Extended high-dose regimens of VEGF antagonists for the treatment of intraocular neovascular disease

Abstract

The present invention relates to a regimen for the treatment of intraocular neovascular diseases such as nAMD, DR, and DME, characterized by high doses of aflibercept and extended intervals between administrations.

Description

[Technical Field]

[0001] Cross-reference of related applications This application is based on the following U.S. Provisional Patent Applications: 63 / 523,019 filed on June 23, 2023; 63 / 523,335 filed on June 26, 2023; 63 / 531,758 filed on August 9, 2023; 63 / 540,308 filed on September 25, 2023; 63 / 546,476 filed on October 30, 2023; 63 / 601,198 filed on November 20, 2023; 63 / 604,484 filed on November 30, 2023; and 63 / 606,507 filed on December 5, 2023. This document claims the interests of U.S. Provisional Patent Application No. 63 / 606,887 filed on 6 December 2023, U.S. Provisional Patent Application No. 63 / 608,138 filed on 8 December 2023, U.S. Provisional Patent Application No. 63 / 622,675 filed on 19 January 2024, U.S. Provisional Patent Application No. 63 / 625,146 filed on 25 January 2024, U.S. Provisional Patent Application No. 63 / 552,571 filed on 12 February 2024, U.S. Provisional Patent Application No. 63 / 556,308 filed on 21 February 2024, and U.S. Provisional Patent Application No. 63 / 566,163 filed on 15 March 2024, each of which is incorporated herein by reference in whole.

[0002] Sequence listing reference This application refers by reference to a computer-readable sequence listing in ST.26 XML format, titled 11554WO01_Sequence, prepared on 21 June 2024, containing 5,467 bytes.

[0003] The field of the present invention relates to a method for treating or preventing intraocular neovascular disease by administering a VEGF antagonist. [Background technology]

[0004] The PHOTON clinical trial in DR / DME and the PULSAR clinical trial in wAMD are multicenter, double-blind, active-controlled pivotal trials conducted worldwide. In both trials, patients were randomized to one of three treatment groups, receiving either aflibercept 8 mg every 12 weeks, aflibercept 8 mg every 16 weeks, or Eylea every 8 weeks.

[0005] In both trials, patients treated with aflibercept 8 mg received three initial doses at one-month intervals, while patients treated with Eylea received five initial doses at one-month intervals in the PHOTON trial and three initial doses at one-month intervals in the PULSAR trial. In the first year, patients in the aflibercept 8 mg group were able to shorten their dosing interval to as frequent as every eight weeks if the disease progression criteria defined in the protocol were observed. They were not able to extend the interval until the second year of the trial. Patients in both Eylea groups (control groups in both PHOTON and PULSAR) maintained a fixed eight-week dosing regimen throughout their participation in the clinical trial. [Overview of the project]

[0006] This invention relates to intraocular neovascular diseases (e.g., age-related macular degeneration (nAMD)), macular edema (ME), post-retinal vein occlusion (ME-RVO), retinal vein occlusion (RVO), central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), diabetic macular edema (DME), choroidal neovascularization (CNV), iris neovascularization, neovascular glaucoma, postoperative fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), optic disc neovascularization, corneal neovascularization, and reticular neovascularization. A method for treating or preventing membrane neovascularization, vitreous neovascularization, pannus, pterygium, vascular retinopathy, diabetic retinopathy (DR) (e.g., non-proliferative diabetic retinopathy (e.g., characterized by a Diabetic Retinopathy Severity Scale (DRSS) level of approximately 47 or 53) or proliferative diabetic retinopathy, e.g., in subjects without DME), and / or diabetic retinopathy in subjects with diabetic macular edema (DME)), wherein the eye of the subject (preferably) (By intravitreal injection) one or more doses of aflibercept (e.g., ≥8 mg (±0.8 mg)) are administered, the clearance of free aflibercept from the ocular compartment after intravitreal injection of aflibercept is approximately 0.367 to 0.457 mL / day (e.g., 0.41 mL / day), and the time it takes for the amount of free aflibercept in the target ocular compartment after said intravitreal injection to reach the lower limit of quantification (LLOQ) is approximately 15 weeks. The present invention also provides a method in which aflibercept is administered such that the time it takes for free aflibercept to reach the lower limit of quantification (LLOQ) (e.g., about 0.0156 mg / L) in the target plasma after intravitreal injection is about 3.5 weeks, for example, aflibercept is administered in an aqueous pharmaceutical formulation, and aflibercept has less than about 3.5% high molecular weight molecular species immediately after manufacturing and purification, and / or less than about 6% high molecular weight molecular species after storage for about 24 months at about 2-8°C.In one embodiment of the present invention, the aqueous pharmaceutical formulation comprises at least about 100 mg / ml of VEGF receptor fusion protein, each containing two polypeptides, the second immunoglobin-like (Ig) domain of VEGFR1, the third Ig domain of VEGFR2, and a polymerizing component, and about 10-100 mM of L-arginine, sucrose, a histidine-based buffer, and a surfactant, wherein the formulation has a pH of about 5.0-6.8, and the VEGF receptor fusion protein contains less than about 3.5% high molecular weight molecular species immediately after manufacturing and purification, and / or less than 6% high molecular weight molecular species after storage at about 2-8°C for about 24 months. In one embodiment of the present invention, the method comprises administering a single initial dose of approximately 8 mg (±0.8 mg) or more of aflibercept, followed by one or more secondary doses of approximately 8 mg (±0.8 mg) or more of aflibercept, followed by one or more tertiary doses of approximately 8 mg (±0.8 mg) or more of aflibercept, with each secondary dose administered approximately 2 to 4 weeks (preferably 4 weeks) after the immediately preceding dose, and each tertiary dose administered approximately 8, 12, 16, 20, 8 to 24, 12 to 24, 16 to 24, 20 to 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 intravitreous injection, compared to the clearance rate of aflibercept from the ocular compartment after intravitreous injection of ≤4 mg of aflibercept, comprising intravitreous injection of a single initial dose of approximately 8 mg (±0.8 mg) or more of aflibercept, followed by one or more secondary doses of approximately 8 mg (±0.8 mg) or more of aflibercept, and then one or more tertiary doses of approximately 8 mg (±0.8 mg) or more of aflibercept into the target eye in need, wherein each secondary dose is administered approximately 2 to 4 weeks after the immediately preceding dose, and each tertiary dose is administered approximately 24 weeks after the immediately preceding dose. In one embodiment of the present invention, the clearance of free aflibercept from the ocular compartment is approximately 34% slower than the clearance from the ocular compartment after intravitreal injection of ≤4 mg of aflibercept. For example, the clearance of free aflibercept from the ocular compartment is approximately 0.367 to 0.457 mL / day or 0.41 mL / day after intravitreal injection of ≥8 mg (±0.8 mg) of aflibercept.

[0008] The present invention also provides a method for increasing the time it takes for the amount of free aflibercept in the ocular compartment of a subject to reach the lower limit of quantification (LLOQ) after intravitreal injection of approximately 2 mg of aflibercept, compared to the time it takes for the amount of free aflibercept in the ocular compartment of a subject to reach the LLOQ, for example, more than 1.3 weeks, for example between approximately 6 weeks and more than 10 weeks, for example up to approximately 15 weeks, to the required eye of the subject. The present invention provides a method comprising administering a single initial dose of approximately 8 mg (±0.8 mg) or more of aflibercept, followed by one or more secondary doses of approximately 8 mg (±0.8 mg) or more of aflibercept, and then one or more tertiary doses of approximately 8 mg (±0.8 mg) or more of aflibercept, administered intravitreally, wherein each secondary dose is administered approximately 2 to 4 weeks after the immediately preceding dose, and each tertiary dose is administered approximately 8 to 24, 12 to 24, 16 to 24, 20 to 24, or 24 weeks after the immediately preceding dose.

[0009] The present invention also provides a method for increasing the time it takes for free aflibercept in the plasma of a subject to reach the lower limit of quantification (LLOQ) (e.g., about 0.0156 mg / L) after intravitreal injection of about 2 mg of aflibercept, compared to the time it takes for free aflibercept in the plasma of a subject to reach the LLOQ after intravitreal injection of about 2 mg of aflibercept, for example, by more than 1.5 weeks, and for example by about 2 to 3.5 weeks, comprising intravitreal injection of 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 aflibercept, followed by one or more tertiary doses of about 8 mg (±0.8 mg) or more of aflibercept, into the eye of a subject requiring treatment, wherein each secondary dose is administered about 2 to 4 weeks after the most recent dose, and each tertiary dose is administered about 24 weeks after the most recent dose. In one embodiment of the present invention, ≥8 mg (±0.8 mg) of aflibercept is administered in an aqueous pharmaceutical formulation having a pH of approximately 5.8, comprising a histidine-based buffer, arginine (e.g., L-arginine hydrochloride), sugars such as sucrose, or polyols. In another embodiment of the present invention, the aflibercept has less than approximately 3.5% high molecular weight molecular species immediately after manufacturing and purification, and / or less than approximately 6% high molecular weight molecular species after storage at approximately 2-8°C for approximately 24 months, for example, ≥8 mg (±0.8 mg) of aflibercept is at least approximately 100 mg / ml of VEGF receptor fusion protein, each containing the second immunoglobin-like (Ig) domain of VEGFR1, the third Ig domain of VEGFR2, and a multimer-forming component. The formulation contains an aqueous pharmaceutical preparation comprising at least about 100 mg / ml of VEGF receptor fusion protein containing two polypeptides, about 10-100 mM L-arginine, sucrose, a histidine-based buffer, and a surfactant, wherein the preparation has a pH of about 5.0-6.8, and the VEGF receptor fusion protein has less than about 3.5% high molecular weight molecular species immediately after manufacturing and purification, and / or less than 6% high molecular weight molecular species after storage at about 2-8°C for about 24 months.

[0010] The present invention relates to intraocular neovascular diseases (e.g., age-related macular degeneration (nAMD)), macular edema (ME), macular edema after retinal vein occlusion (ME-RVO), retinal vein occlusion (RVO), central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), diabetic macular edema (DME), choroidal neovascularization (CNV), iris neovascularization, neovascular glaucoma, postoperative fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), optic disc neovascularization, corneal neovascularization, retinal neovascularization, vitreous neovascularization, pannus, pterygium, vascular retinopathy, diabetic retinopathy (DR) (e.g., non-proliferative diabetic retinopathy (e.g., characterized by a Diabetic Retinopathy Severity Scale (DRSS) level of approximately 47 or 53) or proliferative diabetic retinopathy). For example, if you do not have DME The present invention provides a method for subjects with nAMD, DR and / or DME who require treatment or prevention of diabetic retinopathy (in subjects with diabetic macular edema (DME)), or for subjects with nAMD, DR and / or DME who require improvement of best corrected visual acuity (BCVA), or for subjects with nAMD, DR and / or DME who require promotion of retinal dryness, comprising administering one or more doses of aflibercept, preferably about 8 mg (±0.8 mg) or more of VEGF receptor fusion protein, to the eye of the subject (preferably by intravitreal injection) once every 24 weeks. One embodiment of the present invention provides a method comprising administering to the target eye aflibercept, preferably 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 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 (preferably 4 weeks) after the immediately preceding dose, and each tertiary dose is administered about 8 to 24, 12 to 24, 16 to 24, 20 to 24, or 24 weeks after the immediately preceding dose.

[0011] The present invention relates to intraocular neovascular diseases (e.g., age-related macular degeneration (nAMD)), macular edema (ME), macular edema after retinal vein occlusion (ME-RVO), retinal vein occlusion (RVO), central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), diabetic macular edema (DME), choroidal neovascularization (CNV), iris neovascularization, neovascular glaucoma, postoperative fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), optic disc neovascularization, corneal neovascularization, retinal neovascularization, vitreous neovascularization, pannus, pterygium, vascular retinopathy, diabetic retinopathy (DR) (e.g., non-proliferative diabetic retinopathy (e.g., characterized by a Diabetic Retinopathy Severity Scale (DRSS) level of approximately 47 or 53) or proliferative diabetic retinopathy, e.g., in subjects not suffering from DME), and In subjects who require treatment or prevention of diabetic retinopathy (in subjects having diabetic macular edema (DME)), a method for providing such treatment or prevention includes administering to the eye of the subject (preferably by intravitreal injection) aflibercept, preferably as 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 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 (preferably 4 weeks) after the immediately preceding dose, and each tertiary dose is administered about 8 to 24, 12 to 24, 16 to 24, 20 to 24, or 24 weeks after the immediately preceding dose.

[0012] In embodiments of the present invention, the subject includes intraocular neovascular diseases (e.g., age-related macular degeneration (nAMD)), macular edema (ME), macular edema after retinal vein occlusion (ME-RVO), retinal vein occlusion (RVO), central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), diabetic macular edema (DME), choroidal neovascularization (CNV), iris neovascularization, neovascular glaucoma, postoperative fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), optic disc neovascularization, corneal neovascularization, retinal neovascularization, vitreous neovascularization, pannus, pterygium, vascular retinopathy, diabetic retinopathy (DR) (e.g., non-proliferative diabetic retinopathy (characterized by a Diabetic Retinopathy Severity Scale (DRSS) level of approximately 47 or 53)) or proliferative diabetes mellitus. A method for treating or preventing diseased retinopathy (for example, in subjects without DME), and / or diabetic retinopathy in subjects with diabetic macular edema (DME), comprises administering, preferably by intravitreal injection, ≥8 mg (±0.8 mg) of aflibercept (in a volume of 0.07 mL or 70 microliters) of VEGF receptor fusion protein (in a volume of 0.07 mL) to subjects in need, preferably by intravitreal injection, as a first three-dose regimen, every four weeks (approximately every 28 days + / - 7 days, monthly), followed by one intravitreal injection every 8-24, 12-24, 16-24, 20-24, or 24 weeks (6 months, + / - 7 days).

[0013] The present invention also addresses intraocular neovascular diseases (e.g., age-related macular degeneration (nAMD)), macular edema (ME), post-retinal vein occlusion (ME-RVO), retinal vein occlusion (RVO), central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), diabetic macular edema (DME), choroidal neovascularization (CNV), iris neovascularization, neovascular glaucoma, postoperative fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), optic disc neovascularization, corneal neovascularization, retinal neovascularization, vitreous neovascularization, pannus, pterygium, vascular retinopathy, diabetic retina A method for treating or preventing diabetic retinopathy (DR) (for example, non-proliferative diabetic retinopathy (e.g., characterized by a Diabetic Retinopathy Severity Scale (DRSS) level of approximately 47 or 53) or proliferative diabetic retinopathy, e.g., in subjects without DME), and / or diabetic macular edema (DME) in subjects where treatment or prevention is necessary, wherein (1) the subject is administered an initial dose of 2 mg of VEGF receptor fusion protein, and then, one month later, the subject receives the initial dose (1) The treatment includes administering ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, followed by a first ≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein one month later, followed by a second ≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein one month later, and then one or more maintenance doses of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein every 24 weeks thereafter, according to the HDq24 administration regimen, or (2) the subject has received an initial dose of 2 mg of VEGF receptor fusion protein, and then The method includes administering to the subject, after one month, a first secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, then, after one month, a second secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, and then, every 24 weeks thereafter, one or more maintenance doses of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein according to the HDq24 administration regimen, or (3) the subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein, and the method is to administer to the subject, after one month, a second dose of ≥8 mg (±0.(4) The method includes administering a second dose of VEGF receptor fusion protein (8 mg) followed by one or more maintenance doses of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein every 24 weeks thereafter, according to the HDq24 administration regimen, or (4) the subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein, and then, one month later, the subject is given a first maintenance dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein followed by further maintenance doses of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein every 24 weeks according to the HDq24 administration regimen. (5) The method involves administering all of the receptor fusion proteins, or the subject has been administered 2 mg of VEGF receptor fusion protein as an initial dose and 2 mg of VEGF receptor fusion protein as a first dose one month later, and the method further involves administering ≥8 mg (±0.8 mg) of VEGF receptor fusion protein as an initial dose one month later, and then ≥8 mg (±0.8 mg) of VEGF receptor fusion protein as a second dose one month later, and then ≥8 mg (±0.8 mg) of VEGF receptor fusion protein as a second dose one month later, and then 24 (6) The method includes administering at least one maintenance dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein weekly according to the HDq24 administration regimen, or the method includes administering an initial dose of 2 mg of VEGF receptor fusion protein, and one month later a first secondary dose of 2 mg of VEGF receptor fusion protein, and then one month later the subject receives a first secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, and then one month later a second secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, and then (7) The method includes administering, then every 24 weeks, one or more maintenance doses of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein according to the HDq24 administration regimen, or (7) the subject has received an initial dose of 2 mg of VEGF receptor fusion protein, and one month later, a first secondary dose of 2 mg of VEGF receptor fusion protein, and then one month later, the subject receives a second secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, and then every 24 weeks thereafter, one or more doses of ≥8 mg (±0.8 mg) according to the HDq24 administration regimen.(8) The method includes administering a maintenance dose of VEGF receptor fusion protein (8 mg), or the subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein, and one month later, a first secondary dose of 2 mg of VEGF receptor fusion protein, and then one month later, the method includes administering to the subject a first ≥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 administration regimen, or the method includes administering to the subject an initial dose of 2 mg of VEGF receptor fusion protein, and one month later, a first secondary dose of 2 mg of VEGF receptor fusion protein, and then one month later, the method includes administering to the subject an initial dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, and then one month later (10) The regimen includes administering a first ≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein, followed by a second ≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein one month later, and then one or more maintenance doses of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein every 24 weeks thereafter, according to the HDq24 administration regimen, or (10) an initial dose of 2 mg of VEGF receptor fusion protein, followed by a first 2 mg dose one month later. The subjects received a second dose of VEGF receptor fusion protein, followed one month later by a second dose of 2 mg of VEGF receptor fusion protein. Then, one month later, they received a first dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, followed one month later by a second dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, and then every 24 weeks thereafter, according to the HDq24 administration regimen, one or more doses of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein.(11) A subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein, a first secondary dose of 2 mg of VEGF receptor fusion protein one month later, and a second secondary dose of 2 mg of VEGF receptor fusion protein one month later, and the method then includes administering to the subject a second secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein one month later, and then one or more maintenance doses of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein every 24 weeks thereafter according to the HDq24 administration regimen, or (12) A subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein, and a first secondary dose of 2 mg one month later (13) The subject was administered VEGF receptor fusion protein, followed by a second 2 mg secondary dose of VEGF receptor fusion protein one month later, and the method further includes administering to the subject, two months later, a first ≥8 mg (±0.8 mg) maintenance dose of VEGF receptor fusion protein, and all of the additional ≥8 mg (±0.8 mg) maintenance doses of VEGF receptor fusion protein every 24 weeks according to the HDq24 administration regimen, (13) the subject was administered an initial dose of 2 mg of VEGF receptor fusion protein, followed by a first 2 mg secondary dose of VEGF receptor fusion protein one month later, followed by a second 2 mg secondary dose of VEGF receptor fusion protein one month later, and a third 2 mg secondary dose of VEGF receptor fusion protein one month later. The method then includes administering to the subject, after one month, an initial dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, then, after one month thereafter, a first secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, then, after one month thereafter, a second secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, and then, every 24 weeks thereafter, one or more maintenance doses of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein according to the HDq24 administration regimen, or (14) the subject receives an initial dose of 2 mg of VEGF receptor fusion protein. The patient was administered the protein, followed by a first 2 mg secondary dose of VEGF receptor fusion protein one month later, a second 2 mg secondary dose of VEGF receptor fusion protein one month later, and a third 2 mg secondary dose of VEGF receptor fusion protein one month later. Subsequently, after one month, the patient received a first ≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein, followed by a second ≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein one month later, and then every 24 weeks thereafter, according to the HDq24 administration regimen. (15) The method includes administering a maintenance dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, or (15) the subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein, a first secondary dose of 2 mg of VEGF receptor fusion protein one month later, a second secondary dose of 2 mg of VEGF receptor fusion protein one month later, and a third secondary dose of 2 mg of VEGF receptor fusion protein one month later, and then the method includes administering a second secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein to the subject one month later, and then Thereafter, every 24 weeks, the regimen includes administering one or more maintenance doses of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein according to the HDq24 administration regimen, or (16) the subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein, a first secondary dose of 2 mg of VEGF receptor fusion protein one month later, a second secondary dose of 2 mg of VEGF receptor fusion protein one month later, and a third secondary dose of 2 mg of VEGF receptor fusion protein one month later, and then, two months later, the subject is given a first dose of ≥8 mg (±0.(17) The method includes administering a maintenance dose of 8 mg of VEGF receptor fusion protein and, according to the HDq24 administration regimen, all of the additional ≥8 mg (±0.8 mg) of maintenance doses of VEGF receptor fusion protein every 24 weeks, or (17) a subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein, a first secondary dose of 2 mg of VEGF receptor fusion protein one month later, a second secondary dose of 2 mg of VEGF receptor fusion protein one month later, a third secondary dose of 2 mg of VEGF receptor fusion protein one month later, and a fourth secondary dose of 2 mg of VEGF receptor fusion protein one month later, and then, two months later, the subject has been administered an initial dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, a first secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein one month later, and a second secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein one month later. (18) The method involves administering a receptor fusion protein, followed by one or more maintenance doses of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein every 24 weeks thereafter, according to the HDq24 administration regimen, or (18) a subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein, followed by a first secondary dose of 2 mg of VEGF receptor fusion protein one month later, a second secondary dose of 2 mg of VEGF receptor fusion protein one month later, a third secondary dose of 2 mg of VEGF receptor fusion protein one month later, and a fourth secondary dose of 2 mg of VEGF receptor fusion protein one month later, and then, two months later, the subject is administered a first secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, followed by a second secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein one month thereafter, and then one or more maintenance doses of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein every 24 weeks thereafter, according to the HDq24 administration regimen.(19) The method includes administering a maintenance dose of VEGF receptor fusion protein at 8 mg, or (19) the subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein, a first secondary dose of 2 mg of VEGF receptor fusion protein one month later, a second secondary dose of 2 mg of VEGF receptor fusion protein one month later, a third secondary dose of 2 mg of VEGF receptor fusion protein one month later, and a fourth secondary dose of 2 mg of VEGF receptor fusion protein one month later, and then, two months later, the subject is given a second dose of ≥8 mg (±0.8 mg) (20) The treatment regimen includes administering a secondary dose of VEGF receptor fusion protein and then, over the next 24 weeks, one or more 24-week maintenance doses of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein according to the HDq24 administration regimen, or (20) the treatment regimen includes an initial dose of 2 mg of VEGF receptor fusion protein, a first secondary dose of 2 mg of VEGF receptor fusion protein one month later, a second secondary dose of VEGF receptor fusion protein one month later, a third secondary dose of 2 mg of VEGF receptor fusion protein one month later, and a fourth 2 mg one month later. (21) The subject has been administered a second dose of VEGF receptor fusion protein, and the method then includes administering to the subject, two months later, a first maintenance dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein and all of the additional ≥8 mg (±0.8 mg) of maintenance doses of VEGF receptor fusion protein every 24 weeks according to the HDq24 administration regimen, or (21) the subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein, a first second dose of 2 mg of VEGF receptor fusion protein one month later, and a second second dose of 2 mg of VEGF receptor fusion protein one month later. The patient was administered VEGF receptor fusion protein, followed by a third 2 mg secondary dose of VEGF receptor fusion protein one month later, a fourth 2 mg secondary dose of VEGF receptor fusion protein one month later, and then a maintenance dose of 2 mg at least once every 8 weeks. Subsequently, two months after the last maintenance dose of VEGF receptor fusion protein, the patient was given an initial dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, followed by a first ≥8 mg (±0.8 mg) secondary dose of VEGF receptor fusion protein one month later, and then a second ≥8 mg (±0.(22) The method includes administering a secondary dose of VEGF receptor fusion protein (8 mg) followed by one or more maintenance doses of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein every 24 weeks thereafter, according to the HDq24 administration regimen, or (22) a subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein, a first secondary dose of 2 mg of VEGF receptor fusion protein one month later, a second secondary dose of VEGF receptor fusion protein one month later, a third secondary dose of 2 mg of VEGF receptor fusion protein one month later, a fourth secondary dose of VEGF receptor fusion protein one month later, followed by one or more maintenance doses of 2 mg every 8 weeks thereafter, and then two months after the last maintenance dose of VEGF receptor fusion protein, the subject is given a first secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, followed by a second secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein one month thereafter. (23) The method includes administering a receptor fusion protein, and then, every 24 weeks thereafter, one or more maintenance doses of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein according to the HDq24 administration regimen, or (23) a subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein, a first secondary dose of 2 mg of VEGF receptor fusion protein one month later, a second secondary dose of 2 mg of VEGF receptor fusion protein one month later, a third secondary dose of 2 mg of VEGF receptor fusion protein one month later, a fourth secondary dose of VEGF receptor fusion protein one month later, and thereafter, one or more maintenance doses of 2 mg every 8 weeks, and then, two months after the last maintenance dose of VEGF receptor fusion protein, the subject is given a second secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, and 24 weeks thereafter, one or more maintenance doses of ≥8 mg (±0.8 mg) every 24 weeks according to the HDq24 administration regimen.(24) The method includes administering a maintenance dose of VEGF receptor fusion protein (8 mg), or (24) the subject has been administered an initial dose of 2 mg of VEGF receptor fusion protein, a first secondary dose of 2 mg of VEGF receptor fusion protein one month later, a second secondary dose of VEGF receptor fusion protein one month later, a third secondary dose of VEGF receptor fusion protein one month later, a fourth secondary dose of VEGF receptor fusion protein one month later, and then at least one maintenance dose of 2 mg every 8 weeks thereafter, and the method then includes administering a first maintenance dose of VEGF receptor fusion protein (≥8 mg (±0.8 mg)) to the subject two months after the last maintenance dose of VEGF receptor fusion protein. The present invention provides a method comprising administering a VEGF receptor fusion protein and, according to the HDq24 administration regimen, a further ≥8 mg (±0.8 mg) maintenance dose of all VEGF receptor fusion proteins every 24 weeks, wherein the HDq24 administration regimen comprises a single initial dose of approximately ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, followed by one or more secondary doses of approximately ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, followed by one or more tertiary doses of approximately ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, with each secondary dose administered approximately 2-4 weeks after the previous dose, and each tertiary dose administered approximately 24 weeks after the previous dose.

[0014] The present invention also relates to a method for treating or preventing neovascular age-related macular degeneration (nAMD), diabetic retinopathy and / or diabetic macular edema in a subject who is receiving a drug regimen for the treatment or prevention of the said disorders, wherein (a) the subject has been administered an initial dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, and the method then administers to the subject a first secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein one month later, and then a second dose of ≥8 mg ( (b) The method includes administering a secondary dose of VEGF receptor fusion protein (±0.8 mg) and then, every 24 weeks thereafter, administering one or more maintenance doses of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein according to the HDq24 administration regimen, or (b) the subject has received an initial dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein and, one month later, a first secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, and then, one month later, the subject receives a second dose of ≥8 mg (±0. (c) The treatment includes administering a secondary dose of VEGF receptor fusion protein (8 mg) followed by one or more maintenance doses of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein every 24 weeks thereafter, according to the HDq24 administration regimen, or (c) the subject receives an initial dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, a first secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein one month later, and a second secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein one month later. The method then includes administering to the subject, after 24 weeks, a first maintenance dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, and then, according to the HDq24 administration regimen, all of the additional ≥8 mg (±0.8 mg) of VEGF receptor fusion protein every 24 weeks, or (d) the subject receives an initial dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, a first secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein one month later, and a second dose of ≥8 mg (±0.8 mg) one month later.The subject received a secondary dose of VEGF receptor fusion protein (8 mg), followed by one or more maintenance doses of VEGF receptor fusion protein (≥8 mg ±0.8 mg) every 24 weeks, and then, 24 weeks after the last maintenance dose of VEGF receptor fusion protein, the subject received one or more maintenance doses of VEGF receptor fusion protein (≥8 mg ±0.8 mg), and further maintenance doses of VEGF receptor fusion protein (≥8 mg ±0.8 mg) every 24 weeks according to the HDq24 administration regimen. The present invention provides a method for administering all of the following: the HDq24 administration regimen comprises a single initial dose of approximately ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, followed by one or more secondary doses of approximately ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, followed by one or more tertiary doses of approximately ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, with each secondary dose administered approximately 2-4 weeks after the previous dose, and each tertiary dose administered approximately 24 weeks after the previous dose.

[0015] The present invention relates to a method for treating or preventing age-related macular degeneration with neovascularization (nAMD), diabetic retinopathy, or diabetic macular edema in subjects who require such treatment or prevention, comprising administering to the eye of the subject (preferably by intravitreal injection) a single initial dose of approximately 8 mg (±0.8 mg) or more of aflibercept, followed by one or more secondary doses of approximately 8 mg (±0.8 mg) or more of VEGF receptor fusion protein, and one or more tertiary doses of approximately 8 mg (±0.8 mg) or more of VEGF receptor fusion protein, wherein each secondary dose is immediately The method provides administering a third dose approximately 2 to 4 weeks after the previous dose, with each third dose administered approximately 8, 12, 16, or 20 weeks after the most recent dose, and further including evaluating the patient's suitability for extending the interval between third doses when the 8, 12, 16, or 20-week third dose is completed, and increasing the interval in 4-week increments if, based on the patient's visual acuity and / or central retinal thickness, the treating physician determines that extending the interval is appropriate, for example, the interval may be extended up to approximately 24 weeks after one or more 4-week increases in the interval.

[0016] The present invention also relates to a subject who requires treatment or prevention of intraocular neovascular disease (preferably nAMD, DR, and / or DME), and who is receiving a dosage regimen for the treatment or prevention of the said disorder, which preferably requires 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 VEGF receptor fusion protein, and followed by one or more tertiary doses of about 2 mg of VEGF receptor fusion protein, wherein each secondary dose is administered about 4 weeks after the immediately preceding dose, and each tertiary dose The present invention provides a method in which the administration is performed approximately 8 weeks after the most recent administration, the subject is in any stage of a 2 mg VEGF receptor fusion protein administration regimen, the method includes administering an 8 mg (±0.8 mg) dose of VEGF receptor fusion protein to the subject's eye (preferably by intravitreal injection), evaluating the subject approximately 4, 8, 10, or 12 weeks after administration, and, if the treating physician determines that administration every 24 weeks is appropriate, continuing to administer ≥8 mg (±0.8 mg) of VEGF receptor fusion protein to the subject every 24 weeks thereafter.

[0017] In one embodiment of the present invention, the method of the present invention is for the treatment or prevention of age-related macular degeneration with neovascularization, diabetic retinopathy and / or diabetic macular edema, and aflibercept is administered in a preferred single initial dose of about 2 mg of VEGF receptor fusion protein, followed by two, three or four secondary doses of about 2 mg of VEGF receptor fusion protein, followed by one or more tertiary doses of about 2 mg of VEGF receptor fusion protein, with each secondary dose administered about four weeks after the previous dose, and each tertiary dose administered about eight weeks after the previous dose.

