VEGF receptor fusion protein for use in the treatment of ocular vascular disorders.

Abstract

The invention relates to treatment regimens for ocular vascular disorders such as nAMD, DR, and DME, characterized by high doses of aflibercept and prolonged intervals between doses.

Description

Extended, High Dose VEGF Antagonist Regimens for Treatment of Angiogenic Eye Disorders CROSS- REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. provisional patent application no. 63 / 523,019, filed June 23, 2023; U.S. provisional patent application no.63 / 523,335, filed June 26, 2023; U.S. provisional patent application no.63 / 531,758, filed August 9, 2023; U.S. provisional patent application no.63 / 540,308, filed September 25, 2023; U.S. provisional patent application no.63 / 546,476, filed October 30, 2023; U.S. provisional patent application no. 63 / 601,198, filed November 20, 2023; U.S. provisional patent application no.63 / 604,484, filed November 30, 2023; U.S. provisional patent application no.63 / 606,507, filed December 5, 2023; U.S. provisional patent application no.63 / 606,887, filed December 6, 2023; U.S. provisional patent application no.63 / 608,138, filed December 8, 2023; U.S. provisional patent application no.63 / 622,675, filed January 19, 2024; U.S. provisional patent application no. 63 / 625,146, filed January 25, 2024; U.S. provisional patent application no.63 / 552,571, filed February 12, 2024; U.S. provisional patent application no.63 / 556,308, filed February 21, 2024; U.S. provisional patent application no.63 / 566,163, filed March 15, 2024; each of which is herein incorporated by reference in its entirety. REFERENCE TO A SEQUENCE LISTING

[0002] This application incorporates by reference a computer readable Sequence Listing in ST.26 XML format, titled 11554WO01_Sequence, created on June 21, 2024, and containing 5,467 bytes. FIELD OF THE INVENTION

[0003] The field of the present invention relates to methods for treating or preventing angiogenic eye disorders by administering a VEGF antagonist. BACKGROUND OF THE INVENTION

[0004] The PHOTON clinical trial in DR / DME and the PULSAR clinical trial in wAMD are double-masked, active-controlled pivotal trials conducted in multiple centers globally. In both trials, patients were randomized into 3 treatment groups to receive either: aflibercept 8 mg every 12 weeks, aflibercept 8 mg every 16 weeks, or EYLEA every 8 weeks.

[0005] Patients treated with aflibercept 8 mg in both trials had 3 initial monthly doses, and patients treated with EYLEA received 5 initial monthly doses in PHOTON and 3 in PULSAR. In the first year, patients in the aflibercept 8 mg groups could have their dosing intervals shortened to as frequent as every 8-weeks if protocol-defined criteria for disease progression were observed. Intervals could not be extended until the second year of the study. Patients in both EYLEA groups (the control group for both PHOTON and PULSAR) maintained a fixed 8-week dosing regimen throughout their participation in the trials. SUMMARY OF THE INVENTION

[0006] The present invention provides methods for treating or preventing an angiogenic eye disorder (e.g., age-related macular degeneration (neovascular (nAMD)), macular edema (ME), macular edema following retinal vein occlusion (ME-RVO), retinal vein occlusion (RVO), central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), diabetic macular edema (DME), choroidal neovascularization (CNV), iris neovascularization, neovascular glaucoma, post-surgical fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), optic disc neovascularization, corneal neovascularization, retinal neovascularization, vitreal neovascularization, pannus, pterygium, vascular retinopathy, diabetic retinopathies (DR) (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., in a subject that does not suffer from DME), and / or Diabetic retinopathy in a subject who has diabetic macular edema (DME)) comprising administering to an eye of the subject (preferably by intravitreal injection) one or more doses (e.g., of >8 mg (±0.8 mg)) of aflibercept such that the clearance of free aflibercept from the ocular compartment is about 0.367-0.457 mL / day (e.g., 0.41 mL / day) after an intravitreal injection of aflibercept and the time for the amount for free aflibercept to reach the lower limit of quantitation (LLOQ) in the ocular compartment of a subject after said intravitreal injection of aflibercept is about 15 weeks; and the time for free aflibercept to reach the lower limit of quantitation (LLOQ) in the plasma (e.g., about 0.0156 mg / L) of a subject after said intravitreal injection of aflibercept is about 3.5 weeks; for example, wherein the aflibercept is administered in an aqueous pharmaceutical formulation wherein the aflibercept has less than about 3.5% high molecular weight species immediately after manufacture and purification and / or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C. In an embodiment of the invention, the aqueous pharmaceutical formulation comprises an aqueous pharmaceutical formulation comprising: at least about 100 mg / ml of a VEGF receptor fusion protein comprising two polypeptides that each comprises animmunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of VEGFR2, and a multimerizing component; about 10-100 mM L-arginine; sucrose; a histidine-based buffer; and a surfactant; wherein the formulation has a pH of about 5.0 to about 6.8; wherein the VEGF receptor fusion protein has less than about 3.5% high molecular weight species immediately after manufacture and purification and / or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C. In an embodiment of the invention, the method comprises administering a single initial dose of about 8 mg (±0.8 mg) or more of aflibercept, followed by one or more secondary doses of about 8 mg (±0.8 mg) or more of the aflibercept, followed by one or more tertiary doses of about 8 mg (±0.8 mg) or more of the aflibercept; wherein each secondary dose is administered about 2 to 4 (preferably 4) weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 8, 12, 16, 20, 8-24, 12-24, 16-24, 20-24 or 24 weeks after the immediately preceding dose.

[0007] The present invention provides a method for slowing the clearance of free aflibercept from the ocular compartment after an intravitreal injection relative to the rate of clearance of aflibercept from the ocular compartment after an intravitreal injection of < 4 mg aflibercept comprising intravitreally injecting into an eye of a subject in need thereof, a single initial dose of about 8 mg (±0.8 mg) or more of aflibercept, followed by one or more secondary doses of about 8 mg (±0.8 mg) or more of the aflibercept, followed by one or more tertiary doses of about 8 mg (±0.8 mg) or more of the aflibercept; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 24 weeks after the immediately preceding dose. In an embodiment of the invention, the clearance of free aflibercept from the ocular compartment is about 34% slower than that from the ocular compartment after an intravitreal injection of < 4 mg aflibercept, e.g., wherein the clearance of free aflibercept from the ocular compartment is about 0.367-0.457 mL / day or 0.41 mL / day after an intravitreal injection of > 8 mg (±0.8 mg) aflibercept.

[0008] The present invention also provides a method for increasing the time for the amount of free aflibercept to reach the lower limit of quantitation (LLOQ) in the ocular compartment of a subject after an intravitreal injection of aflibercept relative to the time to reach LLOQ of the amount of free aflibercept in the ocular compartment of a subject after an intravitreal injection of about 2 mg aflibercept, e.g., increasing by greater than 1.3 weeks, for example, by about 6 weeks-to more than 10 weeks, for example, to about 15 weeks, comprising intravitreally injecting into an eye of a subject in need thereof, a single initial dose of about 8 mg (±0.8 mg) or more of aflibercept, followed by one or more secondary doses of about 8 mg (±0.8 mg) or more of the aflibercept, followed by one or more tertiary doses of about 8 mg (±0.8 mg) or more of theaflibercept; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 8-24, 12-24, 16-24, 20-24 or 24 weeks after the immediately preceding dose.

[0009] The present invention also provides a method for increasing the time for free aflibercept to reach the lower limit of quantitation (LLOQ) in the plasma (e.g., about 0.0156 mg / L) of a subject after an intravitreal injection of aflibercept relative to the time to reach LLOQ of free aflibercept in the plasma of a subject after an intravitreal injection of about 2 mg aflibercept, e.g., increased by more than 1.5 weeks, for example by about 2 weeks-to about 3.5 weeks, comprising intravitreally injecting into an eye of a subject in need thereof, a single initial dose of about 8 mg (±0.8 mg) or more of aflibercept, followed by one or more secondary doses of about 8 mg (±0.8 mg) or more of the aflibercept, followed by one or more tertiary doses of about 8 mg (±0.8 mg) or more of the aflibercept; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 24 weeks after the immediately preceding dose. In an embodiment of the invention, the >8 mg (±0.8 mg) aflibercept is administered in an aqueous pharmaceutical formulation including aflibercept which includes one or more of histidine-based buffer, arginine (e.g., L-arginine, for example, L-arginine HCl), a sugar or polyol such as sucrose and having a pH of about 5.8. In an embodiment of the invention, the aflibercept has less than about 3.5% high molecular weight species immediately after manufacture and purification and / or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C; for example, wherein the >8 mg (±0.8 mg) aflibercept is in an aqueous pharmaceutical formulation comprising an aqueous pharmaceutical formulation comprising: at least about 100 mg / ml of a VEGF receptor fusion protein comprising two polypeptides that each comprises an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of VEGFR2, and a multimerizing component; about 10-100 mM L-arginine; sucrose; a histidine-based buffer; and a surfactant; wherein the formulation has a pH of about 5.0 to about 6.8; wherein the VEGF receptor fusion protein has less than about 3.5% high molecular weight species immediately after manufacture and purification and / or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C.

[0010] The present invention provides a method for treating or preventing an angiogenic eye disorder (e.g.,age-related macular degeneration (neovascular (nAMD)), macular edema (ME), macular edema following retinal vein occlusion (ME-RVO), retinal vein occlusion (RVO), central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), diabetic macular edema (DME), choroidal neovascularization (CNV), iris neovascularization, neovascular glaucoma,post-surgical fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), optic disc neovascularization, corneal neovascularization, retinal neovascularization, vitreal neovascularization, pannus, pterygium, vascular retinopathy, diabetic retinopathies (DR) (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., in a subject that does not suffer from DME), and / or Diabetic retinopathy in a subject who has diabetic macular edema (DME)) in a subject in need thereof, for improving best corrected visual acuity (BCVA) in a subject in need thereof with nAMD, DR and / or DME; or for promoting retinal drying in a subject with nAMD, DR and / or DME in need thereof; comprising administering to an eye of the subject (preferably by intravitreal injection), one or more doses of about 8 mg (±0.8 mg) or more of VEGF receptor fusion protein, preferably aflibercept, once every 24 weeks. In an embodiment of the invention, the method comprises administering to an eye of the subject, a single initial dose of about 8 mg (±0.8 mg) or more of a VEGF receptor fusion protein, preferably aflibercept, followed by one or more secondary doses of about 8 mg (±0.8 mg) or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 (preferably 4) weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 8-24, 12-24, 16-24, 20-24 or 24 weeks after the immediately preceding dose.

[0011] The present invention includes a method for treating or preventing an angiogenic eye disorder (e.g.,age-related macular degeneration (neovascular (nAMD)), macular edema (ME), macular edema following retinal vein occlusion (ME-RVO), retinal vein occlusion (RVO), central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), diabetic macular edema (DME), choroidal neovascularization (CNV), iris neovascularization, neovascular glaucoma, post-surgical fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), optic disc neovascularization, corneal neovascularization, retinal neovascularization, vitreal neovascularization, pannus, pterygium, vascular retinopathy, diabetic retinopathies (DR) (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., in a subject that does not suffer from DME), and / or Diabetic retinopathy in a subject who has diabetic macular edema (DME)) in a subject in need thereof, comprising administering to an eye of the subject (preferably by intravitreal injection), a single initial dose of about 8 mg (±0.8 mg) or more of a VEGF receptor fusion protein, preferably aflibercept, followed by one or more secondary doses of about 8 mg (±0.8 mg) or more of the VEGF receptor fusion protein, followed by one or moretertiary doses of about 8 mg (±0.8 mg) or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 (preferably 4) weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 8-24, 12-24, 16-24, 20-24 or 24 weeks after the immediately preceding dose.

[0012] In an embodiment of the invention, the method for treating or preventing an angiogenic eye disorder (e.g.,age-related macular degeneration (neovascular (nAMD)), macular edema (ME), macular edema following retinal vein occlusion (ME-RVO), retinal vein occlusion (RVO), central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), diabetic macular edema (DME), choroidal neovascularization (CNV), iris neovascularization, neovascular glaucoma, post-surgical fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), optic disc neovascularization, corneal neovascularization, retinal neovascularization, vitreal neovascularization, pannus, pterygium, vascular retinopathy, diabetic retinopathies (DR) (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., in a subject that does not suffer from DME), and / or Diabetic retinopathy in a subject who has diabetic macular edema (DME)) in a subject comprises comprising administering, to a subject in need thereof (preferably by intravitreal injection), >8 mg (±0.8 mg) VEGF receptor fusion protein, preferably aflibercept, (e.g., in a volume of 0.07 mL or 70 microliters) administered by intravitreal injection every 4 weeks (approximately every 28 days + / - 7 days, monthly) for the first three doses, followed by >8 mg (±0.8 mg) VEGF receptor fusion protein (e.g., in a volume of 0.07 mL) via intravitreal injection once every 8-24, 12-24, 16-24, 20-24 or 24 weeks (6 months, + / - 7 days).

[0013] The present invention also provides a method for treating or preventing an angiogenic eye disorder (e.g.,age-related macular degeneration (neovascular (nAMD)), macular edema (ME), macular edema following retinal vein occlusion (ME-RVO), retinal vein occlusion (RVO), central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), diabetic macular edema (DME), choroidal neovascularization (CNV), iris neovascularization, neovascular glaucoma, post-surgical fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), optic disc neovascularization, corneal neovascularization, retinal neovascularization, vitreal neovascularization, pannus, pterygium, vascular retinopathy, diabetic retinopathies (DR) (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., in a subject that does not suffer from DME), and / or Diabetic retinopathy in a subject who has diabetic macular edema (DME)), in a subject in need thereof: (1) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein, then the method comprises, after 1 month, administeringto the subject the initial >8 mg (±0.8 mg) dose of VEGF receptor fusion protein and, 1 month thereafter, the 1st>8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein; and, 1 month thereafter, the 2nd>8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein; and then, every 24 weeks thereafter, one or more >8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein according to the HDq24 dosing regimen; (2) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein, then the method comprises, after 1 month, administering to the subject the first >8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein and, 1 month thereafter, the 2nd>8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein; and then, every 24 weeks thereafter, one or more > 8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein according to the HDq24 dosing regimen; (3) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein, then the method comprises, after 1 month, administering to the subject the 2nd>8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein and then, every 24 weeks thereafter, one or more >8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein according to the HDq24 dosing regimen; (4) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein, then the method comprises, after 1 month, administering to the subject the 1st>8 mg (±0.8 mg) maintenance dose of VEGF receptor fusion protein and all further >8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein every 24 weeks according to the HDq24 dosing regimen; (5) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein and a 1st2 mg secondary dose of VEGF receptor fusion protein after 1 month, then the method comprises, after another 1 month, administering to the subject the initial >8 mg (±0.8 mg) dose of VEGF receptor fusion protein and, 1 month thereafter, the 1st>8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein; and 1 month thereafter, the 2nd>8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein; and then, every 24 weeks thereafter, one or more ≥ 8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein according to the HDq24 dosing regimen; (6) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein and a 1st2 mg secondary dose of VEGF receptor fusion protein after 1 month, then the method comprises, after another 1 month, administering to the subject a first >8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein and, 1 month thereafter, the 2nd>8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein; and then, every 24 weeks thereafter, one or more ≥8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein according to the HDq24 dosing regimen; (7) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein and a 1st2 mg secondary dose of VEGF receptor fusion protein after 1 month, then the method comprises, after another 1 month,administering to the subject the 2nd≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein and then, every 24 weeks thereafter, one or more ≥ 8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein according to the HDq24 dosing regimen; (8) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein and a 1st2 mg secondary dose of VEGF receptor fusion protein after 1 month, then the method comprises, after another 1 month, administering to the subject the 1st≥8 mg (±0.8 mg) maintenance dose of VEGF receptor fusion protein and all further ≥8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein every 24 weeks according to the HDq24 dosing regimen; (9) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein and a 1st2 mg secondary dose of VEGF receptor fusion protein after 1 month and a 2nd2 mg secondary dose of VEGF receptor fusion protein after another 1 month, then the method comprises, after another 1 month, administering to the subject the initial ≥8 mg (±0.8 mg) dose of VEGF receptor fusion protein and, 1 month thereafter, the 1st≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein; and 1 month thereafter, the 2nd≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein; and then, every 24 weeks thereafter, one or more ≥8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein according to the HDq24 dosing regimen; (10) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein and a 1st2 mg secondary dose of VEGF receptor fusion protein after 1 month and a 2nd2 mg secondary dose of VEGF receptor fusion protein after another 1 month, then the method comprises, after another 1 month, administering to the subject the first ≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein and, 1 month thereafter, the 2nd≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein; and then, every 24 weeks thereafter, one or more ≥8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein according to the HDq24 dosing regimen; (11) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein and a 1st2 mg secondary dose of VEGF receptor fusion protein after 1 month and a 2nd2 mg secondary dose of VEGF receptor fusion protein after another 1 month, then the method comprises, after another 1 month, administering to the subject the 2nd≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein and then, every 24 weeks thereafter, one or more ≥8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein according to the HDq24 dosing regimen; (12) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein and a 1st2 mg secondary dose of VEGF receptor fusion protein after 1 month and a 2nd2 mg secondary dose of VEGF receptor fusion protein after another 1 month, then the method comprises, after 2 months, administering to the subject the 1st≥8 mg (±0.8 mg) maintenance dose of VEGF receptor fusion protein and, all further ≥8 mg (±0.8 mg)maintenance doses of VEGF receptor fusion protein every 24 weeks according to the HDq24 dosing regimen; (13) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein and a 1st2 mg secondary dose of VEGF receptor fusion protein after 1 month and a 2nd2 mg secondary dose of VEGF receptor fusion protein after another 1 month and a 3rd2 mg secondary dose of VEGF receptor fusion protein after 1 month, then the method comprises, after 1 month, administering to the subject the initial ≥8 mg (±0.8 mg) dose of VEGF receptor fusion protein and 1 month thereafter, the 1st≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein; and 1 month thereafter, the 2nd≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein; and then, every 24 weeks thereafter, one or more ≥8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein according to the HDq24 dosing regimen; (14) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein and a 1st2 mg secondary dose of VEGF receptor fusion protein after 1 month and a 2nd2 mg secondary dose of VEGF receptor fusion protein after another 1 month and a 3rd2 mg secondary dose of VEGF receptor fusion protein after 1 month, then the method comprises, after 1 month, administering to the subject the first ≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein and 1 month thereafter, the 2nd≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein; and then, every 24 weeks thereafter, one or more ≥8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein according to the HDq24 dosing regimen; (15) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein and a 1st2 mg secondary dose of VEGF receptor fusion protein after 1 month and a 2nd2 mg secondary dose of VEGF receptor fusion protein after another 1 month and a 3rd2 mg secondary dose of VEGF receptor fusion protein after 1 month, then the method comprises, after 1 month, administering to the subject the 2nd≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein and then, every 24 weeks thereafter, one or more ≥8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein according to the HDq24 dosing regimen; (16) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein and a 1st2 mg secondary dose of VEGF receptor fusion protein after 1 month and a 2nd2 mg secondary dose of VEGF receptor fusion protein after another 1 month and a 3rd2 mg secondary dose of VEGF receptor fusion protein after 1 month, then the method comprises, after 2 months, administering to the subject the 1st≥8 mg (±0.8 mg) maintenance dose of VEGF receptor fusion protein and all further ≥8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein every 24 weeks according to the HDq24 dosing regimen; (17) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein and a 1st2 mg secondary dose of VEGF receptor fusion protein after 1 month and a 2nd2 mg secondary dose of VEGFreceptor fusion protein after another 1 month and a 3rd2 mg secondary dose of VEGF receptor fusion protein after 1 month; and a 4th2 mg secondary dose of VEGF receptor fusion protein after 1 month; thereafter, then the method comprises, after 2 months, administering to the subject the initial ≥8 mg (±0.8 mg) dose of VEGF receptor fusion protein and, 1 month thereafter, the 1st≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein; and 1 month thereafter, the 2nd≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein; and then, every 24 weeks thereafter, one or more ≥8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein according to the HDq24 dosing regimen; (18) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein and a 1st2 mg secondary dose of VEGF receptor fusion protein after 1 month and a 2nd2 mg secondary dose of VEGF receptor fusion protein after another 1 month and a 3rd2 mg secondary dose of VEGF receptor fusion protein after 1 month; and a 4th2 mg secondary dose of VEGF receptor fusion protein after 1 month; thereafter, then the method comprises, after 2 months, administering to the subject the first ≥ 8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein and, 1 month thereafter, the 2nd≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein; and then, every 24 weeks thereafter, one or more ≥8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein according to the HDq24 dosing regimen; (19) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein and a 1st2 mg secondary dose of VEGF receptor fusion protein after 1 month and a 2nd2 mg secondary dose of VEGF receptor fusion protein after another 1 month and a 3rd2 mg secondary dose of VEGF receptor fusion protein after 1 month, and a 4th2 mg secondary dose of VEGF receptor fusion protein after 1 month; thereafter, then the method comprises, after 2 months, administering to the subject the 2nd≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein and, 24 weeks thereafter, one or more 24 weekly ≥8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein according to the HDq24 dosing regimen; (20) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein and a 1st2 mg secondary dose of VEGF receptor fusion protein after 1 month and a 2nd2 mg secondary dose of VEGF receptor fusion protein after another 1 month and a 3rd2 mg secondary dose of VEGF receptor fusion protein after 1 month, and a 4th2 mg secondary dose of VEGF receptor fusion protein after 1 month, thereafter, then the method comprises, after 2 months, administering to the subject the 1st>8 mg (±0.8 mg) maintenance dose of VEGF receptor fusion protein and, all further >8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein every 24 weeks according to the HDq24 dosing regimen; (21) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein and a 1st2 mg secondary dose of VEGF receptor fusion protein after 1 month anda 2nd2 mg secondary dose of VEGF receptor fusion protein after another 1 month and a 3rd2 mg secondary dose of VEGF receptor fusion protein after 1 month, and a 4th2 mg secondary dose of VEGF receptor fusion protein after 1 month; and one or more 2 mg maintenance doses every 8 weeks thereafter, then the method comprises, 2 months after the last VEGF receptor fusion protein maintenance dose, administering to the subject the initial >8 mg (±0.8 mg) dose of VEGF receptor fusion protein and, 1 month thereafter, the 1st>8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein; and 1 month thereafter, the 2nd>8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein; and then, every 24 weeks thereafter, one or more >8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein according to the HDq24 dosing regimen; (22) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein and a 1st2 mg secondary dose of VEGF receptor fusion protein after 1 month and a 2nd2 mg secondary dose of VEGF receptor fusion protein after another 1 month and a 3rd2 mg secondary dose of VEGF receptor fusion protein after 1 month; and a 4th2 mg secondary dose of VEGF receptor fusion protein after 1 month; and one or more 2 mg maintenance doses every 8 weeks thereafter, then the method comprises, 2 months after the last VEGF receptor fusion protein maintenance dose administering to the subject the first 8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein and, 1 month thereafter, the 2nd>8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein; and then, every 24 weeks thereafter, one or more >8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein according to the HDq24 dosing regimen; (23) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein and a 1st2 mg secondary dose of VEGF receptor fusion protein after 1 month and a 2nd2 mg secondary dose of VEGF receptor fusion protein after another 1 month and a 3rd2 mg secondary dose of VEGF receptor fusion protein after 1 month; and a 4th2 mg secondary dose of VEGF receptor fusion protein after 1 month; and one or more 2 mg maintenance doses every 8 weeks thereafter, then the method comprises, 2 months after the last VEGF receptor fusion protein maintenance dose, administering to the subject the 2nd>8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein and, 24 weeks thereafter, one or more 24 weekly >8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein according to the HDq24 dosing regimen; or (24) wherein the subject has received an initial 2 mg dose of VEGF receptor fusion protein and a 1st2 mg secondary dose of VEGF receptor fusion protein after 1 month and a 2nd2 mg secondary dose of VEGF receptor fusion protein after another 1 month and a 3rd2 mg secondary dose of VEGF receptor fusion protein after 1 month; and a 4th2 mg secondary dose of VEGF receptor fusion protein after 1 month; and one or more 2 mg maintenance doses every 8 weeks thereafter, then the method comprises, 2 months after thelast VEGF receptor fusion protein maintenance dose, administering to the subject the 1st>8 mg (±0.8 mg) maintenance dose of VEGF receptor fusion protein and, all further >8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein every 24 weeks according to the HDq24 dosing regimen; wherein, said HDq24 dosing regimen comprises: a single initial dose of about >8 mg (±0.8 mg) or more of VEGF receptor fusion protein, followed by one or more secondary doses of about >8 mg (±0.8 mg) or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about >8 mg (±0.8 mg) or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 24 weeks after the immediately preceding dose.

[0014] The present invention also provides a method for treating or preventing neovascular age related macular degeneration (nAMD), diabetic retinopathy and / or diabetic macular edema, in a subject in need thereof who has been on a dosing regimen for treating or preventing said disorder wherein: (a) the subject has received an initial >8 mg (±0.8 mg) dose of VEGF receptor fusion protein then the method comprises, after 1 month, administering to the subject the first >8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein and 1 month thereafter, administering the 2nd>8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein; and then, every 24 weeks thereafter, administering one or more >8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein according to the HDq24 dosing regimen; or (b) the subject has received an initial >8 mg (±0.8 mg) dose of VEGF receptor fusion protein & 1st>8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein after 1 month, then the method comprises, after another 1 month, administering to the subject the 2nd>8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein; and then, every 24 weeks thereafter, one or more >8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein according to the HDq24 dosing regimen; or (c) the subject has received an initial >8 mg (±0.8 mg) dose of VEGF receptor fusion protein & 1st>8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein after 1 month & the 2nd>8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein after another month, then the method comprises, after 24 weeks administering to the subject the 1st>8 mg (±0.8 mg) maintenance dose of VEGF receptor fusion protein and all further >8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein every 24 weeks according to the HDq24 dosing regimen; or (d) the subject has received an initial >8 mg (±0.8 mg) dose of VEGF receptor fusion protein & a 1st> 8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein after 1 month & the 2nd>8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein after another month, then every 24 weeks thereafter, the subject hasreceived one or more >8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein; and, then the method comprises, after 24 weeks from the last maintenance dose of VEGF receptor fusion protein, administering to the subject one or more >8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein and all further >8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein every 24 weeks according to the HDq24 dosing regimen; wherein, said HDq24 dosing regimen comprises: a single initial dose of about >8 mg (±0.8 mg) or more of VEGF receptor fusion protein, followed by one or more secondary doses of about >8 mg (±0.8 mg) or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about >8 mg (±0.8 mg) or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 24 weeks after the immediately preceding dose.

[0015] The present invention provides a method for treating or preventing neovascular age related macular degeneration (nAMD), diabetic retinopathy or diabetic macular edema, in a subject in need thereof, comprising administering to an eye of the subject (preferably, by intravitreal injection), a single initial dose of about 8 mg (±0.8 mg) or more of a VEGF receptor fusion protein, preferably aflibercept, followed by one or more secondary doses of about 8 mg (±0.8 mg) or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 8, 12 or 16 or 20 weeks after the immediately preceding dose; further comprising, when a 8, 12, 16 or 20 week tertiary dose is due, evaluating the patient for suitability to lengthen the teritary dose interval, and if, in the judgment of a treating physician based on the patient’s visual acuity and / or central retinal thickness, lengthening the tertiary dose interval is appropriate, increasing the tertiary dose interval by an increment of 4 weeks, for example, wherein the interval is lengthened up to about 24 weeks, e.g., after one or more 4 week increases in the interval.

[0016] The present invention also provides a method for treating or preventing an angiogenic eye disorder (preferably nAMD, DR and / or DME), in a subject in need thereof who has been on a dosing regimen for treating or preventing the disorder calling for a single initial dose of about 2 mg of VEGF receptor fusion protein, preferably aflibercept, followed by one or more secondary doses of about 2 mg of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 2 mg of the VEGF receptor fusion protein; wherein each secondary dose is administered about 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 8 weeks after the immediately preceding dose; and wherein thesubject is at any phase of the 2 mg VEGF receptor fusion protein dosing regimen, comprising administering to an eye of the subject (preferably by intravitreal injection), an 8 mg (±0.8 mg) dose of VEGF receptor fusion protein, evaluating the subject in about 4 or 8 or 10 or 12 weeks after said administering and, if, in the judgment of the treating physician dosing every 24 weeks is appropriate, then continuing to dose the subject every 24 weeks with ≥8 mg (±0.8 mg) VEGF receptor fusion protein.

[0017] In an embodiment of the invention, a subject in a method of the present invention has been on a dosing regimen for treating or preventing neovascular age related macular degeneration, diabetic retinopathy and / or diabetic macular edema of a single initial dose of about 2 mg of a VEGF receptor fusion protein, preferably aflibercept, followed by 2, 3 or 4 secondary doses of about 2 mg of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 2 mg of the VEGF receptor fusion protein; wherein each secondary dose is administered about 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 8 weeks after the immediately preceding dose.

[0018] The present invention also provides a method for treating or preventing neovascular age related macular degeneration, diabetic retinopathy or diabetic macular edema, in a subject in need thereof, comprising administering to an eye of the subject (preferably by intravitreal injection), a single initial dose of about 8 mg (±0.8 mg) or more of a VEGF receptor fusion protein, preferably aflibercept, followed by one or more secondary doses of about 8 mg (±0.8 mg) or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 (preferably 4) weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12 or 16 weeks after the immediately preceding dose; further comprising, after receiving one or more of said tertiary doses about 12 or 16 after the immediately preceding dose, lengthening the tertiary dose interval from 12, 16 or 20 to 24 weeks, after the immediately preceding dose. For example, in an embodiment of the invention, during said treatment, the subject exhibits (a) <5 letter loss in BCVA; and / or (b) central retinal thickness (CRT) <300 or 320 µm. In an embodiment of the invention, the method further comprises evaluating BVCA and / or CRT in the subject and, if the subject exhibits (a) <5 letter loss in BCVA; and / or (b) CRT <300 or 320 µm, lengthening the tertiary dose interval.

[0019] The present invention also provides a method treating or preventing neovascular age related macular degeneration, diabetic retinopathy and / or diabetic macular edema, in a subject in need thereof, comprising administering to an eye of the subject (preferably by intravitreal injection), a single initial dose of about >8 mg (±0.8 mg) or more of a VEGF receptor fusionprotein, preferably aflibercept, followed by one or more secondary doses of about 8 mg (±0.8 mg) or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 (preferably 4) weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 24 weeks after the immediately preceding dose; further comprising, after receiving one or more of said tertiary doses about 24 weeks after the immediately preceding dose, shortening the tertiary dose interval from 24 to 12, 16 or 20. In an embodiment of the invention, during said treatment, the subject exhibits (a) > 10 letter loss in BCVA relative to baseline; and / or (b) > 50 µm increase in CRT relative to baseline. For example, in an embodiment of the invention, the method further comprises evaluating BVCA and / or CRT in the subject and, if the subject exhibits (a) > 10 letter loss in BCVA relative to baseline; and / or (b) > 50 µm increase in CRT relative to baseline, shortening the tertiary dose interval.

[0020] In an embodiment of the invention, if (a) greater than 5 letters are lost in BCVA (ETDRS), relative to the BCVA observed at about 12 weeks after treatment initiation; (b) a greater than 25 micrometers increase in CRT is observed relative to the CRT observed at about 12 weeks after treatment initiation; and / or (c) there is a new onset foveal neovascularization or foveal hemorrhage; e.g., at week 16 or week 20 after treatment initiation, then, the interval between tertiary doses is decreased from 24 to 12, 16 or 20 weeks; or (a) greater than 5 letters are lost in BCVA (ETDRS), relative to the BCVA observed at about 12 weeks after treatment initiation; (b) a greater than 25 micrometers increase in CRT is observed relative to the CRT observed at about 12 weeks after treatment initiation; and / or (c) there is a new onset foveal neovascularization or foveal hemorrhage; e.g., at week 24 after treatment initiation, then, the interval between tertiary doses is decreased from 24 to 12, 16 or 20 weeks.

[0021] The present invention provides a method for treating or preventing neovascular age related macular degeneration, diabetic retinopathy and / or diabetic macular edema, in a subject in need thereof, comprising administering to an eye of the subject (preferably by intravitreal injection), 3 doses of about ≥8 mg (±0.8 mg) VEGF receptor fusion protein, preferably aflibercept, in a formulation that comprises about 114.3 mg / ml VEGF receptor fusion protein atan interval of once every 4 weeks; wherein after said 3 doses, administering one or more doses of the VEGF receptor fusion protein at an interval which is lengthened up to 24 weeks.

[0022] The present invention includes a method for treating or preventing neovascular age related macular degeneration, diabetic retinopathy and / or diabetic macular edema, in a subject in need thereof, comprising administering to an eye of the subject (preferably by intravitreal injection), a single initial dose of about 8 mg (±0.8 mg) or more of VEGF receptor fusion protein, preferably aflibercept, followed by 2 secondary doses of about 8 mg (±0.8 mg) or more of the VEGF receptor fusion protein, wherein each secondary dose is administered about 2 to 4 (preferably 4) weeks after the immediately preceding dose; followed by one or more tertiary doses every 12, 16, 20 or 24 weeks and, after said doses, a) determining if the subject meets at least one criterion for reducing or lengthening one or more tertiary dose intervals by 2 weeks, 3 weeks, 4 weeks or 2-4 weeks between tertiary doses of the VEGF receptor fusion protein; and b) if said determination is made, administering further doses of the VEGF receptor fusion protein at said reduced or lengthened intervals between doses wherein criteria for lengthening the interval include: 1. <5 letter loss in BCVA; and / or 2. CRT <300 or 320 micrometers; and, wherein criteria for reducing the interval include: 1. >10 letter loss in BCVA; 2. persistent or worsening DME; and / or 3. >50 micrometers increase in CRT. In an embodiment of the invention, wherein criteria for lengthening the interval include both: 1. <5 letter loss in BCVA from week 12; and 2. CRT <300 or 320 micrometers as measured by SD-OCT; and / or wherein criteria for reducing the interval include both: 1. >10 letter loss in BCVA, e.g., from week 12 in association with persistent or worsening DME; and 2. >50 micrometers increase in CRT, e.g., from week 12. In an embodiment of the invention, if said criteria are met, said interval is lengthened to 24 weeks.

[0023] The present invention provides a method for treating or preventing neovascular age related macular degeneration, diabetic retinopathy and / or diabetic macular edema, in a subject in need thereof that has been pre-treated with one or more 2 mg doses of VEGF receptor fusion protein, preferably aflibercept, comprising administering to an eye of the subject (preferably by intravitreal injection), a single initial dose of about 8 mg (±0.8 mg) or more of a VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg (±0.8 mg) or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 (preferably 4) weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 24 weeks after the immediately preceding dose.

