg VEGF receptor fusion protein every 12 or 16 weeks, (20) in which subjects received an initial dose of 2 mg VEGF receptor fusion protein and 1 month later , a first secondary dose of 2 mg VEGF receptor fusion protein, followed one month later by a second secondary dose of 2 mg VEGF receptor fusion protein, and one month later a third dose of 2 mg VEGF receptor. a second dose of VEGF receptor fusion protein and, one month later, a fourth 2 mg second dose of VEGF receptor fusion protein; Administer the first 8 mg VEGF receptor fusion protein maintenance dose, then every 12 or 16 or 20 weeks, administer all additional 8 mg VEGF receptor fusion protein maintenance doses according to the HDq12 or HDq16 or HDq20 dosing regimen. including doing; (21) 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 one month later by a third dose of 2 mg of VEGF receptor fusion protein, and one month later, a fourth dose of 2 mg of VEGF receptor fusion protein; one or more maintenance doses of 2 mg every 8 weeks thereafter; An initial dose of the fusion protein was administered, followed one month later by 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. 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, 22) Subjects received an initial dose of 2 mg of VEGF receptor fusion protein, followed one month later by a second dose of 2 mg of VEGF receptor fusion protein, and one month later, a second dose of 2 mg of VEGF receptor fusion protein. A second dose of protein, followed one month later by a third dose of 2 mg of VEGF receptor fusion protein, then one month later, a fourth dose of 2 mg of VEGF receptor fusion protein, then one or more maintenance doses of 2 mg every 8 weeks, and then the method involves subjecting the subject to a first 8 mg VEGF dose 2 months after the last maintenance 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 (23) in which subjects receive 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, one month later a third dose of 2 mg VEGF receptor A second dose of the fusion protein was administered, followed one month later by a fourth secondary dose of 2 mg of the VEGF receptor fusion protein, followed by one or more maintenance doses of 2 mg every 8 weeks. , the method then administers to the subject a second 8 mg secondary dose of VEGF receptor fusion protein 2 months after the last maintenance dose of VEGF receptor fusion protein, and then 12 or 16 or 20 weeks later. , administering one or more maintenance doses of 8 mg VEGF receptor fusion protein every 12 or 16 or 20 weeks according to an HDq12 or HDq16 or HDq20 dosing regimen, (24) in which the subject received 2 mg VEGF receptor fusion protein. an initial dose of VEGF receptor fusion protein and, 1 month later, a first 2 mg secondary dose of VEGF receptor fusion protein; 1 month later, a second 2 mg secondary dose of VEGF receptor fusion protein; One month later, a third secondary dose of 2 mg VEGF receptor fusion protein, followed one month later by a fourth secondary dose of 2 mg VEGF receptor fusion protein, then one 2 mg dose every 8 weeks. or multiple maintenance doses, and the method then administers to the subject a first 8 mg maintenance dose of VEGF receptor fusion protein two months after the last maintenance dose of VEGF receptor fusion protein. and then every 12 or 16 or 20 weeks, administering every additional 8 mg maintenance dose of VEGF receptor fusion protein according to an HDq12 or HDq16 or HDq20 dosing regimen, wherein (i) said HDq12 dosing regimen is , a single initial dose of a VEGF receptor fusion protein of about 8 mg or more, followed by one or more secondary doses of a VEGF receptor fusion protein of about 8 mg or more, followed by a VEGF receptor fusion of about 8 mg or more administering one or more tertiary doses of the protein, 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 2 to 4 weeks (preferably 4 weeks) after the immediately preceding dose; It is administered approximately 12 weeks after. (ii) the 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; 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 (preferably 4) weeks after the immediately preceding dose; each of the doses is administered about 16 weeks after the immediately preceding dose, and (iii) the HDq20 dosing regimen described above includes a single initial dose of about 8 mg or more of the VEGF receptor fusion protein, followed by a single initial dose of about 8 mg or more of the VEGF receptor fusion protein; comprising one or more secondary doses of protein, followed by one or more third doses of about 8 mg or more of VEGF receptor fusion protein, with each secondary dose about 2 to 4 times the previous dose. (preferably 4) weeks later, each tertiary dose being administered about 20 weeks after the previous dose, and preferably the VEGF receptor fusion protein is aflibercept.

[0018] The invention also provides a method for treating or preventing diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, wherein the subject receives a medication regimen to treat or prevent the disorder. (a) the subject is administered an initial dose of 8 mg of VEGF receptor fusion protein; the method administers to the subject a second dose of 8 mg of VEGF receptor fusion protein one month later; 1 month later, a second 8 mg secondary dose of VEGF receptor fusion protein is administered, then every 12 or 16 or 20 weeks thereafter according to the HDq12 or HDq16 or HDq20 dosing regimen. or (b) the subject receives an initial dose of 8 mg of VEGF receptor fusion protein and, one month later, a first dose of 8 mg of VEGF receptor fusion protein. a second dose of VEGF receptor fusion protein, and then the method involves administering to the subject a second second dose of 8 mg VEGF receptor fusion protein one month later, and then 12 or 16 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; or (c) the subject receives 8 mg of VEGF receptor fusion protein. 1 month later, a second dose of 8 mg VEGF receptor fusion protein, and 1 month later, a second dose of 8 mg VEGF receptor fusion protein. , the method then administers to the subject a first maintenance dose of 8 mg of VEGF receptor fusion protein 12 or 16 or 20 weeks later, and then every 12 or 16 or 20 weeks thereafter, HDq12 or HDq16 or HDq20. or (d) the subject receives an initial dose of 8 mg VEGF receptor fusion protein and, one month later, a first 8 mg maintenance dose of VEGF receptor fusion protein according to the dosing regimen. of VEGF receptor fusion protein, followed one month later by a second secondary dose of 8 mg VEGF receptor fusion protein, and then 12 or 16 or 20 weeks later, a second dose of 8 mg VEGF receptor fusion protein. and one or more maintenance doses, and the method then administers to the subject 8 mg of VEGF receptor fusion protein 12 or 16 or 20 weeks after the last maintenance dose of VEGF receptor fusion protein. and then every 12 or 16 or 20 weeks thereafter every additional 8 mg maintenance dose of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen. (i) the HDq12 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 third doses of about 8 mg or more of the VEGF receptor fusion protein, each second dose about 2 to 4 weeks (preferably 4 weeks) after the previous dose. each tertiary dose is administered approximately 12 weeks after the previous dose. (ii) the 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; 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 (preferably 4) weeks after the immediately preceding dose; each of the doses is administered about 16 weeks after the immediately preceding dose, and (iii) the HDq20 dosing regimen described above includes a single initial dose of about 8 mg or more of the VEGF receptor fusion protein, followed by a single initial dose of about 8 mg or more of the VEGF receptor fusion protein; comprising one or more secondary doses of protein, followed by one or more third doses of about 8 mg or more of VEGF receptor fusion protein, with each secondary dose about 2 to 4 times the previous dose. (preferably 4) weeks later, each tertiary dose being administered about 20 weeks after the previous dose, and preferably the VEGF receptor fusion protein is aflibercept.

[0019] The present invention also provides a method for treating or preventing an angiogenic eye disorder (preferably DR and / or DME) in a subject in need thereof, wherein the subject receives about 2 mg of a VEGF receptor fusion protein, preferably A single initial dose of aflibercept, 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 a disorder requiring doses, each secondary dose being administered approximately 4 weeks after the immediately preceding dose, and each tertiary dose being administered approximately 8 weeks after the immediately preceding dose. the subject is at any stage on a 2 mg VEGF receptor fusion protein dosing regimen, and the method includes administering to the subject's eye an 8 mg dose of the VEGF receptor fusion protein; Evaluate the subject after approximately 8 or 10 or 12 weeks and if, in the judgment of the treating physician, dosing every 12 weeks or every 16 weeks is appropriate, 8 mg of VEGF receptor fusion protein every 12 weeks or every 16 weeks. Continue dosing the subject every 12 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, an additional 8 mg of VEGF receptor fusion dose of protein, re-evaluate the subject approximately 12 weeks later, and continue administering 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.

[0020] In one embodiment of the invention, a subject in a method of the invention receives a single initial dose of about 2 mg of VEGF receptor fusion protein, preferably aflibercept, followed by four doses of about 2 mg of VEGF receptor fusion protein. in a dosing regimen for treating or preventing diabetic retinopathy and / or diabetic macular edema of a second dose of VEGF receptor fusion protein, followed by one or more third doses of about 2 mg of VEGF receptor fusion protein; Each secondary dose is administered about 4 weeks after the previous dose and each tertiary dose is administered about 8 weeks after the previous dose.

[0021] The invention also provides a method of treating or preventing diabetic retinopathy or diabetic macular edema in a subject in need thereof, the method comprising administering to the subject's eye about 8 mg or more of a VEGF receptor fusion protein, preferably 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 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. administered and one or more of the above tertiary doses administered approximately 12 or 16 weeks after the immediately preceding dose, increasing the interval between tertiary doses from 12 weeks to 16 weeks after the immediately preceding dose, from 12 weeks to 20 weeks after the immediately preceding dose. further including extending from 16 weeks to 20 weeks. For example, in one embodiment of the invention, during the treatment, the subject exhibits (a) a loss of BCVA of less than 5 letters, and / or (b) a central retinal thickness (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 interval between tertiary doses if present.

[0022] The present invention provides a method of treating or preventing diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, the method comprising administering to the subject's eye 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 about 12 or 16 or more of the immediately preceding dose. 20 weeks later and one or more of the above tertiary doses administered about 12 or 16 or 20 weeks after the previous dose, increasing the interval between tertiary doses from 12 weeks to 8 weeks, from 16 weeks to 12 It further includes reducing the number of weeks from 16 weeks to 8 weeks, from 20 weeks to 8 weeks, from 20 weeks to 12 weeks, or from 20 weeks to 16 weeks. In one embodiment of the invention, during the treatment, the subject experiences (a) a loss in BCVA of more than 10 letters compared to baseline, and / or (b) a loss of more than 50 μm in CRT compared to baseline. Indicates an increase. For example, in one embodiment of the invention, the method assesses a subject's BVCA and / or CRT and determines whether the subject has (a) a loss in BCVA of more than 10 letters compared to baseline, and / or (b) Further including shortening the tertiary dose interval if CRT increases by >50 μm compared to baseline.

[0023] In one embodiment of the invention, (a) there is a loss of more than 5 letters in the BCVA (ETDRS) compared to the BCVA observed at about 12 weeks after the start of treatment; (b) after the start of treatment; a CRT increase of greater than 25 micrometers is observed compared to the CRT observed at approximately 12 weeks, and / or (c) a newly developed center, e.g., at 16 or 20 weeks after initiation of treatment. If there is foveal neovascularization or foveal hemorrhage, the tertiary dose interval is reduced from 12 or 16 weeks to 8 weeks, or (a) compared to the BCVA observed at approximately 12 weeks after initiation of treatment; , more than 5 letters are lost in BCVA (ETDRS), (b) a CRT increase of more than 25 micrometers is observed compared to the CRT observed approximately 12 weeks after initiation of treatment, and / or (c) if there is new-onset foveal neovascularization or foveal hemorrhage, for example, 24 weeks after initiation of treatment, the interval between tertiary doses is shortened from 16 weeks to 12 weeks.

[0024] The present invention provides a method for treating or preventing diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, wherein about 8 mg / ml of VEGF receptor fusion protein in a formulation comprising about 114.3 mg / ml of VEGF receptor fusion protein. comprising administering three doses of a VEGF receptor fusion protein, preferably aflibercept, to the subject's eye at intervals of once every four weeks, and after said three doses 12, 16, or 20 doses. The method comprises administering one or more doses of the VEGF receptor fusion protein at intervals extended to weeks.

[0025] The present invention provides a method for treating or preventing diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, the method comprising administering about 8 mg or more of a VEGF receptor fusion protein to the eye of a subject. , preferably a single initial dose of aflibercept, followed by two secondary doses of VEGF receptor fusion protein of about 8 mg or more, each secondary dose being about 2 times the previous dose. ~4 (preferably 4) weeks later, after the dose, (a) the subject has one or more of 2 weeks, 3 weeks, 4 weeks, or 2-4 weeks between doses of the VEGF receptor fusion protein; determining whether at least one criterion for shortening or lengthening the interval is met; b) administering additional doses of the VEGF receptor fusion protein at shortened or extended dose intervals, if determined; criteria for extending the interval include: Loss of BCVA less than 1.5 characters and / or CRT less than 2.300 or 320 micrometers. Criteria for reducing the interval include: 1. BCVA loss of >10 letters, and / or 2. Persistent or worsening DME, and / or CRT increase of >3.50 micrometers. In one embodiment of the invention, the criteria for extending the interval include: Criteria for 1. loss of BCVA of less than 5 letters from week 12, and 2. CRT of less than 300 or 320 micrometers, and / or shortened interval, as measured by SD-OCT, include: 1. Loss of BCVA associated with persistent or worsening DME, e.g., more than 10 letters from week 12, and 2. Increase in CRT, e.g., more than 50 micrometers from week 12. In one embodiment of the invention, if the above criteria are met, the interval is extended to 12, 16, or 20 weeks.

[0026] The present invention provides treatment or prevention of diabetic retinopathy and / or diabetic macular edema 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, with each secondary 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 approximately 12 to 20 weeks after the previous dose.

[0027] The present invention provides a method of treating or preventing neovascular eye disorders, preferably DR and / or DME, in a subject in need thereof, the method comprising: (1) receiving about 8 mg or more of VEGF in the subject's eye; a single initial dose of body fusion protein, preferably aflibercept, 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. the administration of one or more tertiary doses of or (2) administering one or more doses of 8 mg or more of the VEGF receptor fusion protein about every 4 weeks.

[0028] In one embodiment of the invention, subjects with certain exclusion criteria are excluded from treatment, or are not excluded from treatment if the exclusion criteria are not met. For example, in one embodiment of the invention, a subject with one or more of an ocular or periocular infection, active intraocular inflammation, and / or hypersensitivity is subject to administration of a VEGF receptor fusion protein to the eye. Excluded from administration. In one embodiment of the invention, the methods herein include the steps of: assessing a subject for ocular or periocular infection, active intraocular inflammation, and / or hypersensitivity; excluding the subject from treatment or prophylaxis if found in the patient.

[0029] 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.

[0030] 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 tip of the syringe and (6) insert the filter needle into the vial 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 submerged 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 tip of the Luer lock syringe; (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 and (13) slowly press down on the plunger so that the tip of the plunger 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.

[0031] In one embodiment of the invention, the subject receives a single initial dose of about 2 mg of VEGF receptor fusion protein, aflibercept, followed by four secondary doses of about 2 mg of VEGF receptor fusion protein, followed by , is in a dosing regimen for treating or preventing diabetic retinopathy and / or diabetic macular edema that requires one or more tertiary doses of about 2 mg of VEGF receptor fusion protein, and the second dose each of the tertiary doses is administered approximately 4 weeks after the immediately preceding dose, and each tertiary dose is administered approximately 8 weeks after the immediately preceding dose, and subjects may receive 2 mg of VEGF receptor fusion protein at any stage of the dosing regimen (initial dose, secondary dose or tertiary dose).

[0032] 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 approximately 12 weeks and one or more secondary doses is 2 secondary doses, 12-20 weeks is approximately 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, 2-4 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, 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.

[0033] In one embodiment of the invention, the VEGF receptor fusion protein is selected from the group consisting of aflibercept and conbercept, comprising amino acids 27-457 of the amino acid sequence set forth in SEQ ID NO: 2; (2) a VEGFR2 component containing amino acids 130-231 of SEQ ID NO: 2, and (3) a multimerization component containing amino acids 232-457 of SEQ ID NO: 2. immunoglobulin-like (lg) domain 2 of VEGFR1, comprising a peptide, the lg domain 3 of VEGFR2, and immunoglobulin-like (lg) domain 2 of VEGFR1, comprising two polypeptides comprising a multimerization component, the lg domain of VEGFR2 3, the lg domain of VEGFR2, and two polypeptides comprising a multimerization component, or two VEGFR1R2-FcΔC1(a) polypeptides encoded by the nucleic acid sequence of SEQ ID NO:1. 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.

[0034] In an embodiment of the invention, the VEGF receptor fusion protein is in an aqueous pharmaceutical formulation selected from the group consisting of A-KKKK. In an embodiment of the invention, the VEGF receptor fusion protein is administered in an aqueous pharmaceutical formulation comprising about 114.3 mg / ml of the VEGF receptor fusion protein, preferably aflibercept.

[0035] In one embodiment of the invention, the VEGF receptor fusion protein is administered to both eyes of the subject.

[0036] In one embodiment of the invention, the VEGF receptor fusion protein, preferably aflibercept, is delivered from a syringe or prefilled syringe, e.g. It is administered intravitreally using a sterile needle.

[0037] In one embodiment of the invention, the subject has previously received 2 mg of a VEGF receptor fusion protein, eg, Eylea, one or more times. One or more additional doses than those specifically mentioned may be administered to the subject.

[0038] In one embodiment of the invention, subjects receiving 2 mg of VEGF receptor fusion protein, preferably aflibercept, receive 40 mg / ml of VEGF receptor fusion protein, 10 mM sodium phosphate, 40 mM NaCl, 0.03% The protein was administered in an aqueous pharmaceutical formulation containing polysorbate 20, and 5% sucrose at pH 6.2.

[0039] In one embodiment of the invention, 8 mg of VEGF receptor fusion protein comprises 100 mg / ml or more of VEGF receptor fusion protein, preferably aflibercept, a histidine-based buffer, and arginine (e.g., L-arginine). , for example, in aqueous pharmaceutical formulations containing sugars or polyols (eg, sucrose). In one embodiment of the invention, the formulation has a pH of about 5.8. For example, a formulation can include about 103-126 mg / ml of VEGF receptor fusion protein, a histidine-based buffer, and arginine. One embodiment of the invention includes about 114.3 mg / ml of VEGF receptor fusion protein, histidine-based buffer, and arginine.

[0040] 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 , 85μl, 86μl, 87μl, 88μl, 89μl, 90μl, 91μl, 92μl, 93μl, 94μl, 95μl, 96μl, 97μl, 98μl, 99μl or 100μl, e.g. administered in a volume of about 70±4 or 5 microliters .

[0041] 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.