[0018] The present invention also provides a method for treating or preventing age-related macular degeneration with neovascularization, diabetic retinopathy, or diabetic macular edema in subjects who require treatment or prevention, comprising administering to the eye of the subject (preferably by intravitreal injection) a single initial dose of aflibercept preferably 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 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, each secondary dose administered about 2 to 4 weeks (preferably 4 weeks) after the most recent dose, and each tertiary dose administered about 12 or 16 weeks after the most recent dose, further comprising extending the interval between tertiary doses to 12, 16 or 20 to 24 weeks after the most recent dose, after receiving one or more tertiary doses about 12 or 16 weeks after the most recent dose. For example, in one embodiment of the present invention, during the aforementioned treatment, the subject exhibits (a) a loss of <5 letters in BCVA and / or (b) a central retinal thickness (CRT) of <300 or 320 μm. In embodiments of the present invention, the method further includes evaluating the BVCA and / or CRT in the subject, and extending the interval between tertiary doses if the subject exhibits (a) a loss of <5 letters in BCVA and / or (b) a CRT of <300 or 320 μm.

[0019] The present invention also provides a method for treating or preventing age-related macular degeneration with neovascularization, diabetic retinopathy and / or diabetic macular edema in subjects requiring such treatment or prevention, comprising administering to the eye of the subject (preferably by intravitreal injection) a single initial dose of aflibercept preferably 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 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, each secondary dose administered about 2 to 4 weeks (preferably 4 weeks) after the most recent dose, and each tertiary dose administered about 24 weeks after the most recent dose, further comprising shortening the interval between tertiary doses from 24 to 12, 16 or 20 after receiving one or more tertiary doses about 24 weeks after the most recent dose. In one embodiment of the present invention, during the treatment, the subject exhibits (a) a loss of >10 letters of BCVA relative to baseline, and / or (b) an increase of >50 μm in CRT relative to baseline. For example, in embodiments of the present invention, the method further includes evaluating the BVCA and / or CRT in the subject, and shortening the interval to a third dose if the subject exhibits (a) a loss of >10 letters of BCVA relative to baseline, and / or (b) an increase of >50 μm in CRT relative to baseline.

[0020] In one embodiment of the present invention, (a) Loss of more than 5 letters in BCVA (ETDRS) compared to BCVA observed approximately 12 weeks after the start of treatment. (b) An increase of more than 25 micrometers in CRT is observed compared to the CRT observed approximately 12 weeks after the start of treatment, and / or (c) Newly occurring foveal neovascularization or foveal hemorrhage, For example, if it is the 16th or 20th week after the start of treatment, the interval between third doses may be reduced from 24 weeks to 12 weeks, 16 weeks, or 20 weeks, or (a) Loss of more than 5 letters in BCVA (ETDRS) compared to BCVA observed approximately 12 weeks after the start of treatment. (b) An increase of more than 25 micrometers in CRT is observed compared to the CRT observed approximately 12 weeks after the start of treatment, and / or (c) Newly occurring foveal neovascularization or foveal hemorrhage, For example, if it is the 24th week after the start of treatment, the interval between third doses should be shortened from 24 weeks to 12 weeks, 16 weeks, or 20 weeks.

[0021] The present invention provides a method for treating or preventing age-related macular degeneration with neovascularization, diabetic retinopathy, and / or diabetic macular edema in subjects who require such treatment or prevention, comprising administering a formulation containing approximately ≥8 mg (±0.8 mg) of aflibercept in three preferred doses to the eye of the subject (preferably by intravitreal injection), with an interval of four weeks between doses, and further comprising administering one or more doses of VEGF receptor fusion protein at intervals extended up to a maximum of 24 weeks after the three doses.

[0022] The present invention relates to a method for treating or preventing age-related macular degeneration with neovascularization, diabetic retinopathy, and / or diabetic macular edema in subjects who require such treatment or prevention, comprising: administering aflibercept, preferably a single initial dose of about 8 mg (±0.8 mg) or more of VEGF receptor fusion protein, to the eye of the subject (preferably by intravitreal injection); followed by two secondary doses of about 8 mg (±0.8 mg) or more of VEGF receptor fusion protein, each administered approximately 2 to 4 weeks (preferably 4 weeks) after the previous dose; and thereafter administering one or more tertiary doses every 12, 16, 20, or 24 weeks; and after administration, determining whether the subject meets at least one criterion for shortening or extending the interval between one or more tertiary doses by 2 weeks, 3 weeks, 4 weeks, or 2 to 4 weeks between the tertiary doses of VEGF receptor fusion protein. b) If a decision is made, the method includes administering an additional dose of VEGF receptor fusion protein at a shortened or extended interval between doses, wherein the criteria for extending the interval include 1. loss of <5 letters of BCVA, and / or 2. CRT <300 or 320 micrometers, and the criteria for shortening the interval include 1. loss of >10 letters of BCVA; 2. persistence or worsening of DME, and / or 3. increase of >50 micrometers in CRT. In one embodiment of the present invention, the criteria for extending the interval include both 1. loss of <5 letters of BCVA from week 12, and 2. CRT <300 or 320 micrometers as measured by SD-OCT; and / or the criteria for shortening the interval include both 1. loss of >10 letters of BCVA in association with, for example, persistent or worsening DME from week 12, and 2. increase of >50 micrometers in CRT from, for example, week 12. In one embodiment of the present invention, if the criteria are met, the interval is extended to 24 weeks.

[0023] The present invention provides a method for treating or preventing age-related macular degeneration with neovascularization, diabetic retinopathy and / or diabetic macular edema in subjects who have been pre-treated with aflibercept, preferably once or more times, at a dose of 2 mg of VEGF receptor fusion protein, and who require treatment or prevention of such disease, comprising administering to the 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, one or more subsequent secondary doses of about 8 mg (±0.8 mg) or more of VEGF receptor fusion protein, and one or more subsequent 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 (preferably 4 weeks) after the most recent dose, and each tertiary dose is administered about 24 weeks after the most recent dose.

[0024] In one embodiment of the present invention, subjects having certain exclusion criteria are excluded from treatment, or are not excluded from treatment if the exclusion criteria are not met. For example, subjects having one or more of the following: ocular or periorbital infection, active endophthalmoinflammation, and / or hypersensitivity are excluded from administration of VEGF receptor fusion protein to the eye. In one embodiment of the present invention, the method of the present invention further includes the steps of evaluating a subject for ocular or periorbital infection, active endophthalmoinflammation, and / or hypersensitivity, and excluding the subject from administration if one or more of these are observed in the subject.

[0025] In one embodiment of the present invention, the subject is monitored for adverse events such as conjunctival hemorrhage, cataracts, vitreous detachment, vitreous floaters, corneal epithelial defects, and / or elevated intraocular pressure. If such AEs are identified, the identified AEs may be treated, and / or such treatment or prevention may be discontinued.

[0026] In one embodiment of the present invention, the method includes pre-administration preparation of a VEGF receptor fusion protein, preferably aflibercept. For example, the method provides or has a glass vial packaged together with a commercially available single-dose glass vial containing an aqueous formulation of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein in approximately 70 microliters, having a protective plastic cap and stopper; the needle of the invention, which is, for example, a 18 gauge × 1.5 inch, 5 micron filter needle including the tip and beveled end; the syringe, which is, for example, a 30 gauge × 0.5 inch injection needle; and a syringe, which is, for example, a 1-mL Luer lock syringe with a graduated line marking a volume of 70 microliters; then (1) visually inspect the aqueous formulation in the vial and, if particles are present, cloudy, or discolored, use another vial of the aqueous formulation containing VEGF receptor fusion protein; (2) remove the protective plastic cap from the vial; and (3) clean the top of the vial with an alcohol wipe. Using aseptic technique, (4) remove the 18 gauge × 1.5 inch, 5 micron filter needle and 1 mL syringe from their packaging; (5) attach the filter needle to the syringe by twisting it onto the tip of the Luer lock syringe; (6) push the filter needle into the center of the vial stopper until the filter needle is fully inserted into the vial and the tip contacts the bottom or bottom edge of the vial; (7) withdraw all the contents of the VEGF receptor fusion protein vial into the syringe by keeping the vial upright and slightly tilting it while ensuring that the slanted end of the filter needle is immersed in the liquid; (8) continue to tilt the vial during withdrawal, keeping the slanted end of the filter needle immersed in the formulation; (9) fully retract the plunger rod when emptying the vial to completely empty the filter needle; (10) remove the filter needle from the syringe and discard the filter needle; and (11) 30 gauge × 0.(12) removing a 5-inch needle from its packaging and twisting the needle onto the tip of a Luer-lock syringe to securely attach the needle to the syringe; (13) holding the syringe with the needle facing upwards, checking the syringe for air bubbles, and if there are any, gently flicking the syringe with a finger until the bubbles rise to the top; and (14) slowly pushing the plunger out so that the tip of the plunger aligns with the graduated line marking 70 microliters on the syringe. In one embodiment of the present invention, the injection of the VEGF receptor fusion protein is performed under controlled sterile conditions, which include surgical hand disinfection, as well as the use of sterile gloves, sterile drapes, and sterile eyelid retractors (or equivalents), and the administration of anesthesia and topical broad-spectrum antimicrobial eye drops prior to the injection.

[0027] In one embodiment of the present invention, the subject is receiving a regimen for the treatment or prevention of age-related macular degeneration with neovascularization, diabetic retinopathy and / or diabetic macular edema, which requires a single initial dose of approximately 2 mg of VEGF receptor fusion protein, followed by two, three, or four secondary doses of approximately 2 mg of VEGF receptor fusion protein, and one or more tertiary doses of approximately 2 mg of VEGF receptor fusion protein, with each secondary dose administered approximately four weeks after the previous dose, and each tertiary dose administered approximately eight weeks after the previous dose, and the subject is at any stage (initial dose, secondary dose, or tertiary dose) of the 2 mg VEGF receptor fusion protein administration regimen.

[0028] In one embodiment of the present invention, 24 weeks is 6 months, 168 days, or twice a year, one or more secondary doses are two secondary doses, 2-4 weeks is approximately 4 weeks, 12-20 weeks is approximately 12 weeks, 12-20 weeks is approximately 16 weeks, 12-20 weeks is approximately 20 weeks, 12-20 weeks is approximately 12-16 weeks, 8-16 weeks is approximately 12 weeks, 8-16 weeks is approximately 16 weeks, 8-16 weeks is approximately 12-16 weeks, 2-4 weeks is approximately 4 weeks, and one or more secondary doses are two secondary doses, 12-20 weeks is approximately 12 weeks, and one or more secondary doses are two secondary doses, 12-20 weeks is approximately 16 weeks, and one or more secondary doses are two secondary doses, 12-20 weeks is approximately 20 weeks, and one or more secondary doses are two secondary doses, 12-20 weeks is approximately 12-16 weeks, and One or more secondary doses are equivalent to two secondary doses, 2-4 weeks is approximately 4 weeks, and one or more secondary doses are equivalent to two secondary doses, and the VEGF receptor fusion protein is aflibercept, 12-20 weeks is approximately 12 weeks, and one or more secondary doses are equivalent to two secondary doses, and the VEGF receptor fusion protein is aflibercept, 12-20 weeks is approximately 16 weeks, and one or more secondary doses are equivalent to two secondary doses, and the VEGF receptor fusion protein is aflibercept, 12-20 weeks is approximately 20 weeks, and one or more secondary doses are equivalent to two secondary doses, and the VEGF receptor fusion protein is aflibercept, and / or 12-20 weeks is approximately 12-16 weeks, and one or more secondary doses are equivalent to two secondary doses, and the VEGF receptor fusion protein is aflibercept.

[0029] In one embodiment of the present invention, the VEGF receptor fusion protein comprises amino acids 27 to 457 of the amino acid sequence described in SEQ ID NO: 2, selected from the group consisting of aflibercept and convercept, and comprises two polypeptides comprising (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 multimerizing component comprising amino acids 232 to 457 of SEQ ID NO: 2, comprising two polypeptides comprising the second immunoglobin-like (Ig) domain of VEGFR1, the third Ig domain of VEGFR2, and a multimerizing component, comprising two polypeptides comprising the second immunoglobin-like (Ig) domain of VEGFR1, the third Ig domain of VEGFR2, the fourth Ig domain of VEGFR2, and a multimerizing component, or comprising two VEGFR1R2-FcΔC1(a) polypeptides encoded by the nucleic acid sequence of SEQ ID NO: 1. In one embodiment of the present invention, the VEGF receptor fusion protein contains or consists of amino acids 27 to 457 of the amino acid sequence described in SEQ ID NO: 2. Preferably, the VEGF receptor fusion protein is aflibercept.

[0030] In one embodiment of the present invention, the VEGF receptor fusion protein is present in an aqueous pharmaceutical formulation selected from the group consisting of A-KKKK. In one embodiment of the present invention, the VEGF receptor fusion protein, preferably aflibercept, is present in an aqueous pharmaceutical formulation containing about 114.3 mg / ml of VEGF receptor fusion protein, preferably aflibercept.

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

[0032] In one embodiment of the present invention, a VEGF receptor fusion protein, preferably aflibercept, is administered from a sterile syringe or pre-filled syringe, for example, made of glass or plastic, and / or sterile, using a sterile needle, for example, a 30 gauge × 0.5 inch needle.

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

[0034] In one embodiment of the present invention, a subject administered 2 mg of VEGF receptor fusion protein, preferably aflibercept, is given an aqueous pharmaceutical formulation containing 40 mg / ml of 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 one embodiment of the present invention, ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, preferably aflibercept, is present in an aqueous pharmaceutical formulation comprising ≥100 mg / ml of VEGF receptor fusion protein, a histidine-based buffer, and arginine (preferably L-arginine), and for example, a sugar or polyol (e.g., sucrose). In one embodiment of the present invention, the formulation has a pH of about 5.8. For example, the formulation may contain about 103-126 mg / ml of VEGF receptor fusion protein, a histidine-based buffer, and arginine, and in one embodiment of the present invention, it contains about 114.3 mg / ml of VEGF receptor fusion protein, a histidine-based buffer, and arginine.

[0036] In one embodiment of the present invention, ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, preferably aflibercept, is used in amounts of approximately 100 μl or less, approximately 75 μl or less, approximately 70 μl or less, or approximately 50 μl, 51 μl, 52 μl, 53 μl, 54 μl, 55 μl, 56 μl, 57 μl, 58 μl, 59 μl, 60 μl, 61 μl, 62 μl, 63 μl, 64 μl, 65 μl, 66 μl, 67 μl, 68 μl, 69 μl, 70 μl It is administered in volumes of 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, for example, in a volume of about 70 ± 4 or 5 microliters.

[0037] In one embodiment of the present invention, the method herein includes the step of administering a VEGF receptor fusion protein, preferably aflibercept, to both eyes of a subject, for example, intravitreally.

[0038] In one embodiment of the present invention, the subject is characterized by: improvement in the Diabetic Retinopathy Severity Scale (DRSS), improvement in best-corrected visual acuity, dry retina, increase in best-corrected visual acuity, BCVA of at least 69 letters, fluid-free fovea, decrease in central retinal thickness (CRT), no vascular leakage as measured by fluorescein angiography (FA), and the National Eye Institute Visual Function Questionnaire (NEI-VFQ). Improvement from pre-treatment baseline in the total score of the Questionnaire), fluid-free retina in the fovea and central subfield (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF]), maintenance of fluid-free retina (total fluid, IRF and / or SRF in the fovea and central subfield), loss of macular edema, fluid-free retina on spectral domain optical coherence tomography (SD-OCT), no deviation from the HDq12, HDq16, or HDq20 treatment regimen once initiated, administered intravitreally as the first 3, 4, or 5 injections of 2 mg approximately every 4 weeks, then once every 8 weeks or once every 2 months, non-inferiority to aflibercept in BVCA, an increase of approximately 7, 8-9 letters in BCVA (according to the ETDRS letter score) by 60 weeks from the start of treatment, with a baseline BCVA of approximately 61, 62 or The score is 63, the BCVA (according to the ETDRS letter score) is at least approximately 69 letters by week 48 or 60 from the start of treatment, there is no loss of 5, 10, 15 or 69 or more BCVA letters after week 12, 24, 36, 48, 60, 72, 84, 90 or 96 from the start of treatment, the BCVA (according to the ETDRS letter score) improves by week 12, 24, 36, 48, 60, 72, 84, 90 or 96 from the start of treatment, treatment Improvement in BVCA by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 from the start of treatment; a BCVA score (following the ETDRS letter score) of approximately 69, 70, 71, 72, or 73 between weeks 48 and 60; and a change in the BCVA score (following the ETDRS letter score) from the start of treatment, which is approximately 7, 8, or 9, between weeks 36 and 48.The criteria for Early Treatment Diabetic Retinopathy (ETDRS) include: a BCVA of approximately 60 or 70 at any point between weeks 36 and 48; a change in the BCVA score from the start of treatment (according to the ETDRS letter score) of approximately 7, 8, or 9 between weeks 48 and 60; and a BCVA of approximately 69, 70, 71, 72, or 73 at any point between weeks 48 and 60. The BCVA, as measured using the visual acuity chart or equivalent Snellen visual acuity in the Study), should increase by ≥4, ≥5, ≥6, ≥7, ≥8, >9, or >10 letters by weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 from the start of treatment; no loss of 5, 10, or 15 letters (according to the ETDRS letter score) by weeks 48 or 60 from the start of treatment; gain of at least 5, 10, or 15 letters (according to the ETDRS letter score) by weeks 48 or 60 from the start of treatment; improvement of approximately 4 or 5 letters (ETDRS or equivalent Snellen visual acuity) in BCVA by 4 weeks after the start of treatment if receiving the HDq12 regimen, or approximately 4 or 5 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 regimen; and improvement of approximately 4 or 5 letters (ETDRS or equivalent Snellen visual acuity) in BCVA by 4 weeks after the start of treatment if receiving the HDq12 regimen. If receiving the HDq16 regimen, an improvement of approximately 6 letters (ETDRS or equivalent Snellen visual acuity) in BCVA; if receiving the HDq12 regimen, an improvement of approximately 5 or 6 letters (ETDRS or equivalent Snellen visual acuity) in BCVA; within 12 weeks of starting treatment, if receiving the HDq12 regimen, an improvement of approximately 6 or 7 letters (ETDRS or equivalent Snellen visual acuity) in BCVA; if receiving the HDq16 regimen, an improvement of approximately 6 letters (ETDRS or equivalent Snellen visual acuity) in BCVA; within 16 weeks of starting treatment, if receiving the HDq12 regimen, an improvement of approximately 6 or 7 letters (ETDRS or equivalent Snellen visual acuity) in BCVA; if receiving the HDq16 regimen, an improvement of 7 letters (ETDRS or equivalent Snellen visual acuity) in BCVA; within 20 weeks of starting treatment, if receiving the HDq12 regimen, an improvement of approximately 6 letters (ETDRS or equivalent Snellen visual acuity) in BCVA;Or, if receiving the HDq16 regimen, an improvement of approximately 6 letters (ETDRS or equivalent Snellen visual acuity) in BCVA; within 24 weeks of starting treatment, if receiving the HDq12 regimen, an improvement of approximately 7 letters (ETDRS or equivalent Snellen visual acuity); or if receiving the HDq16 regimen, an improvement of approximately 5 or 6 letters (ETDRS or equivalent Snellen visual acuity) in BCVA; within 28 weeks of starting treatment, if receiving the HDq12 regimen, an improvement of approximately 7 or 8 letters (ETDRS or equivalent Snellen visual acuity); or if receiving the HDq16 regimen, an improvement of approximately 7 or 8 letters (ETDRS or equivalent Snellen visual acuity) in BCVA; within 32 weeks of starting treatment, if receiving the HDq12 regimen, an improvement of approximately 7 letters (ETDRS or equivalent Snellen visual acuity), Or, if receiving the HDq16 regimen, an improvement of approximately 7 or 8 letters (ETDRS or equivalent Snellen visual acuity) in BCVA, within 36 weeks of starting treatment; if receiving the HDq12 regimen, an improvement of approximately 8 letters (ETDRS or equivalent Snellen visual acuity); or if receiving the HDq16 regimen, an improvement of approximately 6 or 7 letters (ETDRS or equivalent Snellen visual acuity) in BCVA; within 40 weeks of starting treatment; if receiving the HDq12 regimen, an improvement of approximately 8 letters (ETDRS or equivalent Snellen visual acuity); or the HDq16 regimen If you are receiving the HDq12 regimen, you will see an improvement of approximately 6 or 7 letters (ETDRS or equivalent Snellen visual acuity) in BCVA; within 44 weeks of starting treatment, if you are receiving the HDq12 regimen, you will see an improvement of approximately 8 letters (ETDRS or equivalent Snellen visual acuity); if you are receiving the HDq16 regimen, you will see an improvement of approximately 7 or 8 letters (ETDRS or equivalent Snellen visual acuity); within 48 weeks of starting treatment, if you are receiving the HDq12 regimen, you will see an improvement of approximately 8 or 9 letters (ETDRS or equivalent Snellen visual acuity); if you are receiving the HDq16 regimen, you will see an improvement of approximately 6 or 7 letters (ETDRS or equivalent Snellen visual acuity). If present, an improvement of approximately 7 or 8 letters (ETDRS or equivalent Snellen visual acuity), an improvement in BCVA maintained by approximately 8 weeks after the start of treatment and thereafter for at least 48 weeks of the treatment regimen, an improvement of approximately 68 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 regimen by 4 weeks after the start of treatment, or an improvement of approximately 66 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 regimen, and an improvement of approximately 70 letters (ETDRS or equivalent Snellen visual acuity) by 8 weeks after the start of treatment. (ETDRS or equivalent Snellen visual acuity), or approximately 67 letters of BCVA (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 regimen, within 12 weeks of starting treatment, approximately 70 letters of BCVA (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 regimen, or approximately 68 letters of BCVA (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 regimen, within 16 weeks of starting treatment, approximately 71 letters of BCVA (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 regimen,Or, if receiving the HDq16 regimen, approximately 69 letters of BCVA (ETDRS or equivalent Snellen visual acuity), within 20 weeks of starting treatment, if receiving the HDq12 regimen, approximately 70 letters of BCVA (ETDRS or equivalent Snellen visual acuity), or if receiving the HDq16 regimen, approximately 68 letters of BCVA (ETDRS or equivalent Snellen visual acuity), within 24 weeks of starting treatment, if receiving the HDq12 regimen, approximately 71 letters of BCVA (ETDRS or equivalent Snellen visual acuity), or if receiving the HDq16 regimen, approximately 67 letters of BCVA (ETDRS or equivalent Snellen visual acuity), within 28 weeks of starting treatment, if receiving the HDq12 regimen, approximately 72 letters of BCVA (ETDRS or equivalent Snellen visual acuity), or if receiving the HDq16 regimen, approximately 70 letters of BCVA (ETDRS or equivalent Snellen visual acuity), within 3 weeks of starting treatment Within 2 weeks, if receiving the HDq12 regimen, approximately 71 letters of BCVA (ETDRS or equivalent Snellen visual acuity), or if receiving the HDq16 regimen, approximately 70 letters of BCVA (ETDRS or equivalent Snellen visual acuity); within 36 weeks of the start of treatment, approximately 71 letters of BCVA (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 regimen, or approximately 68 letters of BCVA (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 regimen; within 40 weeks of the start of treatment, approximately 72 letters of BCVA (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 regimen, or approximately 69 letters of BCVA (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 regimen; within 44 weeks of the start of treatment, approximately 72 letters of BCVA (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 regimen; Or, if receiving the HDq16 regimen, approximately 70 letters of BCVA (ETDRS or equivalent Snellen visual acuity), within 48 weeks of treatment initiation, if receiving the HDq12 regimen, approximately 73 letters of BCVA (ETDRS or equivalent Snellen visual acuity), or if receiving the HDq16 regimen, approximately 70 letters of BCVA (ETDRS or equivalent Snellen visual acuity), within 48 weeks of treatment initiation, if receiving the HDq12 regimen and baseline BCVA is approximately <73 ETDRS letters, an improvement of approximately 9 or 10 letters of BCVA (ETDRS or If you have received the HDq12 regimen by 48 weeks after the start of treatment and your baseline BCVA is approximately >73 ETDRS letters, then an improvement of approximately 5 or 6 letters in BCVA (ETDRS or equivalent Snellen visual acuity); if you have received the HDq16 regimen by 48 weeks after the start of treatment and your baseline BCVA is approximately <73 ETDRS letters, then an improvement of approximately 8 or 9 letters in BCVA (ETDRS or equivalent Snellen visual acuity); if you have received the HDq16 regimen by 48 weeks after the start of treatment, then baseline BCV If A is approximately >73 ETDRS letters, an improvement of approximately 4 or 5 letters in BCVA (ETDRS or equivalent Snellen visual acuity); if receiving the HDq12 regimen and baseline CRT is approximately <400 micrometers by 48 weeks after the start of treatment, an improvement of approximately 7 or 8 letters in BCVA (ETDRS or equivalent Snellen visual acuity); if receiving the HDq12 regimen and baseline CRT is approximately >400 micrometers by 48 weeks after the start of treatment, an improvement of approximately 9 or 10 letters in BCVA (ETDRS or equivalent Snellen visual acuity) (Nelen visual acuity), if receiving the HDq16 regimen by 48 weeks after the start of treatment and the baseline CRT is approximately <400 micrometers, an improvement of approximately 5 or 6 letters in BCVA (ETDRS or equivalent Snellen visual acuity), if receiving the HDq16 regimen by 48 weeks after the start of treatment and the baseline CRT is approximately >400 micrometers, an improvement of approximately 9 or 10 letters in BCVA (ETDRS or equivalent Snellen visual acuity), if within 12, 24, 36, 48, 60, 72, 84, 90 or 96 weeks from the start of treatment, >5,Achieving a BCVA of >10 or ≥15 letters (according to the ETDRS letter score), improvement of ≥2 or >3 stages on the Diabetic Retinopathy Severity Scale (DRSS) by 12, 24, 36, 48, 60, 72, 84, 90, or 96 weeks from the start of treatment, improvement of ≥2 stages on the Diabetic Retinopathy Severity Scale (DRSS) by 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 weeks from the start of treatment, and fluid in the fovea and central subfield measured by optical coherence tomography (OCT) by 12, 24, 36, 48, 60, 72, 84, 90, or 96 weeks from the start of treatment. Retina free of (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF]), no vascular leakage as measured by fluorescein angiography (FA) from the start of treatment to weeks 12, 24, 36, 48, 60, 72, 84, 90 or 96, maintenance of a fluid-free retina (total fluid, IRF and / or SRF in the fovea and central subfield) from the start of treatment to weeks 12, 24, 36, 48, 60, 72, 84, 90 or 96, total area of ​​fluorescein leakage within the ETDRS grid (mm2) at week 48 or week 60 as measured by fluorescein angiography, 2The above reductions, fluid-free retina measured by spectral domain optical coherence tomography (SD-OCT) within 12, 24, 36, 48, 60, 72, 84, 90, or 96 weeks from the start of treatment, retina free of fluid (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF]) in the fovea within 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 weeks from the start of treatment, dry retina measured by optical coherence tomography (OCT) within 12, 24, 36, 48, 60, 72, 84, 90, or 96 weeks from the start of treatment, and measured within 12 weeks from the start of treatment. By weeks 24, 36, 48, 60, 72, 84, 90, or 96, a fluid-free foveal; by 4 weeks after the start of treatment, a change in central retinal thickness of approximately -118 or -118.3 micrometers if receiving the HDq12 regimen, or approximately -124 or -125 or -124.9 or -125.5 micrometers if receiving the HDq16 regimen; by 8 weeks after the start of treatment, approximately -137 or -137.4 micrometers if receiving the HDq12 regimen, or approximately - A change in central retinal thickness of 139 or -140 or -139.6 or -140.3 micrometers, or within 12 weeks of the start of treatment, approximately -150 or -150.1 micrometers if receiving the HDq12 regimen, or approximately -152 or -153 or -152.7 or -153.4 micrometers if receiving the HDq16 regimen, or within 16 weeks of the start of treatment, approximately -139 or -139.4 micrometers if receiving the HDq12 regimen, or the HDq16 regimen. If receiving the HDq12 regimen, a change in central retinal thickness of approximately -145, -146, -145.5, or -146.4 micrometers; within 20 weeks of the start of treatment, a change in central retinal thickness of approximately -117 or -117.1 micrometers if receiving the HDq12 regimen, or approximately -112, -113, -112.5, or -113.3 micrometers if receiving the HDq16 regimen; within 24 weeks of the start of treatment, a change in central retinal thickness of approximately -158 or -158.1 micrometers if receiving the HDq12 regimen. Or, if receiving the HDq16 regimen, a change in central retinal thickness of approximately -103, -104, -103.8, or -104.3 micrometers, by 28 weeks after the start of treatment; if receiving the HDq12 regimen, a change in central retinal thickness of approximately -146, -147, or -146.7 micrometers; or if receiving the HDq16 regimen, a change in central retinal thickness of approximately -162 or -162.3 micrometers; by 32 weeks after the start of treatment; if receiving the HDq12 regimen, approximately -13 A change in central retinal thickness of 2 micrometers, or approximately -145, -146, or -145.8 micrometers if receiving the HDq16 regimen, within 36 weeks of the start of treatment; a change in central retinal thickness of approximately -168 or -168.1 micrometers if receiving the HDq12 regimen, or approximately -124, -125, -124.7, or -125.2 micrometers if receiving the HDq16 regimen, within 40 weeks of the start of treatment. If present, a change in central retinal thickness of approximately -163 micrometers, or if receiving the HDq16 regimen, approximately -122, -123, -122.5, or -123.1 micrometers; within 44 weeks of the start of treatment, a change in central retinal thickness of approximately -147, -148, or -147.4 micrometers, or if receiving the HDq12 regimen, or approximately -164, -164.1, or -164.3 micrometers, or if receiving the HDq16 regimen; within 48 weeks of the start of treatment. Within one week, a change in central retinal thickness of approximately -171, -172, or -171.7 micrometers is expected if receiving the HDq12 regimen, or approximately -148, -149, -148.3, or -149.4 micrometers if receiving the HDq16 regimen. Within 60 weeks of the start of treatment, a change of approximately -181.95 or -176.24 micrometers is expected if receiving the HDq12 regimen, or approximately -166.26 or -167 micrometers if receiving the HDq16 regimen.A change in central retinal thickness of 18 micrometers, a decrease in central retinal thickness by 4, 5, 6, 7, or 8 weeks after the start of treatment, which is then maintained within a range of approximately ±17, ±18, or ±19 micrometers for at least 48 weeks from the start of treatment during the treatment regimen, a decrease in central retinal thickness of approximately 100, 125, 150, 175, or 200 micrometers by 12, 24, 36, 48, 60, 72, 84, 90, or 96 weeks from the start of treatment, measured by optical coherence tomography (OCT), approximately 48 weeks from the start of treatment. This refers to a decrease of approximately 148-182 micrometers in central retinal thickness up to week 60, with a baseline CRT of approximately 449, 450, 455, or 460 micrometers, and a decrease of at least approximately 100, 125, 130, 135, 140, 145, 149, 150, 155, 160, 165, 170, 171, 172, 173, 174, or 175 micrometers in central retinal thickness (CRT) by weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 from the start of treatment, and the first dose Approximately 0.1667 days later, the plasma concentration of free aflibercept was approximately 0.149 (±0.249) mg / l, and at baseline, the plasma concentration of free aflibercept was undetectable, and the subjects had not received intravitreal aflibercept treatment for at least 12 weeks; Approximately 0.3333 days after the first dose, the plasma concentration of free aflibercept was approximately 0.205 (±0.250) mg / l, and at baseline, the plasma concentration of free aflibercept was undetectable. The subjects were not detectable, had not received intravitreal aflibercept treatment for at least 12 weeks, and had a plasma free aflibercept concentration of approximately 0.266 (±0.211) mg / l about 1 day after the first dose, and at baseline, plasma free aflibercept was undetectable, and the subjects were not receiving intravitreal aflibercept treatment for at least 12 weeks, and had a plasma free aflibercept concentration of approximately 0.218 (±0.The patient's free aflibercept level was 145 mg / l, and at baseline, free aflibercept in plasma was undetectable, and the patient had not received intravitreal aflibercept treatment for at least 12 weeks. Approximately 4 days after the first dose, the free aflibercept level in plasma was approximately 0.140 (±0.0741) mg / l, and at baseline, free aflibercept in plasma was undetectable, and the patient had not received intravitreal aflibercept treatment for at least 12 weeks. Approximately 7 days after administration, the plasma free aflibercept concentration is approximately 0.0767 (±0.0436) mg / l, and at baseline, plasma free aflibercept is undetectable, and the subjects have not received intravitreal aflibercept treatment for at least 12 weeks; Approximately 14 days after the first dose, the plasma free aflibercept concentration is approximately 0.0309 (±0.0241) mg / l, and at baseline, plasma free aflibercept is undetectable, and the subjects have not received intravitreal aflibercept treatment for at least 1 The subjects had not received intravitreal aflibercept treatment for two weeks, and approximately 21 days after the first dose, their plasma free aflibercept level was approximately 0.0171 (±0.0171) mg / l, and at baseline, their plasma free aflibercept level was undetectable. The subjects had not received intravitreal aflibercept treatment for at least 12 weeks, and approximately 28 days after the first dose, their plasma free aflibercept level was approximately 0.00730 (±0.0113) mg / l, and at baseline, Free aflibercept in plasma is undetectable, subjects have not received intravitreal aflibercept treatment for at least 12 weeks, and adjusted conjugated aflibercept in plasma is approximately 0.00698 (±0.0276) mg / l approximately 0.1667 days after the first dose, with adjusted conjugated aflibercept at baseline being approximately 0.00583 mg / l (±0.0280), subjects have not received intravitreal aflibercept treatment for at least 12 weeks, and approximately 0.After 3333 days, the plasma concentration of adjusted conjugated aflibercept was approximately 0.00731 (±0.0279) mg / l, compared to approximately 0.00583 mg / l (±0.0280) at baseline. The subjects were those who had not received intravitreal aflibercept treatment for at least 12 weeks, and approximately 1 day after the first dose, the plasma level of adjusted conjugated aflibercept was approximately 0.0678 (±0.0486) mg / l, with a baseline level of approximately 0.00583 mg / l (±0.0280). The subjects were those who had not received intravitreal aflibercept treatment for at least 12 weeks, and approximately 2 days after the first dose, the plasma level of adjusted conjugated aflibercept was approximately 0.138 (±0.0618) mg / l, with a baseline level of approximately 0.00583 mg / l (±0.0280). The subjects were those who had not received intravitreal aflibercept treatment for at least 12 weeks, and approximately 4 days after the first dose, the plasma level of adjusted conjugated aflibercept The patient's total aflibercept level was approximately 0.259 (±0.126) mg / l, and at baseline, the adjusted conjugated aflibercept level was approximately 0.00583 mg / l (±0.0280), and the subjects had not received intravitreal aflibercept treatment for at least 12 weeks. Approximately 7 days after the first dose, the plasma adjusted conjugated aflibercept level was approximately 0.346 (±0.151) mg / l, and at baseline, the adjusted conjugated aflibercept level was approximately 0.00583 mg / l (±0.0280), and the subjects had not received intravitreal aflibercept treatment for at least 12 weeks. Approximately 14 days after the first dose, the plasma adjusted conjugated aflibercept level was approximately 0.374 (±0.110) mg / l, and at baseline, the adjusted conjugated aflibercept level was approximately 0.00583 mg / l (±0.028). 0) The subjects had not received intravitreal aflibercept treatment for at least 12 weeks, and approximately 21 days after the first dose, the plasma adjusted conjugated aflibercept level was approximately 0.343 (±0.128) mg / l, with the baseline adjusted conjugated aflibercept level being approximately 0.00583 mg / l (±0.0280), and the subjects had not received intravitreal aflibercept treatment for at least 12 weeks, and the first dose Approximately 28 days after administration, the plasma concentration of adjusted conjugated aflibercept was approximately 0.269 (±0.149) mg / l, with a baseline concentration of approximately 0.00583 mg / l (±0.0280), and the subjects had not received intravitreal aflibercept treatment for at least 12 weeks. Approximately 0.965 days after the first dose, the peak plasma concentration of free aflibercept was approximately 0.310 mg / l (±0.263). The goal is to reach the peak plasma concentration of free aflibercept, with the plasma free aflibercept concentration being approximately 0 to 1.08 mg / L, the peak plasma concentration of free aflibercept per dose (mg) being approximately 0.0388 (±0.0328) mg / l / mg, the goal is to reach the peak plasma concentration of adjusted conjugated aflibercept approximately 14 days after the first dose, with the adjusted conjugated aflibercept concentration being approximately 0.387 mg / l (±0.135). Achieve and / or maintain one or more of the following: reach peak plasma concentration of aflibercept; plasma adjusted conjugated aflibercept concentration of approximately 0.137 to 0.774 mg / L; peak plasma adjusted conjugated aflibercept concentration of approximately 0.0483 (±0.0168) mg / l / mg per dose (mg) of aflibercept; be free from anti-drug antibodies against aflibercept after 48 or 60 weeks of treatment; improve total score on the National Eye Institute Visual Function Questionnaire (NEI-VFQ) from pre-treatment baseline; and / or loss of macular edema.For example, in one embodiment of the present invention, dry retina is characterized by the loss of intraretinal fluid and / or subretinal fluid, or retinal dryness is characterized by the absence of intraretinal fluid (IRF) and subretinal fluid (SRF) in the subject's eye after the subject receives three monthly doses of a VEGF receptor fusion protein, preferably aflibercept.