[0024] In an embodiment of the invention, subjects having certain exclusion criteria are excluded from treatment or are not excluded from treatment if exclusion criteria are not met. For example, a subject having any one or more of ocular or periocular infection; active intraocular inflammation; and / or hypersensitivity; is excluded from administration of VEGF receptor fusion protein to the eye. In an embodiment of the invention, a method of the present invention further comprises a step of evaluating the subject for: ocular or periocular infection; active intraocular inflammation; and / or hypersensitivity; and excluding the subject from said administration if any one or more if found in the subject.

[0025] In an embodiment of the invention, subjects are monitored for adverse events, such as conjunctival hemorrhage, cataract, vitreous detachment, vitreous floaters, corneal epithelium defect and / or increased intraocular pressure. If such AEs are identified, the identified AE may be treated and / or such treatment or prevention may be ceased.

[0026] In an embodiment of the invention, a method includes preparation prior to administration of a VEGF receptor fusion protein, preferably aflibercept. For example, wherein the method comprises, prior to each administration, providing or having available- one single- dose glass vial having a protective plastic cap and a stopper containing an aqueous formulation comprising ≥8 mg (±0.8 mg) VEGF receptor fusion protein in about 70 microliters; a filter needle, e.g., one 18-gauge x 1½-inch, 5-micron, filter needle that includes a tip and a bevel; an invention needle, e.g., one 30-gauge x ½-inch injection needle; and a syringe, e.g., one 1-mL Luer lock syringe having a graduation line marking for 70 microliters of volume; packaged together; then (1) visually inspecting the aqueous formulation in the vial and, if particulates, cloudiness, or discoloration are visible, then using another vial of aqueous formulation containing the VEGF receptor fusion protein; (2) removing the protective plastic cap from the vial; and (3) cleaning the top of the vial with an alcohol wipe; then using aseptic technique: (4) removing the 18-gauge x 1½-inch, 5-micron, filter needle and the 1 mL syringe from their packaging; (5) attaching the filter needle to the syringe by twisting it onto the Luer lock syringe tip; (6) pushing the filter needle into the center of the vial stopper until the needle is completely inserted into the vial and the tip touches the bottom or a bottom edge of the vial; (7) withdrawing all of the VEGF receptor fusion protein vial contents into the syringe, keeping the vial in an upright position, slightly inclined, while ensuring the bevel of the filter needle is submerged into the liquid; (8) continuing to tilt the vial during withdrawal keeping the bevel of the filter needle submerged in the formulation; (9) drawing the plunger rod sufficiently back when emptying the vial in order to completely empty the filter needle; (10) removing the filter needle from the syringe and disposing of the filter needle; (11) removing the 30-gauge x ½-inch injection needlefrom its packaging and attaching the injection needle to the syringe by firmly twisting the injection needle onto the Luer lock syringe tip; (12) holding the syringe with the needle pointing up, and checking the syringe for bubbles, wherein if there are bubbles, gently tapping the syringe with a finger until the bubbles rise to the top; and (13) slowly depressing the plunger so that the plunger tip aligns with the graduation line that marks 70 microliters on the syringe. In an embodiment of the invention, injection of VEGF receptor fusion protein is performed under controlled aseptic conditions, which comprise surgical hand disinfection and the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent) and anesthesia and a topical broad–spectrum microbicide are administered prior to the injection.

[0027] In an embodiment of the invention, the subject has been receiving a dosing regimen for treating or preventing neovascular age related macular degeneration, diabetic retinopathy and / or diabetic macular edema calling for: a single initial dose of about 2 mg of VEGF receptor fusion protein, followed by 2, 3 or 4 secondary doses of about 2 mg of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 2 mg of the VEGF receptor fusion protein; wherein each secondary dose is administered about 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 8 weeks after the immediately preceding dose; wherein the subject is at any phase (initial dose, secondary dose or tertiary dose) of the 2 mg VEGF receptor fusion protein dosing regimen.

[0028] In an embodiment of the invention, 24 weeks is 6 months, 168 days or twice per year, one or more secondary doses is 2 secondary doses; 2 to 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; 8–16 weeks is about 12-16 weeks; 2 to 4 weeks is about 4 weeks and one or more secondary doses is 2 secondary doses; 12-20 weeks is about 12 weeks and one or more secondary doses is 2 secondary doses; 12-20 weeks is about 16 weeks and one or more secondary doses is 2 secondary doses; 12-20 weeks is about 20 weeks and one or more secondary doses is 2 secondary doses; 12-20 weeks is about 12-16 weeks and one or more secondary doses is 2 secondary doses; 2 to 4 weeks is about 4 weeks and one or more secondary doses is 2 secondary doses and the VEGF receptor fusion protein is aflibercept; 12- 20 weeks is about 12 weeks and one or more secondary doses is 2 secondary doses and the VEGF receptor fusion protein is aflibercept; 12-20 weeks is about 16 weeks and one or more secondary doses is 2 secondary doses and the VEGF receptor fusion protein is aflibercept; 12- 20 weeks is about 20 weeks and one or more secondary doses is 2 secondary doses and the VEGF receptor fusion protein is aflibercept; and / or 12-20 weeks is about 12-16 weeks and oneor more secondary doses is 2 secondary doses and the VEGF receptor fusion protein is aflibercept.

[0029] In an embodiment of the invention, the VEGF receptor fusion protein: comprises amino acids 27-457 of the amino acid sequence set forth in SEQ ID NO: 2; is selected from the group consisting of: aflibercept and conbercept; comprises two polypeptides that comprise (1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO: 2; (2) a VEGFR2 component comprising amino acids 130-231 of SEQ ID NO: 2; and (3) a multimerization component comprising amino acids 232-457 of SEQ ID NO: 2; comprises two polypeptides that comprise an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of a VEGFR2, and a multimerizing component; comprises two polypeptides that comprise an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of VEGFR2, an Ig domain 4 of VEGFR2 and a multimerizing component; or comprises two VEGFR1R2-Fc∆C1(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 or consists of amino acids 27-457 of the amino acid sequence set forth in SEQ ID NO: 2. Preferably, the VEGF receptor fusion protein is aflibercept.

[0030] 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, preferably aflibercept, is in an aqueous pharmaceutical formulation comprising about 114.3 mg / ml VEGF receptor fusion protein, preferably aflibercept.

[0031] In an embodiment of the invention, the VEGF receptor fusion protein, preferably aflibercept, is administered to both eyes of the subject.

[0032] In an embodiment of the invention, the VEGF receptor fusion protein, preferably aflibercept, is administered from a syringe or pre-filled syringe, e.g., which is glass or plastic, and / or sterile; e.g., with a 30 gauge × ½-inch sterile injection needle.

[0033] In an embodiment of the invention, a subject has previously received one or more doses of 2 mg VEGF receptor fusion protein, e.g., Eylea. One or more further doses than specifically mentioned may be administered to a subject.

[0034] In an embodiment of the invention, a subject who has received 2 mg of VEGF receptor fusion protein, preferably aflibercept, has received the protein in an aqueous pharmaceutical formulation comprising 40 mg / ml VEGF receptor fusion protein, 10 mM sodium phosphate, 40 mM NaCl, 0.03% polysorbate 20 and 5% sucrose, with a pH of 6.2.

[0035] In an embodiment of the invention, the ≥8 mg (±0.8 mg) VEGF receptor fusion protein, preferably aflibercept, is in an aqueous pharmaceutical formulation including >100 mg / ml VEGFreceptor fusion protein, histidine-based buffer and arginine (preferably L-arginine); e.g., comprising a sugar or polyol (e.g., sucrose). In an embodiment of the invention, the formulation has a pH of about 5.8. For example, the formulation may include about 103-126 mg / ml of the VEGF receptor fusion protein, histidine-based buffer and arginine; in an embodiment of the invention, including about 114.3 mg / ml of the VEGF receptor fusion protein, histidine-based buffer and arginine.

[0036] In an embodiment of the invention, the ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, preferably aflibercept, is administered in a volume of 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; 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; 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; e.g., in a volume of about 70 + 4 or 5 microliters.

[0037] In an embodiment of the invention, the methods herein include the step of administering the VEGF receptor fusion protein, preferably aflibercept, to both eyes of the subject, e.g., intravitreally.

[0038] In an embodiment of the invention, the subject achieves and / or maintains one or more of, an improvement in Diabetic Retinopathy Severity Scale (DRSS); an improvement in best corrected visual acuity; a dry retina; a gain in best corrected visual acuity; a BCVA of at least 69 letters; a foveal center without fluid; a decrease in central retinal thickness (CRT); no vascular leakage as measured by fluorescein angiography (FA); an improvement from pre-treatment baseline in National Eye Institute Visual Function Questionnaire (NEI-VFQ) total score; a retina without fluid (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF]) at the foveal center and in center subfield; maintenance of a fluid-free retina (total fluid, IRF and / or SRF at foveal center and in the center subfield); a lack of macular edema; a retina free of fluid on spectral domain optical coherence tomography (SD-OCT); Does not deviate from the HDq12 or HDq16 or HDq20 treatment regimen once started; Non-inferior BVCA compared to that of aflibercept which is intravitreally dosed 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; Increase in BCVA (according to ETDRS letter score) of about 7, 8 or 9 letters by week 60 from start of treatment, wherein the baseline BCVA is about 61, 62 or 63; BCVA (according to ETDRS letter score) of at least about 69 letters by week 48 or 60 from start of treatment; Does not lose 5, 10, 15 or 69 letters or more BCVA after week 12, 24, 36, 48, 60, 72, 84, 90 or 96 from start of treatment; Improvement in BCVA (according to ETDRS letter score) by week 12, 24, 36, 48, 60, 72, 84, 90or 96 from start of treatment; Improvement in BVCA by week 4, week 8, week 12, week 16, week 20, week 24, week 28, week 32, week 36, week 40, week 44, or week 48 from start of treatment; Between weeks 48 and 60, a BCVA score (according to ETDRS letter score) of about 69, 70, 71, 72 or 73; Between weeks 36 and 48, a change in BCVA score (according to ETDRS letter score) from initiation of treatment of about 7, 8 or 9 wherein the BCVA at any point between week 36 to 48 is about 60 or 70; Between weeks 48 and 60, a change in BCVA score (according to ETDRS letter score) from initiation of treatment of about 7, 8 or 9, wherein the BCVA at any point between week 48 to 60 is about 69, 70, 71, 72 or 73; Increase in BCVA as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart or Snellen equivalent by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 or 48 weeks from start of treatment by ≥4 letters, ≥5 letters, ≥6 letters, ≥7 letters, ≥8 letters, > 9 letters or > 10 letters; Does not lose 5, 10 or 15 letters by week 48 or 60 from start of treatment (according to ETDRS letter score); Gains at least 5, 10 or 15 letter by week 48 or 60 from start of treatment (according to ETDRS letter score); Improvement in BCVA, by 4 weeks after initiation of treatment, of about 4 or 5 letters (ETDRS or Snellen equivalent) when on HDq12 regimen; or of about 4 or 5 letters (ETDRS or Snellen equivalent) when on HDq16 regimen; Improvement in BCVA, by 8 weeks after initiation of treatment, of about 6 letters (ETDRS or Snellen equivalent) when on HDq12 regimen; or of about 5 or 6 letters (ETDRS or Snellen equivalent) when on HDq16 regimen; Improvement in BCVA, by 12 weeks after initiation of treatment, of about 6 or 7 letters (ETDRS or Snellen equivalent) when on HDq12 regimen; or of about 6 letters (ETDRS or Snellen equivalent) when on HDq16 regimen; Improvement in BCVA, by 16 weeks after initiation of treatment, of about 6 or 7 letters (ETDRS or Snellen equivalent) when on HDq12 regimen; or of 7 letters (ETDRS or Snellen equivalent) when on HDq16 regimen; Improvement in BCVA, by 20 weeks after initiation of treatment, of about 6 letters (ETDRS or Snellen equivalent) when on HDq12 regimen; or of about 6 letters (ETDRS or Snellen equivalent) when on HDq16 regimen; Improvement in BCVA, by 24 weeks after initiation of treatment, of about 7 letters (ETDRS or Snellen equivalent) when on HDq12 regimen; or of about 5 or 6 letters (ETDRS or Snellen equivalent) when on HDq16 regimen; Improvement in BCVA, by 28 weeks after initiation of treatment, of about 7 or 8 letters (ETDRS or Snellen equivalent) when on HDq12 regimen; or of about 7 or 8 letters (ETDRS or Snellen equivalent) when on HDq16 regimen; Improvement in BCVA, by 32 weeks after initiation of treatment, of about 7 letters (ETDRS or Snellen equivalent) when on HDq12 regimen; or of about 7 or 8 letters (ETDRS or Snellen equivalent) when on HDq16 regimen; Improvement in BCVA, by 36 weeks after initiation of treatment, of 8 letters (ETDRS or Snellen equivalent) when on HDq12 regimen; or of about 6 or 7 letters(ETDRS or Snellen equivalent) when on HDq16 regimen; Improvement in BCVA, by 40 weeks after initiation of treatment, of about 8 letters (ETDRS or Snellen equivalent) when on HDq12 regimen; or of about 6 or 7 letters (ETDRS or Snellen equivalent) when on HDq16 regimen; Improvement in BCVA, by 44 weeks after initiation of treatment, of about 8 letters (ETDRS or Snellen equivalent) when on HDq12 regimen; or of about 7 or 8 letters (ETDRS or Snellen equivalent) when on HDq16 regimen; Improvement in BCVA, by 48 weeks after initiation of treatment, of about 8 or 9 letters (ETDRS or Snellen equivalent) when on HDq12 regimen; or of about 7 or 8 letters (ETDRS or Snellen equivalent) when on HDq16 regimen; An improvement in BCVA by about week 8 after initiation of treatment which is maintained thereafter during the treatment regimen to at least week 48; A BCVA by 4 weeks after initiation of treatment of about 68 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 66 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; A BCVA by 8 weeks after initiation of treatment of about 70 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 67 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; A BCVA by 12 weeks after initiation of treatment of about 70 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 68 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; A BCVA by 16 weeks after initiation of treatment of about 71 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 69 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; A BCVA by 20 weeks after initiation of treatment of about 70 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 68 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; A BCVA by 24 weeks after initiation of treatment of about 71 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 67 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; A BCVA by 28 weeks after initiation of treatment of about 72 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 70 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; A BCVA by 32 weeks after initiation of treatment of about 71 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 70 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; A BCVA by 36 weeks after initiation of treatment of about 71 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 68 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; A BCVA by 40 weeks after initiation of treatment of about 72 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 69 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; A BCVA by 44 weeks after initiation of treatment of about 72 letters(ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 70 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; A BCVA by 48 weeks after initiation of treatment of about 73 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 70 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; A BCVA improvement, by week 48 following treatment initiation, of about 9 or 10 letters (ETDRS or Snellen equivalent) when baseline BCVA is about <73 ETDRS letters when on HDq12 regimen; A BCVA improvement, by week 48 following treatment initiation, of about 5 or 6 letters (ETDRS or Snellen equivalent) when baseline BCVA is about >73 ETDRS letters when on HDq12 regimen; A BCVA improvement, by week 48 following treatment initiation, of about 8 or 9 letters (ETDRS or Snellen equivalent) when baseline BCVA is about <73 ETDRS letters when on HDq16 regimen; A BCVA improvement, by week 48 following treatment initiation, of about 4 or 5 letters (ETDRS or Snellen equivalent) when baseline BCVA is about >73 ETDRS letters when on HDq16 regimen; A BCVA improvement, by week 48 following treatment initiation, of about 7 or 8 letters (ETDRS or Snellen equivalent) when baseline CRT is about < about 400 micrometers when on HDq12 regimen; A BCVA improvement, by week 48 following treatment initiation, of about 9 or 10 letters (ETDRS or Snellen equivalent) when baseline CRT is about >400 micrometers when on HDq12 regimen; A BCVA improvement, by week 48 following treatment initiation, of about 5 or 6 letters (ETDRS or Snellen equivalent) when baseline CRT is about < about 400 micrometers when on HDq16 regimen; A BCVA improvement, by week 48 following treatment initiation, of about 9 or 10 letters (ETDRS or Snellen equivalent) when baseline CRT is about > about 400 micrometers when on HDq16 regimen; Gain of >5, >10 or ≥15 letters BCVA (according to ETDRS letter score) by week 12, 24, 36, 48, 60, 72, 84, 90 or 96 from start of treatment; ≥ 2 or >3 step improvement in Diabetic Retinopathy Severity Scale (DRSS), by week 12, 24, 36, 48, 60, 72, 84, 90 or 96 from start of treatment; ≥ 2 step improvement in diabetic retinopathy severity scale (DRSS) by week 4, week 8, week 12, 16, 20, 24, 28, 32, 36, 40, 44 or 48 weeks from start of treatment; Retina without fluid (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF]) at the foveal center and in center subfield by week 12, 24, 36, 48, 60, 72, 84, 90 or 96 from start of treatment as measured by optical coherence tomography (OCT); No vascular leakage as measured by fluorescein angiography (FA) by week 12, 24, 36, 48, 60, 72, 84, 90 or 96 from start of treatment; Maintenance of a fluid-free retina (total fluid, IRF and / or SRF at foveal center and in the center subfield) by week 12, 24, 36, 48, 60, 72, 84, 90 or 96 from start of treatment; Reduction in total area of fluorescein leakage within ETDRS grid (mm2) at week 48 or 60 by about 12, 13 or 14 mm2or more as measured by fluorescein angiography; Retina free of fluid on spectral domainoptical coherence tomography (SD-OCT) by week 12, 24, 36, 48, 60, 72, 84, 90 or 96 from start of treatment; Retina without fluid (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF]) at the foveal center by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 or 48 weeks from start of treatment; Dry retina by week 12, 24, 36, 48, 60, 72, 84, 90 or 96 from start of treatment; Foveal center without fluid by week 12, 24, 36, 48, 60, 72, 84, 90 or 96 from start of treatment as measured by optical coherence tomography (OCT); A change in central retinal thickness, by 4 weeks after initiation of treatment of about -118 or -118.3 micrometers when on the HDq12 regimen; or of about -124 or -125 or -124.9 or -125.5 micrometers when on the HDq16 regimen; A change in central retinal thickness, by 8 weeks after initiation of treatment of about -137 or - 137.4 micrometers when on the HDq12 regimen; or of about -139 or -140 or -139.6 or -140.3 micrometers when on the HDq16 regimen; A change in central retinal thickness, by 12 weeks after initiation of treatment of about -150 or -150.1 micrometers when on the HDq12 regimen; or of about -152 or -153 or -152.7 or -153.4 micrometers when on the HDq16 regimen; A change in central retinal thickness, by 16 weeks after initiation of treatment of about -139 or -139.4 micrometers when on the HDq12 regimen; or of about -145 or -146 or -145.5 or -146.4 micrometers when on the HDq16 regimen; A change in central retinal thickness, by 20 weeks after initiation of treatment of about -117 or -117.1 micrometers when on the HDq12 regimen; or of about -112 or -113 or -112.5 or -113.3 micrometers when on the HDq16 regimen; A change in central retinal thickness, by 24 weeks after initiation of treatment of about -158 or -158.1 micrometers when on the HDq12 regimen; or of about -103 or -104 or -103.8 or -104.3 micrometers when on the HDq16 regimen; A change in central retinal thickness, by 28 weeks after initiation of treatment of about -146 or -147 or -146.7 micrometers when on the HDq12 regimen; or of about -162 or -162.3 micrometers when on the HDq16 regimen; A change in central retinal thickness, by 32 weeks after initiation of treatment of about -132 micrometers when on the HDq12 regimen; or of about -145 or -146 or -145.8 micrometers when on the HDq16 regimen; A change in central retinal thickness, by 36 weeks after initiation of treatment of about -168 or -168.1 micrometers when on the HDq12 regimen; or of about -124 or -125 or - 124.7 or -125.2 micrometers when on the HDq16 regimen; A change in central retinal thickness, by 40 weeks after initiation of treatment of about -163 micrometers when on the HDq12 regimen; or of about -122 or -123 or -122.5 or -123.1 micrometers when on the HDq16 regimen; A change in central retinal thickness, by 44 weeks after initiation of treatment of about -147 or - 148 or -147.4 micrometers when on the HDq12 regimen; or of about -164 or -164.1 or -164.3 micrometers when on the HDq16 regimen; A change in central retinal thickness, by 48 weeks after initiation of treatment of about -171 or -172 or -171.7 micrometers when on the HDq12regimen; or of about -148 or -149 or -148.3 or -149.4 micrometers when on the HDq16 regimen; A change in central retinal thickness, by 60 weeks after initiation of treatment of about -181.95 or -176.24 micrometers when on the HDq12 regimen; or of about -166.26 or -167.18 micrometers when on the HDq16 regimen; A reduction in central retinal thickness by week 4, 5, 6, 7 or 8 after initiation of treatment which is maintained within about +17, +18 or +19 micrometers thereafter during the treatment regimen to at least week 48 from initiation of treatment; Decrease in central retinal thickness by about 100, 125, 150, 175 or 200 micrometers by week 12, 24, 36, 48, 60, 72, 84, 90 or 96 from start of treatment; Reduction in central retinal thickness of about 148-182 micrometers by about week 48 or 60 from start of treatment as measured by optical coherence tomography (OCT)) wherein the baseline CRT is about 449, 450, 455 or 460 micrometers; Decrease in central retinal thickness (CRT) by at least about 100, 125, 130, 135, 140, 145, 149, 150, 155, 160, 165, 170, 171, 172, 173, 174 or 175 micrometers by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 or 48 from start of treatment; at about 0.1667 days after the first dose, free aflibercept concentration in plasma of about 0.149 (+0.249) mg / l; wherein, at baseline, free aflibercept concentration in plasma was not detectable wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; At about 0.3333 days after the first dose, free aflibercept in plasma of about 0.205 (+0.250) mg / l; wherein, at baseline, free aflibercept in plasma not detectable wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; At about 1 days after the first dose, free aflibercept in plasma of about 0.266 (+0.211) mg / l wherein, at baseline, free aflibercept in plasma not detectable wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; At about 2 days after the first dose, free aflibercept in plasma of about 0.218 (+0.145) mg / l wherein, at baseline, free aflibercept in plasma not detectable wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; At about 4 days after the first dose, free aflibercept in plasma of about 0.140 (+0.0741) mg / l wherein, at baseline, free aflibercept in plasma not detectable wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; At about 7 days after the first dose, free aflibercept in plasma of about 0.0767 (+0.0436) mg / l wherein, at baseline, free aflibercept in plasma not detectable, wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; At about 14 days after the first dose, free aflibercept in plasma of about 0.0309 (+0.0241) mg / l wherein at baseline free aflibercept in plasma not detectable wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; At about 21 days after the first dose, free aflibercept in plasma of about 0.0171 (+0.0171) mg / l wherein, at baseline, free aflibercept in plasma not detectable wherein the subject has not received intravitreal aflibercepttreatment for at least 12 weeks; At about 28 days after the first dose, free aflibercept in plasma of about 0.00730 (+0.0113) mg / l wherein, at baseline, free aflibercept in plasma not detectable wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; At about 0.1667 days after the first dose, adjusted bound aflibercept in plasma of about 0.00698 (+0.0276) mg / l wherein, at baseline, there is about 0.00583 mg / l (+0.0280) adjusted bound aflibercept wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; At about 0.3333 days after the first dose, adjusted bound aflibercept in plasma of about 0.00731 (+0.0279) mg / l wherein, at baseline, there is about 0.00583 mg / l (+0.0280) adjusted bound aflibercept wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; At about 1 days after the first dose, adjusted bound aflibercept in plasma of about 0.0678 (+0.0486) mg / l wherein, at baseline, there is about 0.00583 mg / l (+0.0280) adjusted bound aflibercept wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; At about 2 days after the first dose, adjusted bound aflibercept in plasma of about 0.138 (+0.0618) mg / l wherein at baseline there is about 0.00583 mg / l (+0.0280) adjusted bound aflibercept wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; At about 4 days after the first dose, adjusted bound aflibercept in plasma of about 0.259 (+0.126) mg / l wherein at baseline there is about 0.00583 mg / l (+0.0280) adjusted bound aflibercept wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; At about 7 days after the first dose, adjusted bound aflibercept in plasma of about 0.346 (+0.151) mg / l wherein at baseline there is about 0.00583 mg / l (+0.0280) adjusted bound aflibercept wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; At about 14 days after the first dose, adjusted bound aflibercept in plasma of about 0.374 (+0.110) mg / l wherein at baseline there is about 0.00583 mg / l (+0.0280) adjusted bound aflibercept wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; At about 21 days after the first dose, adjusted bound aflibercept in plasma of about 0.343 (+0.128) mg / l wherein at baseline there is about 0.00583 mg / l (+0.0280) adjusted bound aflibercept wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; At about 28 days after the first dose, adjusted bound aflibercept in plasma of about 0.269 (+0.149) mg / l wherein at baseline there is about 0.00583 mg / l (+0.0280) adjusted bound aflibercept wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; the maximum concentration of free aflibercept in the plasma is reached about 0.965 days after the first dose; Reaches a maximum concentration of about 0.310 mg / l (+0.263) free aflibercept in the plasma; Free aflibercept in the plasma of from about 0 to about 1.08 mg / L; Free aflibercept maximum concentration in the plasma (mg / l) per dose (mg) of aflibercept ofabout 0.0388 (+0.0328) mg / l / mg; The maximum concentration of adjusted bound aflibercept in the plasma is reached about 14 days after the first dose; Reaches a maximum concentration of about 0.387 mg / l (+0.135) adjusted bound aflibercept in the plasma; Adjusted bound aflibercept concentration in the plasma of from about 0.137 to about 0.774 mg / L; Adjusted bound aflibercept in the plasma maximum (mg / l) per dose (mg) of aflibercept of about 0.0483 (+0.0168) mg / l / mg; Does not have anti-drug antibodies against aflibercept after 48 or 60 weeks of treatment; Improvement from pre-treatment baseline in National Eye Institute Visual Function Questionnaire (NEI-VFQ) total score; and / or Lack of macular edema. For example, in an embodiment of the invention, a dry retina lacks intraretinal fluid and / or subretinal fluid; or retinal drying is characterized by no intraretinal fluid (IRF) and no subretinal fluid (SRF) in the eye of the subject, after the subject has received three monthly doses of the VEGF receptor fusion protein, preferably aflibercept.

[0039] In an embodiment of the invention, the subject achieves and / or maintains one or more of: Improvement in BCVA, by 64 weeks after initiation of treatment, of about 9 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or of about 8 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; Improvement in BCVA, by 68 weeks after initiation of treatment, of about 8 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or of about 8 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; Improvement in BCVA, by 72 weeks after initiation of treatment, of about 8 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or of about 6 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; Improvement in BCVA, by 76 weeks after initiation of treatment, of about 8 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or of about 7 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; Improvement in BCVA, by 80 weeks after initiation of treatment, of about 8 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or of about 8 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; Improvement in BCVA, by 84 weeks after initiation of treatment, of about 8 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or of about 8 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; Improvement in BCVA, by 88 weeks after initiation of treatment, of about 9 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or of about 7 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; Improvement in BCVA, by 92 weeks after initiation of treatment, of about 9 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or of about 7 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; Improvement in BCVA, by 96 weeks after initiation of treatment, of about 9 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or ofabout 8 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; A BCVA by 64 weeks after initiation of treatment of about 73 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 70 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; A BCVA by 68 weeks after initiation of treatment of about 72 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 69 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; A BCVA by 72 weeks after initiation of treatment of about 73 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 68 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; A BCVA by 76 weeks after initiation of treatment of about 73 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 68 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; A BCVA by 80 weeks after initiation of treatment of about 72 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 69 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; A BCVA by 84 weeks after initiation of treatment of about 72 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 70 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; A BCVA by 88 weeks after initiation of treatment of about 73 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 69 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; A BCVA by 92 weeks after initiation of treatment of about 73 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 69 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; A BCVA by 96 weeks after initiation of treatment of about 73 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 69 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; A change in central retinal thickness, by 64 weeks after initiation of treatment of about -173.4 micrometers or about -173 micrometers when on the HDq12 regimen; or of about -164.3 micrometers or about -164 micrometers when on the HDq16 regimen; A change in central retinal thickness, by 68 weeks after initiation of treatment of about -159.4 micrometers or about -159 micrometers when on the HDq12 regimen; or of about -153.9 micrometers or about -154 micrometers when on the HDq16 regimen; A change in central retinal thickness, by 72 weeks after initiation of treatment of about -166.6 micrometers or about - 167 micrometers when on the HDq12 regimen; or of about -134.2 micrometers or about -134 micrometers when on the HDq16 regimen; A change in central retinal thickness, by 76 weeks after initiation of treatment of about -181.1 micrometers or about -181 micrometers when on the HDq12 regimen; or of about -160.8 micrometers or about -161 micrometers when on the HDq16 regimen; A change in central retinal thickness, by 80 weeks after initiation of treatment of about-168.9 micrometers or about -169 micrometers when on the HDq12 regimen; or of about -164 micrometers or about -164 micrometers when on the HDq16 regimen; A change in central retinal thickness, by 84 weeks after initiation of treatment of about -177.5 micrometers or about - 178 micrometers when on the HDq12 regimen; or of about -150.2 micrometers or about -150 micrometers when on the HDq16 regimen; A change in central retinal thickness, by 88 weeks after initiation of treatment of about -171.2 micrometers or about -171 micrometers when on the HDq12 regimen; or of about -144.3 micrometers or about -144 micrometers when on the HDq16 regimen; A change in central retinal thickness, by 92 weeks after initiation of treatment of about -166.7 micrometers or about -167 micrometers when on the HDq12 regimen; or of about -155.5 micrometers or about -156 micrometers when on the HDq16 regimen; A change in central retinal thickness, by 96 weeks after initiation of treatment of about -185.3 micrometers or about - 185 micrometers when on the HDq12 regimen; or of about -155 micrometers or about -155 micrometers when on the HDq16 regimen; A central retinal thickness by 64 weeks after initiation of treatment of about 279.4 micrometers when on the HDq12 regimen or of about 289.6 micrometers when on the HDq16 regimen; A central retinal thickness by 68 weeks after initiation of treatment of about 294.5 micrometers when on the HDq12 regimen or of about 305.3 micrometers when on the HDq16 regimen; A central retinal thickness by 72 weeks after initiation of treatment of about 284.2 micrometers when on the HDq12 regimen or of about 327.2 micrometers when on the HDq16 regimen; A central retinal thickness by 76 weeks after initiation of treatment of about 270.6 micrometers when on the HDq12 regimen or of about 302 micrometers when on the HDq16 regimen; A central retinal thickness by 80 weeks after initiation of treatment of about 284.6 micrometers when on the HDq12 regimen or of about 293.5 micrometers when on the HDq16 regimen; A central retinal thickness by 84 weeks after initiation of treatment of about 274.7 micrometers when on the HDq12 regimen or of about 310.8 micrometers when on the HDq16 regimen; A central retinal thickness by 88 weeks after initiation of treatment of about 283.7 micrometers when on the HDq12 regimen or of about 312.3 micrometers when on the HDq16 regimen; A central retinal thickness by 92 weeks after initiation of treatment of about 285.7 micrometers when on the HDq12 regimen or of about 301.8 micrometers when on the HDq16 regimen; and / or A central retinal thickness by 96 weeks after initiation of treatment of about 267.5 micrometers when on the HDq12 regimen or of about 304.2 micrometers when on the HDq16 regimen.

[0040] In an embodiment of the invention, reference to 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56 or 60 weeks from start of treatment is about 48 weeks or 60 weeks from start of treatment.

[0041] In an embodiment of the invention, 1 initial dose, 2 secondary doses and 3 tertiary doses of VEGF receptor fusion protein, preferably aflibercept, are administered to the subject in the first year; 1 initial dose, 2 secondary doses and 2 tertiary doses of VEGF receptor fusion protein, e.g., aflibercept, are administered to the subject in the first year; or 1 initial dose, 2 secondary doses and 3 tertiary doses of VEGF receptor fusion protein, e.g., aflibercept, are administered to the subject in the first year followed by 2 -4 tertiary doses in the second year.

[0042] In an embodiment of the invention, the interval between doses are adjusted (increased / maintained / reduced) based on visual and / or anatomic outcomes, e.g., according to criteria as set forth in Figure 3 and / or Figure 4.

[0043] The present invention also provides a kit comprising a container comprising VEGF receptor fusion protein, preferably aflibercept; and Instruction for use of VEGF receptor fusion protein, wherein the container is a vial or a pre-filled syringe, wherein the container comprises > 100 mg / mL VEGF receptor fusion protein, wherein the container comprises > 114.3 mg / mL VEGF receptor fusion protein, wherein the instruction comprises instruction for the administration of aflibercept to DR, DME and / or nAMD patients, wherein the instruction comprises instruction that aflibercept ≥8 mg (±0.8 mg) treatment is initiated with 1 injection per month (about every 4 weeks) for 3 consecutive doses, wherein the instruction comprises instruction that after the initial 3 consecutive doses the injection interval may be lengthened up to every 24 weeks, and wherein the instruction comprises instruction that the treatment interval may be adjusted based on the physician’s judgement of visual and / or anatomic outcomes.

[0044] The present invention provides aflibercept for use in the treatment or prevention of an angiogenic eye disorder, neovascular age related macular degeneration, diabetic retinopathy and / or diabetic macular edema in a subject in need thereof comprising administering to an eye of the subject (preferably by intravitreal injection), one or more doses of aflibercept at an interval and quantity whereby the clearance of free aflibercept from the ocular compartment is about 0.367-0.457 mL / day after an intravitreal injection of aflibercept, the time for the amount for free aflibercept to reach the lower limit of quantitation (LLOQ) in the ocular compartment of a subject after said intravitreal injection of aflibercept is about 15 weeks; and the time for free aflibercept to reach the lower limit of quantitation (LLOQ) in the plasma of the subject after said intravitreal injection of aflibercept is about 3.5 weeks.

[0045] The present invention provides aflibercept for use in a method for slowing the clearance of free aflibercept from the ocular compartment after an intravitreal injection relative to the rate of clearance of aflibercept from the ocular compartment after an intravitreal injection of< 4 mg aflibercept wherein the method comprises intravitreally injecting into an eye of a subject in need thereof, a single initial dose of about 8 mg (±0.8 mg) or more of aflibercept, followed by one or more secondary doses of about 8 mg (±0.8 mg) or more of the aflibercept, followed by one or more tertiary doses of about 8 mg (±0.8 mg) or more of the aflibercept; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 24 weeks after the immediately preceding dose.

[0046] The present invention provides aflibercept for use a method for increasing the time for the amount of free aflibercept to reach the lower limit of quantitation (LLOQ) in the ocular compartment of a subject after an intravitreal injection of aflibercept relative to the time to reach LLOQ of the amount of free aflibercept in the ocular compartment of a subject after an intravitreal injection of about 2 mg aflibercept, wherein the method comprises intravitreally injecting into an eye of a subject in need thereof, a single initial dose of about 8 mg (±0.8 mg) or more of aflibercept, followed by one or more secondary doses of about 8 mg (±0.8 mg) or more of the aflibercept, followed by one or more tertiary doses of about 8 mg (±0.8 mg) or more of the aflibercept; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 24 weeks after the immediately preceding dose.