[0042] In one embodiment of the invention, the subject achieves and / or maintains one or more of the following: Improvement in Diabetic Retinopathy Severity Scale (DRSS), improvement in best-corrected visual acuity, dry retina, gain in best-corrected visual acuity, BCVA of at least 69 letters, foveal center without fluid, decrease in central retinal thickness (CRT), No vascular leakage as measured by fluorescein angiography (FA), improvement from pre-treatment baseline in National Institute of Ophthalmology Visual Function Questionnaire (NEI-VFQ) total score, fluid in the foveal center and central subfields (total fluid , retina without fluid (intraretinal fluid [IRF] and / or subretinal fluid [SRF]), maintenance of retina without fluid (total fluid, IRF, and / or SRF in the foveal center and central subfields), macula Absence of edema, retina without fluid on spectral domain optical coherence tomography (SD-OCT), no deviation from HDq12 or HDq16 or HDq20 treatment regimen once started, for first 3, 4, or 5 injections has a non-inferior BVCA compared to aflibercept administered intravitreally at 2 mg approximately every 4 weeks, followed by 2 mg once every 8 weeks or once every 2 months, with a baseline BCVA of approximately 61; 62, or 63, an increase in BCVA (by ETDRS letter score) of approximately 7, 8, or 9 letters from the start of treatment to week 60, and at least about 69 letters by week 48 or 60 from the start of treatment BCVA (by ETDRS letter score), no loss of BCVA of 5, 10, 15, or 69 letters or more after 12, 24, 36, 48, 60, 72, 84, 90, or 96 weeks from the start of treatment, treatment Improvement in BCVA (by ETDRS letter score) from the start of treatment to Weeks 12, 24, 36, 48, 60, 72, 84, 90, or 96, Weeks 4, 8, and 12 from the start of treatment , improvement in best-corrected visual acuity (BVCA) by week 16, week 20, week 24, week 28, week 32, week 36, week 40, week 44, or week 48, week 48 BCVA score from the start of treatment (ETDRS between weeks 48 and 60, with a change in BCVA of approximately 7, 8, or 9 (by letter score) of approximately 60 or 70 at any time between weeks 36 and 48 , the change in BCVA score (according to ETDRS letter score) from the start of treatment is approximately 7, 8, or 9, and the BCVA at any time between weeks 48 and 60 is approximately 69, 70, Early treatment diabetic retinopathy test (ETDRS) by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 or 48 after start of treatment, which is 71, 72 or 73 Increase in BCVA of 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or 10 characters as measured by visual acuity chart or Snellen equivalent, 48 or 60 from the start of treatment No loss of 5, 10, or 15 letters by week 1 (according to ETDRS letter score); Gain of at least 5, 10, or 15 letters by week 48 or 60 of treatment (according to ETDRS letter score) By week 4 after the start of treatment, approximately 4 or 5 letters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 4 or 5 letters of BCVA (ETDRS or Snellen equivalent) for HDq16 regimens). By week 8 after starting treatment, approximately 6 letters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 5 or 6 letters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens. By week 12 after treatment initiation, approximately 6 or 7 letters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 6 letters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens. By week 16 after the start of treatment, approximately 6 or 7 letters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 7 letters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens. By week 20 after the start of treatment, approximately 6 letters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 6 letters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens. ), by week 24 after treatment initiation, approximately 7 letters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 5 or 6 letters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens. ), by week 28 after treatment initiation, approximately 7 or 8 letters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 7 or 8 letters of BCVA (ETDRS or Snellen equivalent) for HDq16 regimens. By week 32 after the start of treatment, approximately 7 letter BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 7 or 8 letter BCVA (ETDRS or Snellen equivalent) for HDq16 regimens. By week 36 after treatment initiation, approximately 8 letter BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 6 or 7 letter BCVA (ETDRS or Snellen equivalent) for HDq16 regimens; By week 40 after treatment initiation, approximately 8 letter BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 6 or 7 letter BCVA (ETDRS or Snellen equivalent) for HDq16 regimens; By week 44 after the start of treatment, approximately 8 letter BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 7 or 8 letter BCVA (ETDRS or Snellen equivalent) for HDq16 regimens. Snellen equivalent) improvement, By week 48 after initiation of treatment, approximately 8 or 9 letters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or 7 or 8 letters of BCVA (ETDRS or Snellen equivalent) for HDq16 regimens. improvement, improvement in BCVA by approximately 8 weeks after the start of treatment is achieved and then maintained during the treatment regimen until at least 48 weeks, by 4 weeks after the start of treatment, for HDq12 regimens. is approximately 68 characters BCVA (ETDRS or Snellen equivalent) or approximately 66 characters BCVA (ETDRS or Snellen equivalent) for HDq16 regimens and approximately 70 characters for HDq12 regimens by week 8 after treatment initiation BCVA (ETDRS or Snellen equivalent) or approximately 67 characters (ETDRS or Snellen equivalent) for HDq16 regimens, approximately 70 characters BCVA (ETDRS or Snellen equivalents) for HDq12 regimens by week 12 after treatment initiation or Snellen equivalent) or approximately 68 characters of BCVA (ETDRS or Snellen equivalent) for HDq16 regimens and approximately 71 characters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens by week 16 after treatment initiation. or approximately 69 characters of BCVA (ETDRS or Snellen equivalent) for HDq16 regimens or approximately 70 characters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens by week 20 after treatment initiation. BCVA of approximately 68 characters (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 71 characters of BCVA (ETDRS or Snellen equivalent) for HDq16 regimens by week 24 after treatment initiation. 67-character BCVA (ETDRS or Snellen equivalent), approximately 72-character BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 70-character BCVA for HDq16 regimens by week 28 after treatment initiation (ETDRS or Snellen equivalent), approximately 71 letters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 70 letters of BCVA (ETDRS or Snellen equivalent) for HDq16 regimens by week 32 after treatment initiation. approximately 71 characters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 68 characters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens, by week 36 after the start of treatment. By week 40 after initiation of treatment, approximately 72 letters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 69 letters of BCVA (ETDRS or Snellen equivalent) for HDq16 regimens, 44 letters after initiation of treatment. BCVA of approximately 72 characters (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 70 characters (ETDRS or Snellen equivalent) for HDq16 regimens by week 48 after initiation of treatment. , BCVA of approximately 73 characters (ETDRS or Snellen equivalent) for HDq12 regimen or approximately 70 characters (ETDRS or Snellen equivalent) for HDq16 regimen, baseline BCVA less than approximately 73 ETDRS characters for HDq12 regimen BCVA (ETDRS or Snellen equivalent) improvement of approximately 9 or 10 letters by week 48 after initiation of treatment, when baseline BCVA is greater than approximately 73 ETDRS letters for HDq12 regimens, initiation of treatment BCVA (ETDRS or Snellen equivalent) improvement of approximately 5 or 6 letters by week 48 after initiation of treatment, when baseline BCVA is less than approximately 73 ETDRS letters for HDq16 regimens; BCVA (ETDRS or Snellen equivalent) improvement of approximately 8 or 9 letters; BCVA of approximately 4 or 5 letters by week 48 after initiation of treatment when baseline BCVA is greater than approximately 73 ETDRS letters for HDq16 regimens (ETDRS or Snellen equivalent), BCVA (ETDRS or Snellen equivalent) of approximately 7 or 8 letters by week 48 after treatment initiation when baseline CRT is less than approximately 400 micrometers for HDq12 regimens improvement in BCVA (ETDRS or Snellen equivalent) of approximately 9 or 10 letters by week 48 after treatment initiation, when baseline CRT is greater than approximately 400 micrometers for HDq12 regimens, baseline CRT By week 48 after treatment initiation, approximately 5 or 6 letter BCVA (ETDRS or Snellen equivalent) improvement when baseline CRT is less than approximately 400 micrometers on HDq16 regimen, when baseline CRT is less than approximately 400 micrometers on HDq16 regimen When greater than approximately 400 micrometers, BCVA (ETDRS or Snellen equivalent) improvement of approximately 9 or 10 letters by week 48 after initiation of treatment, 12, 24, 36, 48, 60, 72 from initiation of treatment , BCVA (according to ETDRS letter score) of >5 letters, >10 letters, or >15 letters by week 84, 90, or 96, 12, 24, 36, 48, 60, 72, from start of treatment; Improvement of 2 or more or 3 or more points on the Diabetic Retinopathy Severity Scale (DRSS) by Weeks 84, 90, or 96, from start of treatment to 4, 8, 12, 16, 20, 24, 28; Improvement of 2 or more points on the Diabetic Retinopathy Severity Scale (DRSS) by 32, 36, 40, 44, or 48 weeks, approximately 12, 24, 36, 48, 60, 72, 84 after initiation of treatment; By week 90, or 96, fluid (total fluid, retinal fluid [IRF], and / or subretinal fluid [SRF]) in the foveal center and central subfield as measured by optical coherence tomography (OCT) retina without vascular leakage as measured by fluorescein angiography (FA) by week 12, 24, 36, 48, 60, 72, 84, 90, or 96 from the start of treatment, from the start of treatment Maintenance of the retina without fluid (total fluid in the foveal center and central subfield, IRF and / or SRF), fluorescein, up to 12, 24, 36, 48, 60, 72, 84, 90, or 96 weeks Approximately 12, 13, or 14 mm of the total area of ​​fluorescein leakage within the ETDRS grid (mm2) at week 48 or week 60 as measured by angiography 2 Retina without fluid on spectral domain optical coherence tomography (SD-OCT) by 12, 24, 36, 48, 60, 72, 84, 90, or 96 weeks from the start of treatment; After the start of treatment, fluid (total fluid, retinal fluid [IRF], and retina without subretinal fluid [SRF]), dry retina by 12, 24, 36, 48, 60, 72, 84, 90, or 96 weeks from start of treatment, optical coherence tomography (OCT) measured by, fovea without fluid by week 12, 24, 36, 48, 60, 72, 84, 90, or 96 from the start of treatment; by week 4 after the start of treatment, for HDq12 regimens approximately Change in central retinal thickness of -118 or -118.3 micrometers or approximately -124 or -125 or -124.9 or -125.5 micrometers for HDq16 regimens by week 8 after initiation of treatment for HDq12 regimens. change in central retinal thickness of approximately -137 or -137.4 micrometers or approximately -139 or -140 or -139.6 or -140.3 micrometers for HDq16 regimens, by week 12 after initiation of treatment for HDq12 regimens. Change in central retinal thickness of approximately -150 or -150.1 micrometers in case of HDq16 regimen or -152 or -153 or -152.7 or -153.4 micrometers in case of HDq16 regimen, by week 16 after initiation of treatment, HDq12 Central retinal thickness change of approximately -139 or -139.4 micrometers for HDq16 regimens or -145 or -146 or -145.5 or -146.4 micrometers for HDq16 regimens by week 20 after initiation of treatment. , change in central retinal thickness of approximately −117 or −117.1 micrometers for HDq12 regimens or approximately −112 or −113 or −112.5 or −113.3 micrometers for HDq16 regimens, 24 weeks after initiation of treatment. Change in central retinal thickness of approximately -158 or -158.1 micrometers for HDq12 regimens or -103 or -104 or -103.8 or -104.3 micrometers for HDq16 regimens by 28 days after initiation of treatment By week 32 after initiation of treatment, a change in central retinal thickness of approximately -146 or -147 or -146.7 micrometers for the HDq12 regimen or approximately -162 or -162.3 micrometers for the HDq16 regimen. By week 1, a change in central retinal thickness of approximately -132 micrometers for HDq12 regimens or a change in central retinal thickness of approximately -145 or -146 or -145.8 micrometers for HDq16 regimens, after treatment. By week 36 after initiation, a change in central retinal thickness of about -168 or -168.1 micrometers for HDq12 regimens or about -124 or -125 or -124.7 or -125.2 micrometers for HDq16 regimens; By week 40 after the start of treatment, there is a change in central retinal thickness of approximately -163 micrometers for HDq12 regimens or -122 or -123 or -122.5 or -123.1 micrometers for HDq16 regimens. Change in central retinal thickness, by week 44 after initiation of treatment, approximately -147 or -148 or -147.4 microns for HDq12 regimens or -164 or -164.1 or -164.3 microns for HDq16 regimens Change in central retinal thickness in meters, by week 48 after initiation of treatment, approximately -171 or -172 or -171.7 micrometers for HDq12 regimens or about -148 or -149 micrometers for HDq16 regimens. Change in central retinal thickness of -148.3 or -149.4 micrometers by week 60 after initiation of treatment, approximately 181.95 or -176.24 micrometers for HDq12 regimens or approximately -166.26 or -167.18 for HDq16 regimens change in central retinal thickness in micrometers, a decrease in central retinal thickness maintained within +17, +18, or +19 micrometers by approximately 4, 5, 6, 7, or 8 weeks after initiation of treatment; approximately 100, 125, 150, 175 by week 12, 24, 36, 48, 60, 72, 84, 90, or 96 from the start of treatment, then maintained until at least 48 weeks from the start of treatment. , or a decrease in central retinal thickness of 200 micrometers, with a baseline CRT of approximately 449, 450, 455, or 460 micrometers, as measured by optical coherence tomography (OCT), approximately 48 or 60 from the start of treatment. A decrease in central retinal thickness of approximately 148-182 micrometers by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 after initiation of treatment , for example, a decrease in central retinal thickness (CRT) of at least about 100, 125, 130, 135, 140, 145, 149, 150, 155, 160, 165, 170, 171, 172, 173, 174, or 175 micrometers, a plasma free aflibercept concentration of about 0.149 (±0.249) mg / l at about 0.1667 days after the first dose; If the free aflibercept concentration in the plasma is undetectable at baseline and the subject has not received intravitreal aflibercept treatment for at least 12 weeks, approximately 0.3333 days after the first dose, free aflibercept in the plasma is approximately 0.205 (±0.250) mg / l and there is undetectable free aflibercept in plasma at baseline and the subject has not received intravitreal aflibercept treatment for at least 12 weeks, approximately 1 day after the first dose. Days later, free aflibercept in the plasma was approximately 0.266 (±0.211) mg / l, and at baseline, free aflibercept in the plasma was undetectable and the subject had received at least one intravitreal aflibercept treatment. Approximately 2 days after the first dose, which has not been administered for 12 weeks, free aflibercept in plasma is approximately 0.218 (±0.145) mg / l, and free aflibercept in plasma is undetectable at baseline. , the subject has not received intravitreal aflibercept treatment for at least 12 weeks, approximately 4 days after the first dose, free aflibercept in plasma is approximately 0.140 (±0.0741) mg / l; Approximately 7 days after the first dose, when free aflibercept in plasma is undetectable and the subject has not received intravitreal aflibercept treatment for at least 12 weeks, free aflibercept in plasma is approximately 0.0767 (±0.0436). mg / l and undetectable free aflibercept in the plasma at baseline and approximately 14 days after the first dose when the subject has not received intravitreal aflibercept treatment for at least 12 weeks. free aflibercept is approximately 0.0309 (±0.0241) mg / l, free aflibercept is undetectable in plasma at baseline, and the subject has not received intravitreal aflibercept treatment for at least 12 weeks; Approximately 21 days after administration, free aflibercept in the plasma was approximately 0.0171 (±0.0171) mg / l, and at baseline, free aflibercept in the plasma was undetectable and the subject had no intravitreal aflibercept. Approximately 28 days after the first dose for those who have not received sept treatment for at least 12 weeks, free aflibercept in plasma is approximately 0.00730 (±0.0113) mg / l; undetectable and the subject has not received intravitreal aflibercept treatment for at least 12 weeks, about 0.1667 days after the first dose, the adjusted bound aflibercept in plasma is about 0.00698 (±0.0276) mg / l; At baseline, there is approximately 0.00583 mg / l (±0.0280) of adjusted bound aflibercept in the plasma and approximately 0.3333 days after the first dose, when the subject has not received intravitreal aflibercept treatment for at least 12 weeks. The regulatory bound aflibercept is approximately 0.00731 (±0.0279) mg / l, and at baseline there is approximately 0.00583 mg / l (±0.0280) of regulatory bound aflibercept, and the subject has not received intravitreal aflibercept for at least 12 weeks. Approximately 1 day after the first dose in non-Sept treated patients, adjusted bound aflibercept in plasma was approximately 0.0678 (±0.0486) mg / l and at baseline approximately 0.00583 mg / l (±0.0280). Approximately 2 days after the first dose, when coordinating bound aflibercept is present and the subject has not received intravitreal aflibercept treatment for at least 12 weeks, the coordinating bound aflibercept in plasma is approximately 0.138 (±0.0618) mg / l and there is approximately 0.00583 mg / l (±0.0280) of adjusted bound aflibercept at baseline and approximately 4 days after the first dose if the subject has not received intravitreal aflibercept treatment for at least 12 weeks. , the adjusted bound aflibercept in plasma is approximately 0.259 (±0.126) mg / l, and at baseline there is approximately 0.00583 mg / l (±0.0280) adjusted bound aflibercept and the subject has been present for at least 12 weeks. Approximately 7 days after the first dose, without intravitreal aflibercept treatment, the adjusted bound aflibercept in plasma was approximately 0.346 (±0.151) mg / l, and at baseline, approximately 0.00583 mg / l ( Approximately 14 days after the first dose, if the subject has not received intravitreal aflibercept treatment for at least 12 weeks, the adjusted bound aflibercept in plasma will be approximately 0.374 (±0.0280); 0.110) mg / l and there was approximately 0.00583 mg / l (±0.0280) of adjusted bound aflibercept at baseline and the subject had not received intravitreal aflibercept treatment for at least 12 weeks, After approximately 21 days, the adjusted bound aflibercept in the plasma was approximately 0.343 (±0.128) mg / l, and at baseline there was approximately 0.00583 mg / l (±0.0280) adjusted bound aflibercept; have not received intravitreal aflibercept treatment for at least 12 weeks, approximately 28 days after the first dose, the adjusted bound aflibercept in plasma is approximately 0.269 (±0.149) mg / l and at baseline, approximately 0.00583 mg / l (±0.0280) of adjusted bound aflibercept is present and the subject has not received intravitreal aflibercept treatment for at least 12 weeks, approximately 0.965 days after the first dose, the maximum free aflibercept in plasma The maximum concentration of free aflibercept in plasma reached is approximately 0.310 mg / l (±0.263). Free aflibercept in plasma of about 0 to about 1.08 mg / L, maximum concentration of free aflibercept in plasma (mg) per dose (mg) of aflibercept of about 0.0388 (±0.0328) mg / l / mg / l), the maximum concentration of regulated bound aflibercept in plasma is reached approximately 14 days after the first dose. Adjusted bound aflibercept concentration in plasma of about 0.137 to about 0.774 mg / L, reaching a maximum concentration of adjusted bound aflibercept in plasma of about 0.387 mg / l (±0.135), about 0.0483 (±0.0168) Maximum adjusted binding aflibercept (mg / l) in plasma per dose (mg) of aflibercept in mg / l / mg, not having anti-drug antibodies against aflibercept after 48 or 60 weeks of treatment , improvement from pre-treatment baseline in National Institute of Ophthalmology Visual Function Questionnaire (NEI-VFQ) total score, and / or absence of macular edema. For example, in one embodiment of the invention, the dry retina lacks intraretinal and / or subretinal fluid, or the dry retina lacks intraretinal fluid and / or subretinal fluid, or the subject receives three monthly doses of a VEGF receptor fusion protein, preferably Afliber. Characterized by the absence of intraretinal fluid (IRF) and subretinal fluid (SRF) in the subject's eyes after receiving Sept.

[0043] In one embodiment of the invention, reference to 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56 or 60 weeks from the start of treatment approximately 48 or 60 weeks.

[0044] In one embodiment of the invention, one initial dose, two secondary doses, and three tertiary doses of a VEGF receptor fusion protein, e.g., aflibercept, are administered to the subject in year 1. , one initial dose, two secondary doses, and two tertiary doses of a VEGF receptor fusion protein, e.g., aflibercept, are administered to the subject in year 1; or One initial dose, two secondary doses, and three tertiary doses of protein, e.g., aflibercept, are administered to subjects in year 1, followed by 2 to 4 tertiary doses of 2 Administered in the year.

[0045] In one embodiment of the invention, the interval between doses is adjusted based on visual and / or anatomical results (increase / maintain / reduce ).

[0046] The present invention provides a kit comprising a container containing a VEGF receptor fusion protein and instructions for use of the VEGF receptor fusion protein, the container being a vial or a prefilled syringe, the container containing VEGF of 100 mg / mL or more. contains a receptor fusion protein, the container contains 114.3 mg / mL or more of a VEGF receptor fusion protein, the instructions contain instructions for the administration of aflibercept to DME / AMD patients, the instructions contain aflibercept Includes instructions for Septo 8mg treatment to begin with monthly injections (every 4 weeks) in 3 consecutive doses; instructions may extend injection interval up to every 16 weeks or every 20 weeks after the first 3 consecutive doses The instructions include instructions that the treatment interval may be adjusted based on the physician's judgment regarding visual and / or anatomical results.

[0047] The present invention provides aflibercept for use in the treatment or prevention of diabetic retinopathy and / or diabetic macular edema 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 0.367-0.458 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.

[0048] 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 less than 4 mg of aflibercept. Aflibercept is provided for use in a method comprising: administering a single initial dose of aflibercept of about 8 mg or more to the eye of a subject in need thereof, followed by a single initial dose of aflibercept of about 8 mg or more; 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 approximately 2 to 4 weeks after the immediately preceding dose; Each tertiary dose is administered approximately 12-20 weeks after the previous dose.

[0049] Intravitreal injection of aflibercept compared to the time for the amount of free aflibercept in the ocular compartment of a subject to reach the lower limit of quantification (LLOQ) after an intravitreal injection of approximately 2 mg of aflibercept. providing aflibercept for use in a method for increasing the time after which the amount of free aflibercept in the ocular compartment of a subject reaches the LLOQ; 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 approximately 2 to 4 weeks after the immediately preceding dose; A method in which each tertiary dose is administered about 12 to 20 weeks after the immediately preceding dose.

[0050] The present invention shows that the amount of free aflibercept after an intravitreal injection of aflibercept compared to the time for the amount of free aflibercept to reach the lower limit of quantitation (LLOQ) in the plasma of a subject after an intravitreal injection of approximately 2 mg of aflibercept. Provided is aflibercept for use in a method of increasing the time for the amount of free aflibercept in the plasma of a subject to reach the LLOQ, the method comprising administering about 8 mg or more of aflibercept to the eye of a subject in need thereof. A single initial dose of Sept, 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 intravitreally. injection, with each secondary dose being administered about 2 to 4 weeks after the previous dose and each tertiary dose being administered about 12 to 20 weeks after the previous dose.

[0051] The present invention - To treat or prevent diabetic retinopathy (DR) and / or diabetic macular edema (DME) in a subject in need thereof; - To improve best-corrected visual acuity in subjects in need with DR and / or DME, or - provide VEGF receptor fusion proteins for use in methods for promoting retinal dryness in subjects in need with DR and / or DME; 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.

[0052] The present invention provides aflibercept for use in the treatment or prevention of diabetic retinopathy and / or diabetic macular edema 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 doses is 114.3 mg / mL, or the application volume of each of the above doses is 70 μL. In one embodiment of the invention, the treatment interval between two consecutive administrations of 8 mg aflibercept is determined by BCVA letter gain or letter loss, CRT increase or decrease, presence or absence of subretinal fluid, or hemorrhage or persistence. or adjusted (increase / maintain / reduce) based on visual and / or anatomical results, including but not limited to the presence or absence of worsening DME. In one embodiment of the invention, the subject includes at least one of the following criteria for shortening the treatment interval: loss of BCVA of more than 5 or more than 10 letters, CRT of more than 300 or 320 μm, 50 μm. increase in CRT by more than 2, or 2. If identified as meeting persistent or worsening DME, the treatment interval is 2 to 4 weeks, 2 weeks, 3 weeks, or 4 compared to the previous treatment interval. Weekly reduction. In one embodiment of the invention, the subject meets at least one of the following criteria for reduction in treatment interval: loss of BCVA of less than 5 letters, less than 10 letters, CRT of less than 300 or 320 μm, loss of BCVA of less than 50 μm, Increased treatment interval by 2-4 weeks, 2 weeks, 3 weeks, or 4 weeks compared to the previous treatment interval if identified as meeting: decreased CRT, absence of subretinal fluid, or absence of hemorrhage be done.

[0053] The present invention provides a VEGF receptor fusion protein for use in the treatment or prevention of diabetic macular edema 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 every 7 days, monthly), followed by every 8 to 16 weeks (2 to 4 months, + / - 7 days) or once every 8 to 20 weeks (2 to 5 months, + / -7 days) by administering 8 mg of VEGF receptor fusion protein (0.07 mL) by intravitreal injection.

[0054] The present invention provides a VEGF receptor fusion protein for use in the treatment or prevention of diabetic retinopathy (DR) 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 every 28 days + / - 7 days, monthly), followed by every 8 to 16 weeks (2 to 4 months, + / -7 days) or once every 8-20 weeks (2-5 months, + / -7 days) by administering 8 mg of VEGF receptor fusion protein (0.07 mL) by intravitreal injection.

[0055] The present invention provides a VEGF receptor fusion protein for use in the treatment or prevention of diabetic macular edema (DME) 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 every 28 days + / -7 days, monthly), followed by every 12 weeks (2-4 months, + / - -7 days) by administering 8 mg of VEGF receptor fusion protein (0.07 mL) by single intravitreal injection.

[0056] The present invention provides a VEGF receptor fusion protein for use in the treatment or prevention of diabetic retinopathy (DR) 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 every 28 days + / -7 days, monthly), followed by every 12 weeks (2-4 months, + / - -7 days) by administering 8 mg of VEGF receptor fusion protein (0.07 mL) by single intravitreal injection.

[0057] The present invention provides a VEGF receptor fusion protein for use in the treatment or prevention of diabetic macular edema (DME) 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 every 28 days + / -7 days, monthly), followed by every 16 weeks (2-4 months, + / - -7 days) by administering 8 mg of VEGF receptor fusion protein (0.07 mL) by single intravitreal injection.

[0058] The present invention provides a VEGF receptor fusion protein for use in the treatment or prevention of diabetic retinopathy (DR) 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 every 28 days + / -7 days, monthly), followed by every 16 weeks (2-4 months, + / - -7 days) by administering 8 mg of VEGF receptor fusion protein (0.07 mL) by single intravitreal injection.

[0059] The present invention provides a VEGF receptor fusion protein for use in the treatment or prevention of diabetic macular edema (DME) 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 every 28 days + / -7 days, monthly), followed by every 20 weeks (2-4 months, + / - -7 days) by administering 8 mg of VEGF receptor fusion protein (0.07 mL) by single intravitreal injection.

[0060] The present invention provides a VEGF receptor fusion protein for use in the treatment or prevention of diabetic retinopathy (DR) 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 approximately every 28 days + / - 7 days, monthly), followed by every 20 weeks (2-4 months, + This includes administering 8 mg of VEGF receptor fusion protein (0.07 mL) by intravitreal injection once on days / -7).