[0039] In embodiments of the present invention, the subjects are those receiving an HDq12 regimen and an improvement of approximately 9 letters (ETDRS or equivalent Snellen visual acuity) or approximately 8 letters (ETDRS or equivalent Snellen visual acuity) within 64 weeks of the start of treatment, those receiving an HDq16 regimen and an improvement of approximately 8 letters (ETDRS or equivalent Snellen visual acuity) within 68 weeks of the start of treatment, and those receiving an HDq12 regimen and an improvement of approximately 8 letters (ETDRS or equivalent Snellen visual acuity) within 68 weeks of the start of treatment, and those receiving an HDq16 regimen and an improvement of approximately 8 letters (ETDRS or equivalent Snellen visual acuity) within 72 weeks of the start of treatment. If receiving the HDq16 regimen, an improvement of approximately 8 letters (ETDRS or equivalent Snellen visual acuity) in BCVA; if receiving the HDq12 regimen, an improvement of approximately 8 letters (ETDRS or equivalent Snellen visual acuity) in BCVA by 76 weeks after the start of treatment; if receiving the HDq16 regimen, an improvement of approximately 7 letters (ETDRS or equivalent Snellen visual acuity) in BCVA; if receiving the HDq12 regimen, an improvement of approximately 8 letters (ETDRS or equivalent Snellen visual acuity) by 80 weeks after the start of treatment. If receiving the HDq16 regimen, an improvement of approximately 8 letters (ETDRS or equivalent Snellen visual acuity) in BCVA, by 84 weeks after the start of treatment, if receiving the HDq12 regimen, an improvement of approximately 8 letters (ETDRS or equivalent Snellen visual acuity), or if receiving the HDq16 regimen, an improvement of approximately 8 letters (ETDRS or equivalent Snellen visual acuity), by 88 weeks after the start of treatment, if receiving the HDq12 regimen, an improvement of approximately 9 letters (ETDRS or equivalent Snellen visual acuity), or if receiving the HDq16 regimen, an improvement of approximately 7 letters (ETDRS or Improvement in BCVA (corresponding to Snellen visual acuity), by 92 weeks after the start of treatment, an improvement of approximately 9 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 regimen, or approximately 7 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 regimen, by 96 weeks after the start of treatment, an improvement of approximately 9 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 regimen, or approximately 8 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 regimen, by 64 weeks after the start of treatment,If receiving the HDq12 regimen, approximately 73 letters (ETDRS or equivalent Snellen visual acuity) of BCVA, or if receiving the HDq16 regimen, approximately 70 letters (ETDRS or equivalent Snellen visual acuity) of BCVA, within 68 weeks of the start of treatment, if receiving the HDq12 regimen, approximately 72 letters (ETDRS or equivalent Snellen visual acuity) of BCVA, or if receiving the HDq16 regimen, approximately 69 letters (ETDRS or equivalent Snellen visual acuity) of BCVA, within 72 weeks of the start of treatment, if receiving the HDq12 regimen, approximately 73 letters (ETDRS BCVA of S or equivalent Snellen visual acuity, or BCVA of approximately 68 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 regimen, within 76 weeks of the start of treatment, BCVA of approximately 73 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 regimen, or BCVA of approximately 68 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 regimen, within 80 weeks of the start of treatment, BCVA of approximately 72 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 regimen, or HDq16 If receiving a regimen, approximately 69 letters (ETDRS or equivalent Snellen visual acuity) of BCVA; within 84 weeks of starting treatment, if receiving an HDq12 regimen, approximately 72 letters (ETDRS or equivalent Snellen visual acuity) of BCVA; or if receiving an HDq16 regimen, approximately 70 letters (ETDRS or equivalent Snellen visual acuity) of BCVA; within 88 weeks of starting treatment, if receiving an HDq12 regimen, approximately 73 letters (ETDRS or equivalent Snellen visual acuity) of BCVA; or if receiving an HDq16 regimen, approximately 69 letters (ETDRS or equivalent Snellen visual acuity) of BCVA. BCVA of Snellen visual acuity, by 92 weeks after the start of treatment, if receiving the HDq12 regimen, BCVA of approximately 73 letters (ETDRS or equivalent Snellen visual acuity), or if receiving the HDq16 regimen, BCVA of approximately 69 letters (ETDRS or equivalent Snellen visual acuity), by 96 weeks after the start of treatment, if receiving the HDq12 regimen, BCVA of approximately 73 letters (ETDRS or equivalent Snellen visual acuity), or if receiving the HDq16 regimen, BCVA of approximately 69 letters (ETDRS or equivalent Snellen visual acuity), by 64 weeks after the start of treatment,If receiving the HDq12 regimen, a change in central retinal thickness of approximately -173.4 micrometers or approximately -173 micrometers; if receiving the HDq16 regimen, a change in central retinal thickness of approximately -164.3 micrometers or approximately -164 micrometers; within 68 weeks of the start of treatment; if receiving the HDq12 regimen, a change in central retinal thickness of approximately -159.4 micrometers or approximately -159 micrometers; if receiving the HDq16 regimen, a change in central retinal thickness of approximately -153.9 micrometers or approximately -154 micrometers; within 72 weeks of the start of treatment. If receiving the HDq12 regimen, a change in central retinal thickness of approximately -166.6 micrometers or approximately -167 micrometers, or if receiving the HDq16 regimen, a change in central retinal thickness of approximately -134.2 micrometers or approximately -134 micrometers, by 76 weeks after the start of treatment; if receiving the HDq12 regimen, a change in central retinal thickness of approximately -181.1 micrometers or approximately -181 micrometers, or if receiving the HDq16 regimen, a change in central retinal thickness of approximately -160.8 micrometers or approximately -161 micrometers, by 80 weeks after the start of treatment. If receiving the HDq12 regimen, a change in central retinal thickness of approximately -168.9 micrometers or approximately -169 micrometers, or if receiving the HDq16 regimen, a change in central retinal thickness of approximately -164 micrometers or approximately -164 micrometers, by 84 weeks after the start of treatment; if receiving the HDq12 regimen, a change in central retinal thickness of approximately -177.5 micrometers or approximately -178 micrometers, or if receiving the HDq16 regimen, a change in central retinal thickness of approximately -150.2 micrometers or approximately -150 micrometers, by 88 weeks after the start of treatment; If receiving the HDq12 regimen, a change in central retinal thickness of approximately -171.2 micrometers or approximately -171 micrometers, or if receiving the HDq16 regimen, a change in central retinal thickness of approximately -144.3 micrometers or approximately -144 micrometers, by 92 weeks after the start of treatment; if receiving the HDq12 regimen, a change in central retinal thickness of approximately -166.7 micrometers or approximately -167 micrometers, or if receiving the HDq16 regimen, a change in central retinal thickness of approximately -155.5 micrometers or approximately -156 micrometers, by 96 weeks after the start of treatment;If receiving the HDq12 regimen, a change in central retinal thickness of approximately -185.3 micrometers or approximately -185 micrometers; if receiving the HDq16 regimen, a change in central retinal thickness of approximately -155 micrometers or approximately -155 micrometers; within 64 weeks of the start of treatment, a change in central retinal thickness of approximately 279.4 micrometers if receiving the HDq12 regimen, or approximately 289.6 micrometers if receiving the HDq16 regimen; within 68 weeks of the start of treatment, a change in central retinal thickness of approximately 294.5 micrometers if receiving the HDq12 regimen, or approximately 305.3 micrometers if receiving the HDq16 regimen; within 72 weeks of the start of treatment, a change in central retinal thickness of approximately 284.2 micrometers if receiving the HDq12 regimen, or approximately 327.2 micrometers if receiving the HDq16 regimen; within 76 weeks of the start of treatment, a change in central retinal thickness of approximately 270.6 micrometers if receiving the HDq12 regimen, or approximately 302 micrometers if receiving the HDq16 regimen. Within 80 weeks of the start of treatment, the central retinal thickness should be approximately 284.6 micrometers if receiving the HDq12 regimen, or approximately 293.5 micrometers if receiving the HDq16 regimen. Within 84 weeks of the start of treatment, the central retinal thickness should be approximately 274.7 micrometers if receiving the HDq12 regimen, or approximately 310.8 micrometers if receiving the HDq16 regimen. Within 88 weeks of the start of treatment, the central retinal thickness should be approximately 283.7 micrometers if receiving the HDq12 regimen, or approximately 283.7 micrometers if receiving the HDq16 regimen. If receiving the HDq12 regimen, achieve and / or maintain a central retinal thickness of approximately 312.3 micrometers; within 92 weeks of the start of treatment, achieve and / or maintain one or more of the following: within 92 weeks of the start of treatment, within 92 weeks of the start of treatment, within 285.7 micrometers if receiving the HDq12 regimen, or within 96 weeks of the start of treatment, within 267.5 micrometers if receiving the HDq12 regimen, or within 304.2 micrometers if receiving the HDq16 regimen.

[0040] In one embodiment of the present invention, references to 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, or 60 weeks from the start of treatment mean approximately 48 or 60 weeks from the start of treatment.

[0041] In one embodiment of the present invention, in the first year, a VEGF receptor fusion protein, preferably aflibercept, is administered to the subject in one initial dose, two secondary doses, and three tertiary doses; or in the first year, a VEGF receptor fusion protein, for example aflibercept, is administered to the subject in one initial dose, two secondary doses, and two tertiary doses; or in the first year, a VEGF receptor fusion protein, for example aflibercept, is administered in one initial dose, two secondary doses, and three tertiary doses, and then in the second year, two to four tertiary doses are administered to the subject.

[0042] In one embodiment of the present invention, the interval between doses is adjusted (increased / maintained / decreased) based on visual and / or anatomical outcomes, for example, according to the criteria shown in Figures 3 and / or 4.

[0043] The present invention also relates to a kit comprising a container preferably containing aflibercept VEGF receptor fusion protein and instructions for use of the VEGF receptor fusion protein, wherein the container is a vial or a pre-filled syringe, the container contains ≥100 mg / mL of VEGF receptor fusion protein, the container contains ≥114.3 mg / mL of VEGF receptor fusion protein, the instructions include instructions for administering aflibercept to DR, DME and / or nAMD patients, the instructions include instructions that aflibercept ≥8 mg (±0.8 mg) treatment is initiated with three consecutive doses of one injection once every month (approximately every four weeks), the instructions include instructions that after the initial three consecutive doses, the injection interval may be extended up to every 24 weeks, and the instructions also include instructions that the treatment interval may be adjusted based on the physician's judgment regarding visual and / or anatomical outcomes.

[0044] The present invention provides aflibercept for use in treating or preventing intraocular neovascular disease, age-related macular degeneration with neovascularization, diabetic retinopathy and / or diabetic macular edema in subjects requiring such treatment or prevention, comprising administering aflibercept to the subject's eye (preferably by intravitreous injection) in one or more doses at intervals and in amounts such that the clearance of free aflibercept from the ocular compartment after intravitreous injection of aflibercept is approximately 0.367 to 0.457 mL / day, wherein the time to reach the lower limit of quantification (LLOQ) of free aflibercept in the subject's ocular compartment after intravitreous injection of aflibercept is approximately 15 weeks, and the time to reach the lower limit of quantification (LLOQ) of free aflibercept in the subject's plasma after intravitreous injection of aflibercept is approximately 3.5 weeks.

[0045] The present invention relates to aflibercept for use in a method of slowing the clearance of free aflibercept from the ocular compartment after intravitreal injection, compared to the clearance rate of aflibercept from the ocular compartment after intravitreal injection of <4 mg of aflibercept, the method comprising a single initial dose of about 8 mg (±0.8 mg) or more of aflibercept to the eye of a subject requiring it, and then Aflibercept administered as a secondary dose of approximately 8 mg (±0.8 mg) or more, followed by This includes intravitreal injection of approximately 8 mg (±0.8 mg) or more of aflibercept as a third-line dose, Each secondary dose is administered approximately 2 to 4 weeks after the previous dose. The present invention provides aflibercept, in which each third dose is administered approximately 24 weeks after the previous dose.

[0046] The present invention relates to aflibercept for use in a method for increasing the time it takes for the amount of free aflibercept in the target ocular compartment to reach the lower limit of quantification (LLOQ) after intravitreal injection of approximately 2 mg of aflibercept, compared to the time it takes for the amount of free aflibercept in the target ocular compartment to reach the LLOQ after intravitreal injection of aflibercept. This method is intended for the eyes of those who require it. A single initial dose of aflibercept of approximately 8 mg (±0.8 mg) or more, followed by Aflibercept administered as a secondary dose of approximately 8 mg (±0.8 mg) or more, followed by This includes intravitreal injection of approximately 8 mg (±0.8 mg) or more of aflibercept as a third-line dose, Each secondary dose is administered approximately 2 to 4 weeks after the previous dose. The present invention provides aflibercept, in which each third dose is administered approximately 24 weeks after the previous dose.

[0047] The present invention provides aflibercept for use in a method for increasing the time it takes for free aflibercept in the plasma of a subject to reach the lower limit of quantification (LLOQ) after intravitreal injection of approximately 2 mg of aflibercept, compared to the time it takes for free aflibercept in the plasma of a subject to reach the LLOQ after intravitreal injection of approximately 2 mg of aflibercept, wherein the method comprises intravitreal injection of approximately 8 mg (±0.8 mg) or more of aflibercept as a single initial dose, followed by one or more secondary doses of approximately 8 mg (±0.8 mg) or more of aflibercept, followed by one or more tertiary doses of approximately 8 mg (±0.8 mg) or more of aflibercept, each secondary dose administered approximately 2 to 4 weeks after the most recent dose, and each tertiary dose administered approximately 24 weeks after the most recent dose.

[0048] The present invention - In subjects requiring treatment or prevention of intraocular neovascular disease, nAMD, diabetic retinopathy (DR), and / or diabetic macular edema (DME), the means of providing such treatment or prevention, - In subjects with intraocular neovascular disease, nAMD, DR, and / or DME, who require improvement of best corrected visual acuity, or A VEGF receptor fusion protein for use in a method for promoting retinal dryness in subjects having DR and / or DME, The present invention provides a VEGF receptor fusion protein, wherein the method involves administering approximately 8 mg (±0.8 mg) or more of the VEGF receptor fusion protein to the target eye once every 24 weeks.

[0049] The present invention provides aflibercept for use in treating or preventing intraocular neovascular disease, age-related macular degeneration with neovascularization, diabetic retinopathy and / or diabetic macular edema in subjects requiring such treatment or prevention, wherein the treatment or prevention comprises initiating treatment with three consecutive injections of 8 mg (±0.8 mg) of aflibercept every month (every 4 weeks), followed by one or more injections every 24 weeks, wherein the concentration of aflibercept in each of the injections is 114.3 mg / mL, or the volume of each injection is 70 μL. In one embodiment of the present invention, the treatment interval between two subsequent 8 mg (±0.8 mg) aflibercept injections is adjusted (increased / maintained / shortened) based on visual and / or anatomical outcomes, including but not limited to acquisition or loss of letters in BCVA, increase or decrease in CRT, presence or absence of subretinal fluid, presence or absence of hemorrhage, or persistence or worsening of DME. In one embodiment of the present invention, the treatment interval is shortened by 2-4 weeks, 2 weeks, 3 weeks, or 4 weeks compared to the previous treatment interval if the subject is identified as meeting at least one of the criteria for a reduction in treatment duration, which is: loss of >5 or >10 letters in BCVA, CRT >300 or 320 μm, CRT >50 μm increase, or 2. persistence or worsening of DME. In another embodiment of the present invention, the treatment interval is extended by 2-4 weeks, 2 weeks, 3 weeks, or 4 weeks compared to the previous treatment interval if the subject is identified as meeting at least one of the criteria for a lengthening of treatment interval, which is: loss of <5 or <10 letters in BCVA, CRT <300 or 320 μm, CRT >50 μm decrease, absence of subretinal fluid, or absence of hemorrhage.

[0050] The present invention provides a VEGF receptor fusion protein for use in treating or preventing intraocular neovascular disease or diabetic macular edema in subjects requiring such treatment or prevention, wherein the method comprises administering 8 mg (±0.8 mg) of VEGF receptor fusion protein (e.g., in a volume of 0.07 mL or 70 microliters) by intravitreous injection as the first three doses, every four weeks (approximately every 28 days + / - 7 days, monthly), and then administering 8 mg (±0.8 mg) of VEGF receptor fusion protein (e.g., in a volume of 0.07 mL) once every 24 weeks (±7 days) by intravitreous injection.

[0051] The present invention provides a VEGF receptor fusion protein for use in treating or preventing diabetic retinopathy (DR) in subjects requiring such treatment or prevention, wherein the method comprises administering 8 mg (±0.8 mg) of VEGF receptor fusion protein (e.g., in a volume of 0.07 mL or 70 microliters) by intravitreous injection as the first three doses, every four weeks (approximately every 28 days + / - 7 days, monthly), and then administering 8 mg (±0.8 mg) of VEGF receptor fusion protein (e.g., in a volume of 0.07 mL) once every 24 weeks (±7 days) by intravitreous injection.

[0052] The present invention provides a VEGF receptor fusion protein for use in treating or preventing age-related macular degeneration with neovascularization in subjects requiring such treatment or prevention, wherein the method comprises administering 8 mg (±0.8 mg) of VEGF receptor fusion protein (e.g., in a volume of 0.07 mL or 70 microliters) by intravitreous injection as the first three doses, every four weeks (approximately every 28 days + / - 7 days, monthly), and then administering 8 mg (±0.8 mg) of VEGF receptor fusion protein (e.g., in a volume of 0.07 mL) once every 24 weeks (±7 days) by intravitreous injection.

[0053] The present invention provides aflibercept for use in treating or preventing intraocular neovascular disease, age-related macular degeneration with neovascularization, diabetic macular edema, or diabetic retinopathy in subjects requiring such treatment or prevention, comprising administering a single initial dose of ≥8 mg (±0.8 mg) of aflibercept to the eye of the subject (preferably by intravitreal injection), followed by one or more tertiary doses of approximately ≥8 mg (±0.8 mg) of aflibercept, each tertiary dose administered approximately 24 weeks after the most recent dose. In one embodiment of the present invention, the subject is not a treatment-naïve subject, or the subject has been pre-treated with a VEGF antagonist, or preferably the subject has been pre-treated with ≥8 mg (±0.8 mg) of aflibercept or 2 mg of aflibercept.

[0054] The present invention provides aflibercept for use in the treatment or prevention of intraocular neovascular disease, age-related macular degeneration with neovascularization, diabetic macular edema, or diabetic retinopathy in subjects pre-treated with 2 mg of aflibercept, comprising administering a single initial dose of approximately ≥8 mg (±0.8 mg) of aflibercept to the eye of the subject (preferably by intravitreal injection), followed by one or more secondary doses of approximately ≥8 mg (±0.8 mg) of aflibercept, followed by one or more tertiary doses of approximately ≥8 mg (±0.8 mg) of aflibercept, each secondary dose administered approximately 4 weeks after the most recent dose, and each tertiary dose administered approximately 24 weeks after the most recent dose. In one embodiment of the present invention, the administration of one or more doses of ≥8 mg (±0.8 mg) of aflibercept to the eye of the subject follows the HDq24 administration regimen or the Treat and Extent administration regimen.

[0055] The present invention relates to a VEGF receptor fusion protein for use in the treatment or prevention of intraocular neovascular disease, nAMD, diabetic retinopathy, and / or diabetic macular edema in subjects who are receiving an administration regimen for the treatment or prevention of such treatment or prevention, (a) The subject has received an initial dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, and the method then includes administering a first secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein to the subject one month later, a second secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein one month thereafter, and then administering one or more maintenance doses of 8 mg of VEGF receptor fusion protein every 24 weeks thereafter, according to the HDq24 administration regimen. or (b) A subject has received an initial dose of 8 mg of VEGF receptor fusion protein and a first secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein one month later, and the method further includes administering a second secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein to the subject one month later, and then administering one or more maintenance doses of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein every 24 weeks thereafter, according to the HDq24 administration regimen. or (c) The subject has received an initial dose of 8 mg of VEGF receptor fusion protein, a first secondary dose of 8 mg of VEGF receptor fusion protein one month later, and a second secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein one month later, and the method then includes administering to the subject, after 24 weeks, a first maintenance dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, and all of the additional maintenance doses of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein every 24 weeks according to the HDq24 administration regimen. or (d) The subject has received an initial dose of ≥8 mg of VEGF receptor fusion protein, a first secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein one month later, and a second secondary dose of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein one month later, and thereafter every 24 weeks the subject has received one or more maintenance doses of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, and the following method includes administering to the subject one or more maintenance doses of ≥8 mg of VEGF receptor fusion protein 24 weeks after the final maintenance dose of VEGF receptor fusion protein, and all of the further maintenance doses of ≥8 mg (±0.8 mg) of VEGF receptor fusion protein every 24 weeks according to the HDq24 administration regimen. The HDq24 administration regimen is A single initial dose (preferably by intravitreal injection) of approximately ≥8 mg (±0.8 mg) or more of VEGF receptor fusion protein, followed by One or more secondary doses (preferably by intravitreal injection) of approximately ≥8 mg (±0.8 mg) or more of VEGF receptor fusion protein, followed by A single or more third-line dose (preferably by intravitreal injection) containing approximately ≥8 mg (±0.8 mg) or more of VEGF receptor fusion protein, Each secondary dose is administered approximately 2 to 4 weeks after the previous dose. The present invention provides a VEGF receptor fusion protein, with each third dose administered approximately 24 weeks after the previous dose.

[0056] The present invention relates to a subject receiving a regimen for the treatment or prevention of intraocular neovascular disease, which requires a single initial dose of approximately 2 mg of VEGF receptor fusion protein, followed by one or more secondary doses of approximately 2 mg of VEGF receptor fusion protein, followed by one or more tertiary doses of approximately 2 mg of VEGF receptor fusion protein, and wherein the VEGF receptor fusion protein is used for the treatment or prevention of said disorder in subjects requiring treatment or prevention of said disorder, with each secondary dose administered approximately 4 weeks after the immediately preceding dose, and each tertiary dose administered approximately 8 weeks after the immediately preceding dose. The present invention provides a VEGF receptor fusion protein, which is administered to a subject who is in any stage of a 2 mg VEGF receptor fusion protein administration regimen, and includes administering an ≥8 mg (±0.8 mg) dose of VEGF receptor fusion protein to the subject's eye (preferably by intravitreal injection), evaluating the subject approximately 4 weeks, 8 weeks, 10 weeks, or 12 weeks after administration, and, if the treating physician deems administration every 24 weeks appropriate, continuing to administer an ≥8 mg (±0.8 mg) dose of VEGF receptor fusion protein to the subject every 24 weeks.

[0057] The present invention relates to a VEGF receptor fusion protein for use in treating and preventing intraocular neovascular disease, nAMD, diabetic retinopathy, or diabetic macular edema in subjects requiring such treatment and prevention, wherein the treatment or prevention comprises administering to the subject's eye a single initial dose of approximately ≥8 mg (±0.8 mg) or more of VEGF receptor fusion protein, followed by one or more, preferably two, secondary doses of approximately ≥8 mg (±0.8 mg) or more of VEGF receptor fusion protein, followed by one or more tertiary doses of approximately ≥8 mg (±0.8 mg) or more of VEGF receptor fusion protein, each secondary dose administered approximately 2 to 4 weeks after the previous dose, and each tertiary dose administered approximately 12, 16, or 20 weeks after the previous dose, wherein after receiving one or more tertiary doses approximately 12, 16, or 20 weeks after the previous dose, the interval between tertiary doses is extended to the interval between the previous doses. • After 12 to 24 weeks, • After 26 to 24 weeks, or • After 20 to 24 weeks, The present invention provides a VEGF receptor fusion protein, which further includes extension.

[0058] The present invention relates to a VEGF receptor fusion protein for use in treating and preventing intraocular neovascular disease, diabetic retinopathy and / or diabetic macular edema in subjects requiring such treatment and prevention, comprising administering to the eye of the subject (preferably by intravitreal injection) a single initial dose of approximately 8 mg (±0.8 mg) or more of VEGF receptor fusion protein, followed by one or more secondary doses of approximately 8 mg (±0.8 mg) or more of VEGF receptor fusion protein, followed by one or more tertiary doses of approximately 8 mg (±0.8 mg) or more of VEGF receptor fusion protein, each secondary dose administered approximately 2 to 4 weeks after the previous dose, and each tertiary dose administered approximately 24 weeks after the previous dose, wherein after receiving one or more tertiary doses approximately 24 weeks after the previous dose, the interval between tertiary doses is extended. • From 24 weeks to 8 weeks, • From 24 weeks to 12 weeks, From 24 weeks to 16 weeks, The invention provides a VEGF receptor fusion protein, which further includes shortening the duration from 24 weeks to 20 weeks.

[0059] The present invention provides a VEGF receptor fusion protein for use in the treatment and prevention of intraocular neovascular disease, nAMD, diabetic retinopathy and / or diabetic macular edema in subjects requiring such treatment and prevention, comprising a formulation containing approximately 114.3 mg / ml of VEGF receptor fusion protein to be administered to the eye of the subject (preferably by intravitreal injection), comprising administering three doses of approximately 8 mg (±0.8 mg) of VEGF receptor fusion protein at intervals of four weeks, and administering one or more doses of VEGF receptor fusion protein after the three doses, with intervals extended up to a maximum of 24 weeks.