[0047] The present invention provides aflibercept for use in a method for increasing the time for free aflibercept to reach the lower limit of quantitation (LLOQ) in the plasma of a subject after an intravitreal injection of aflibercept relative to the time to reach LLOQ of free aflibercept in the plasma of a subject after an intravitreal injection of about 2 mg aflibercept, wherein the method comprises intravitreally injecting into an eye of a subject in need thereof, a single initial dose of about 8 mg (±0.8 mg) or more of aflibercept, followed by one or more secondary doses of about 8 mg (±0.8 mg) or more of the aflibercept, followed by one or more tertiary doses of about 8 mg (±0.8 mg) or more of the aflibercept; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 24 weeks after the immediately preceding dose.

[0048] The present invention provides a VEGF receptor fusion protein for use in a method - for treating or preventing an angiogenic eye disorder, nAMD, diabetic retinopathy (DR) and / or diabetic macular edema (DME), in a subject in need thereof,- for improving best corrected visual acuity in a subject in need thereof with an angiogenic eye disorder, nAMD, DR and / or DME; or - for promoting retinal drying in a subject with DR and / or DME in need thereof; wherein the method comprises administering to an eye of the subject, one or more doses of about 8 mg (±0.8 mg) or more of VEGF receptor fusion protein once every 24 weeks.

[0049] The present invention provides aflibercept for use in the treatment or prevention of an angiogenic eye disorder, neovascular age related macular degeneration, diabetic retinopathy and / or diabetic macular edema, in a subject in need thereof, wherein the treatment or prevention comprises initiating the treatment with 1 injection of 8 mg (±0.8 mg) aflibercept per month (every 4 weeks) for three consecutive doses followed by one or more injection once every 24 weeks, wherein the concentration of aflibercept of each said dose is 114.3 mg / mL or wherein the application volume of each said dose is 70 µL. In an embodiment of the invention the treatment interval between two subsequent administrations of 8 mg (±0.8 mg) aflibercept is adjusted (increased / maintained / reduced) based on visual and / or anatomic outcomes such as but not limited to letter gain or letter loss in BCVA; increase or reduction in CRT; presence or absence of subretinal fluid; or presence or absence of hemorraghe or persistent or worsening DME. In an embodiment of the invention the treatment interval is reduced by 2-4 weeks, 2 weeks, 3 weeks or by 4 weeks compared to the previous treatment interval in case said subject has been identified as one with meeting at least one of the following criteria for reduction of the treatment interval: > 5 letter or > 10 letter loss in BCVA; CRT of >300 or 320 µm; > 50 µm increase in CRT; or 2. persistent or worsening DME. In an embodiment of the invention the treatment interval is extended by 2-4 weeks, 2 weeks, 3 weeks or by 4 weeks compared to the previous treatment interval in case said subject has been identified as one with meeting at least one of the following criteria for extending the treatment interval: < 5 letter < 10 letter loss in BCVA; CRT <300 or 320 µm; > 50 µm decrease in CRT; absence of subretinal fluid; or absence of hemorraghe.

[0050] The present invention provides a VEGF receptor fusion protein for use in the treatment or prevention of an angiogenic eye disorder or diabetic macular edema, in a subject in need thereof wherein the method comprises administering 8 mg (±0.8 mg) VEGF receptor fusion protein (e.g., in a volume of 0.07 mL or 70 microliters) administered by intravitreal injection every 4 weeks (approximately every 28 days + / - 7 days, monthly) for the first three doses, followed by 8 mg (±0.8 mg) VEGF receptor fusion protein (e.g., in a volume of 0.07 mL) via intravitreal injection once every 24 weeks (+ / - 7 days).

[0051] 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 , wherein the method comprises administering 8 mg (±0.8 mg) VEGF receptor fusion protein (e.g., in a volume of 0.07 mL or 70 microliters) administered by intravitreal injection every 4 weeks (approximately every 28 days + / - 7 days, monthly) for the first three doses, followed by 8 mg (±0.8 mg) VEGF receptor fusion protein (e.g., in a volume of 0.07 mL) via intravitreal injection once every 24 weeks (+ / - 7 days).

[0052] The present invention provides a VEGF receptor fusion protein for use in the treatment or prevention of neovascular age related macular degeneration, in a subject in need thereof , wherein the method comprises administering 8 mg (±0.8 mg) VEGF receptor fusion protein (e.g., in a volume of 0.07 mL or 70 microliters) administered by intravitreal injection every 4 weeks (approximately every 28 days + / - 7 days, monthly) for the first three doses, followed by 8 mg (±0.8 mg) VEGF receptor fusion protein (e.g., in a volume of 0.07 mL) via intravitreal injection once every 24 weeks (+ / - 7 days).

[0053] The present invention provides aflibercept for use in the treatment or prevention of an angiogenic eye disorder, neovascular age related macular degeneration, diabetic macular edema or diabetic retinopathy, in a subject in need thereof, comprising administering to an eye of the subject (preferably by intravitreal injection), a single initial dose ≥8 mg (±0.8 mg) aflibercept, followed by one or more tertiary doses of about ≥8 mg (±0.8 mg) of aflibercept; wherein each tertiary dose is administered about 24 weeks after the immediately preceding dose. In an embodiment of the invention, the subject is not a treatment naïve subject, or the subject was pre-treated with a VEGF antagonist or preferably the subject was pre-treated with ≥8 mg (±0.8 mg) aflibercept or with 2 mg aflibercept.

[0054] The present invention provides aflibercept for use in the treatment or prevention of an angiogenic eye disorder, neovascular age related macular degeneration, diabetic macular edema or diabetic retinopathy, in a subject which was pre-treated with 2 mg aflibercept, comprising administering to an eye of the subject (preferably by intravitreal injection), a single initial dose of about ≥8 mg (±0.8 mg) aflibercept, followed by one or more secondary doses of about ≥8 mg (±0.8 mg) of aflibercept, followed by one or more tertiary doses of about ≥8 mg (±0.8 mg) aflibercept, wherein each secondary dose is administered about 4 weeks after the immediately preceding dose and wherein each tertiary dose is administered about 24 weeks after the immediately preceding dose. In an embodiment of the invention, the administration of one or more doses of ≥8 mg (±0.8 mg) aflibercept to an eye of the subject is according to HDq24 or treat and extent dosing regimen.

[0055] The present invention provides a VEGF receptor fusion protein for use in the treatment or prevetion of an angiogenic eye disorder, nAMD, diabetic retinopathy and / or diabetic macular edema, in a subject in need thereof who has been on a dosing regimen for treating or preventing said disorder wherein: (a) the subject has received an initial ≥8 mg (±0.8 mg) dose of VEGF receptor fusion protein then the method comprises, after 1 month, administering to the subject the first ≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein and 1 month thereafter, administering the 2nd≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein; and then, every 24 weeks thereafter, administering one or more 8 mg maintenance doses of VEGF receptor fusion protein according to the HDq24 dosing regimen; or (b) the subject has received an initial 8 mg dose of VEGF receptor fusion protein & 1st≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein after 1 month, then the method comprises, after another 1 month, administering to the subject the 2nd≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein; and then, every 24 weeks thereafter, one or more ≥8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein according to the HDq24 dosing regimen; or (c) the subject has received an initial 8 mg dose of VEGF receptor fusion protein & 1st 8 mg secondary dose of VEGF receptor fusion protein after 1 month & the 2nd≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein after another month, then the method comprises, after 24 weeks administering to the subject the 1st≥8 mg (±0.8 mg) maintenance dose of VEGF receptor fusion protein and all further ≥8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein every 24 weeks according to the HDq24 dosing regimen; or (d) the subject has received an initial ≥8 mg dose of VEGF receptor fusion protein & a 1st≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein after 1 month & the 2nd≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein after another month, then every 24 weeks thereafter, the subject has received one or more ≥8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein; and, then the method comprises, after 24 weeks from the last maintenance dose of VEGF receptor fusion protein, administering to the subject one or more ≥8 mg maintenance doses of VEGF receptor fusion protein and all further ≥8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein every 24 weeks according to the HDq24 dosing regimen;wherein, said HDq24 dosing regimen comprises: a single initial dose (preferably by intravitreal injection) of about ≥8 mg (±0.8 mg) or more of VEGF receptor fusion protein, followed by one or more secondary doses (preferably by intravitreal injection) of about ≥8 mg (±0.8 mg) or more of the VEGF receptor fusion protein, followed by one or more tertiary doses (preferably by intravitreal injection) of about ≥8 mg (±0.8 mg) or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 24 weeks after the immediately preceding dose.

[0056] The present invention provides a VEGF receptor fusion protein for use in the treatment or prevention of an angiogenic eye disorder, in a subject in need thereof who has been on a dosing regimen for treating or preventing the disorder calling for a single initial dose of about 2 mg of VEGF receptor fusion protein, followed by one or more secondary doses of about 2 mg of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 2 mg of the VEGF receptor fusion protein; wherein each secondary dose is administered about 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 8 weeks after the immediately preceding dose; and wherein the subject is at any phase of the 2 mg VEGF receptor fusion protein dosing regimen,comprising administering to an eye of the subject (preferably by intravitreal injection), an ≥8 mg(±0.8 mg) dose of VEGF receptor fusion protein, evaluating the subject in about 4 or 8 or 10 or 12 weeks after said administering and, if, in the judgment of the treating physician dosing every 24 weeks is appropriate, then continuing to dose the subject every 24 weeks with ≥8 mg (±0.8 mg) VEGF receptor fusion protein.

[0057] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of an angiogenic eye disorder, nAMD, diabetic retinopathy or diabetic macular edema, in a subject in need thereof, wherein the treatment or prevention comprises administering to an eye of the subject, a single initial dose of about ≥8 mg (±0.8 mg) or more of a VEGF receptor fusion protein, followed by one or more secondary doses, preferably 2 doses, of about ≥8 mg(±0.8 mg) or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about ≥8 mg (±0.8 mg) or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12, 16 or 20 weeks after the immediatelypreceding dose; further comprising, after receiving one or more of said tertiary doses about 12, 16 or 20 after the immediately preceding dose, lengthening the tertiary dose interval from • 12 weeks to 24 weeks; • 26 weeks to 24 weeks; or • 20 weeks to 24 weeks, after the immediately preceding dose.

[0058] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of an angiogenic eye disorder, diabetic retinopathy and / or diabetic macular edema, in a subject in need thereof, comprising administering to an eye of the subject (preferably by intravitreal injection), a single initial dose of about 8 mg(±0.8 mg) or more of a VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg(±0.8 mg) or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg(±0.8 mg) or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 24 weeks after the immediately preceding dose; further comprising, after receiving one or more of said tertiary doses about 24 weeks after the immediately preceding dose, shortening the tertiary dose interval from • 24 weeks to 8 weeks; • 24 weeks to 12 weeks; • 24 weeks to 16 weeks, or • 24 weeks to 20 weeks.

[0059] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of an angiogenic eye disorder, nAMD, diabetic retinopathy and / or diabetic macular edema, in a subject in need thereof, comprising administering to an eye of the subject (preferably by intravitreal injection), 3 doses of about 8 mg(±0.8 mg) VEGF receptor fusion protein in a formulation that comprises about 114.3 mg / ml VEGF receptor fusion protein at an interval of once every 4 weeks; wherein after said 3 doses, administering one or more doses of the VEGF receptor fusion protein at an interval which is lengthened up to 24 weeks.

[0060] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of an angiogenic eye disorder, neovascular age related macular degeneration, diabetic retinopathy and / or diabetic macular edema, in a subject in need thereof, comprising administering to an eye of the subject (preferably by intravitreal injection), a single initial dose of about 8 mg (±0.8 mg) or more of VEGF receptor fusion protein, followed by 2 secondary doses of about 8 mg (±0.8 mg) or more of the VEGF receptor fusion protein,followed by one or more tertiary doses of about 8 mg (±0.8 mg) or more of VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose and wherein each tertiary dose is administered about 24 weeks after the immediately preceding dose; and, after said doses, a) determining if the subject meets at least one criterion for reducing or lengthening one or more intervals by 2 weeks, 3 weeks, 4 weeks or 2-4 weeks between doses of the VEGF receptor fusion protein; and b) if said determination is made, administering further doses of the VEGF receptor fusion protein at said reduced or lengthened intervals between doses wherein criteria for lengthening the interval include: 1. <5 letter loss in BCVA; and / or 2. CRT <300 or 320 micrometers; and, wherein criteria for reducing the interval include: 1. >10 letter loss in BCVA; 2. persistent or worsening DME; and / or 3. >50 micrometers increase in CRT.

[0061] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of an angiogenic eye disorder, nAMD, diabetic retinopathy and / or diabetic macular edema, in a subject in need thereof that has been pre-treated with one or more 2 mg doses of VEGF receptor fusion protein, comprising administering to an eye of the subject (preferably by intravitreal injection), a single initial dose of about 8 mg (±0.8 mg) or more of a VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg (±0.8 mg) or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 24 weeks after the immediately preceding dose.

[0062] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of an angiogenic eye disorder, in a subject in need thereof, comprising administering to an eye of the subject (preferably by intravitreal injection), one or more doses of 8 mg (±0.8 mg) or more of VEGF receptor fusion protein about every 24 weeks.

[0063] A VEGF receptor fusion protein for use in the treatment and prevention of an angiogenic eye disorder wherein the treatment or prevention comprises, prior to each administration, providing• one single-dose glass vial having a protective plastic cap and a stopper containing an aqueous formulation comprising 8 mg (±0.8 mg) or more VEGF receptor fusion protein in about 70 microliters; • one 18-gauge x 1½-inch, 5-micron, filter needle that includes a tip and a bevel; packaged together; then (1) visually inspecting the aqueous formulation in the vial and, if particulates, cloudiness, or discoloration are visible, then using another vial of aqueous formulation containing the VEGF receptor fusion protein; (2) removing the protective plastic cap from the vial; and (3) cleaning the top of the vial with an alcohol wipe; then using aseptic technique: (4) removing the 18-gauge x 1½-inch, 5-micron, filter needle and the 1 mL syringe from their packaging; (5) attaching the filter needle to the syringe by twisting it onto the Luer lock syringe tip; (6) pushing the filter needle into the center of the vial stopper until the needle is completely inserted into the vial and the tip touches the bottom or a bottom edge of the vial; (7) withdrawing all of the VEGF receptor fusion protein vial contents into the syringe, keeping the vial in an upright position, slightly inclined, while ensuring the bevel of the filter needle is submerged into the liquid; (8) continuing to tilt the vial during withdrawal keeping the bevel of the filter needle submerged in the formulation; (9) drawing the plunger rod sufficiently back when emptying the vial in order to completely empty the filter needle; (10) removing the filter needle from the syringe and disposing of the filter needle; (11) removing the 30-gauge x ½-inch injection needle from its packaging and attaching the injection needle to the syringe by firmly twisting the injection needle onto the Luer lock syringe tip; (12) holding the syringe with the needle pointing up, and checking the syringe for bubbles, wherein if there are bubbles, gently tapping the syringe with a finger until the bubbles rise to the top; and (13) slowly depressing the plunger so that the plunger tip aligns with the graduation line that marks 70 microliters on the syringe.

[0064] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of an angiogenic eye disorder, neovascular age related macular degeneration,diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, wherein the subject has been receiving a dosing regimen for treating or preventing diabetic retinopathy and / or diabetic macular edema calling for: a single initial dose of about 2 mg of VEGF receptor fusion protein, followed by 4 secondary doses of about 2 mg of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 2 mg of the VEGF receptor fusion protein; wherein each secondary dose is administered about 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 8 weeks after the immediately preceding dose;wherein the subject is at any phase (initial dose, secondary dose or tertiary dose) of the 2 mg VEGF receptor fusion protein dosing regimen.

[0065] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of an angiogenic eye disorder, nAMD, diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, wherein 8 mg (±0.8 mg) or more of a VEGF receptor fusion protein is in an aqueous pharmaceutical formulation comprising about 103-126 mg / ml VEGF receptor fusion protein, histidine-based buffer and arginine.

[0066] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of an angiogenic eye disorder, nAMD, diabetic retinopathy and / or diabetic macular edema in a subject in need thereof wherein ≥8 mg (±0.8 mg) of a VEGF receptor fusion protein is an aqueous pharmaceutical formulation comprising about 114.3 mg / ml VEGF receptor fusion protein, histidine-based buffer and arginine.

[0067] The present invention provides aflibercept for use in the treatment and prevention of an angiogenic eye disorder, nAMD, diabetic retinopathy and / or diabetic macular edema in a subject in need thereof wherein the >8 mg (±0.8 mg) aflibercept is in an aqueous pharmaceutical formulation wherein the aflibercept has less than about 3.5% high molecular weight species immediately after manufacture and purification and / or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C.

[0068] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of an angiogenic eye disorder, nAMD, diabetic retinopathy and / or diabetic macular edema in a subject in need thereof wherein the >8 mg (±0.8 mg) VEGF receptor fusion protein is in an aqueous pharmaceutical formulation comprising: at least about 100 mg / ml of a VEGF receptor fusion protein; about 10-100 mM L-arginine; sucrose; a histidine-based buffer; and a surfactant;wherein the formulation has a pH of about 5.0 to about 6.8; wherein the VEGF receptor fusion protein has less than about 3.5% high molecular weight species immediately after manufacture and purification and / or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C.

[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 wherein >8 mg (±0.8 mg) of VEGF receptor fusion protein is in an aqueous pharmaceutical formulation comprising • ≥100 mg / ml VEGF receptor fusion protein, histidine-based buffer and L-arginine; • 140 mg / ml aflibercept; 20 mM histidine-based buffer; 5 % sucrose; 0.03 % polysorbate 20; 10 mM L-arginine; pH 5.8; • 150 ± 15 mg / ml aflibercept, 10 mM phosphate-based buffer, 8 ± 0.8% (w / v) sucrose, 0.02-0.04% (w / v) polysorbate 20 and 50 mM L-arginine, pH 5.9-6.5; • 103-126 mg / ml aflibercept, 10 ± 1 mM histidine-based buffer, 5 ± 0.5% (w / v) sucrose, 0.02-0.04% (w / v) polysorbate 20, and 50 ± 5 mM L-arginine, pH 5.5-6.1; • 140 mg / ml aflibercept, 10 mM histidine-based 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-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20 and 50 mM L-arginine, pH 5.8; • ≥100 mg / ml aflibercept, histidine-based buffer and L-arginine; • ≥100 mg / ml aflibercept at about pH 5.8, wherein the formulation forms <3% HMW aggregates after incubation at 5°C for 2 months; • About 114.3 mg / mL aflibercept; 10 mM – 50 mM histidine-based buffer, sugar, non- ionic surfactant, L-Arginine, pH 5.8; • About 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; or • about 114.3 mg / mL aflibercept; arginine monohydrochloride; histidine; histidine hydrochloride, monohydrate; polysorbate 20; sucrose and water for injection.

[0070] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of an angiogenic eye disorder, nAMD, diabetic retinopathy and / or diabetic macular edema in a subject in need thereof wherein the subject achieves and / or maintains one or more of, • an improvement in Diabetic Retinopathy Severity Scale (DRSS), e.g., by at least 2 or 3 steps;• an improvement in best corrected visual acuity; • a dry retina; • a gain in best corrected visual acuity; • a gain in best corrected visual acuity of at least 5, 10 or 15 letters • a BCVA of at least 69 letters; • a decrease in central retinal thickness (CRT); • no vascular leakage as measured by fluorescein angiography (FA); • an improvement from pre-treatment baseline in National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) total score; • a retina without fluid (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF]) at the foveal center and in center subfield; • maintenance of a fluid-free retina (total fluid, IRF and / or SRF at foveal center and in the center subfield); • a lack of macular edema; • a retina free of fluid on spectral domain optical coherence tomography (SD-OCT); and / or • Does not deviate from the HDq12 or HDq16 treatment regimen once started.

[0071] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of an angiogenic eye disorder, nAMD, diabetic retinopathy and / or diabetic macular edema in a subject in need thereof, wherein the subject achieves and / or maintains one or more of: • Non-inferior BVCA compared to that of aflibercept which is intravitreally dosed 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; • Increase in BCVA (according to ETDRS letter score) of about 7, 8 or 9 letters by week 60 from start of treatment, wherein the baseline BCVA is about 61, 62 or 63; • BCVA (according to ETDRS letter score) of at least about 69 letters by week 48 or 60 from start of treatment; • Does not lose 5, 10, 15 or 69 letters or more BCVA after week 12, 24, 36, 49, 60, 72, 84 or 90 from start of treatment; • Improvement in BCVA (according to ETDRS letter score) by week 12, 24, 36, 49, 60, 72, 84 or 90 from start of treatment; • Improvement in BVCA by week 4, week 8, week 12, week 16, week 20, week 24, week 28, week 32, week 36, week 40, week 44, or week 48 from start of treatment;• Between weeks 48 and 60, a BCVA score (according to ETDRS letter score) of about 69, 70, 71, 72 or 73; • Between weeks 36 and 48, a change in BCVA score (according to ETDRS letter score) from initiation of treatment of about 7, 8 or 9 wherein the BCVA at any point between week 36 to 48 is about 60 or 70; • Between weeks 48 and 60, a change in BCVA score (according to ETDRS letter score) from initiation of treatment of about 7, 8 or 9, wherein the BCVA at any point between week 48 to 60 is about 69, 70, 71, 72 or 73; • Increase in BCVA as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart or Snellen equivalent by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 or 48 weeks from start of treatment by ≥4 letters, ≥5 letters, ≥6 letters, ≥7 letters, ≥8 letters, > 9 letters or > 10 letters; • Does not lose 5, 10 or 15 letters by week 48 or 60 from start of treatment (according to ETDRS letter score); • Gains at least 5, 10 or 15 letter by week 48 or 60 from start of treatment (according to ETDRS letter score); • Improvement in BCVA, by 4 weeks after initiation of treatment, of about 4 or 5 letters (ETDRS or Snellen equivalent) when on HDq12 regimen; or of about 4 or 5 letters (ETDRS or Snellen equivalent) when on HDq16 regimen; • Improvement in BCVA, by 8 weeks after initiation of treatment, of about 6 letters (ETDRS or Snellen equivalent) when on HDq12 regimen; or of about 5 or 6 letters (ETDRS or Snellen equivalent) when on HDq16 regimen; • Improvement in BCVA, by 12 weeks after initiation of treatment, of about 6 or 7 letters (ETDRS or Snellen equivalent) when on HDq12 regimen; or of about 6 letters (ETDRS or Snellen equivalent) when on HDq16 regimen; • Improvement in BCVA, by 16 weeks after initiation of treatment, of about 6 or 7 letters (ETDRS or Snellen equivalent) when on HDq12 regimen; or of 7 letters (ETDRS or Snellen equivalent) when on HDq16 regimen; • Improvement in BCVA, by 20 weeks after initiation of treatment, of about 6 letters (ETDRS or Snellen equivalent) when on HDq12 regimen; or of about 6 letters (ETDRS or Snellen equivalent) when on HDq16 regimen; • Improvement in BCVA, by 24 weeks after initiation of treatment, of about 7 letters (ETDRS or Snellen equivalent) when on HDq12 regimen; or of about 5 or 6 letters (ETDRS or Snellen equivalent) when on HDq16 regimen;• Improvement in BCVA, by 28 weeks after initiation of treatment, of about 7 or 8 letters (ETDRS or Snellen equivalent) when on HDq12 regimen; or of about 7 or 8 letters (ETDRS or Snellen equivalent) when on HDq16 regimen; • Improvement in BCVA, by 32 weeks after initiation of treatment, of about 7 letters (ETDRS or Snellen equivalent) when on HDq12 regimen; or of about 7 or 8 letters (ETDRS or Snellen equivalent) when on HDq16 regimen; • Improvement in BCVA, by 36 weeks after initiation of treatment, of 8 letters (ETDRS or Snellen equivalent) when on HDq12 regimen; or of about 6 or 7 letters (ETDRS or Snellen equivalent) when on HDq16 regimen; • Improvement in BCVA, by 40 weeks after initiation of treatment, of about 8 letters (ETDRS or Snellen equivalent) when on HDq12 regimen; or of about 6 or 7 letters (ETDRS or Snellen equivalent) when on HDq16 regimen; • Improvement in BCVA, by 44 weeks after initiation of treatment, of about 8 letters (ETDRS or Snellen equivalent) when on HDq12 regimen; or of about 7 or 8 letters (ETDRS or Snellen equivalent) when on HDq16 regimen; • Improvement in BCVA, by 48 weeks after initiation of treatment, of about 8 or 9 letters (ETDRS or Snellen equivalent) when on HDq12 regimen; or of about 7 or 8 letters (ETDRS or Snellen equivalent) when on HDq16 regimen; • An improvement in BCVA by about week 8 after initiation of treatment which is maintained thereafter during the treatment regimen to at least week 48; • A BCVA by 4 weeks after initiation of treatment of about 68 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 66 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; • A BCVA by 8 weeks after initiation of treatment of about 70 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 67 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; • A BCVA by 12 weeks after initiation of treatment of about 70 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 68 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; • A BCVA by 16 weeks after initiation of treatment of about 71 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 69 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen;• A BCVA by 20 weeks after initiation of treatment of about 70 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 68 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; • A BCVA by 24 weeks after initiation of treatment of about 71 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 67 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; • A BCVA by 28 weeks after initiation of treatment of about 72 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 70 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; • A BCVA by 32 weeks after initiation of treatment of about 71 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 70 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; • A BCVA by 36 weeks after initiation of treatment of about 71 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 68 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; • A BCVA by 40 weeks after initiation of treatment of about 72 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 69 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; • A BCVA by 44 weeks after initiation of treatment of about 72 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 70 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; • A BCVA by 48 weeks after initiation of treatment of about 73 letters (ETDRS or Snellen equivalent) when on the HDq12 regimen; or a BCVA of about 70 letters (ETDRS or Snellen equivalent) when on the HDq16 regimen; A BCVA improvement, by week 48 following treatment initiation, of about 9 or 10 letters (ETDRS or Snellen equivalent) when baseline BCVA is about <73 ETDRS letters when on HDq12 regimen; • A BCVA improvement, by week 48 following treatment initiation, of about 5 or 6 letters (ETDRS or Snellen equivalent) when baseline BCVA is about >73 ETDRS letters when on HDq12 regimen; • A BCVA improvement, by week 48 following treatment initiation, of about 8 or 9 letters (ETDRS or Snellen equivalent) when baseline BCVA is about <73 ETDRS letters when on HDq16 regimen;• A BCVA improvement, by week 48 following treatment initiation, of about 4 or 5 letters (ETDRS or Snellen equivalent) when baseline BCVA is about >73 ETDRS letters when on HDq16 regimen; • A BCVA improvement, by week 48 following treatment initiation, of about 7 or 8 letters (ETDRS or Snellen equivalent) when baseline CRT is about < about 400 micrometers when on HDq12 regimen; • A BCVA improvement, by week 48 following treatment initiation, of about 9 or 10 letters (ETDRS or Snellen equivalent) when baseline CRT is about >400 micrometers when on HDq12 regimen; • A BCVA improvement, by week 48 following treatment initiation, of about 5 or 6 letters (ETDRS or Snellen equivalent) when baseline CRT is about < about 400 micrometers when on HDq16 regimen; • A BCVA improvement, by week 48 following treatment initiation, of about 9 or 10 letters (ETDRS or Snellen equivalent) when baseline CRT is about > about 400 micrometers when on HDq16 regimen; • Gain of >5, >10 or ≥15 letters BCVA (according to ETDRS letter score) by week 12, 24, 36, 49, 60, 72, 84 or 90 from start of treatment; • ≥ 2 or >3 step improvement in Diabetic Retinopathy Severity Scale (DRSS), by week 12, 24, 36, 49, 60, 72, 84 or 90 from start of treatment; • ≥ 2 step improvement in diabetic retinopathy severity scale (DRSS) by week 4, week 8, week 12, 16, 20, 24, 28, 32, 36, 40, 44 or 48 weeks from start of treatment; • Retina without fluid (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF]) at the foveal center and in center subfield by week 12, 24, 36, 49, 60, 72, 84 or 90 from start of treatment as measured by optical coherence tomography (OCT); • No vascular leakage as measured by fluorescein angiography (FA) by week 12, 24, 36, 49, 60, 72, 84 or 90 from start of treatment; • Maintenance of a fluid-free retina (total fluid, IRF and / or SRF at foveal center and in the center subfield) by week 12, 24, 36, 49, 60, 72, 84 or 90 from start of treatment; • Reduction in total area of fluorescein leakage within ETDRS grid (mm2) at week 48 or 60 by about 12, 13 or 14 mm2 or more as measured by fluorescein angiography; • Retina free of fluid on spectral domain optical coherence tomography (SD-OCT) by week 12, 24, 36, 49, 60, 72, 84 or 90 from start of treatment;• Retina without fluid (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF]) at the foveal center by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 or 48 weeks from start of treatment; • Dry retina by week 12, 24, 36, 49, 60, 72, 84 or 90 from start of treatment; • Foveal center without fluid by week 12, 24, 36, 49, 60, 72, 84 or 90 from start of treatment as measured by optical coherence tomography (OCT); • A change in central retinal thickness, by 4 weeks after initiation of treatment of about - 118 or -118.3 micrometers when on the HDq12 regimen; or of about -124 or -125 or - 124.9 or -125.5 micrometers when on the HDq16 regimen; • A change in central retinal thickness, by 8 weeks after initiation of treatment of about - 137 or -137.4 micrometers when on the HDq12 regimen; or of about -139 or -140 or - 139.6 or -140.3 micrometers when on the HDq16 regimen; • A change in central retinal thickness, by 12 weeks after initiation of treatment of about -150 or -150.1 micrometers when on the HDq12 regimen; or of about -152 or -153 or - 152.7 or -153.4 micrometers when on the HDq16 regimen; • A change in central retinal thickness, by 16 weeks after initiation of treatment of about -139 or -139.4 micrometers when on the HDq12 regimen; or of about -145 or -146 or - 145.5 or -146.4 micrometers when on the HDq16 regimen; • A change in central retinal thickness, by 20 weeks after initiation of treatment of about -117 or -117.1 micrometers when on the HDq12 regimen; or of about -112 or -113 or - 112.5 or -113.3 micrometers when on the HDq16 regimen; • A change in central retinal thickness, by 24 weeks after initiation of treatment of about -158 or -158.1 micrometers when on the HDq12 regimen; or of about -103 or -104 or - 103.8 or -104.3 micrometers when on the HDq16 regimen; • A change in central retinal thickness, by 28 weeks after initiation of treatment of about -146 or -147 or -146.7 micrometers when on the HDq12 regimen; or of about -162 or - 162.3 micrometers when on the HDq16 regimen; • A change in central retinal thickness, by 32 weeks after initiation of treatment of about -132 micrometers when on the HDq12 regimen; or of about -145 or -146 or -145.8 micrometers when on the HDq16 regimen; • A change in central retinal thickness, by 36 weeks after initiation of treatment of about -168 or -168.1 micrometers when on the HDq12 regimen; or of about -124 or -125 or - 124.7 or -125.2 micrometers when on the HDq16 regimen;• A change in central retinal thickness, by 40 weeks after initiation of treatment of about -163 micrometers when on the HDq12 regimen; or of about -122 or -123 or -122.5 or - 123.1 micrometers when on the HDq16 regimen; • A change in central retinal thickness, by 44 weeks after initiation of treatment of about -147 or -148 or -147.4 micrometers when on the HDq12 regimen; or of about -164 or - 164.1 or -164.3 micrometers when on the HDq16 regimen; • A change in central retinal thickness, by 48 weeks after initiation of treatment of about -171 or -172 or -171.7 micrometers when on the HDq12 regimen; or of about -148 or - 149 or -148.3 or -149.4 micrometers when on the HDq16 regimen; • A change in central retinal thickness, by 60 weeks after initiation of treatment of about -181.95 or -176.24 micrometers when on the HDq12 regimen; or of about -166.26 or - 167.18 micrometers when on the HDq16 regimen; • A change in central retinal thickness of about -118 or -119 or -118.3 micrometers, between initiation of treatment (week 0) and week 4 when on the HDq12 regimen; • A change in central retinal thickness of about -19, -20 or -19.1 micrometers, between weeks 4 and 8 when on the HDq12 regimen; • A change in central retinal thickness of about -12, -13 or -12.7 micrometers, between weeks 8 and 12 when on the HDq12 regimen; • A change in central retinal thickness of about -40, or -41 micrometers, between weeks 20 and 24 when on the HDq12 regimen; • A change in central retinal thickness of about -36, -37 or -36.1 micrometers, between weeks 32 and 36 when on the HDq12 regimen; • A change in central retinal thickness of about -24, -25 or -24.3 micrometers, between weeks 44 and 48 when on the HDq12 regimen; • A change in central retinal thickness of -4, -5 or -4.5 micrometers, between weeks 48 and 60 when on the HDq12 regimen; • A change in central retinal thickness of about -124, -125 or -124.9 micrometers, between initiation of treatment (week 0) and week 4 when on the HDq16 regimen; • A change in central retinal thickness of about –14, -15 or -14.7 micrometers, between weeks 4 and 8 when on the HDq16 regimen; • A change in central retinal thickness of about -13, -14 or -13.1 micrometers, between weeks 8 and 12 when on the HDq16 regimen; • A change in central retinal thickness of about -58, -59 or -58.5 micrometers, between weeks 24 and 28 when on the HDq16 regimen;• A change in central retinal thickness of about -41, -42 or -41.6 micrometers, between weeks 40 and 44 when on the HDq16 regimen; • A reduction in central retinal thickness by week 4, 5, 6, 7 or 8 after initiation of treatment which is maintained within about +17, +18 or +19 micrometers thereafter during the treatment regimen to at least week 48 from initiation of treatment; • Decrease in central retinal thickness by about 100, 125, 150, 175 or 200 micrometers by week 12, 24, 36, 49, 60, 72, 84 or 90 from start of treatment; • Reduction in central retinal thickness of about 148-182 micrometers by about week 48 or 60 from start of treatment as measured by optical coherence tomography (OCT)) wherein the baseline CRT is about 449, 450, 455 or 460 micrometers; • Decrease in central retinal thickness (CRT) by at least about 100, 125, 130, 135, 140, 145, 149, 150, 155, 160, 165, 170, 171, 172, 173, 174 or 175 micrometers by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 or 48 from start of treatment; • At about 0.1667 days after the first dose, free aflibercept in plasma of about 0.149 (+0.249) mg / l; wherein, at baseline, free aflibercept in was plasma not detectable wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; • At about 0.3333 days after the first dose, free aflibercept in plasma of about 0.205 (+0.250) mg / l; wherein, at baseline, free aflibercept in plasma not detectable wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; • At about 1 days after the first dose, free aflibercept in plasma of about 0.266 (+0.211) mg / l wherein, at baseline, free aflibercept in plasma not detectable wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; • At about 2 days after the first dose, free aflibercept in plasma of about 0.218 (+0.145) mg / l wherein, at baseline, free aflibercept in plasma not detectable wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; • At about 4 days after the first dose, free aflibercept in plasma of about 0.140 (+0.0741) mg / l wherein, at baseline, free aflibercept in plasma not detectable wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; • At about 7 days after the first dose, free aflibercept in plasma of about 0.0767 (+0.0436) mg / l wherein, at baseline, free aflibercept in plasma not detectable, wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks;• At about 14 days after the first dose, free aflibercept in plasma of about 0.0309 (+0.0241) mg / l wherein at baseline free aflibercept in plasma not detectable wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; • At about 21 days after the first dose, free aflibercept in plasma of about 0.0171 (+0.0171) mg / l wherein, at baseline, free aflibercept in plasma not detectable wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; • At about 28 days after the first dose, free aflibercept in plasma of about 0.00730 (+0.0113) mg / l wherein, at baseline, free aflibercept in plasma not detectable wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; • At about 0.1667 days after the first dose, adjusted bound aflibercept in plasma of about 0.00698 (+0.0276) mg / l wherein, at baseline, there is about 0.00583 mg / l (+0.0280) adjusted bound aflibercept wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; • At about 0.3333 days after the first dose, adjusted bound aflibercept in plasma of about 0.00731 (+0.0279) mg / l wherein, at baseline, there is about 0.00583 mg / l (+0.0280) adjusted bound aflibercept wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; • At about 1 days after the first dose, adjusted bound aflibercept in plasma of about 0.0678 (+0.0486) mg / l wherein, at baseline, there is about 0.00583 mg / l (+0.0280) adjusted bound aflibercept wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; • At about 2 days after the first dose, adjusted bound aflibercept in plasma of about 0.138 (+0.0618) mg / l wherein at baseline there is about 0.00583 mg / l (+0.0280) adjusted bound aflibercept wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; • At about 4 days after the first dose, adjusted bound aflibercept in plasma of about 0.259 (+0.126) mg / l wherein at baseline there is about 0.00583 mg / l (+0.0280) adjusted bound aflibercept wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; • At about 7 days after the first dose, adjusted bound aflibercept in plasma of about 0.346 (+0.151) mg / l wherein at baseline there is about 0.00583 mg / l (+0.0280) adjusted bound aflibercept wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks;• At about 14 days after the first dose, adjusted bound aflibercept in plasma of about 0.374 (+0.110) mg / l wherein at baseline there is about 0.00583 mg / l (+0.0280) adjusted bound aflibercept wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; • At about 21 days after the first dose, adjusted bound aflibercept in plasma of about 0.343 (+0.128) mg / l wherein at baseline there is about 0.00583 mg / l (+0.0280) adjusted bound aflibercept wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; • At about 28 days after the first dose, adjusted bound aflibercept in plasma of about 0.269 (+0.149) mg / l wherein at baseline there is about 0.00583 mg / l (+0.0280) adjusted bound aflibercept wherein the subject has not received intravitreal aflibercept treatment for at least 12 weeks; • The maximum level of free aflibercept in the plasma is reached about 0.965 days after the first dose; • Reaches a maximum level of about 0.310 mg / l (+0.263) free aflibercept in the plasma; • Free aflibercept in the plasma of from about 0 to about 1.08 mg / L; • Free aflibercept in the plasma maximum (mg / l) per dose (mg) of aflibercept of about 0.388 (+0.0328) mg / l / mg; • The maximum level of adjusted bound aflibercept in the plasma is reached about 14 days after the first dose; • Reaches a maximum level of about 0.387 mg / l (+0.135) adjusted bound aflibercept in the plasma; • Adjusted bound aflibercept in the plasma of from about 0.137 to about 0.774 mg / L; • Adjusted bound aflibercept in the plasma maximum (mg / l) per dose (mg) of aflibercept of about 0.483 (+0.0168) mg / l / mg; • Does not have anti-drug antibodies against aflibercept after 48 or 60 weeks of treatment; • Improvement from pre-treatment baseline in National Eye Institute Visual Function Questionnaire (NEI-VFQ) total score; and / or • Lack of macular edema.