[0061] The present invention provides VEGF receptor fusion proteins for use in the treatment or prevention of diabetic retinopathy and / or diabetic macular edema 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 of VEGF receptor fusion protein; After 1 month, administer the first 8 mg secondary dose of VEGF receptor fusion protein, and 1 month later, administer the second 8 mg VEGF receptor fusion protein secondary dose, then 12 or 16 days later. 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; (2) 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 dose of 8 mg of VEGF receptor fusion protein one month later; one month later, a second 8 mg VEGF receptor fusion protein sub-dose, followed by 8 mg VEGF receptor fusion protein every 12 or 16 or 20 weeks thereafter according to HDq12 or HDq16 or HDq20 dosing regimens. administering one or more maintenance doses of the body fusion protein; (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 of VEGF receptor fusion protein one month later; and then every 12 or 16 or 20 weeks thereafter, administering one or more maintenance doses of 8 mg of VEGF receptor fusion protein according to an HDq12 or HDq16 or HDq20 dosing regimen; (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 of VEGF receptor fusion protein one month later; , then every 12 or 16 or 20 weeks, comprising administering every additional 8 mg maintenance dose of VEGF receptor fusion protein according to the 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; , one month later, an initial dose of 8 mg of VEGF receptor fusion protein was administered, one month later a second dose of 8 mg of VEGF receptor fusion protein was administered, and one month later, a second dose of VEGF receptor fusion protein was administered. of 8 mg of VEGF receptor fusion protein and then every 12 or 16 or 20 weeks thereafter, one or more doses of 8 mg of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen. comprising administering a maintenance dose of (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; , 1 month later, administer a first 8 mg secondary dose of VEGF receptor fusion protein, 1 month later administer a second 8 mg VEGF receptor fusion protein secondary dose, and then administering one or more maintenance doses of 8 mg of VEGF receptor fusion protein every 12 or 16 or 20 weeks according to a HDq12 or HDq16 or HDq20 dosing regimen; (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; , followed by a second 8 mg VEGF receptor fusion protein sub-dose one month later, followed by 8 mg VEGF receptor 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 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 VEGF receptor fusion protein one month later, followed by all additional 8 mg VEGF receptor fusion protein every 12 or 16 or 20 weeks following HDq12 or HDq16 or HDq20 dosing regimens. administering a maintenance dose of the 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 of VEGF receptor fusion protein, and one month later, a second dose of 8 mg of VEGF receptor fusion protein. of VEGF receptor fusion protein, followed one month later by a second 8 mg VEGF receptor fusion protein, and then every 12 or 16 or 20 weeks thereafter, HDq12 or administering one or more maintenance doses of 8 mg of VEGF receptor fusion protein according to an 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. and a second dose of the fusion protein, the method then administers to the subject, one month later, a first 8 mg second dose of the VEGF receptor fusion protein, and one month later, the method includes: Administer a second secondary dose of 8 mg VEGF receptor fusion protein, then every 12 or 16 or 20 weeks thereafter, one dose of 8 mg VEGF receptor fusion protein or comprising administering multiple maintenance doses; (11) 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 VEGF receptor fusion protein, the method then administers to the subject a second second dose of 8 mg of VEGF receptor fusion protein one month later, and then 12 or comprising administering one or more maintenance doses of 8 mg of VEGF receptor fusion protein every 16 or 20 weeks according to a HDq12 or HDq16 or HDq20 dosing regimen; (12) 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. 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 of the VEGF receptor fusion protein, followed by 12 or 16 or 20 doses of the VEGF receptor fusion protein. weekly, administering every additional 8 mg maintenance dose of VEGF receptor fusion protein 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. a second dose of VEGF receptor fusion protein and, one month later, a third dose of 2 mg of VEGF receptor fusion protein; An initial dose of VEGF receptor fusion protein was administered, followed one month later by a second dose of 8 mg VEGF receptor fusion protein, followed one month later by a second dose of 8 mg VEGF receptor fusion protein. and then every 12 or 16 or 20 weeks thereafter one or more maintenance doses of 8 mg VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen. including, (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 and, one month later, a third dose of 2 mg of the VEGF receptor fusion protein; A second dose of 8 mg of VEGF receptor fusion protein is administered, followed by a second dose of 8 mg of VEGF receptor fusion protein one month later, and then every 12 or 16 or 20 weeks thereafter. , administering one or more maintenance doses of 8 mg of 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 and, one month later, a third 2 mg second dose of the VEGF receptor fusion protein; of 8 mg of VEGF receptor fusion protein and then every 12 or 16 or 20 weeks thereafter, one or more doses of 8 mg of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen. comprising administering a maintenance dose of (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 and, one month later, a third dose of 2 mg of the VEGF receptor fusion protein; administering a maintenance dose of 8 mg VEGF receptor fusion protein, followed by every 12 or 16 or 20 weeks, administering all additional maintenance doses of 8 mg VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen; including; (17) 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 fusion protein, followed one month later by a third dose of 2 mg of VEGF receptor fusion protein, followed one month later by a fourth dose of 2 mg of VEGF receptor fusion protein. The method then involves administering an initial dose of 8 mg of VEGF receptor fusion protein two months later, and then administering a second dose of 8 mg of VEGF receptor fusion protein one month later. one month later, a second 8 mg VEGF receptor fusion protein sub-dose, followed by 8 mg VEGF receptor fusion protein every 12 or 16 or 20 weeks thereafter according to HDq12 or HDq16 or HDq20 dosing regimens. administering one or more maintenance doses of the body fusion protein; (18) 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 fusion protein, followed one month later by a third dose of 2 mg of VEGF receptor fusion protein, followed one month later by a fourth dose of 2 mg of VEGF receptor fusion protein. The method then administers to the subject, two months later, a first 8 mg secondary dose of VEGF receptor fusion protein, and one month later, a second 8 mg VEGF receptor fusion protein. and then every 12 or 16 or 20 weeks thereafter one or more maintenance doses of 8 mg VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen. including, (19) 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 fusion protein, followed one month later by a third dose of 2 mg of VEGF receptor fusion protein, followed one month later by a fourth dose of 2 mg of VEGF receptor fusion protein. and the method then administers to the subject a second 8 mg secondary dose of VEGF receptor fusion protein two months later and then 12 or 16 or 20 weeks later for 12 or 16 weeks. each time, according to a HDq12 or HDq16 or HDq20 dosing regimen, administering one or more maintenance doses of 8 mg of VEGF receptor fusion protein; (20) 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 fusion protein, followed one month later by a third dose of 2 mg of VEGF receptor fusion protein, and one month later a fourth dose of 2 mg of VEGF receptor fusion protein. and the method then administers to the subject, two months 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 administering every additional 8 mg VEGF receptor fusion protein maintenance dose according to the HDq20 dosing regimen; (21) 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 one month later by a third dose of 2 mg of VEGF receptor fusion protein, and one month later, a fourth dose of 2 mg of VEGF receptor fusion protein; one or more maintenance doses of 2 mg every 8 weeks thereafter; An initial dose of fusion protein is administered, followed one month later by 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. 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; (22) 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 one month later by a third dose of 2 mg of VEGF receptor fusion protein, and one month later, a fourth dose of 2 mg of VEGF receptor fusion protein; one or more maintenance doses of 2 mg every 8 weeks thereafter, and then the method involves subjecting the subject to a first 8 mg maintenance dose of A second dose of VEGF 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 administering one or more maintenance doses of 8 mg of VEGF receptor fusion protein according to an HDq16 or HDq20 dosing regimen; (23) 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 one month later by a third dose of 2 mg of VEGF receptor fusion protein, and one month later, a fourth dose of 2 mg of VEGF receptor fusion protein; one or more maintenance doses of 2 mg every 8 weeks thereafter, and the method then involves subjecting the subject to a second 8 mg maintenance dose 2 months after the last VEGF receptor fusion protein maintenance dose Administer a second dose of VEGF receptor fusion protein, followed by one dose of 8 mg of VEGF receptor fusion protein every 12 or 16 or 20 weeks, or comprising administering multiple maintenance doses; or (24) 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 one month later by a third dose of 2 mg of VEGF receptor fusion protein, and one month later, a fourth dose of 2 mg of VEGF receptor fusion protein; one or more maintenance doses of 2 mg every 8 weeks thereafter; administering a maintenance dose of VEGF receptor fusion protein, and then every 12 or 16 or 20 weeks, administering every additional 8 mg maintenance dose of VEGF receptor fusion protein according to a HDq12 or HDq16 or HDq20 dosing regimen. , (i) 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 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 approximately 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 approximately 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.

[0062] The present invention provides aflibercept for use in the treatment or prevention of diabetic macular edema or diabetic retinopathy in a subject in need thereof, comprising administering a single initial dose of 8 mg of aflibercept to the eye of the subject; Subsequently, the method comprises administering one or more third doses of aflibercept of about 8 mg, each third dose being administered about 8, 12, 16, or 20 weeks after the previous dose. 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.

[0063] The present invention provides aflibercept for use in the treatment or prevention of diabetic macular edema or diabetic retinopathy in a subject pretreated with 2 mg of aflibercept, and administers about 8 mg of aflibercept to the subject's eye. administering a single initial dose of bercept, followed by one or more secondary doses of aflibercept of about 8 mg, followed by one or more tertiary doses of aflibercept of about 8 mg; 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. 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.

[0064] The present invention provides VEGF receptor fusion proteins for use in the treatment or prevention of diabetic retinopathy and / or diabetic macular edema in a subject in need thereof; is on a dosing regimen; (a) the subject has been administered an initial dose of 8 mg of VEGF receptor fusion protein; the method then administers to the subject, one month later, a second dose of 8 mg of VEGF receptor fusion protein; one month later, administer a second 8 mg secondary dose 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 a VEGF receptor fusion protein; or (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; One month later, a second 8 mg secondary dose of VEGF receptor fusion protein was administered, followed by an 8 mg VEGF receptor fusion protein every 12 or 16 or 20 weeks thereafter according to HDq12 or HDq16 or HDq20 dosing regimen. administering one or more maintenance doses of the protein; or (c) Subjects received an initial dose of 8 mg VEGF receptor fusion protein, 1 month later a first secondary dose of 8 mg VEGF receptor fusion protein, and 1 month later a second dose of ≥8 mg VEGF receptor fusion protein. and a second dose of the VEGF receptor fusion protein, the method then administers to the subject, 12 or 16 or 20 weeks later, a first maintenance dose of 8 mg of the VEGF receptor fusion protein; administering every 12 or 16 or 20 weeks a maintenance dose of every additional 8 mg of VEGF receptor fusion protein according to a HDq12 or HDq16 or HDq20 dosing regimen; or (d) subjects received an initial dose of 8 mg VEGF receptor fusion protein, 1 month later a first secondary dose of 8 mg VEGF receptor fusion protein, and 1 month later a second dose of 8 mg VEGF receptor fusion protein; has been administered a second dose of the fusion protein and, 12 or 16 or 20 weeks later, one or more maintenance doses of 8 mg of the VEGF receptor fusion protein; One or more maintenance doses of 8 mg of VEGF receptor fusion protein are administered 12 or 16 or 20 weeks after the last maintenance dose of receptor fusion protein, and then every 12 or 16 or 20 weeks thereafter. administering every additional 8 mg maintenance dose of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen; (i) 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 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 approximately 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 approximately 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.

[0065] The invention also provides the use of a VEGF receptor fusion protein for use in the treatment or prevention of neovascular eye disorders in a subject in need thereof, wherein the subject receives a single initial dose of about 2 mg of the 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 to treat the disorder. or prophylaxis, each secondary dose is administered approximately 4 weeks after the immediately preceding dose, each tertiary dose is administered approximately 8 weeks after the immediately preceding dose, and the subject receives 2 mg at any stage of a VEGF receptor fusion protein administration regimen, the method includes administering to the subject's eye an 8 mg dose of a VEGF receptor fusion protein and about 8 or 10 or 12 weeks after said administering. If, in the evaluation of the subject and in the judgment of the treating physician, dosing every 12 weeks or every 16 weeks is appropriate, continue to administer 8 mg of VEGF receptor fusion protein to the subject every 12 weeks or every 16 weeks. , or about 8 or 10 or 12 weeks after administering, and if in the judgment of the treating physician, administration every 12 weeks is appropriate, administering an additional dose of 8 mg of VEGF receptor fusion protein and administering about re-evaluating the subject after 12 weeks and continuing to administer to the subject 8 mg of VEGF receptor fusion protein every 16 weeks if, in the judgment of the treating physician, dosing every 16 weeks is appropriate.

[0066] The present invention provides VEGF receptor fusion proteins for use in the treatment and prevention of diabetic retinopathy or diabetic macular edema in a subject in need thereof, wherein the treatment or prevention comprises administering about 8 mg or more to the eye of the subject. A single initial dose of VEGF receptor fusion protein is administered, followed by one or more secondary doses, preferably two doses, of VEGF receptor fusion protein of about 8 mg or more, followed by administration of about 8 mg or more of VEGF receptor fusion protein. administering one or more tertiary doses 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 being administered about 2 to 4 weeks after the immediately preceding dose; 12 or 16 weeks after the previous dose and one or more tertiary doses administered approximately 12 or 16 weeks after the previous dose; ●From 12 weeks to 16 weeks, ●From 12 weeks to 20 weeks, or ●Includes further extension from 16 weeks to 20 weeks.

[0067] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, wherein the subject's eye receives about 8 mg or more of VEGF receptor. A single initial dose of the fusion protein, followed by one or more secondary doses 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. tertiary doses, each of the secondary doses being administered about 2 to 4 weeks after the immediately preceding dose, each of the tertiary doses being administered about 12 or 16 or 20 weeks after the immediately preceding dose, and each of the tertiary doses being administered about 12 or 16 or 20 weeks after the immediately preceding dose; Interval between tertiary doses after one or more tertiary doses are administered approximately 12 or 16 or 20 weeks after the 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 ●Includes further shortening from 20 weeks to 16 weeks.

[0068] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of diabetic retinopathy and / or diabetic macular edema in a subject in need thereof; comprising administering to the subject's eye three doses of about 8 mg of a VEGF receptor fusion protein in a formulation containing the VEGF receptor fusion protein at four-week intervals, and at 12, 16, or 20 weeks after said three doses. comprising administering one or more doses of the VEGF receptor fusion protein at extended intervals.

[0069] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, the method comprising administering about 8 mg or more to the eye of a subject. of VEGF receptor fusion protein, followed by two secondary doses of about 8 mg or more of VEGF receptor fusion protein, each secondary dose about 2 times the previous dose. ~4 weeks later, after the above administration, 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 further doses of the VEGF receptor fusion protein at said reduced or extended dose intervals; Criteria for extending the interval include: Loss of BCVA of less than 1.5 characters, and / or CRT less than 2.300 or 320 micrometers. Criteria for reducing spacing include: 1. Loss of BCVA of more than 10 characters; 2. Persistent or worsening DME, and / or 3.3. CRT increase above 50 micrometers.

[0070] The present invention provides VEGF receptor fusion proteins for use in the treatment and prevention of diabetic retinopathy and / or diabetic macular edema in subjects in need thereof, pretreated with one or more 2 mg doses of 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 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 Each dose is administered approximately 12 to 20 weeks after the previous dose.

[0071] 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. to be 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;

[0072] 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 tip of the Luer Lock syringe; (6) pushing the filter needle into the center of the stopper of the vial 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 submerged 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 tip of the Luer lock syringe; (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 tip of the plunger is aligned with the line marking 70 microliters on the syringe;

[0073] The present invention also provides the use of a VEGF receptor fusion protein for use in the treatment or prevention of diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, wherein the subject receives approximately 2 mg of VEGF receptor fusion protein. Requiring a single initial dose of fusion protein, followed by four 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 diabetic retinopathy and / or diabetic macular edema, in which each of the secondary doses is administered approximately 4 weeks after the immediately preceding dose and each of the tertiary doses is administered approximately 4 weeks after the immediately preceding dose; The subject is at any stage (initial dose, second dose, or tertiary dose) of the 2 mg VEGF receptor fusion protein dosing regimen.

[0074] The present invention provides VEGF receptor fusion proteins for use in the treatment and prevention of diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, wherein 8 mg of VEGF receptor fusion protein comprises approximately 10 in an aqueous pharmaceutical formulation containing 126 mg / ml of VEGF receptor fusion protein, histidine-based buffer, and arginine.

[0075] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, wherein 8 mg of VEGF receptor fusion protein is approximately 114.3 mg / ml of VEGF receptor fusion protein, histidine-based buffer, and arginine in an aqueous pharmaceutical formulation.

[0076] The present invention provides aflibercept for use in the treatment and prevention of diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, wherein greater than 8 mg 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.

[0077] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, wherein greater than 8 mg 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.

[0078] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, wherein 8 mg of the VEGF receptor fusion protein comprises: ●More than 100 mg / ml of VEGF receptor fusion protein, histidine-based buffer, and L-arginine, ●140mg / ml aflibercept, 20mM histidine 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, ●>100mg / ml of aflibercept, histidine-based buffer, and L-arginine; ●Aflibercept >100 mg / ml, pH approximately 5.8, where the formulation forms less than 3% HMW aggregates after 2 months incubation at 5°C; ●About 114.3mg / mL aflibercept, 10mM~50mM histidine buffer, sugar, nonionic surfactant, L-arginine, pH5.8, ●Approximately 114.3mg / mL aflibercept, 10mM His / His-HCl buffer, 5% sucrose, 0.03% polysorbate-20, 50mM 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.

[0079] The present invention provides VEGF receptor fusion proteins for use in the treatment and prevention of diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, the subject receiving one or more of the following: achieve and / or maintain. ● Improvement on the Diabetic Retinopathy Severity Scale (DRSS), e.g. by at least 2 or 3 stages; ●Improvement of best-corrected visual acuity, ●Dry retina, ● Gain in best-corrected visual acuity, ● Obtaining at least 5, 10, or 15 letters of best corrected visual acuity (BCVA); ● BCVA of at least 69 characters, ●Decrease in central retinal thickness (CRT), ●No vascular leakage as measured by fluorescein angiography (FA), ●Improvement from pre-treatment baseline in National Ophthalmological Society Visual Function Questionnaire (NEI-VFQ-25) total score; ● Retina without fluid (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF]) in the foveal center and central subfield; • Maintenance of a fluid-free retina (total fluid, IRF, and / or SRF in the foveal center and central subfield); ● Lack of macular edema, ●Retina without fluid on spectral domain optical coherence tomography (SD-OCT) and / or • Do not deviate from HDq12 or HDq16 treatment regimens once initiated.