[0060] The present invention relates to a VEGF receptor fusion protein for use in treating and preventing intraocular neovascular disease, age-related macular degeneration with neovascularization, diabetic retinopathy, and / or diabetic macular edema in subjects requiring such treatment and prevention, wherein the VEGF receptor fusion protein is administered to the eye of the subject (preferably by intravitreal injection) as a single initial dose of approximately 8 mg (±0.8 mg) or more of VEGF receptor fusion protein, followed by two secondary doses of approximately 8 mg (±0.8 mg) or more of VEGF receptor fusion protein. The treatment then includes administering one or more tertiary doses of approximately 8 mg (±0.8 mg) or more of VEGF receptor fusion protein, with each secondary dose administered approximately 2 to 4 weeks after the previous dose, and each tertiary dose administered approximately 24 weeks after the previous dose. a) To determine whether the subject meets at least one criterion for shortening or extending one or more intervals between administrations of VEGF receptor fusion protein by 2 weeks, 3 weeks, 4 weeks, or 2-4 weeks, b) If such decision is made, this includes administering a further dose of VEGF receptor fusion protein at a shortened or extended interval between doses, The criteria for extending that interval are, 1. Loss of <5 letters in BCVA, and / or 2. The CRT is <300 or 320 micrometers, The criteria for shortening that interval is, 1. Loss of >10 characters in BCVA, 2. Persistence or worsening of DME, and / or 3. Provides a VEGF receptor fusion protein that includes a CRT increase of >50 micrometers.

[0061] The present invention provides a VEGF receptor fusion protein for use in treating and preventing intraocular neovascular disease, nAMD, diabetic retinopathy and / or diabetic macular edema in subjects who have been pre-treated with one or more doses of 2 mg of VEGF receptor fusion protein, comprising administering a single initial dose of approximately 8 mg (±0.8 mg) or more of VEGF receptor fusion protein to the eye of the subject (preferably by intravitreal injection), followed by one or more secondary doses of approximately 8 mg (±0.8 mg) or more of VEGF receptor fusion protein, followed by one or more tertiary doses of approximately 8 mg (±0.8 mg) or more of VEGF receptor fusion protein, wherein each secondary dose is administered approximately 2 to 4 weeks after the previous dose, and each tertiary dose is administered approximately 24 weeks after the previous dose.

[0062] The present invention provides a VEGF receptor fusion protein for use in treating and preventing intraocular neovascular disease in subjects requiring such treatment and prevention, comprising administering 8 mg (±0.8 mg) or more of the VEGF receptor fusion protein to the subject's eye (preferably by intravitreal injection) at least once every 24 weeks.

[0063] A VEGF receptor fusion protein for use in the treatment and prevention of intraocular neovascular disease, wherein the treatment or prevention is carried out before each administration, packaged together. A single-dose glass vial with a protective plastic cap and stopper contains an aqueous formulation containing 8 mg (±0.8 mg) or more of VEGF receptor fusion protein in approximately 70 microliters. To provide a single filter needle with 18 gauge x 1.5 inches, 5 microns, including the tip and beveled end. Next, (1) Visually inspect the aqueous formulation in the vial, and if particles, turbidity, or discoloration are observed, then use another vial of the aqueous formulation containing the VEGF receptor fusion protein. (2) Remove the protective plastic cap from the vial, (3) Clean the top of the vial with an alcohol wipe, and then, By using aseptic techniques, (4) Remove the 18 gauge × 1.5 inch, 5 micron filter needle and the 1 mL syringe from their packaging. (5) Attach the filter needle to the syringe by twisting it onto the tip of the Luer lock syringe, (6) Push the filter needle into the center of the vial stopper until the needle is fully inserted into the vial and the tip of the needle contacts the bottom or bottom edge of the vial. (7) With the vial upright and slightly tilted, while ensuring that the angled end of the filter needle is immersed in the liquid, withdraw all of the contents of the VEGF receptor fusion protein vial into the syringe, (8) During withdrawal, tilt the vial to keep the slanted end of the filter needle immersed in the formulation, (9) When emptying the vial to completely empty the filter needle, pull the plunger rod back fully, (10) Remove the filter needle from the syringe and discard the filter needle, (11) Remove the 30 gauge x 0.5 inch injection needle from its packaging and attach the injection needle to the syringe by twisting it firmly onto the tip of the Luer lock syringe. (12) Hold the syringe with the needle pointing upwards and check for air bubbles in the syringe. If air bubbles are present, gently flick the syringe with your finger until the bubbles rise to the top. (13) Slowly push the plunger out so that the tip of the plunger aligns with the graduation mark on the syringe that marks 70 microliters.

[0064] The present invention provides a VEGF receptor fusion protein for use in treating and preventing intraocular neovascular disease, age-related macular degeneration with neovascularization, diabetic retinopathy and / or diabetic macular edema in subjects requiring such treatment and prevention, wherein the subject is receiving a regimen for treating or preventing diabetic retinopathy and / or diabetic macular edema, which requires a single initial dose of approximately 2 mg of VEGF receptor fusion protein, followed by four secondary doses of approximately 2 mg of VEGF receptor fusion protein, followed by one or more tertiary doses of approximately 2 mg of VEGF receptor fusion protein, with each secondary dose administered approximately 4 weeks after the previous dose, and each tertiary dose administered approximately 8 weeks after the previous dose, and the subject is at any stage (initial dose, secondary dose, or tertiary dose) of the 2 mg VEGF receptor fusion protein administration regimen.

[0065] The present invention provides a VEGF receptor fusion protein for use in treating and preventing intraocular neovascular disease, nAMD, diabetic retinopathy, and / or diabetic macular edema in subjects requiring such treatment and prevention, wherein 8 mg (±0.8 mg) or more of the VEGF receptor fusion protein is contained in an aqueous pharmaceutical formulation containing approximately 103-126 mg / ml of VEGF receptor fusion protein, a histidine-based buffer, and arginine.

[0066] The present invention provides a VEGF receptor fusion protein for use in treating and preventing intraocular neovascular disease, nAMD, diabetic retinopathy, and / or diabetic macular edema in subjects requiring such treatment and prevention, wherein ≥8 mg (±0.8 mg) of VEGF receptor fusion protein is an aqueous pharmaceutical formulation containing approximately 114.3 mg / ml of VEGF receptor fusion protein, a histidine-based buffer, and arginine.

[0067] The present invention provides aflibercept for use in treating and preventing intraocular neovascular disease, nAMD, diabetic retinopathy and / or diabetic macular edema in subjects requiring such treatment and prevention, wherein ≥8 mg (±0.8 mg) of aflibercept is present in an aqueous pharmaceutical formulation, and the aflibercept contains less than approximately 3.5% of high molecular weight molecular species immediately after manufacturing and purification, and / or less than approximately 6% of high molecular weight molecular species after storage at approximately 2-8°C for approximately 24 months.

[0068] The present invention relates to a VEGF receptor fusion protein for use in treating and preventing intraocular neovascular disease, nAMD, diabetic retinopathy, and / or diabetic macular edema in subjects requiring such treatment and prevention, wherein ≥8 mg (±0.8 mg) of the VEGF receptor fusion protein is present in an aqueous pharmaceutical formulation, and the aqueous pharmaceutical formulation is At least approximately 100 mg / ml of VEGF receptor fusion protein, Approximately 10-100 mM L-arginine, Sucrose and, Histidine-based buffer and Contains surfactants, The present invention provides a VEGF receptor fusion protein having a pH of approximately 5.0 to approximately 6.8, and the VEGF receptor fusion protein having less than approximately 3.5% of high molecular weight molecular species immediately after manufacturing and purification, and / or less than approximately 6% of high molecular weight molecular species after storage at approximately 2 to 8°C for approximately 24 months.

[0069] The present invention relates to a VEGF receptor fusion protein for use in treating and preventing diabetic retinopathy and / or diabetic macular edema in subjects requiring such treatment and prevention, wherein ≥8 mg (±0.8 mg) of the VEGF receptor fusion protein is present in an aqueous pharmaceutical formulation, and the aqueous pharmaceutical formulation is • Contains ≥100 mg / ml of VEGF receptor fusion protein, histidine-based buffer, and L-arginine, • Contains 140 mg / ml aflibercept, 20 mM histidine buffer, 5% sucrose, 0.03% polysorbate 20, 10 mM L-arginine, pH 5.8, • Contains 150±15 mg / ml of aflibercept, 10 mM phosphate 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, • Contains 103-126 mg / ml of 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, with a pH of 5.5-6.1. • Contains 140 mg / ml aflibercept, 10 mM histidine buffer, 2.5% (w / v) sucrose, 2.0% (w / v) proline, 0.03% (w / v) polysorbate 20, and 50 mM L-arginine, pH 5.8, • Contains 114.3 mg / ml aflibercept, 10 mM histidine buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 50 mM L-arginine, pH 5.8. • Contains aflibercept, histidine-based buffer, and L-arginine at a concentration of ≥100 mg / ml. • Aflibercept at a concentration of ≥100 mg / ml with a pH of approximately 5.8, wherein the formulation contains ≥100 mg / ml of aflibercept, and the formulation forms <3% HMW aggregates after incubation at 5°C for 2 months. • Contains approximately 114.3 mg / mL of aflibercept, 10 mM to 50 mM histidine-based buffer, sugar, nonionic surfactant, L-arginine, and pH 5.8. • Contains approximately 114.3 mg / mL of aflibercept; 10 mM His / His-HCl buffer, 5% sucrose, 0.03% polysorbate-20, 50 mM L-arginine, pH 5.8, or This product provides a VEGF receptor fusion protein containing approximately 114.3 mg / mL of aflibercept, arginine monohydrochloride, histidine, histidine hydrochloride monohydrate, polysorbate 20, sucrose, and water for injection.

[0070] The present invention relates to a VEGF receptor fusion protein for use in treating and preventing intraocular neovascular disease, nAMD, diabetic retinopathy, and / or diabetic macular edema in subjects requiring such treatment and prevention, wherein the subject is • Improvement of, for example, at least 2 or 3 levels on the Diabetic Retinopathy Severity Scale (DRSS), • Improvement of the best corrected vision, • Dry retina, • Achieving the best corrected vision, • Achieving the best corrected visual acuity of at least 5, 10, or 15 characters. BCVA must be at least 69 characters long. • Decrease in central retinal thickness (CRT) • No vascular leakage as measured by fluorescein angiography (FA). • Improvement in the total score of the National Ophthalmological Institute's Visual Function Questionnaire (NEI-VFQ-25) from baseline before treatment. • The retina does not contain fluid (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF]) in the fovea and central subfield. • Maintenance of the fluid-free retina (total fluid in the fovea and central subfield, IRF and / or SRF) • Loss of macular edema, • Spectrum domain optical coherence tomography (SD-OCT) to remove fluid-free retina, and / or The present invention provides a VEGF receptor fusion protein that achieves and / or maintains one or more of the following: once initiated, does not deviate from the HDq12 or HDq16 treatment regimen.

[0071] The present invention relates to a VEGF receptor fusion protein for use in treating and preventing intraocular neovascular disease, nAMD, diabetic retinopathy, and / or diabetic macular edema in subjects requiring such treatment and prevention, wherein the subject is BVCA is non-inferior to aflibercept administered intravitreously as 2 mg approximately every 4 weeks as the first 3, 4, or 5 injections, followed by 2 mg once every 8 weeks or once every 2 months. • BCVA (according to the ETDRS letter score) increases by approximately 7, 8, or 9 letters by week 60 from the start of treatment, with a baseline BCVA of approximately 61, 62, or 63. • BCVA (according to the ETDRS letter score) must be at least approximately 69 letters by week 48 or week 60 from the start of treatment. • No loss of 5, 10, 15, or 69 or more BCVA characters at 12, 24, 36, 49, 60, 72, 84, or 90 weeks after the start of treatment. • BCVA (following the ETDRS letter score) should improve by weeks 12, 24, 36, 49, 60, 72, 84, or 90 from the start of treatment. • BVCA improvement within 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 weeks from the start of treatment. Between 48 and 60 weeks, the BCVA score (according to the ETDRS letter score) should be approximately 69, 70, 71, 72, or 73. • Between weeks 36 and 48, the change in BCVA score from the start of treatment (according to the ETDRS letter score) is approximately 7, 8, or 9, and the BCVA score at any point between weeks 36 and 48 is approximately 60 or 70. • Between weeks 48 and 60, the change in BCVA score from the start of treatment (according to the ETDRS letter score) is approximately 7, 8, or 9, and the BCVA at any point between weeks 48 and 60 is approximately 69, 70, 71, 72, or 73. • By weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 from the start of treatment, the increase in BCVA, as measured by the Early Treatment Study for Diabetic Retinopathy (ETDRS) visual acuity chart or the equivalent Snellen visual acuity chart, must be ≥4 letters, ≥5 letters, ≥6 letters, ≥7 letters, ≥8 letters, >9 letters, or >10 letters. • No loss of 5, 10, or 15 letters by week 48 or week 60 of treatment (according to the ETDRS letter score). • Achieve at least 5, 10, or 15 letters by week 48 or week 60 of treatment (according to the ETDRS letter score). • Within 4 weeks of starting treatment, BCVA should improve by approximately 4 or 5 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 regimen, or by approximately 4 or 5 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 regimen. • Within 8 weeks of starting treatment, BCVA should improve by approximately 6 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 regimen, or by approximately 5 or 6 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 regimen. • Within 12 weeks of starting treatment, BCVA should improve by approximately 6 or 7 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 regimen, or by approximately 6 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 regimen. • Within 16 weeks of starting treatment, BCVA should improve by approximately 6 or 7 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 regimen, or by 7 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 regimen. • Within 20 weeks of starting treatment, BCVA should improve by approximately 6 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 regimen, or by approximately 6 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 regimen. • Within 24 weeks of starting treatment, BCVA should improve by approximately 7 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 regimen, or by approximately 5 or 6 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 regimen. • Within 28 weeks of starting treatment, BCVA should improve by approximately 7 or 8 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 regimen, or by approximately 7 or 8 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 regimen. • Within 32 weeks of starting treatment, BCVA should improve by approximately 7 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 regimen, or by approximately 7 or 8 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 regimen. • Within 36 weeks of the start of treatment, BCVA should improve by 8 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 regimen, or by approximately 6 or 7 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 regimen. • Within 40 weeks of the start of treatment, BCVA should improve by approximately 8 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 regimen, or by approximately 6 or 7 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 regimen. • Within 44 weeks of the start of treatment, BCVA should improve by approximately 8 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 regimen, or by approximately 7 or 8 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 regimen. • Within 48 weeks of the start of treatment, BCVA should improve by approximately 8 or 9 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 regimen, or by approximately 7 or 8 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 regimen. • BCVA should improve by approximately 8 weeks after the start of treatment and be maintained thereafter for at least 48 weeks of the treatment regimen. • Within 4 weeks of starting treatment, if BCVA is receiving the HDq12 regimen, the patient should have approximately 68 letters (ETDRS or equivalent Snellen visual acuity), or if BCVA is receiving the HDq16 regimen, the patient should have approximately 66 letters (ETDRS or equivalent Snellen visual acuity). • Within 8 weeks of the start of treatment, if BCVA is receiving the HDq12 regimen, the BCVA should have approximately 70 letters (ETDRS or equivalent Snellen visual acuity), or if BCVA is receiving the HDq16 regimen, the BCVA should have approximately 67 letters (ETDRS or equivalent Snellen visual acuity). • Within 12 weeks of the start of treatment, if BCVA is receiving the HDq12 regimen, the BCVA should have approximately 70 letters (ETDRS or equivalent Snellen visual acuity), or if BCVA is receiving the HDq16 regimen, the BCVA should have approximately 68 letters (ETDRS or equivalent Snellen visual acuity). • Within 16 weeks of the start of treatment, if BCVA is receiving the HDq12 regimen, the BCVA should have approximately 71 letters (ETDRS or equivalent Snellen visual acuity), or if BCVA is receiving the HDq16 regimen, the BCVA should have approximately 69 letters (ETDRS or equivalent Snellen visual acuity). • Within 20 weeks of the start of treatment, if BCVA is receiving the HDq12 regimen, the BCVA should have approximately 70 letters (ETDRS or equivalent Snellen visual acuity), or if BCVA is receiving the HDq16 regimen, the BCVA should have approximately 68 letters (ETDRS or equivalent Snellen visual acuity). • Within 24 weeks of the start of treatment, if BCVA is receiving the HDq12 regimen, the BCVA should have approximately 71 letters (ETDRS or equivalent Snellen visual acuity), or if BCVA is receiving the HDq16 regimen, the BCVA should have approximately 67 letters (ETDRS or equivalent Snellen visual acuity). • Within 28 weeks of the start of treatment, if BCVA is receiving the HDq12 regimen, the BCVA should have approximately 72 letters (ETDRS or equivalent Snellen visual acuity), or if BCVA is receiving the HDq16 regimen, the BCVA should have approximately 70 letters (ETDRS or equivalent Snellen visual acuity). • Within 32 weeks of the start of treatment, if BCVA is receiving the HDq12 regimen, the BCVA should have approximately 71 letters (ETDRS or equivalent Snellen visual acuity), or if BCVA is receiving the HDq16 regimen, the BCVA should have approximately 70 letters (ETDRS or equivalent Snellen visual acuity). • Within 36 weeks of the start of treatment, if BCVA is receiving the HDq12 regimen, the BCVA should have approximately 71 letters (ETDRS or equivalent Snellen visual acuity), or if BCVA is receiving the HDq16 regimen, the BCVA should have approximately 68 letters (ETDRS or equivalent Snellen visual acuity). • Within 40 weeks of the start of treatment, if BCVA is receiving the HDq12 regimen, the BCVA should have approximately 72 letters (ETDRS or equivalent Snellen visual acuity), or if BCVA is receiving the HDq16 regimen, the BCVA should have approximately 69 letters (ETDRS or equivalent Snellen visual acuity). • Within 44 weeks of the start of treatment, if BCVA is receiving the HDq12 regimen, the BCVA should have approximately 72 letters (ETDRS or equivalent Snellen visual acuity), or if BCVA is receiving the HDq16 regimen, the BCVA should have approximately 70 letters (ETDRS or equivalent Snellen visual acuity). • Within 48 weeks of the start of treatment, if BCVA is receiving the HDq12 regimen, the patient should have approximately 73 letters (ETDRS or equivalent Snellen visual acuity), or if BCVA is receiving the HDq16 regimen, the patient should have approximately 70 letters (ETDRS or equivalent Snellen visual acuity). Within 48 weeks of starting treatment, in patients receiving the HDq12 regimen, if the baseline BCVA is approximately <73 ETDRS letters, then an improvement of approximately 9 or 10 letters (ETDRS or equivalent Snellen visual acuity) in BCVA is expected. • Within 48 weeks of starting treatment, if the patient is receiving the HDq12 regimen and their baseline BCVA is approximately >73 ETDRS letters, then their BCVA should improve by approximately 5 or 6 letters (ETDRS or equivalent Snellen visual acuity). • Within 48 weeks of starting treatment, if the patient is receiving the HDq16 regimen and their baseline BCVA is approximately <73 ETDRS letters, then their BCVA should improve by approximately 8 or 9 letters (ETDRS or equivalent Snellen visual acuity). • Within 48 weeks of starting treatment, if the patient is receiving the HDq16 regimen and their baseline BCVA is approximately >73 ETDRS letters, then their BCVA should improve by approximately 4 or 5 letters (ETDRS or equivalent Snellen visual acuity). • Within 48 weeks of starting treatment, if receiving the HDq12 regimen, and with a baseline CRT of approximately <400 micrometers, the BCVA should improve by approximately 7 or 8 letters (ETDRS or equivalent Snellen visual acuity). • Within 48 weeks of starting treatment, if receiving the HDq12 regimen, and with a baseline CRT of approximately >400 micrometers, BCVA should improve by approximately 9 or 10 letters (ETDRS or equivalent Snellen visual acuity). • Within 48 weeks of starting treatment, if receiving the HDq16 regimen, and with a baseline CRT of approximately <400 micrometers, BCVA should improve by approximately 5 or 6 letters (ETDRS or equivalent Snellen visual acuity). • Within 48 weeks of starting treatment, if receiving the HDq16 regimen, and with a baseline CRT of approximately >400 micrometers, BCVA should improve by approximately 9 or 10 letters (ETDRS or equivalent Snellen visual acuity). • Achieve a BCVA of >5, >10, or ≥15 letters (according to the ETDRS letter score) by week 12, 24, 36, 49, 60, 72, 84, or 90 from the start of treatment. • Improvement of ≥2 or >3 stages on the Diabetic Retinopathy Severity Scale (DRSS) by weeks 12, 24, 36, 49, 60, 72, 84, or 90 from the start of treatment; • Improvement of ≥2 stages on the Diabetic Retinopathy Severity Scale (DRSS) by weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 from the start of treatment. • By 12, 24, 36, 49, 60, 72, 84, or 90 weeks from the start of treatment, the retina in the fovea and central subfield should not contain fluid (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF]), as measured by optical coherence tomography (OCT). • No vascular leakage as measured by fluorescein angiography (FA) by the 12th, 24th, 36th, 49th, 60th, 72nd, 84th, or 90th week from the start of treatment. • Maintenance of fluid-free retina (total fluid in the fovea and central subfield, IRF and / or SRF) from the start of treatment until weeks 12, 24, 36, 49, 60, 72, 84, or 90. • The total area of ​​fluorescein leakage within the ETDRS grid (mm2), as measured by fluorescein angiography, should decrease by approximately 12, 13, or 14 mm2 or more at 48 or 60 weeks. • By weeks 12, 24, 36, 49, 60, 72, 84, or 90 from the start of treatment, the retina must not contain fluid as measured by spectral domain optical coherence tomography (SD-OCT). • By the 4th, 8th, 12th, 16th, 20th, 24th, 28th, 32nd, 36th, 40th, 44th, or 48th week from the start of treatment, the retina in the fovea should not contain fluid (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF]). • Dry retina is present at 12, 24, 36, 49, 60, 72, 84, or 90 weeks from the start of treatment. • The fovea should not contain fluid, as measured by optical coherence tomography (OCT) at 12, 24, 36, 49, 60, 72, 84, or 90 weeks from the start of treatment. • Within 4 weeks of starting treatment, a change in central retinal thickness of approximately -118 or -118.3 micrometers if receiving the HDq12 regimen, or approximately -124, -125, -124.9, or -125.5 micrometers if receiving the HDq16 regimen. • Within 8 weeks of starting treatment, a change in central retinal thickness of approximately -137 or -137.4 micrometers if receiving the HDq12 regimen, or approximately -139 or -140 or -139.6 or -140.3 micrometers if receiving the HDq16 regimen. • Within 12 weeks of starting treatment, a change in central retinal thickness of approximately 150 or -150.1 micrometers if receiving the HDq12 regimen, or approximately -152, -153, -152.7, or -153.4 micrometers if receiving the HDq16 regimen. • Within 16 weeks of starting treatment, a change in central retinal thickness of approximately 139 or -139.4 micrometers if receiving the HDq12 regimen, or approximately -145, -146, -145.5, or -146.4 micrometers if receiving the HDq16 regimen. • Within 20 weeks of starting treatment, a change in central retinal thickness of approximately -117 or -117.1 micrometers if receiving the HDq12 regimen, or approximately -112 or -113 or -112.5 or -113.3 micrometers if receiving the HDq16 regimen. • Within 24 weeks of starting treatment, a change in central retinal thickness of approximately -158 or -158.1 micrometers if receiving the HDq12 regimen, or approximately -103 or -104 or -103.8 or -104.3 micrometers if receiving the HDq16 regimen. • Within 28 weeks of starting treatment, a change in central retinal thickness of approximately -146, -147, or -146.7 micrometers if receiving the HDq12 regimen, or approximately -162 or -162.3 micrometers if receiving the HDq16 regimen. • Within 32 weeks of starting treatment, a change in central retinal thickness of approximately -132 micrometers if receiving the HDq12 regimen, or approximately -145, -146, or -145.8 micrometers if receiving the HDq16 regimen. • Within 36 weeks of the start of treatment, a change in central retinal thickness of approximately -168 or -168.1 micrometers if receiving the HDq12 regimen, or approximately -124 or -125 or -124.7 or -125.2 micrometers if receiving the HDq16 regimen. • Within 40 weeks of starting treatment, a change in central retinal thickness of approximately -163 micrometers if receiving the HDq12 regimen, or approximately -122, -123, -122.5, or -123.1 micrometers if receiving the HDq16 regimen. • Within 44 weeks of starting treatment, a change in central retinal thickness of approximately -147, -148, or -147.4 micrometers if receiving the HDq12 regimen, or approximately -164, -164.1, or -164.3 micrometers if receiving the HDq16 regimen. • Within 48 weeks of the start of treatment, a change in central retinal thickness of approximately -171, -172, or -171.7 micrometers if receiving the HDq12 regimen, or approximately -148, -149, -148.3, or -149.4 micrometers if receiving the HDq16 regimen. • Within 60 weeks of the start of treatment, a change in central retinal thickness of approximately -181.95 or -176.24 micrometers if receiving the HDq12 regimen, or approximately -166.26 or -167.18 micrometers if receiving the HDq16 regimen. • If you are receiving the HDq12 regimen, between the start of treatment (week 0) and week 4, there is a change in central retinal thickness of approximately -118, -119, or -118.3 micrometers. • If you are receiving the HDq12 regimen, between weeks 4 and 8, you should expect a change in central retinal thickness of approximately -19, -20, or -19.1 micrometers. • If you are receiving the HDq12 regimen, between weeks 8 and 12, you should expect a change in central retinal thickness of approximately -12, -13, or -12.7 micrometers. • If you are receiving the HDq12 regimen, between weeks 20 and 24, you should expect a change in central retinal thickness of approximately -40 or -41 micrometers. • If you are receiving the HDq12 regimen, between weeks 32 and 36, you should expect a change in central retinal thickness of approximately -36, -37, or -36.1 micrometers. • If you are receiving the HDq12 regimen, between weeks 44 and 48, you should expect a change in central retinal thickness of approximately -24, -25, or -24.3 micrometers. • If you are receiving the HDq12 regimen, between weeks 48 and 60, a change in central retinal thickness of -4, -5, or -4.5 micrometers is observed. • If you are receiving the HDq16 regimen, between the start of treatment (week 0) and week 4, a change in central retinal thickness of approximately -124, -125, or -124.9 micrometers is observed. • If you are receiving the HDq16 regimen, between weeks 4 and 8, you should expect a change in central retinal thickness of approximately -14, -15, or -14.7 micrometers. • If you are receiving the HDq16 regimen, between weeks 8 and 12, you should expect a change in central retinal thickness of approximately -13, -14, or -13.1 micrometers. • If you are receiving the HDq16 regimen, between weeks 24 and 28, you should expect a change in central retinal thickness of approximately -58, -59, or -58.5 micrometers. • If you are receiving the HDq16 regimen, between weeks 40 and 44, you should expect a change in central retinal thickness of approximately -41, -42, or -41.6 micrometers. • Central retinal thickness should decrease by the 4th, 5th, 6th, 7th, or 8th week after the start of treatment, and this should be maintained within approximately +17 micrometers, +18 micrometers, or +19 micrometers for the remainder of the treatment regimen, at least until the 48th week from the start of treatment. • A decrease in central retinal thickness of approximately 100, 125, 150, 175, or 200 micrometers by the 12th, 24th, 36th, 49th, 60th, 72nd, 84th, or 90th week of treatment. • A decrease of approximately 148-182 micrometers in central retinal thickness, as measured by optical coherence tomography (OCT), by approximately 48 or 60 weeks from the start of treatment, with a baseline CRT of approximately 449, 450, 455, or 460 micrometers. • By weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 of treatment initiation, the central retinal thickness (CRT) should decrease by at least approximately 100, 125, 130, 135, 140, 145, 149, 150, 155, 160, 165, 170, 171, 172, 173, 174, or 175 micrometers. • Approximately 0.1667 days after the first dose, the free aflibercept level in plasma is approximately 0.149 (±0.249) mg / l, free aflibercept is undetectable in plasma at baseline, and the subjects have not received intravitreal aflibercept treatment for at least 12 weeks. • Approximately 0.3333 days after the first dose, the free aflibercept level in plasma is approximately 0.205 (±0.250) mg / l, free aflibercept is undetectable in plasma at baseline, and the subjects have not received intravitreal aflibercept treatment for at least 12 weeks. • Approximately one day after the first dose, the free aflibercept level in plasma is approximately 0.266 (±0.211) mg / l, free aflibercept is undetectable in plasma at baseline, and the subjects have not received intravitreal aflibercept treatment for at least 12 weeks. • Approximately two days after the first dose, the free aflibercept level in plasma is approximately 0.218 (±0.145) mg / l, free aflibercept is undetectable in plasma at baseline, and the subjects have not received intravitreal aflibercept treatment for at least 12 weeks. • Approximately 4 days after the first dose, the free aflibercept level in plasma is approximately 0.140 (±0.0741) mg / l, free aflibercept is undetectable in plasma at baseline, and the subjects have not received intravitreal aflibercept treatment for at least 12 weeks. • Approximately 7 days after the first dose, the free aflibercept level in plasma is approximately 0.0767 (±0.0436) mg / l, free aflibercept is undetectable in plasma at baseline, and the subjects have not received intravitreal aflibercept treatment for at least 12 weeks. • Approximately 14 days after the first dose, the free aflibercept level in plasma is approximately 0.0309 (±0.0241) mg / l, free aflibercept is undetectable in plasma at baseline, and the subjects have not received intravitreal aflibercept treatment for at least 12 weeks. • Approximately 21 days after the first dose, the free aflibercept level in plasma is approximately 0.0171 (±0.0171) mg / l, free aflibercept is undetectable in plasma at baseline, and the subjects have not received intravitreal aflibercept treatment for at least 12 weeks. Approximately 28 days after the first dose, the free aflibercept level in plasma is approximately 0.00730 (±0.0113) mg / l, free aflibercept is undetectable in plasma at baseline, and the subjects have not received intravitreal aflibercept treatment for at least 12 weeks. • Approximately 0.1667 days after the first dose, the plasma concentration of adjusted conjugated aflibercept is approximately 0.00698 (±0.0276) mg / l, and the baseline concentration of adjusted conjugated aflibercept is approximately 0.00583 mg / l (±0.0280), and the subjects have not received intravitreal aflibercept treatment for at least 12 weeks. • Approximately 0.3333 days after the first dose, the plasma concentration of adjusted conjugated aflibercept is approximately 0.00731 (±0.0279) mg / l, and the baseline concentration of adjusted conjugated aflibercept is approximately 0.00583 mg / l (±0.0280), and the subjects have not received intravitreal aflibercept treatment for at least 12 weeks. • Approximately one day after the first dose, the plasma concentration of adjusted conjugated aflibercept is approximately 0.0678 (±0.0486) mg / l, and the baseline concentration of adjusted conjugated aflibercept is approximately 0.00583 mg / l (±0.0280), and the subjects have not received intravitreal aflibercept treatment for at least 12 weeks. • Approximately two days after the first dose, the plasma concentration of adjusted conjugated aflibercept is approximately 0.138 (±0.0618) mg / l, and the baseline concentration of adjusted conjugated aflibercept is approximately 0.00583 mg / l (±0.0280), and the subjects have not received intravitreal aflibercept treatment for at least 12 weeks. • Approximately 4 days after the first dose, the plasma concentration of adjusted conjugated aflibercept is approximately 0.259 (±0.126) mg / l, and the baseline concentration of adjusted conjugated aflibercept is approximately 0.00583 mg / l (±0.0280), and the subjects have not received intravitreal aflibercept treatment for at least 12 weeks. • Approximately 7 days after the first dose, the plasma concentration of adjusted conjugated aflibercept is approximately 0.346 (±0.151) mg / l, and the baseline concentration of adjusted conjugated aflibercept is approximately 0.00583 mg / l (±0.0280), and the subjects have not received intravitreal aflibercept treatment for at least 12 weeks. • Approximately 14 days after the first dose, the plasma concentration of adjusted conjugated aflibercept is approximately 0.374 (±0.110) mg / l, and the baseline concentration of adjusted conjugated aflibercept is approximately 0.00583 mg / l (±0.0280), and the subjects have not received intravitreal aflibercept treatment for at least 12 weeks. • Approximately 21 days after the first dose, the plasma concentration of adjusted conjugated aflibercept is approximately 0.343 (±0.128) mg / l, and the baseline concentration of adjusted conjugated aflibercept is approximately 0.00583 mg / l (±0.0280), and the subjects have not received intravitreal aflibercept treatment for at least 12 weeks. • Approximately 28 days after the first dose, the plasma concentration of adjusted conjugated aflibercept is approximately 0.269 (±0.149) mg / l, and the baseline concentration of adjusted conjugated aflibercept is approximately 0.00583 mg / l (±0.0280), and the subjects have not received intravitreal aflibercept treatment for at least 12 weeks. • The peak plasma concentration of free aflibercept is reached approximately 0.965 days after the first dose. • Free aflibercept reaches a peak plasma concentration of approximately 0.310 mg / l (±0.263). • The free aflibercept concentration in plasma should be approximately 0 to 1.08 mg / L. • The peak free aflibercept concentration in plasma (mg / l) per dose (mg) of aflibercept is approximately 0.388 (±0.0328) mg / l / mg. • The peak plasma concentration of the adjusted conjugated aflibercept should be reached approximately 14 days after the first dose. • The adjusted conjugated aflibercept reaches a peak plasma concentration of approximately 0.387 mg / l (±0.135). • The plasma concentration of adjusted conjugated aflibercept is approximately 0.137 to 0.774 mg / L. • The peak value of adjusted conjugated aflibercept in plasma per dose (mg) of aflibercept is approximately 0.483 (±0.0168) mg / l / mg. • No anti-drug antibodies against aflibercept after 48 or 60 weeks of treatment. • Improvement from pre-treatment baseline in the total score of the National Eye Institute's Visual Function Questionnaire (NEI-VFQ), and / or Achieve and / or maintain one or more of the following: loss of macular edema.