[0072] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of neovascular age related macular degeneration, diabetic retinopathy and / or diabetic macular edema in a subject in need thereof wherein the interval between doses of ≥8mg (±0.8 mg) VEGF receptor fusion protein is adjusted (increased / maintained / reduced) based on visual and / or anatomic outcomes.

[0073] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of neovascular age related macular degeneration, diabetic retinopathy and / or diabetic macular edema in a subject in need thereof wherein the doses of ≥8 mg (±0.8 mg) VEGF receptor fusion protein are administered according to pro re nata (PRN), capped PRN or treat and extend (T&E) dosing regimen.

[0074] The present invention also provides a kit comprising i) a container comprising a VEGF receptor fusion protein, preferably aflibercept and ii) instruction for use of the VEGF fusion protein. In an embodiment of the invention, the container is a vial or a pre-filled syringe. The vial a type I glass vial containing a nominal fill volume of abut 0.26 mL solution for intravitreal injection. In an embodiment of the invention the container comprises the VEGF receptor fusion protein at a concentration of more or equal to 100 mg / mL or the container comprises aflibercept at a concentration of about 114.3 mg / mL. In an embodiment of the invention, the instruction for use comprising instruction for use of the VEGF fusion protein or aflibercept for the treatment of DME and / or AMD. In an embodiment of the invention, the instruction for use comprises the information that i) the container comprises ≥8 mg (±0.8 mg) (114.3 mg / mL) aflibercept solution for intravitreal injection, ii) each single-dose vial provides a usable amount to deliver a single dose of 70 microliters containing ≥8 mg (±0.8 mg) aflibercept to adult patients, iii) the recommended dose is ≥8 mg (±0.8 mg) aflibercept (equivalent to 70 microliters solution for injection), iv) ≥8 mg (±0.8 mg) aflibercept treatment is initiated with 1 injection per month (every 4 weeks) for 3 consecutive doses, v) injection intervals may then be extended up to every 16 weeks or 20 weeks, vi) the treatment interval may be adjusted based on the physician’s judgement of visual and / or anatomic outcomes and / or vii) that ≥8 mg (±0.8 mg) aflibercept / 0.07 mL is provided as a sterile, aqueous solution containing arginine monohydrochloride; histidine; histidine hydrochloride, monohydrate; polysorbate 20; sucrose and water for injection. BRIEF DESCRIPTION OF THE FIGURES

[0075] Figure 1: Summary of PHOTON clinical trial.

[0076] Figure 2: Key eligibility criteria (inclusion criteria and exclusion criteria) of PHOTON clinical trial.

[0077] Figure 3: Dosing schedule and dose regimen modification (DRM) criteria of PHOTON clinical trial (to week 48).

[0078] Figure 4: Criteria for dose regimen modifications of PHOTON clinical trial.

[0079] Figure 5: Patient disposition at week 48 in PHOTON clinical trial.

[0080] Figure 6: Baseline demographics of subjects in PHOTON clinical trial.

[0081] Figure 7: Baseline characteristics of the study eye of subjects in PHOTON clinical trial.

[0082] Figure 8: Mean number of injections through week 48 in PHOTON clinical trial.

[0083] Figure 9: Mean change in Best Corrected Visual Acuity (BCVA) through week 48 in PHOTON clinical trial. Least squares mean change from baseline at week 48 shown.

[0084] Figure 10: Percentage of subjects maintaining Q12 week and Q16 week intervals through week 48 in PHOTON clinical trial.

[0085] Figure 11: Key secondary endpoint (EP) of percentage of subjects with ≥2 step improvement in Diabetic Retinopathy Severity Scale (DRSS) at week 48 in PHOTON clinical trial.

[0086] Figure 12: Percentage of subjects without retinal fluid at foveal center at week 48 in PHOTON clinical trial.

[0087] Figure 13: Mean change from baseline in central retinal thickness through week 48 in PHOTON clinical trial. Various matched intervals are highlighted in three insets.

[0088] Figures 14A, 14B and 14C: Ocular serious Treatment Emergent Adverse Events (TEAEs) through week 48 in PHOTON clinical trial (Fig.14A); Most Frequent Adverse Events (AEs) through week 48 (Fig.14B); Non-Ocular Safety through week 48 (Fig.14C).

[0089] Figure 15: Treatment emergent intraocular inflammation through week 48 in PHOTON clinical trial.

[0090] Figure 16: Mean change from baseline in intraocular pressure through week 48 in PHOTON clinical trial.

[0091] Figure 17: Percentage of subjects meeting intraocular pressure criteria in PHOTON clinical trial.

[0092] Figure 18: Non-Ocular Serious TEAEs ≥1% through week 48 in PHOTON clinical trial.

[0093] Figure 19: Treatment emergent Anti-Platelet Trialists’ Collaboration (APTC) events through week 48 in PHOTON clinical trial.

[0094] Figure 20: Treatment emergent hypertension events though week 48 in PHOTON clinical trial.

[0095] Figure 21: Potentially Clinically Significant Values (PCSVs) for blood pressure through week 48 in PHOTON clinical trial.

[0096] Figure 22: Mean change from baseline in systolic blood pressure through week 48 in PHOTON clinical trial. Baseline to week 9 SBP and mean baseline SBP shown in insets.

[0097] Figure 23: Mean change from baseline in diastolic blood pressure through week 48 in PHOTON clinical trial. Baseline to week 9 DBP and mean baseline DBP shown in insets.

[0098] Figure 24: Deaths through week 48 in PHOTON clinical trial.