[0080] The present invention provides VEGF receptor fusion proteins for use in the treatment and prevention of diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, the subject receiving one or more of the following: achieve and / or maintain. Compare with aflibercept administered intravitreally at 2 mg approximately every 4 weeks for the first 3, 4, or 5 injections, followed by 2 mg approximately once every 8 weeks or once every 2 months. non-inferior BVCA, ● An increase in BCVA (by ETDRS letter score) of approximately 7, 8, or 9 letters from the start of treatment to week 60, with a baseline BCVA of approximately 61, 62, or 63; ● BCVA of at least approximately 69 letters (according to ETDRS letter score) by week 48 or 60 from the start of treatment; have not lost more than 5, 10, 15, or 69 characters of BCVA after 12, 24, 36, 49, 60, 72, 84, or 90 weeks from the start of treatment; ● Improvement in BCVA (according to ETDRS letter score) from the start of treatment to weeks 12, 24, 36, 49, 60, 72, 84, or 90; ●4th week, 8th week, 12th week, 16th week, 20th week, 24th week, 28th week, 32nd week, 36th week, 40th week, 44th week from the start of treatment, or Improvement in BVCA by week 48, ● Between weeks 48 and 60, a BCVA score of approximately 69, 70, 71, 72, or 73 (according to ETDRS letter score); ● Between weeks 36 and 48, the change in BCVA score (according to ETDRS letter score) from the start of treatment is approximately 7, 8, or 9, and any change between weeks 36 and 48 BCVA at the time is approximately 60 or 70, ● Between weeks 48 and 60, the change in BCVA score (according to ETDRS letter score) from the start of treatment is approximately 7, 8, or 9, and any change between weeks 48 and 60 have a current BCVA of approximately 69, 70, 71, 72, or 73; ● By 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 weeks after initiation of treatment, by Early Treatment Diabetic Retinopathy Screening (ETDRS) visual acuity chart or Snellen equivalent. Increase in BCVA measured by 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or 10 characters, ● No loss of 5, 10, or 15 letters by week 48 or 60 from start of treatment (according to ETDRS letter score); ● Gain at least 5, 10, or 15 letters by week 48 or 60 from the start of treatment (according to ETDRS letter score); -By week 4 after initiation of treatment, approximately 4 or 5 letters BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or 4 or 5 letters BCVA (ETDRS or Snellen equivalent) for HDq16 regimens improvement, By week 8 after treatment initiation, approximately 6 letter BCVA (ETDRS or Snellen equivalent) improvement for HDq12 regimens or approximately 5 or 6 letter BCVA (ETDRS or Snellen equivalent) improvement for HDq16 regimens , By week 12 after treatment initiation, approximately 6 or 7 letter BCVA (ETDRS or Snellen equivalent) improvement for HDq12 regimens or approximately 6 letter BCVA (ETDRS or Snellen equivalent) improvement for HDq16 regimens , ●By week 16 after initiation of treatment, improvement in BCVA of approximately 6 or 7 letters (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 7 letters (ETDRS or Snellen equivalent) for HDq16 regimens , ●By week 20 after the start of treatment, an improvement in BCVA of approximately 6 letters (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 6 letters of BCVA (ETDRS or Snellen equivalent) for HDq16 regimens; By week 24 after treatment initiation, approximately 7 letter BCVA (ETDRS or Snellen equivalent) improvement for HDq12 regimens or approximately 5 or 6 letter BCVA (ETDRS or Snellen equivalent) improvement for HDq16 regimens , -By week 28 after initiation of treatment, approximately 7 or 8 letters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 7 or 8 letters of BCVA (ETDRS or Snellen equivalent) for HDq16 regimens improvement, By week 32 after treatment initiation, approximately 7 letter BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 7 or 8 letter BCVA (ETDRS or Snellen equivalent) improvement for HDq16 regimens , By week 36 after treatment initiation, BCVA improvement of approximately 8 letters (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 6 or 7 letters (ETDRS or Snellen equivalent) for HDq16 regimens , ●By week 40 after treatment initiation, approximately 8 letter BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 6 or 7 letter BCVA (ETDRS or Snellen equivalent) improvement for HDq16 regimens , ●By week 44 after initiation of treatment, improvement in BCVA (ETDRS or Snellen equivalent) of approximately 8 letters for HDq12 regimens or approximately 7 or 8 letters for HDq16 regimens (ETDRS or Snellen equivalent) , -By week 48 after initiation of treatment, approximately 8 or 9 letters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 7 or 8 letters of BCVA (ETDRS or Snellen equivalent) for HDq16 regimens improvement, ● Improvement in BCVA is achieved by approximately 8 weeks after initiation of treatment and is then maintained during the treatment regimen until at least 48 weeks; ●By week 4 after initiation of treatment, approximately 68 characters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 66 characters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens; ●By week 8 after initiation of treatment, approximately 70 characters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 67 characters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens; ●By week 12 after initiation of treatment, approximately 70 characters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 68 characters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens; ●By week 16 after initiation of treatment, approximately 71 characters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 69 characters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens; ●By week 20 after the start of treatment, approximately 70 characters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 68 characters of BCVA (ETDRS or Snellen equivalent) for HDq16 regimens; ●By week 24 after initiation of treatment, approximately 71 characters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 67 characters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens; ●By week 28 after the start of treatment, approximately 72 characters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 70 characters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens; ●By week 32 after initiation of treatment, approximately 71 characters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 70 characters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens; ●By week 36 after initiation of treatment, approximately 71 characters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 68 characters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens; ●By week 40 after initiation of treatment, approximately 72 characters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 69 characters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens; ●By week 44 after initiation of treatment, approximately 72 characters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 70 characters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens; ●By week 48 after the start of treatment, approximately 73 characters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 70 characters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens; Improvement in BCVA (ETDRS or Snellen equivalent) of approximately 9 or 10 letters by week 48 after initiation of treatment when baseline BCVA is less than approximately 73 ETDRS letters for HDq12 regimens; ● Improvement in BCVA (ETDRS or Snellen equivalent) of approximately 5 or 6 letters by week 48 after initiation of treatment when baseline BCVA is greater than approximately 73 ETDRS letters for HDq12 regimens; ● Improvement in BCVA (ETDRS or Snellen equivalent) of approximately 8 or 9 letters by week 48 after initiation of treatment when baseline BCVA is less than approximately 73 ETDRS letters for HDq16 regimens; ● Improvement in BCVA (ETDRS or Snellen equivalent) of approximately 4 or 5 letters by week 48 after initiation of treatment when baseline BCVA is greater than approximately 73 ETDRS letters for HDq16 regimens; ● Improvement in BCVA (ETDRS or Snellen equivalent) of approximately 7 or 8 letters by week 48 after initiation of treatment when baseline CRT is less than approximately 400 micrometers for HDq12 regimens; ● Improvement in BCVA (ETDRS or Snellen equivalent) of approximately 9 or 10 letters by week 48 after initiation of treatment when baseline CRT is greater than approximately 400 micrometers for HDq12 regimens; ● Improvement in BCVA (ETDRS or Snellen equivalent) of approximately 5 or 6 letters by week 48 after initiation of treatment when baseline CRT is less than approximately 400 micrometers for HDq16 regimens; ● Improvement in BCVA (ETDRS or Snellen equivalent) of approximately 9 or 10 letters by week 48 after initiation of treatment when baseline CRT is greater than approximately 400 micrometers for HDq16 regimens; ● Obtaining a BCVA (according to ETDRS letter score) of >5, >10, or >15 letters by week 12, 24, 36, 49, 60, 72, 84, or 90 from the start of treatment; Improvement of 2 or more or 3 or more points on the Diabetic Retinopathy Severity Scale (DRSS) by 12, 24, 36, 49, 60, 72, 84, or 90 weeks from the start of treatment; ● Improvement of 2 or more points on the Diabetic Retinopathy Severity Scale (DRSS) by 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 weeks from the start of treatment; Fluid (total fluid , retina without intraretinal fluid [IRF] and / or subretinal fluid [SRF]), ● No vascular leakage as measured by fluorescein angiography (FA) by week 12, 24, 36, 49, 60, 72, 84, or 90 from the start of treatment; ● Retina free of fluid (total fluid in the foveal center and central subfields, IRF and / or SRF) by week 12, 24, 36, 49, 60, 72, 84, or 90 from the start of treatment. maintain, - A reduction in the total area of ​​fluorescein leakage within the ETDRS grid (mm2) at week 48 or week 60 by approximately 12, 13, or 14 mm2 or more, as measured by fluorescein angiography; ●Retina without fluid on spectral domain optical coherence tomography (SD-OCT) by 12, 24, 36, 49, 60, 72, 84, or 90 weeks from the start of treatment; ● By 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 weeks after the start of treatment, fluid (total fluid, retinal fluid [IRF], and / or retina without subretinal fluid [SRF]); Dry retina by 12, 24, 36, 49, 60, 72, 84, or 90 weeks from start of treatment, Fovea free of fluid by week 12, 24, 36, 49, 60, 72, 84, or 90 from the start of treatment, as measured by optical coherence tomography (OCT); -By week 4 after initiation of treatment, central retinal thickness of approximately -118 or -118.3 micrometers for HDq12 regimens or -124 or -125 or -124.9 or -125.5 micrometers for HDq16 regimens. change of, - Central retinal thickness of approximately -137 or -137.4 micrometers for HDq12 regimens or -139 or -140 or -139.6 or -140.3 micrometers for HDq16 regimens by week 8 after initiation of treatment. change of, - Central retinal thickness of approximately -150 or -150.1 micrometers for HDq12 regimens or -152 or -153 or -152.7 or -153.4 micrometers for HDq16 regimens by week 12 after the start of treatment. change of, - Central retinal thickness of approximately -139 or -139.4 micrometers for HDq12 regimens or -145 or -146 or -145.5 or -146.4 micrometers for HDq16 regimens by week 16 after the start of treatment. change of, - Central retinal thickness of approximately -117 or -117.1 micrometers for HDq12 regimens or -112 or -113 or -112.5 or -113.3 micrometers for HDq16 regimens by week 20 after the start of treatment. change of, - Central retinal thickness of approximately -158 or -158.1 micrometers for HDq12 regimens or -103 or -104 or -103.8 or -104.3 micrometers for HDq16 regimens by week 24 after initiation of treatment. change of, ●By week 28 after the start of treatment, a change in central retinal thickness of approximately -146 or -147 or -146.7 micrometers for HDq12 regimens or -162 or -162.3 micrometers for HDq16 regimens; ●By week 32 after the start of treatment, a change in central retinal thickness of approximately -132 micrometers for HDq12 regimens or -145 or -146 or -145.8 micrometers for HDq16 regimens; - Central retinal thickness of approximately -168 or -168.1 micrometers for HDq12 regimens or -124 or -125 or -124.7 or -125.2 micrometers for HDq16 regimens by week 36 after the start of treatment. change of, -By week 40 after the start of treatment, a change in central retinal thickness of approximately -163 micrometers for HDq12 regimens or -122 or -123 or -122.5 or -123.1 micrometers for HDq16 regimens; - Central retinal thickness of approximately -147 or -148 or -147.4 micrometers for HDq12 regimens or -164 or -164.1 or -164.3 micrometers for HDq16 regimens by week 44 after initiation of treatment. change of, By week 48 after the start of treatment, approximately -171 or -172 or -171.7 micrometers for HDq12 regimens or about -148 or -149 or -148.3 or -149.4 micrometers for HDq16 regimens. changes in central retinal thickness, • By week 60 after the start of treatment, a change in central retinal thickness of approximately -181.95 or -176.24 micrometers for HDq12 regimens or -166.26 or -167.18 micrometers for HDq16 regimens; ● Change in central retinal thickness between the start of treatment (week 0) and week 4 of approximately -118 or -119 or -118.3 micrometers for HDq12 regimens; ● Change in central retinal thickness between weeks 4 and 8 of approximately -19, -20, or -19.1 micrometers for HDq12 regimens; ● Change in central retinal thickness between weeks 8 and 12 of approximately -12, -13, or -12.7 micrometers for HDq12 regimens; ● Change in central retinal thickness between weeks 20 and 24 of approximately -40 or -41 micrometers for HDq12 regimens; ● Change in central retinal thickness between weeks 32 and 36 of approximately -36, -37, or -36.1 micrometers for HDq12 regimens; ● Change in central retinal thickness between weeks 44 and 48 of approximately -24, -25, or -24.3 micrometers for HDq12 regimens; ● Change in central retinal thickness between weeks 48 and 60 of approximately -4, -5, or -4.5 micrometers for HDq12 regimens; ● Change in central retinal thickness between the start of treatment (week 0) and week 4 of approximately -124, -125, or -124.9 micrometers for HDq16 regimens; ● Change in central retinal thickness between weeks 4 and 8 of approximately -14, -15, or -14.7 micrometers for HDq16 regimens; ● Change in central retinal thickness between weeks 8 and 12 of approximately -13, -14, or -13.1 micrometers for HDq16 regimens; ● Change in central retinal thickness between weeks 24 and 28 of approximately -58, -59, or -58.5 micrometers for HDq16 regimens; ● Change in central retinal thickness between weeks 40 and 44 of approximately -41, -42, or -41.6 micrometers for HDq16 regimens; ● Central retinal thickness reduction maintained within +17, +18, or +19 micrometers by approximately 4, 5, 6, 7, or 8 weeks after the start of treatment, and then at least 48 will be maintained until the end of the week, A decrease in central retinal thickness of approximately 100, 125, 150, 175, or 200 micrometers by 12, 24, 36, 49, 60, 72, 84, or 90 weeks from the start of treatment; ●A baseline CRT of approximately 449, 450, 455, or 460 micrometers, approximately 148 to 182 micrometers from the start of treatment to approximately 48 or 60 weeks, as measured by optical coherence tomography (OCT). decrease in central retinal thickness, ● 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, 145 , 149, 150, 155, 160, 165, 170, 171, 172, 173, 174, or 175 micrometer central retinal thickness (CRT) decrease; - Approximately 0.1667 days after the first dose, free aflibercept in the plasma is approximately 0.149 (± 0.249) mg / l, and at baseline, free aflibercept is undetectable in the plasma and the subject has been present for at least 12 weeks. not received intravitreal aflibercept treatment; ●About 0.3333 days after the first dose, free aflibercept in plasma was approximately 0.205 (±0.250) mg / l, and at baseline, free aflibercept in plasma was undetectable, and the subject have not received intracorporeal aflibercept treatment for at least 12 weeks; ●Approximately 1 day after the first administration, free aflibercept in plasma was approximately 0.266 (±0.211) mg / l, and at baseline, free aflibercept in plasma was undetectable, and the subject have not received aflibercept treatment for at least 12 weeks; ●Approximately 2 days after the first administration, free aflibercept in the plasma was approximately 0.218 (±0.145) mg / l, and at baseline, free aflibercept in the plasma was undetectable, and the subject have not received aflibercept treatment for at least 12 weeks; ●Approximately 4 days after the first dose, free aflibercept in the plasma was approximately 0.140 (±0.0741) mg / l, and at baseline, free aflibercept in the plasma was undetectable and the subject have not received aflibercept treatment for at least 12 weeks; Approximately 7 days after the first dose, free aflibercept in plasma is approximately 0.0767 (±0.0436) mg / l, and free aflibercept in plasma is undetectable at baseline and the subject has been present for at least 12 weeks. not received intravitreal aflibercept treatment; Approximately 14 days after the first dose, free aflibercept in plasma is approximately 0.0309 (± 0.0241) mg / l, and free aflibercept in plasma is undetectable at baseline and the subject has been present for at least 12 weeks. not received intravitreal aflibercept treatment; ●Approximately 21 days after the first dose, free aflibercept in the plasma was approximately 0.0171 (±0.0171) mg / l, and at baseline, free aflibercept in the plasma was undetectable, and the subject have not received aflibercept treatment for at least 12 weeks; ●Approximately 28 days after the first dose, free aflibercept in the plasma was approximately 0.00730 (±0.0113) mg / l, and at baseline, free aflibercept in the plasma was undetectable and the subject was in the vitreous have not received aflibercept treatment for at least 12 weeks; ● Approximately 0.1667 days after the first dose, there was approximately 0.00698 (±0.0276) mg / l of adjusted bound aflibercept in plasma; at baseline, there was approximately 0.00583 mg / l (±0.0280) adjusted bound aflibercept; , the subject has not received intravitreal aflibercept treatment for at least 12 weeks, - Approximately 0.3333 days after the first dose, there was approximately 0.00731 (±0.0279) mg / l of adjusted bound aflibercept in the plasma, and at baseline there was approximately 0.00583 mg / l (±0.0280) adjusted bound aflibercept. , the subject has not received intravitreal aflibercept treatment for at least 12 weeks, ● Approximately 1 day after the first dose, there was approximately 0.0678 (±0.0486) mg / l of adjusted bound aflibercept in plasma; at baseline, there was approximately 0.00583 mg / l (±0.0280) adjusted bound aflibercept. , the subject has not received intravitreal aflibercept treatment for at least 12 weeks, - Approximately 2 days after the first dose, there is approximately 0.138 (± 0.0618) mg / l of adjusted bound aflibercept in plasma, and at baseline approximately 0.00583 mg / l (± 0.0280) adjusted bound aflibercept; the subject has not received intravitreal aflibercept treatment for at least 12 weeks; - Approximately 4 days after the first dose, there is approximately 0.259 (± 0.126) mg / l of adjusted bound aflibercept in plasma, and approximately 0.00583 mg / l (± 0.0280) adjusted bound aflibercept at baseline; the subject has not received intravitreal aflibercept treatment for at least 12 weeks; - Approximately 7 days after the first dose, there is approximately 0.346 (± 0.151) mg / l of adjusted bound aflibercept in plasma, and approximately 0.00583 mg / l (± 0.0280) adjusted bound aflibercept at baseline; the subject has not received intravitreal aflibercept treatment for at least 12 weeks; - Approximately 14 days after the first dose, there is approximately 0.374 (± 0.110) mg / l of adjusted bound aflibercept in plasma, and approximately 0.00583 mg / l (± 0.0280) adjusted bound aflibercept at baseline; the subject has not received intravitreal aflibercept treatment for at least 12 weeks; - Approximately 21 days after the first dose, the adjusted bound aflibercept in plasma was approximately 0.343 (± 0.128) mg / l, and at baseline there was approximately 0.00583 mg / l (± 0.0280) adjusted bound aflibercept. and the subject has not received intravitreal aflibercept treatment for at least 12 weeks, - Approximately 28 days after the first dose, the adjusted bound aflibercept in plasma is approximately 0.269 (± 0.149) mg / l, and there is approximately 0.00583 mg / l (± 0.0280) adjusted bound aflibercept at baseline. and the subject has not received intravitreal aflibercept treatment for at least 12 weeks, ●Maximum concentration of free aflibercept in plasma is reached approximately 0.965 days after the first dose; ●Free aflibercept in plasma reaches a maximum concentration of approximately 0.310 mg / l (±0.263), ● Free aflibercept in plasma of about 0 to about 1.08 mg / L, ● Maximum free aflibercept (mg / l) in plasma per dose (mg) of aflibercept of approximately 0.388 (±0.0328) mg / l / mg; Maximum concentration of regulated aflibercept in plasma is reached approximately 14 days after the first dose; ● reach a maximum concentration of regulated bound aflibercept of approximately 0.387 mg / l (±0.135) in plasma; ●Adjusted binding aflibercept in plasma of about 0.137 to about 0.774 mg / L, ● Maximum adjusted bound aflibercept (mg / l) in plasma per dose (mg) of aflibercept of approximately 0.483 (±0.0168) mg / l / mg; ● not have anti-drug antibodies to aflibercept after 48 or 60 weeks of treatment; ● Improvement from pre-treatment baseline in National Institute of Ophthalmology Visual Function Questionnaire (NEI-VFQ) total score, and / or ● Lack of macular edema.

[0081] The present invention provides VEGF receptor fusion proteins for use in the treatment and prevention of diabetic retinopathy and / or diabetic macular edema in a subject in need thereof; One initial dose, two secondary doses, and three tertiary doses of VEGF receptor fusion protein of greater than 8 mg are administered to subjects in year 1; One initial dose, two secondary doses, and two tertiary doses of VEGF receptor fusion protein of greater than 8 mg are administered to the subject in year 1, or One initial dose, two secondary doses, and three tertiary doses of >8 mg 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.

[0082] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, wherein the interval between administrations of 8 mg of the VEGF receptor fusion protein is , adjusted (increase / maintain / decrease) based on visual and / or anatomical results.

[0083] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of diabetic retinopathy and / or diabetic macular edema 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.

[0084] 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 comprises a VEGF receptor fusion protein at a concentration of 100 mg / mL or more, or the container comprises 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 (114.3 mg / mL) of aflibercept intravitreal injection solution; ii) each single-dose vial is intended for use in adult patients. iii) the recommended dose is 8 mg aflibercept (equivalent to 70 microliter solution for injection); iv) 8 mg aflibercept treatment is initiated with 3 consecutive doses of monthly injections (every 4 weeks); v) injection intervals may then be extended to every 16 weeks or every 20 weeks; vi) The treatment interval may be adjusted based on the physician's judgment regarding visual and / or anatomical results, and / or vii) 8 mg aflibercept / 0.07 mL is combined with arginine monohydrochloride, histidine, histidine hydrochloride monohydrate. Supplemented as a sterile aqueous solution containing Polysorbate 20, Sucrose, and Water for Injection. [Brief explanation of the drawing]

[0085]

Figure 1

Figure 2

table 1

[0086] 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.

[0087] EYLEA has become a standard treatment for diabetic macular edema (DME) and diabetic retinopathy (DR). Eylea is prescribed for DME and DR at a dose of 2 mg once a month for 5 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 durability 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 DR or DME. The data presented herein demonstrate that 12- and 16-week dosing regimens of aflibercept 8 mg maintain a high bar of improvement in visual acuity and retinal fluid anatomical measures over 48 weeks in subjects with diabetic macular edema. demonstrated that it had been achieved. 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.

[0088] 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 that 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.

[0089] The predicted population PK median time for plasma free aflibercept concentration to reach the lower limit of quantification (LLOQ) after 2 mg aflibercept IVT is 1.5 weeks compared to 3.50 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).

[0090] The standard method in molecular biology is Sambrook, Fritsch and Maniatis (1982&1989 2 nd Edition,2001 3 rd Edition), Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., Sambrook and Russell (2001) Molecular Cloning, 3 rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., Wu (1993) Recombinant DNA, Vol. 217, Academic Press, San Diego, CA). Standard methods are also found in Ausbel, et al. (2001) Current Protocols in Molecular Biology, Vols. 1-4, John Wiley and Sons, Inc., which describes cloning and DNA mutations in bacterial cells. Covers mutagenesis (Volume 1), cloning in mammalian cells and yeast (Volume 2), glycoconjugates and protein expression (Volume 3), and bioinformatics (Volume 4).

[0091] General methods for protein purification are described, including immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization (Coligan et 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).

[0092] Methods of flow cytometry are available, including fluorescence-activated cell sorting (FACS) (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).

[0093] 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).

[0094] "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.

[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, including, for example, parafoveal lesions affecting the fovea of ​​the eye; 3. About 78-24, 73-78, less than 73, 58, 59, 60, 61, 62, or 63 (20 / 40, 20 / 63, 20 / 50, 20 have a best-corrected visual acuity (BCVA) early treatment diabetic retinopathy test (ETDRS) letter score) of / 32, or Snellen equivalent of 20 / 320); 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 (insulin dependent or non-insulin dependent) (e.g. for about 15 years or more); 8. Hemoglobin A1C (%) of about 7 or 8 or higher, 9. Body mass index of approximately 30 or 31 or higher, and / or 10. Diabetic retinal edema, diabetic retinopathy, dry eye, vitreous detachment, retinopathy hypersensitivity, fundus hemorrhage, cataract surgery, retinal laser coagulation, and intraocular lens implants, hypertension, Having or lacking any one or more of the following characteristics: 1. Evidence of macular edema from any cause other than diabetes mellitus in the eye, 2. IOP of 25 mmHg or more in the eye, 3. History of past glaucoma filtration surgery or likely need for future ocular filtration surgery; 4. Evidence of infectious blepharitis, keratitis, scleritis, or conjunctivitis in either eye within 4 weeks (28 days) of treatment; 5. Any intraocular inflammation and / or ocular infection in the eye within 12 weeks (84 days) of treatment; 6. History of idiopathic or autoimmune uveitis in the eye, 7. Vitreous macular traction or premacular membrane in the eye evident on intravital microscopy or OCT, thought to affect central vision; 8. Anterior retinal fibrosis, including the macula of the eye, 9. Any history of stage 2 or higher macular hole in the eye, 10. Current iris neovascularization, vitreous hemorrhage, or tractional retinal detachment visible on ocular screening evaluation; 11. History of ocular corneal transplant surgery or corneal dystrophy; 12. Concomitant ocular conditions in the eye that, in the opinion of the treating physician, increase the risk to the subject beyond what would be expected from the standard procedure for IVT injection or that may otherwise interfere with the VEGF antagonist injection procedure; 13. History of other diseases, metabolic dysfunction, physical examination findings, or laboratory findings that give a reasonable suspicion of a disease or condition that contraindicates the use of a VEGF antagonist; 14. Any prior systemic (IV) anti-VEGF administration; uncontrolled diabetes mellitus defined by hemoglobin A1c (HbA1c) greater than 15.12%; 16. Uncontrolled blood pressure (defined as >160 mmHg systolic or >95 mmHg diastolic); 17. History of cerebrovascular accident or myocardial infarction within 24 weeks (168 days) of treatment; 18. History of renal failure, dialysis, or renal transplant; 19. Known sensitivity to any of the compounds administered in the treatment, and / or 20. Women who are pregnant or breastfeeding.

[0096] Accordingly, the present invention includes methods of treating or preventing DR and / or DME in a subject in need thereof. 1. Age is 50 years or older, 2. Has active subfoveal CNV; 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. No evidence of macular edema from any cause other than diabetes mellitus in the eye, 2. Does not have an IOP of 25 mmHg or more in the eye, 3. Has no past history of glaucoma filtration surgery or is unlikely to require future filtration surgery in the eye; 4. Has no evidence of infectious blepharitis, keratitis, scleritis, or conjunctivitis in either eye within 4 weeks (28 days) of treatment; 5. Does not have intraocular inflammation and / or ocular infection in the eye within 12 weeks (84 days) of treatment; 6. No history of corneal transplant surgery or corneal dystrophy in the eye; 7. Does not have vitreomacular traction or premacular membrane in the eye; 8. Does not have preretinal fibrosis involving the macula in the eye; 9. No history of stage 2 or higher macular hole in the eye; 10. Does not have visible current iris neovascularization, vitreous hemorrhage, or tractional retinal detachment; 11. No history of corneal transplant surgery or corneal dystrophy in the eye; 12. Has a comorbid ocular condition that, in the opinion of the treating physician, increases the risk to the subject beyond what would be expected from the standard procedure for IVT injection or that may otherwise interfere with the VEGF antagonist injection procedure. I haven't done it, 13. Does not have a history of other diseases, metabolic dysfunction, physical examination findings, or laboratory findings that would give a reasonable suspicion of a disease or condition that contraindicates the use of VEGF antagonists; 14. No previous systemic (IV) anti-VEGF administration; not have uncontrolled diabetes mellitus as defined by hemoglobin A1c (HbA1c) greater than 15.12%; 16. Does not have uncontrolled blood pressure (defined as >160 mmHg systolic or >95 mmHg diastolic); 17. No history of CVA or myocardial infarction within 24 weeks (168 days) of treatment; 18. No history of renal failure, dialysis, and / or renal transplantation; 19. Has no known sensitivity to any of the compounds administered in the treatment and / or 20. Not pregnant or breastfeeding; 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. 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.