[0072] The present invention provides a VEGF receptor fusion protein for use in treating and preventing age-related macular degeneration with neovascularization, diabetic retinopathy, and / or diabetic macular edema in subjects requiring such treatment and prevention, wherein the interval between administrations of ≥8 mg (±0.8 mg) of the VEGF receptor fusion protein is adjusted (increased / maintained / shortened) based on visual and / or anatomical outcomes.

[0073] The present invention provides a VEGF receptor fusion protein for use in treating and preventing age-related macular degeneration with neovascularization, diabetic retinopathy, and / or diabetic macular edema in subjects requiring such treatment and prevention, wherein an ≥8 mg (±0.8 mg) dose of the VEGF receptor fusion protein is administered as needed, according to an ad-hoc (PRN (pro re nata)), capped PRN, or Treat and Extend (T&E) administration regimen.

[0074] The present invention also provides a kit comprising i) a container containing a VEGF receptor fusion protein, preferably aflibercept, and ii) instructions for use of the VEGF fusion protein. In one embodiment of the present invention, the container is a vial or a pre-filled syringe. The vial is a Type I glass vial containing a nominal fill volume of about 0.26 mL of solution for intravitreal injection. In one embodiment of the present invention, the container contains a VEGF receptor fusion protein at a concentration of 100 mg / mL or more, or the container contains aflibercept at a concentration of about 114.3 mg / mL. In one embodiment of the present invention, the instructions for use include instructions for use of the VEGF fusion protein or aflibercept for the treatment of DME and / or AMD. In one embodiment of the present invention, the instructions for use state that: i) the container contains an aflibercept solution of ≥8 mg (±0.8 mg) (114.3 mg / mL) for intravitreal injection; ii) each single-dose vial provides a quantity usable to deliver a single dose of 70 microliters containing ≥8 mg (±0.8 mg) of aflibercept to an adult patient; iii) the recommended dose is ≥8 mg (±0.8 mg) of aflibercept (equivalent to 70 microliters of injection solution); and iv) the treatment of ≥8 mg (±0.8 mg) of aflibercept. The information includes, however, that it is initiated as three consecutive doses, with one injection per month (every four weeks); v) the injection interval may then be extended up to every 16 or 20 weeks; vi) the treatment interval may be adjusted based on the physician's visual and / or anatomical outcome assessment; and / or vii) aflibercept ≥ 8 mg (±0.8 mg) / 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 explanation of the drawing]

[0075] [Figure 1] Figure 1 shows an overview of the PHOTON clinical trial. [Figure 2] Figure 2 shows the key eligibility criteria (inclusion and exclusion criteria) for the PHOTON clinical trial. [Figure 3]Figure 3 shows the dosing schedule and regimen change (DRM) criteria for the PHOTON clinical trial (up to week 48). [Figure 4] Figure 4 shows the criteria for changing the dosing regimen in the PHOTON clinical trial. [Figure 5] Figure 5 shows the patient trends at week 48 in the PHOTON clinical trial. [Figure 6] Figure 6 shows the baseline demographic data of the subjects in the PHOTON clinical trial. [Figure 7] Figure 7 shows the baseline characteristics of the test eye in the PHOTON clinical trial. [Figure 8] Figure 8 shows the average number of injections up to week 48 in the PHOTON clinical trial. [Figure 9] Figure 9 shows the mean change in best corrected visual acuity (BCVA) up to week 48 in the PHOTON clinical trial. It represents the least squares mean change from baseline at week 48. [Figure 10] Figure 10 shows the percentage of subjects in the PHOTON clinical trial who maintained intervals of 12 weeks and 16 weeks up to week 48. [Figure 11] Figure 11 shows the proportion of participants in the PHOTON clinical trial who showed an improvement of ≥2 stages on the Diabetic Retinopathy Severity Scale (DRSS) at week 48, which is an important secondary endpoint (EP). [Figure 12] Figure 12 shows the percentage of subjects in the PHOTON clinical trial who did not have retinal fluid in the fovea at week 48. [Figure 13] Figure 13 shows the mean change from baseline in central retinal thickness up to week 48 in the PHOTON clinical trial. Several matched intervals are highlighted in three insets. [Figure 14A] Figures 14A, 14B, and 14C show the serious ocular adverse events (TEAEs) that occurred under treatment up to week 48 in the PHOTON clinical trial (Figure 14A), the most frequent adverse events (AEs) up to week 48 (Figure 14B), and non-ocular safety up to week 48 (Figure 14C). [Figure 14B] Same as above. [Figure 14C] Same as above. [Figure 15] Figure 15 shows intraocular inflammation that occurred during treatment up to week 48 in the PHOTON clinical trial. [Figure 16] Figure 16 shows the mean change from baseline in intraocular pressure up to week 48 in the PHOTON clinical trial. [Figure 17] Figure 17 shows the percentage of subjects who met the intraocular pressure criteria in the PHOTON clinical trial. [Figure 18] Figure 18 shows the percentage of serious non-ocular TEAEs (Triple External Event Expected) up to week 48 in the PHOTON clinical trial (≥1%). [Figure 19] Figure 19 shows the events defined as Anti-Platelet Trialists' Collaboration (APTC) that occurred during treatment up to week 48 in the PHOTON clinical trial. [Figure 20] Figure 20 shows the hypertensive events that occurred during treatment up to week 48 in the PHOTON clinical trial. [Figure 21] Figure 21 shows the clinically significant blood pressure values ​​(PCSV) up to week 48 in the PHOTON clinical trial. [Figure 22] Figure 22 shows the mean change from baseline in systolic blood pressure up to week 48 in the PHOTON clinical trial. The SBP from baseline to week 9 and the mean baseline SBP are shown in the inserted table. [Figure 23] Figure 23 shows the mean change from baseline in diastolic blood pressure up to week 48 in the PHOTON clinical trial. The DBP from baseline to week 9 and the mean baseline DBP are shown in the inserted table. [Figure 24] Figure 24 shows the mortality figures up to week 48 in the PHOTON clinical trial. [Figure 25A]Figures 25A and 25B show (A) the mean change from baseline in the BCVA score (ETDRS letters) in the test eye up to week 60 in the OC (largest analysis population), and (B) the least squares mean change from baseline in the BCVA score (ETDRS letters) in the test eye up to week 60 (largest analysis population). 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 acuity, ETDRS = early treatment diabetic retinopathy trial, HD = high dose, OC = observed cases, SE = standard error. OC: Observations after ICE as defined for the primary estimand were excluded. [Figure 25B] Same as above. [Figure 26A] Figures 26A and 26B show (A) the mean change from baseline in central retinal thickness (microns) at each visit up to week 60 in the OC (largest analysis population), and (B) the least squares mean change from baseline in central retinal thickness (microns) at each visit up to week 60 in the OC (largest analysis population). 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 = intermediate event, OC = observed case, SE = standard error. OC = observations after the defined ICE for the primary estimate were excluded. [Figure 26B] Same as above. [Figure 27]Figure 27 shows the nominal time and mean (±SD) plasma free aflibercept concentration (mg / l) per treatment in subjects with unilaterally treated DME in the Dense PK Sampling substudy (VGFTe-HD-DME-1934 study, log-scale, [DPKS]). N = number of subjects; SD = standard deviation; DME = diabetic macular edema; 2q8 = aflibercept 2 mg intravitreally every 8 weeks after 5 initial doses every month; HDq12 = high-dose (8 mg) aflibercept intravitreally every 12 weeks after 3 initial doses every month; HDq16 = high-dose (8 mg) aflibercept intravitreally every 16 weeks after 3 initial doses every month; LLOQ = lower limit of quantification; D = day; H = hour. Note: The table below the figure shows the number of subjects contributing to the statistics for the corresponding visit / time and treatment. The concentration below LLOQ was set as LLOQ / 2. HDq12 + HDq16 = composite data from the HDq12 and HDq16 treatment groups. Patients in the dense PK substudy received aflibercept injection in only one eye. [Figure 28]Figure 28 shows the mean (±SD) plasma concentration (mg / l) of adjusted conjugated aflibercept for each treatment in subjects with unilaterally treated DME in the Dense PK Sampling substudy (VGFTe-HD-DME-1934 study, log-scale, [DPKS]). N = number of subjects; SD = standard deviation; DME = diabetic macular edema; 2q8 = aflibercept 2 mg intravitreally every 8 weeks after 5 initial doses every month; HDq12 = high-dose (8 mg) aflibercept intravitreally every 12 weeks after 3 initial doses every month; HDq16 = high-dose (8 mg) aflibercept intravitreally every 16 weeks after 3 initial doses every month; LLOQ = lower limit of quantification; D = day; H = hour. Note: The table below the figure shows the number of subjects contributing to the statistics for the corresponding visit / time and treatment. The concentration below LLOQ was set as LLOQ / 2. Adjusted conjugated aflibercept = 0.717 * conjugated aflibercept. HDq12 + HDq16 = composite data from the HDq12 and HDq16 treatment groups. Patients in the dense PK substudy received aflibercept injection in only one eye. [Figure 29]Figure 29 shows the mean (±SD) plasma free aflibercept concentration (mg / l) for each treatment group and nominal time in subjects with diabetic macular edema (DME) in the Sparse PK Sampling Study (VGFTe-HD-DME-1934 study, log-scale, [PKAS]). N = number of subjects; SD = standard deviation; DME = diabetic macular edema; 2q8 = 2 mg aflibercept administered intravitreally every 8 weeks after 5 initial doses every month; HDq12 = high-dose (8 mg) aflibercept administered intravitreally every 12 weeks after 3 initial doses every month; HDq16 = high-dose (8 mg) aflibercept administered intravitreally every 16 weeks after 3 initial doses every month; LLOQ = lower limit of quantification; PKAS = population for pharmacokinetic analysis. Note: The table below the figure shows the number of subjects contributing to the statistics for the corresponding visit / time and treatment group. Concentrations below LLOQ were defined as LLOQ / 2. Post-administration samples and samples collected during the multi-point PK substudy (from day 0 after administration to day 21) were excluded. [Figure 30] Figure 30 shows the mean (±SD) plasma concentrations (mg / l) of adjusted conjugated aflibercept for each treatment group and nominal time in subjects with DME in the Sparse PK Sampling Study (VGFTe-HD-DME-1934 study, log-scale, [PKAS]). N = number of subjects; SD = standard deviation; DME = diabetic macular edema; 2q8 = 2 mg of aflibercept intravitreously every 8 weeks after 5 initial doses every month; HDq12 = high-dose (8 mg) aflibercept intravitreously every 12 weeks after 3 initial doses every month; HDq16 = high-dose (8 mg) aflibercept intravitreously every 16 weeks after 3 initial doses every month; LLOQ = 3 / 4 lower limit of quantification. Note: The table below the figure shows the number of subjects contributing to the statistics for the corresponding visit / time and treatment group. Concentrations below LLOQ were defined as LLOQ / 2. Adjusted conjugated aflibercept = 0.717 * conjugated aflibercept. Post-administration samples and samples collected during the multi-point PK substudy (from day 0 to day 21) were excluded. [Figure 31] Figure 31 structurally represents the population pharmacokinetic model of aflibercept after IV, SC, and IVT administration. CMT = compartment, IV = intravenous, IVT = intravitreous, K20 = elimination rate constant of free aflibercept, K40 = elimination rate constant of modified conjugated aflibercept, K62 = absorption rate from subcutaneous injection depot compartment, K70 = elimination rate constant from tissue (platelet) compartment, QE = intercompartmental clearance of free aflibercept between the ocular compartment and the central compartment, QF1 and QF2 = intercompartmental clearance of free aflibercept, VMK24, KM = saturated Michaelis-Menten type binding of free aflibercept to VEGF, VMK27, KMK27 = saturated elimination from the plasma compartment to the tissue compartment (platelets). CMT2 and CMT4 both represent the plasma compartment, and their volumes are assumed to be equal. [Figure 32]Figure 32 shows the mean (±SD) concentrations (mg / l) of free aflibercept and adjusted conjugated aflibercept over 28 days following a single in vitro administration of 2 mg and 8 mg of aflibercept in patients with nAMD or DME in the Dense PK Sub-study (DPKS, log-scale). LQ = less than the limit of quantification, DME = diabetic macular edema, DPKS = dense pharmacokinetic sub-study, HDq12 = aflibercept 8 mg administered every 12 weeks after three initial injections every month, HDq16 = aflibercept 8 mg administered every 16 weeks after three initial injections every month, IVT = intravitreous, LLOQ = lower limit of quantification, N = number of subjects, nAMD = age-related macular degeneration with neovascularization, SD = standard deviation, adjusted conjugated aflibercept = 0.717* conjugated aflibercept. Note: Concentrations below LLOQ (0.0156 mg / L for free aflibercept and 0.0224 mg / L for adjusted conjugated aflibercept) were set as LLOQ / 2. Note: The 8 mg HD aflibercept data for the first 28 days (obtained from PULSAR or PHOTON) is composite data from subjects who received HDq12 or HDq16. One subject from PULSAR with an outlier free aflibercept concentration greater than 10 times the mean concentration on day 28 has been excluded. Records after treatment of the other eye have been excluded. Data sources: Drug concentration data from the 48-week database lock of PULSAR and PHOTON, as well as the final lock of CANDELA. [Figure 33]Figure 33 shows the observed and model-predicted concentrations (mg / l) of free aflibercept and adjusted conjugated aflibercept in plasma over 28 days after a single IVT injection in subjects with nAMD or DME in a dose- and population-stratified dense PK sub-study (DPKS). DME = diabetic macular edema, IVT = intravitreous, LLOQ = limit of quantification, nAMD = age-related macular degeneration with neovascularization, PK = pharmacokinetics. Observed concentrations below the limit of quantification (LLOQ; 0.0156 mg / L for free aflibercept and 0.0224 mg / L for adjusted conjugated aflibercept) were set as LLOQ / 2. Data sources: Drug concentration data from dense PK sub-studies in PHOTON, PULSAR, and CANDELA. [Figure 34] Figure 34 is an overlay of observed and model-predicted concentrations (mg / l) of free aflibercept and adjusted conjugated aflibercept in plasma for a composite population of nAMD and DME. 2q8 = aflibercept 2 mg administered every 8 weeks after three initial injections at 4-week intervals; 2q12 = aflibercept 2 mg administered every 12 weeks after three initial injections at 4-week intervals; DME = diabetic macular edema; HDq12 = aflibercept 8 mg administered every 12 weeks after three initial injections at one-month intervals; HDq16 = aflibercept 8 mg administered every 16 weeks after three initial injections at one-month intervals; IVT = intravitreous; LLOQ = lower limit of quantification; nAMD = age-related macular degeneration with neovascularization. Observed concentrations below the lower limit of quantification (LLOQ; 0.0156 mg / L for free aflibercept and 0.0224 mg / L for adjusted conjugated aflibercept) were set as LLOQ / 2. Data sources: Drug concentration data from CANDELA, PHOTON, and PULSAR. [Figure 35]Figure 35 shows the model predicted exposure (mg) of aflibercept after a single IVT injection, stratified by administration regimen in composite subjects with nAMD and DME. DME = diabetic macular edema, HD = aflibercept 8 mg, IVT = intravitreous, nAMD = neovascular age-related macular degeneration, PI = predicted interval, PK = pharmacokinetic, QE = intercompartmental clearance of free aflibercept between the ocular compartment and the central compartment, adjusted LLOQ (0.0624 μg) is set as LLOQ of free aflibercept in plasma (i.e., 0.0156 mg / L) × assumed volume of the test ocular compartment in the PK model (i.e., 4 mL). In clinical trials included in the population PK analysis dataset, the concentration of aflibercept (free or conjugated) was not measured in the test eye; therefore, this target was arbitrarily selected based on plasma LLOQ and used as a reference for comparisons between dosing regimens to evaluate the effect of HD aflibercept on QE. [Figure 36]Figure 36 shows the mean (±SD) concentrations (mg / l), without outliers, of free aflibercept and adjusted conjugated aflibercept over 28 days following a single in vitro administration of 2 mg and 8 mg of aflibercept in subjects with nAMD in the Dense PK Sub-study (DPKS, log-scale). DME = Diabetic macular edema, DPKS = Dense pharmacokinetic sub-study, HDq12 = Aflibercept 8 mg administered every 12 weeks after three initial injections every month, HDq16 = Aflibercept 8 mg administered every 16 weeks after three initial injections every month, IVT = Intravitreous, LLOQ = Lower limit of quantification, N = Number of subjects, nAMD = Age-related macular degeneration with neovascularization, PK = Pharmacokinetic, SD = Standard deviation, Adjusted conjugated aflibercept = 0.717* Conjugated aflibercept Note: Concentrations below LLOQ (0.0156 mg / L for free aflibercept and 0.0224 mg / L for adjusted conjugated aflibercept) were set as LLOQ / 2. Note: Data for 8 mg during the first 28 days (obtained from PULSAR or PHOTON) are composite data from subjects who received HDq12 or HDq16. Data sources: Drug concentrations from the 48-week lock of PULSAR and PHOTON, and from the final lock of CANDELA. Records after treatment of the other eye are excluded. [Figure 37]Figure 37 shows the mean (±SD) concentrations (mg / l), without outliers, of free aflibercept and adjusted conjugated aflibercept over 28 days following a single in vitro administration of 2 mg and 8 mg of aflibercept in subjects with nAMD in the Dense PK Sub-study (DPKS, log-scale). DME = Diabetic macular edema, DPKS = Dense pharmacokinetic sub-study, HDq12 = Aflibercept 8 mg administered every 12 weeks after three initial injections every month, HDq16 = Aflibercept 8 mg administered every 16 weeks after three initial injections every month, IVT = Intravitreous, LLOQ = Lower limit of quantification, N = Number of subjects, nAMD = Age-related macular degeneration with neovascularization, PK = Pharmacokinetic, SD = Standard deviation, Adjusted conjugated aflibercept = 0.717 * Conjugated aflibercept Note: Concentrations below the lower limit of quantification (LLOQ, 0.0156 mg / L for free aflibercept and 0.0224 mg / L for adjusted conjugated aflibercept) were set as LLOQ / 2. Data sources: Drug concentrations from the 48-week lock in PULSAR, and from the final lock in CANDELA. Data from VGFTOD-0702 are included for reference (concentrations in the PK substudy are subtracted by the pre-administration concentration if >LLOQ). Records after treatment of the other eye are excluded. [Figure 38]Figure 38 shows the mean (±SD) concentrations (mg / l) of free aflibercept and adjusted conjugated aflibercept over 28 days in subjects with DME status in the Dense PK Sub-study (DPKS, log-scale) following a single in vitro administration of 2 mg and 8 mg of aflibercept. BLQ = below the limit of quantification, DME = diabetic macular edema, DPKS = pharmacokinetic analysis population with multiple sample points (dense), HDq12 = aflibercept 8 mg administered every 12 weeks after three initial injections every month, HDq16 = aflibercept 8 mg administered every 16 weeks after three initial injections every month, IVT = intravitreous, LLOQ = lower limit of quantification, N = number of subjects, nAMD = age-related macular degeneration with neovascularization, SD = standard deviation. Note: Concentrations below LLOQ (0.0156 mg / L for free aflibercept and 0.0224 mg / L for adjusted conjugated aflibercept) were set as LLOQ / 2. Adjusted conjugated aflibercept = 0.717 * conjugated aflibercept. Note: Data for 8 mg during the first 28 days (obtained from PULSAR or PHOTON) are composite data from subjects who received HDq12 or HDq16. Note: If a subject took aflibercept within 12 weeks prior to initiating the investigational drug and the baseline concentration was >BLQ, the concentration was subtracted by the baseline concentration. Data source: Drug concentration data from the 48-week lock of PHOTON. Drug concentration data from VGFT-OD-0706 (historical data) is included for reference. Records after treatment of the other eye are excluded. [Figure 39]Figure 39 is an overlay of observed and model-predicted concentrations (mg / l) of free aflibercept and adjusted conjugated aflibercept in plasma for subjects with nAMD. 2q8 = aflibercept 2 mg administered every 8 weeks after three initial injections at 4-week intervals, 2q12 = aflibercept 2 mg administered every 12 weeks after three initial injections at 4-week intervals, DME = diabetic macular edema, HDq12 = aflibercept 8 mg administered every 12 weeks after three initial injections at one-month intervals, HDq16 = aflibercept 8 mg administered every 16 weeks after three initial injections at one-month intervals, IVT = intravitreous, LLOQ = lower limit of quantification, nAMD = age-related macular degeneration with neovascularization, PK = pharmacokinetics. Observed concentrations below the lower limit of quantification (LLOQ; 0.0156 mg / L for free aflibercept and 0.0224 mg / L for adjusted conjugated aflibercept) were defined as LLOQ / 2. Data from PULSAR and CANDELA. [Figure 40] Figure 40 is an overlay of observed and model-predicted concentrations (mg / l) of free aflibercept and adjusted conjugated aflibercept in plasma for subjects with diabetic macular edema in the PHOTON trial. 2q8 = aflibercept 2 mg administered every 8 weeks after three initial injections at 4-week intervals; HDq12 = aflibercept 8 mg administered every 12 weeks after three initial injections at 4-week intervals; HDq16 = aflibercept 8 mg administered every 16 weeks after three initial injections at 4-week intervals; IVT = intravitreous; LLOQ = lower limit of quantification; data from PHOTON. [Figure 41] Figure 41 shows the administration schedule and regimen change (DRM) criteria for the PULSAR clinical trial (up to week 48). [Figure 42] Figure 42 shows the key eligibility criteria (inclusion and exclusion criteria) for the PULSAR clinical trial. [Figure 43] Figure 43 shows the dosing schedule and drug regimen change (DRM) criteria for the PULSAR clinical trial. [Figure 44] Figure 44 shows the criteria for regimen change (DRM) in the PULSAR clinical trial. [Figure 45] Figure 45 shows the patient trends at week 48 in the PULSAR clinical trial. [Figure 46] Figure 46 shows the baseline demographic data of the subjects in the PULSAR clinical trial. [Figure 47] Figure 47 shows the baseline characteristics of the test eyes in the PULSAR clinical trial. [Figure 48] Figure 48 shows the average number of injections up to week 48 in the PULSAR clinical trial. [Figure 49] Figure 49 shows the mean change in best corrected visual acuity (BCVA) up to week 48 in the PULSAR clinical trial. The table shows the least squares mean change from baseline at week 48. [Figure 50] Figure 50 shows the percentage of subjects in the PULSAR clinical trial who maintained the Q12 and Q16 intervals up to week 48. [Figure 51] Figure 51 shows the percentage of subjects in the PULSAR clinical trial at week 16 that did not have retinal fluid in the central subfield, which is an important secondary endpoint. [Figure 52] Figure 52 shows the percentage of subjects in the PULSAR clinical trial who did not have retinal fluid in the central subfield at week 48. [Figure 53A] Figure 53(A-B) shows the mean change from baseline in central retinal thickness up to week 48 (A), and the central retinal thickness up to week 48 (B). [Figure 53B] Same as above. [Figure 54A] Figure 54(A-B) shows the serious adverse events (TEAEs) (A) and the most frequent adverse events (AEs) (B) up to week 48 in the PULSAR clinical trial. [Figure 54B] Same as above. [Figure 55] Figure 55 shows intraocular inflammation that occurred under treatment up to week 48 in the PULSAR clinical trial. [Figure 56]Figure 56 shows the mean change from baseline in intraocular pressure up to week 48 in the PULSAR clinical trial. [Figure 57] Figure 57 shows the percentage of subjects who met the intraocular pressure criteria in the PULSAR clinical trial. [Figure 58] Figure 58 shows the non-ocular serious TEAEs (Triple External Exposures) that accounted for ≥0.5% of the PULSAR clinical trial up to week 48. [Figure 59A] Figure 59 (A-B) shows the events defined by Anti-Platelet Trialists' Collaboration (APTC) that occurred under treatment up to week 48 in the PULSAR clinical trial (A), and non-ocular safety up to week 48 (B). [Figure 59B] Same as above. [Figure 60] Figure 60 shows the hypertensive events that occurred under treatment up to week 48 in the PULSAR clinical trial. [Figure 61] Figure 61 shows the clinically significant blood pressure values ​​(PCSV) up to week 48 in the PULSAR clinical trial. [Figure 62] Figure 62 shows the mean change from baseline in systolic blood pressure up to week 48 in the PULSAR clinical trial. The mean change from baseline to week 9, and the mean baseline blood pressure, are shown in the inserted table. [Figure 63] Figure 63 shows the mean change from baseline in diastolic blood pressure up to week 48 in the PULSAR clinical trial. The mean change from baseline to week 9, and the mean baseline blood pressure, are shown in the inserted table. [Figure 64] Figure 64 shows mortality up to week 48 in the PULSAR clinical trial. [Figure 65] Figure 65 shows the PULSAR administration schedule up to week 60. Criteria for changing the administration regimen are inserted. [Figure 66]Figure 66 shows the absolute BCVA and the change in BCVA from baseline (ETDRS letters) [PULSAR] up to week 60. It represents the least squares mean change from baseline at week 60. [Figure 67] Figure 67 shows the percentage of PULSAR patients who maintain HDq12 (8q12) and HDq16 (8q16) intervals up to week 60. [Figure 68] Figure 68 shows the average number of injections [PULSAR] up to week 60 in each group. [Figure 69A] Figure 69(A-C) shows central retinal thickness (CRT) and change from baseline [PULSAR] up to week 60. (A) Central retinal thickness (micrometers) over time (observed values ​​- data from ICE onwards are censored), (B) Mean change from baseline of CST (central subfield retinal thickness (replaceable with CRT), micrometers) at each visit up to week 60, OC before ICE in the largest analysis population, (C) Change in LSmean (95% CI) of CST (micrometers) from baseline at each visit, MMRM (mixed model for repeated measures) in the largest analysis population (up to week 48). [Figure 69B] Same as above. [Figure 69C] Same as above. [Figure 70A] Figures 70(A-G) provide an overview of the PULSAR safety data, showing (Figure 70A) ≥2% of ocular TEAEs up to week 60, (Figure 70B) severe ocular TEAEs up to week 60, (Figure 70C) ≥2% of non-ocular TEAEs up to week 60, (Figure 70D) ≥0.5% of severe non-ocular TEAEs up to week 60, (Figure 70E) mortality up to week 60, (Figure 70F) mean change in systolic blood pressure at week 60, and (Figure 70G) mean change in diastolic blood pressure at week 60. [Figure 70B] Same as above. [Figure 70C] Same as above. [Figure 70D] Same as above. [Figure 70E] Same as above. [Figure 70F] Same as above. [Figure 70G] Same as above. [Figure 71] Figure 71 shows the changes in 5, 10, and 15 letters at week 60. Observed (OC) (data from ICE onwards censored) [PULSAR]. [Figure 72] Figure 72 shows the percentage of PULSAR subjects without retinal fluid in the central subfield for each visit (showing the week and schedule of administration) up to week 60. LOCF (LOCF - data from ICE onwards is censored). [Figure 73] Figure 73 shows the percentage of PHOTON patients who maintained or extended the interval up to week 96. Patients completed treatment at week 96. Values ​​may not add up to 100% due to rounding. Q8 is every 8 weeks, Q12 every 12 weeks, Q16 every 16 weeks, Q20 every 20 weeks, and Q24 every 24 weeks. [Figure 74A] Figure 74(A&B) shows the time-series BCVA and CRT of a patient in PULSAR Case Report 1. (A) Patient characteristics are shown along with retinal images of the patient at baseline, week 12, and week 96. The timeline of absolute BCVA and absolute CRV achieved by the patient is shown below. The specific maintenance dosing intervals (q16, q20, or q24) to which the patient was assigned at various time points are shown. Dosage regimen change evaluations were performed in the weeks enclosed in squares. (B) Intervals assigned to patients in the overall PULSAR subject population. [Figure 74B] Same as above. [Figure 75A] Figure 75(A&B) shows the time-series BCVA and CRT of a patient in PULSAR Case Report 2. (A) Patient characteristics are shown along with retinal images of the patient at baseline, week 12, and week 96. The timeline of absolute BCVA and absolute CRV achieved by the patient is shown below. The specific maintenance dosing intervals (q12 and q16) to which the patient was assigned at various time points are shown. Dosage regimen change evaluations were performed in the weeks enclosed in squares. (B) Intervals assigned to patients in the overall PULSAR population. [Figure 75B] Same as above. [Figure 76] Figure 76 shows the time-series BCVA and CRT of a patient in the PHOTON case report. (A) Patient characteristics are shown along with retinal images of the patient at baseline, week 12, and week 96. The timeline of absolute BCVA and absolute CRV achieved by the patient is shown below. The specific maintenance dosing intervals (q16, q20, and q24) to which the patient was assigned at various time points are shown. Dosage regimen change evaluations were performed in the weeks enclosed in squares. [Figure 77] Figure 77 is a forest plot of the geometric mean ratios (90% confidence intervals) of post-hoc model-based predictions of exposure indicators for free aflibercept and adjusted conjugated aflibercept in subjects from the CANDELA, PULSAR, and PHOTON trials at HDq12. * = includes 6 subjects with renal failure, ** = includes 5 subjects with moderate hepatic failure; [or] indicates that the respective limits are included in the interval; (or) indicates that the respective limits are not included in the interval. Dashed lines indicate the standard reference limits of 0.8 and 1.25. AUC 56-68 = Area under the concentration-time curve between weeks 56 and 68, Cmax; 8-12 = Maximum concentration between weeks 8 and 12; DME = Diabetic macular edema; HDq12 = 8 mg of aflibercept administered every 12 weeks after three initial injections at one month; nAMD = Age-related macular degeneration with neovascularization. [Figure 78] Figure 78 shows a probabilistic simulation of aflibercept concentrations in the eyes of 5,000 virtual subjects with age-related macular degeneration with neovascularization and 5,000 virtual subjects with diabetic macular edema after repeated intravitreal injections of 2 mg or 8 mg of aflibercept. IVT = intravitreous; KD = dissociation constant; LLOQ = lower limit of quantification; VEGF-A = vascular endothelial growth factor-A; a. Concentration of free aflibercept after intravitreal injection at the end of an 8-week interval of 2 mg aflibercept administration; b. 1×, 9×, and 99× KD represent the free aflibercept concentrations required to inhibit VEGF-A by 50%, 90%, or 99% in an in vitro setting. [Figure 79]Figure 79 is a forest plot of the geometric mean ratio (90% confidence interval) of post hoc model-based predictions of exposure indices of free aflibercept and adjusted conjugated aflibercept in subjects from the CANDELA, PULSAR, and PHOTON trials at HDq12, stratified by the manufacturing process of HD aflibercept. AUC week 56 to week 68 = area under the concentration-time curve from week 56 to week 68; CV = coefficient of variation, Cmax, week 8 to week 12 = maximum concentration from week 8 to week 12; Cmax, week 56 to week 60 = maximum concentration from week 56 to week 60; n = number of subjects in each group; HDq12 = 8 mg of aflibercept, after 3 initial injections every month, every 12 weeks [or] indicates that each limit is included in the interval; (or) indicates that each limit is not included in the interval. The dashed lines indicate the standard reference limits of 0.8 and 1.25. [Figure 80] Figure 80 is a distribution of ocular disposition clearance in patients with age-related macular degeneration with neovascularization in the PULSAR trial, stratified by the assigned dosing intervals at the final study eye dose of high-dose aflibercept up to week 96. [Figure 81] Figure 81 is a distribution of ocular disposition clearance in patients with diabetic macular edema in the PHOTON trial, stratified by the assigned dosing intervals at the final study eye dose of high-dose aflibercept up to week 96. [Figure 82] Figure 82 is a distribution of baseline central retinal thickness in patients with age-related macular degeneration with neovascularization in the PULSAR trial, stratified by the assigned dosing intervals at the final study eye dose of high-dose aflibercept up to week 96. [Figure 83] Figure 83 is a distribution of baseline central retinal thickness in patients with diabetic macular edema in the PHOTON trial, stratified by the assigned dosing intervals at the final study eye dose of high-dose aflibercept up to week 96. [Figure 84]Figure 84 is a visual predictive check of the probability of assignment to a 24-week dosing interval at the final dose of high-dose aflibercept up to 96 weeks, stratified by disease population, and the tertiles of ocular distribution clearance and baseline central retinal thickness. [Figure 85] Figure 85 is a Kaplan-Meier plot of the time to the first dosing regimen change of high-dose aflibercept, stratified by the age-related macular degeneration with neovascularization vs. diabetic macular edema population. [Figure 86] Figure 86 is a Kaplan-Meier plot of the time to the first dosing regimen change of high-dose aflibercept, stratified by the age-related macular degeneration with neovascularization vs. diabetic macular edema population and the tertiles of exposure in the study eye. [Figure 87] Figure 87 is a model-predicted hazard ratio for the dosing regimen change of high-dose aflibercept, by the age-related macular degeneration with neovascularization vs. diabetic macular edema population and ocular distribution clearance. [Figure 88] Figure 88 is a Kaplan-Meier plot of the time to the first dosing regimen extension of high-dose aflibercept, stratified by the randomized dosing regimen. [Figure 89] Figure 89 is a Kaplan-Meier plot of the time to the first dosing regimen extension of high-dose aflibercept, stratified by the age-related macular degeneration with neovascularization vs. diabetic macular edema population and the tertiles of exposure in the study eye. [Figure 90] Figure 90 is a model-predicted hazard ratio for the dosing regimen extension of high-dose aflibercept, by randomized dosing regimen and ocular distribution clearance. [Figure 91] Figure 91 is the distribution of the individual ocular distribution clearance estimates over time for the final study eye dose of high-dose aflibercept, by study and overall stratification. [Figure 92]Figure 92 is a visual predictive check of the probability of final dosing interval assignment in patients with age-related macular degeneration with neovascularization receiving high-dose aflibercept, stratified by tertile of ocular distributed clearance and baseline central retinal thickness. [Figure 93] Figure 93 is a visual predictive check of the probability of final dosing interval assignment in patients with diabetic macular edema receiving high-dose aflibercept, stratified by tertile of ocular distributed clearance and baseline central retinal thickness. [Modes for carrying out the invention]