[0099] Figure 25A and 25B: (A)Mean Change from Baseline in BCVA Score (ETDRS Letters) in Study Eye through Week 60, OC (Full Analysis Set); (B) Least Square Mean Change from Baseline in BCVA Score (ETDRS Letters) in Study Eye through Week 60 (Full Analysis Set). Abbreviations: 2q8: Aflibercept 2 mg administered every 8 weeks after 5 initial injections at 4-week intervals; HDq12: High dose aflibercept 8 mg administered every 12 weeks after 3 initial injections at 4-week intervals; HDq16: High dose aflibercept 8 mg administered every 16 weeks after 3 initial injections at 4-week intervals. BCVA=best-corrected visual activity; ETDRS=Early Treatment of Diabetic Retinopathy Study; HD=high dose; OC=observed cases, SE=standard error. OC: Observations after an ICE defined for the primary estimand were excluded. [000100] Figure 26A and 26B: (A) Mean Change from Baseline in Central Retinal Thickness (microns) by Visit through Week 60, OC (Full Analysis Set) (B) Least Square Mean Change from Baseline in Central Retinal Thickness (microns) by Visit through Week 60, OC (Full Analysis Set). Abbreviations: 2q8= Aflibercept 2 mg administered every 8 weeks after 5 initial injections at 4-week intervals; HDq12= High dose aflibercept 8 mg administered every 12 weeks after 3 initial injections at 4-week intervals; HDq16= High dose aflibercept 8 mg administered every 16 weeks after 3 initial injections at 4-week intervals. ICE=intercurrent events; OC=observed case; SE=standard error. OC= observations after an ICE defined for the primary estimand were excluded. [000101] Figure 27: Mean (+SD) Concentrations (mg / l) of Free Aflibercept in Plasma by Nominal Time and Treatment in Participants with DME with Unilateral Treatment in the Dense PK Sampling sub-study (Study VGFTe-HD-DME-1934, Log-Scaled, [DPKS]). N=Number of subjects; SD=Standard deviation; DME=Diabetic macular edema; 2q8=2 mg intravitreal aflibercept every 8 weeks following 5 initial monthly doses; HDq12=High-dose (8 mg) intravitreal aflibercept every 12 weeks following 3 initial monthly doses; HDq16=High-dose (8 mg) intravitreal aflibercept every 16 weeks following 3 initial monthly doses; LLOQ=Lower limit of quantitation; D=Day; H=Hour Note: Table under the figure presents the number of subjects contributing to the statistics for the corresponding visits / timepoints and treatments. Concentrations below the LLOQ were set to LLOQ / 2. HDq12+HDq16 = combined data from treatment groups HDq12 and HDq16. Patients in the dense PK sub-study only received aflibercept injections unilaterally.[000102] Figure 28: Mean (+SD) Concentrations (mg / l) of Adjusted Bound Aflibercept in Plasma by Nominal Time and Treatment in Participants with DME with Unilateral Treatment in the Dense PK Sampling sub-study (Study VGFTe‑HD-DME-1934, Log-Scaled, [DPKS]). N=Number of subjects; SD=Standard deviation; DME=Diabetic macular edema; 2q8=2 mg intravitreal aflibercept every 8 weeks following 5 initial monthly doses; HDq12=High-dose (8 mg) intravitreal aflibercept every 12 weeks following 3 initial monthly doses; HDq16=High-dose (8 mg) intravitreal aflibercept every 16 weeks following 3 initial monthly doses; LLOQ=Lower limit of quantitation; D=Day; H=Hour. Note: Table under the figure presents the number of subjects contributing to the statistics for the corresponding visits / timepoints and treatments. Concentrations below the LLOQ were set to LLOQ / 2. Adjusted bound aflibercept = 0.717*bound aflibercept. HDq12+HDq16 = combined data from treatment groups HDq12 and HDq16. Patients in the dense PK sub-study only received aflibercept injections unilaterally. [000103] Figure 29: Mean (+SD) Concentrations (mg / l) of Free Aflibercept in Plasma by Nominal Time and Treatment Group in Participants with DME in the Sparse PK Sampling Study (Study VGFTe-HD-DME-1934, Log-Scaled, [PKAS]). N=Number of subjects; SD=Standard deviation; DME=Diabetic macular edema; 2q8=2 mg intravitreal aflibercept every 8 weeks following 5 initial monthly doses; HDq12=High-dose (8 mg) intravitreal aflibercept every 12 weeks following 3 initial monthly doses; HDq16=High-dose (8 mg) intravitreal aflibercept every 16 weeks following 3 initial monthly doses; LLOQ=Lower limit of quantitation; PKAS=Pharmacokinetics analysis set. Note: Table under the figure presents the number of subjects contributing to the statistics for the corresponding visits / timepoints and treatment groups. Concentrations below the LLOQ were set to LLOQ / 2. Post-dose samples and samples collected during the dense PK sub-study (from post dose on Day 0 through Day 21) were excluded. [000104] Figure 30: Mean (+SD) Concentrations (mg / l) of Adjusted Bound Aflibercept in Plasma by Nominal Time and Treatment Group in Participants with DME in the Sparse PK Sampling Study (Study VGFTe-HD-DME-1934, Log-Scaled, [PKAS]); N=Number of subjects; SD=Standard deviation; DME=Diabetic macular edema; 2q8=2 mg intravitreal aflibercept every 8 weeks following 5 initial monthly doses; HDq12=High-dose (8 mg) intravitreal aflibercept every 12 weeks following 3 initial monthly doses; HDq16=High-dose (8 mg) intravitreal aflibercept every 16 weeks following 3 initial monthly doses; LLOQ =¾Lower limit of quantitation. Note: Table under the figure presents the number of subjects contributing to the statistics for the corresponding visits / timepoints and treatment groups. Concentrations below the LLOQ were set to LLOQ / 2. Adjusted bound aflibercept = 0.717*bound aflibercept. Post-dose samples andsamples collected during the dense PK sub-study (from post dose on Day 0 through Day 21) were excluded. [000105] Figure 31: Structural Representation of a Population Pharmacokinetic Model Following IV, SC, and IVT Administration of Aflibercept. CMT = compartment, IV = intravenous, IVT = intravitreal, K20 = elimination rate constant for free aflibercept, K40 = elimination rate constant for adjusted bound aflibercept, K62 = rate of absorption from subcutaneous injection depot compartment, K70 = elimination rate constant from tissue (platelet) compartment; QE = inter-compartmental clearance between ocular compartment and central compartment of free aflibercept, QF1 and QF2 = inter-compartmental clearances of free aflibercept, VMK24, KM = saturable Michaelis-Menten type binding of free aflibercept with VEGF; VMK27, KMK27 = saturable elimination from plasma compartment to tissue compartment (platelets) CMT 2 and CMT 4 are both representative of the plasma compartment and volumes are assumed to be equal. [000106] Figure 32: Mean (+SD) Concentrations (mg / l) of Free and Adjusted Bound Aflibercept Over 28 Days for Single 2 mg and 8 mg IVT Doses of Aflibercept in nAMD or DME in the Dense PK Sub-studies (DPKS, Log-Scaled). LQ = below limit of quantification, DME = Diabetic Macular Edema, DPKS = dense pharmacokinetic sub-studies, HDq12 = aflibercept 8 mg administered every 12 weeks following 3 initial monthly injections, HDq16 = aflibercept 8 mg administered every 16 weeks following 3 initial monthly injections, IVT = intravitreally, LLOQ = lower limit of quantification, N = number of participants, nAMD = neovascular age-related macular degeneration, SD = standard deviation Adjusted Bound Aflibercept = 0.717*Bound Aflibercept Note: Concentrations below the LLOQ (0.0156 mg / L for Free and 0.0224 mg / L for Adjusted Bound Aflibercept) were set to LLOQ / 2. Note: 8 mg HD aflibercept data for the first 28 days (obtained from PULSAR or PHOTON) is a combination of data from participants who received HDq12 or HDq16. One participant in PULSAR with an outlier free aflibercept concentration at day 28 that is greater than 10-fold of the mean concentration is excluded. Records after fellow-eye treatment are excluded. Data Source: drug concentration data from the week 48 database lock for PULSAR and PHOTON and final lock for CANDELA. [000107] Figure 33: Observed and Model-Predicted Concentrations (mg / l) of Free and Adjusted Bound Aflibercept in Plasma Over 28 days After a Single IVT Injection for Participants with nAMD or DME in the Dense PK Sub-studies (DPKS), Stratified by Dose and Population. DME = diabetic macular edema, IVT = intravitreally, LLOQ = lower limit of quantitation, nAMD = neovascular age-related macular degeneration, PK = pharmacokinetic Observed concentrations below the lower limit of quantitation (LLOQ; 0.0156 mg / L for free and 0.0224 mg / L for adjustedbound aflibercept) were set to LLOQ / 2. Data source: Drug concentration data from dense PK sub-study in PHOTON, PULSAR, and CANDELA. [000108] Figure 34: Overlay of Observed and Model-Predicted Concentrations (mg / l) of Free and Adjusted Bound Aflibercept in Plasma for Combined nAMD and DME Populations.2q8 = aflibercept 2 mg administered every 8 weeks, after 3 initial injections at 4-week intervals, 2q12 = aflibercept 2 mg administered every 12 weeks, after 3 initial injections at 4-week intervals, DME = diabetic macular edema, HDq12 = aflibercept 8 mg administered every 12 weeks following 3 initial monthly injections, HDq16 = aflibercept 8 mg administered every 16 weeks following 3 initial monthly injections, IVT = intravitreally, LLOQ = lower limit of quantification, nAMD = neovascular age-related macular degeneration Observed concentrations below the lower limit of quantitation (LLOQ; 0.0156 mg / L for free and 0.0224 mg / L for adjusted bound aflibercept) were set to LLOQ / 2. Data source: Drug concentration data from CANDELA, PHOTON, and PULSAR. [000109] Figure 35: Model-Predicted Amounts (mg) of Aflibercept Exposures After a Single IVT Injection, Stratified by Dosing Regimen in Combined Participants with nAMD and DME. DME = diabetic macular edema, HD = aflibercept 8 mg, IVT = intravitreal, nAMD = neurovascular age- related macular degeneration, PI = prediction interval, PK = pharmacokinetics, QE = inter- compartmental clearance between ocular compartment and central compartment of free aflibercept Adjusted LLOQ (0.0624 μg), set as the LLOQ of free aflibercept in plasma (that is, 0.0156 mg / L) times the assumed volume of the study eye compartment in the PK model (that is, 4 mL). Since the concentrations of (free or bound) aflibercept were not measured in the study eye in the clinical studies included in the Population PK analysis dataset, this target was selected arbitrarily on the basis of the LLOQ in plasma and was used as reference for comparison across dosing regimens and to assess the effect of the effect of HD aflibercept on QE. [000110] Figure 36: Mean (+SD) Concentrations (mg / l) of Free and Adjusted Bound Aflibercept Over 28 Days for Single 2 mg and 8 mg IVT Doses of Aflibercept in Participants with nAMD in the Dense PK Sub-studies (DPKS, Log-Scaled) - No Outlier. DME = diabetic macular edema, DPKS = dense pharmacokinetic sub-studies, HDq12 = aflibercept 8 mg administered every 12 weeks following 3 initial monthly injections, HDq16 = aflibercept 8 mg administered every 16 weeks following 3 initial monthly injections, IVT = intravitreally, LLOQ = lower limit of quantification, N = number of participants, nAMD = neovascular age-related macular degeneration, PK = pharmacokinetic, SD = standard deviation Adjusted Bound Aflibercept = 0.717*Bound Aflibercept. Note: Concentrations below the LLOQ (0.0156 mg / L for Free and 0.0224 mg / L for Adjusted Bound Aflibercept) were set to LLOQ / 2. Note: 8 mg data for the first28 days (obtained from PULSAR or PHOTON) is a combination of data from participants who received HDq12 or HDq16 Data source: drug concentration from the week 48 lock for PULSAR and PHOTON and final lock for CANDELA. Records after fellow-eye treatment are excluded. [000111] Figure 37: Mean (+SD) Concentrations (mg / l) of Free and Adjusted Bound Aflibercept Over 28 Days for Single 2 mg and 8 mg IVT Doses of Aflibercept in Participants with nAMD in the Dense PK Sub-study (DPKS, Log-Scaled) -Outlier Included. DME = diabetic macular edema, DPKS = dense pharmacokinetic sub-studies, HDq12 = aflibercept 8 mg administered every 12 weeks following 3 initial monthly injections, HDq16 = aflibercept 8 mg administered every 16 weeks following 3 initial monthly injections, IVT = intravitreally, LLOQ = lower limit of quantification, N = number of participants, nAMD = neovascular age-related macular degeneration, PK = pharmacokinetic, SD = standard deviation Adjusted Bound Aflibercept = 0.717*Bound Aflibercept. Note: Concentrations below the lower limit of quantification (LLOQ, 0.0156 mg / L for Free and 0.0224 mg / L for Adjusted Bound Aflibercept) were set to LLOQ / 2. Data source: drug concentration from the week 48 lock for PULSAR and final lock for CANDELA. Data from VGFTOD-0702 are included as a reference (the concentration in PK sub- study is subtracted by pre-dose concentration when it is >LLOQ). Records after fellow-eye treatment are excluded. [000112] Figure 38: Mean (+SD) Concentrations (mg / l) of Free and Adjusted Bound Aflibercept Over 28 Days for Single 2 mg and 8 mg IVT Doses of Aflibercept in Participants with DME in the Dense PK Sub-studies (DPKS, Log-Scaled). BLQ = below limit of quantification, DME = diabetic macular edema, DPKS = dense pharmacokinetic analysis set, HDq12 = aflibercept 8 mg administered every 12 weeks following 3 initial monthly injections, HDq16 = aflibercept 8 mg administered every 16 weeks following 3 initial monthly injections, IVT = intravitreally, LLOQ = lower limit of quantification, N = number of participants, nAMD = neovascular age-related macular degeneration, SD = standard deviation Note: Concentrations below the LLOQ (0.0156 mg / L for Free and 0.0224 mg / L for Adjusted Bound Aflibercept) were set to LLOQ / 2. Adjusted Bound Aflibercept = 0.717*Bound Aflibercept. Note: 8 mg data for the first 28 days (obtained from PULSAR or PHOTON) is a combination of data from participants who received HDq12 or HDq16. Note: The Concentration is subtracted by baseline concentration if participants took the Aflibercept prior to study drug started within 12 weeks and the baseline concentration is > BLQ. Data source: drug concentration data from the week 48 lock for PHOTON. Drug concentration data from VGFT-OD-0706 (historical data) are included as a reference. Records after fellow-eye treatment are excluded.[000113] Figure 39: Overlay of Observed and Model-Predicted Concentrations (mg / l) of Free and Adjusted Bound Aflibercept in Plasma for Participants with nAMD. 2q8 = aflibercept 2 mg administered every 8 weeks, after 3 initial injections at 4-week intervals, 2q12 = aflibercept 2 mg administered every 12 weeks, after 3 initial injections at 4-week intervals, DME = diabetic macular edema, HDq12 = aflibercept 8 mg administered every 12 weeks following 3 initial monthly injections, HDq16 = aflibercept 8 mg administered every 16 weeks following 3 initial monthly injections, IVT = intravitreally, LLOQ = lower limit of quantitation, nAMD = neovascular age-related macular degeneration, PK = pharmacokinetics Observed concentrations below the lower limit of quantitation (LLOQ; 0.0156 mg / L for free and 0.0224 mg / L for adjusted bound aflibercept) were set to LLOQ / 2. Data from PULSAR and CANDELA. [000114] Figure 40: Overlay of Observed and Model-Predicted Concentrations (mg / l) of Free and Adjusted Bound Aflibercept in Plasma for Participants with Diabetic Macular Edema in study PHOTON. 2q8 = aflibercept 2 mg administered every 8 weeks, after 3 initial injections at 4-week intervals, HDq12 = aflibercept 8 mg administered every 12 weeks, after 3 initial injections at 4-week intervals, HDq16 = aflibercept 8 mg administered every 16 weeks, after 3 initial injections at 4-week intervals, IVT = intravitreally, LLOQ = lower limit of quantitation Data from PHOTON. [000115] Figure 41: Dosing schedule and dose regimen modification (DRM) criteria of PULSAR clinical trial (to week 48). [000116] Figure 42: Key eligibility criteria (inclusion criteria and exclusion criteria) of PULSAR clinical trial. [000117] Figure 43: Dosing schedule and dose regimen modification (DRM) criteria for PULSAR clinical trial. [000118] Figure 44: Criteria for dose regimen modifications (DRMs) of PULSAR clinical trial. [000119] Figure 45: Patient disposition at week 48 in PULSAR clinical trial. [000120] Figure 46: Baseline demographics of subjects in PULSAR clinical trial. [000121] Figure 47: Baseline characteristics of the study eye of subjects in PULSAR clinical trial. [000122] Figure 48: Mean number of injections through week 48 in PULSAR clinical trial. [000123] Figure 49: Mean change in Best Corrected Visual Acuity (BCVA) through week 48 in PULSAR clinical trial. Least squares mean change from baseline at week 48 shown in table. [000124] Figure 50: Percentage of subjects maintaining Q12 and Q16 week intervals through week 48 in PULSAR clinical trial.[000125] Figure 51: Key secondary endpoint of percentage of subjects without retinal fluid in center subfield at week 16 in PULSAR clinical trial. [000126] Figure 52: Percentage of subjects without retinal fluid in center subfield at week 48 in PULSAR clinical trial. [000127] Figure 53A and 53B: Mean change from baseline in central retinal thickness through week 48 (A); and central retinal thickness through week 48 (B). [000128] Figure 54A and 54B: Ocular serious Treatment Emergent Adverse Events (TEAEs) through week 48 (A); and Most Frequent Ocular Adverse Events (AEs) through week 48 in PULSAR clinical trial (B). [000129] Figure 55: Treatment emergent intraocular inflammation through week 48 in PULSAR clinical trial. [000130] Figure 56: Mean change from baseline in intraocular pressure through week 48 in PULSAR clinical trial. [000131] Figure 57: Percentage of subjects meeting intraocular pressure criteria in PULSAR clinical trial. [000132] Figure 58: Non-Ocular Serious TEAEs ≥0.5% through week 48 in PULSAR clinical trial. [000133] Figures 59A and 59B: Treatment emergent Anti-Platelet Trialists’ Collaboration (APTC) events through week 48 (A); Non-Ocular Safety through week 48 (B) in PULSAR clinical trial. [000134] Figure 60: Treatment emergent hypertension events though week 48 in PULSAR clinical trial. [000135] Figure 61: Potentially Clinically Significant Values (PCSVs) for blood pressure through week 48 in PULSAR clinical trial. [000136] Figure 62: Mean change from baseline in systolic blood pressure through week 48 in PULSAR clinical trial. Mean change from baseline to week 9 and mean baseline pressure shown in insets. [000137] Figure 63: Mean change from baseline in diastolic blood pressure through week 48 in PULSAR clinical trial. Mean change from baseline to week 9 and mean baseline pressure shown in insets. [000138] Figure 64: Deaths through week 48 in PULSAR clinical trial. [000139] Figure 65: PULSAR dosing schedule out to week 60. Dose regimen modification criteria are set forth in the inset.[000140] Figure 66: Absolute BCVA and change in BCVA from baseline (ETDRS letters) out to week 60 [PULSAR]. Least squares mean change from baseline at week 60 shown. [000141] Figure 67: Proportion of PULSAR Patients Maintaining HDq12 (8q12)- and HDq16 (8q16) Intervals Through Week 60. [000142] Figure 68: Mean Number of Injections through Week 60 in each group [PULSAR]. [000143] Figure 69A, 69B and 69C: Central Retinal Thickness (CRT) and Change from Baseline to through Week 60 [PULSAR]. (A) central retinal thickness (micrometers) over time (observed values-censoring data post ICE); (B) Mean change from baseline in CST (central subfield retinal thickness (interchangeable with CRT); micrometers) by visit through week 60, OC prior to ICE in the full analysis set; (C) LSmean (95% CIs) changes from baseline in CST (micrometers) by visit, MMRM (mixed model for repeated measurements) in the full analysis set (to week 48). [000144] Figure 70A, 70B, 70C, 70D, 70E, 70F and 70G: PULSAR Safety data Summary, (Fig. 70A) Ocular TEAEs ≥2% through Week 60, (Fig.70B) Ocular Serious TEAEs through Week 60, (Fig.70C) Non-Ocular TEAEs ≥2% through Week 60, (Fig.70D) Non-Ocular Serious TEAEs ≥0.5% through Week 60, (Fig.70E) Deaths through Week 60, (Fig.70F) Mean Change in Systolic Blood Pressure at week 60, and (Fig.70G) Mean Change in Diastolic Blood Pressure at week 60, for PULSAR. [000145] Figure 71: Changes of 5, 10 and 15 letters at Week 60. Observed (OC) (censoring data post ICE) [PULSAR]. [000146] Figure 72: % PULSAR Subjects Without Retinal Fluid in Center Subfield by Visit (weeks and schedules doses shown) to week 60. LOCF (censoring data post ICE). [000147] Figure 73: Proportion of PHOTON Patients Who Maintained or Extended Intervals Through Week 96. Patients completing Week 96. Values may not add up to 100% due to rounding. Q8, every 8 weeks; Q12, every 12 weeks; Q16, every 16 weeks; Q20, every 20 weeks; Q24, every 24 weeks. [000148] Figure 74A and 74B: BCVA and CRT in PULSAR Case Report 1 Patient Over Time. (A) Displayed are the patient’s characteristics along with images of the patient’s retina at baseline, at week 12 and at week 96. A timeline of the absolute BCVA and absolute CRV achieved by the patient is set forth at the bottom. The particular maintenance dosing interval (q16, q20 or q24) to which the patient was assigned at various times is indicated. Dosage regimen modification assessments were performed at the weeks indicated with a box. (B) Patient’s assigned interval among that of the overall population of PULSAR participants.[000149] Figure 75A and 75B: BCVA and CRT in PULSAR Case Report 2 Patient Over Time. (A) Displayed are the patient’s characteristics along with images of the patient’s retina at baseline, at week 12 and at week 96. A timeline of the absolute BCVA and absolute CRV achieved by the patient is set forth at the bottom. The particular maintenance dosing interval (q12 and q16) to which the patient was assigned at various times is indicated. Dosage regimen modification assessments were performed at the weeks indicated with a box. (B) Patient’s assigned interval among that of the overall population of PULSAR participants. [000150] Figure 76: BCVA and CRT in PHOTON Case Report Patient Over Time. (A) Displayed are the patient’s characteristics along with images of the patient’s retina at baseline, at week 12 and at week 96. A timeline of the absolute BCVA and absolute CRV achieved by the patient is set forth at the bottom. The particular maintenance dosing interval (q16, q20 and q24) to which the patient was assigned at various times is indicated. Dosage regimen modification assessments were performed at the weeks indicated with a box. [000151] Figure 77: Forest Plots of Geometric Mean Ratios (90% Confidence Interval) of Post Hoc Model-Based Predictions of Exposure Metrics of Free and Adjusted Bound Aflibercept in Participants From the CANDELA, PULSAR, and PHOTON Studies for HDq12. * = includes 6 participants with renal failure ; ** = includes 5 participants with moderate hepatic failure; [or] indicates that the respective limit is included in the interval; (or ) indicates that the respective limit is not included in the interval. Dashed lines indicate standard reference limits of 0.8 and 1.25; AUCweek56-68 = Area under the concentration versus time curve between week 56 and week 68; Cmax,week8-12 = Maximum concentration between week 8 and week 12; DME = Diabetic macular edema; HDq12 = 8 mg aflibercept every 12 weeks following 3 initial monthly injections; nAMD = Neovascular age-related macular degeneration. [000152] Figure 78: Stochastic Simulations of Aflibercept Concentrations in the Eye in 5,000 Virtual Participants With Neovascular Age-Related Macular Degeneration and 5,000 Virtual Participants With Diabetic Macular Edema After Repeated Intravitreal Injections of 2 mg or 8 mg Aflibercept. IVT = lntravitreal ; KD= Dissociation constant; LLOQ = Lower limit of quantitation; VEGF-A = Vascular endothelial growth factor-A;aConcentration of free aflibercept, fo llowing intravitreal injection, at the end of an 8-week dosing interval with aflibercept 2 mg; b 1 x, 9x, and 99x KDrepresent the free aflibercept concentrations required to inhibit VEGF-A by 50%, 90%, or 99% in an in vitro setting.[000153] Figure 79: Forest Plots of Geometric Mean Ratios (90% Confidence Interval) of Post Hoc Model-Based Predictions of Exposure Metrics of Free and Adjusted Bound Aflibercept in Participants From the CANDELA, PULSAR, and PHOTON Studies for HDq12, Stratified by Manufacturing Process of HD Aflibercept. AUCweek56-68 = Area under the concentration curve from weeks 56 to 68; CV= Coefficient of variation, Cmax,week8-12 =Maximum concentration from weeks 8 to 12; Cmax,week56-60 = Maximum concentration from weeks 56 to 60; n = Number of participants in each group; HDq12 = 8 mg aflibercept every 12 weeks following 3 initial monthly injections [ or ] indicates that the respective limit is included in the interval ; ( or ) indicates that the respective limit is not included in the interval. Dashed lines indicate standard reference limits 0.8 and 1.25. [000154] Figure 80: Distribution of Ocular Distribution Clearance in Patients With Neovascular Age-Related Macular Degeneration in the PULSAR Study, Stratified by Assigned Dosing Interval at the Last Study Eye Dose of High Dose Aflibercept Through Week 96 [000155] Figure 81: Distribution of Ocular Distribution Clearance in Patients With Diabetic Macular Edema in the PHOTON Study, Stratified by Assigned Dosing Interval at the Last Study Eye Dose of High Dose Aflibercept Through Week 96. [000156] Figure 82: Distribution of Baseline Central Retinal Thickness in Patients With Neovascular Age-Related Macular Degeneration in the PULSAR Study, Stratified by Assigned Dosing Interval at the Last Study Eye Dose of High Dose Aflibercept Through Week 96. [000157] Figure 83: Distribution of Baseline Central Retinal Thickness in Patients With Diabetic Macular Edema in the PHOTON Study, Stratified by Assigned Dosing Interval at the Last Study Eye Dose of High Dose Aflibercept Through Week 96. [000158] Figure 84: Visual Predictive Check for Probability of Assignment to a 24-Week Dosing Interval at the Last Dose of High Dose Aflibercept Through Week 96, Stratified by Disease Population and Tertiles of Ocular Distribution Clearance and Baseline Central Retinal Thickness. [000159] Figure 85: Kaplan-Meier Plot of Time to First Dose Regimen Modification of High Dose Aflibercept, Stratified by Neovascular Age-Related Macular Degeneration Versus Diabetic Macular Edema Population. [000160] Figure 86: Kaplan-Meier Plot of Time to First Dose Regimen Modification of High Dose Aflibercept, Stratified by Neovascular Age-Related Macular Degeneration Versus Diabetic Macular Edema Population and Tertile of Exposure in the Study Eye.[000161] Figure 87: Model-Predicted Hazard Ratio for Dose Regimen Modification of High Dose Aflibercept by Neovascular Age-Related Macular Degeneration Versus Diabetic Macular Edema Population and Ocular Distribution Clearance. [000162] Figure 88: Kaplan-Meier Plot of Time to First Dose Regimen Extension of High Dose Aflibercept, Stratified by Dose Regimen at Randomization. [000163] Figure 89: Kaplan-Meier Plot of Time to First Dose Regimen Extension of High Dose Aflibercept, Stratified by Neovascular Age-Related Macular Degeneration Versus Diabetic Macular Edema Population and Tertile of Exposure in the Study Eye. [000164] Figure 90: Model-Predicted Hazard Ratio for Dose Regimen Extension of High Dose Aflibercept by Randomized Dosing Regimen and Ocular Distribution Clearance. [000165] Figure 91: Distribution of Individual Ocular Distribution Clearance Estimates Versus Time of Last Study Eye Dose of H.igh Dose Aflibercept Stratified by Study and Overall. [000166] Figure 92: Visual Predictive Check for Probability of Last Dosing Interval Assignment in Participants With Neovascular Age-Related Macular Degeneration Receiving High Dose Aflibercept, Stratified by Tertile of Ocular Distribution Clearance and Baseline Central Retinal Thickness. [000167] Figure 93: Visual Predictive Check for Probability of Last Dosing Interval Assignment in Participants With Diabetic Macular Edema Receiving High Dose Aflibercept, Stratified by Tertile of Ocular Distribution Clearance and Baseline Central Retinal Thickness. DETAILED DESCRIPTION OF THE INVENTION [000168] The present invention provides, in part, a safe and effective high-dose aflibercept IVT injection which extends the maintenance dosing interval past 8 weeks, with at least similar functional and potentially improved anatomic outcomes. The regimen exhibited an unexpectedly high level of durability in subjects which exceeded that which would have been expected simply based on administration of more aflibercept. [000169] EYLEA has become the standard-of-care for neovascular age related macular degeneration (nAMD), 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 present invention has demonstrated that a remarkably high percentage of subjects can be maintained on 12- and 16- week dosing intervals. In trials testing these dosing regimens, nearly 90% of subjects with diabetic macular edema were able to maintain a 16-week dosing regimen. The HDq12 and HDq16 PHOTON trial groups achieved similar BCVA gains compared to 2q8 at Week 96, withup to 6 fewer injections. Through Week 96, 88% of HDq12 patients and 84% of HDq16 patients maintained ≥12- and ≥16-week dosing intervals, respectively. At Week 96, 43% of HDq12 patients and 47% of HDq16 patients had a last assigned dosing interval of ≥20 weeks. Of the participants assigned to a 24-week interval as their last assigned dosing interval prior to week 96 in the PULSAR and PHOTON clinical trial studies, a subset entered into the extension phase and successfully completed a 24-week dosing interval between weeks 96 and 108 without the need for shortening based on dose regimen modification (DRM) criteria. 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 angiogenic eye disorders such as DR or DME. [000170] Standard methods in molecular biology are described Sambrook, Fritsch and Maniatis (1982 & 19892ndEdition, 20013rdEdition) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Sambrook and Russell (2001) Molecular Cloning, 3rded., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Wu (1993) Recombinant DNA, Vol.217, Academic Press, San Diego, Calif.). Standard methods also appear in Ausbel, et al. (2001) Current Protocols in Molecular Biology, Vols.1-4, John Wiley and Sons, Inc. New York, N.Y., which describes cloning in bacterial cells and DNA mutagenesis (Vol.1), cloning in mammalian cells and yeast (Vol.2), glycoconjugates and protein expression (Vol.3), and bioinformatics (Vol.4). [000171] General methods for protein purification including immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization are described (Coligan et al. (2000) 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, glycosylation of proteins are described (see e.g., Coligan 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; 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) 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 for characterizing ligand / receptor interactions are available (see, e.g., Coligan et al. (2001) Current Protocols in Immunology, Vol.4, John Wiley, Inc., New York).[000172] Methods for flow cytometry, including fluorescence activated cell sorting (FACS), are available (see, e.g., Owens et al. (1994) Flow Cytometry Principles for Clinical Laboratory Practice, John Wiley and Sons, Hoboken, N.J.; Givan (2001) Flow Cytometry, 2nded.; Wiley- Liss, Hoboken, N.J.; Shapiro (2003) Practical Flow Cytometry, John Wiley and Sons, Hoboken, N.J.). Fluorescent reagents suitable for modifying nucleic acids, including nucleic acid primers and probes, polypeptides, and antibodies, for use, e.g., as diagnostic reagents, are available (Molecular Probes (2003) Catalogue, Molecular Probes, Inc., Eugene, Oreg.; Sigma-Aldrich (2003) Catalogue, St. Louis, Mo.). [000173] Standard methods of histology of the immune system are described (see 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, Phila, Pa.; Louis et al. (2002) Basic Histology: Text and Atlas, McGraw-Hill, New York, N.Y.). [000174] "Isolated" VEGF antagonists and VEGF receptor fusion proteins (e.g., aflibercept), polypeptides, polynucleotides and vectors, are at least partially free of other biological molecules from the cells or cell culture from which they are produced. Such biological molecules include nucleic acids, proteins, other VEGF antagonists and VEGF receptor fusion proteins, lipids, carbohydrates, or other material such as cellular debris and growth medium. 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 a host cell or of the growth medium thereof. Generally, the term "isolated" is not intended to refer to a complete absence of such biological molecules (e.g., minor or insignificant amounts of impurity may remain) or to an absence of water, buffers, or salts or to components of a pharmaceutical formulation that includes the VEGF antagonists or VEGF receptor fusion proteins. [000175] Subject and patient are used interchangeably herein. A subject or patient is a mammal, for example a human, mouse, rabbit, monkey or non-human primate, preferably a human. A subject or patient may be said to be “suffering from” an angiogenic eye disorder such as nAMD. Such a subject or patient has the disorder in one or both eyes. In an embodiment of the invention, a subject or patient (preferably a human) has one or more of the following characteristics (presently or in the past): 1. ≥50 years of age, e.g., 61, 62, 63, 74 or 75; 2. Has active subfoveal CNV secondary to nAMD, e.g., including juxtafoveal lesions that affect the fovea in an eye; 3. Has Best Corrected Visual Acuity (BCVA) Early Treatment Diabetic Retinopathy Study(ETDRS) letter score of about 78 to 24, 73-78, <73, 58, 59, 60, 61, 62 or 63 (Snellen equivalent of 20 / 40, 20 / 63, 20 / 50, 20 / 32 or 20 / 320), e.g., due to DME or wet AMD; 4. Central retinal thickness of >300 micrometers or >320 micrometers, or about 367, 368, 369, 370, 450, 451, 452, 453, 454 or 455 micrometers; or and / or DME with central involvement in an eye with CRT ≥300 micrometers (or ≥320 micrometers on Spectralis); 5. Total lesion area of about 6 or 7 mm2, e.g., wherein the lesion type is occult, predominantly classic or minimally classic; 6. DRSS score of better or equal to Level 43, Level 47 or worse; 7. Type 1 or type 2 diabetes mellitus (insulin dependent or non-insulin dependent) (e.g., for about 15 or more years); 8. Hemoglobin A1C (%) of about 7 or 8 or more; 9. Body mass index of about 30 or 31 or more; and / or 10. A history of diabetic retinal oedema, diabetic retinopathy, dry eye, vitreous detachment, retihopathy hypersensitive, retinal hemorrhage, cataract operation, retinal laser coagulation, and intraocular lens implant, hypertension, and / or, has or lacks any one or more of the following characteristics: 1. Evidence of macular edema due to any cause other than diabetes mellitus in an eye; 2. IOP ≥ 25 mmHg in an eye; 3. History of glaucoma filtration surgery in the past, or likely to need filtration surgery in the future in an eye; 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 an eye within 12 weeks (84 days) of treatment; 6. History of idiopathic or autoimmune uveitis in an eye; 7. Vitreomacular traction or epiretinal membrane in an eye, e.g., as evident on biomicroscopy or OCT that is thought to affect central vision; 8. Preretinal fibrosis involving the macula in an eye; 9. Any history of macular hole of stage 2 and above in an eye; 10. Current iris neovascularization, vitreous hemorrhage, or tractional retinal detachment visible at the screening assessments in an eye; 11. History of corneal transplant or corneal dystrophy in an eye; 12. Any concurrent ocular condition in an eye which, in the opinion of the treating physician, could either increase the risk to the subject beyond what is to be expectedfrom standard procedures of IVT injections, or which otherwise may interfere with the VEGF antagonist injection procedure; 13. History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of the VEGF antagonist; 14. Any prior systemic (IV) anti-VEGF administration; 15. Uncontrolled diabetes mellitus as defined by hemoglobin A1c (HbA1c) >12%; 16. Uncontrolled blood pressure (defined as systolic >160 mmHg or diastolic >95 mmHg); 17. History of cerebrovascular accident or myocardial infarction within 24 weeks (168 days) of treatment; 18. Renal failure, dialysis, or history of renal transplant; 19. Known sensitivity to any of the compounds to be administered in treatment; and / or 20. Pregnant or breastfeeding woman [000176] Thus, the present invention includes a method for treating or preventing DR and / or DME, in a subject in need thereof 1. who is ≥50 years of age; 2. who has active subfoveal CNV; 3. who has Best Corrected Visual Acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score of about 78 to 24; 4. who has a central retinal thickness of >300 micrometers or >320 micrometers; 5. who has a lesion area of about 6 or 7 mm2; 6. who has a DRSS score of better or equal to Level 43, Level 47 or worse; and / or 7. has Type 1 or type 2 diabetes mellitus; and / or, 1. who lacks evidence of macular edema due to any cause other than diabetes mellitus in an eye; 2. does not have an IOP ≥ 25 mmHg in an eye; 3. who does not have a history of glaucoma filtration surgery in the past, or is not likely to need filtration surgery in the future in an eye; 4. who does not have evidence of infectious blepharitis, keratitis, scleritis, or conjunctivitis in either eye within 4 weeks (28 days) of treatment; 5. who does not have any intraocular inflammation and / or ocular infection in an eye within 12 weeks (84 days) of treatment;6. who does not have a history of idiopathic or autoimmune uveitis in an eye; 7. who does not have vitreomacular traction or epiretinal membrane in an eye; 8. who does not have preretinal fibrosis involving the macula in an eye; 9. who does not have any history of macular hole of stage 2 and above in an eye; 10. who does not have current iris neovascularization, vitreous hemorrhage, and / or tractional retinal detachment; 11. who does not have a history of corneal transplant or corneal dystrophy in an eye; 12. who does not have any concurrent ocular condition in an eye which, in the opinion of the treating physician, could either increase the risk to the subject beyond what is to be expected from standard procedures of IVT injections, or which otherwise may interfere with the VEGF antagonist injection procedure; 13. who does not have a history of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of the VEGF antagonist; 14. who has not had any prior systemic (IV) anti-VEGF administration; 15. who does not have uncontrolled diabetes mellitus as defined by hemoglobin A1c (HbA1c) >12%; 16. who does not have uncontrolled blood pressure (defined as systolic >160 mmHg or diastolic >95 mmHg); 17. who does not have a history of cerebrovascular accident or myocardial infarction within 24 weeks (168 days) of treatment; 18. who does not have renal failure, dialysis, or history of renal transplant; 19. who does not have a known sensitivity to any of the compounds to be administered in treatment; and / or 20. who is not pregnant or a breastfeeding woman; comprising administering to an eye of the subject (preferably by intravitreal injection), a single initial dose of about 8 mg or more of a VEGF receptor 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 one or more tertiary doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 24 weeks after the immediately preceding dose.VEGF Antagonists [000177] The present invention includes methods for using a VEGF antagonist for treating or preventing angiogenic eye disorders. VEGF antagonists include molecules which interfere with the interaction between VEGF and a natural VEGF receptor, e.g., molecules which bind to VEGF or a VEGF receptor and prevent or otherwise hinder the interaction between VEGF and a VEGF receptor. Specific, exemplary VEGF antagonists include anti-VEGF antibodies, anti- VEGF receptor antibodies, and VEGF receptor fusion proteins. Though VEGF receptor fusion proteins, such as aflibercept, are preferred for use in connection with the methods set forth herein, the scope of the present invention includes such methods wherein any of the VEGF antagonists described herein (e.g., scFvs, DARPins, anti-VEGF antibodies) are used in place of such fusion proteins. [000178] For purposes herein, a “VEGF receptor fusion protein” refers to a molecule that comprises one or more VEGF receptors or domains thereof, fused to another polypeptide, which interferes with the interaction between VEGF and a natural VEGF receptor, e.g., wherein two of such fusion polypeptides are associated thereby forming a homodimer or other multimer. Such VEGF receptor fusion proteins may be referred to as a "VEGF-Trap" or “VEGF Trap”. VEGF receptor fusion proteins within the context of the present disclosure that fall within this definition include chimeric polypeptides which comprise two or more immunoglobulin (Ig)-like domains of a VEGF receptor such as VEGFR1 (also known as Flt1) and / or VEGFR2 (also known as Flk1 or KDR), and may also contain a multimerizing domain (for example, an Fc domain). Preferably, the VEGF receptor fusion protein is aflibercept. [000179] An exemplary VEGF receptor fusion protein is a molecule referred to as VEGF1R2- FcΔC1(a) which is encoded by the nucleic acid sequence of SEQ ID NO:1 or nucleotides 79- 1374 or 79-1371 thereof. [000180] VEGF1R2-FcΔC1(a) comprises three components: (1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO:2; (2) a VEGFR2 component comprising amino acids 130 to 231 of SEQ ID NO:2; and (3) a multimerization component ("FcΔC1(a)") comprising amino acids 232 to 457 of SEQ ID NO:2 (the C-terminal amino acids of SEQ ID NO:2, i.e., K458, may or may not be included in the VEGF receptor fusion proteins, see U.S. Patent No.7,396,664 or 7,354,579, incorporated herein for all purposes). Note that amino acids 1 to 26 of SEQ ID NO:2 are the signal sequence. [000181] If the multimerizing component (MC) of a VEGF receptor fusion protein is derived from an IgG (e.g., IgG1) Fc domain, then the MC has no fewer amino acids than are in amino acids232 to 457 of SEQ ID NO:2. Thus, the IgG of the MC cannot be truncated to be shorter than 226 amino acids. [000182] In an embodiment of the invention, the VEGF receptor fusion protein comprises amino acids 27-458 or 27-457 of SEQ ID NO: 2 (e.g., in the form of a homodimer). atggtcagctactgggacaccggggtcctgctgtgcgcgctgctcagctgtctgcttctcacaggatctagttccgg aagtgataccggtagacctttcgtagagatgtacagtgaaatccccgaaattatacacatgactgaaggaagggagc tcgtcattccctgccgggttacgtcacctaacatcactgttactttaaaaaagtttccacttgacactttgatccct gatggaaaacgcataatctgggacagtagaaagggcttcatcatatcaaatgcaacgtacaaagaaatagggcttct gacctgtgaagcaacagtcaatgggcatttgtataagacaaactatctcacacatcgacaaaccaatacaatcatag atgtggttctgagtccgtctcatggaattgaactatctgttggagaaaagcttgtcttaaattgtacagcaagaact gaactaaatgtggggattgacttcaactgggaatacccttcttcgaagcatcagcataagaaacttgtaaaccgaga cctaaaaacccagtctgggagtgagatgaagaaatttttgagcaccttaactatagatggtgtaacccggagtgacc aaggattgtacacctgtgcagcatccagtgggctgatgaccaagaagaacagcacatttgtcagggtccatgaaaag gacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaa acccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctg aggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaac agcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggt ctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgt acaccctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatccc agcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactc cgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgct ccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaatga (SEQ ID NO: 1) MVSYWDTGVLLCALLSCLLLTGSSSGSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTS PNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLT HRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRD LKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 2) [000183] In an embodiment of the invention, the VEGF receptor fusion protein comprises (1) an immunoglobin-like (Ig) domain 2 of a first VEGF receptor (e.g., VEGFR1), and (2) an Ig domain 3 of a second VEGF receptor (e.g., VEGFR2), (3) and, optionally, further including an Ig domain 4 of the second VEGF receptor (e.g., VEGFR2) and (4) a multimerizing component (e.g., Fc domain of IgG including the hinge, CH2 and CH3 domains). [000184] For example, in an embodiment of the invention, the VEGF receptor fusion protein has the following arrangement of said domains: • [VEGFR1 Ig domain 2]-[VEGFR2 Ig domain 3]-[MC] (e.g., a homodimer thereof) or• [VEGFR1 Ig domain 2]-[VEGFR2 Ig domain 3]-[VEGFR2 Ig domain 4]-[MC] (e.g., a homodimer thereof). [000185] Note that the present disclosure also includes, within its scope, high concentration formulations including, instead of a VEGF receptor fusion protein, a VEGF binding molecule or anti-VEGF antibody or antigen-binding fragments thereof or biopolymer conjugate thereof (e.g., KSI-301), e.g., • bevacizumab (e.g., at a concentration of about 80-90 or 88 mg / ml), • ranibizumab (e.g., at a concentration of about 20-40 mg / ml, e.g., 21-35, 21 or 35 mg / ml), • an anti-VEGF aptamer such as pegaptanib (e.g., pegaptanib sodium), • a single chain (e.g., VL-VH) anti-VEGF antibody such as brolucizumab (e.g., at a concentration of about 200-400 or 200, 210, 400 or 420 mg / ml), • an anti-VEGF DARPin such as the Abicipar Pegol DARPin (e.g., at a concentration of about 70-140, 70 or 140 mg / ml), or • a bispecific anti-VEGF antibody, e.g., which also binds to ANG2, such as RG7716 (faricimab) (e.g., at a concentration of about 100-400, 100, 105, 400 or 420 mg / ml). [000186] In order to minimize the repetitiveness of the embodiments discussed herein, it is contemplated that the scope of the present invention includes embodiments wherein any of the formulations discussed herein include, in place of a VEGF receptor fusion protein, an anti-VEGF antibody or antibody fragment or other VEGF binding molecule as discussed herein (e.g., substituted with an anti-VEGF DARPin) at any of the concentrations discussed herein. For example, the present invention includes a formulation having 35 or 80 mg / ml ranibizumab, a buffer, a thermal stabilizer, a viscosity reducing agent and a surfactant. [000187] DARPins are Designed Ankyrin Repeat Proteins. DARPins generally contain three to four tightly packed repeats of approximately 33 amino acid residues, with each repeat containing a β-turn and two anti-parallel α-helices. This rigid framework provides protein stability whilst enabling the presentation of variable regions, normally comprising six amino acid residues per repeat, for target recognition. [000188] An “anti-VEGF” antibody or antigen-binding fragment of an antibody refers to an antibody or fragment that specifically binds to VEGF. [000189] Illustrative 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 productcomprising the identical amino acid sequence, but includes products which are biosimilar under the U.S. Biologics Price Competition and Innovation Act. [000190] The present invention also includes embodiments including administering one or more further therapeutic agents in addition to VEGF antagonist, for example, administering (one or more doses of) a second VEGF antagonist, an antibiotic, anesthetic (e.g., local anesthetic) to the eye receiving an injection, a non-steroidal anti-inflammatory drug (NSAID), a steroid (e.g., a corticosteroid, dexamethasone), triamcinolone acetonide (TA), methotrexate, rapamycin, an anti-tumor necrosis factor alpha drug (e.g., infliximab), daclizumab, and / or a complement component (e.g., C3 or C5) inhibitor. Pharmaceutical Formulations [000191] The present invention includes methods in which the VEGF antagonist that is administered to the subject’s eye is contained within a pharmaceutical formulation. 