[0100] 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.

[0101] 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. atggtcagctactgggacaccggggtcctgctgtgcgcgctgctcagctgtctgcttctcacaggatctagttccggaagtgataccggtagacctttcgtagagatgtacagtgaaatccccgaaattatacacatgactgaaggaagggagctcgtcattccctgccgggttacgtcacctaacatcactgttactttaaaaaagt ttccacttgacactttgatccctgatggaaaacgcataatctgggacagtagaaagggcttcatcatatcaaatgcaacgtacaaagaaatagggcttctgacctgtgaagcaacagtcaatgggcatttgtataagacaaactatctcacacatcgacaaaccaatacaatcatagatgtggttctgagtccgtctcatggaattgaactatctgtt ggagaaaagcttgtcttaaattgtacagcaagaactgaactaaatgtggggattgacttcaactgggaatacccttcttcgaagcatcagcataagaaacttgtaaaccgagacctaaaaacccagtctgggagtgagatgaagaaattttttgagcaccttaactatagatggtgtaacccggagtgaccaaggattgtacacctgtgcagcatccagt gggctgatgaccaagaagaacagcacatttgtcagggtccatgaaaaggacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaag ttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggca gccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgt ggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaatga (Sequence number 1) MVSYWDTGVLLCALLSCLLLTGSSSGSDTGRPFVEMYSEIPEIIIHMTEGRELVIPCRVTS PNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLT HRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRD LKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (Sequence number 2)

[0102] 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).

[0103] For example, in an embodiment of the invention, a VEGF receptor fusion protein has the following arrangement of the 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).

[0104] 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 approximately 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 abiciper pegol 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

[0105] 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.

[0106] 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.

[0107] An "anti-VEGF" antibody or antigen-binding fragment of an antibody refers to an antibody or fragment that specifically binds to VEGF.

[0108] 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.

[0109] 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).

[0110] 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 are available in the formulary known to all pharmacists: Remington's Pharmaceutical Sciences (No. 15). (Ed., Mack Publishing Company, Easton, Pennsylvania, 1975), for example, by Blaug, Seymour, chapter 87.

[0111] 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, eg, 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 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.

[0112] 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 discussed herein, no more than about 100 μl, no more than about 75 μl, or no more than 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.

[0113] 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").

[0114] 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 and histidine hydrochloride or histidine acetate. Buffers for inclusion in the formulations herein may alternatively be phosphate-based buffers, e.g. sodium phosphate, acetate-based buffers, e.g. sodium acetate or acetic acid, or citrate-based, e.g. , sodium citrate or 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 solutions are 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 It can be 20mM, about 21mM, about 22mM, about 23mM, about 24mM, or about 25mM.

[0115] In one embodiment of the invention, a histidine-based buffer is prepared using histidine and histidine monohydrochloride.

[0116] 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).

[0117] 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.

[0118] 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.

[0119] 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).

[0120] 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).

[0121] 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.

[0122] 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.).

[0123] 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 (e.g., L-arginine hydrochloride), lysine, or other viscosity-lowering agents.

[0124] 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.

[0125] 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, with 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; 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 mM L-arginine (e.g. L-arginine). hydrochloride) Formulation UUU: 30 mg / ml VEGF receptor fusion protein (e.g. aflibercept), 10% sucrose, 10 mM phosphate, 0.03% polysorbate 20, 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 50 mM L-arginine (e.g., L-arginine hydrochloride), 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 (e.g. L-arginine hydrochloride), (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 (e.g. 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 (e.g. 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 (e.g. 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 (e.g. 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 50mM L-arginine (e.g. 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 (e.g. L-arginine monohydrochloride) (e.g. ±5mM),

[0126] See International Patent Application Publication No. WO2019 / 217927.

[0127] 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 containing 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.

[0128] 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 at least about 100 mg / ml of a VEGF receptor fusion protein (e.g., aflibercept) comprising two polypeptides each containing a chemical component, about 10 to 100 mM L-arginine, sucrose, and a histidine-based buffer; a surfactant, the formulation has a pH of about 5.0 to about 6.8, and the VEGF receptor fusion protein contains less than about 3.5% high molecular weight species and / or about It has about 6% or less high molecular weight species after being stored at 2-8°C for about 24 months.

[0129] In one embodiment of the invention, the aqueous pharmaceutical formulation comprises: ·About 100 mg / ml or more of a VEGF receptor fusion protein (e.g., aflibercept), a histidine-based buffer, and L-arginine, ·Approximately 140mg / ml aflibercept, 20mM histidine-based buffer, 5% sucrose, 0.03% polysorbate 20, 10mM arginine, pH 5.8, ·Approximately 150 ± 15 mg / ml aflibercept, 10 mM phosphate buffer, 8 ± 0.8% (w / v) sucrose, 0.02-0.04% (w / v) polysorbate 20, and 50 mM 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, 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 of incubation at 5°C; ·About 114.3mg / mL aflibercept, 10mM~50mM histidine-based buffer, sugar, nonionic surfactant, L-arginine, pH5.8, Or · Contains approximately 114.3 mg / mL aflibercept, 10 mM His / His-HCl based buffer, 5% sucrose, 0.03% polysorbate 20, 50 mM L-arginine, pH 5.8.

[0130] 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 L-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).

[0131] 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.

[0132] 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.

[0133] 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.

[0134] Treatment and administration The present invention provides an initial loading dose (e.g., 2 mg or more, 4 mg or more, or preferably about 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). or every 3 to 5 weeks) followed by sequential administration of additional doses every 12 to 20 weeks, preferably every 12 to 16 weeks, 12 weeks, 16 weeks, or 20 weeks. (eg, DR and / or DME). For example, the present invention provides a dose of about 8 mg or more of a VEGF antagonist (e.g., African One or more (e.g., 3 or 4 or 5) consecutive administrations of a VEGF receptor fusion protein, such as bercept, followed by about 8 mg or more of a VEGF receptor fusion protein, such as aflibercept. fusion protein) every 12 weeks (or about 3 months or about 1 / 4 year or about 84 days) or every 16 weeks (or about 4 months or about 1 / 3 year or about The present invention provides a method for treating or preventing neovascular eye disorders such as diabetic macular edema (DME) and / or diabetic retinopathy (DR) by administering a 12-week tertiary treatment (every 112 days) or every 20 weeks. Dosing regimens that include intervals of doses may be referred to herein as 12-week dosing regimens or 8q12 or HDq12. Dosing regimens that include tertiary dose intervals of 16 weeks may be referred to herein as 16-week dosing regimens. or 8q16 or HDq16, a dosing regimen comprising a 20 week tertiary dose interval may be referred to herein as a 20 week dosing regimen or 8q20 or HDq20.

[0135] 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 for 3, 4, or 5 doses of angiogenic eye disorders (e.g., DR and / or DME) every 4 weeks, followed by one or more doses about every 8 weeks. including methods of treating.

[0136] In one embodiment of the invention, subjects begin receiving a monthly loading dose of 8 mg followed by a maintenance dose of 8 mg or more every 12 or 16 or 20 weeks, without intervention doses. 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 or 16 or 20 weeks without any intervention doses.

[0137] 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.

[0138] The invention also provides one or more (e.g., 3 or 4 or 5) doses in subjects with type 1 or type 2 diabetes mellitus (e.g., subjects with diabetic macular edema or diabetic retinopathy). about every month (or about every 28 days, every 28±5 days or about every 4 weeks), followed by one or more doses every 12 weeks (or about every 3 months or about every 4 years or about every 84 days) or 16 Methods are provided for improving visual acuity by sequential administration every week (or about every 4 months or about every 1 / 3 year or about every 112 days) or every 20 weeks.

[0139] 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).

[0140] Therefore, the dosing regimen of the present invention can be expressed as follows. Method (I) for treating a neovascular eye disorder (e.g., DME or DR) in a subject in need thereof comprises administering a single initial dose (e.g., about 8 mg or more, e.g., about 100 μl or less) to a subject in need thereof. , 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, 63 μl, 64 μl, 65 μl, 66 μl, 67 μl, 68 μl , 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 , 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), 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 tertiary dose is administered 12 or 16 or 20 weeks (preferably about 12-16, 12 or 16 or 20 weeks) after the immediately preceding dose.

[0141] 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 of treating neovascular eye disorders based on PRN.

[0142] A pro re nata (PRN) treatment protocol consists of fixed physician visit intervals (e.g., once every 2, 3, 4, 8, 12, 16, or 20 weeks) and anatomical findings at each visit. requires a decision to perform a VEGF receptor fusion protein injection based on 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.

[0143] 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.

[0144] 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 then HDq12-20, HDq12, HDq16, or HDq20 regimens may be continued at any stage. will be resumed. There may be a period of PRN, capped PRN, and / or T&E before or after any HDq12-20, HDq12, HDq16 or HDq20 regimen.

[0145] The present invention provides a method comprising administering the required doses of an HDq12 or HDq16 regimen, each tertiary dose being administered 12 or 16 weeks after the immediately preceding dose, e.g. The treatment interval between two tertiary doses (e.g., from 12 weeks to 13, 14, 15, 16, or 20 weeks, or from 16 weeks to 17, 18, 19, or 20 weeks) until worsening or relapse. and then continuing administration at the last tertiary interval used or the penultimate tertiary interval used.

[0146] 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 19, 18, 17, 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 (to 2 weeks), then optionally the interval between doses can be extended, eg, back to a longer interval length.

[0147] For example, in one embodiment of the invention, the intervals between dosing phases, e.g. or from 16 weeks to 20 weeks). · For example, from week 12, loss of less than 5 letters of BCVA, and / or ·CRT <300 μm on SD-OCT (or <320 μm on Spectralis SD-OCT). 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] In one embodiment of the invention, the methods of treating neovascular eye disorders such as DR or DME described herein include the steps of: assessing BCVA and / or CRT; and if one or both of the criteria are met. and extending the spacing as described in .

[0149] For example, in one embodiment of the invention, during the administration phase of, for example, 12 to 20 weeks or 12 weeks or 16 weeks or 20 weeks, the interval between doses is (e.g., from 12 or 16 or 20 weeks to 8 week, 16 or 20 weeks to 12 weeks, or 20 weeks to 16 weeks). For example, due to persistent or worsening DR or DME (e.g., compared to the BCVA observed approximately 12 or 16 weeks after the start of treatment), a BCVA of more than 5 or 10 letters (ETDRS or Snellen equivalent) has been lost and / or · An increase in CRT of more than 25 or 50 micrometers is observed (e.g., compared to CRT observed at approximately 12 weeks after initiation of treatment).

[0150] In one embodiment of the invention, the interval between dosing is shortened to 8 weeks if, for example, the criteria for shortening the interval between dosing are met in a subject receiving the HDq12 regimen at week 16 or week 20. In one embodiment of the invention, the dose interval is shortened to 8 weeks, e.g., if the criteria for shortening the dose interval are met in a subject receiving an HDq16 regimen at week 16 or week 20, e.g. If the criteria for shortening the dose interval are met for subjects receiving the HDq16 regimen at week 24, the dose interval will be shortened to 12 weeks. In one embodiment of the invention, the interval is not reduced to less than 8 weeks. In one embodiment of the invention, the methods of treating neovascular eye disorders such as DR or DME described herein include the steps of: assessing BCVA and / or CRT; and if one or both of the criteria are met. and shortening the spacing as described in .

[0151] Please refer to Figure 3 or Figure 4.

[0152] 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 or 9 doses (e.g., about 5 doses or 6 doses) of 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) , 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 , 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) of a VEGF antagonist (e.g., Aflibel VEGF receptor fusion proteins such as sept) for about 48 weeks.

[0153] 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). 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.

[0154] 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). Administration “every 8 weeks” or after “8 weeks” refers to administration after about 2 months (±5 days) or about 56 days (±5 days).

[0155] 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. Administration “every 16 weeks” or after “16 weeks” refers to administration after about 4 months or about 112 days (±5 days).

[0156] 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).

[0157] 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).

[0158] 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.

[0159] 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.

[0160] 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) .

[0161] 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.

[0162] Baseline value refers to the value before the start of treatment (pre-administration).

[0163] "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 angiogenesis, ·Neovascular glaucoma, ·Postoperative fibrosis of glaucoma, ·Proliferative vitreoretinopathy (PVR), ·Optic disc neovascularization, ·Cornea neovascularization, ·Retinal neovascularization, ·Vitreous neovascularization, ·Pannus, ·pterygia, ·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).

[0164] The present invention provides methods for treating neovascular eye disorders (e.g., DR and / or DME) in a subject in need thereof, the methods comprising administering an initial loading dose (e.g., 2 mg or more, 4 mg or more, or Preferably about 8 mg or more of a 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 every 3 weeks). initial loading dose), followed by consecutive administrations every 12 to 20 weeks, preferably every 12 to 16 weeks, 12 weeks, 16 weeks, or 20 weeks; Weeks 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 achieve and / or maintain: ● Improvement in the Diabetic Retinopathy Severity Scale (DRSS), e.g. by at least 2 or 3 steps; ●Improvement of best-corrected visual acuity, ●Dry retina, ● Gain in best-corrected visual acuity, ● Obtaining best-corrected visual acuity of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 letters, or 5 or more, 10 or more, or 15 or more letters; ● BCVA of at least 69 characters, ● a decrease in central retinal thickness (CRT), e.g., approximately 100, 125, 150, 175, or 200 micrometers; ●No vascular leakage as measured by fluorescein angiography (FA), ●Improvement from pre-treatment baseline in National Ophthalmological Society Visual Function Questionnaire (NEI-VFQ-25) total score; ● Retina without fluid (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF]) in the foveal center and central subfield; • Maintenance of a fluid-free retina (total fluid, IRF, and / or SRF in the foveal center and central subfield); ● Lack of macular edema, ●Retina without fluid on spectral domain optical coherence tomography (SD-OCT) and / or • Do not deviate from HDq12 or HDq16 treatment regimens once initiated.