[0076] The present invention provides a safe and effective high-dose IVT injection of aflibercept that, in part, extends the maintenance dosing interval beyond eight weeks and has at least similar functional and potentially improved anatomical outcomes. This regimen showed unexpectedly high persistence in subjects, which exceeded what would be expected simply based on a higher dose of aflibercept.

[0077] Eylea has become the standard treatment for age-related macular degeneration with neovascularization (nAMD), diabetic macular edema (DME), and diabetic retinopathy (DR). For DME and DR, Eylea is prescribed as five monthly doses of 2 mg, followed by maintenance doses every eight weeks. The dosing regimens of this invention have been demonstrated to be maintained at 12-week and 16-week intervals in significantly higher proportions of subjects. In clinical trials testing these dosing regimens, nearly 90% of subjects with diabetic macular edema were able to maintain the 16-week dosing regimen. The HDq12 and HDq16 PHOTON groups achieved similar increases in BCVA at week 96 compared to 2q8 with up to six fewer injections. Up to week 96, 88% of HDq12 patients and 84% of HDq16 patients maintained dosing intervals of ≥12 weeks and ≥16 weeks, respectively. At week 96, 43% of HDq12 patients and 47% of HDq16 patients had a final assigned dosing interval of ≥20 weeks. Of the subjects assigned a 24-week interval as their last assigned dosing interval before week 96 in the PULSAR and PHOTON clinical trials, a subset entered the extension phase and successfully completed the 24-week dosing interval between weeks 96 and 108 without requiring shortening based on the Dosing Regimen Change (DRM) criteria. These sustained data, coupled with a safety profile consistent with that of Eylea, support high-dose aflibercept as a potential new standard of treatment for intraocular neovascular diseases such as DR or DME.

[0078] Standard methods in molecular biology include Sambrook, Fritsch and Maniatis (1982 & 1989 2 nd Edition, 2001 3 rd Edition)Molecular Cloning,A Laboratory Manual,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY,Sambrook and Russell (2001)Molecular Cloning,3 rdStandard methods are also found in Ausbel, et al. (2001) Current Protocols in Molecular Biology, Vols. 1-4, John Wiley and Sons, Inc., New York, NY, which describes cloning and DNA mutagenesis in bacterial cells (Vol. 1), cloning in mammalian cells and yeast (Vol. 2), glycoconjugates and protein expression (Vol. 3), and bioinformatics (Vol. 4).

[0079] A general set of methods for protein purification, including immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization, is 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, fusion protein production, and protein glycosylation are described (see, for example, 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, NY, 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, NJ, pp.384-391). The production, purification, and fragmentation of polyclonal and monoclonal antibodies are described (Coligan et al. (2001) Current Protocols 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, NY; Harlow and Lane, see above). Standard techniques for characterizing ligand / receptor interactions are available (see, for example, Coligan et al. (2001) Current Protocols in Immunology, Vol. 4, John Wiley, Inc., New York).

[0080] Flow cytometry methods, including fluorescence-activated cell sorting (FACS), are available (e.g., Owens et al. (1994) Flow Cytometry Principles for Clinical Laboratory Practice, John Wiley and Sons, Hoboken, NJ, Givan (2001) Flow Cytometry, 2 nd See ed.;Wiley-Liss, Hoboken, NJ and Shapiro (2003) Practical Flow Cytometry, John Wiley and Sons, Hoboken, NJ. For example, fluorescent reagents suitable for modifying nucleic acids, polypeptides, and antibodies, including nucleic acid primers and probes, are available for use as diagnostic reagents (Molecular Probes (2003) Catalogue, Molecular Probes, Inc., Eugene, Oreg.; Sigma-Aldrich (2003) Catalogue, St. Louis, Mo.).

[0081] Standard methods for histology of the immune system are described (see, for example, Muller-Harmelink (ed.) (1986) Human Thymus: Histopathology and Pathology, Springer Verlag, New York, NY; Hiatt et al. (2000) Color Atlas of Histology, Lippincott, Williams, and Wilkins, Phila, Pa.; and Louis et al. (2002) Basic Histology: Text and Atlas, McGraw-Hill, New York, NY).

[0082] "Isolated" VEGF antagonists and VEGF receptor fusion proteins (e.g., aflibercept), polypeptides, polynucleotides, and vectors are at least partially free from other biomolecules from cells or the cell cultures in which they are produced. Such biomolecules include nucleic acids, proteins, other VEGF antagonists and VEGF receptor fusion proteins, lipids, carbohydrates, or other substances such as cell debris and growth media. Isolated VEGF antagonists or VEGF receptor fusion proteins may further be at least partially free from expression system components such as biomolecules from host cells or their growth media. In general, the term "isolated" is not intended to refer to the complete absence of such biomolecules (although small or minute amounts of impurities may remain), or the absence of water, buffers, or salts, or to components of pharmaceutical formulations containing VEGF antagonists or VEGF receptor fusion proteins.

[0083] Subjects and patients are used interchangeably herein. Subjects or patients are mammals, e.g., humans, mice, rabbits, monkeys, or non-human primates, preferably humans. Subjects or patients can be said to be “suffering” from an intraocular neovascular disease such as nAMD. Such subjects or patients have impairment in one or both eyes. In embodiments of the present invention, subjects or patients (preferably humans) have the following characteristics (current or past): 1. The applicant's age must be ≥ 50 years, for example, 61, 62, 63, 74, or 75 years old. 2. Having active subfoveal CNV secondary to nAMD, including, for example, a parafoveal lesion affecting the fovea of ​​the eye. 3. Research on early treatment of diabetic retinopathy using best corrected visual acuity (BCVA) The ETDRS character score is approximately 78-24, 73-78, <73, 58, 59, 60, 61, 62, or 63 (corresponding to Snellen visual acuity scores of 20 / 40, 20 / 63, 20 / 50, 20 / 32, or 20 / 320), for example, due to DME or exudative AMD. 4. A central retinal thickness of ≥300 micrometers or ≥320 micrometers, or about 367, 368, 369, 370, 450, 451, 452, 453, 454, or 455 micrometers, and / or DME involving the center of an eye having a CRT ≥300 micrometers (or ≥320 micrometers with Spectralis), 5. A total lesion area of about 6 or 7 mm 2 where, for example, the lesion type is Occult, predominantly classic, or minimally classic, 6. A DRSS score that is ≥43 or ≤47, 7. Type 1 diabetes or type 2 diabetes (insulin-dependent or non-insulin-dependent) (e.g., for about 15 years or more), 8. A hemoglobin A1C (%) of about 7 or 8 or more, 9. A obesity index of about 30 or 31 or more, and / or 10. Having one or more of diabetic retinal edema, diabetic retinopathy, dry eye, vitreous detachment, retinal hypersensitivity, retinal hemorrhage, cataract surgery, retinal laser photocoagulation therapy, and intraocular lens implant, a history of hypertension, And / or the following characteristics: 1. Evidence of macular edema due to some cause other than true diabetes in the eye, 2. An IOP in the eye ≥25 mmHg, 3. A history of having had glaucoma filtration surgery in the eye in the past or a likelihood of needing filtration surgery in the future, 4. Evidence of infectious blepharitis, keratitis, scleritis, or conjunctivitis in any eye within 4 weeks (28 days) of treatment, 5. Any intraocular inflammation and / or eye infection in the eye within 12 weeks (84 days) of treatment, 6. A history of idiopathic or autoimmune uveitis of the eye, 7. For example, vitreomacular traction or epiretinal membrane in the eye, as revealed on a biological microscope or OCT, which is thought to affect central vision. 8. Preretinal fibrosis involving the macula of the retina of the eye. 9. Any history of macular hole of stage 2 or higher in the eye, 10. Current iris neovascularization, vitreous hemorrhage, or tractional retinal detachment visible during eye screening. 11. History of corneal transplantation or corneal dystrophy, 12. Any simultaneous eye symptoms, Based on the findings of the treating physician, It may increase the risk to the subject beyond what is expected from the standard procedure for IVT injection, or it may otherwise interfere with the injection procedure for VEGF antagonists, ocular symptoms, 13. A history of other diseases, metabolic dysfunction, physical examination findings, or clinical laboratory findings that give reasonable suspicion of a disease or condition for which the use of a VEGF antagonist is contraindicated. 14. Past systemic (IV) administration of any anti-VEGF antibody, 15. Uncontrolled diabetes mellitus, defined as hemoglobin A1c (HbA1c) >12%. 16. Uncontrolled blood pressure (defined as systolic >160 mmHg or diastolic >95 mmHg), 17. History of cerebrovascular disease or myocardial infarction within 24 weeks (168 days) of treatment. 18. History of renal failure, dialysis, or kidney transplantation. 19. Known susceptibility to any of the compounds administered in treatment, and / or 20. Having one or more of the following conditions: pregnant or breastfeeding.

[0084] Therefore, the present invention relates to subjects who require treatment or prevention of DR and / or DME, 1. Persons whose age is ≥ 50 years old, 2. Individuals with active subcentral foveal CNV, 3. Research on early treatment of diabetic retinopathy using best corrected visual acuity (BCVA) Those whose (ETDRS) letter score was approximately 78-24, 4. Persons whose central retinal thickness is ≥300 micrometers or ≥320 micrometers, 5. Approximately 6 or 7 mm 2 Persons with a lesion area of ​​the above, 6. Those with a DRSS score of level 43 or higher and level 47 or lower, and / or 7. Whether the person has type 1 diabetes or type 2 diabetes, and / or 1. Individuals lacking evidence of macular edema caused by any reason other than diabetes mellitus in the eye, 2. Persons whose IOP in the eye is not ≥ 25 mmHg, 3. Individuals who have no history of glaucoma filtration surgery, or who are unlikely to require filtration surgery in the future. 4. Individuals who have no evidence of infectious blepharitis, keratitis, scleritis, or conjunctivitis in any eye within 4 weeks (28 days) of treatment. 5. Persons who do not have any intraocular inflammation and / or eye infections within 12 weeks (84 days) of treatment. 6. Persons who have no history of idiopathic or autoimmune uveitis of the eye, 7. Persons who do not have vitreomacular traction syndrome or epiretinal membrane in their eyes. 8. Persons who do not have preretinal fibrosis with retinal macular degeneration in the eye. 9. Persons who do not have any history of macular hole of stage 2 or higher in the eye. 10. Persons who do not currently have iris neovascularization, vitreous hemorrhage, and / or tractional retinal detachment. 11. Persons who have not had a corneal transplant or have a history of corneal dystrophy. 12. Any simultaneous eye symptoms, Based on the findings of the treating physician, In individuals without ocular symptoms, the procedure may increase the risk to the subject beyond what is expected from the standard procedure for IVT injection, or may otherwise interfere with the injection procedure for VEGF antagonists. 13. Individuals who do not have a history of other diseases, metabolic dysfunction, physical examination findings, or clinical laboratory findings that would reasonably suggest a disease or condition for which the use of VEGF antagonists is contraindicated. 14. Individuals who have not previously received any systemic (IV) administration of anti-VEGF antibodies. 15. Persons who do not have uncontrolled diabetes mellitus, as defined by hemoglobin A1c (HbA1c) >12%. 16. Persons who do not have uncontrolled blood pressure (defined as systolic >160 mmHg or diastolic >95 mmHg), 17. Persons who have not had a history of cerebrovascular disease or myocardial infarction within 24 weeks (168 days) of treatment. 18. Persons who do not have a history of renal failure, dialysis, or kidney transplantation. 19. Persons who do not have known susceptibility to any of the compounds administered in treatment, and / or 20. In subjects who are not pregnant or breastfeeding women, including methods for treating or preventing DR and / or DME, The method involves administering to the target eye (preferably by intravitreal injection) a single initial dose of aflibercept of approximately 8 mg or more of VEGF receptor fusion protein, followed by one or more secondary doses of approximately 8 mg or more of VEGF receptor fusion protein, and then one or more tertiary doses of approximately 8 mg or more of VEGF receptor fusion protein, with each secondary dose administered approximately 2 to 4 weeks after the previous dose, and each tertiary dose administered approximately 24 weeks after the previous dose.

[0085] VEGF Antagonist The present invention includes methods for using VEGF antagonists to treat or prevent intraocular neovascular disease. VEGF antagonists include molecules that interfere with the interaction between VEGF and the innate VEGF receptor, such as molecules that bind to VEGF or the VEGF receptor and prevent or otherwise interfere with the interaction between VEGF and the VEGF receptor. Specific exemplary VEGF antagonists include anti-VEGF antibodies, anti-VEGF receptor antibodies, and VEGF receptor fusion proteins. VEGF receptor fusion proteins, such as aflibercept, are preferred for use in connection with the methods described herein, but the scope of the present invention includes such methods in which any of the VEGF antagonists described herein (e.g., scFv, DARPin, anti-VEGF antibodies) is used instead of such fusion proteins.

[0086] For the purposes of this specification, “VEGF receptor fusion protein” means a molecule containing one or more VEGF receptors or their domains fused to another polypeptide, which interferes with the interaction between VEGF and the native VEGF receptor, for example, by the association of two of such fusion polypeptides, thereby forming a homodimer or other multimer. Such VEGF receptor fusion proteins may be referred to as “VEGF-Trap” or “VEGF Trap.” VEGF receptor fusion proteins in the context of this disclosure as included in this definition include chimeric polypeptides containing two or more immunoglobulin (Ig)-like domains of VEGF receptors such as VEGFR1 (also known as Flt1) and / or VEGFR2 (also known as Flk1 or KDR), and which may also contain a multimerizing domain (e.g., an Fc domain). Preferably, the VEGF receptor fusion protein is aflibercept.

[0087] An exemplary VEGF receptor fusion protein is a molecule called VEGF1R2-FcΔC1(a), which is encoded by the nucleic acid sequence of SEQ ID NO: 1 or its nucleotides 79-1374 or 79-1371.

[0088] VEGF1R2-FcΔC1(a) contains the following three components: (1) The VEGFR1 component containing amino acids 27-129 of SEQ ID NO: 2, (2) VEGFR2 component containing amino acids 130-231 of Sequence ID No. 2, (3) A multimer-forming component containing amino acids 232-457 of SEQ ID NO: 2 ("FcΔC1(a)") (the C-terminal amino acid of SEQ ID NO: 2, i.e., K458, may or may not be included in the VEGF receptor fusion protein; see U.S. Patent No. 7,396,664 or No. 7,354,579, which are incorporated herein for all purposes). Note that amino acids 1-26 of SEQ ID NO: 2 are a signal sequence.

[0089] If the multimerizing component (MC) of a VEGF receptor fusion protein is derived from the IgG (e.g., IgG1)Fc domain, the MC has approximately the same number of amino acids as those in amino acids 232-457 of SEQ ID NO: 2. Therefore, the IgG in the MC cannot be cleaved into any shorter segments than 226 amino acids.

[0090] In one embodiment of the present invention, the VEGF receptor fusion protein contains amino acids 27-458 or 27-457 of SEQ ID NO: 2 (for example, in homodimer form). (Sequence ID 1) MVSYWDTGVLLCALLSCLLLTGSSSGSDTGRPFVEMYSEIPEIIIHMTEGRELVIPCRVTS PNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLT HRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRD LKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (Sequence 2)

[0091] In one embodiment of the present invention, the VEGF receptor fusion protein is (1) The second immunoglobin-like (Ig) domain of the first VEGF receptor (e.g., VEGFR1), (2) The third Ig domain of the second VEGF receptor (e.g., VEGFR2), (3) Optionally further comprising the fourth Ig domain of a second VEGF receptor (e.g., VEGFR2), and (4) A multimerizing component (for example, the Fc domain of IgG including the hinge domain, CH2 domain, and CH3 domain).

[0092] For example, in one embodiment of the present invention, the VEGF receptor fusion protein has the following arrangement of the domains: · [The second Ig domain of VEGFR1] - [The third Ig domain of VEGFR2] - [MC] (for example, its homodimer), or · [The second Ig domain of VEGFR1] - [The third Ig domain of VEGFR2] - [The fourth Ig domain of VEGFR2] - [MC] (for example, its homodimer).

[0093] The present disclosure also includes, within its scope, high-concentration formulations containing, instead of the VEGF receptor fusion protein, a VEGF binding molecule or an anti-VEGF antibody or an antigen-binding fragment thereof, or a biopolymer conjugate thereof (for example, KSI-301), for example, · Bevacizumab (for example, at a concentration of about 80-90 or 88 mg / ml), · Ranibizumab (for example, at a concentration of about 20-40 mg / ml, for example 21-35, 21, or 35 mg / ml), · Anti-VEGF aptamers such as pegaptanib (for example, pegaptanib sodium), · Single-chain (for example, V L -V H ) anti-VEGF antibodies such as brolucizumab (for example, at a concentration of about 200-400 or 200, 210, 400, or 420 mg / ml), · Anti-VEGF DARPins such as abicipar pegol (for example, at a concentration of about 70-140, 70, or 140 mg / ml), or · Bispecific anti-VEGF antibodies that also bind to ANG2, such as, for example, RG7716 (faricimab) (for example, at a concentration of about 100-400, 100, 105, 400, or 420 mg / ml).

[0094] To minimize repetition of the embodiments discussed herein, the scope of the present invention is intended to include embodiments in which any of the formulations discussed herein comprises, instead of a VEGF receptor fusion protein, an anti-VEGF antibody or antibody fragment, or another VEGF-binding molecule (e.g., substituted with anti-VEGF DARPin) at any of the concentrations discussed herein. For example, the present invention includes formulations comprising 35 or 80 mg / ml of ranibizumab, a buffer, a heat stabilizer, a viscosity reducer, and a surfactant.

[0095] DARPin is a designed ankyrin repeat protein. DARPin typically contains three to four densely packed repeats of approximately 33 amino acid residues, each repeat containing a β-turn and two antiparallel α-helices. This rigid framework provides protein stability for target recognition, while also allowing for the presentation of a variable region, typically containing six amino acid residues per repeat.

[0096] An "anti-VEGF" antibody or antigen-binding fragment of an antibody refers to an antibody or fragment that specifically binds to VEGF.

[0097] Examples of VEGF receptor fusion proteins include aflibercept (EYLEA®, Regeneron Pharmaceuticals, Inc.) or conbercept (marketed by Chengdu Kanghong Biotechnology Co., Ltd.). See International Patent Publication No. 2005 / 121176 or International Patent Publication No. 2007 / 112675. The terms “Aflibercept” and “Conbercept” include their biosimilar versions. Biosimilar versions of a reference product (e.g., aflibercept) generally refer to products containing the same amino acid sequence, but include products that are biosimilars under the U.S. Biologics Price Competition and Innovation Act.

[0098] The present invention also includes embodiments comprising administering one or more additional therapeutic agents in addition to a VEGF antagonist, for example, a second VEGF antagonist (in one or more doses), an antibiotic, an anesthetic for the eye receiving the injection (e.g., a local anesthetic), a nonsteroidal anti-inflammatory drug (NSAID), a steroid (e.g., a corticosteroid, dexamethasone), triamcinolone acetonide (TA), methotrexate, rapamycin, an antitumor necrosis factor alpha agent (e.g., infliximab), daxizumab, and / or a complement component (e.g., C3 or C5) inhibitor.

[0099] Pharmaceutical preparations The present invention includes a method for incorporating a VEGF antagonist into a pharmaceutical formulation for administration to a target eye. The pharmaceutical formulation comprises the VEGF antagonist together with a pharmaceutically acceptable carrier. Other agents may be incorporated into the pharmaceutical formulation to provide improvements in transport, delivery, tolerability, etc. The term "pharmaceutically acceptable" means approved by a federal or state regulatory authority, or listed in the United States Pharmacopeia or other commonly recognized pharmacopoeia for use in animals, more specifically for use in humans. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle together with which the VEGF antagonist is administered. Numerous suitable formulations can be found in the prescription collection known to all pharmacists, Remington's Pharmaceutical Sciences (15th edition, Mack Publishing Company, Easton, Pennsylvania, 1975), particularly in its chapter 87 by Blaug and Seymour.

[0100] Pharmaceutical formulations for use in the method of the present invention can be "high-concentration." High-concentration pharmaceutical formulations of the present invention include a VEGF antagonist, such as a VEGF receptor fusion protein, at a concentration of at least 41 mg / ml, at least 80 mg / ml, at least 100 mg / ml, at least 125 mg / ml, at least 140 mg / ml, at least 150 mg / ml, at least 175 mg / ml, at least 200 mg / ml, at least 225 mg / ml, at least 250 mg / ml, or at least 275 mg / ml. "High concentration" may refer to formulations containing a VEGF antagonist concentration of about 140 mg / ml to about 160 mg / ml, at least about 140 mg / ml but less than 160 mg / ml, about 41 mg / ml to about 275 mg / ml, about 70 mg / ml to about 75 mg / ml, or about 80 mg / ml to about 250 mg / ml. In some embodiments, the concentration of the VEGF antagonist in the formulation is approximately 41 mg / ml; 42 mg / ml; 43 mg / ml; 44 mg / ml; 45 mg / ml; 46 mg / ml; 47 mg / ml; 48 mg / ml; 49 mg / ml; 50 mg / 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;76mg / ml;77mg / ml;78mg / ml;79mg / ml;80mg / ml;81mg / ml;82mg / ml;83mg / ml;84mg / ml;85mg / ml;86mg / ml;87mg / ml;88mg / ml;89mg / ml;90mg / ml;91mg / ml;92mg / ml;93mg / ml;94m g / ml;95mg / ml;96mg / ml;97mg / ml;98mg / ml;99mg / ml;100mg / ml;101mg / ml;102mg / ml;103m g / ml;104mg / ml;105mg / ml;106mg / ml;107mg / ml;108mg / ml;109mg / ml;110mg / ml;111mg / ml;112mg / ml;113mg / ml;113.3mg / ml;114mg / ml;114.1mg / ml;114.2mg / ml;114.3mg / ml;114.4mg / ml;114.5mg / ml;114.6mg / ml,114.7mg / ml,114.8mg / ml;114.9mg / ml;115mg / ml;116mg / ml;117mg / ml;118mg / ml;119mg / ml;120mg / ml;121mg / ml;122mg / ml;123mg / ml;124mg / ml;125mg / ml;126mg / ml;127mg / ml;128mg / ml;129mg / ml;130mg / ml;131mg / ml;132mg / ml;133mg / ml;133.3mg / ml;133.4mg / ml,134mg / ml;135mg / ml;136mg / ml;137mg / ml;138mg / ml;139mg / ml;140mg / ml;141mg / ml;142mg / ml;143mg / ml;144mg / ml;145mg / ml;146mg / ml;147mg / ml;148mg / ml;149mg / ml;150mg / ml;151mg / ml;152mg / ml;153mg / ml;154mg / ml;155mg / ml;156mg / ml;157mg / ml;158mg / ml;159mg / ml;160mg / ml;161mg / ml;162mg / ml;163mg / ml;164mg / ml;165mg / ml;166mg / ml;167mg / ml;168mg / ml;169mg / ml;170mg / ml;171mg / ml;172mg / ml;173mg / ml;174mg / ml;175mg / ml;176mg / ml;177mg / ml;178mg / ml;179mg / ml;180mg / ml;181mg / ml;182mg / ml;183mg / ml;184mg / ml;185mg / ml;186mg / ml;187mg / ml;188mg / ml;189mg / ml;190mg / ml;191mg / ml;192mg / ml;193mg / ml;194mg / ml;195mg / ml;196mg / ml;197mg / ml;198mg / ml;199mg / ml;200mg / ml;201mg / ml;202mg / ml;203mg / ml;204mg / ml;205mg / ml;206mg / ml;207mg / ml;208mg / ml;209mg / ml;210mg / ml;211mg / ml;212mg / ml;213mg / ml;214mg / ml;215mg / ml;216mg / ml;217mg / ml;218mg / ml;219mg / ml;220mg / ml;221mg / ml;222mg / ml;223mg / ml;224mg / ml;225 mg / ml;226mg / ml;227mg / ml;228mg / ml;229mg / ml;230mg / ml;231mg / ml;232mg / ml;233mg / ml; 234mg / ml;235mg / ml;236mg / ml;237mg / ml;238mg / ml;239mg / ml;240mg / ml;241mg / ml;242mg / ml;243mg / ml;244mg / ml;245mg / ml;246mg / ml;247mg / ml;248mg / ml;249mg / ml;250mg / ml;251 mg / ml;252mg / ml;253mg / ml;254mg / ml;255mg / ml;256mg / ml;257mg / ml;258mg / ml;259mg / ml; 260mg / ml;261mg / ml;262mg / ml;263mg / ml;264mg / ml;265mg / ml;266mg / ml;267mg / ml;268mg / 269 ​​mg / ml; 270 mg / ml; 271 mg / ml; 272 mg / ml; 273 mg / ml; 274 mg / ml; or 275 mg / ml. Other concentrations of VEGF antagonists are contemplated herein, provided that they function according to the embodiments described herein.

[0101] In one embodiment of the present invention, the pharmaceutical formulation for use in the method of the present invention is at a concentration containing about 4, 6, 8, 10, 12, 14, 16, 18, or 20 mg of VEGF receptor fusion protein (e.g., aflibercept), or at any of the acceptable doses considered herein, in amounts of about 100 μl or less, about 75 μl or less, or about 70 μl or less, for example, about 50 μl, 51 μl, 52 μl, 53 μl, 54 μl, 55 μl, 56 μl, 57 μl, 58 μl, 59 μl, 60 μl, This refers to the amount of the protein in 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.

[0102] The present invention includes a method using any of the formulations described in the “Exemplary Formulations” section of this specification (as discussed herein), wherein the concentration of the VEGF receptor fusion protein (e.g., aflibercept) is substituted with the concentration described in that section ("VEGF Receptor Fusion Proteins and Other VEGF Inhibitors").