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 transfer, delivery, tolerance, and the like. The term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly, in humans. The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the VEGF antagonist is administered. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences (15thed, Mack Publishing Company, Easton, Pa., 1975), e.g., Chapter 87 by Blaug, Seymour, therein. [000192] Pharmaceutical formulations for use in a method of the present invention can be “high concentration”. High concentration pharmaceutical formulations of the present invention include VEGF antagonist, e.g., VEGF receptor fusion protein, at a concentration of at least 41 mg / ml, of at least 80 mg / ml, of at least 100 mg / ml, of at least 125 mg / ml, of at least 140 mg / ml, of at least 150 mg / ml, of at least 175 mg / ml, of at least 200 mg / ml, of at least 225 mg / ml, of at least 250 mg / ml, or of at least 275 mg / ml. "High concentration” can refer to formulations that include a concentration of VEGF antagonist of from about 140 mg / ml to about 160 mg / ml, at least about 140 mg / ml but less than 160 mg / ml, from about 41 mg / ml to about 275 mg / ml, from about 70 mg / ml to about 75 mg / ml or from about 80 mg / ml to about 250 mg / ml. In some aspects, the VEGF antagonist concentration in the formulation is about 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; 48 mg / ml; 49mg / ml; 50mg / ml; 51 mg / ml; 52 mg / ml; 53 mg / ml; 54 mg / ml; 55 mg / ml; 56 mg / ml; 57 mg / ml; 58 mg / ml; 59 mg / ml; 60 mg / ml; 61 mg / ml; 62 mg / ml; 63 mg / ml; 64 mg / ml; 65 mg / ml; 66 mg / ml; 67 mg / ml; 68 mg / ml; 69 mg / ml; 70 mg / ml; 71 mg / ml; 72 mg / ml; 73 mg / ml; 74 mg / ml; 75 mg / ml; 76 mg / ml; 77 mg / ml; 78 mg / ml; 79 mg / ml; 80 mg / ml; 81 mg / ml; 82mg / ml; 83 mg / ml; 84 mg / ml; 85 mg / ml; 86 mg / ml; 87mg / ml; 88 mg / ml; 89 mg / ml; 90 mg / ml; 91 mg / ml; 92 mg / ml; 93 mg / ml; 94 mg / ml; 95mg / ml; 96 mg / ml; 97 mg / ml; 98 mg / ml; 99 mg / ml; 100 mg / ml; 101 mg / ml; 102 mg / ml; 103 mg / ml; 104 mg / ml; 105 mg / ml; 106mg / ml; 107 mg / ml; 108 mg / ml; 109 mg / ml; 110 mg / ml; 111 mg / ml; 112 mg / ml; 113 mg / ml; 113.3 mg / ml; 114 mg / ml; 114.1 mg / ml; 114.2 mg / ml; 114.3 mg / ml; 114.4 mg / ml; 114.5 mg / ml; 114.6 mg / ml, 114.7 mg / ml, 114.8 mg / ml; 114.9 mg / ml; 115 mg / ml; 116 mg / ml; 117 mg / ml; 118 mg / ml; 119 mg / ml; 120 mg / ml; 121 mg / ml; 122 mg / ml; 123 mg / ml; 124 mg / ml; 125 mg / ml; 126 mg / ml; 127mg / ml; 128 mg / ml; 129 mg / ml; 130 mg / ml; 131 mg / ml; 132 mg / ml; 133 mg / ml; 133.3 mg / ml; 133.4 mg / ml, 134 mg / ml; 135 mg / ml; 136 mg / ml; 137 mg / ml; 138 mg / ml; 139 mg / ml; 140 mg / ml; 141 mg / ml; 142 mg / ml; 143 mg / ml; 144 mg / ml; 145 mg / ml; 146 mg / ml; 147 mg / ml; 148 mg / ml; 149 mg / ml; 150 mg / ml; 151 mg / ml; 152 mg / ml; 153 mg / ml; 154mg / ml; 155 mg / ml; 156 mg / ml; 157mg / ml; 158 mg / ml; 159 mg / ml; 160 mg / ml; 161 mg / ml; 162 mg / ml; 163 mg / ml; 164 mg / ml; 165 mg / ml; 166 mg / ml; 167 mg / ml; 168 mg / ml; 169 mg / ml; 170 mg / ml; 171 mg / ml; 172 mg / ml; 173 mg / ml; 174 mg / ml; 175 mg / ml; 176 mg / ml; 177 mg / ml; 178 mg / ml; 179 mg / ml; 180 mg / ml; 181 mg / ml; 182 mg / ml; 183 mg / ml; 184 mg / ml; 185 mg / ml; 186 mg / ml; 187 mg / ml; 188 mg / ml; 189 mg / ml; 190 mg / ml; 191 mg / ml; 192 mg / ml; 193 mg / ml; 194 mg / ml; 195 mg / ml; 196 mg / ml; 197 mg / ml; 198 mg / ml; 199 mg / ml; 200 mg / ml; 201 mg / ml; 202 mg / ml; 203 mg / ml; 204 mg / ml; 205 mg / ml; 206 mg / ml; 207 mg / ml; 208 mg / ml; 209 mg / ml; 210 mg / ml; 211 mg / ml; 212 mg / ml; 213 mg / ml; 214 mg / ml; 215 mg / ml; 216 mg / ml; 217 mg / ml; 218 mg / ml; 219 mg / ml; 220 mg / ml; 221 mg / ml; 222 mg / ml; 223 mg / ml; 224 mg / ml; 225 mg / ml; 226 mg / ml; 227 mg / ml; 228 mg / ml; 229 mg / ml; 230 mg / ml; 231 mg / ml; 232 mg / ml; 233 mg / ml; 234 mg / ml; 235 mg / ml; 236 mg / ml; 237mg / ml; 238 mg / ml; 239 mg / ml; 240 mg / ml; 241 mg / ml; 242 mg / ml; 243 mg / ml; 244 mg / ml; 245 mg / ml; 246 mg / ml; 247 mg / ml; 248 mg / ml; 249 mg / ml; 250 mg / ml; 251 mg / ml; 252 mg / ml; 253 mg / ml; 254 mg / ml; 255 mg / ml; 256 mg / ml; 257 mg / ml; 258 mg / ml; 259 mg / ml; 260 mg / ml; 261 mg / ml; 262 mg / ml; 263 mg / ml; 264 mg / ml; 265 mg / ml; 266 mg / ml; 267 mg / 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. Other VEGF antagonist concentrations are contemplated herein, as long as the concentration functions in accordance with embodiments herein.[000193] In an embodiment of the invention, a pharmaceutical formulation for use in a method of the present invention is of such a concentration as to contain about 4, 6, 8, 10, 12, 14, 16, 18 or 20 mg VEGF receptor fusion protein (e.g., aflibercept), or the amount of such protein in any of the acceptable doses thereof which are discussed herein, in 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; 64 µl; 65 µl; 66 µl; 67 µl; 68 µl; 69 µl; 70 µl; 71 µl; 72 µl; 73 µl; 74 µl; 75 µl; 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. [000194] The present invention includes methods of using (as discussed herein) any of the formulations set forth under “Illustrative Formulations” herein, but wherein the concentration of the VEGF receptor fusion protein (e.g., aflibercept) is substituted with a concentration which is set forth in this section (“VEGF Receptor Fusion Proteins and Other VEGF inhibitors”). [000195] Buffers for use in pharmaceutical formulations herein that may be used in a method of the present invention refer to solutions that resist pH change by use of acid-base conjugates. Buffers are capable of maintaining pH in the range of from about 5.0 to about 6.8, and more typically, from about 5.8 to about 6.5, and most typically, from about 6.0 to about 6.5. In some cases, the pH of the formulation of the present 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. Example buffers for inclusion in formulations herein include histidine-based buffers, for example, histidine and histidine hydrochloride or histidine acetate. Buffers for inclusion in formulations herein can alternatively be phosphate-based buffers, for example, sodium phosphate, acetate-based buffers, for example, sodium acetate or acetic acid, or can be citrate-based, for example, sodium citrate or citric acid. It is also recognized that buffers can be a mix of the above, as long as the buffer functions to buffer the formulations in the above described pH ranges. In some cases, the buffer is from about 5 mM to about 25 mM, or more typically, about 5 mM to about 15 mM. Buffers can be about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM, about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM, about 20 mM, about 21 mM, about 22 mM, about 23 mM, about 24 mM, or about 25 mM. [000196] In an embodiment of the invention, a histidine-based buffer is prepared using histidine and histidine monohydrochloride. [000197] Surfactant for use herein refers to ingredients that protect the higher concentration of VEGF antagonist, e.g., VEGF receptor fusion protein, from various surface and interfacialinduced stresses. As such, surfactants can be used to limit or minimize VEGF receptor fusion protein aggregation, and promote protein solubility. Suitable surfactants herein have been shown to be non-ionic, and can include surfactants that have a polyoxyethylene moiety. Illustrative surfactants in this category include: polysorbate 20, polysorbate 80, poloxamer 188, polyethylene glycol 3350, and mixtures thereof. Surfactants in the formulations can be present at from about 0.02% to about 0.1% weight per volume (w / v), and 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). [000198] Thermal stabilizers for use in pharmaceutical formulations that may be used in methods set forth herein refers to ingredients that provide thermal stability against thermal denaturation of the VEGF antagonist, e.g., VEGF receptor fusion protein, as well as protect against loss of VEGF receptor fusion protein potency or activity. Suitable thermal stabilizers include sugars, and can be sucrose, trehalose, sorbitol or mannitol, or can be amino acids, for example L-proline, L-arginine (e.g., L-arginine monohydrochloride), or taurine. Additionally, thermal stabilizers may also include substituted acrylamides or propane sulfonic acid, or may be compounds like glycerol. [000199] In some cases, the pharmaceutical formulations for use in a method herein include both a sugar and taurine, a sugar and an amino acid, a sugar and propane sulfonic acid, a sugar and taurine, glycerol and taurine, glycerol and propane sulfonic acid, an amino acid and taurine, or an amino acid and propane sulfonic acid. In addition, formulations can include a sugar, taurine and propane sulfonic acid, glycerol, taurine and propane sulfonic acid, as well as L-proline, taurine and propane sulfonic acid. [000200] Embodiments herein may have thermal stabilizers present alone, each independently present at a concentration of, or present in combination at a total concentration of, from about 2% (w / v) to about 10% (w / v) or 4% (w / v) to about 10% (w / v), or about 4% (w / v) to about 9% (w / v), or about 5% (w / v) to about 8% (w / v). Thermal stabilizers in the formulation can be at a concentration of about 2% (w / v), about 2.5% (w / v), about 3% (w / v), about 4% (w / v), about 5% (w / v), about 6% (w / v), about 7% (w / v), about 8% (w / v), about 9% (w / v), about 10% (w / v) or about 20% (w / v). [000201] With respect to taurine and propane sulfonic acid, in an embodiment of the invention, these thermal stabilizers can be present in the formulations at about from 25 mM to about 100 mM, and more typically from about 50 mM to about 75 mM (as compared to the other thermal stabilizers).[000202] Viscosity reducing agents typically are used to reduce or prevent protein aggregation. Viscosity reducing agents for inclusion herein include: sodium chloride, magnesium chloride, D- or L-arginine (e.g., L-arginine monohydrochloride), lysine, or mixtures thereof. When present herein, viscosity reducing agents can be present at from about 10 mM to about 100 mM, and more typically from about 30 mM to about 75 mM, and even more typically from about 40 mM to about 70 mM. In some cases, the viscosity reducing agent is present at about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM, about 95 mM or about 100 mM. [000203] Pharmaceutical formulations for use in a method as set forth herein can also have a pharmaceutically acceptable viscosity for ocular administration, for example, intravitreal injection. Viscosity generally refers to the measure of resistance of a fluid which is being deformed by either shear stress or tensile stress (typically measured by techniques known in the art, viscometer or rheometer, for example). Typical viscosities of formulations for use in a method set forth 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. As such, formulation viscosity herein can be 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 cP, 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 (e.g., when measured at 20oC). [000204] Various embodiments herein do not require inclusion of an inorganic salt, or other viscosity reducing agent, to maintain these highly useful viscosities. Typically, high concentration protein solutions require viscosity reducing agents to avoid protein aggregation and higher viscosity, making the formulations difficult for intravitreal injection and reducing the potency of the VEGF receptor fusion protein. As such, embodiments herein include methods of using formulations that have had substantially no, or no added, sodium chloride (NaCl), magnesium chloride (MgCl2), D- or L-arginine (e.g., L-arginine hydrochloride), lysine or other viscosity reducing agent. [000205] Osmolality is a critical attribute for injectable pharmaceutical formulations for use in a method of the present invention. It is desirable to have products match physiological osmotic conditions. Furthermore, osmolality provides confirmation of soluble content in solution. In an embodiment of the invention, the osmolality of a formulation for use in a method of the present invention is less than or equal to about 506 mmol / Kg or from about 250 to about 506 mmol / Kg., e.g., 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 an embodiment of the invention, the osmolality is lower than about 250 mmol / Kg. [000206] Illustrative pharmaceutical formulations for use in the methods of the present invention include the following: Formulation A: 80 mg / ml aflibercept, 10 mM histidine-based buffer, 5 % (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2. Formulation B: 80 mg / ml aflibercept, 10 mM phosphate-based buffer, 5 % (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2. Formulation C: 80 mg / ml aflibercept, 10 mM citrate-based buffer, 5 % (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2. Formulation D: 80 mg / ml aflibercept, 10 mM histidine-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 80, and 40 mM sodium chloride, with a pH of 6.2. Formulation E: 80 mg / ml aflibercept, 10 mM phosphate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2. Formulation F: 80 mg / ml aflibercept, 10 mM citrate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2. Formulation G: 80 mg / ml aflibercept, 10 mM histidine-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent. Formulation H: 80 mg / ml aflibercept, 10 mM phosphate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent. Formulation I: 80 mg / ml aflibercept, 10 mM citrate-based buffer, 8 % (w / v) sucrose, and 0.03% (w / v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent. Formulation J: 80 mg / ml aflibercept, 10 mM histidine-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent. Formulation K: 80 mg / ml aflibercept, 10 mM phosphate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent. Formulation L: 80 mg / ml aflibercept, 10 mM citrate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.Formulation M: 150 mg / ml aflibercept, 10 mM histidine-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2. Formulation N: 150 mg / ml aflibercept, 10 mM phosphate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2. Formulation O: 150 mg / ml aflibercept, 10 mM citrate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2. Formulation P: 150 mg / ml aflibercept, 10 mM histidine-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 80, and 40 mM sodium chloride, with a pH of 6.2. Formulation Q: 150 mg / ml aflibercept, 10 mM phosphate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2. Formulation R: 150 mg / ml aflibercept, 10 mM citrate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2. Formulation S: 150 mg / ml aflibercept, 10 mM histidine-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent. Formulation T: 150 mg / ml aflibercept, 10 mM phosphate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 20, with a pH of 5.8 to 6.2 (e.g., 6.2), and, optionally, specifically excluding a 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 a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent. Formulation V: 150 mg / ml aflibercept, 10 mM histidine-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent. Formulation W: 150 mg / ml aflibercept, 10 mM phosphate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent. Formulation X: 150 mg / ml aflibercept, 10 mM citrate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent. Formulation Y: 80 mg / ml conbercept, 10 mM histidine-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2. Formulation Z: 80 mg / ml conbercept, 10 mM phosphate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.Formulation AA: 80 mg / ml conbercept, 10 mM citrate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2. 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 a pH of 6.2. Formulation CC: 80 mg / ml conbercept, 10 mM phosphate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2. Formulation DD: 80 mg / ml conbercept, 10 mM citrate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2. Formulation EE: 80 mg / ml conbercept, 10 mM histidine-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent. Formulation FF: 80 mg / ml conbercept, 10 mM phosphate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent. Formulation GG: 80 mg / ml conbercept, 10 mM citrate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent. Formulation HH: 80 mg / ml conbercept, 10 mM histidine-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent. Formulation II: 80 mg / ml conbercept, 10 mM phosphate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent. Formulation JJ: 80 mg / ml conbercept, 10 mM citrate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent. Formulation KK: 150 mg / ml conbercept, 10 mM histidine-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2. Formulation LL: 150 mg / ml conbercept, 10 mM phosphate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2. Formulation MM: 150 mg / ml conbercept, 10 mM citrate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2. 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 a pH of 6.2.Formulation OO: 150 mg / ml conbercept, 10 mM phosphate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2. Formulation PP: 150 mg / ml conbercept, 10 mM citrate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2. Formulation QQ: 150 mg / ml conbercept, 10 mM histidine-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent. Formulation RR: 150 mg / ml conbercept, 10 mM phosphate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent. Formulation SS: 150 mg / ml conbercept, 10 mM citrate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent. Formulation TT: 150 mg / ml conbercept, 10 mM histidine-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent. Formulation UU: 150 mg / ml conbercept, 10 mM phosphate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent. Formulation VV: 150 mg / ml conbercept, 10 mM citrate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent. 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) polysorbate 20, and 50 mM taurine, with a pH of 5.8. 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) polysorbate 20, and 50 mM arginine (e.g., arginine hydrochloride), with a pH of 5.8. 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) proline, 0.03 % (w / v) polysorbate 20, and 50 mM taurine, with a pH of 5.8. 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) proline, 0.03 % (w / v) polysorbate 20, and 50 mM arginine (e.g., arginine hydrochloride), with a pH of 5.8.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) polysorbate 20, and 50 mM PSA, with a pH of 5.8. 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) proline, 0.03 % (w / v) polysorbate 20, and 50 mM PSA, with a pH of 5.8. 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, 0.03 % (w / v) polysorbate 20, and 50 mM arginine (e.g., arginine hydrochloride), with a pH of 5.8. 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) polysorbate 20, and 50 mM PSA, with a pH of 5.8. Formulation EEE: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine- based buffer, 5 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 20 and, optionally, no thermal stabilizer, with a pH of 5.8. Formulation FFF: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 10mM sodium phosphate, 5 % (w / v) sucrose and 0.03 % polysorbate 20 with a pH of 6.2. Formulation GGG: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5% sucrose; 0.03 % polysorbate 20; 50 mM sodium sulfate Formulation HHH: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5% sucrose; 0.03 % polysorbate 20; 50 mM sodium thiocyanate Formulation III: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose, 0.03 % polysorbate 20; 40 mM sodium citrate Formulation JJJ: 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 Formulation KKK: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose, 0.03 % polysorbate 20; 50 mM sodium chloride Formulation LLL: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose; 0.03 % polysorbate 20; 50 mM lysine Formulation MMM: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose; 0.03% polysorbate 20; 50 mM sodium aspartate Formulation NNN: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose; 0.03 % polysorbate 20; 50 mM sodium glutamate Formulation OOO: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose; 0.03% polysorbate 20; 50 mM sodium citrate; 50 mM 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., arginine hydrochloride) Formulation QQQ: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose; 0.03% polysorbate 20; 50 mM sodium aspartate; 50 mM arginine (e.g., arginine hydrochloride) Formulation RRR: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose; 0.03% polysorbate 20; 50 mM sodium glutamate; 50 mM arginine (e.g., arginine hydrochloride) Formulation SSS: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM His, pH 5.8; 5 % sucrose; 0.03 % polysorbate 20; 10 mM L-arginine (e.g., L-arginine hydrochloride) Formulation TTT: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM His, 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, pH 6.2 Formulation VVV: 30 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 20 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, pH 6.2 Formulation WWW: 60 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 10 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, pH 6.2 Formulation XXX: 60 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 20 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, pH 6.2 Formulation YYY: 120 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 10 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, pH 6.2 Formulation ZZZ: 120 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 20 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, 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, 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, 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, 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) polysorbate 20, and 50 mM L-arginine (e.g., L- arginine hydrochloride), with a pH of 5.8.Formulation EEEE: 120.0 mg / ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., + 12 mg / ml), 20 mM histidine-based buffer (e.g., + 2 mM), 5 % (w / v) sucrose (e.g., + 0.5%), 0.03 % (w / v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine (e.g., L-arginine hydrochloride) (e.g., + 5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1). Formulation FFFF: 113.3 mg / ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., 102-125 mg / ml), 20 mM histidine-based buffer (e.g., + 2 mM), 5 % (w / v) sucrose (e.g., + 0.5%), 0.03 % (w / v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine (e.g., L-arginine monohydrochloride) (e.g., + 5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1). Formulation GGGG: 114.3 mg / ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., 103-126 mg / ml), 10 mM histidine-based buffer, for example, including Histidine and Histine-HCl (e.g., + 1 mM), 5 % (w / v) sucrose (e.g., + 0.5%), 0.03 % (w / v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine (e.g., L-arginine monohydrochloride) (e.g., + 5 mM), with a pH of 5.8 (e.g., 5.6- 6.0 or 5.5-6.1). Formulation HHHH: 100.0 mg / ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., + 10 mg / ml), 20 mM histidine-based buffer (e.g., + 2 mM), 5 % (w / v) sucrose (e.g., + 0.5%), 0.03 % (w / v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine (e.g., L-arginine monohydrochloride) (e.g., + 5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1). Formulation IIII: 133.3 mg / ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., + 13 mg / ml), 20 mM histidine-based buffer (e.g., + 2 mM), 5 % (w / v) sucrose (e.g., + 0.5%), 0.03 % (w / v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine (e.g., L-arginine monohydrochloride) (e.g., + 5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1). Formulation JJJJ: 150 mg / ml aflibercept (e.g., aflibercept) (e.g., + 15 mg / ml), 10 mM sodium phosphate, 8% (w / v) sucrose (e.g., + 0.8%), 0.03% (w / v) polysorbate 20 (e.g., 0.02-0.04%) and 50 mM L-arginine (e.g., arginine hydrochloride), pH 6.2 (e.g., 6.0-6.4 or 5.9-6.5). Formulation KKKK: 114.3 mg / ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., + 14 mg / ml), 20 mM histidine-based buffer (e.g., + 2 mM), 5% (w / v) sucrose (e.g., + 0.5%), 0.03% (w / v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine (e.g., arginine monohydrochloride) (e.g., + 5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1); [000207] See International Patent Application Publication No. WO2019 / 217927. [000208] In an embodiment of the invention, the >8 mg VEGF receptor fusion protein, preferably aflibercept, when administered, is in an aqueous pharmaceutical formulation comprising: a VEGF receptor fusion protein comprising two polypeptides that each comprises an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of VEGFR2, and a multimerizing component (e.g., which comprises amino acids 27-457 of SEQ ID NO: 2) at a concentration ofat least about 100 mg / ml; about 5% sucrose; L-arginine (e.g., L-arginine monohydrochloride); a histidine-based buffer (e.g., containing histidine HCl); and about 0.03% surfactant; wherein the formulation has a pH of about 5.0 to about 6.8 (e.g., 5.8 to 6.5, for example 5.8). Preferably the formulation is suitable for intravitreal administration. Other components that may be included are sodium sulfate, sodium thiocyanate, glycine, NaCl, sodium aspartate and / or sodium glutamate. In an embodiment of the invention, the VEGF receptor fusion protein is at a concentration of: 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; 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 from about 6-15 cP at 20°C. The surfactant may be a non-ionic surfactant such as polysorbate 20, polysorbate 80, poloxamer 188, polyethylene glycol 3350 or mixtures thereof. The histidine-based buffer may be at a concentration of about 10 mM to 20 mM. In an embodiment of the invention, the VEGF receptor fusion protein has less than about 3.5% high molecular weight species immediately after manufacture and purification and / or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2- 8°C. [000209] In an embodiment of the invention, the >8 mg VEGF receptor fusion protein is, when administered in an aqueous pharmaceutical formulation, comprising: at least about 100 mg / ml of a VEGF receptor fusion protein comprising two polypeptides that each comprises an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of VEGFR2, and a multimerizing component (e.g., aflibercept); about 10-100 mM L-arginine; sucrose; a histidine-based buffer; and a surfactant; wherein the formulation has a pH of about 5.0 to about 6.8; wherein the VEGF receptor fusion protein has less than about 3.5% high molecular weight species immediately after manufacture and purification and / or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C. [000210] In an embodiment of the invention, the aqueous pharmaceutical formulation includes: • > about 100 mg / ml VEGF receptor fusion protein (e.g., aflibercept), histidine-based buffer and L-arginine; • about 140 mg / ml aflibercept; 20 mM histidine-based buffer; 5% sucrose; 0.03 % polysorbate 20; 10 mM L-arginine; pH 5.8; • about 150 + 15 mg / ml aflibercept, 10 mM phosphate-based buffer, 8 + 0.8% (w / v) sucrose, 0.02-0.04% (w / v) polysorbate 20 and 50 mM L-arginine, pH 5.9-6.5;• about 103-126 mg / ml aflibercept, 10 + 1 mM histidine-based buffer, 5 + 0.5% (w / v) sucrose, 0.02-0.04% (w / v) polysorbate 20, and 50 + 5 mM L-arginine, pH 5.5-6.1; • about 140 mg / ml aflibercept, 10 mM histidine-based 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; • about 114.3 mg / ml aflibercept, 10 mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20 and 50 mM L-arginine, pH 5.8; • > about 100 mg / ml aflibercept, histidine-based buffer and L-arginine; • > about 100 mg / ml aflibercept at about pH 5.8, wherein the formulation forms <3% HMW aggregates after incubation at 5°C for 2 months; • about 114.3 mg / mL aflibercept; 10 mM – 50 mM histidine-based buffer, sugar, non-ionic surfactant, L-Arginine, pH 5.8; or • about 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. [000211] In an embodiment of the invention, the >8 mg VEGF receptor fusion protein is, when administered in an aqueous pharmaceutical formulation comprising 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); a thermal stabilizer which is a sugar, an amino acid, sucrose, mannitol, sorbitol, trehalose, L- proline, glycine, glycerol, taurine or propane sulfonic acid (e.g., at about 2% (w / v) to about 10% (w / v), for example, 5% (w / v)); a buffer which is a histidine-based buffer, a phosphate-based buffer, an acetate-based buffer (e.g., at a concentration of about 5-25 mM, e.g., 10 mM or 20 mM); or a citrate-based buffer; a non-ionic surfactant, such as for example, polyoxyethylene-based, polysorbate 20, polysorbate 80, poloxamer 188 or polyethylene glycol 3350 (e.g., at a concentration of about 0.02% to about 0.1 % (w / v), e.g., 0.03% (w / v)); and a viscosity reducing agent which is NaCl, MgCl2, D-arginine, L-arginine or L-lysine (e.g., at a concentration of about 10-100 mM, e.g., 50 mM), wherein the formulation has a pH of about 5.0 to about 6.8 (e.g., 5.0-6.0 or 5.8). [000212] In an embodiment of the invention, the aflibercept is at a concentration in the 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; 108 mg / ml; 109 mg / ml; 110 mg / ml; 111 mg / ml; 112 mg / ml; 113 mg / ml; 113.3 mg / ml; 114 mg / ml; 114.1 mg / ml; 114.2 mg / ml; 114.3 mg / ml; 114.4 mg / ml;114.5 mg / ml; 114.6 mg / ml, 114.7 mg / ml, 114.8 mg / ml; 114.9 mg / ml; 115 mg / ml; 116 mg / ml; 117 mg / ml; 118 mg / ml; 119 mg / ml; 120 mg / ml; 121 mg / ml; 122 mg / ml; 123 mg / ml; 124 mg / ml; 125 mg / ml; 126 mg / ml; 127 mg / ml; 128 mg / ml; 129 mg / ml; 130 mg / ml; 131 mg / ml; 132 mg / ml; 133 mg / ml; 133.3 mg / ml; 133.4 mg / ml, 134 mg / ml; 135 mg / ml; 136 mg / ml; 137 mg / ml; 138 mg / ml; 139 mg / ml; 140 mg / ml; 141 mg / ml; 142 mg / ml; 143 mg / ml; 144 mg / ml; 145 mg / ml; 146 mg / ml; 147 mg / ml; 148 mg / ml; 149 mg / ml; 150 mg / ml; 151 mg / ml; 152 mg / ml; 153 mg / ml; 154mg / ml; 155 mg / ml; 156 mg / ml; 157mg / ml; 158 mg / ml; 159 mg / ml; 160 mg / ml; 161 mg / ml; 162 mg / ml; 163 mg / ml; 164 mg / ml; 165 mg / ml; 166 mg / ml; 167 mg / ml; 168 mg / ml; 169 mg / ml; 170 mg / ml; 171 mg / ml; 172 mg / ml; 173 mg / ml; 174 mg / ml; 175 mg / ml; 176 mg / ml; 177 mg / ml; 178 mg / ml; 179 mg / ml; 180 mg / ml; 181 mg / ml; 182 mg / ml; 183 mg / ml; 184 mg / ml; 185 mg / ml; 186 mg / ml; 187 mg / ml; 188 mg / ml; 189 mg / ml; 190 mg / ml; 191 mg / ml; 192 mg / ml; 193 mg / ml; 194 mg / ml; 195 mg / ml; 196 mg / ml; 197 mg / ml; 198 mg / ml; 199 mg / ml; 200 mg / ml; 201 mg / ml; 202 mg / ml; 203 mg / ml; 204 mg / ml; 205 mg / ml; 206 mg / ml; 207 mg / ml; 208 mg / ml; 209 mg / ml; 210 mg / ml; 211 mg / ml; 212 mg / ml; 213 mg / ml; 214 mg / ml; 215 mg / ml; 216 mg / ml; 217 mg / ml; 218 mg / ml; 219 mg / ml; 220 mg / ml; 221 mg / ml; 222 mg / ml; 223 mg / ml; 224 mg / ml; 225 mg / ml; 226 mg / ml; 227 mg / ml; 228 mg / ml; 229 mg / ml; 230 mg / ml; 231 mg / ml; 232 mg / ml; 233 mg / ml; 234 mg / ml; 235 mg / ml; 236 mg / ml; 237mg / ml; 238 mg / ml; 239 mg / ml; 240 mg / ml; 241 mg / ml; 242 mg / ml; 243 mg / ml; 244 mg / ml; 245 mg / ml; 246 mg / ml; 247 mg / ml; 248 mg / ml; 249 mg / ml; 250 mg / ml; 251 mg / ml; 252 mg / ml; 253 mg / ml; 254 mg / ml; 255 mg / ml; 256 mg / ml; 257 mg / ml; 258 mg / ml; 259 mg / ml; 260 mg / ml; 261 mg / ml; 262 mg / ml; 263 mg / ml; 264 mg / ml; 265 mg / ml; 266 mg / ml; 267 mg / 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. [000213] In an embodiment of the invention, the aqueous pharmaceutical formulation includes aflibercept at a concentration of at least about 100 mg / ml; sucrose, mannitol, sorbitol, trehalose; a histidine-based buffer; polysorbate 20 or polysorbate 80; and L-arginine, at a pH of about 5.0 to about 6.8; wherein the aflibercept has less than about 3.5% high molecular weight species immediately after manufacture and purification and / or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8oC. [000214] In an embodiment of the invention, the sucrose, mannitol, sorbitol or trehalose is at a concentration of about 2-10% (w / v); the L-arginine is at a concentration of about 10-100 mM; the polysorbate 20 or polysorbate 80 is at a concentration of about 0.02-0.1% (w / v); and the histidine-based buffer is at a concentration of about 5-25 mM; at a pH of about 5.0 to about 6.8.Treatment and Administration [000215] The present invention provides methods for treating angiogenic eye disorders (e.g., nAMD, DR and / or DME) in a subject in need thereof including the step of administering to an eye of the subject (preferably by intravitreal injection), about 8 mg or more of VEGF antagonist or inhibitor, for example, a VEGF receptor fusion protein, preferably aflibercept, about every 8- 24, 12-24, 16-24, 20-24, 21-24, 21, 22, 23 or 24 weeks (preferably, about 24 weeks). [000216] The present invention provides methods for treating angiogenic eye disorders (e.g., nAMD, DR and / or DME) by sequentially administering to an eye of the subject (preferably by intravitreal injection) an initial loading dose (e.g., 2 mg or more, 4 mg or more or, preferably, about 8 mg or more of VEGF antagonist or inhibitor, for example, a VEGF receptor fusion protein, preferably, aflibercept) (e.g., about every 2-4 or 3-5 weeks, preferably 4) followed by additional doses about every 8-24, 12-24, 16-24, 20-24, 21-24, 21, 22, 23 or 24 weeks (preferably, about 24 weeks). For example, the present invention provides methods for treating or preventing angiogenic eye disorders, such as neovascular age related macular degeneration (nAMD), diabetic macular edema (DME) and / or diabetic retinopathy (DR), by administering to an eye of the subject (preferably, by intravitreal injection), sequentially, one or more (e.g., 3 or 4 or 5) doses of about 8 mg or more of VEGF antagonist (e.g., a VEGF receptor fusion protein, preferably, aflibercept) about every 2-4 or 3-5 weeks, e.g., every month (or about every 28 days, 28 + 5 days or about every 4 weeks), followed by one or more doses of about 8 mg or more VEGF antagonist (e.g., a VEGF receptor fusion protein, preferably, aflibercept) every 8- 24, 12-24, 16-24, 20-24, 21-24, 21, 22, 23 or 24 weeks (preferably, about 24 weeks) (or about every 6 months or about every other quarter year or about every 168 days). The dosing regimen including the about 24 week tertiary dosing interval may be referred to herein as a 24 week dosing regimen or 8q24 or HDq24. The teritary dosing interval may, in an embodiment of the invention, be 8-24, 12-24, 16-24, 20-24, 21-24, 21, 22, 23 or 24 weeks (preferably, about 24 weeks) weeks. [000217] “8 mg (±0.8 mg)” includes, for example, 7.2, 8.0, and 8.8 mg. [000218] The present invention also provides methods for treating angiogenic eye disorders (e.g., nAMD, DR and / or DME) by sequentially administering to any eye of the subject (preferably, by intravitreal injection) an initial loading dose (e.g., 2 mg or more, 4 mg or more or, preferably, about 8 mg or more of VEGF antagonist or inhibitor, for example, a VEGF receptor fusion protein, preferably, aflibercept) (e.g., about every 2-4 or 3-5 weeks) followed by additional doses every 12, 16, 20, 12-16, 12-20, 16-20, 16-24, 8-24, 12-24, 16-24, 20-24, 21-24, 21, 22,23 or 24 weeks (preferably, about 24 weeks) wherein the patient receives such treatment of at least 60, 64, 68, 72, 76, 80, 84, 88, 92 or 96 or more weeks. [000219] In addition, the present invention includes methods for treating angiogenic eye disorders (e.g., nAMD, DR and / or DME) by administering to an eye of the subject (preferably by intravitreal injection), one or more times, >8 mg VEGF receptor fusion protein, preferably aflibercept, about every 24 weeks; as well as about every 4 weeks for the first 3, 4 or 5 doses followed by dosing about every 24 weeks. [000220] In an embodiment of the invention, a subject begins receiving the >8 mg maintenance doses (preferably by intravitreal injection) of about every 24 weeks after the ≥8 mg monthly loading doses with no intervening doses. The subject enters the maintenance dose phase rapidly / immediately after the loading dose phase. In an embodiment of the invention, the subject continues receiving the >8 mg 24-week doses without any intervening doses. [000221] For example, the present invention also provides methods for treating angiogenic eye disorders (preferably, nAMD, DME or DR) by administering to an eye of the subject (preferably by intravitreal injection): doses of about >8 mg (for example, in 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; 64 µl; 65 µl; 66 µl; 67 µl; 68 µl; 69 µl; 70 µl; 71 µl; 72 µl; 73 µl; 74 µl; 75 µl; 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) about once every 24 weeks. [000222] In an embodiment of the invention, the subject does not receive a dosing regimen modification (DRM) and / or does not terminate treatment for at least 1, 2, 3, 4 or 5 years. [000223] The present invention also provides methods for improving visual acuity in subjects with type 1 or type 2 diabetes mellitus (e.g., subjects with neovascular age related macular degeneration (nAMD), diabetic macular edema or diabetic retinopathy), by administering to an eye of the subject (preferably by intravitreal injection), sequentially, one or more (e.g., 3 or 4 or 5) doses about every month (or about every 28 days, 28 + 5 days or about every 4 weeks), followed by one or more doses every 24 weeks. [000224] The terms "initial dose," "secondary doses," and "tertiary doses," refer to the temporal sequence of administration of the VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept). Thus, the "initial dose" is the dose which is administered (preferably by intravitreal injection) at the beginning of the treatment regimen (also referred to as the "baseline dose"); the "secondary doses" are the doses which are administered (preferably by intravitrealinjection) after the initial dose; and the "tertiary doses" are the doses which are administered (preferably by intravitreal injection) after the secondary doses. The initial, secondary, and tertiary doses may all contain the same amount of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), but will generally differ from one another in terms of frequency of administration. In certain embodiments, however, the amount of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) contained in the initial, secondary and / or tertiary doses will vary from one another (e.g., adjusted up or down as appropriate) during the course of treatment. [000225] Thus, a dosing regimen of the present invention may be expressed as follows: a method for treating an angiogenic eye disorder (e.g., nAMD, DME or DR) in a subject in need thereof including administering to an eye of the subject in need thereof (preferably by intravitreal injection), a single initial dose of about >8 mg (for example, in 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; 64 µl; 65 µl; 66 µl; 67 µl; 68 µl; 69 µl; 70 µl; 71 µl; 72 µl; 73 µl; 74 µl; 75 µl; 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) of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), followed by one or more (e.g., 2, or 3 or 4, preferably 2) secondary doses of the VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), followed by one or more tertiary doses of the VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept); wherein each secondary dose is administered about 2 to 4 weeks (preferably, about 4 weeks) after the immediately preceding dose; and wherein each tertiary dose is administered about 24 weeks after the immediately preceding dose. [000226] The present invention also provides methods for treating angiogenic eye disorders (e.g., nAMD, DR or DME) by administering to an eye of the subject in need thereof (preferably by intravitreal injection) about >8 mg (for example, in 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; 64 µl; 65 µl; 66 µl; 67 µl; 68 µl; 69 µl; 70 µl; 71 µl; 72 µl; 73 µl; 74 µl; 75 µl; 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; 91µl; 92 µl; 93 µl; 94 µl; 95 µl; 96 µl; 97 µl; 98 µl; 99 µl; or 100 µl) of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) on a PRN basis. [000227] A pro re nata (PRN) treatment protocol calls for intervals between doctor visits to remain fixed (e.g., once every 2, 3, 4, 8, 12, 16, 20 or 24 weeks) and decisions to carry out an injection of VEGF receptor fusion protein to be based on the anatomic findings at each respective visit. A capped PRN dosing regimen is PRN wherein subjects must be treated at a certain minimal frequency, e.g., at least once every 2 or 3 or 4 or 6 months. [000228] Treat & Extend (T&E) regimens call for the time interval between doctor visits to be adjusted based on the patient’s clinical course—e.g., if a subject shows no sign of an active disease (e.g., the macula remains dry, without any leakage), the next one or more intervals can be extended; if there is fluid accumulation, the next interval will be shortened. At each visit following T&E, an injection of VEGF receptor fusion protein will be performed; the current clinical status only has an impact on the duration of the next injection interval. [000229] The present invention includes embodiments wherein, at any point during a HDq24 treatment regimen, the patient can be switched to a PRN, capped PRN or T&E regimen. The PRN, capped PRN and / or T&E may be continued indefinitely or can be stopped at any point and then the HDq24 regimen is re-initiated at any phase thereof. Any HDq24 regimen can be preceded or followed by a period of PRN, capped PRN and / or T&E. [000230] The present invention includes methods wherein one or more additional, non- scheduled doses, in addition to any of the scheduled initial, secondary and / or tertiary doses of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) are administered to a subject. Such doses are typically administered at the discretion of the treating physician depending on the particular needs of the subject. [000231] Thus, the present invention includes methods comprising administering the required doses of the HDq24 regimen, wherein each of the tertiary doses is administered about 24 weeks after the immediately preceding dose, wherein the treatment interval between two tertiary doses is extended (e.g., from about 4, 8, 12, 16 or 20 weeks to about 24 weeks), for example, until signs of disease activity recur or vision deteriorates and then either continuing dosing at the last tertiary interval used or the penultimate tertiary interval used. [000232] The present invention includes methods comprising administering the required doses of the HDq24 regimen, wherein the treatment interval between any two tertiary doses is reduced (e.g., from about 24 weeks to about 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 weeks), for example, until signs of disease activity decrease or vision improves(e.g., BCVA stabilizes or improves and / or CRT stabilizes or reduces) whereupon, optionally, the interval between doses can be extended, e.g., back to a greater interval length. [000233] For example, in an embodiment of the invention, the interval between doses, e.g., during the 12, 16, 20 or 24 week dosing phase, can be lengthened, for example by 4 week increments as appropriate (e.g., from 20 weeks to 24 weeks), for example if: • <5 letter loss in BCVA, e.g., from week 12; and / or • CRT <300 µm on SD-OCT (or <320 µm on Spectralis SD-OCT). In an embodiment of the invention, the subject receives the initial dose, the secondary doses and, then, 20 week tertiary intervals and, then, after about 1 year, extending the tertiary intervals to about 24 weeks. [000234] In an embodiment of the invention, a method of treating an angiogenic eye disorder, such as nAMD, DR or DME, as set forth herein includes the step of evaluating BCVA and / or CRT and lengthening the interval as discussed if one or both of the criteria are met. [000235] For example, in an embodiment of the invention, the interval between doses, e.g., during the 24 week dosing phase, can be shortened (e.g., from 24 weeks to 20, 16, 12 or 8 weeks), for example if: • greater than 5 or 10 letters are lost in BCVA (ETDRS or Snellen equivalent) (e.g., relative to the BCVA observed at about 12 or 16 weeks after treatment initiation) occurs, for example, due to or in association with persistent or worsening nAMD, DR and / or DME; and / or • greater than 25 or 50 micrometers increase in CRT is observed (e.g., relative to the CRT observed at about 12 weeks after treatment initiation). [000236] In an embodiment of the invention, a tertiary dosing interval is increased or decreased at increments of 4 weeks. Decisions to increase or decrease a tertiary dosing interval can be made at one or more office visits to the treating physician. [000237] In an embodiment of the invention, if the criteria for reducing the interval between doses is met in a subject receiving the HDq24 regimen, the interval between doses is decreased to 20 weeks. In an embodiment of the invention, the interval is not decreased to anything shorter than 8 weeks. In an embodiment of the invention, a method of treating an angiogenic eye disorder such as nAMD, DR or DME as set forth herein includes the step of evaluating BCVA and / or CRT and shortening the interval as discussed if one or both of the criteria are met. [000238] See Figure 3 or Figure 4.