[0165] In one embodiment of the invention, subjects receiving HDq12 or HDq16 or HDq20 treatment for neovascular eye disorders (e.g., DR and / or DME) described herein are one of the following: Accomplish one or more. - At least 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, Reduced from HDq12-20 or HDq12 or HDq16 or HDq20 treatment regimen for 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, or 96 weeks. ● 100% of all scheduled doses, e.g. at least 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72 , administered for 76, 80, 84, 88, 92, or 96 weeks; Compare with aflibercept administered intravitreally at 2 mg approximately every 4 weeks for the first 3, 4, or 5 injections, followed by 2 mg approximately once every 8 weeks or once every 2 months. non-inferior BVCA, For example, baseline BCVA is approximately 61, 62 and 63; an increase in BCVA (by ETDRS letter score) of approximately 7, 8, or 9 letters by weeks 72, 76, 80, 84, 88, 92, or 96; -By week 4 after initiation of treatment, approximately 4 or 5 letters BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or 4 or 5 letters BCVA (ETDRS or Snellen equivalent) for HDq16 regimens improvement, By week 8 after treatment initiation, approximately 6 letter BCVA (ETDRS or Snellen equivalent) improvement for HDq12 regimens or approximately 5 or 6 letter BCVA (ETDRS or Snellen equivalent) improvement for HDq16 regimens , By week 12 after treatment initiation, approximately 6 or 7 letter BCVA (ETDRS or Snellen equivalent) improvement for HDq12 regimens or approximately 6 letter BCVA (ETDRS or Snellen equivalent) improvement for HDq16 regimens , ●By week 16 after initiation of treatment, improvement in BCVA of approximately 6 or 7 letters (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 7 letters (ETDRS or Snellen equivalent) for HDq16 regimens , ●By week 20 after the start of treatment, an improvement in BCVA of approximately 6 letters (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 6 letters of BCVA (ETDRS or Snellen equivalent) for HDq16 regimens; By week 24 after treatment initiation, approximately 7 letter BCVA (ETDRS or Snellen equivalent) improvement for HDq12 regimens or approximately 5 or 6 letter BCVA (ETDRS or Snellen equivalent) improvement for HDq16 regimens , -By week 28 after initiation of treatment, approximately 7 or 8 letters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 7 or 8 letters of BCVA (ETDRS or Snellen equivalent) for HDq16 regimens improvement, ●By week 32 after treatment initiation, approximately 7 letter BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 7 or 8 letter BCVA (ETDRS or Snellen equivalent) improvement for HDq16 regimens , By week 36 after treatment initiation, BCVA improvement of approximately 8 letters (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 6 or 7 letters (ETDRS or Snellen equivalent) for HDq16 regimens , ●By week 40 after initiation of treatment, improvement in BCVA of approximately 8 letters (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 6 or 7 letters (ETDRS or Snellen equivalent) for HDq16 regimens , By week 44 after treatment initiation, BCVA improvement of approximately 8 letters (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 7 or 8 letters (ETDRS or Snellen equivalent) for HDq16 regimens , ●By week 48 after initiation of treatment, BCVA of approximately 8 or 9 letters for HDq12 regimens (ETDRS or Snellen equivalent) or approximately 7 or 8 letters for HDq16 regimens (ETDRS or Snellen equivalent, e.g. Baseline BCVA improved by approximately 61, 62, or 63 characters (ETDRS or Snellen equivalent); ●By week 60 after initiation of treatment, approximately 8 or 9 letters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 7 or 8 letters (ETDRS or Snellen equivalent improvement) for HDq16 regimens; For example, the baseline BCVA is approximately 61, 62, or 63 characters (ETDRS or Snellen equivalent); ● Between weeks 48 and 60, for example, when the baseline BCVA is approximately 63 or 64, approximately 8 or 9 letters or up to 40 letters (ETDRS or Snellen equivalent) for HDq12 regimens. BCVA or between weeks 48 and 60, for example, when baseline BCVA is approximately 61 or 62, approximately 7 or 8 or up to 40 characters (ETDRS or Snellen equivalent) for HDq16 regimens improvement of BCVA, ● Improvement in BCVA (e.g., within ±1 or ±2 ETDRS letters or Snellen equivalents) is achieved by about 8 weeks after initiation of treatment and maintained during subsequent treatment regimens, e.g., until at least 48 weeks; ● Improvement in best-corrected visual acuity (by ETDRS letter score) (e.g., by week 12, 24, 36, 48, 60, 72, 84, 90, or 96 after initiation of treatment); ●4th week, 8th week, 12th week, 16th week, 20th week, 24th week, 28th week, 32nd week, 36th week, 40th week, 44th week from the start of treatment, or Improvement in best corrected visual acuity (BVCA) by week 48; ● (e.g., by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 after the start of treatment) e.g. Early Treatment Diabetic Retinopathy Screening (ETDRS) visual acuity BCVA increase of 5 or more, 6 or more, 4 or more, 7 or more, 8 or more, 9 or 10 characters as measured by table or Snellen equivalent; ● Approximately 7, 8, or 9 change in BCVA score (according to ETDRS letter score) from the start of treatment between weeks 36 and 48, e.g. BCVA at the moment is about 60 or 70, ● Between weeks 36 and 48, change in BCVA score (according to ETDRS letter score) of up to 38 letters from the start of treatment for HDq12 or HDq16 regimens, e.g., BCVA at baseline is ~27~ 79, ● Approximately 7, 8, or 9 change in BCVA score (according to ETDRS letter score) from the start of treatment between weeks 48 and 60, e.g. The BCVA at the time is approximately 69, 70, 71, 72, or 73, ● Improvement in BCVA (ETDRS or Snellen equivalent) of approximately 9 or 10 letters, e.g., by week 48 after initiation of treatment, when baseline BCVA is approximately 73 ETDRS letters or less on an HDq12 regimen; ● Improvement in BCVA (ETDRS or Snellen equivalent) of approximately 5 or 6 letters, e.g., by week 48 after initiation of treatment, when baseline BCVA is greater than approximately 73 ETDRS letters on an HDq12 regimen; ● Improvement in BCVA (ETDRS or Snellen equivalent) of approximately 8 or 9 letters, e.g., by week 48 after initiation of treatment, when baseline BCVA is approximately 73 ETDRS letters or less on an HDq16 regimen; ● Improvement in BCVA (ETDRS or Snellen equivalent) of approximately 4 or 5 letters, e.g., by week 48 after initiation of treatment, when baseline BCVA is greater than approximately 73 ETDRS letters on an HDq16 regimen; ● Improvement in BCVA (ETDRS or Snellen equivalent) of approximately 7 or 8 letters, e.g. by week 48 after initiation of treatment, when baseline CRT is less than approximately 400 micrometers for HDq12 regimens; ● Improvement in BCVA (ETDRS or Snellen equivalent) of approximately 9 or 10 letters, e.g., by week 48 after initiation of treatment, when baseline CRT is approximately 400 micrometers or greater for HDq12 regimens; ● Improvement in BCVA (ETDRS or Snellen equivalent) of approximately 5 or 6 letters, e.g., by week 48 after initiation of treatment, when baseline CRT is less than approximately 400 micrometers for HDq16 regimens; ● Improvement in BCVA (ETDRS or Snellen equivalent) of approximately 9 or 10 letters, e.g. by week 48 after initiation of treatment, when baseline CRT is approximately 400 micrometers or greater for HDq16 regimens; ●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 did not lose 5, 10, or 15 letters by date (according to ETDRS letter score); ●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 Gain at least 5, 10, or 15 characters by (according to ETDRS character score), ●(For example, 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 96 weeks) have not lost more than 5, 10, 15, or 69 characters of ETDRS; ● BCVA score of approximately 69, 70, 71, 72, or 73 (according to ETDRS letter score) between weeks 48 and 60; ● For example, by week 48 or 60, a BCVA of at least approximately 69 letters (according to ETDRS letter score); ●By week 4 after initiation of treatment, approximately 68 characters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 66 characters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens; ●By week 8 after initiation of treatment, approximately 70 characters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 67 characters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens; ●By week 12 after initiation of treatment, approximately 70 characters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 68 characters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens; ●By week 16 after initiation of treatment, approximately 71 characters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 69 characters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens; ●By week 20 after the start of treatment, approximately 70 characters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 68 characters of BCVA (ETDRS or Snellen equivalent) for HDq16 regimens; ●By week 24 after initiation of treatment, approximately 71 characters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 67 characters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens; ●By week 28 after the start of treatment, approximately 72 characters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 70 characters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens; ●By week 32 after initiation of treatment, approximately 71 characters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 70 characters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens; ●By week 36 after initiation of treatment, approximately 71 characters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 68 characters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens; ●By week 40 after initiation of treatment, approximately 72 characters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 69 characters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens; ●By week 44 after initiation of treatment, approximately 72 characters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 70 characters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens; ●By week 48 after the start of treatment, approximately 73 characters of BCVA (ETDRS or Snellen equivalent) for HDq12 regimens or approximately 70 characters of BCVA (ETDRS or Snellen equivalents) for HDq16 regimens; ● Between weeks 36 and 48, for example, when baseline BCVA is approximately 57, 58, 59, 60, 61, 62, 63, or 64, approximately 71, 72 for HDq12 regimens , 73, or 74 (ETDRS or Snellen equivalent) or, for example, between weeks 36 and 48, a baseline BCVA of approximately 55, 56, 57, 58, 59, 60, 61, or 62. At some times, a BCVA of approximately 69, 70, 71, 72, or 73 (ETDRS or Snellen equivalent) for HDq16 regimens; Between weeks 48 and 60, for example, when the baseline BCVA is approximately 63 or 64, for HDq12 regimens a BCVA of approximately 69 or 70 or up to 94 (ETDRS or Snellen equivalent) or 48 Between weeks 1 and 60, for example, when the baseline BCVA is about 61 or 62, a BCVA of about 72 or 73 or up to 89 (ETDRS or Snellen equivalent) for HDq16 regimens; ●(For example, 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 , by week 88, 92, or 96) of gaining a BCVA (according to ETDRS letter score) of 5 or more, 10 or 15 or more letters; (e.g., by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 72, 84, 90, or 96 from the start of treatment) ) Improvement of 2 or more stages on the Diabetic Retinopathy Severity Scale (DRSS), (e.g., by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 72, 84, 90, or 96 from the start of treatment) ) Improvement of 3 or more stages on the Diabetic Retinopathy Severity Scale (DRSS), Measured by optical coherence tomography (OCT) (e.g. approximately 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) in the foveal center and central subfield (total fluid, intraretinal fluid [IRF] and / or subretinal fluid) retina without fluid [SRF]); (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 vascular leak by fluorescein angiography (FA); ● Retinal fluid (total fluid in the central subfield, IRF, and / or SRF) (e.g., after the start of the procedure, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, by week 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, or 96), ● ETDRS grid at week 48 or week 60 (mm 2 ) of approximately 12, 12.6, 13, 13.6, 13.9, or 14 mm of the total area of ​​fluorescein leakage within 2 reduction of more than or up to about 57 or 68mm 2 (as measured by e.g. fluorescein angiography), ●For HDq12 regimens, the ETDRS grid (mm 2 ) of approximately 13, 13.3, 13.9, or 14 mm of the total area of ​​fluorescein leakage within 2 or more (for example, maximum approximately 52mm) 2 ) reduction (e.g., measured by fluorescein angiography), ●For HDq16 regimens, ETDRS grid (mm 2 ) approximately 7, 7.7, 8, 9, 9.4, or 10 mm of the total area of ​​fluorescein leakage within 2 or more (e.g. up to about 55mm) 2 ) reduction (e.g., measured by fluorescein angiography), ● Retina without fluid on spectral domain optical coherence tomography (SD-OCT) (e.g. by week 12, 24, 36, 48, 60, 72, 84, 90 or 96 from the start of treatment); ● Fluid (total fluid, retinal fluid [IRF ], and / or retina without subretinal fluid [SRF]); ●(For example, 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) dry retina, ●(For example, 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) foveal center without fluid as measured by optical coherence tomography (OCT); ●By the fourth week after the start of treatment, approximately -118 or -118.3 micrometers (±17, 18, or 19 micrometers) for HDq12 regimens or approximately -124 or -125 or change in central retinal thickness of -124.9 or -125.5 micrometers (±17, 18, or 19 micrometers); -By week 8 after starting treatment, approximately -137 or -137.4 micrometers (±17, 18, or 19 micrometers) for HDq12 regimens or approximately -139 or -140 micrometers for HDq16 regimens. change in central retinal thickness of -139.6 or -140.3 micrometers (±17, 18, or 19 micrometers); ●By week 12 after initiation of treatment, approximately -150 or -150.1 micrometers (±17, 18, or 19 micrometers) for HDq12 regimens or approximately -152 or -153 or change in central retinal thickness of -152.7 or -153.4 micrometers (±17, 18, or 19 micrometers); ●By week 16 after initiation of treatment, approximately -139 or -139.4 micrometers (±17, 18, or 19 micrometers) for HDq12 regimens or approximately -145 or -146 or change in central retinal thickness of -145.5 or -146.4 micrometers (±17, 18, or 19 micrometers); ●By week 20 after initiation of treatment, approximately -117 or -117.1 micrometers (±17, 18, or 19 micrometers) for HDq12 regimens or approximately -112 or -113 or change in central retinal thickness of -112.5 or -113.3 micrometers (±17, 18, or 19 micrometers); ●By week 24 after initiation of treatment, approximately -158 or -158.1 micrometers (±17, 18, or 19 micrometers) for HDq12 regimens or approximately -103 or -104 or change in central retinal thickness of -103.8 or -104.3 micrometers (±17, 18, or 19 micrometers); ●By week 28 after initiation of treatment, approximately -146 or -147 or -146.7 micrometers (±17, 18, or 19 micrometers) for HDq12 regimens or approximately -162 or -146.7 micrometers for HDq16 regimens. -162.3 micrometers (±17, 18, or 19 micrometers) change in central retinal thickness; ●By week 32 after the start of treatment, approximately -132 micrometers (±17, 18, or 19 micrometers) for HDq12 regimens or approximately -145 or -146 or -145.8 micrometers for HDq16 regimens. change in central retinal thickness in meters (±17, 18, or 19 micrometers); ●By week 36 after initiation of treatment, approximately -168 or -168.1 micrometers (±17, 18, or 19 micrometers) for HDq12 regimens or approximately -124 or -125 or change in central retinal thickness of -124.7 or -125.2 micrometers (±17, 18, or 19 micrometers); ●By week 40 after the start of treatment, approximately -163 micrometers (±17, 18, or 19 micrometers) for HDq12 regimens or approximately -122 or -123 or -122.5 or -123.1 micrometers (±17, 18, or 19 micrometers) change in central retinal thickness; -By week 44 after initiation of treatment, approximately -147 or -148 or -147.4 micrometers (±17, 18, or 19 micrometers) for HDq12 regimens or approximately -164 or -147.4 micrometers for HDq16 regimens. change in central retinal thickness of -164.1 or -164.3 micrometers (±17, 18, or 19 micrometers); ●By week 48 after the start of treatment, approximately -171 or -172 or -171.7, -172, -173, -174, -175, -176, or -176.77 micrometers (±5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 micrometers) or about -148 or -149 or -148.3 or - for HDq16 regimens. 149.4 (±9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 micrometers) (e.g., baseline CRT is approximately 449, 450, 455, or 460 micrometers) changes in central retinal thickness, ●By week 60 after initiation of treatment, approximately -181, -182, -181.95, -176, -176.24, or -177 (±6, 10, 17, 18, or 19 micrometers for HDq12 regimens) ) (e.g., baseline CRT is approximately 460 micrometers) or approximately -166, -166.26, -167, or -167.18 (±8, 9, 10, 17, 18, or 19 micrometers for HDq16 regimens) change in central retinal thickness in meters (e.g., baseline CRT is approximately 457 micrometers); ● Change in central retinal thickness between the start of treatment (week 0) and week 4 of approximately -118 or -119 or -118.3 micrometers for HDq12 regimens; ● Change in central retinal thickness between weeks 4 and 8 of approximately -19, -20, or -19.1 micrometers for HDq12 regimens; ● Change in central retinal thickness between weeks 8 and 12 of approximately -12, -13, or -12.7 micrometers for HDq12 regimens; ● Change in central retinal thickness between weeks 20 and 24 of approximately -40 or -41 micrometers for HDq12 regimens; ● Change in central retinal thickness between weeks 32 and 36 of approximately -36, -37, or -36.1 micrometers for HDq12 regimens; ● Change in central retinal thickness between weeks 44 and 48 of approximately -24, -25, or -24.3 micrometers for HDq12 regimens; ● Change in central retinal thickness between the start of treatment (week 0) and week 4 of approximately -124, -125, or -124.9 micrometers for HDq16 regimens; ● Change in central retinal thickness between weeks 4 and 8 of approximately -14, -15, or -14.7 micrometers for HDq16 regimens; ● Change in central retinal thickness between weeks 8 and 12 of approximately -13, -14, or -13.1 micrometers for HDq16 regimens; ● Change in central retinal thickness between weeks 24 and 28 of approximately -58, -59, or -58.5 micrometers for HDq16 regimens; ● Change in central retinal thickness between weeks 40 and 44 of approximately -41, -42, or -41.6 micrometers for HDq16 regimens; ● By approximately 4, 5, 6, 7, or 8 weeks after initiation of treatment, a reduction in CRT (e.g., within approximately ±17, ±18, or ±19 micrometers) is achieved and then during the treatment regimen. maintained until at least 48 weeks, - A decrease in central retinal thickness (CRT), e.g., approximately 100, 125, 150, 175, or 200 micrometers (e.g., 12, 24, 36, 48, 60, 72, 84, 90, or by week 96), ● Approximately 148-182 micrometers of CRT (e.g., 148, 149, 150, 151, 152, 153, 154, as measured by optical coherence tomography (OCT)) by week 48 or 60; 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183 micrometers), the baseline CRT is approximately 449, 450, 455 or 460 micrometers, ● 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, 145 a decrease in central retinal thickness (CRT) of , 149, 150, 155, 160, 165, 170, 171, 172, 173, 174, or 175 micrometers; ●For aflibercept administered intravitreally at 2 mg approximately every 4 weeks for the first 3, 4, or 5 injections, followed by 2 mg approximately once every 8 weeks or once every 2 months. Intraocular safety (e.g., intraocular pressure) and non-intraocular safety (e.g., hypertensive events or APTC events) or mortality in subjects suffering from neovascular ocular disorders, e.g., DR or DME, similar to ● Approximately 0.1667 days after the first dose, the plasma free aflibercept concentration is approximately 0.149 (±0.249) mg / l, e.g., the baseline plasma free aflibercept concentration is undetectable, e.g. have not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks, ● Approximately 0.3333 days after the first dose, the plasma free aflibercept concentration is approximately 0.205 (±0.250) mg / l, e.g., the baseline plasma free aflibercept concentration is undetectable, e.g. have not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks, ● Approximately 1 day after the first dose, the plasma free aflibercept concentration is approximately 0.266 (±0.211) mg / l, e.g., the baseline plasma free aflibercept concentration is undetectable, e.g. have not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks, ● Approximately 2 days after the first dose, the plasma free aflibercept concentration is approximately 0.218 (±0.145) mg / l, e.g., the baseline plasma free aflibercept concentration is undetectable, e.g. have not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks, ● Approximately 4 days after the first dose, the plasma free aflibercept concentration is approximately 0.140 (±0.0741) mg / l, e.g., the baseline plasma free aflibercept concentration is undetectable, e.g. have not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks, ● Approximately 7 days after the first dose, the plasma free aflibercept concentration is approximately 0.0767 (±0.0436) mg / l, e.g., the baseline plasma free aflibercept concentration is undetectable, e.g. have not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks, ● Approximately 14 days after the first dose, the plasma free aflibercept concentration is approximately 0.0309 (±0.0241) mg / l, e.g., the baseline plasma free aflibercept concentration is undetectable, e.g. have not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks, ● Approximately 21 days after the first dose, the plasma free aflibercept concentration is approximately 0.0171 (±0.0171) mg / l, e.g., the baseline plasma free aflibercept concentration is undetectable, e.g. have not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks, ● Approximately 28 days after the first dose, the plasma free aflibercept concentration is approximately 0.00730 (±0.0113) mg / l, e.g., the baseline plasma free aflibercept concentration is undetectable, e.g. have not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks, ● About 0.1667 days after the first dose, the adjusted bound aflibercept concentration in plasma is about 0.00698 (±0.0276) mg / l, and for example, at baseline, the adjusted bound aflibercept concentration is about 0.00583 mg / l (±0.0280). bercept concentrations are present, e.g., the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks; - About 0.3333 days after the first dose, the adjusted bound aflibercept concentration in plasma is about 0.00731 (±0.0279) mg / l, and for example, at baseline, the adjusted bound aflibercept concentration is about 0.00583 mg / l (±0.0280). bercept concentrations are present, e.g., the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks; - Approximately 1 day after the first dose, the adjusted binding aflibercept concentration in plasma is approximately 0.0678 (± 0.0486) mg / l; bercept concentrations are present, e.g., the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks; ● Approximately 2 days after the first dose, the adjusted binding aflibercept concentration in plasma is approximately 0.138 (± 0.0618) mg / l, and for example, at baseline, the adjusted binding aflibercept concentration is approximately 0.00583 mg / l (± 0.0280). bercept concentrations are present, e.g., the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks; ● Approximately 4 days after the first dose, the adjusted binding aflibercept concentration in plasma is approximately 0.259 (± 0.126) mg / l; bercept concentrations are present, e.g., the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks; ● Approximately 7 days after the first dose, the adjusted binding aflibercept concentration in the plasma is approximately 0.346 (± 0.151) mg / l; bercept concentrations are present, e.g., the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks; - Approximately 14 days after the first dose, the adjusted binding aflibercept concentration in the plasma is approximately 0.374 (± 0.110) mg / l; bercept concentrations are present, e.g., the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks; ● Approximately 21 days after the first dose, the adjusted binding aflibercept concentration in the plasma is approximately 0.343 (± 0.128) mg / l; bercept concentrations are present, e.g., the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks; ● Approximately 28 days after the first dose, the adjusted binding aflibercept concentration in plasma is approximately 0.269 (± 0.149) mg / l; bercept concentrations are present, e.g., the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks; ● Maximum concentration of free aflibercept in plasma is reached approximately 0.965 (e.g., 1) days after the first dose; ●The maximum concentration of free aflibercept in plasma reaches approximately 0.310 mg / l (±0.263), ● Individual free aflibercept concentrations in plasma (C max ), ● Maximum free aflibercept (mg / l) in plasma per dose (mg) of aflibercept of approximately 0.0388 (±0.00328) mg / l / mg; ●Maximum concentration of regulated aflibercept in plasma is reached approximately 14 days after the first dose; ● A maximum concentration of regulated bound aflibercept of approximately 0.387 mg / l (±0.135) in plasma is reached; ● Adjusted bound aflibercept concentration in plasma of about 0.137 to about 0.774 mg / L (0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8 mg / l), ● Maximum adjusted bound aflibercept concentration (mg / l) in plasma per dose (mg) of aflibercept of approximately 0.0483 (±0.0168) mg / l / mg; ● not have anti-drug antibodies to aflibercept after 48 or 60 weeks of treatment; ● (e.g., by week 12, 24, 36, 48, 60, 72, 84, 90, or 96 from the start of treatment), e.g., about 4, 5, or 6 if on an HDq12 regimen; or an improvement from pre-treatment baseline in National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) total score of about 2, 3, or 4 if on an HDq16 regimen, e.g., a baseline score of about 76 or 77. is, ● Absence of macular edema (e.g., by week 12, 24, 36, 48, 60, 72, 84, 90, or 96 from start of treatment) and / or In subjects with pterygium, DR or DME, the first 5 injections are 2 mg approximately every 4 weeks, followed by 2 mg intravitreally once every 8 weeks or once every 2 months. Efficacy and / or safety similar to that of administered aflibercept, e.g., efficacy measured as improved BCVA and / or decreased central retinal thickness; e.g., safety measured as increased blood pressure, increased intraocular pressure, visual acuity. vitreous disease, vitreous detachment, iris neovascularization, and / or vitreous hemorrhage (treatment-emergent events occurring any time within 30 days after injection). Ru.

[0166] That is, the present invention provides the following. In requiring subjects with neovascular eye disorders (preferably DR and / or DME), 2 mg approximately every 4 weeks for the first 3, 4, or 5 injections, followed by approximately every 8 weeks. A method for achieving non-inferior BVCA compared to aflibercept administered intravitreally at 2 mg once or every two months, the method comprising: administering to the eye of a subject about 8 mg or more of a single VEGF receptor fusion protein; 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 secondary dose is administered approximately 2-4 weeks after the immediately preceding dose, and each tertiary dose is administered approximately 12-20 weeks (HDq12-20 regimen) or 12 weeks (HDq12 regimen) after the immediately preceding dose. ) or after 16 weeks (HDq16 regimen) or 20 weeks (HDq20 regimen). · In eligible subjects with neovascular eye disorders (preferably DR and / or DME) with a baseline BCVA of approximately 61, 62 and 63, approximately 7, 8 or 9 letters of BCVA by week 60 ( ETDRS letter score) in the eye of a subject, comprising administering a single initial dose of about 8 mg or more of VEGF receptor fusion protein to the eye of a subject, followed by administering to the eye of a subject a single initial dose of about 8 mg or more of VEGF receptor fusion protein; administering one or more secondary doses followed by one or more third doses of about 8 mg or more of the VEGF receptor fusion protein, each secondary dose about 2 times the previous dose. ~4 weeks later, with each tertiary dose administered approximately 12 to 20 weeks (HDq12-20 regimen) or 12 weeks (HDq12 regimen) or 16 weeks (HDq16 regimen) or 20 weeks (HDq20 regimen) after the previous dose. The way it is done. A method for achieving a BCVA (according to ETDRS letter score) of at least about 69 letters by week 48 or week 60 in a subject with a neovascular eye disorder (preferably DR and / or DME), comprising: A single initial dose of VEGF receptor fusion protein of about 8 mg or more, followed by one or more secondary doses of VEGF receptor fusion protein of about 8 mg or more, followed by administering to the subject's eye a single initial dose of about 8 mg or more of VEGF receptor fusion protein; administering one or more tertiary doses 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 being administered about 2 to 4 weeks after the immediately preceding dose; The method is administered after 12 to 20 weeks (HDq12-20 regimen) or 12 weeks (HDq12 regimen) or 16 weeks (HDq16 regimen) or 20 weeks (HDq20 regimen). 5, 10, 12, 24, 36, 48, 60, 72, 84, 90, or 96 weeks after the start of treatment in requiring subjects with neovascular ocular disorders (preferably DR and / or DME); A method for achieving a BCVA with no loss of 15 or 69 characters or more, comprising administering to the eye of a subject a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, followed by about 8 mg or more of a VEGF receptor fusion protein. administering one or more secondary doses of the 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 being the same as the immediately preceding dose. each tertiary dose approximately 12 to 20 weeks (HDq12-20 regimen) or 12 weeks (HDq12 regimen) or 16 weeks (HDq16 regimen) or 20 weeks (HDq20 regimen) of the previous dose. ) administered after the method. Best correction by week 12, 24, 36, 48, 60, 72, 84, 90, or 96 from the start of treatment in requiring subjects with neovascular eye disorders (preferably DR and / or DME) A method for achieving an improvement in visual acuity (by ETDRS letter score), comprising administering to the eye of a subject a single initial dose of a VEGF receptor fusion protein of about 8 mg or more, followed by a VEGF receptor fusion protein of about 8 mg or more. administering one or more secondary doses of the protein, followed by one or more third doses of about 8 mg or more of the VEGF receptor fusion protein, each secondary dose being a fraction of the immediately preceding dose. Administered approximately 2-4 weeks later, each tertiary dose is administered approximately 12-20 weeks (HDq12-20 regimen) or 12 weeks (HDq12 regimen) or 16 weeks (HDq16 regimen) or 20 weeks (HDq20 regimen) of the previous dose. administered later, the method. · In deserving subjects with neovascular eye disorders (preferably DR and / or DME), at 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks after the start of treatment; A method for achieving improvement in best-corrected visual acuity (BVCA) by week 28, week 32, week 36, week 40, week 44, week 48, or week 60, the method comprising: to the eye, a single initial dose of VEGF receptor fusion protein of about 8 mg or more, followed by one or more secondary doses of VEGF receptor fusion protein of about 8 mg or more, followed by about 8 mg or more of VEGF receptor 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 12 to 4 weeks after the immediately preceding dose. The method is administered after 20 weeks (HDq12-20 regimen) or 12 weeks (HDq12 regimen) or 16 weeks (HDq16 regimen) or 20 weeks (HDq20 regimen). BCVA of approximately 69, 70, 71, 72, or 73 between weeks 48 and 60 from the start of treatment in requiring subjects with neovascular eye disorders (preferably DR and / or DME) 1. A method for achieving a score (according to ETDRS letter score), comprising administering to the eye of a subject a single initial dose of about 8 mg or more of a VEGF receptor fusion protein, followed by a single initial dose of about 8 mg or more of a VEGF receptor fusion protein. administering one or more secondary doses followed by one or more third doses of about 8 mg or more of the VEGF receptor fusion protein, each secondary dose about 2 times the previous dose. ~4 weeks later, with each tertiary dose administered approximately 12 to 20 weeks (HDq12-20 regimen) or 12 weeks (HDq12 regimen) or 16 weeks (HDq16 regimen) or 20 weeks (HDq20 regimen) after the previous dose. The way it is done. BCVA at any time between weeks 36 and 48 between weeks 36 and 48 in requiring subjects with neovascular eye disorders (preferably DR and / or DME) A method for achieving a change in BCVA score (according to ETDRS letter score) from the start of treatment of about 7, 8, or 9 that is about 60 or 70, wherein the subject's eye receives about 8 mg or more of VEGF. A single initial dose of receptor fusion protein, followed by one or more secondary doses of about 8 mg or more of VEGF receptor fusion protein, followed by one or more about 8 mg or more of VEGF receptor fusion protein. (HDq12-20 regimen), with each secondary d...

Claims

1. A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method for treating or preventing diabetic retinopathy and / or diabetic macular edema in a subject in need, 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 free VEGF receptor fusion protein 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 a VEGF receptor fusion protein to reach its lower limit of quantification (LLOQ) compared to the time it takes for 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 the VEGF receptor fusion protein, wherein the method involves the vegetarian 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.

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 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 free VEGF receptor fusion protein in the subject's plasma to reach LLOQ after intravitreous injection of about 2 mg of the 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 diabetic retinopathy and / or diabetic macular edema.

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 aqueous pharmaceutical formulation comprises an aqueous pharmaceutical formulation comprising at least about 100 mg / ml of VEGF receptor fusion protein, each comprising two polypeptides, each comprising the immunoglobulin-like (Ig) domain 2 of VEGFFR1, the Ig domain 3 of VEGFFR2, and a polymerizing component, and about 10 to 100 mM of L-arginine, sucrose, a histidine-based buffer, and a surfactant, wherein the formulation has a pH of about 5.0 to about 6.8, and the VEGF receptor fusion protein has 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. - In subjects requiring treatment, to treat or prevent diabetic retinopathy (DR) and / or diabetic macular edema (DME), - To improve best corrected visual acuity in subjects who require DR and / or DME, or A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method for promoting retinal dryness in subjects requiring DR and / or DME, 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 use in a method for treating or preventing neovascular age-related macular degeneration (DME) in a subject in need, each of which is administered approximately 12 to 20 weeks after the immediately 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 use in a method for treating or preventing neovascular age-related macular degeneration (DME) in a subject in need, each of which is administered approximately 12 weeks after the preceding dose.