[0103] Buffers for use in the pharmaceutical formulations herein, which may be used in the methods of the present invention, refer to solutions that are resistant to pH changes caused by the use of acid-base complexes. Buffers can maintain a pH within the range of about 5.0 to about 6.8, more typically about 5.8 to about 6.5, and most typically about 6.0 to about 6.5. In some cases, the pH of the formulations 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. Examples of buffers for inclusion in the formulations herein include histidine-based buffers, such as histidine and histidine hydrochloride or histidine acetate. Alternatively, the buffer contained in the formulations herein may be a phosphate-based buffer, such as sodium phosphate; an acetate-based buffer, such as sodium acetate or acetic acid; or a citrate-based buffer, such as sodium citrate or citric acid. It is also recognized that the buffer may be a mixture of the above, insofar as the buffer functions to buffer the formulations within the above-mentioned pH range. In some cases, the buffer is about 5 mM to about 25 mM, or more typically, about 5 mM to about 15 mM. The buffer may 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.

[0104] In one embodiment of the present invention, a histidine-based buffer is prepared using histidine and histidine monohydrochloride.

[0105] In this specification, surfactants for use refer to components that protect higher concentrations of VEGF antagonists, such as VEGF receptor fusion proteins, from various surface and interface-induced stresses. Therefore, surfactants can be used to limit or minimize aggregation of VEGF receptor fusion proteins and to promote protein solubility. Suitable surfactants in this specification are known to be nonionic and may include surfactants having a polyoxyethylene moiety. Exemplary surfactants in this category include polysorbate 20, polysorbate 80, poloxamer 188, polyethylene glycol 3350, and mixtures thereof. Surfactants in formulations may be present in concentrations of about 0.02% to about 0.1% (w / v) per volume, more typically about 0.02% to about 0.04% (w / v). In some cases, the surfactant content is approximately 0.02% (w / v), 0.03% (w / v), 0.04% (w / v), 0.05% (w / v), 0.06% (w / v), 0.07% (w / v), 0.08% (w / v), 0.09% (w / v), or 0.1% (w / v).

[0106] The heat stabilizers for use in pharmaceutical formulations that may be used by the methods described herein refer to components that provide heat stability against thermal denaturation of VEGF antagonists, such as VEGF receptor fusion proteins, and components that protect VEGF receptor fusion proteins from loss of potency or activity. Suitable heat stabilizers include sugars, which may be sucrose, trehalose, sorbitol, or mannitol, or amino acids, such as L-proline, L-arginine (e.g., L-arginine monohydrochloride), or taurine. Furthermore, the heat stabilizers may include substituted acrylamide or propanesulfonic acid, or compounds such as glycerol.

[0107] In some cases, pharmaceutical formulations for use in the methods described herein include sugars and taurine, sugars and amino acids, sugars and propanesulfonic acid, sugars and taurine, glycerol and taurine, glycerol and propanesulfonic acid, amino acids and taurine, or both amino acids and propanesulfonic acid. Furthermore, formulations may include sugars, taurine and propanesulfonic acid, glycerol, taurine and propanesulfonic acid, and L-proline, taurine and propanesulfonic acid.

[0108] Embodiments of this specification may have heat stabilizers present individually, each independently present at concentrations of about 2% to about 10% (w / v), 4% to about 10% (w / v), 4% to about 9% (w / v), or 5% to about 8% (w / v), or in a combined total concentration. The heat stabilizers in the formulation may be present at concentrations 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).

[0109] With respect to taurine and propanesulfonic acid, in one embodiment of the present invention, these heat stabilizers may be present in the formulation at a concentration of about 25 mM to about 100 mM, more typically about 50 mM to about 75 mM (compared to other heat stabilizers).

[0110] Viscosity-reducing agents are typically used to reduce or prevent protein aggregation. Viscosity-reducing agents included herein include sodium chloride, magnesium chloride, D-arginine or L-arginine (e.g., L-arginine monohydrochloride), lysine, or mixtures thereof. Where present herein, viscosity-reducing agents may be present at about 10 mM to about 100 mM, more typically at about 30 mM to about 75 mM, and even more typically at about 40 mM to about 70 mM. In some cases, viscosity-reducing agents may be 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.

[0111] Pharmaceutical formulations for use in the methods described herein may also have a pharmaceutically acceptable viscosity for ocular administration, for example, intravitreal injection. Viscosity generally refers to a measure of the resistance of a fluid to deformation by either shear stress or tensile stress (typically measured by, for example, techniques known in the art, a viscometer or a rheometer). Typical viscosities of formulations for use in the methods described herein are about 5.0 cP (centipoise) to about 15 cP, about 11 cP to about 14 cP, about 12 cP to about 15 cP, or about 11 cP to about 12 cP. Thus, the viscosity of the formulations described herein may be approximately 5.0 cP, approximately 6.0, approximately 7.1 cP, approximately 7.2 cP, approximately 7.3 cP, approximately 7.4 cP, approximately 7.5 cP, approximately 7.6 cP, approximately 10 cP, approximately 10.5 cP, approximately 11.0 cP, approximately 11.5 cP, approximately 12.0 cP, approximately 12.5 cP, approximately 13.0 cP, approximately 13.5 cP, approximately 14.0 cP, approximately 14.5 cP, or approximately 15.0 cP (for example, when measured at 20°C).

[0112] Various embodiments of this specification do not require the inclusion of inorganic salts or other viscosity-reducing agents to maintain these highly useful viscosities. Typically, high-concentration protein solutions require viscosity-reducing agents to avoid protein aggregation and increased viscosity, which makes intravitreal injection of the formulation difficult and reduces the potency of the VEGF receptor fusion protein. Accordingly, embodiments of this specification include methods using formulations that substantially lack or do not contain sodium chloride (NaCl), magnesium chloride (MgCl2), D-arginine or L-arginine (e.g., L-arginine hydrochloride), lysine, or other viscosity-reducing agents.

[0113] Osmotic pressure is an important characteristic for injectable pharmaceutical formulations to be used in the method of the present invention. It is desirable that the formulation matches physiological osmotic conditions. Furthermore, osmotic pressure determines the soluble contents in the solution. In one embodiment of the present invention, the osmotic pressure of the formulation to be used in the method of the present invention is about 506 mmol / Kg or less, or about 250 to about 506 mmol / Kg, for example, about 250, 260, 270, 280, 290, 299, 300, 310, 314, 315, 316, 324, 343, 346, 349, 369, 384, 403, 426, 430, or 506 mmol / Kg. In one embodiment of the present invention, the osmotic pressure is lower than about 250 mmol / Kg.

[0114] Examples of pharmaceutical formulations for use in the method of the present invention include the following: Preparation A: 80 mg / ml aflibercept, 10 mM histidine buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 40 mM sodium chloride, pH 5.8-6.2. Formulation B: 80 mg / ml aflibercept, 10 mM phosphate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 40 mM sodium chloride, pH 5.8-6.2. Formulation C: 80 mg / ml aflibercept, 10 mM citrate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 40 mM sodium chloride, pH 5.8-6.2. Formulation D: 80 mg / ml aflibercept, 10 mM histidine buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80, and 40 mM sodium chloride, pH 6.2. Preparation E: 80 mg / ml aflibercept, 10 mM phosphate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80, and 40 mM sodium chloride, pH 5.8-6.2. 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, pH 5.8-6.2. Formulation G: 80 mg / ml aflibercept, 10 mM histidine buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 20, pH 5.8-6.2, with the optional exclusion of viscosity-reducing agents. Formulation H: 80 mg / ml aflibercept, 10 mM phosphate buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 20, pH 5.8-6.2, with optional, particularly viscosity-reducing agents excluded. Formulation I: 80 mg / ml aflibercept, 10 mM citrate-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 20, pH 5.8-6.2, with optional, particularly viscosity-reducing agents excluded. Formulation J: 80 mg / ml aflibercept, 10 mM histidine-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 80, pH 5.8-6.2, with the optional exclusion of viscosity-reducing agents. Formulation K: 80 mg / ml aflibercept, 10 mM phosphate buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 80, pH 5.8-6.2, with the optional exclusion of viscosity-reducing agents. Preparation L: 80 mg / ml aflibercept, 10 mM citrate-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 80, pH 5.8-6.2, with the optional exclusion of viscosity-reducing agents. Formulation M: 150 mg / ml aflibercept, 10 mM histidine buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 40 mM sodium chloride, pH 5.8-6.2. Preparation N: 150 mg / ml aflibercept, 10 mM phosphate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 40 mM sodium chloride, pH 5.8-6.2. Preparation 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, pH 5.8-6.2. Formulation P: 150 mg / ml aflibercept, 10 mM histidine buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80, and 40 mM sodium chloride, pH 6.2. Formulation Q: 150 mg / ml aflibercept, 10 mM phosphate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80, and 40 mM sodium chloride, pH 5.8-6.2. 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, pH 5.8-6.2. Formulation S: 150 mg / ml aflibercept, 10 mM histidine-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 20, pH 5.8-6.2, with the optional exclusion of viscosity-reducing agents. Formulation T: 150 mg / ml aflibercept, 10 mM phosphate buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 20, pH 5.8-6.2 (e.g., 6.2), optionally excluding viscosity-reducing agents. Formulation U: 150 mg / ml aflibercept, 10 mM citrate-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 20, pH 5.8-6.2, with optional, particularly viscosity-reducing agents excluded. Formulation V: 150 mg / ml aflibercept, 10 mM histidine buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 80, pH 5.8-6.2, with optional, particularly viscosity-reducing agents excluded. Formulation W: 150 mg / ml aflibercept, 10 mM phosphate buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 80, pH 5.8-6.2, with the optional exclusion of viscosity-reducing agents. Formulation X: 150 mg / ml aflibercept, 10 mM citrate-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 80, pH 5.8-6.2, with optional, particularly viscosity-reducing agents excluded. Formulation Y: 80 mg / ml Convercept, 10 mM histidine buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 40 mM sodium chloride, pH 5.8-6.2. Formulation Z: 80 mg / ml of Convercept, 10 mM phosphate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 40 mM sodium chloride, pH 5.8-6.2. Preparation AA: 80 mg / ml of Convercept, 10 mM citrate-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 40 mM sodium chloride, pH 5.8-6.2. Formulation BB: 80 mg / ml of Convercept, 10 mM histidine buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80, and 40 mM sodium chloride, pH 6.2. Formulation CC: 80 mg / ml Convercept, 10 mM phosphate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80, and 40 mM sodium chloride, pH 5.8-6.2. Preparation DD: 80 mg / ml Convercept, 10 mM citrate-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80, and 40 mM sodium chloride, pH 5.8-6.2. Preparation EE: 80 mg / ml of Convercept, 10 mM histidine-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 20, pH 5.8-6.2, with optional, particularly viscosity-reducing agents excluded. The formulation FF consists of 80 mg / ml of Convercept, 10 mM phosphate buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 20, with a pH of 5.8-6.2. Optionally, viscosity-reducing agents are excluded. Formulation GG: 80 mg / ml of Convercept, 10 mM citrate-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 20, pH 5.8-6.2, with optional, particularly viscosity-reducing agents excluded. The formulation consists of Convercept at HH: 80 mg / ml, 10 mM histidine-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 80, with a pH of 5.8-6.2. Optionally, viscosity-reducing agents are excluded. Formulation II: 80 mg / ml of Convercept, 10 mM phosphate buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 80, pH 5.8-6.2, with optional, particularly viscosity-reducing agents excluded. Preparation JJ: 80 mg / ml of Convercept, 10 mM citrate-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 80, pH 5.8-6.2, with optional, particularly viscosity-reducing agents excluded. Formulation KK: 150 mg / ml of Convercept, 10 mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 40 mM sodium chloride, pH 5.8-6.2. Formulation LL: 150 mg / ml of Convercept, 10 mM phosphate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 40 mM sodium chloride, pH 5.8-6.2. Formulation MM: 150 mg / ml Convercept, 10 mM citrate-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 40 mM sodium chloride, pH 5.8-6.2. Formulation NN: 150 mg / ml Convercept, 10 mM histidine buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80, and 40 mM sodium chloride, pH 6.2. Formulation OO: 150 mg / ml of Convercept, 10 mM phosphate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80, and 40 mM sodium chloride, pH 5.8~6.2. Preparation PP: 150 mg / ml Convercept, 10 mM citrate-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80, and 40 mM sodium chloride, pH 5.8-6.2. Formulation QQ: 150 mg / ml of Convercept, 10 mM histidine-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 20, pH 5.8-6.2, with optional, particularly viscosity-reducing agents excluded. The formulation RR consists of 150 mg / ml of Convercept, 10 mM phosphate buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 20, with a pH of 5.8-6.2. Optionally, viscosity-reducing agents are excluded. The formulation SS consists of 150 mg / ml of Convercept, 10 mM citrate-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 20, with a pH of 5.8-6.2. Optionally, viscosity-reducing agents are excluded. The formulation TT consists of 150 mg / ml of Convercept, 10 mM histidine-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 80, with a pH of 5.8-6.2. Optionally, viscosity-reducing agents are excluded. The formulation consists of 150 mg / ml of Convercept, 10 mM phosphate buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 80, with a pH of 5.8-6.2, and optionally, viscosity-reducing agents are excluded. Formulation VV: 150 mg / ml of Convercept, 10 mM citrate-based buffer, 8% (w / v) sucrose, and 0.03% (w / v) polysorbate 80, pH 5.8-6.2, with optional, particularly viscosity-reducing agents excluded. Preparation WW: 140 mg / ml of 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, pH 5.8. Formulation XX: 140 mg / ml of 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), pH 5.8. Formulation YY: 140 mg / ml of 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, pH 5.8. Formulation ZZ: 140 mg / ml of 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), pH 5.8. Formulation AAA: 140 mg / ml of 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, pH 5.8. Preparation BBB: 140 mg / ml of 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, pH 5.8. Preparation CCC: 80, 100, 120, or 140 mg / ml of 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), pH 5.8. Preparation DDD: 140 mg / ml of 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, pH 5.8. Preparation EEE: 140 mg / ml of VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine-based buffer, 5% (w / v) sucrose, and 0.03% (w / v) polysorbate 20, optionally without heat stabilizers, pH 5.8. Formulation FFF: 140 mg / ml of VEGF receptor fusion protein (e.g., aflibercept), 10 mM sodium phosphate, 5% (w / v) sucrose, and 0.03% polysorbate 20, pH 6.2. Preparation GGG: 140 mg / ml of VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine, pH 5.8, 5% sucrose, 0.03% polysorbate 20, 50 mM sodium sulfate. Preparation HHH: 140 mg / ml of VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine, pH 5.8, 5% sucrose, 0.03% polysorbate 20, 50 mM sodium sulfate. Formulation III: 140 mg / ml of 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 of VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine, pH 5.8, 5% sucrose, 0.03% polysorbate 20, 50 mM glycine. Preparation KKK: 140 mg / ml of 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 of VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine, pH 5.8, 5% sucrose, 0.03% polysorbate 20, 50 mM lysine. Preparation MMM: 140 mg / ml of VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine, pH 5.8, 5% sucrose, 0.03% polysorbate 20, 50 mM sodium aspartate. Preparation NNN: 140 mg / ml of VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine, pH 5.8, 5% sucrose, 0.03% polysorbate 20, 50 mM monosodium glutamate. Formulation OOO: 140 mg / ml of 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 of 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 of 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 RRR: 140 mg / ml of 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 SSS: 140 mg / ml of VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine, pH 5.8, 5% sucrose, 0.03% polysorbate 20, 10 mM L-arginine (e.g., L-arginine hydrochloride), Formulation TTT: 140 mg / ml of VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine, pH 5.8, 5% sucrose, 0.03% polysorbate 20, 100 mM L-arginine (e.g., L-arginine hydrochloride), Formulation UUU: 30 mg / ml of VEGF receptor fusion protein (e.g., aflibercept), 10% sucrose, 10 mM phosphate, 0.03% polysorbate 20, pH 6.2. Formulation VVV: 30 mg / ml of VEGF receptor fusion protein (e.g., aflibercept), 20% sucrose, 10 mM phosphate, 0.03% polysorbate 20, pH 6.2. Formulation WWW: 60 mg / ml of VEGF receptor fusion protein (e.g., aflibercept), 10% sucrose, 10 mM phosphate, 0.03% polysorbate 20, pH 6.2. Formulation XXX: 60 mg / ml of VEGF receptor fusion protein (e.g., aflibercept), 20% sucrose, 10 mM phosphate, 0.03% polysorbate 20, pH 6.2. Formulation YYY: 120 mg / ml of VEGF receptor fusion protein (e.g., aflibercept), 10% sucrose, 10 mM phosphate, 0.03% polysorbate 20, pH 6.2. Formulation ZZZ: 120 mg / ml of VEGF receptor fusion protein (e.g., aflibercept), 20% sucrose, 10 mM phosphate, 0.03% polysorbate 20, pH 6.2. Formulation AAAA: 120 mg / ml of VEGF receptor fusion protein (e.g., aflibercept), 10% sucrose, 10 mM phosphate, 0.03% polysorbate 20, 50 mM NaCl, pH 6.2. Preparation BBBB: 120 mg / ml of VEGF receptor fusion protein (e.g., aflibercept), 20% sucrose, 10 mM phosphate, 0.03% polysorbate 20, 50 mM NaCl, pH 6.2. Preparation CCCC: 140 mg / ml of 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 of 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), pH 5.8. Formulation EEEE: 120.0 mg / ml of 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), pH 5.8 (e.g., 5.6-6.0 or 5.5-6.1). Formulation FFFF: 113.3 mg / ml of VEGF receptor fusion protein (e.g., aflibercept) (e.g., 102-125 mg / ml), 20 mM histidine 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), pH 5.8 (e.g., 5.6-6.0 or 5.5-6.1). Preparation GGGG: 114.3 mg / ml of VEGF receptor fusion protein (e.g., aflibercept) (e.g., 103-126 mg / ml), 10 mM histidine-based buffer containing, for example, histidine and histidine-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), pH 5.8 (e.g., 5.6-6.0 or 5.5-6.1). Preparation HHHH: 100.0 mg / ml of 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), pH 5.8 (e.g., 5.6-6.0 or 5.5-6.1), Formulation IIII: 133.3 mg / ml of 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), pH 5.8 (e.g., 5.6-6.0 or 5.5-6.1), Formulation JJJJ: 150 mg / ml of 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 of VEGF receptor fusion protein (e.g., aflibercept) (e.g., ±14 mg / ml), 20 mM histidine 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), pH 5.8 (e.g., 5.6-6.0 or 5.5-6.1).

[0115] Please refer to International Publication No. 2019 / 217927, which is the publication of the international patent application.

[0116] In one embodiment of the present invention, aflibercept preferably contains ≥8 mg of VEGF receptor fusion protein in an aqueous pharmaceutical formulation upon administration. The formulation contains two polypeptides, each containing at least about 100 mg / ml of the VEGF receptor fusion protein, each containing the second immunoglobin-like (Ig) domain of VEGFR1, the third Ig domain of VEGFR2, and a polymerizing component (e.g., amino acids 27-457 of SEQ ID NO: 2), respectively; about 5% sucrose; L-arginine (e.g., L-arginine monohydrochloride); a histidine-based buffer (e.g., containing histidine hydrochloride); and about 0.03% surfactant. The formulation has a pH of about 5.0 to about 6.8 (e.g., 5.8 to 6.5, e.g., 5.8). The formulation is preferably suitable for intravitreal administration. Other possible components include sodium sulfate, sodium thiocyanate, glycine, NaCl, sodium aspartate, and / or sodium glutamate. In one embodiment of the present invention, the VEGF receptor fusion protein is present in concentrations of approximately 100 mg / ml, approximately 111.5 mg / ml, approximately 112.0 mg / ml, approximately 113.3 mg / ml, approximately 114.3 mg / ml, approximately 115.6 mg / ml, approximately 116.3 mg / ml, approximately 120 mg / ml, approximately 133 mg / ml, approximately 140 mg / ml, approximately 150 mg / ml, approximately 200 mg / ml, or approximately 250 mg / ml. The formulation may be characterized by (i) an osmotic pressure of approximately 299 to approximately 506 mmol / Kg and / or (ii) a viscosity of approximately 6 to 15 cP at 20°C. The surfactant may be a nonionic surfactant such as polysorbate 20, polysorbate 80, poloxamer 188, polyethylene glycol 3350, or a mixture thereof. The histidine buffer may be present in a concentration of approximately 10 mM to 20 mM. In one embodiment of the present invention, the VEGF receptor fusion protein has less than 3.5% high molecular weight molecular species immediately after production and purification, and / or less than 6% high molecular weight molecular species after storage at approximately 2-8°C for approximately 24 months.

[0117] In one embodiment of the present invention, when administered, an aqueous pharmaceutical formulation contains at least about 100 mg / ml of VEGF receptor fusion protein, each containing two polypeptides, one of which is the second immunoglobin-like (Ig) domain of VEGFR1, the other of which is the third Ig domain of VEGFR2, and a polymerizing component (e.g., aflibercept), and about 10-100 mM L-arginine, sucrose, a histidine-based buffer, and a surfactant, wherein the formulation has a pH of about 5.0-6.8, and the VEGF receptor fusion protein contains less than about 3.5% high molecular weight molecular species immediately after manufacturing and purification, and / or less than 6% high molecular weight molecular species after storage at about 2-8°C for about 24 months.

[0118] In one embodiment of the present invention, the pharmaceutical formulation includes the following: • VEGF receptor fusion protein (e.g., aflibercept) ≥ approximately 100 mg / ml, histidine-based buffer, and L-arginine. • Approximately 140 mg / ml of aflibercept, 20 mM histidine buffer, 5% sucrose, 0.03% polysorbate 20, 10 mM L-arginine, pH 5.8. • Approximately 150 ± 15 mg / ml of aflibercept, 10 mM phosphate 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. • Approximately 103-126 mg / ml of 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. • Approximately 140 mg / ml of aflibercept, 10 mM histidine buffer, 2.5% (w / v) sucrose, 2.0% (w / v) proline, 0.03% (w / v) polysorbate 20, and 50 mM L-arginine, pH 5.8. • Approximately 114.3 mg / ml of aflibercept, 10 mM histidine buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 50 mM L-arginine, pH 5.8. • Aflibercept, histidine-based buffer, and L-arginine at a concentration of approximately 100 mg / ml. • Aflibercept with a pH of approximately 5.8 and a concentration of ≥ approximately 100 mg / ml, wherein the formulation forms <3% HMW aggregates after incubation at 5°C for 2 months, and is an aflibercept with a concentration of ≥ approximately 100 mg / ml. • Approximately 114.3 mg / mL of aflibercept, 10 mM to 50 mM histidine-based buffer, sugar, nonionic surfactant, L-arginine, pH 5.8. or • Approximately 114.3 mg / mL of aflibercept, 10 mM His / His-HCl buffer, 5% sucrose, 0.03% polysorbate-20, 50 mM L-arginine, pH 5.8.

[0119] In one embodiment of the present invention, when administered, ≥8 mg of VEGF receptor fusion protein is present in the aqueous pharmaceutical formulation. Aflibercept at a concentration of at least approximately 100 mg / ml (for example, approximately 111.5 mg / ml, 112.0 mg / ml, 113.3 mg / ml, approximately 114.3 mg / ml, approximately 115.6 mg / ml, or approximately 116.3 mg / ml), A heat stabilizer which is sugar, amino acid, sucrose, mannitol, sorbitol, trehalose, L-proline, glycine, glycerol, taurine, or propanesulfonic acid (for example, 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 (for example, at a concentration of about 5 to 25 mM, for example, 10 mM or 20 mM), or a citrate-based buffer. Nonionic surfactants, such as polyoxyethylene-based surfactants, polysorbate 20, polysorbate 80, poloxamer 188, or polyethylene glycol 3350 (for example, at concentrations of about 0.02% to about 0.1% (w / v), for example, 0.03% (w / v)), and A viscosity-reducing agent comprising NaCl, MgCl2, D-arginine, L-arginine, or L-lysine (for example, at a concentration of about 10 to 100 mM, for example, 50 mM), The formulation has a pH of approximately 5.0 to 6.8 (for example, 5.0 to 6.0 or 5.8).

[0120] In one embodiment of the present invention, the concentration of aflibercept in an aqueous pharmaceutical formulation is 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, 154 mg / ml, 155 mg / ml, 156 mg / ml, 157 mg / 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; 237 mg / 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.

[0121] In one embodiment of the present invention, an aqueous pharmaceutical preparation comprises aflibercept, sucrose, mannitol, sorbitol, trehalose, histidine-based buffer, polysorbate 20 or polysorbate 80, and L-arginine at a concentration of at least about 100 mg / ml, with a pH of about 5.0 to about 6.8, and the aflibercept contains less than about 3.5% high molecular weight molecular species immediately after manufacturing and purification, and / or less than 6% high molecular weight molecular species after storage at about 2 to 8°C for about 24 months.

[0122] In one embodiment of the present invention, sucrose, mannitol, sorbitol, or trehalose are present at a concentration of approximately 2-10% (w / v), L-arginine at a concentration of approximately 10-100 mM, polysorbate 20 or polysorbate 80 at a concentration of approximately 0.02-0.1% (w / v), and histidine-based buffer at a concentration of approximately 5-25 mM, with a pH of approximately 5.0-6.8.

[0123] Treatment and administration The present invention provides a method for treating an intraocular neovascular disease (e.g., nAMD, DR, and / or DME) in a subject requiring treatment, the method comprising the step of administering to the eye of the subject (preferably by intravitreal injection) about 8 mg or more of a VEGF antagonist or inhibitor, such as a VEGF receptor fusion protein, preferably aflibercept, every 8 to 24, 12 to 24, 16 to 24, 20 to 24, 21 to 24, 21, 22, 23, or 24 weeks (preferably about 24 weeks).

[0124] The present invention provides a method for treating intraocular neovascular disease (e.g., nAMD, DR, and / or DME) by administering an initial loading dose (e.g., 2 mg or more, 4 mg or more, or preferably about 8 mg or more of a VEGF antagonist or inhibitor, such as a VEGF receptor fusion protein, preferably aflibercept) to the target eye (preferably by intravitreal injection) (e.g., every 2 to 4 weeks or every 3 to 5 weeks, preferably every 4 weeks), followed by successive additional doses every 8 to 24, 12 to 24, 16 to 24, 20 to 24, 21 to 24, 21, 22, 23, or 24 weeks (preferably about 24 weeks). For example, the present invention is a method for treating or preventing intraocular neovascular diseases such as age-related macular degeneration with neovascularization (nAMD), diabetic macular edema (DME), and / or diabetic retinopathy (DR), comprising administering to the target eye (preferably by intravitreal injection) one or more times (e.g., 3, 4, or 5 times) about 8 mg or more of a VEGF antagonist (e.g., VEGF) at intervals of about 2 to 4 weeks or 3 to 5 weeks, for example, monthly (or every 28 days, 28 ± 5 days, or every 4 weeks). The present invention provides a method of administering a receptor fusion protein (preferably aflibercept), followed by one or more doses of about 8 mg or more of a 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 every 6 months, or every 168 days). A dosing regimen including a tertiary dosing interval of about 24 weeks may be referred to herein as a 24-week dosing regimen, 8q24, or HDq24. In one embodiment of the present invention, the tertiary dosing interval may be 8-24, 12-24, 16-24, 20-24, 21-24, 21, 22, 23, or 24 weeks (preferably about 24 weeks).

[0125] "8 mg (±0.8 mg)" includes, for example, 7.2, 8.0, and 8.8 mg.

[0126] The present invention also provides a method for treating intraocular neovascular disease (e.g., nAMD, DR and / or DME) by administering an initial loading dose (e.g., 2 mg or more, 4 mg or more, or preferably about 8 mg or more of a VEGF antagonist or inhibitor, e.g., a VEGF receptor fusion protein, preferably aflibercept) (e.g., every about 2 to 4 weeks or 3 to 5 weeks) to any eye of the subject (preferably by intravitreal injection) followed by successive additional doses every 12, 16, 20, 12 to 16, 12 to 20, 16 to 20, 16 to 24, 8 to 24, 12 to 24, 16 to 24, 20 to 24, 21 to 24, 21, 22, 23, or 24 weeks (preferably about 24 weeks), wherein the patient receives such treatment for at least 60, 64, 68, 72, 76, 80, 84, 88, 92, or 96 weeks.

[0127] Furthermore, the present invention includes a method for treating intraocular neovascular disease (e.g., nAMD, DR, and / or DME) by administering to a target eye (preferably by intravitreal injection) at least once every 24 weeks in an amount of ≥8 mg of a VEGF receptor fusion protein, preferably aflibercept, and by a first three, four, or five doses administered at approximately four-week intervals, followed by doses administered at approximately 24-week intervals.

[0128] In one embodiment of the present invention, the subject begins receiving a loading dose of ≥8 mg every month, followed by a maintenance dose of ≥8 mg approximately every 24 weeks (preferably by intravitreal injection) without any intervening doses. The subject enters the maintenance dose phase rapidly / immediately after the loading dose phase. In one embodiment of the present invention, the subject continues to receive a ≥8 mg dose for 24 weeks without any intervening doses.

[0129] For example, the present invention also relates to a method for treating an intraocular neovascular disease (preferably nAMD, DME, or DR), wherein the treatment is administered to the target eye (preferably by intravitreal injection), Approximately ≥ 8 mg (for example, approximately 100 μl or less, approximately 75 μl or less, or approximately 70 μl or less, for example, approximately 50 μl, 51 μl; 52 μl; 53 μl; 54 μl; 55 μl; 56 μl; 57 μl; 58 μl; 59 μl; 60 μl; 61 μl; 62 μl; 63 μl; 64 μl; 65 μl; 66 μl; 67 μl; 68 μl; 69 μl; 70 μl; 71 μl; 72 μl; 73 μl; 74 μl; 75 μl) The present invention provides a method of treatment by administering a dose of 1 (76μl;77μl;78μl;79μl;80μl;81μl;82μl;83μl;84μl;85μl;86μl;87μl;88μl;89μl;90μl;91μl;92μl;93μl;94μl;95μl;96μl;97μl;98μl;99μl, or 100μl) once every approximately 24 weeks.

[0130] In one embodiment of the present invention, the subject does not undergo a drug regimen change (DRM) and / or does not discontinue treatment for at least 1, 2, 3, 4, or 5 years.

[0131] The present invention also provides a method for improving visual acuity in subjects with type 1 or type 2 diabetes (for example, subjects with age-related macular degeneration with neovascularization (nAMD), diabetic macular edema, or diabetic retinopathy), comprising administering to the subject's eye (preferably by intravitreal injection) once or twice (e.g., three, four, or five times) about once every month (or about every 28 days, 28 ± 5 days, or about every four weeks), followed by one or more doses every 24 weeks.

[0132] The terms “initial dose,” “secondary dose,” and “tertiary dose” refer to the time series of VEGF antagonist administrations (e.g., VEGF receptor fusion proteins such as aflibercept). Therefore, the “initial dose” is the dose administered at the start of the treatment regimen (preferably by intravitreal injection) (also referred to as the “baseline dose”), the “secondary dose” is the dose administered after the initial dose (preferably by intravitreal injection), and the “tertiary dose” is the dose administered after the secondary dose (preferably by intravitreal injection). The initial, secondary, and tertiary doses may all contain the same amount of VEGF antagonist (e.g., VEGF receptor fusion proteins such as aflibercept), but may generally differ from each other in terms of the number of doses. However, in certain embodiments, the amounts of VEGF antagonist (e.g., VEGF receptor fusion proteins such as aflibercept) contained in the initial, secondary, and / or tertiary doses will vary from each other during the course of treatment (e.g., adjusted upward or downward as appropriate).