[000239] Dosing every “24 weeks” refers to dosing about every 6 months, about every 168 days (+ 5 days) or about every other quarter or about twice per year. [000240] Dosing every “month” or after a “month” refers to dosing after about 28 days, about 4 weeks, or about 28 + 5 days and may encompass up to 5 weeks + 5 days. Dosing every “4 weeks” or after “4 weeks” refers to dosing after about 28 days (+ 5 days), about a month or about 28 (+ 5 days), and may encompass up to every 5 weeks (+ 5 days). [000241] Dosing every “2-4 weeks” or after “2-4 weeks” refers to dosing after about 2 weeks (+ 5 days), 3 weeks (+ 5 days) or 4 weeks (+ 5 days). Dosing every “8 weeks” or after “8 weeks” refers to dosing after about 2 months (+ 5 days) or about 56 (+ 5 days). [000242] Dosing every “12 weeks” or after “12 weeks” refers to dosing after about 3 months, about 84 days (+ 5 days), about 90 days (+ 5 days) or about 84 (+ 5 days). Dosing every “16 weeks” or after “16 weeks” refers to dosing after about 4 months or about 112 days (+ 5 days). [000243] Dosing every “12-20 weeks” or after “12-20 weeks” refers to dosing after 12, 13, 14, 15, 16, 17, 18, 19 or 20 weeks (+ 5 days), preferably about 12-16 weeks (+ 5 days), about 12 weeks (+ 5 days), about 16 weeks (+ 5 days) or about 20 weeks (+ 5 days). [000244] Dosing every “12-20 weeks” refers to dosing after about 12, 13, 14, 15, 16, 17, 18, 19 or 20 weeks (+ 5 days), preferably about 12-16 weeks (+ 5 days), about 12 weeks (+ 5 days), about 16 weeks (+ 5 days) or about 20 weeks (+ 5 days). [000245] A dose of > 8 mg encompasses a dose of about 8 mg or doses exceeding 8 mg, for example, about 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg. [000246] Any dosing frequency specified herein may, in an embodiment of the invention, be expressed as the specific frequency “+ 5 days” (e.g., where “24 weeks” is stated, the present invention also includes embodiments such as 24 weeks + 5 days). The term + 5 days includes +1, +2, +3, +4 and / or +5 days. [000247] "Sequentially administering" means that each dose of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) is administered to the eye of a subject at a different point in time, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks or months). The present invention includes methods which comprise sequentially administering to the eye of a subject a single initial dose of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), followed by one or more secondary doses of the VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), followed by one or more tertiary doses of the VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept).[000248] An effective or therapeutically effective dose of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), for treating or preventing an angiogenic eye disorder refers to the amount of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) sufficient to alleviate one or more signs and / or symptoms of the disease or condition in the treated subject, whether by inducing the regression or elimination of such signs and / or symptoms or by inhibiting the progression of such signs and / or symptoms. In an embodiment of the invention, an effective or therapeutically effective dose of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) is about >8 mg every month, for 3 doses, followed by once every 24 weeks. In an embodiment of the invention, the alleviation of signs and / or symptoms is achievement, e.g., by 1 year, of a gain of ≥5, 10 or 15 letters BCVA (relative to baseline) (e.g., >5 letters improvement in a nAMD subject and / or 8-14 letters improvement in a DME patient / subject); achieving a BCVA ≥ 69 letters; achieving no fluid at foveal center; reduction in central retinal thickness (CRT) by about 150 micrometers or more (e.g., below 300 micrometers in an nAMD subject / patient; and / or reduction by at least about 200 micrometers in a DR or RVO patient / subject) or achievement of normal CRT (e.g., about 300 micrometers or less); and / or achievement of no leakage on fluorescein angiography. [000249] Baseline values refer to values prior to initiation of a treatment (pre-dose). [000250] An "angiogenic eye disorder" means any disease of the eye which is caused by or associated with the growth or proliferation of blood vessels or by blood vessel leakage. Non- limiting examples of angiogenic eye disorders that are treatable or preventable using the methods of the present invention include: • age-related macular degeneration (neovascular (nAMD)), • macular edema (ME), • macular edema following retinal vein occlusion (ME-RVO), • retinal vein occlusion (RVO), • central retinal vein occlusion (CRVO), • branch retinal vein occlusion (BRVO), • diabetic macular edema (DME), • choroidal neovascularization (CNV), • iris neovascularization, • neovascular glaucoma, • post-surgical fibrosis in glaucoma, • optic disc neovascularization,• corneal neovascularization, • retinal neovascularization, • vitreal neovascularization, • pannus, • pterygium, • vascular retinopathy, • diabetic retinopathies (DR) (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., in a subject that does not suffer from DME), and • Diabetic retinopathy in a subject who has diabetic macular edema (DME). [000251] The scope of the present invention includes any method set forth herein relating to, for example, nAMD, DR and / or DME, as well as methods relating to an angiogenic eye disorder set forth herein (e.g., ME-RVO). [000252] The present invention provides methods for treating angiogenic eye disorders (e.g., nAMD, DR and / or DME) in an eye of a subject in need thereof (preferably by intravitreal injection), by sequentially administering initial loading doses (e.g., 2 mg or more, 4 mg or more or, preferably, about 8 mg or more of VEGF antagonist or inhibitor, for example, a VEGF receptor fusion protein such as aflibercept) (e.g., about every 2-4 or 3-5 weeks, preferably every 4 weeks; preferably, three initial loading doses) followed by additional doses about every 24 weeks, wherein the subject achieves and / or maintains, e.g., by week 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 after treatment initiation,: • an improvement in Diabetic Retinopathy Severity Scale (DRSS), e.g., by at least 2 or 3 steps; • an improvement in best corrected visual acuity; • a dry retina; • a gain in best corrected visual acuity; • a gain in best corrected visual acuity of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 letters or >5, >10 or >15 letters; • a BCVA of at least 69 letters; • a decrease in central retinal thickness (CRT), e.g., by about 100, 125, 150, 175 or 200 micrometers; • no vascular leakage as measured by fluorescein angiography (FA);• an improvement from pre-treatment baseline in National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) total score; • a retina without fluid (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF]) at the foveal center and in center subfield; • maintenance of a fluid-free retina (total fluid, IRF and / or SRF at foveal center and in the center subfield); • a lack of macular edema; • a retina free of fluid on spectral domain optical coherence tomography (SD- OCT); and / or • Does not deviate from the HDq24 treatment regimen once started. [000253] In an embodiment of the invention, a subject receiving a HDq24 treatment for an angiogenic eye disorder (e.g., nAMD, DR and / or DME) as set forth herein achieves one or more of the following: • Does not receive a dose regimen modification, e.g., wherein the interval between doses (e.g., tertiary doses) is reduced from the HDq24, HDq12-20 or HDq12 or HDq16 or HDq20 treatment regimen once started, e.g., for at least 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; • Receives 100% of all scheduled doses, e.g., for at least 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; • Non-inferior BVCA compared to that of aflibercept which is intravitreally dosed 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; • Increase in BCVA (according to ETDRS letter score) of about 7, 8 or 9 letters by week 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, e.g., wherein the baseline BCVA is about 61, 62 and 63; • Improvement in BCVA, by 4 weeks after initiation of treatment, of about 4 or 5 letters (ETDRS or Snellen equivalent) when on HDq12 or HDq24 regimen; or of about 4 or 5 letters (ETDRS or Snellen equivalent) when on HDq16 or HDq24 regimen; • Improvement in BCVA, by 8 weeks after initiation of treatment, of about 6 letters (ETDRS or Snellen equivalent) when on HDq12 or HDq24 regimen; or of about 5 or 6 letters (ETDRS or Snellen equivalent) when on HDq16 or HDq24 regimen;• Improvement in BCVA, by 12 weeks after initiation of treatment, of about 6 or 7 letters (ETDRS or Snellen equivalent) when on HDq12 or HDq24 regimen; or of about 6 letters (ETDRS or Snellen equivalent) when on HDq16 or HDq24 regimen; • Improvement in BCVA, by 16 weeks after initiation of treatment, of about 6 or 7 letters (ETDRS or Snellen equivalent) when on HDq12 or HDq24 regimen; or of 7 letters (ETDRS or Snellen equivalent) when on HDq16 or HDq24 regimen; • Improvement in BCVA, by 20 weeks after initiation of treatment, of about 6 letters (ETDRS or Snellen equivalent) when on HDq12 or HDq24 regimen; or of about 6 letters (ETDRS or Snellen equivalent) when on HDq16 or HDq24 regimen; • Improvement in BCVA, by 24 weeks after initiation of treatment, of about 7 letters (ETDRS or Snellen equivalent) when on HDq12 or HDq24 regimen; or of about 5 or 6 letters (ETDRS or Snellen equivalent) when on HDq16 or HDq24 regimen; • Improvement in BCVA, by 28 weeks after initiation of treatment, of about 7 or 8 letters (ETDRS or Snellen equivalent) when on HDq12 or HDq24 regimen; or of about 7 or 8 letters (ETDRS or Snellen equivalent) when on HDq16 or HDq24 regimen; • Improvement in BCVA, by 32 weeks after initiation of treatment, of about 7 letters (ETDRS or Snellen equivalent) when on HDq12 or HDq24 regimen; or of about 7 or 8 letters (ETDRS or Snellen equivalent) when on HDq16 or HDq24 regimen; • Improvement in BCVA, by 36 weeks after initiation of treatment, of 8 letters (ETDRS or Snellen equivalent) when on HDq12 or HDq24 regimen; or of about 6 or 7 letters (ETDRS or Snellen equivalent) when on HDq16 or HDq24 regimen; • Improvement in BCVA, by 40 weeks after initiation of treatment, of about 8 letters (ETDRS or Snellen equivalent) when on HDq12 or HDq24 regimen; or of about 6 or 7 letters (ETDRS or Snellen equivalent) when on HDq16 or HDq24 regimen; • Improvement in BCVA, by 44 weeks after initiation of treatment, of about 8 letters (ETDRS or Snellen equivalent) when on HDq12 or HDq24 regimen; or of about 7 or 8 letters (ETDRS or Snellen equivalent) when on HDq16 or HDq24 regimen; • Improvement in BCVA, by 48 weeks after initiation of treatment, of about 8 or 9 letters (ETDRS or Snellen equivalent) when on HDq12 or HDq24 regimen; or of about 7 or 8 letters (ETDRS or Snellen equivalent) when on HDq16 or HDq24 regimen e.g., wherein the baseline BCVA is about 61, 62 or 63 letters (ETDRS or Snellen equivalent); • Improvement in BCVA, by 60 weeks after initiation of treatment, of about 8 or 9 letters (ETDRS or Snellen equivalent) when on HDq12 or HDq24 regimen; or of about 7 or 8 letters(ETDRS or Snellen equivalent) when on HDq16 or HDq24 regimen, e.g., wherein the baseline BCVA is about 61, 62 or 63 letters (ETDRS or Snellen equivalent); • Improvement in BCVA, by 96 weeks after initiation of treatment, of about 5 or 6 letters (ETDRS or Snellen equivalent) when on HDq12 or HDq24 regimen; or of about 5, 6 or 7 letters (ETDRS or Snellen equivalent) when on HDq16 or HDq24 regimen, e.g., wherein the baseline BCVA is about 60, 61, 62 or 63 letters (ETDRS or Snellen equivalent); • An improvement in BCVA between weeks 48 and 60 of about 8 or 9 letters, or up to 40 letters (ETDRS or Snellen equivalent) when on the HDq12 or HDq24 regimen, e.g., when the basline BCVA is about 63 or 64; or an improvement in BCVA between weeks 48 and 60 of about 7 or 8 letters or up to 40 letters (ETDRS or Snellen equivalent) when on the HDq16 or HDq24 regimen e.g., when the basline BCVA is about 61 or 62; • An improvement in BCVA by about week 8 after initiation of treatment which is maintained (e.g., within about +1 or +2 ETDRS letters or Snellen equivalent) thereafter during the treatment regimen, e.g., to at least week 48; • Improvement in best corrected visual acuity (according to ETDRS letter score) (e.g., by week 12, 24, 36, 48, 60, 72, 84, 90 or 96 from start of treatment); • Improvement in best corrected visual acuity (BVCA) by week 4, week 8, week 12, week 16, week 20, week 24, week 28, week 32, week 36, week 40, week 44, or week 48 from start of treatment; • Increase in BCVA, e.g., as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart or Snellen equivalent (e.g., by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 or 48 weeks from start of treatment) by ≥4 letters, ≥5 letters, ≥6 letters, ≥7 letters, ≥8 letters, > 9 letters or > 10 letters; • Between weeks 36 and 48, a change in BCVA score (according to ETDRS letter score) from initiation of treatment of about 7, 8 or 9, e.g., wherein the BCVA at any point between week 36 to 48 is about 60 or 70; • Between weeks 36 and 48, a change in BCVA score (according to ETDRS letter score) from initiation of treatment of up to 38 letters when on the HDq12 or HDq16 regimen, e.g., wherein BCVA at baseline is between about 27 and 79; • Between weeks 48 and 60, a change in BCVA score (according to ETDRS letter score) from initiation of treatment of about 7, 8 or 9; e.g., wherein the BCVA at any point between week 48 to 60 is about 69, 70, 71, 72 or 73;• A BCVA improvement, e.g., by week 48 following treatment initiation, of about 9 or 10 letters (ETDRS or Snellen equivalent) when baseline BCVA is about <73 ETDRS letters when on HDq12 or HDq24regimen; • A BCVA improvement, e.g., by week 48 following treatment initiation, of about 5 or 6 letters (ETDRS or Snellen equivalent) when baseline BCVA is about >73 ETDRS letters when on HDq12 or HDq24 regimen; • A BCVA improvement, e.g., by week 48 following treatment initiation, of about 8 or 9 letters (ETDRS or Snellen equivalent) when baseline BCVA is about <73 ETDRS letters when on HDq16 or HDq24 regimen; • A BCVA improvement, e.g., by week 48 following treatment initiation, of about 4 or 5 letters (ETDRS or Snellen equivalent) when baseline BCVA is about >73 ETDRS letters when on HDq16 or HDq24 regimen; • A BCVA improvement, e.g., by week 48 following treatment initiation, of about 7 or 8 letters (ETDRS or Snellen equivalent) when baseline CRT is < about 400 micrometers when on HDq12 or HDq24 regimen; • A BCVA improvement, e.g., by week 48 following treatment initiation, of about 9 or 10 letters (ETDRS or Snellen equivalent) when baseline CRT is >400 micrometers when on HDq12 or HDq24 regimen; • A BCVA improvement, e.g., by week 48 following treatment initiation, of about 5 or 6 letters (ETDRS or Snellen equivalent) when baseline CRT is < about 400 micrometers when on HDq16 or HDq24 regimen; • A BCVA improvement, e.g., by week 48 following treatment initiation, of about 9 or 10 letters (ETDRS or Snellen equivalent) when baseline CRT is > about 400 micrometers when on HDq16 or HDq24 regimen; • Did not lose 5, 10 or 15 letters by week 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 (according to ETDRS letter score); • Gains at least 5, 10 or 15 letter by week 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 (according to ETDRS letter score); • Does not lose 5, 10, 15 or 69 letters or more BCVA (e.g., after week 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 from start of treatment); • Between weeks 48 and 60, a BCVA score (according to ETDRS letter score) of about 69, 70, 71, 72 or 73;• BCVA (according to ETDRS letter score) of at least about 69 letters, e.g., by week 48 or 60; • A BCVA by 4 weeks after initiation of treatment of about 68 letters (ETDRS or Snellen equivalent) when on the HDq12 or HDq24 regimen; or a BCVA of about 66 letters (ETDRS or Snellen equivalent) when on the or HDq24 HDq16 regimen; • A BCVA by 8 weeks after initiation of treatment of about 70 letters (ETDRS or Snellen equivalent) when on the HDq12 or HDq24 regimen; or a BCVA of about 67 letters (ETDRS or Snellen equivalent) when on the HDq16 or HDq24 regimen; • A BCVA by 12 weeks after initiation of treatment of about 70 letters (ETDRS or Snellen equivalent) when on the HDq12 or HDq24 regimen; or a BCVA of about 68 letters (ETDRS or Snellen equivalent) when on the HDq16 or HDq24 regimen; • A BCVA by 16 weeks after initiation of treatment of about 71 letters (ETDRS or Snellen equivalent) when on the HDq12 or HDq24 regimen; or a BCVA of about 69 letters (ETDRS or Snellen equivalent) when on the HDq16 or HDq24 regimen; • A BCVA by 20 weeks after initiation of treatment of about 70 letters (ETDRS or Snellen equivalent) when on the HDq12 or HDq24 regimen; or a BCVA of about 68 letters (ETDRS or Snellen equivalent) when on the HDq16 or HDq24 regimen; • A BCVA by 24 weeks after initiation of treatment of about 71 letters (ETDRS or Snellen equivalent) when on the HDq12 or HDq24 regimen; or a BCVA of about 67 letters (ETDRS or Snellen equivalent) when on the HDq16 or HDq24 regimen; • A BCVA by 28 weeks after initiation of treatment of about 72 letters (ETDRS or Snellen equivalent) when on the HDq12 or HDq24 regimen; or a BCVA of about 70 letters (ETDRS or Snellen equivalent) when on the HDq16 or HDq24 regimen; • A BCVA by 32 weeks after initiation of treatment of about 71 letters (ETDRS or Snellen equivalent) when on the HDq12 or HDq24 regimen; or a BCVA of about 70 letters (ETDRS or Snellen equivalent) when on the HDq16 or HDq24 regimen; • A BCVA by 36 weeks after initiation of treatment of about 71 letters (ETDRS or Snellen equivalent) when on the HDq12 or HDq24 regimen; or a BCVA of about 68 letters (ETDRS or Snellen equivalent) when on the HDq16 or HDq24 regimen; • A BCVA by 40 weeks after initiation of treatment of about 72 letters (ETDRS or Snellen equivalent) when on the HDq12 or HDq24 regimen; or a BCVA of about 69 letters (ETDRS or Snellen equivalent) when on the HDq16 or HDq24 regimen;• A BCVA by 44 weeks after initiation of treatment of about 72 letters (ETDRS or Snellen equivalent) when on the HDq12 or HDq24regimen; or a BCVA of about 70 letters (ETDRS or Snellen equivalent) when on the HDq16 or HDq24 regimen; • A BCVA by 48 weeks after initiation of treatment of about 73 letters (ETDRS or Snellen equivalent) when on the HDq12 or HDq24regimen; or a BCVA of about 70 letters (ETDRS or Snellen equivalent) when on the HDq16 or HDq24 regimen; • A BCVA by 96 weeks after initiation of treatment of about 66, 67, 68, 69 or 70 letters (ETDRS or Snellen equivalent) when on the HDq12 or HDq24 regimen; or a BCVA of about 66, 67, 68, 69 or 70 letters (ETDRS or Snellen equivalent) when on the HDq16 or HDq24 regimen; • A BCVA between weeks 36 and 48 of about 71, 72, 73 or 74 (ETDRS or Snellen equivalent) when on the HDq12 or HDq24 regimen, e.g., when the basline BCVA is about 57, 58, 59, 60, 61, 62, 63 or 64; or a BCVA between weeks 36 and 48 of about 69, 70, 71, 72 or 73 (ETDRS or Snellen equivalent) when on the HDq16 or HDq24 regimen e.g., when the basline BCVA is about 55, 56, 57, 58, 59, 60, 61, or 62; • A BCVA between weeks 48 and 60 of about 69 or 70 or up to 94 (ETDRS or Snellen equivalent) when on the HDq12 or HDq24 regimen, e.g., when the basline BCVA is about 63 or 64; or a BCVA between weeks 48 and 60 of about 72 or 73 or up to 89 (ETDRS or Snellen equivalent) when on the HDq16 or HDq24regimen e.g., when the basline BCVA is about 61 or 62; • Gain of >5, >10 or ≥15 letters BCVA (according to ETDRS letter score) (e.g., by week 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 from start of treatment); • ≥ 2 step improvement in 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 start of treatment); • ≥ 3 step improvement in 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 weeks from start of treatment); • Retina without fluid (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF]) at the foveal center or center subfield (e.g., by week 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 from start of treatment) (e.g., as measured by optical coherence tomography (OCT); • No vascular leakage in the retina as measured by fluorescein angiography (FA) (e.g., by week 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 from start of treatment);• Maintenance of a fluid-free retina (total fluid, IRF and / or SRF at foveal center and in the center subfield) (e.g., by week 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 from start of treatment); • Reduction in total area of fluorescein leakage within ETDRS grid (mm2) at week 48 or 60 by about 12, 12.6, 13, 13.6, 13.9 or 14 mm2or more, or up to abou 57 or 68 mm2(e.g., as measured by fluorescein angiography); • Reduction in total area of fluorescein leakage within ETDRS grid (mm2) at week 48 by about 13.13.3, 13.9 or 14 mm2or more (e.g., up to about 52 mm2) (e.g., as measured by fluorescein angiography) when on the HDq12 or HDq24 regimen; • Reduction in total area of fluorescein leakage within ETDRS grid (mm2) at week 48 by about 7, 7.7, 8, 9, 9.4 or 10 mm2or more (e.g., up to about 55 mm2) (e.g., as measured by fluorescein angiography) when on the HDq16 or HDq24 regimen; • Retina free of fluid on spectral domain optical coherence tomography (SD-OCT) (e.g., by week 12, 24, 36, 48, 60, 72, 84, 90 or 96 from start of treatment); • Retina without fluid (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF]) at the foveal center (e.g., by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 or 48 weeks from start of treatment); • Dry retina (e.g., by week 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 from start of treatment); • Foveal center without fluid (e.g., by week 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 from start of treatment) (e.g., as measured by optical coherence tomography (OCT); • A change in central retinal thickness, by 4 weeks after initiation of treatment of about - 118 or -118.3 micrometers (+17, 18 or 19 micrometers) when on the HDq12 or HDq24 regimen; or of about -124 or -125 or -124.9 or -125.5 micrometers (+17, 18 or 19 micrometers) when on the HDq16 or HDq24 regimen; • A change in central retinal thickness, by 8 weeks after initiation of treatment of about - 137 or -137.4 micrometers (+17, 18 or 19 micrometers) when on the HDq12 or HDq24 regimen; or of about -139 or -140 or -139.6 or -140.3 micrometers (+17, 18 or 19 micrometers) when on the HDq16 or HDq24 regimen; • A change in central retinal thickness, by 12 weeks after initiation of treatment of about -150 or -150.1 micrometers (+17, 18 or 19 micrometers) when on the HDq12 or HDq24 regimen; or of about -152 or -153 or -152.7 or -153.4 micrometers (+17, 18 or 19 micrometers) when on the HDq16 or HDq24regimen;• A change in central retinal thickness, by 16 weeks after initiation of treatment of about -139 or -139.4 micrometers (+17, 18 or 19 micrometers) when on the HDq12 or HDq24 regimen; or of about -145 or -146 or -145.5 or -146.4 micrometers (+17, 18 or 19 micrometers) when on the HDq16 or HDq24 regimen; • A change in central retinal thickness, by 20 weeks after initiation of treatment of about -117 or -117.1 micrometers (+17, 18 or 19 micrometers) when on the HDq12 or HDq24 regimen; or of about -112 or -113 or -112.5 or -113.3 micrometers (+17, 18 or 19 micrometers) when on the HDq16 or HDq24 regimen; • A change in central retinal thickness, by 24 weeks after initiation of treatment of about -158 or -158.1 micrometers (+17, 18 or 19 micrometers) when on the HDq12 or HDq24 regimen; or of about -103 or -104 or -103.8 or -104.3 micrometers (+17, 18 or 19 micrometers) when on the HDq16 or HDq24 regimen; • A change in central retinal thickness, by 28 weeks after initiation of treatment of about -146 or -147 or -146.7 micrometers (+17, 18 or 19 micrometers) when on the HDq12 or HDq24 regimen; or of about -162 or -162.3 micrometers (+17, 18 or 19 micrometers) when on the HDq16 or HDq24 regimen; • A change in central retinal thickness, by 32 weeks after initiation of treatment of about -132 micrometers (+17, 18 or 19 micrometers) when on the HDq12 or HDq24 regimen; or of about -145 or -146 or -145.8 micrometers (+17, 18 or 19 micrometers) when on the HDq16 or HDq24 regimen; • A change in central retinal thickness, by 36 weeks after initiation of treatment of about -168 or -168.1 micrometers (+17, 18 or 19 micrometers) when on the HDq12 or HDq24 regimen; or of about -124 or -125 or -124.7 or -125.2 micrometers (+17, 18 or 19 micrometers) when on the HDq16 or HDq24 regimen; • A change in central retinal thickness, by 40 weeks after initiation of treatment of about -163 micrometers (+17, 18 or 19 micrometers) when on the HDq12 or HDq24regimen; or of about -122 or -123 or -122.5 or -123.1 micrometers (+17, 18 or 19 micrometers) when on the HDq16 or HDq24 regimen; • A change in central retinal thickness, by 44 weeks after initiation of treatment of about -147 or -148 or -147.4 micrometers (+17, 18 or 19 micrometers) when on the HDq12 or HDq24regimen; or of about -164 or -164.1 or -164.3 micrometers (+17, 18 or 19 micrometers) when on the HDq16 or HDq24 regimen; • A change in central retinal thickness, by 48 weeks after initiation of treatment of about -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) when on the HDq12 or HDq24 regimen; or of about -148 or -149 or -148.3 or -149.4 micrometers (+9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 micrometers) when on the HDq16 or HDq24 regimen, e.g., wherein baseline CRT is about 449, 450, 455 or 460 micrometers; • A change in central retinal thickness, by 96 weeks after initiation of treatment of about - 115; -116; -117; -118; -119; -120; -121; -122; -123; -124; -125; -126; -127; -128; -129; -130; - 131; -132; -133; -134; -135; -136; -137; -138; -139; -140; -141; -142; -143; or -144 micrometers (+ 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 micrometers) when on the HDq12 or HDq24 regimen; or of about -121; -122; -123; -124; -125; -126; -127; -128; -129; -130; -131; - 132; -133; -134; -135; -136; -137; -138; -139; -140; -141; -142; -143; -144; -145; -146; -147; - 148; -149; -150; -151; -152; -153; micrometers (+9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 micrometers) when on the HDq16 or HDq24 regimen, e.g., wherein baseline CRT is about 350 or 370 micrometers; • A change in central retinal thickness, by 60 weeks after initiation of treatment of about -181, -182, -181.95, -176, -176.24 or -177 (+ 6, 10, 17, 18 or 19 micrometers) micrometers when on the HDq12 or HDq24 regimen (e.g., wherein the baseline CRT is about 460 micrometers); or of about -166, -166.26, -167 or -167.18 micrometers (+8, 9, 10, 17, 18 or 19 micrometers) when on the HDq16 or HDq24 regimen (e.g., wherein the baseline CRT is about 457 micrometers); • A change in central retinal thickness of about -118 or -119 or -118.3 micrometers, between initiation of treatment (week 0) and week 4 when on the HDq12 or HDq24 regimen; • A change in central retinal thickness of about -19, -20 or -19.1 micrometers, between weeks 4 and 8 when on the HDq12 or HDq24 regimen; • A change in central retinal thickness of about -12, -13 or -12.7 micrometers, between weeks 8 and 12 when on the HDq12 or HDq24regimen; • A change in central retinal thickness of about -40, or -41 micrometers, between weeks 20 and 24 when on the HDq12 or HDq24 regimen; • A change in central retinal thickness of about -36, -37 or -36.1 micrometers, between weeks 32 and 36 when on the HDq12 or HDq24 regimen; • A change in central retinal thickness of about -24, -25 or -24.3 micrometers, between weeks 44 and 48 when on the HDq12 or HDq24 regimen; • A change in central retinal thickness of about -124, -125 or -124.9 micrometers, between initiation of treatment (week 0) and week 4 when on the HDq16 or HDq24 regimen;• A change in central retinal thickness of about –14, -15 or -14.7 micrometers, between weeks 4 and 8 when on the HDq16 or HDq24 regimen; • A change in central retinal thickness of about -13, -14 or -13.1 micrometers, between weeks 8 and 12 when on the HDq16 or HDq24 regimen; • A change in central retinal thickness of about -58, -59 or -58.5 micrometers, between weeks 24 and 28 when on the HDq16 or HDq24 regimen; • A change in central retinal thickness of about -41, -42 or -41.6 micrometers, between weeks 40 and 44 when on the HDq16 or HDq24 regimen; • By week 60, a change in BCVA of at least 9 letters when on the HDq12 or HDq24 dosing regimen; and / or a change in BCVA of at least 8 letters when in the HDq16 or HDq24 dosing regimen; • By week 64, a change in BCVA of at least 9 letters when on the HDq12 or HDq24 dosing regimen; and / or a change in BCVA of at least 8 letters when in the HDq16 or HDq24 dosing regimen; • By week 68, a change in BCVA of at least 8 letters when on the HDq12 or HDq24 dosing regimen; and / or a change in BCVA of at least 8 letters when in the HDq16 or HDq24 dosing regimen; • By week 72 , a change in BCVA of at least 8 letters when on the HDq12 or HDq24 dosing regimen; and / or a change in BCVA of at least 6 letters when in the HDq16 or HDq24 dosing regimen; • By week 76, a change in BCVA of at least 8 letters when on the HDq12 or HDq24 dosing regimen; and / or a change in BCVA of at least 7 letters when in the HDq16 or HDq24 dosing regimen; • By week 80, a change in BCVA of at least 8 letters when on the HDq12 or HDq24 dosing regimen; and / or a change in BCVA of at least 8 letters when in the HDq16 or HDq24 dosing regimen; • By week 84, a change in BCVA of at least 8 letters when on the HDq12 or HDq24 dosing regimen; and / or a change in BCVA of at least 8 letters when in the HDq16 or HDq24 dosing regimen; • By week 88, a change in BCVA of at least 9 letters when on the HDq12 or HDq24 dosing regimen; and / or a change in BCVA of at least 7 letters when in the HDq16 or HDq24 dosing regimen;• By week 92, a change in BCVA of at least 9 letters when on the HDq12 or HDq24 dosing regimen; and / or a change in BCVA of at least 7 letters when in the HDq16 or HDq24 dosing regimen; • By week 96, 9 letters when on the HDq12 or HDq24 dosing regimen; and / or a change in BCVA of at least 8letters when in the HDq16 or HDq24 dosing regimen • By week 60 a BCVA of at least 73 letters and / or when on the HDq12 or HDq24 regimen; and / or a BCVA or at least 70 letters when on the HDq16 or HDq24 regimen; • By week 64 a BCVA of at least 73 letters and / or when on the HDq12 or HDq24 regimen; and / or a BCVA or at least 70 letters when on the HDq16 or HDq24 regimen; • By week 68 a BCVA of at least 72 letters and / or when on the HDq12 or HDq24 regimen; and / or a BCVA or at least 69 letters when on the HDq16 or HDq24 regimen; • By week 72, a BCVA of at least 73 letters and / or when on the HDq12 or HDq24 regimen; and / or a BCVA or at least 68 letters when on the HDq16 or HDq24 regimen; • By week 76, a BCVA of at least 73 letters and / or when on the HDq12 or HDq24 regimen; and / or a BCVA or at least 68 letters when on the HDq16 or HDq24 regimen; • By week 80, a BCVA of at least 72 letters and / or when on the HDq12 or HDq24 regimen; and / or a BCVA or at least 69 letters when on the HDq16 or HDq24 regimen; • By week 84, a BCVA of at least 72 letters and / or when on the HDq12 or HDq24 regimen; and / or a BCVA or at least 70 letters when on the HDq16 or HDq24 regimen; • By week 88, a BCVA of at least 73 letters and / or when on the HDq12 or HDq24 regimen; and / or a BCVA or at least 69 letters when on the HDq16 or HDq24 regimen; • By week 92, a BCVA of at least 73 letters and / or when on the HDq12 or HDq24 regimen; and / or a BCVA or at least 69 letters when on the HDq16 or HDq24 regimen; • By week 96, a BCVA of at least 73 letters and / or when on the HDq12 or HDq24 regimen; and / or a BCVA or at least 69 letters when on the HDq16 or HDq24 regimen; • By week 60, a change in CRT of at least -176.2 micrometers when on the HDq12 or HDq24 regimen; and / or a change in CRT of at least -167.2 micrometers when on the HDq16 or HDq24 regimen; • By week 64, a change in CRT of at least -173.4 micrometers when on the HDq12 or HDq24 regimen; and / or a change in CRT of at least -164.3 micrometers when on the HDq16 or HDq24 regimen;• By week 68, a change in CRT of at least -159.4 micrometers when on the HDq12 or HDq24 regimen; and / or a change in CRT of at least -153.9 micrometers when on the HDq16 or HDq24 regimen; • By week 72, a change in CRT of at least -166.6 micrometers when on the HDq12 or HDq24 regimen; and / or a change in CRT of at least -134.2 micrometers when on the HDq16 or HDq24 regimen; • By week 76, a change in CRT of at least -181.1 micrometers when on the HDq12 or HDq24 regimen; and / or a change in CRT of at least -160.8 micrometers when on the HDq16 or HDq24 regimen; • By week 80 a change in CRT of at least -168.9 micrometers when on the HDq12 or HDq24 regimen; and / or a change in CRT of at least -164 micrometers when on the HDq16 or HDq24 regimen; • By week 84, a change in CRT of at least -177.5 micrometers when on the HDq12 or HDq24 regimen; and / or a change in CRT of at least -150.2 micrometers when on the HDq16 or HDq24 regimen; • By week 88, a change in CRT of at least -171.2micrometers when on the HDq12 or HDq24 regimen; and / or a change in CRT of at least -144.3 micrometers when on the HDq16 or HDq24 regimen; • By week 92, a change in CRT of at least -166.7 micrometers when on the HDq12 or HDq24 regimen; and / or a change in CRT of at least -155.5 micrometers when on the HDq16 or HDq24 regimen; • By week 96, a change in CRT of at least -185.3 micrometers when on the HDq12 or HDq24 regimen; and / or a change in CRT of at least -155 micrometers when on the HDq16 or HDq24 regimen; • By week 60, a CRT of 275.5 micrometers when on the HDq12 or HDq24 regimen; and / or 289.5 micrometers when on the HDq16 or HDq24 regimen; • By week 64 a CRT of 279.4 micrometers when on the HDq12 or HDq24 regimen; and / or 289.6 micrometers when on the HDq16 or HDq24 regimen; • By week 68, a CRT of 294.5 micrometers when on the HDq12 or HDq24 regimen; and / or 305.3 micrometers when on the HDq16 or HDq24 regimen; • By week 72, a CRT of 284.2 micrometers when on the HDq12 or HDq24 regimen; and / or 327.2 micrometers when on the HDq16 or HDq24 regimen;• By week 76, a CRT of 270.6 micrometers when on the HDq12 or HDq24 regimen; and / or 302 micrometers when on the HDq16 or HDq24 regimen; • By week 80, a CRT of 284.6 micrometers when on the HDq12 or HDq24 regimen; and / or 293.5 micrometers when on the HDq16 or HDq24 regimen; • By week 84, a CRT of 274.7 micrometers when on the HDq12 or HDq24 regimen; and / or 310.8 micrometers when on the HDq16 or HDq24 regimen; • By week 88, a CRT of 283.7 micrometers when on the HDq12 or HDq24 regimen; and / or 312.3 micrometers when on the HDq16 or HDq24 regimen; • By week 92, a CRT of 285.7 micrometers when on the HDq12 or HDq24 regimen; and / or 301.8 micrometers when on the HDq16 or HDq24 regimen; • By week 60, a change in BCVA of at least 7 letters when on the HDq12 or HDq24 regimen; and / or a change in BCVA of at least 7 letters when on the HDq16 or HDq24; • By week 64, a change in BCVA of at least 7 letters when on the HDq12 or HDq24 regimen; and / or a change in BCVA of at least 6 letters when on the HDq16 or HDq24; • By week 68, a change in BCVA of at least 6 letters when on the HDq12 or HDq24 regimen; and / or a change in BCVA of at least 6 letters when on the HDq16 or HDq24; • By week 72 a change in BCVA of at least 6 letters when on the HDq12 or HDq24 regimen; and / or a change in BCVA of at least 6 letters when on the HDq16 or HDq24; • By week 76 a change in BCVA of at least 6 letters when on the HDq12 or HDq24 regimen; and / or a change in BCVA of at least 6 letters when on the HDq16 or HDq24; • By week 80 a change in BCVA of at least 6 letters when on the HDq12 or HDq24 regimen; and / or a change in BCVA of at least 6 letters when on the HDq16 or HDq24; • By week 84 a change in BCVA of at least 6 when on the HDq12 or HDq24 regimen; and / or a change in BCVA of at least 6 when on the HDq16 or HDq24; • By week 88 a change in BCVA of at least 6 letters when on the HDq12 or HDq24 regimen; and / or a change in BCVA of at least 6 letters when on the HDq16 or HDq24; • By week 92 a change in BCVA of at least 6 letters when on the HDq12 or HDq24 regimen; and / or a change in BCVA of at least 6 letters when on the HDq16 or HDq24; • By week 96 a change in BCVA of at least 6 letters when on the HDq12 or HDq24 regimen; and / or a change in BCVA of at least 6 letters when on the HDq16 or HDq24; • By week 60 a BCVA of 67 letters when on the HDq12 or HDq24 regimen; • By week 64 a BCVA of 67 letters when on the HDq12 or HDq24 regimen; • By week 68 a BCVA of 67 letters when on the HDq12 or HDq24 regimen;• By week 72 a BCVA of 66 letters when on the HDq12 or HDq24 regimen; • By week 76 a BCVA of 67 letters when on the HDq12 or HDq24 regimen; • By week 80 a BCVA of 67 letters when on the HDq12 or HDq24 regimen; • By week 84 a BCVA of 66 letters when on the HDq12 or HDq24 regimen; • By week 88 a BCVA of 67 letters when on the HDq12 or HDq24 regimen; • By week 92 a BCVA of 67 letters when on the HDq12 or HDq24 regimen; • By week 96 a BCVA of 67 letters when on the HDq12 or HDq24 regimen; • By week 60 a BCVA of 67 letters when on the HDq16 or HDq24 regimen; • By week 64 a BCVA of 66 letters when on the HDq16 or HDq24 regimen; • By week 68 a BCVA of 67 letters when on the HDq16 or HDq24 regimen; • By week 72 a BCVA of 66 letters when on the HDq16 or HDq24 regimen; • By week 76 a BCVA of 66 letters when on the HDq16 or HDq24 regimen; • By week 80 a BCVA of 66 letters when on the HDq16 or HDq24 regimen; • By week 84 a BCVA of 66 letters when on the HDq16 or HDq24 regimen; • By week 88 a BCVA of 66 letters when on the HDq16 or HDq24 regimen; • By week 92 a BCVA of 66 letters when on the HDq16 or HDq24 regimen; • By week 96 a BCVA of 66 letters when on the HDq16 or HDq24 regimen; • By week 60 a central subfield retinal thickness of 219 micrometers when on the HDq12 or HDq24 regimen; • By week 64 a central subfield retinal thickness of 226 micrometers when on the HDq12 or HDq24 regimen; • By week 68 a central subfield retinal thickness of 230 micrometers when on the HDq12 or HDq24 regimen; • By week 72 a central subfield retinal thickness of 227 micrometers when on the HDq12 or HDq24 regimen; • By week 76 a central subfield retinal thickness of 226 micrometers when on the HDq12 or HDq24 regimen; • By week 80 a central subfield retinal thickness of 228 micrometers when on the HDq12 or HDq24 regimen; • By week 84 a central subfield retinal thickness of 223 micrometers when on the HDq12 or HDq24 regimen; • By week 88 a central subfield retinal thickness of 226 micrometers when on the HDq12 or HDq24 regimen;• By week 92 a central subfield retinal thickness of 230 micrometers when on the HDq12 or HDq24 regimen; • By week 96 a central subfield retinal thickness of 222 micrometers when on the HDq12 or HDq24 regimen; • By week 60 a central subfield retinal thickness of 222 micrometers when on the HDq16 or HDq24 regimen; • By week 64 a central subfield retinal thickness of 222 micrometers when on the HDq16 or HDq24 regimen; • By week 68 a central subfield retinal thickness of 228 micrometers when on the HDq16 or HDq24 regimen; • By week 72 a central subfield retinal thickness of 234 micrometers when on the HDq16 or HDq24 regimen; • By week 76 a central subfield retinal thickness of 218 micrometers when on the HDq16 or HDq24 regimen; • By week 80 a central subfield retinal thickness of 221 micrometers when on the HDq16 or HDq24 regimen; • By week 84 a central subfield retinal thickness of 223 micrometers when on the HDq16 or HDq24 regimen; • By week 88 a central subfield retinal thickness of 224 micrometers when on the HDq16 or HDq24 regimen; • By week 92 a central subfield retinal thickness of 218 micrometers when on the HDq16 or HDq24 regimen; • By week 96 a central subfield retinal thickness of 221 micrometers when on the HDq16 or HDq24 regimen; • By week 60 a choroidal neovascularization size (mm2) of 2.15when on the HDq12 or HDq24 regimen; • By week 60 a choroidal neovascularization size (mm2) of 2.65 when on the HDq16 or HDq24 regimen; • By week 96a choroidal neovascularization size (mm2) of 2.22 when on the HDq12 or HDq24 regimen; • By week 96a choroidal neovascularization size (mm2) of 1.78 when on the HDq16 or HDq24 regimen; • By week 60 a total lesion area (mm2) of 5.9 when on the HDq12 or HDq24 regimen;• By week 60 a total lesion area (mm2) of 6.3 when on the HDq16 or HDq24 regimen; • By week 96 a total lesion area (mm2) of 6.2 when on the HDq12 or HDq24 regimen; • By week 96 a total lesion area (mm2) of 6.5 when on the HDq16 or HDq24 regimen; • Any of the improvements in anatomical (e.g., reduction in central retinal thickness, absolute central retinal thickness or lack of retinal fluid) or visual parameters (e.g., improvement in BCVA or absolute BCVA) specified in Example 1 or Example 2 herein at the particular timepoint indicated (e.g., at week 48, 60, 64, 68, 72, 76, 80, 84, 88, 92 or 96), in the tables and / or figures therein, for that parameter; • A reduction in CRT by week 4, 5, 6, 7 or 8 after initiation of treatment which is maintained (e.g., within about +17, +18 or +19 micrometers) thereafter during the treatment regimen, e.g., to at least week 48; • Decrease in central retinal thickness (CRT), for example, by about 100, 125, 150, 175 or 200 micrometers (e.g., by week 12, 24, 36, 48, 60, 72, 84, 90 or 96 from start of treatment); • Reduction in CRT of about 148-182 micrometers (e.g., 148, 149, 150, 151, 152, 153, 154, 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) by week 48 or 60 (e.g., as measured by optical coherence tomography (OCT)), for example, wherein the baseline CRT is about 449, 450, 455 or 460 micrometers; • Decrease in central retinal thickness (CRT), for example, by at least about 100, 125, 130, 135, 140, 145, 149, 150, 155, 160, 165, 170, 171, 172, 173, 174 or 175 micrometers (e.g., by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 or 48 from start of treatment); • Ocular (e.g., intraocular pressure) and non-ocular safety (e.g., hypertensive events or APTC events) or death rate, in a subject suffering from an angiogenic eye disorder, e.g., DR or DME, similar to that of aflibercept which is intravitreally dosed 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; • At about 0.1667 days after the first dose, free aflibercept concentration in plasma of about 0.149 (+0.249) mg / l; e.g., wherein at baseline free aflibercept concentration in plasma not detectable, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks; • At about 0.3333 days after the first dose, free aflibercept concentration in plasma of about 0.205 (+0.250) mg / l; e.g., wherein at baseline free aflibercept concentration in plasma not detectable, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks;• At about 1 day after the first dose, free aflibercept concentration in plasma of about 0.266 (+0.211) mg / l; e.g., wherein at baseline free aflibercept concentration in plasma not detectable, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks; • At about 2 days after the first dose, free aflibercept concentration in plasma of about 0.218 (+0.145) mg / l; e.g., wherein at baseline free aflibercept concentration in plasma not detectable, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks; • At about 4 days after the first dose, free aflibercept concentration in plasma of about 0.140 (+0.0741) mg / l; e.g., wherein at baseline free aflibercept concentration in plasma not detectable, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks; • At about 7 days after the first dose, free aflibercept concentration in plasma of about 0.0767 (+0.0436) mg / l; e.g., wherein at baseline free aflibercept concentration in plasma not detectable, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks; • At about 14 days after the first dose, free aflibercept concentration in plasma of about 0.0309 (+0.0241) mg / l; e.g., wherein at baseline free aflibercept concentration in plasma not detectable, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks; • At about 21 days after the first dose, free aflibercept concentration in plasma of about 0.0171 (+0.0171) mg / l; e.g., wherein at baseline free aflibercept concentration in plasma not detectable, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks; • At about 28 days after the first dose, free aflibercept concentration in plasma of about 0.00730 (+0.0113) mg / l; e.g., wherein at baseline free aflibercept concentration in plasma not detectable, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks; • At about 0.1667 days after the first dose, adjusted bound aflibercept concentration in plasma of about 0.00698 (+0.0276) mg / l; e.g., wherein at baseline there is about 0.00583 mg / l (+0.0280) adjusted bound aflibercept concentration, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks; • At about 0.3333 days after the first dose, adjusted bound aflibercept concentration in plasma of about 0.00731 (+0.0279) mg / l; e.g., wherein at baseline there is about 0.00583 mg / l(+0.0280) adjusted bound aflibercept concentration, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks; • At about 1 days after the first dose, adjusted bound aflibercept concentration in plasma of about 0.0678 (+0.0486) mg / l; e.g., wherein at baseline there is about 0.00583 mg / l (+0.0280) adjusted bound aflibercept concentration, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks; • At about 2 days after the first dose, adjusted bound aflibercept concentration in plasma of about 0.138 (+0.0618) mg / l; e.g., wherein at baseline there is about 0.00583 mg / l (+0.0280) adjusted bound aflibercept concentration, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks; • At about 4 days after the first dose, adjusted bound aflibercept concentration in plasma of about 0.259 (+0.126) mg / l; e.g., wherein at baseline there is about 0.00583 mg / l (+0.0280) adjusted bound aflibercept concentration, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks; • At about 7 days after the first dose, adjusted bound aflibercept concentration in plasma of about 0.346 (+0.151) mg / l; e.g., wherein at baseline there is about 0.00583 mg / l (+0.0280) adjusted bound aflibercept concentration, for example, wherein the subject has not received intravitreal VEGF inhibitor (e.g., aflibercept) treatment for at least 12 weeks; • At about 14 days after the first dose, adjusted bound aflibercept concentration in plasma of about 0.374 (+0.110) mg / l; e.g., wherein at baseline there is about 0.00583 mg / l (+0.0280) adjusted bound...