27. 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 use in a method for treating or preventing diabetic retinopathy (DR) and / or neovascular age-related macular degeneration (DME) in a subject in need, each of which is administered approximately 16 weeks after the immediately preceding dose.

28. The above method involves the subject's eyes, A pharmaceutical composition according to any one of claims 1 to 14 and 24, for use in a method for treating or preventing diabetic retinopathy (DR) and / or neovascular age-related macular degeneration (DME) in a subject in need, comprising 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 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 diabetic macular edema in subjects in need, 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 8 to 16 weeks (2 to 4 months + / - 7 days) by intravitreal injection.

30. A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method for treating or preventing diabetic retinopathy (DR) in subjects in need, 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 8 to 16 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 diabetic macular edema in subjects in need, 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.

32. A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method for treating or preventing diabetic retinopathy (DR) in subjects in need, wherein the method involves administering 8 mg of VEGF receptor fusion protein (0.07 mL or 70 microliters) by intravitreal injection in the first three doses every four weeks (approximately every 28 days + / - 7 days, monthly), followed by 8 mg of VEGF receptor fusion protein (0.07 mL) A pharmaceutical composition comprising administration by intravitreal injection once every two weeks (2 to 4 months + / - 7 days).

33. A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method for treating or preventing diabetic macular edema in subjects in need, 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.

34. A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method for treating or preventing diabetic retinopathy (DR) in subjects in need, 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.

35. A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method for treating or preventing diabetic macular edema in subjects in need, 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 (2 to 4 months + / - 7 days) by intravitreal injection.

36. A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method for treating or preventing diabetic retinopathy (DR) in subjects in need, 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 (2 to 4 months + / - 7 days) by intravitreal injection.

37. 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 diabetic macular edema (DME) or diabetic retinopathy (DR) in a subject in need, the method comprising administering to the subject three consecutive doses of the 8 mg VEGF receptor fusion protein by injection once a month (every four weeks), and then administering injections of the 8 mg VEGF receptor fusion protein at intervals that can be extended up to every 16 weeks based on the physician's judgment regarding visual and / or anatomical results.

38. A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method of treating or preventing diabetic retinopathy and / or diabetic macular edema in subjects requiring it, (1) The subject is 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 the VEGF receptor fusion protein one month later, and one month later the first dose of 8 mg of VEGF receptor fusion protein The regimen includes administering a secondary dose of 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. (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, 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. (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 was 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 then, The method comprises administering 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 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. (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 third 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. (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 a third 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. (15) The subject receives 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 third dose one month later. The subject has been administered a secondary dose of 2 mg of VEGF receptor fusion protein, and the method then comprises administering to the subject 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. (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 a third secondary dose of 2 mg of VEGF receptor fusion protein one month later, and the method then administers the subject a first maintenance dose of 8 mg of VEGF receptor fusion protein two months later, 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 administration regimen. (17) 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, a third secondary dose of 2 mg of VEGF receptor fusion protein one month later, and a fourth secondary dose of 2 mg of VEGF receptor fusion protein one month later, and the method thereafter administers an initial dose of 8 mg of VEGF receptor fusion protein two months 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 thereafter, according to an HDq12, HDq16, or HDq20 administration regimen. (18) 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, a third secondary dose of 2 mg of VEGF receptor fusion protein one month later, and a fourth 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 two months 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. (19) 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, a third secondary dose of 2 mg of VEGF receptor fusion protein one month later, and a fourth secondary dose of 2 mg of VEGF receptor fusion protein one month later, and the method then administers the subject a second secondary dose of 8 mg of VEGF receptor fusion protein two months later, and 12, 16, or 20 weeks thereafter, one or more maintenance doses of 8 mg of VEGF receptor fusion protein every 12 or 16 weeks according to an HDq12, HDq16, or HDq20 administration regimen. (20) The subject is 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, a third secondary dose of 2 mg of VEGF receptor fusion protein one month later, and a fourth secondary dose of 2 mg of VEGF receptor fusion protein one month later, and then the method is to administer the subject a first maintenance dose of 8 mg of VEGF receptor fusion protein two months later, and thereafter every 12, 16, or 20 weeks, HDq12 or HDq16 Alternatively, the regimen may include administering all additional 8 mg of VEGF receptor fusion protein maintenance doses according to the HDq20 administration regimen. (21) The subject is 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, a third secondary dose of 2 mg of VEGF receptor fusion protein one month later, a fourth secondary dose of 2 mg of VEGF receptor fusion protein one month later, and thereafter one or more maintenance doses of 2 mg every eight weeks, and then the method is used to administer VE to the subject. The regimen includes administering an initial dose of 8 mg of VEGF receptor fusion protein two months after the last maintenance dose of GF receptor fusion protein, administering a first secondary dose of 8 mg of VEGF receptor fusion protein one month thereafter, administering 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. (22) 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, a third secondary dose of 2 mg of VEGF receptor fusion protein one month later, a fourth secondary dose of 2 mg of VEGF receptor fusion protein one month later, and thereafter one or more maintenance doses of 2 mg every eight weeks, and the method then comprises administering the subject a first secondary dose of 8 mg of VEGF receptor fusion protein two months after the last maintenance dose of VEGF receptor fusion protein, a second secondary dose of 8 mg of VEGF receptor fusion protein one month later, and thereafter 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. (23) 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, a third secondary dose of 2 mg of VEGF receptor fusion protein one month later, a fourth secondary dose of 2 mg of VEGF receptor fusion protein one month later, and thereafter one or more maintenance doses of 2 mg every eight weeks, and the method then includes administering the subject a second secondary dose of 8 mg of VEGF receptor fusion protein two months after the last maintenance dose of VEGF receptor fusion protein, and thereafter 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. or (24) 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, a third secondary dose of 2 mg of VEGF receptor fusion protein one month later, a fourth secondary dose of 2 mg of VEGF receptor fusion protein one month later, and thereafter one or more maintenance doses of 2 mg every eight weeks, and the method then comprises administering the subject a first maintenance dose of 8 mg of VEGF receptor fusion protein two months after the last maintenance dose of VEGF receptor fusion protein, 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. (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, There, 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. 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, 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. 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, 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 in which each of the tertiary doses is administered approximately 20 weeks after the immediately preceding dose.

39. A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method for treating or preventing diabetic retinopathy and / or diabetic macular edema, wherein in a subject receiving and requiring a drug regimen for treating or preventing the said disorder, (a) The subject has been administered an initial dose of 8 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. or (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. or (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 thereafter, according to an HDq12, HDq16, or HDq20 administration regimen. or (d) The subject received an initial dose of 8 mg of VEGF receptor fusion protein and one month later The subject is administered a first secondary dose of 8 mg of VEGF receptor fusion protein, a second secondary dose of 8 mg of VEGF receptor fusion protein one month thereafter, and one or more maintenance doses of 8 mg of VEGF receptor fusion protein 12, 16, or 20 weeks thereafter; the method then includes 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 then administering 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, 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. 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, 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. 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, 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 in which each of the tertiary doses is administered approximately 20 weeks after the immediately preceding dose.

40. A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method for treating or preventing neovascular ophthalmic disorders in subjects requiring it, The subject is in an administration regimen for treating or preventing neovascular eye disorder requiring 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 preceding dose, and each of which is administered approximately 8 weeks after the preceding 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 The subject shall be evaluated approximately 8, 10, or 12 weeks after the administration of the aforementioned drug, and the treating physician shall evaluate the subject. A pharmaceutical composition comprising: administering an additional dose of 8 mg of VEGF receptor fusion protein if, in the judgment of the treating physician, administration every 12 weeks is appropriate; re-evaluating the subject after approximately 12 weeks; and, if, in the judgment of the treating physician, administration every 16 weeks is appropriate, continuing to administer 8 mg of VEGF receptor fusion protein to the subject every 16 weeks.

41. The aforementioned subject, A pharmaceutical composition according to any one of claims 1 to 14, 24, and 29 to 40, in a dosage regimen for treating or preventing diabetic retinopathy and / or diabetic macular edema, requiring a single initial dose of approximately 2 mg of VEGF receptor fusion protein, followed by four secondary doses of approximately 2 mg of the VEGF receptor fusion protein, followed by one or more tertiary doses of approximately 2 mg of the VEGF receptor fusion protein, wherein each secondary dose is administered approximately four weeks after the preceding dose, and each tertiary dose is administered approximately eight weeks after the preceding dose.

42. A pharmaceutical composition according to any one of claims 1 to 14, 24 and 29 to 40, for use in a method for treating or preventing diabetic retinopathy or diabetic macular edema in a subject in need, the method comprising administering to the eye of the 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 the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein, each of which secondary doses are administered about 2 to 4 weeks after the preceding dose, and each of which tertiary doses are administered about 12 or 16 weeks after the preceding dose. After administering one or more tertiary doses approximately 12 or 16 weeks after the previous dose, the interval between tertiary doses is set to the interval after the previous dose. ・From 12 to 16 weeks, ・12 to 20 weeks, or A pharmaceutical composition that includes extending the duration from 16 weeks to 20 weeks.

43. During the procedure, the subject, (a) Loss of BCVAs of less than 5 characters, and / or (b) The pharmaceutical composition according to claim 42, which exhibits a CRT of less than 300 or 320 μm.

44. To evaluate the BVCA and / or CRT of the subject, (a) Loss of BCVAs 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 42, further comprising extending the interval between the tertiary doses.

45. A pharmaceutical composition according to any one of claims 1 to 14, 24 and 29 to 40, for use in a method for treating or preventing diabetic retinopathy and / or diabetic macular edema in a subject in need, the method comprising administering to the eye of the 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, followed by one or more tertiary doses of about 8 mg or more of VEGF receptor fusion protein, each of which secondary doses are administered about 2 to 4 weeks after the preceding dose, and each of which tertiary doses are administered about 12, 16, or 20 weeks after the preceding dose. After administering one or more of the tertiary doses approximately 12, 16, or 20 weeks after the previous dose, the interval between the tertiary doses 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 further comprising shortening the duration from 20 weeks to 16 weeks.

46. During the procedure, the subject, (a) Loss of more than 10 BCVA characters compared to baseline, and / or (b) The pharmaceutical composition according to claim 45, which exhibits an increase of more than 50 μm in CRT compared to baseline.

47. 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 45, further comprising shortening the interval between the tertiary doses.

48. 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 tertiary doses is shortened from 12 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 40, wherein the interval between the tertiary doses is shortened from 16 weeks to 12 weeks.

49. A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method for treating or preventing diabetic retinopathy and / or diabetic macular edema in a subject requiring such treatment, the method comprising administering to the eye of the subject 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 at intervals of four weeks, and then administering one or more doses of the VEGF receptor fusion protein at intervals extended to 12, 16, or 20 weeks after the three doses.

50. A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method for treating and preventing diabetic retinopathy and / or diabetic macular edema in a subject in need, wherein the method involves administering a single initial dose of about 8 mg or more of the VEGF receptor fusion protein to the eye of the subject, followed by two secondary 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 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 extending the aforementioned interval are, 1. Loss of BCVAs with fewer than 1.5 characters, and / or 2. Includes CRTs less than 300 or 320 micrometers, The criteria for shortening the aforementioned interval are, 1. Loss of BCVA exceeding 10 characters. Persistent or worsening DME, and / or A pharmaceutical composition comprising an increase in CRT exceeding 3.50 micrometers.

51. The criteria for extending the aforementioned interval are, 1. BCVA of less than 5 letters from week 12, and This includes both CRTs of less than 300 or 320 micrometers, as measured by SD-OCT. and / or, the criteria for shortening the interval are Loss of more than 10 BCVAs from week 12 due to persistent or worsening DME, and 2. The pharmaceutical composition according to claim 50, comprising an increase in CRT of more than 50 micrometers from week 12.

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

53. A pharmaceutical composition comprising a VEGF receptor fusion protein for use in a method of treating or preventing diabetic retinopathy and / or diabetic macular edema in a subject requiring treatment who has been pretreated with one or more doses of the VEGF receptor fusion protein, the method comprising administering to the eye of the subject 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 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 previous dose. A pharmaceutical composition in which each of the tertiary doses is administered approximately 12 to 20 weeks after the immediately preceding dose.

54. 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 the VEGF receptor fusion protein, followed by one or more tertiary doses of approximately 8 mg or more of the 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.

55. The pharmaceutical composition according to claim 54, wherein the neovascular eye disorder is diabetic retinopathy and / or diabetic macular edema.

56. The pharmaceutical composition according to claim 54, wherein one or more secondary doses are two, three, or four secondary doses, and / or about two to four weeks is about four weeks.

57. 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 40, and 49 to 56, which is excluded from the administration of the VEGF receptor fusion protein to the eye.

58. Infection of the eye or around the eye, Active intraocular inflammation, and / or A step of evaluating the subject for hypersensitivity, The pharmaceutical composition according to claim 57, further comprising the step of excluding the subject from the administration if one or more of the following are found in the subject.

59. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, 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.

60. The above method, before each administration, ● A single-dose glass vial containing an aqueous formulation with 8 mg of VEGF receptor fusion protein in approximately 70 microliters, with a protective plastic cap and stopper. ●One 18-gauge x 1.5-inch, 5-micron filter needle including tip and bevel. ●One 30 gauge x 1 / 2 inch hypodermic needle, and ● One 1 mL Luer lock syringe with graduated markings for a 70 microliter capacity. To package and provide them together, and then, (1) If the aqueous formulation in the vial is visually inspected and particulate matter, cloudiness, or discoloration is observed, use another vial of the aqueous formulation containing the VEGF receptor fusion protein, (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 1 mL syringe from their packaging, (5) Attaching the filter needle to the syringe by twisting the filter needle 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 submerged 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 facing upwards and check the syringe for air bubbles. 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 40 and 49 to 56, comprising: (13) slowly pushing down the plunger so that the tip of the plunger aligns with the line marking 70 microliters on the syringe.

61. A pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, wherein the injection of a VEGF receptor fusion protein is performed under controlled sterile conditions, the sterile conditions comprising 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 prior to the injection.

62. The aforementioned subject, A patient is receiving a regimen for the treatment or prevention of diabetic retinopathy and / or diabetic macular edema, requiring a single initial dose of approximately 2 mg of VEGF receptor fusion protein, followed by four secondary doses of approximately 2 mg of the VEGF receptor fusion protein, followed by one or more tertiary doses of approximately 2 mg of the VEGF receptor fusion protein, with each secondary dose administered approximately four weeks after the preceding dose, and each tertiary dose administered approximately eight weeks after the preceding dose. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, wherein the subject is in any stage (initial dose, secondary dose, or tertiary dose) of the 2 mg VEGF receptor fusion protein administration regimen.

63. - 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 is 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 - 12 to 20 weeks is approximately 12 to 16 weeks, and one or more secondary doses are two The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40 and 49 to 56, wherein the dose is as follows, and the VEGF receptor fusion protein is aflibercept.

64. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, wherein the VEGF receptor fusion protein comprises amino acids 27 to 457 of the amino acid sequence shown in SEQ ID NO:

2.

65. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, wherein the 8 mg of VEGF receptor fusion protein is selected from the group consisting of aflibercept and convercept.

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

2. (ii) comprising two polypeptides including the immunoglobulin-like (lg) domain 2 of VEGFR1, the lg domain 3 of VEGFR2, and a polymerizing component, (iii) comprising two polypeptides containing immunoglobulin-like (lg) domain 2 of VEGFR1, lg domain 3 of VEGFR2, lg domain 4 of VEGFR2, and a polymerizing component, or (vi) A pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, comprising two VEGFR1R2-FcΔC1(a) polypeptides encoded by the nucleic acid sequence of Sequence ID No.

1.

67. The pharmaceutical composition according to claim 66, wherein the VEGF receptor fusion protein comprises two polypeptides including an immunoglobulin-like (lg) domain 2 of VEGFR1, an lg domain 3 of VEGFR2, and a polymerizing component.

68. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, wherein the VEGF receptor fusion protein is present in an aqueous pharmaceutical formulation selected from the group consisting of A to KKKK.

69. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, wherein the VEGF receptor fusion protein is present in an aqueous pharmaceutical formulation containing approximately 114.3 mg / ml of VEGF receptor fusion protein.

70. A pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, comprising administering the VEGF receptor fusion protein to both eyes of the subject.

71. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, wherein the VEGF receptor fusion protein is administered from a pre-filled syringe.

72. The pharmaceutical composition according to claim 71, wherein the pre-filled syringe is made of glass or plastic and / or is sterile.

73. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, wherein the VEGF receptor fusion protein is injected intravitreously with a 30 gauge × 1 / 2 inch sterile injection needle.

74. The subject received one or more doses of 2 mg of VEGF receptor fusion protein. A pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, which has been administered previously.

75. A pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, wherein one or more additional doses of VEGF receptor fusion protein are administered.

76. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, wherein 2 mg of VEGF receptor fusion protein is present in an aqueous pharmaceutical formulation containing 40 mg / ml of VEGF receptor fusion protein.

77. 2 mg of VEGF receptor fusion protein, The pharmaceutical composition according to claim 76, 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.

78. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, wherein 8 mg of VEGF receptor fusion protein is present in an aqueous pharmaceutical formulation containing a sugar or a polyol.

79. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, wherein 8 mg of VEGF receptor fusion protein is present in an aqueous pharmaceutical formulation containing sucrose.

80. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, wherein 8 mg of VEGF receptor fusion protein is present in an aqueous pharmaceutical formulation having a pH of approximately 5.

8.

81. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, 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.

82. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, 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.

83. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, 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 about 6% after being stored at about 2 to 8°C for about 24 months.

84. 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 A surfactant is present in an aqueous pharmaceutical preparation containing the following: The formulation has a pH of approximately 5.0 to approximately 6.8, and the VEGF receptor fusion protein is less than 3.5% high molecular weight species immediately after manufacturing and purification and / or can be stored at approximately 2 to 8°C for approximately 24 months. A pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, which has approximately 6% or less of high molecular weight species after storage.

85. 8 mg of VEGF receptor fusion protein, ●VEGF receptor fusion protein in a concentration exceeding 100 mg / ml, 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 buffer, 5 + 0.5% (w / v) sucrose, 0.02-0.04% (w / v) polysorbate 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, aflibercept concentration exceeding 100 mg / ml, pH 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 40, and 49 to 56, 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.

86. 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 A pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, administered in an amount of 76 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.

87. The pharmaceutical composition according to claim 86, wherein the VEGF receptor fusion protein is administered in an amount of about 70 ± 4 or 5 microliters.

88. A pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, comprising administering the VEGF receptor fusion protein to both eyes of the subject.

89. The aforementioned subject, - Improvement in the Diabetic Retinopathy Severity Scale (DRSS), - Improvement of the best corrected vision, Dry retina, - Achieving the best corrected visual acuity, ・At least 69 characters of BCVA, - Foveal center without fluid, - Decrease in central retinal thickness (CRT) of more than 25 micrometers, - No vascular leakage as measured by fluorescein angiography (FA), - Improvement from pre-treatment baseline in the total score of the National Ophthalmological Society Visual Function Questionnaire (NEI-VFQ), - Retina without fluid (total fluid, intraretinal fluid [IRF], and / or subretinal fluid [SRF]) in the foveal center and central subfield. - Retinal maintenance without fluid (total fluid, IRF, and / or SRF in the foveal center and central subfield), - Absence of macular edema, - Retinal without fluid, and / or on spectral optical coherence tomography (SD-OCT). A pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, which achieves and / or maintains one or more of the following: - Once initiated, does not deviate from the HDq12 or HDq16 treatment regimen.

90. The aforementioned subject, ● Compared to aflibercept, which is administered intravitreally at a dose of 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, BVCA is non-inferior. ●Baseline BCVA is approximately 61, 62, or 63; an increase of approximately 7, 8, or 9 letters in BCVA (as measured by ETDRS letter score) from the start of treatment to week 60. ● At least approximately 69 BCVA characters (based on ETDRS character score) within 48 or 60 weeks from the start of treatment. ● No loss of 5, 10, 15, or 69 or more BCVA characters after 12, 24, 36, 48, 60, 72, 84, 90, or 96 weeks from the start of treatment. ● Improvement in BCVA (as measured by ETDRS letter score) from the start of treatment to weeks 12, 24, 36, 48, 60, 72, 84, 90, or 96. ●Improvement in best corrected visual acuity (BVCA) by the 4th, 8th, 12th, 16th, 20th, 24th, 28th, 32nd, 36th, 40th, 44th, or 48th week from the start of treatment. ● Between weeks 48 and 60, a BCVA score of approximately 69, 70, 71, 72, or 73 (based on ETDRS letter scores), ● Between weeks 36 and 48, the change in the BCVA score (as measured by the ETDRS letter score) from the start of treatment is approximately 7, 8, or 9, and the BCVA at any point between weeks 36 and 48 is approximately 60 or 70. ● Between weeks 48 and 60, the change in the BCVA score (as measured by the ETDRS letter score) from the start of treatment is approximately 7, 8, or 9, and the BCVA at any point between weeks 48 and 60 is approximately 69, 70, 71, 72, or 73. ● An increase of BCVA of 4 or more letters, 5 or more letters, 6 or more letters, 7 or more letters, 8 or more letters, 9 or more letters, or 10 or more letters, as measured by the Early Treatment Diabetic Retinopathy Screening (ETDRS) visual acuity chart or Snellen equivalent, within 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 weeks after the start of treatment. ● No loss of 5, 10, or 15 letters within 48 or 60 weeks from the start of treatment (based on the ETDRS letter score). ● Acquire at least 5, 10, or 15 letters (based on ETDRS letter score) by week 48 or 60 of treatment. ● Within four weeks of starting treatment, an improvement of approximately 4 or 5 letters in BCVA (equivalent to ETDRS or Snellen) should be observed for the HDq12 regimen, or approximately 4 or 5 letters in BCVA (equivalent to ETDRS or Snellen) should be observed for the HDq16 regimen. ● Within 8 weeks of the start of treatment, an improvement of approximately 6 letters in BCVA (equivalent to ETDRS or Snellen) for the HDq12 regimen, or approximately 5 or 6 letters in BCVA (equivalent to ETDRS or Snellen) for the HDq16 regimen. ●By the 12th week after the start of treatment, an improvement of approximately 6 or 7 letters in BCVA (equivalent to ETDRS or Snellen) should be observed for the HDq12 regimen, or approximately 6 letters in BCVA (equivalent to ETDRS or Snellen) should be observed for the HDq16 regimen. ●By the 16th week after the start of treatment, an improvement of approximately 6 or 7 letters in BCVA (equivalent to ETDRS or Snellen) should be observed for the HDq12 regimen, or approximately 7 letters in BCVA (equivalent to ETDRS or Snellen) should be observed for the HDq16 regimen. ●By the 20th week after the start of treatment, an improvement of approximately 6 letters in BCVA (equivalent to ETDRS or Snellen) should be observed for the HDq12 regimen, or approximately 6 letters in BCVA (equivalent to ETDRS or Snellen) should be observed for the HDq16 regimen. ●By the 24th week after the start of treatment, an improvement of approximately 7 letters in BCVA (equivalent to ETDRS or Snellen) should be observed for the HDq12 regimen, or approximately 5 or 6 letters in BCVA (equivalent to ETDRS or Snellen) should be observed for the HDq16 regimen. ●By the 28th week after the start of treatment, an improvement of approximately 7 or 8 letters in BCVA (equivalent to ETDRS or Snellen) should be observed for the HDq12 regimen, or approximately 7 or 8 letters in BCVA (equivalent to ETDRS or Snellen) should be observed for the HDq16 regimen. ●By the 32nd week after the start of treatment, an improvement of approximately 7 letters in BCVA (equivalent to ETDRS or Snellen) for the HDq12 regimen, or approximately 7 or 8 letters in BCVA (equivalent to ETDRS or Snellen) for the HDq16 regimen. ●By the 36th week after the start of treatment, an improvement of approximately 8 letters in BCVA (equivalent to ETDRS or Snellen) for the HDq12 regimen, or approximately 6 or 7 letters in BCVA (equivalent to ETDRS or Snellen) for the HDq16 regimen. ●By the 40th week after the start of treatment, an improvement of approximately 8 letters in BCVA (equivalent to ETDRS or Snellen) for the HDq12 regimen, or approximately 6 or 7 letters in BCVA (equivalent to ETDRS or Snellen) for the HDq16 regimen. ●By the 44th week after the start of treatment, an improvement of approximately 8 letters in BCVA (equivalent to ETDRS or Snellen) for the HDq12 regimen, or approximately 7 or 8 letters in BCVA (equivalent to ETDRS or Snellen) for the HDq16 regimen. ●By 48 weeks after the start of treatment, an improvement of approximately 8 or 9 letters in BCVA (equivalent to ETDRS or Snellen) should be observed for the HDq12 regimen, or approximately 7 or 8 letters in BCVA (equivalent to ETDRS or Snellen) should be observed for the HDq16 regimen. ●Improvement in BCVA is achieved by approximately 8 weeks after the start of treatment, and then maintained for at least 48 weeks during the treatment regimen. ● Between weeks 36 and 48, in the case of the HDq12 or HDq16 regimen, improvement in the BCVA score (based on the ETDRS character score) up to 38 characters from the start of treatment. ●By the fourth week after the start of treatment, a BCVA of approximately 68 characters (equivalent to ETDRS or Snellen) for the HDq12 regimen, or a BCVA of approximately 66 characters (equivalent to ETDRS or Snellen) for the HDq16 regimen, ● Within 8 weeks of the start of treatment, a BCVA of approximately 70 characters (equivalent to ETDRS or Snellen) for the HDq12 regimen, or a BCVA of approximately 67 characters (equivalent to ETDRS or Snellen) for the HDq16 regimen. ●By the 12th week after the start of treatment, a BCVA of approximately 70 characters (equivalent to ETDRS or Snellen) for the HDq12 regimen, or a BCVA of approximately 68 characters (equivalent to ETDRS or Snellen) for the HDq16 regimen. ●By the 16th week after the start of treatment, in the case of the HDq12 regimen, approximately 71 characters of BCVA (ETDRS or Snellen equivalent) or in the case of the HDq16 regimen, approximately 69 characters of BCVA (ETDRS or Snellen equivalent), ●By the 20th week after the start of treatment, a BCVA of approximately 70 characters (equivalent to ETDRS or Snellen) for the HDq12 regimen, or a BCVA of approximately 68 characters (equivalent to ETDRS or Snellen) for the HDq16 regimen, ●By the 24th week after the start of treatment, a BCVA of approximately 71 characters (equivalent to ETDRS or Snellen) for the HDq12 regimen or a BCVA of approximately 67 characters (equivalent to ETDRS or Snellen) for the HDq16 regimen. ●By the 28th week after the start of treatment, a BCVA of approximately 72 characters (equivalent to ETDRS or Snellen) for the HDq12 regimen or a BCVA of approximately 70 characters (equivalent to ETDRS or Snellen) for the HDq16 regimen. ●By the 32nd week after the start of treatment, a BCVA of approximately 71 characters (equivalent to ETDRS or Snellen) for the HDq12 regimen, or a BCVA of approximately 70 characters (equivalent to ETDRS or Snellen) for the HDq16 regimen, ●By the 36th week after the start of treatment, a BCVA of approximately 71 characters (equivalent to ETDRS or Snellen) for the HDq12 regimen or a BCVA of approximately 68 characters (equivalent to ETDRS or Snellen) for the HDq16 regimen. ●By the 40th week after the start of treatment, a BCVA of approximately 72 characters (equivalent to ETDRS or Snellen) for the HDq12 regimen or a BCVA of approximately 69 characters (equivalent to ETDRS or Snellen) for the HDq16 regimen. ●By the 44th week after the start of treatment, a BCVA of approximately 72 characters (equivalent to ETDRS or Snellen) for the HDq12 regimen or a BCVA of approximately 70 characters (equivalent to ETDRS or Snellen) for the HDq16 regimen. ●By the 48th week after the start of treatment, a BCVA of approximately 73 characters (equivalent to ETDRS or Snellen) for the HDq12 regimen or a BCVA of approximately 70 characters (equivalent to ETDRS or Snellen) for the HDq16 regimen. ● Between weeks 36 and 48, for the HDq12 regimen, a BCVA of approximately 71, 72, 73, or 74 characters (equivalent to ETDRS or Snellen) or between weeks 36 and 48, for the HDq16 regimen, a BCVA of approximately 69, 70, 71, 72, or 73 characters (equivalent to ETDRS or Snellen), ●When baseline BCVA is approximately 73 ETDRS letters or less in the HDq12 regimen, an improvement of approximately 9 or 10 letters in BCVA (ETDRS or Snellen equivalent) is expected by 48 weeks after the start of treatment. ●When baseline BCVA is more than approximately 73 ETDRS letters in the HDq12 regimen, an improvement of approximately 5 or 6 letters in BCVA (ETDRS or Snellen equivalent) should be observed by 48 weeks after the start of treatment. ●When baseline BCVA is approximately 73 ETDRS characters or less in the HDq16 regimen, an improvement of approximately 8 or 9 characters in BCVA (ETDRS or Snellen equivalent) is expected by 48 weeks after the start of treatment. ●When baseline BCVA is more than approximately 73 ETDRS letters in the HDq16 regimen, an improvement of approximately 4 or 5 letters in BCVA (ETDRS or Snellen equivalent) should be observed by 48 weeks after the start of treatment. ●When baseline CRT is less than approximately 400 micrometers in the HDq12 regimen, an improvement of approximately 7 or 8 letters in BCVA (ETDRS or Snellen equivalent) should be observed by 48 weeks after the start of treatment. ●When baseline CRT is approximately 400 micrometers or more in the HDq12 regimen, an improvement of approximately 9 or 10 letters in BCVA (ETDRS or Snellen equivalent) should be observed by 48 weeks after the start of treatment. ●When baseline CRT is less than approximately 400 micrometers in the HDq16 regimen, approximately 5 or 6 letters of BCVA (ETDRS or Improvement (equivalent to Snellen), ●When baseline CRT is approximately 400 micrometers or more in the HDq16 regimen, an improvement of approximately 9 or 10 letters in BCVA (ETDRS or Snellen equivalent) should be observed by 48 weeks after the start of treatment. ● Acquisition of 5 or more letters, 10 or more letters, or 15 or more letters in a BCVA (based on ETDRS letter score) by weeks 12, 24, 36, 48, 60, 72, 84, 90, or 96 from the start of treatment. ● Improvement of two or more levels on the Diabetic Retinopathy Severity Scale (DRSS) within 12, 24, 36, 48, 60, 72, 84, 90, or 96 weeks from the start of treatment. ● Improvement of two or more levels on the Diabetic Retinopathy Severity Scale (DRSS) from the start of treatment to weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48. ●The retina, measured by optical coherence tomography (OCT), is free of fluid (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF]) in the foveal center and central subfield, by 12, 24, 36, 48, 60, 72, 84, 90, or 96 weeks from the start of treatment. ● No vascular leakage as measured by fluorescein angiography (FA) within 12, 24, 36, 48, 60, 72, 84, 90, or 96 weeks from the start of treatment. ● Retinal maintenance without fluid (total fluid in the foveal center and central subfield, IRF and / or SRF) from the start of treatment to weeks 12, 24, 36, 48, 60, 72, 84, 90, or 96. ● ETDRS grid (mm) at 48 or 60 weeks, as measured by fluorescein angiography. 2 Approximately 12, 13, or 14 mm of the total area of ​​fluorescein leakage within the fluorescein leak. 2 The above decrease, ●By weeks 12, 24, 36, 48, 60, 72, 84, 90, or 96 from the start of treatment, the retina without fluid was observed on spectral optical coherence tomography (SD-OCT). ● Within 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 weeks after the start of treatment, the retina is free of fluid (total fluid, retinal fluid [IRF], and / or subretinal fluid [SRF]) in the foveal center. ●Dry retina occurs within 12, 24, 36, 48, 60, 72, 84, 90, or 96 weeks from the start of treatment. ●Fove without fluid, as measured by optical coherence tomography (OCT), within 12, 24, 36, 48, 60, 72, 84, 90, or 96 weeks from the start of treatment. ● Within four weeks after the start of treatment, a change in central retinal thickness of approximately -118 or -118.3 micrometers for the HDq12 regimen, or approximately -124, -125, -124.9, or -125.5 micrometers for the HDq16 regimen. ● Within 8 weeks after the start of treatment, a change in central retinal thickness of approximately -137 or -137.4 micrometers for the HDq12 regimen, or approximately -139 or -140 or -139.6 or -140.3 micrometers for the HDq16 regimen. ●By the 12th week after the start of treatment, the change in central retinal thickness should be approximately -150 or -150.1 micrometers for the HDq12 regimen, or approximately -152, -153, -152.7, or -153.4 micrometers for the HDq16 regimen. ●By the 16th week after the start of treatment, a change in central retinal thickness of approximately -139 or -139.4 micrometers for the HDq12 regimen, or approximately -145 or -146 or -145.5 or -146.4 micrometers for the HDq16 regimen. ●By the 20th week after the start of treatment, the change in central retinal thickness is approximately -117 or -117.1 micrometers for the HDq12 regimen, or approximately -112, -113, -112.5, or -113.3 micrometers for the HDq16 regimen. 、 ●By the 24th week after the start of treatment, the change in central retinal thickness should be approximately -158 or -158.1 micrometers for the HDq12 regimen, or approximately -103, -104, -103.8, or -104.3 micrometers for the HDq16 regimen. ●By the 28th week after the start of treatment, a change in central retinal thickness of approximately -146, -147, or -146.7 micrometers should be observed for the HDq12 regimen, or approximately -162 or -162.3 micrometers for the HDq16 regimen. ●By the 32nd week after the start of treatment, a change in central retinal thickness of approximately -132 micrometers for the HDq12 regimen or approximately -145, -146, or -145.8 micrometers for the HDq16 regimen. ●By the 36th week after the start of treatment, a change in central retinal thickness of approximately -168 or -168.1 micrometers for the HDq12 regimen, or approximately -124 or -125 or -124.7 or -125.2 micrometers for the HDq16 regimen. ●By the 40th week after the start of treatment, a change in central retinal thickness of approximately -163 micrometers for the HDq12 regimen or approximately -122, -123, -122.5, or -123.1 micrometers for the HDq16 regimen. ●By the 44th week after the start of treatment, a change in central retinal thickness of approximately -147, -148, or -147.4 micrometers for the HDq12 regimen, or approximately -164, -164.1, or -164.3 micrometers for the HDq16 regimen. ●By 48 weeks after the start of treatment, a change in central retinal thickness of approximately -171, -172, or -171.7 micrometers for the HDq12 regimen, or approximately -148, -149, -148.3, or -149.4 micrometers for the HDq16 regimen. ●By 60 weeks after the start of treatment, a change in central retinal thickness of approximately -181.95 or -176.24 micrometers for the HDq12 regimen, or approximately -166.26 or -167.18 micrometers for the HDq16 regimen. ● In the case of the HDq12 regimen, the change in central retinal thickness between the start of treatment (week 0) and week 4 is approximately -118, -119, or -118.3 micrometers. ● Between weeks 4 and 8, in the case of the HDq12 regimen, the change in central retinal thickness is approximately -19, -20, or -19.1 micrometers. ● Between weeks 8 and 12, in the case of the HDq12 regimen, the change in central retinal thickness is approximately -12, -13, or -12.7 micrometers. ● Between weeks 20 and 24, in the case of the HDq12 regimen, the change in central retinal thickness is approximately -40 or -41 micrometers. ● Between weeks 32 and 36, in the case of the HDq12 regimen, the change in central retinal thickness is approximately -36, -37, or -36.1 micrometers. ● Between weeks 44 and 48, in the case of the HDq12 regimen, the change in central retinal thickness is approximately -24, -25, or -24.3 micrometers. ● Between weeks 48 and 60, in the case of the HDq12 regimen, the change in central retinal thickness is approximately -4, -5, or -4.5 micrometers. ● In the case of the HDq16 regimen, the change in central retinal thickness between the start of treatment (week 0) and week 4 is approximately -124, -125, or -124.9 micrometers. ● Between weeks 4 and 8, in the case of the HDq16 regimen, the change in central retinal thickness is approximately -14, -15, or -14.7 micrometers. ● Between weeks 8 and 12, in the case of the HDq16 regimen, the change in central retinal thickness is approximately -13, -14, or -13.1 micrometers. ● Between weeks 24 and 28, in the case of the HDq16 regimen, approximately -58, -59, A change in central retinal thickness of -58.5 micrometers, ● Between weeks 40 and 44, in the case of the HDq16 regimen, the change in central retinal thickness is approximately -41, -42, or -41.6 micrometers. ● The reduction in central retinal thickness is maintained within +17, +18, or +19 micrometers for approximately 4, 5, 6, 7, or 8 weeks after the start of treatment, and thereafter maintained for at least 48 weeks from the start of treatment. ● A decrease in central retinal thickness of approximately 100, 125, 150, 175, or 200 micrometers between the start of treatment and weeks 12, 24, 36, 48, 60, 72, 84, 90, or 96. ● A decrease in central retinal thickness of approximately 148–182 micrometers from the start of treatment to approximately 48 or 60 weeks, as measured by optical coherence tomography (OCT), with a baseline CRT of approximately 449, 450, 455, or 460 micrometers. ● After the start of treatment, by weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48, for example, a reduction in central retinal thickness (CRT) of at least approximately 100, 125, 130, 135, 140, 145, 149, 150, 155, 160, 165, 170, 171, 172, 173, 174, or 175 micrometers, ●Approximately 0.1667 days after the first dose, the free aflibercept level in the plasma was approximately 0.149 (±0.249) mg / l, free aflibercept was undetectable in the plasma at baseline, and the subject had not received intravitreal aflibercept treatment for at least 12 weeks. ● Approximately 0.3333 days after the first dose, the free aflibercept level in plasma was approximately 0.205 (±0.250) mg / l, free aflibercept in plasma was undetectable at baseline, and the subject had not received intravitreal aflibercept treatment for at least 12 weeks. ●Approximately one day after the first dose, the free aflibercept level in plasma was approximately 0.266 (±0.211) mg / l, free aflibercept in plasma was undetectable at baseline, and the subject had not received intravitreous aflibercept treatment for at least 12 weeks. ●Approximately two days after the initial dose, the free aflibercept level in plasma was approximately 0.218 (±0.145) mg / l, free aflibercept in plasma was undetectable at baseline, and the subject had not received intravitreous aflibercept treatment for at least 12 weeks. ●Approximately 4 days after the initial dose, the free aflibercept level in plasma was approximately 0.140 (±0.0741) mg / l, free aflibercept in plasma was undetectable at baseline, and the subject had not received intravitreous aflibercept treatment for at least 12 weeks. ●Approximately 7 days after the initial dose, the free aflibercept level in plasma was approximately 0.0767 (±0.0436) mg / l, free aflibercept in plasma was undetectable at baseline, and the subject had not received intravitreal aflibercept treatment for at least 12 weeks. ●Approximately 14 days after the initial dose, the free aflibercept level in plasma was approximately 0.0309 (±0.0241) mg / l, free aflibercept in plasma was undetectable at baseline, and the subject had not received intravitreal aflibercept treatment for at least 12 weeks. ●Approximately 21 days after the initial dose, the free aflibercept level in plasma was approximately 0.0171 (±0.0171) mg / l, free aflibercept in plasma was undetectable at baseline, and the subject had not received intravitreous aflibercept treatment for at least 12 weeks. ●Approximately 28 days after the initial dose, the free aflibercept level in plasma was approximately 0.00730 (±0.0113) mg / l, free aflibercept in plasma was undetectable at baseline, and the subject had not received intravitreous aflibercept treatment for at least 12 weeks. ●Approximately 0.1667 days after the first dose, the plasma concentration of modified conjugated aflibercept was approximately 0.00698 (±0.0276) mg / l, and at baseline, approximately 0.00583 mg / l (±0.0280) of modified conjugated aflibercept was present, and the subject had at least 1 I haven't received intravitreal aflibercept treatment for two weeks. ●Approximately 0.3333 days after the first dose, the plasma concentration of modified conjugated aflibercept was approximately 0.00731 (±0.0279) mg / l, and at baseline, approximately 0.00583 mg / l (±0.0280) of modified conjugated aflibercept was present, and the subject had not received intravitreal aflibercept treatment for at least 12 weeks. ●Approximately one day after the first dose, the plasma concentration of modified conjugated aflibercept was approximately 0.0678 (±0.0486) mg / l, and at baseline, approximately 0.00583 mg / l (±0.0280) of modified conjugated aflibercept was present, and the subject had not received intravitreal aflibercept treatment for at least 12 weeks. ●Approximately two days after the initial dose, the plasma concentration of modified conjugated aflibercept was approximately 0.138 (±0.0618) mg / l, with a baseline concentration of approximately 0.00583 mg / l (±0.0280) of modified conjugated aflibercept, and the subject had not received intravitreal aflibercept treatment for at least 12 weeks. ●Approximately 4 days after the initial dose, the plasma concentration of modified conjugated aflibercept was approximately 0.259 (±0.126) mg / l, with a baseline concentration of approximately 0.00583 mg / l (±0.0280) of modified conjugated aflibercept, and the subject had not received intravitreal aflibercept treatment for at least 12 weeks. ●Approximately 7 days after the initial dose, the plasma concentration of modified conjugated aflibercept was approximately 0.346 (±0.151) mg / l, with a baseline concentration of approximately 0.00583 mg / l (±0.0280) of modified conjugated aflibercept, and the subject had not received intravitreal aflibercept treatment for at least 12 weeks. ●Approximately 14 days after the initial dose, the plasma concentration of modified conjugated aflibercept was approximately 0.374 (±0.110) mg / l, with a baseline concentration of approximately 0.00583 mg / l (±0.0280) of modified conjugated aflibercept, and the subject had not received intravitreal aflibercept treatment for at least 12 weeks. ●Approximately 21 days after the initial dose, the plasma concentration of modified conjugated aflibercept was approximately 0.343 (±0.128) mg / l, with a baseline concentration of approximately 0.00583 mg / l (±0.0280) of modified conjugated aflibercept, and the subject had not received intravitreal aflibercept treatment for at least 12 weeks. ●Approximately 28 days after the initial dose, the plasma level of modified conjugated aflibercept was approximately 0.269 (±0.149) mg / l, with a baseline level of approximately 0.00583 mg / l (±0.0280) of modified conjugated aflibercept, and the subject had not received intravitreal aflibercept treatment for at least 12 weeks. ●The maximum concentration of free aflibercept in plasma is reached approximately 0.965 days after the initial dose. ● Free aflibercept in plasma reaches a maximum level of approximately 0.310 mg / l (±0.263). ●Free aflibercept in plasma at approximately 0 to 1.08 mg / L ●Maximum free aflibercept in plasma (mg / l) per dose (mg) of aflibercept of approximately 0.388 (±0.0328) mg / l / mg, ●The maximum concentration of modified conjugated aflibercept in plasma is reached approximately 14 days after the initial dose. ● Reaches the maximum level of modified conjugated aflibercept in plasma at approximately 0.387 mg / l (±0.135). ● Approximately 0.137 to 0.774 mg / L of modified conjugated aflibercept in plasma. ●Maximum adjusted conjugated aflibercept in plasma (mg / l) per dose (mg) of aflibercept of approximately 0.483 (±0.0168) mg / l / mg, ● No anti-drug antibodies against aflibercept are present 48 or 60 weeks after treatment. ● Pre-treatment baseline in the total score of the National Ophthalmological Society Visual Function Questionnaire (NEI-VFQ) Improvements from, and / or A pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, which achieves and / or maintains one or more of the following: macular edema absence.

91. The pharmaceutical composition according to claim 89, wherein the dry retina lacks intraretinal fluid and / or subretinal fluid.

92. The pharmaceutical composition according to claim 89, wherein retinal dryness 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 the VEGF receptor fusion protein.

93. The pharmaceutical composition according to claim 89, wherein the period from the start of treatment to 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, or 60 weeks is approximately 48 or 60 weeks from the start of treatment.

94. - The subject is administered a single initial dose, two secondary doses, and three tertiary doses of 8 mg or more of the aforementioned VEGF receptor fusion protein during the first year. - The subject is administered a single initial dose, two secondary doses, and two tertiary doses of 8 mg or more of the VEGF receptor fusion protein during the first year, or The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, 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.

95. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, wherein the dose interval is adjusted (increased / maintained / decreased) based on visual and / or anatomical results.

96. A pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, further comprising one or more periods of pro re nata (PRN), capped PRN, or treat and extend (T&E) administration.

97. The pharmaceutical composition according to any one of claims 1 to 14, 24, 29 to 40, and 49 to 56, wherein the VEGF receptor fusion protein is aflibercept.

98. It's a kit, A container containing a 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 100 mg / mL or more of VEGF receptor fusion protein, or the container contains 114.3 mg / mL or more of VEGF receptor fusion protein. The aforementioned instruction includes an instruction for the administration of aflibercept to DME and / or DR patients, The aforementioned instruction includes instructions that treatment with 8 mg of aflibercept should be initiated with three consecutive doses administered by monthly injections (every four weeks), The instruction includes a statement that after the initial three consecutive doses, the injection interval may be extended 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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