Claims

We claim:

1. A method - for treating or preventing an angiogenic eye disorder, neovascular age related macular degeneration (nAMD), diabetic retinopathy (DR) and / or diabetic macular edema (DME), in a subject in need thereof, - for improving best corrected visual acuity in a subject in need thereof with nAMD, DR and / or DME; or - for promoting retinal drying in a subject with an angiogenic eye disorder, nAMD, DR and / or DME in need thereof; comprising administering to an eye of the subject, one or more doses of about 8 mg (±0.8 mg) or more of VEGF receptor fusion protein about once every 8-24, 12-24, 16-24, 20-24, 21-24, 21, 22, 23 or 24 weeks.

2. The method of claim 1 for treating or preventing an angiogenic eye disorder, neovascular age related macular degeneration (nAMD), diabetic retinopathy (DR) and / or diabetic macular edema (DME), in a subject in need thereof, comprising administering to an eye of the subject, a single initial dose of about 8 mg (±0.8 mg) or more of a 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; wherein each secondary dose is administered about 2, 3, 4 or 2-4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 8-24, 12-24, 16-24, 20-24, 21-24, 21, 22, 23 or 24 weeks after the immediately preceding dose.

3. The method of any one of claims 1-2 for treating or preventing an angiogenic eye disorder, neovascular age related macular degeneration (nAMD), diabetic retinopathy (DR) and / or diabetic macular edema (DME), in a subject in need thereof, comprising administering to an eye of the subject, a single initial dose of about 8 mg (±0.8 mg) or more of a VEGF receptor fusion protein, followed bytwo secondary doses of about 8 mg (±0.8 mg) or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 8-24, 12-24, 16-24, 20-24, 21-24, 21, 22, 23 or 24 weeks after the immediately preceding dose.

4. A method for treating or preventing an angiogenic eye disorder, neovascular age related macular degeneration (nAMD), diabetic retinopathy and / or diabetic macular edema, in a subject in need thereof, comprising administering to an eye of the subject, about 3 doses of about 8 mg (±0.8 mg) VEGF receptor fusion protein in a formulation that comprises about 114.3 mg / ml VEGF receptor fusion protein at an interval of about once every 4 weeks; wherein after said 3 doses, administering one or more doses of the VEGF receptor fusion protein at an interval which is lengthened up to about 24 weeks.

5. A method for slowing the clearance of free aflibercept from the ocular compartment after an intravitreal injection relative to the rate of clearance of aflibercept from the ocular compartment after an intravitreal injection of 2 mg or ≤4 mg aflibercept comprising intravitreally injecting into an eye of a subject in need thereof, a single initial dose of about 8 mg (±0.8 mg)or more of aflibercept, followed by one or more secondary doses of about 8 mg (±0.8 mg) or more of the aflibercept, followed by one or more tertiary doses of about 8 mg (±0.8 mg) or more of the aflibercept; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 8-24, 12-24, 16-24, 20-24, 21-24, 21, 22, 23 or 24 weeks after the immediately preceding dose.

6. The method of any one of claims 1-5 wherein the clearance of free aflibercept from the ocular compartment is about 34% slower than that from the ocular compartment after an intravitreal injection of 2 or ≤4 mg aflibercept.

7. The method of any one of claims 1-6 wherein the clearance of free aflibercept from the ocular compartment is about 0.37-0.46 mL / day or 0.41 mL / day after an intravitreal injection of ≥8 mg (±0.8 mg) aflibercept.

8. A method for increasing the duration of efficacy and / or the time for the amount of free aflibercept to reach the lower limit of quantitation (LLOQ) in the ocular compartment of a subject after an intravitreal injection of aflibercept, relative to the time to reach LLOQ of the amount of free aflibercept in the ocular compartment of a subject after an intravitreal injection of about 2 mg or <4 mg aflibercept, comprising intravitreally injecting into an eye of a subject in need thereof, a single initial dose of about 8 mg (±0.8 mg) or more of aflibercept, followed by one or more secondary doses of about 8 mg (±0.8 mg) or more of the aflibercept, followed by one or more tertiary doses of about 8 mg (±0.8 mg) or more of the aflibercept; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 8-24, 12-24, 16-24, 20-24, 21-24, 21, 22, 23 or 24 weeks after the immediately preceding dose.

9. The method of any one of claims 1-8 wherein the duration of efficacy and / or the time for the amount of free aflibercept to reach the lower limit of quantitation (LLOQ) in the ocular compartment of a subject after said intravitreal injection of aflibercept is increased by about 5 or 6 weeks, relative to the time to reach LLOQ of the amount of free aflibercept in the ocular compartment of a subject after an intravitreal injection of about 2 or ≤4 mg aflibercept.

10. The method of any one of claims 1-9 wherein the time for the amount of free aflibercept to reach the lower limit of quantitation (LLOQ) in the ocular compartment of a subject after said intravitreal injection of aflibercept is increased by more than about 1, 2, 1.2 or 1.3 weeks relative to the time to reach LLOQ of free aflibercept in the ocular compartment of a subject after an intravitreal injection of about 2 or ≤4 mg aflibercept. 11 The method of any one of claims 1-10 wherein the time for the amount for free aflibercept to reach the lower limit of quantitation (LLOQ) in the ocular compartment of a subject after said intravitreal injection of ≥8 mg (±0.8 mg) aflibercept is about 15 weeks.

12. The method of any one of claims 1-11 wherein the time for the amount of free aflibercept to reach the lower limit of quantitation (LLOQ) in the ocular compartment of a subject after said intravitreal injection of ≥8 mg (±0.8 mg) aflibercept is greater than about 8, 8.7, 8.71, 9, 9.2, 9.21 or 10 weeks.

13. A method for increasing the time for free aflibercept to reach the lower limit of quantitation (LLOQ) in the plasma of a subject after an intravitreal injection of aflibercept relative to the time to reach LLOQ of free aflibercept in the plasma of a subject after an intravitreal injection of about 2 or ≤4 mg aflibercept, comprising intravitreally injecting into an eye of a subject in need thereof, a single initial dose of about 8 mg (±0.8 mg) or more of aflibercept, followed by one or more secondary doses of about 8 mg (±0.8 mg) or more of the aflibercept, followed by one or more tertiary doses of about 8 mg (±0.8 mg) or more of the aflibercept; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 8-24, 12-24, 16-24, 20-24, 21-24, 21, 22, 23 or 24 weeks after the immediately preceding dose.

14. The method of claim 13 wherein said LLOQ of free aflibercept measured in plasma is about 0.0156 mg / L.

15. The method of any one of claims 1-14 wherein the time for free aflibercept to reach the lower limit of quantitation (LLOQ) in the plasma of a subject after said intravitreal injection of aflibercept is increased by about 2 weeks relative to the time to reach LLOQ of free aflibercept in the plasma of a subject after an intravitreal injection of about 2 mg aflibercept.

16. The method of any one of claims 1-15 wherein the time for free aflibercept to reach the lower limit of quantitation (LLOQ) in the plasma of a subject after said intravitreal injection of ≥8 mg (±0.8 mg) aflibercept is about 3, 3.5, 3.8 or 4 weeks.

17. The method of any one of claims 1-16 wherein the time for free aflibercept to reach the lower limit of quantitation (LLOQ) in the plasma of a subject after said intravitreal injection of ≥8 mg (±0.8 mg) aflibercept is greater than about 1.5 or 1.6 weeks.

18. The method of any one of claims 5-17 wherein ≤4mg is about 2 mg or 2-4 mg.

19. The method of any one of claims 13-18 wherein the subject suffers from an angiogenic eye disorder, neovascular age related macular degeneration, diabetic retinopathy and / or diabetic macular edema.

20. The method of any one of claims 1-19 wherein the ≥8 mg (±0.8 mg) aflibercept is in an aqueous pharmaceutical formulation comprising histidine-based buffer.

21. The method of any one of claims 1-20 wherein the ≥8 mg (±0.8 mg) aflibercept is in an aqueous pharmaceutical formulation comprising arginine. 22.The method of any one of claims 1-21 wherein the ≥8 mg (±0.8 mg) aflibercept is in an aqueous pharmaceutical formulation having a pH of about 5.

8. 23.The method of any one of claims 1-22 wherein the ≥8 mg (±0.8 mg) aflibercept is in an aqueous pharmaceutical formulation comprising a sugar or polyol. 24.The method of any one of claims 1-23 wherein the ≥8 mg (±0.8 mg) aflibercept is in an aqueous pharmaceutical formulation comprising a sucrose. 25.The method of any one of claims 1-24 wherein the ≥8 mg (±0.8 mg) aflibercept is in an aqueous pharmaceutical formulation wherein the aflibercept has less than about 3.5% high molecular weight species immediately after manufacture and purification and / or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2- 8°C.

26. The method of any one of claims 1-25 wherein the ≥8 mg (±0.8 mg) aflibercept is in an aqueous pharmaceutical formulation comprising an aqueous pharmaceutical formulation comprising: at least about 100 mg / ml of a VEGF receptor fusion protein comprising two polypeptides that each comprises an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of VEGFR2, and a multimerizing component; about 10-100 mM L-arginine; sucrose; a histidine-based buffer; and a surfactant; wherein the formulation has a pH of about 5.0 to about 6.8; wherein the VEGF receptor fusion protein has less than about 3.5% high molecular weightspecies immediately after manufacture and purification and / or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C.

27. A method - for treating or preventing an angiogenic eye disorder, neovascular age related macular degeneration (nAMD), diabetic retinopathy (DR) and / or diabetic macular edema (DME), in a subject in need thereof, - for improving best corrected visual acuity in a subject in need thereof with nAMD, DR and / or DME; or - for promoting retinal drying in a subject with an angiogenic eye disorder, nAMD, DR and / or DME in need thereof; comprising administering to an eye of the subject, a single initial dose of about 8 mg (±0.8 mg) or more of a VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg (±0.8 mg) or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2, 3, 4 or 2-4 weeks after the immediately preceding dose; and each tertiary dose is administered about 8-23, 20, 21, 22, or 23 weeks after the immediately preceding dose, wherein if the subject exhibits:

1. <5 letter loss in BCVA; 2. CRT <300 μm or <320 μm; 3. No fluid at the central subfield on OCT; and / or 4. No new onset foveal hemorrhage or foveal neovascularization; lengthening the interval between tertiary doses by one or more weeks.

28. The method of claim 27 wherein the interval between tertiary doses was lengthened one or more times prior.

29. The method of claim 27-28 wherein the interval between tertiary doses was lengthened one or more times prior, to 24 weeks;or, from: 8 weeks to 12, 16 or 20 weeks; 12 weeks to 16 or 20; and / or 16 weeks to 20 weeks.

30. The method of any one of claims 27-29 wherein lengthening the interval between tertiary doses by one or more weeks is lengthening the interval between tertiary doses by one or more 4 week increments.

31. The method of any one of claims 27-30 wherein said 8-23 weeks is 8, 12, 16 or 20 weeks.

32. The method of claim 31 wherein said 8-23 weeks is 20 weeks.

33. The method of any one of claims 27-32 wherein said interval between tertiary doses is lengthened if the subject exhibits 1. <5 letter loss in BCVA; and 2. CRT <300 μm or <320 μm.

34. The method of claim 33 wherein the subject has DR and / or DME.

35. The method of any one of claims 27-32 wherein said interval between tertiary doses is lengthened if the subject exhibits 1. BCVA loss <5 letters; and 2. No fluid at the central subfield; and 3. No new onset foveal hemorrhage or foveal neovascularization.

36. The method of claim 35 wherein the subject has nAMD.

37. The method of any one of claims 27-36 wherein said: • <5 letter loss in BCVA is <5 letter loss in BCVA from week 12 from treatment initiation; • CRT <300 μm or <320 μm is from SD-OCT; • CRT <300 μm is from Cirrus SD-OCT; • CRT <320 μm is from Spectralis SD-OCT; and / or • No fluid at the central subfield is on OCT.

38. A method - for treating or preventing an angiogenic eye disorder, neovascular age related macular degeneration (nAMD), diabetic retinopathy (DR) and / or diabetic macular edema (DME), in a subject in need thereof, - for improving best corrected visual acuity in a subject in need thereof with nAMD, DR and / or DME; or - for promoting retinal drying in a subject with an angiogenic eye disorder, nAMD, DR and / or DME in need thereof; comprising administering to an eye of the subject, a single initial dose of about 8 mg (±0.8 mg) or more of a VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg (±0.8 mg) or more of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) or more of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 8-24, 12-24, 16-24, 20-24, 21-24, 21, 22, 23 or 24 weeks after the immediately preceding dose wherein if the subject exhibits 1. BCVA loss >5 or >10 letters; 2. >25 μm or >50 μm increase in central retinal thickness (CRT); 3. new foveal hemorrhage; 4. new foveal neovascularization; and / or 5. persistent or worsening DME shortening the interval between tertiary doses by one or more weeks.

39. The method of claim 38 wherein shortening the interval between tertiary doses by one or more weeks is shortening the interval between tertiary doses by one or more 4 week increments.

40. The method of any one of claims 38-39 wherein said interval between tertiary doses is shortened if the subject exhibits 1. >10 letter loss in BCVA in association with persistent or worsening DME; and 2. >50 μm increase in CRT.

41. The method of claim 40 wherein the subject has DR and / or DME.

42. The method of any one of claims 38-39 wherein said interval between tertiary doses is lengthened if the subject exhibits 1. BCVA loss >5 letters, and 2. >25 μm increase in central retinal thickness (CRT) or new foveal hemorrhage or new foveal neovascularization.

43. The method of claim 42 wherein the subject has nAMD.

44. The method of any one of claims 38-43 wherein said: • >10 letter loss in BCVA, in association with persistent or worsening DME is >10 letter loss in BCVA from week 12 from treatment initiation or 4 weeks after the last secondary dose, in association with persistent or worsening DME; • >50 μm increase in CRT is from week 12 from treatment initiation • BCVA loss >5 letters is from week 12 from treatment initiation, and • >25 μm increase in central retinal thickness (CRT) or new foveal hemorrhage or new foveal neovascularization is >25 μm increase in central retinal thickness (CRT) from week 12 from treatment initiation or new foveal hemorrhage or new foveal neovascularization.

45. The method of any one or claims 1-44 wherein by week 96 from treatment initiation, the subject exhibits one or more of: • A BCVA improvement of about 6, 7, 8 or 9 letters; • A BCVA improvement of 39, 40, 41, 42, 43, 44, 45, 46 or 47 letters; • Does not lose 5 or more, 10 or more or 15 or more letters BCVA; • A BCVA of about 65, 66, 67, 68, 69, 70, 71, 72 or 73 letters; • gains 5 or more, 10 or more or 15 or more letters BCVA; • 2 or more step improvement in DRSS; • A decrease in CRT of about 149, 152, 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; 184; 185, 194 micrometers;• Between week 48 and week 96 of treatment, further improvement or maintenance of BCVA improvement from baseline ± 1 or 2 letters; • Between week 48 and week 96 of treatment, maintenance of BCVA or about 66 ± 2 letters; • Between week 48 and week 96 of treatment, maintenance of a fluid-free retinal center subfield; • A CRT of about 267; 268; 269; 270; 271; 272; 273; 274; 275; 276; 277; 278; 279; 280; 281; 282; 283; 284; 285; 286; 287; 288; 289; 290; 291; 292; 293; 294; 295; 296; 297; 298; 299; 300; 301; 302; 303; or 304 micrometers; • Between week 48 and week 96 of treatment further reduction or maintenance of central subfield thickness or central retinal thickness reduction from baseline ± 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; micrometers; • No IRF; • No SRF; • No IRF and no SRF; • No significant change in intraocular pressure; • No significant change in systolic blood pressure; and / or • No significant change in diastolic blood pressure.

46. The method of claim 45 wherein the subject has DR and / or DME.

47. The method of any one or claims 1-46 wherein by week 96 from treatment initiation, the subject exhibits one or more of: • A BCVA improvement of about 5, 6 or 7 letters; • A BCVA improvement of 43, 44, 45, 46, 47 or 48 letters; • A BCVA of 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93 or 94 letters; • Does not lose 5 or more, 10 or more or 15 or more letters BCVA; • gains 5 or more, 10 or more or 15 or more letters BCVA; • 2 or more step improvement in DRSS; • A decrease in CRT of about 12; 13; 14; 15; 16; 17; 18; 19; 20; 21; 22; 23; 24; 25; 26; 27; 28; 29; 30; 31; 32; 33; 34; 35; 36; 37; 38; 39; 40; 41; 42; 43; 44; 45; 46; 47; 48; 49; 50; 51; 52; 53; 54; 55; 56; 57; 58; 59; 60; 61; 62; 63; 64; 65; 66; 67; 68; 69; 70; 71; 72; 73; 74; 75; 76; 77; 78; 79; 80; 81; 82; 83; 84; 85; 86; 87; 88; 89; 90; 91; 92; 93; 94; 95; 96;97; 98; 99; 100; 101; 102; 103; 104; 105; 106; 107; 108; 109; 110; 111; 112; 113; 114; 115; 116; 117; 118; 119; 120; 121; 122; 123; 124; 125; 126; 127; 128; 129; 130; 131; 132; 133; 134; 135; 136; 137; 138; 139; 140; 141; 142; 143; 144; 145; 146; 147; 148; 149; 150; 151; 152; 153; 154; 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; 184; 185; 186; 187; 188; 189; 190; 191; 192; 193; 194; 195; 196; 197; 198; 199; 200; 201; 202; 203; 204; 205; 206; 207; 208; 209; 210; 211; 212; 213; 214; 215; 216; 217; 218; 219; 220; 221; 222; 223; 224; 225; 226; 227; 228; 229; 230; 231; 232; 233; 234; 235; 236; 237; 238; 239; 240; 241; 242; 243; 244; 245; 246; 247; 248; 249; 250; 251; 252; 253; 254; 255; 256; 257; 258; 259; 260; 261; 262; 263; 264; 265; 266; 267; 268; 269; 270; 271; 272; 273; 274; 275; 276; 277; 278; 279; 280; 281; 282; 283; 284; 285; 286; 287; 288; 289; 290; 291; 292; 293; or 294 micrometers; • A CRT of about 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; 184; 185; 186; 187; 188; 189; 190; 191; 192; 193; 194; 195; 196; 197; 198; 199; 200; 201; 202; 203; 204; 205; 206; 207; 208; 209; 210; 211; 212; 213; 214; 215; 216; 217; 218; 219; 220; 221; 222; 223; 224; 225; 226; 227; 228; 229; 230; 231; 232; 233; 234; 235; 236; 237; 238; 239; 240; 241; 242; 243; 244; 245; 246; 247; 248; 249; 250; 251; 252; 253; 254; 255; 256; 257; 258; 259; 260; 261; 262; 263; 264; 265; 266; 267; 268; 269; 270; 271; 272; 273; 274; 275; 276; 277; 278; 279; 280; 281; 282; 283; 284; 285; or 286 micrometers; • A choroidal neovascularization size decrease of about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mm2; • A choroidal neovascularization size of about 0, 1, 2 or 3 mm2; • No leakage observed on fluorescein angiography; • Total lesion size of about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mm2; • Decrease in total lesion size of about 0, 0.1, 0.2 or 0.3 mm2; • A NEI-VFQ-25 total score of about 80; • A NEI-VFQ-25 total score change from baseline of about 2 or 3; • No IRF; • No SRF; • No IRF and no SRF; • No significant change in pre-dose intraocular pressure; • No significant change in systolic blood pressure; and / or• No significant change in diastolic blood pressure.

48. The method of claim 47 wherein the subject has nAMD.

49. The method of any one of claims 1-48 wherein a subject having any one or more of ocular or periocular infection; active intraocular inflammation; and / or hypersensitivity; is excluded from administration of VEGF receptor fusion protein to the eye.

50. The method of claim 49 further comprising a step of evaluating the subject for: ocular or periocular infection; active intraocular inflammation; and / or hypersensitivity; and excluding the subject from said administration if any one or more if found in the subject.

51. The method of any one of claims 49-50 further comprising monitoring the subject during said treatment or prevention for conjunctival hemorrhage, cataract, vitreous detachment, vitreous floaters, corneal epithelium defect and / or increased intraocular pressure.

52. The method of any one of claims 1-51 comprising, prior to each administration, providing • one single-dose glass vial having a protective plastic cap and a stopper containing an aqueous formulation comprising 8 mg (±0.8 mg) VEGF receptor fusion protein in about 70 microliters; • one 18-gauge x 1½-inch, 5-micron, filter needle that includes a tip and a bevel; • one 30-gauge x ½-inch injection needle; and • one 1-mL Luer lock syringe having a graduation line marking for 70 microliters of volume; packaged together; then (1) visually inspecting the aqueous formulation in the vial and, if particulates, cloudiness, or discoloration are visible, then using another vial of aqueous formulation containing the VEGF receptor fusion protein; (2) removing the protective plastic cap from the vial; and(3) cleaning the top of the vial with an alcohol wipe; then using aseptic technique: (4) removing the 18-gauge x 1½-inch, 5-micron, filter needle and the 1 mL syringe from their packaging; (5) attaching the filter needle to the syringe by twisting it onto the Luer lock syringe tip; (6) pushing the filter needle into the center of the vial stopper until the needle is completely inserted into the vial and the tip touches the bottom or a bottom edge of the vial; (7) withdrawing all of the VEGF receptor fusion protein vial contents into the syringe, keeping the vial in an upright position, slightly inclined, while ensuring the bevel of the filter needle is submerged into the liquid; (8) continuing to tilt the vial during withdrawal keeping the bevel of the filter needle submerged in the formulation; (9) drawing the plunger rod sufficiently back when emptying the vial in order to completely empty the filter needle; (10) removing the filter needle from the syringe and disposing of the filter needle; (11) removing the 30-gauge x ½-inch injection needle from its packaging and attaching the injection needle to the syringe by firmly twisting the injection needle onto the Luer lock syringe tip; (12) holding the syringe with the needle pointing up, and checking the syringe for bubbles, wherein if there are bubbles, gently tapping the syringe with a finger until the bubbles rise to the top; and (13) slowly depressing the plunger so that the plunger tip aligns with the graduation line that marks 70 microliters on the syringe.

53. The method of any one of claims 1-52 wherein injection of VEGF receptor fusion protein is performed under controlled aseptic conditions, which comprise surgical hand disinfection and the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent) and anesthesia and a topical broad–spectrum microbicide are administered prior to the injection.

54. The method of any one of claims 1-53, wherein the VEGF receptor fusion protein comprises amino acids 27-457 of the amino acid sequence set forth in SEQ ID NO:

2.

55. The method of any one of claims 1-53, wherein the VEGF receptor fusion protein is selected from the group consisting of: aflibercept and conbercept.

56. The method of any one of claims 1-53, wherein the VEGF receptor fusion protein: (i) comprises two polypeptides that comprise (1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO: 2; (2) a VEGFR2 component comprising amino acids 130-231 of SEQ ID NO: 2; and (3) a multimerization component comprising amino acids 232-457 of SEQ ID NO: 2; (ii) comprises two polypeptides that comprise an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of a VEGFR2, and a multimerizing component; (iii) comprises two polypeptides that comprise an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of VEGFR2, an Ig domain 4 of VEGFR2 and a multimerizing component; or (iv) comprises two VEGFR1R2-Fc∆C1(a) polypeptides encoded by the nucleic acid sequence of SEQ ID NO:

1.

57. The method of claim 1-53, wherein the VEGF receptor fusion protein comprises two polypeptides that comprise an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of a VEGFR2, and a multimerizing component.

58. The method of any one of claims 1-57, wherein the VEGF receptor fusion protein is in an aqueous pharmaceutical formulation selected from the group consisting of A-KKKK.

59. The method of any one of claims 1-58 wherein said VEGF receptor fusion protein is in an aqueous pharmaceutical formulation comprising about 114.3 mg / ml VEGF receptor fusion protein.

60. The method of any one of claims 1-59 comprising administering the VEGF receptor fusion protein to both eyes of the subject.

61. The method of any one of claims 1-60, wherein the VEGF receptor fusion protein is administered from a syringe or pre-filled syringe.

62. The method of claim 61, wherein the syringe or pre-filled syringe is glass or plastic, and / or sterile.

63. The method of any one of claims 1-62 wherein the VEGF receptor fusion protein is intravitreally injected with a 30 gauge × ½-inch sterile injection needle.

64. The method of any one of claims 1-63 wherein the subject has previously received one or more doses of 2 mg VEGF receptor fusion protein.

65. The method of any one of claims 1-64 wherein one or more further doses of VEGF receptor fusion protein are administered.

66. The method of any one of claims 5-26, 64 or 65 wherein 2 mg VEGF receptor fusion protein is in an aqueous pharmaceutical formulation comprising 40 mg / ml VEGF receptor fusion protein.

67. The method of claim 5-26 or 64-66 wherein 2 mg of VEGF receptor fusion protein is in a pharmaceutical formulation comprising: 40 mg / ml VEGF receptor fusion protein, 10 mM sodium phosphate, 40 mM NaCl, 0.03% polysorbate 20 and 5% sucrose, with a pH of 6.

2. 68 The method of any one of claims 1-67 wherein >8 mg (±0.8 mg) of VEGF receptor fusion protein is in an aqueous pharmaceutical formulation that comprises a sugar or polyol.

69. The method of any one of claims 1-68 wherein >8 mg (±0.8 mg) VEGF receptor fusion protein in an aqueous pharmaceutical formulation that comprises sucrose.

70. The method of any one of claims 1-69 wherein >8 mg (±0.8 mg) of a VEGF receptor fusion protein is in an aqueous pharmaceutical formulation that has a pH of about 5.

8.

71. The method of any one of claims 1-70 wherein >8 mg (±0.8 mg) of a VEGF receptor fusion protein is in an aqueous pharmaceutical formulation comprising about 103-126 mg / ml VEGF receptor fusion protein, histidine-based buffer and arginine.

72. The method of any one of claims 1-71 wherein >8 mg (±0.8 mg) of a VEGF receptor fusion protein is an aqueous pharmaceutical formulation comprising about 114.3 mg / ml VEGF receptor fusion protein, histidine-based buffer and arginine.

73. The method of any one of claims 1-72 wherein the >8 mg (±0.8 mg) aflibercept is in an aqueous pharmaceutical formulation wherein the aflibercept has less than about 3.5% high molecular weight species immediately after manufacture and purification and / or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2- 8° C.

74. The method of any one of claims 1-73 wherein the >8 mg VEGF receptor fusion protein is in an aqueous pharmaceutical formulation comprising: at least about 100 mg / ml of a VEGF receptor fusion protein; about 10-100 mM L-arginine; sucrose; a histidine-based buffer; and a surfactant; wherein the formulation has a pH of about 5.0 to about 6.8; wherein the VEGF receptor fusion protein has less than about 3.5% high molecular weight species immediately after manufacture and purification and / or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C.

75. The method of claim 1-74 wherein > about 8 mg (±0.8 mg) of VEGF receptor fusion protein is in an aqueous pharmaceutical formulation comprising • ≥100 mg / ml VEGF receptor fusion protein, histidine-based buffer and L-arginine; • 140 mg / ml aflibercept; 20 mM histidine-based buffer; 5 % sucrose; 0.03 % polysorbate 20; 10 mM L-arginine; pH 5.8; • 150 ± 15 mg / ml aflibercept, 10 mM phosphate-based buffer, 8 ± 0.8% (w / v) sucrose, 0.02-0.04% (w / v) polysorbate 20 and 50 mM L-arginine, pH 5.9-6.5; • 103-126 mg / ml aflibercept, 10 ± 1 mM histidine-based buffer, 5 ± 0.5% (w / v) sucrose, 0.02-0.04% (w / v) polysorbate 20, and 50 ± 5 mM L-arginine, pH 5.5-6.1; • 140 mg / ml aflibercept, 10 mM histidine-based 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-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20 and 50 mM L-arginine, pH 5.8; • ≥100 mg / ml aflibercept, histidine-based buffer and L-arginine;• ≥100 mg / ml aflibercept at about pH 5.8, wherein the formulation forms <3% HMW aggregates after incubation at 5°C for 2 months; • About 114.3 mg / mL aflibercept; 10 mM – 50 mM histidine-based buffer, sugar, non-ionic surfactant, L-Arginine, pH 5.8; or • About 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.

76. The method of any one of claims 1-75 wherein the ≥8 mg (±0.8 mg) of VEGF receptor fusion protein is administered in a volume of 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; 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; 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.

77. The method of claim 76 wherein said VEGF receptor fusion protein is administered in a volume of about 70 ± 4 or 5 microliters.

78. The method of any one of claims 1-77 wherein the interval between doses are adjusted (increased / maintained / reduced) based on visual and / or anatomic outcomes.

79. The method of any one of claims 1-78 further including one or more periods of pro re nata (PRN), capped PRN or treat and extend (T&E) dosing.

80. The method of any one of claims 1-79 wherein the VEGF receptor fusion protein is aflibercept.

81. The method of any one of claims 1-80 wherein the subject is treated for at least 96 weeks.

82. The method of any one of claims 1-81 wherein the VEGF receptor fusion protein is administered by intraocular or intravitreal injection.

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