[0133] Therefore, the administration regimen of the present invention can be expressed as follows: A method for providing treatment to a patient requiring treatment for an intraocular neovascular disease (e.g., nAMD, DME, or DR), wherein the patient is injected into the eye of the patient requiring treatment (preferably by intravitreal injection). A single initial dose of approximately ≥8 mg (for example, approximately 100 μl or less, approximately 75 μl or less, or approximately 70 μl or less, for example, approximately 50 μl, 51 μl; 52 μl; 53 μl; 54 μl; 55 μl; 56 μl; 57 μl; 58 μl; 59 μl; 60 μl; 61 μl; 62 μl; 63 μl; 64 μl; 65 μl; 66 μl; 67 μl; 68 μl; 69 μl; 70 μl; 71 μl; 72 μl; 73 μl; 74 μl; 75 A VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) in μl; 76μl; 77μl; 78μl; 79μl; 80μl; 81μl; 82μl; 83μl; 84μl; 85μl; 86μl; 87μl; 88μl; 89μl; 90μl; 91μl; 92μl; 93μl; 94μl; 95μl; 96μl; 97μl; 98μl; 99μl, or 100μl (in a VEGF receptor fusion protein such as aflibercept), then One or more (e.g., two, three, or four times, preferably two) secondary doses of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), followed by This includes administering a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) as one or more third-line doses. Each secondary dose is administered approximately 2 to 4 weeks (preferably approximately 4 weeks) after the immediately preceding dose, and A method in which each third dose is administered approximately 24 weeks after the previous dose.

[0134] The present invention also relates to a method for treating intraocular neovascular disease (e.g., nAMD, DR, or DME), comprising administering approximately ≥ 8 mg (e.g., approximately 100 μl or less, approximately 75 μl or less, or approximately 70 μl or less, for example, approximately 50 μl, 51 μl; 52 μl; 53 μl; 54 μl; 55 μl; 56 μl; 57 μl; 58 μl; 59 μl; 60 μl; 61 μl; 62 μl; 63 μl; 64 μl; 65 μl; 66 μl; 67 μl; 68 μl; 69 μl; 70 μl; 71 μl) to the target eye (preferably by intravitreal injection). The present invention provides a method for treatment by administering a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) in a PRN-based manner in amounts of 1; 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).

[0135] As needed, an ad-hoc (PRN) treatment protocol requires that the interval between visits to the physician remain fixed (e.g., once every 2, 3, 4, 8, 12, 16, 20, or 24 weeks), and that the decision to administer the VEGF receptor fusion protein injection be based on anatomical findings at each visit. A capped PRN administration regimen is a PRN method in which the subject must be treated for a specific minimum number of times, for example, once every 2, 3, 4, or 6 months.

[0136] The Treat & Extend (T&E) regimen requires that the time interval between visits to the physician be adjusted based on the patient's clinical course. For example, if the patient shows no signs of active disease (e.g., the macula remains dry and there is no leakage), the interval between visits can be extended by one or more times, while if fluid accumulation is present, the interval will be shortened. In T&E, VEGF receptor fusion protein is administered by injection at each visit, and only the patient's current clinical condition influences the interval between injections.

[0137] The present invention includes embodiments in which a patient can switch to a PRN, capped PRN, or T&E regimen at any point during an HDq24 treatment regimen. The PRN, capped PRN, and / or T&E may be continued indefinitely or stopped at any point, after which the HDq24 regimen is restarted at any stage thereof. Any HDq24 regimen can be performed prior to or following any period of the PRN, capped PRN, and / or T&E.

[0138] The present invention includes a method of administering one or more unplanned additional doses to a subject in addition to any of the planned initial, secondary, and / or tertiary doses of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept). Such doses are typically administered at the discretion of the treating physician, depending on the specific needs of the subject.

[0139] Accordingly, the present invention includes a method comprising administering the required dose of the HDq24 regimen, wherein each tertiary dose is administered approximately 24 weeks after the immediately preceding dose, and the interval between two tertiary doses is extended until, for example, signs of disease activity recur or vision deteriorates (e.g., from approximately 4, 8, 12, 16, or 20 weeks to approximately 24 weeks), and then either continuing administration at the last tertiary interval used or continuing administration at the second to last tertiary interval used.

[0140] The present invention includes a method comprising administering the required dose of the HDq24 regimen, wherein the treatment interval between any two tertiary doses is shortened (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) until, for example, signs of disease activity decrease or visual acuity improves (e.g., BCVA stabilizes or improves and / or CRT stabilizes or decreases), and thereafter optionally, the interval between doses can be extended, for example, back to a longer interval.

[0141] For example, in one embodiment of the present invention, for example, in a 12, 16, 20, or 24-week administration phase, the interval between administrations is, for example, • BCVA is lost, for example, from week 12, <5 letters, and / or If the CRT is <300 μm on SD-OCT (or <320 μm on Spectralis SD-OCT), the treatment can be extended in increments of 4 weeks (e.g., from 20 weeks to 24 weeks) as needed. In one embodiment of the present invention, the subject receives an initial dose, a secondary dose, then a 20-week tertiary interval, and then approximately one year later, the tertiary interval is extended to approximately 24 weeks.

[0142] In one embodiment of the present invention, a method for treating an intraocular neovascular disease such as nAMD, DR, or DME as described herein includes the steps of evaluating BCVA and / or CRT, and extending the interval as described if one or both of the criteria are met.

[0143] For example, in one embodiment of the present invention, during the 24-week administration phase, the interval between administrations is, for example, For example, there is a loss of more than 5 or 10 letters in BCVA (ETDRS or equivalent Snellen visual acuity) (for example, compared to BCVA observed approximately 12 or 16 weeks after the start of treatment) resulting from or in connection with the persistence or worsening of nAMD, DR and / or DME, and / or If an increase of 25 micrometers or more than 50 micrometers is observed in CRT (for example, compared to CRT observed approximately 12 weeks after the start of treatment), the treatment period can be shortened (for example, from 24 weeks to 20, 16, 12, or 8 weeks).

[0144] In one embodiment of the present invention, the interval between tertiary doses is increased or decreased in increments of four weeks. The decision to increase or decrease the interval between tertiary doses may be made during one or more visits to the treating physician.

[0145] In one embodiment of the present invention, in a subject receiving the HDq24 regimen, if the criteria for shortening the interval between doses are met, the interval between doses is reduced to 20 weeks. In one embodiment of the present invention, the interval is not shortened to a period shorter than 8 weeks. In one embodiment of the present invention, the method for treating an intraocular neovascular disease such as nAMD, DR, or DME described herein includes the steps of evaluating BCVA and / or CRT, and shortening the interval as described if one or both of the criteria are met.

[0146] Please refer to Figure 3 or Figure 4.

[0147] "Administering every 24 weeks" refers to administering the medication approximately every 6 months, every 168 days (±5 days), every quarter, or twice a year.

[0148] "Monthly" or "after one month" means administration approximately 28 days later, approximately 4 weeks later, or approximately 28 ± 5 days later, and may encompass up to 5 weeks ± 5 days. "Every 4 weeks" or "after 4 weeks" means administration approximately 28 days (± 5 days) later, approximately one month later, or approximately 28 (± 5 days) later, and may encompass up to 5 weeks (± 5 days) every 5 weeks.

[0149] "Administration every 2-4 weeks" or "after 2-4 weeks" refers to administration approximately 2 weeks (±5 days), 3 weeks (±5 days), or 4 weeks (±5 days) later. "Administration every 8 weeks" or "after 8 weeks" refers to administration approximately 2 months (±5 days) or approximately 56 days (±5 days) later.

[0150] Dosing every 12 weeks or after 12 weeks means administering the medication approximately 3 months later, 84 days (±5 days) later, 90 days (±5 days) later, or 84 days (±5 days) later. Dosing every 16 weeks or after 16 weeks means administering the medication approximately 4 months later or 112 days (±5 days) later.

[0151] The administration every "12 to 20 weeks" or "after 12 to 20 weeks" refers to administration after 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks (±5 days), preferably approximately 12 to 16 weeks (±5 days), approximately 12 weeks (±5 days), approximately 16 weeks (±5 days), or approximately 20 weeks (±5 days).

[0152] The "administration every 12 to 20 weeks" refers to administration approximately 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks (±5 days) later, preferably approximately 12 to 16 weeks (±5 days), approximately 12 weeks (±5 days), approximately 16 weeks (±5 days), or approximately 20 weeks (±5 days).

[0153] A dose of ≥8 mg includes a dose of approximately 8 mg, or a dose greater than 8 mg, for example, approximately 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg.

[0154] Any dosing frequency specified herein may be expressed in embodiments of the present invention as a specific frequency "±5 days" (for example, where it is stated as "24 weeks", 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.

[0155] "Continuous administration" means that each dose of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) is administered to the target eye at different times, for example, on different days separated by a predetermined interval (e.g., hours, days, weeks, or months). The present invention includes a method comprising administering to the target eye 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 a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), followed by one or more tertiary doses of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), in succession.

[0156] An effective or therapeutically effective dose of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) for treating or preventing intraocular neovascular disease means an 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 subject being treated, either by inducing regression or elimination of such signs and / or symptoms, or by inhibiting the progression of such signs and / or symptoms. In one embodiment of the present invention, an effective or therapeutically effective dose of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) is administered in three doses: approximately ≥8 mg once a month, followed by once every 24 weeks. In one embodiment of the present invention, a reduction in signs and / or symptoms may be achieved, for example, within one year; an improvement of ≥5, 10, or 15 letters in BCVA (compared to baseline) is achieved (e.g., an improvement of ≥5 letters in nAMD subjects and / or an improvement of 8 to 14 letters in DME patients / subjects); a BCVA of ≥69 letters is achieved; the absence of fluid in the fovea is achieved; the central retinal thickness (CRT) is reduced by approximately 150 micrometers or more (e.g., less than 300 micrometers in nAMD subjects / patients and / or reduced by at least approximately 200 micrometers in DR or RVO patients / subjects); or normal CRT is achieved (e.g., less than or equal to approximately 300 micrometers); and / or the absence of leakage on fluorescein angiography is achieved.

[0157] Baseline values ​​refer to the values ​​before treatment initiation (before administration).

[0158] "Intraocular neovascular disease" means any disease within the eye caused by or related to the growth or proliferation of blood vessels, or vascular leakage. Non-limiting examples of intraocular neovascular diseases treatable or preventable using the methods of the present invention include: • Age-related macular degeneration (nAMD) with neovascularization ·Macular edema (ME), Macular edema after retinal vein occlusion (ME-RVO), Retinal vein occlusion (RVO), • Central retinal vein occlusion (CRVO) • Retinal vein branch occlusion (BRVO), ·Diabetic macular edema (DME), ·Choroidal neovascularization (CNV), ·iris neovascularization, Neovascular glaucoma, Postoperative fibrosis in glaucoma, ·New blood vessels on the optic nerve disc, ·Corneal neovascularization, ·Retinal neovascularization, • Vitreous neovascularization, Pannus, ·Pterygium, ·Vascular retinopathy, • Diabetic retinopathy (DR) (e.g., non-proliferative diabetic retinopathy (e.g., characterized by a Diabetic Retinopathy Severity Scale (DRSS) level of approximately 47 or 53) or proliferative diabetic retinopathy, e.g., in subjects not affected by DME), and • Diabetic retinopathy in patients with diabetic macular edema (DME).

[0159] The scope of the present invention includes, for example, any of the methods described herein relating to nAMD, DR and / or DME, and methods described herein relating to intraocular neovascular disease (e.g., ME-RVO).

[0160] The present invention relates to a method for treating an intraocular neovascular disease (e.g., nAMD, DR, and / or DME) in the eye of a subject requiring treatment (preferably by intravitreal injection), comprising administering an initial loading dose (e.g., 2 mg or more, 4 mg or more, or preferably about 8 mg or more of a VEGF antagonist or inhibitor, such as aflibercept or other VEGF receptor fusion protein) (e.g., every 2-4 weeks or 3-5 weeks, preferably every 4 weeks, preferably three initial loading doses), followed by additional doses every 24 weeks, wherein the subject, for example, reaches 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 the start of treatment. • Improvement of, for example, at least 2 or 3 levels on the Diabetic Retinopathy Severity Scale (DRSS), • Improvement of the best corrected vision, • Dry retina, • Achieving the best corrected vision, • Achieving the best corrected visual acuity of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 characters, or ≥ 5, ≥ 10, or ≥ 15 characters. BCVA must be at least 69 characters long. For example, a decrease in central retinal thickness (CRT) by approximately 100, 125, 150, 175, or 200 micrometers. • No vascular leakage as measured by fluorescein angiography (FA). • Improvement in the total score of the National Ophthalmological Institute's Visual Function Questionnaire (NEI-VFQ-25) from baseline before treatment. • The retina does not contain fluid (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF]) in the fovea and central subfield. • Maintenance of the fluid-free retina (total fluid in the fovea and central subfield, IRF and / or SRF) • Loss of macular edema, • Spectrum domain optical coherence tomography (SD-OCT) to remove fluid-free retina, and / or The method provides a way to achieve and / or maintain not deviating from the HDq24 treatment regimen once initiated.

[0161] In embodiments of the present invention, subjects receiving HDq24 treatment for the intraocular neovascular disease described herein (e.g., nAMD, DR, and / or DME) achieve one or more of the following: For example, once the interval between administrations (e.g., between third-line administrations) is started, it will be shortened from the HDq24, HDq12-20 or HDq12 or HDq16 or HDq20 treatment regimen, for example, by 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, and the administration regimen will not be changed. For example, receiving 100% of all planned doses 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. BVCA is non-inferior to aflibercept administered intravitreously as 2 mg approximately every 4 weeks as the first 3, 4, or 5 injections, followed by 2 mg once every 8 weeks or once every 2 months. • The BCVA (according to the ETDRS character score) increases by approximately 7, 8, or 9 characters 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, for example, the baseline BCVA is approximately 61, 62, and 63. • Within 4 weeks of starting treatment, BCVA should improve by approximately 4 or 5 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 or HDq24 regimen, or by approximately 4 or 5 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 or HDq24 regimen. • Within 8 weeks of starting treatment, BCVA should improve by approximately 6 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 or HDq24 regimen, or by approximately 5 or 6 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 or HDq24 regimen. • Within 12 weeks of starting treatment, BCVA should improve by approximately 6 or 7 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 or HDq24 regimen, or by approximately 6 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 or HDq24 regimen. • Within 16 weeks of starting treatment, BCVA should improve by approximately 6 or 7 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 or HDq24 regimen, or by approximately 7 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 or HDq24 regimen. • Within 20 weeks of starting treatment, BCVA should improve by approximately 6 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 or HDq24 regimen, or by approximately 6 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 or HDq24 regimen. • Within 24 weeks of starting treatment, BCVA should improve by approximately 7 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 or HDq24 regimen, or by approximately 5 or 6 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 or HDq24 regimen. • Within 28 weeks of starting treatment, BCVA should improve by approximately 7 or 8 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 or HDq24 regimen, or by approximately 7 or 8 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 or HDq24 regimen. • Within 32 weeks of the start of treatment, BCVA should improve by approximately 7 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 or HDq24 regimen, or by approximately 7 or 8 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 or HDq24 regimen. • Within 36 weeks of the start of treatment, BCVA should improve by 8 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 or HDq24 regimen, or by approximately 6 or 7 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 or HDq24 regimen. • Within 40 weeks of the start of treatment, BCVA should improve by approximately 8 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 or HDq24 regimen, or by approximately 6 or 7 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 or HDq24 regimen. • Within 44 weeks of the start of treatment, BCVA should improve by approximately 8 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 or HDq24 regimen, or by approximately 7 or 8 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 or HDq24 regimen. • Within 48 weeks of the start of treatment, the BCVA should improve by approximately 8 or 9 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 or HDq24 regimen, or by approximately 7 or 8 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 or HDq24 regimen, for example, the baseline BCVA should be approximately 61, 62, or 63 letters (ETDRS or equivalent Snellen visual acuity). • By 60 weeks after the start of treatment, the BCVA should improve by approximately 8 or 9 letters (ETDRS or equivalent Snellen visual acuity) if the patient is receiving the HDq12 or HDq24 regimen, or by approximately 7 or 8 letters (ETDRS or equivalent Snellen visual acuity) if the patient is receiving the HDq16 or HDq24 regimen, for example, the baseline BCVA should be approximately 61, 62, or 63 letters (ETDRS or equivalent Snellen visual acuity). • By 96 weeks after the start of treatment, BCVA should improve by approximately 5 or 6 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq12 or HDq24 regimen, or by approximately 5, 6, or 7 letters (ETDRS or equivalent Snellen visual acuity) if receiving the HDq16 or HDq24 regimen, for example, with a baseline BCVA of approximately 60, 61, 62, or 63 letters (ETDRS or equivalent Snellen visual acuity). • If you are receiving the HDq12 or HDq24 regimen, for example, if your baseline BCVA is approximately 63 or 64, you should expect an improvement of approximately 8 or 9 letters, or up to 40 letters (ETDRS or equivalent Snellen visual acuity) in BCVA between weeks 48 and 60, or if you are receiving the HDq16 or HDq24 regimen, for example, if your baseline BCVA is approximately 61 or 62, you should expect an improvement of approximately 7 or 8 letters, or up to 40 letters (ETDRS or equivalent Snellen visual acuity) in BCVA between weeks 48 and 60. • BCVA should improve by approximately 8 weeks after the start of treatment, and this improvement should be maintained thereafter during the treatment regimen, for example, until at least 48 weeks (e.g., within a range of approximately ±1 or ±2 ETDRS letters or equivalent Snellen visual acuity). • Improvement in best corrected visual acuity (according to the ETDRS letter score) (for example, by weeks 12, 24, 36, 48, 60, 72, 84, 90, or 96 from the start of treatment), • The best corrected visual acuity (BVCA) should improve by the 4th, 8th, 12th, 16th, 20th, 24th, 28th, 32nd, 36th, 40th, 44th, or 48th week from the start of treatment. For example, when measured using the visual acuity chart of the Early Treatment Study for Diabetic Retinopathy (ETDRS) or an equivalent Snellen visual acuity, an increase in BCVA of ≥4, ≥5, ≥6, ≥7, ≥8, ≥9, or ≥10 letters (for example, by weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 from the start of treatment), • Between weeks 36 and 48, the BCVA score changes from approximately 7, 8, or 9 since the start of treatment (according to the ETDRS letter score), and the BCVA is approximately 60 or 70 at any point between weeks 36 and 48. • Between weeks 36 and 48, if receiving the HDq12 or HDq16 regimen, the BCVA score from the start of treatment changes (according to the ETDRS letter score), which is up to 38 letters, for example, the baseline BCVA is approximately 27-79. • Between weeks 48 and 60, the BCVA score changes from approximately 7, 8, or 9 at the start of treatment (according to the ETDRS letter score), and the BCVA at any point between weeks 48 and 60 is approximately 69, 70, 71, 72, or 73. • In patients receiving the HDq12 or HDq24 regimen, if baseline BCVA is approximately ≤73 ETDRS letters, then BCVA should improve by approximately 9 or 10 letters (ETDRS or equivalent Snellen visual acuity) by, for example, 48 weeks after the start of treatment. • In patients receiving the HDq12 or HDq24 regimen, if baseline BCVA is approximately ≥73 ETDRS letters, then BCVA should improve by approximately 5 or 6 letters (ETDRS or equivalent Snellen visual acuity) by, for example, 48 weeks after the start of treatment. • In patients receiving the HDq16 or HDq24 regimen, if baseline BCVA is approximately ≤73 ETDRS letters, then BCVA should improve by approximately 8 or 9 letters (ETDRS or equivalent Snellen visual acuity) by, for example, 48 weeks after the start of treatment. • In patients receiving the HDq16 or HDq24 regimen, if baseline BCVA is approximately ≥73 ETDRS letters, then BCVA should improve by approximately 4 or 5 letters (ETDRS or equivalent Snellen visual acuity) by, for example, 48 weeks after the start of treatment. • In patients receiving the HDq12 or HDq24 regimen, with a baseline CRT of <approximately 400 micrometers, BCVA should improve by approximately 7 or 8 letters (ETDRS or equivalent Snellen visual acuity) by, for example, 48 weeks after the start of treatment. • In patients receiving the HDq12 or HDq24 regimen, with a baseline CRT of ≥400 micrometers, BCVA should improve by approximately 9 or 10 letters (ETDRS or equivalent Snellen visual acuity) by, for example, 48 weeks after the start of treatment. • In patients receiving the HDq16 or HDq24 regimen, with a baseline CRT of <approximately 400 micrometers, BCVA should improve by approximately 5 or 6 letters (ETDRS or equivalent Snellen visual acuity) by, for example, 48 weeks after the start of treatment. • In patients receiving the HDq16 or HDq24 regimen, with a baseline CRT of ≥ approximately 400 micrometers, BCVA should improve by approximately 9 or 10 letters (ETDRS or equivalent Snellen visual acuity) by, for example, 48 weeks after the start of treatment. • No loss of 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 the ETDRS letter score). 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, you must acquire at least 5, 10, or 15 characters (according to the ETDRS character score). • No loss of 5, 10, 15, or 69 or more BCVA characters (for example, 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 the start of treatment). Between 48 and 60 weeks, the BCVA score (according to the ETDRS letter score) should be approximately 69, 70, 71, 72, or 73. • The BCVA (according to the ETDRS character score) should be at least approximately 69 characters by, for example, week 48 or week 60. • Within 4 weeks of the start of treatment, if the BCVA is receiving the HDq12 or HDq24 regimen, the BCVA should have approximately 68 letters (ETDRS or equivalent Snellen visual acuity), or if the BCVA is receiving the HDq24 or HDq16 regimen, the BCVA should have approximately 66 letters (ETDRS or equivalent Snellen visual acuity). • Within 8 weeks of the start of treatment, if the BCVA is receiving the HDq12 or HDq24 regimen, the BCVA should have approximately 70 letters (ETDRS or equivalent Snellen visual acuity), or if the BCVA is receiving the HDq16 or HDq24 regimen, the BCVA should have approximately 67 letters (ETDRS or equivalent Snellen visual acuity). • Within 12 weeks of the start of treatment, if the BCVA is receiving the HDq12 or HDq24 regimen, the BCVA should have approximately 70 letters (ETDRS or equivalent Snellen visual acuity), or if the BCVA is receiving the HDq16 or HDq24 regimen, the BCVA should have approximately 68 letters (ETDRS or equivalent Snellen visual acuity). • Within 16 weeks of the start of treatment, if the BCVA is receiving the HDq12 or HDq24 regimen, the BCVA should have approximately 71 letters (ETDRS or equivalent Snellen visual acuity), or if the BCVA is receiving the HDq16 or HDq24 regimen, the BCVA should have approximately 69 letters (ETDRS or equivalent Snellen visual acuity). • Within 20 weeks of the start of treatment, if the BCVA is receiving the HDq12 or HDq24 regimen, the BCVA should have approximately 70 letters (ETDRS or equivalent Snellen visual acuity), or if the BCVA is receiving the HDq16 or HDq24 regimen, the BCVA should have approximately 68 letters (ETDRS or equivalent Snellen visual acuity). • Within 24 weeks of the start of treatment, if the BCVA is receiving the HDq12 or HDq24 regimen, the BCVA should have approximately 71 letters (ETDRS or equivalent Snellen visual acuity), or if the BCVA is receiving the HDq16 or HDq24 regimen, the BCVA should have approximately 67 letters (ETDRS or equivalent Snellen visual acuity). • Within 28 weeks of the start of treatment, if BCVA is receiving the HDq12 or HDq24 regimen, the BCVA should have approximately 72 letters (ETDRS or equivalent Snellen visual acuity), or if BCVA is receiving the HDq16 or HDq24 regimen, the BCVA should have approximately 70 letters (ETDRS or equivalent Snellen visual acuity). • Within 32 weeks of the start of treatment, if the BCVA is receiving the HDq12 or HDq24 regimen, the BCVA should have approximately 71 letters (ETDRS or equivalent Snellen visual acuity), or if the BCVA is receiving the HDq16 or HDq24 regimen, the BCVA should have approximately 70 letters (ETDRS or equivalent Snellen visual acuity). • Within 36 weeks of the start of treatment, if the BCVA is receiving the HDq12 or HDq24 regimen, the BCVA should have approximately 71 letters (ETDRS or equivalent Snellen visual acuity), or if the BCVA is receiving the HDq16 or HDq24 regimen, the BCVA should have approximately 68 letters (ETDRS or equivalent Snellen visual acuity). • Within 40 weeks of the start of treatment, if the BCVA is receiving the HDq12 or HDq24 regimen, the BCVA should have approximately 72 letters (ETDRS or equivalent Snellen visual acuity), or if the BCVA is receiving the HDq16 or HDq24 regimen, the BCVA should have approximately 69 letters (ETDRS or equivalent Snellen visual acuity). • Within 44 weeks of the start of treatment, if BCVA is receiving the HDq12 or HDq24 regimen, the BCVA should have approximately 72 letters (ETDRS or equivalent Snellen visual acuity), or if BCVA is receiving the HDq16 or HDq24 regimen, the BCVA should have approximately 70 letters (ETDRS or equivalent Snellen visual acuity). • Within 48 weeks of the start of treatment, if BCVA is receiving the HDq12 or HDq24 regimen, the BCVA should have approximately 73 letters (ETDRS or equivalent Snellen visual acuity), or if BCVA is receiving the HDq16 or HDq24 regimen, the BCVA should have approximately 70 letters (ETDRS or equivalent Snellen visual acuity). • Within 96 weeks of the start of treatment, if BCVA is receiving the HDq12 or HDq24 regimen, the BCVA should have approximately 66, 67, 68, 69, or 70 letters (ETDRS or equivalent Snellen visual acuity), or if BCVA is receiving the HDq16 or HDq24 regimen, the BCVA should have approximately 66, 67, 68, 69, or 70 letters (ETDRS or equivalent Snellen visual acuity). • Between weeks 36 and 48, if receiving the HDq12 or HDq24 regimen, for example, if the baseline BCVA is approximately 57, 58, 59, 60, 61, 62, 63, or 64, the BCVA should be approximately 71, 72, 73, or 74 (ETDRS or equivalent Snellen visual acuity), or between weeks 36 and 48, if receiving the HDq16 or HDq24 regimen, for example, if the baseline BCVA is approximately 55, 56, 57, 58, 59, 60, 61, or 62, the BCVA should be approximately 69, 70, 71, 72, or 73 (ETDRS or equivalent Snellen visual acuity), • If you are receiving an HDq12 or HDq24 regimen, for example, if your baseline BCVA is approximately 63 or 64, then between weeks 48 and 60, your BCVA should be approximately 69 or 70, or up to 94 (ETDRS or equivalent Snellen visual acuity), or if you are receiving an HDq16 or HDq24 regimen, for example, if your baseline BCVA is approximately 61 or 62, then between weeks 48 and 60, your BCVA should be approximately 72 or 73 letters, or up to 89 (ETDRS or equivalent Snellen visual acuity), • Achieving a BCVA of ≥5, ≥10, or ≥15 letters (according to the ETDRS letter score) (for example, by weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, or 96 from the start of treatment). • Improvement of ≥2 stages on the Diabetic Retinopathy Severity Scale (DRSS) (for example, by weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 72, 84, 90, or 96 from the start of treatment), • Improvement of ≥3 stages on the Diabetic Retinopathy Severity Scale (DRSS) (for example, by weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 72, 84, 90, or 96 from the start of treatment), • The retina in the fovea or central subfield must not contain fluid (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF]) (e.g., by weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, or 96 from the start of treatment) (e.g., measured by optical coherence tomography (OCT)). • No intraretinal vascular leakage as measured by fluorescein angiography (FA) (e.g., from the start of treatment until weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, or 96). • Maintenance of fluid-free retina (total fluid in the fovea and central subfield, IRF and / or SRF) (e.g., by weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92 or 96 from the start of treatment), • At week 48 or week 60, the ETDRS grid (mm 2 The total area of ​​fluorescein leakage within the container is approximately 12, 12.6, 13, 13.6, 13.9, or 14 mm². 2 Above, or a maximum of approximately 57 or 68 mm 2 To reduce (for example, as measured by fluorescein angiography), • At week 48, ETDRS grid (mm 2 The total area of ​​fluorescein leakage within the ) is approximately 13, 13.3, 13.9, or 14 mm² when receiving the HDq12 or HDq24 regimen. 2 (For example, a maximum of approximately 52mm) 2 ) reducing (for example, as measured by fluorescein angiography), • At week 48, ETDRS grid (mm 2 The total area of ​​fluorescein leakage within the fluorescein area is approximately 7, 7.7, 8, 9, 9.4, or 10 mm² when the HDq16 or HDq24 regimen is being administered. 2 (For example, a maximum of approximately 55mm) 2 ) reducing (for example, as measured by fluorescein angiography), • Spectrum domain optical coherence tomography (SD-OCT) confirms that the retina is free of fluid (by weeks 12, 24, 36, 48, 60, 72, 84, 90, or 96 from the start of treatment). • The retina in the fovea should not contain fluid (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF]) (for example, by weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 from the start of treatment). • Dry retina (for example, within 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 from the start of treatment), • Fovea without fluid (e.g., by weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, or 96 from the start of treatment) (e.g., measured by optical coherence tomography (OCT)), • Within 4 weeks of starting treatment, if receiving the HDq12 or HDq24 regimen, a change in central retinal thickness of approximately -118 or -118.3 micrometers (±17, 18, or 19 micrometers), or if receiving the HDq16 or HDq24 regimen, a change of approximately -124 or -125 or -124.9 or -125.5 micrometers (±17, 18, or 19 micrometers), • Within 8 weeks of starting treatment, if receiving the HDq12 or HDq24 regimen, a change in central retinal thickness of approximately -137 or -137.4 micrometers (±17, 18, or 19 micrometers), or if receiving the HDq16 or HDq24 regimen, a change of approximately -139 or -140 or -139.6 or -140.3 micrometers (±17, 18, or 19 micrometers), • Within 12 weeks of starting treatment, a change in central retinal thickness of approximately -150 or -150.1 micrometers (±17, 18, or 19 micrometers) if receiving the HDq12 or HDq24 regimen, or approximately -152 or -153 or -152.7 or -153.4 micrometers (±17, 18, or 19 micrometers) if receiving the HDq16 or HDq24 regimen. • Within 16 weeks of starting treatment, if receiving the HDq12 or HDq24 regimen, a change in central retinal thickness of approximately -139 or -139.4 micrometers (±17, 18, or 19 micrometers), or if receiving the HDq16 or HDq24 regimen, a change of approximately -145 or -146 or -145.5 or -146.4 micrometers (±17, 18, or 19 micrometers), • Within 20 weeks of starting treatment, a change in central retinal thickness of approximately -117 or -117.1 micrometers (±17, 18, or 19 micrometers) if receiving the HDq12 or HDq24 regimen, or approximately -112 or -113 or -112.5 or -113.3 micrometers (±17, 18, or 19 micrometers) if receiving the HDq16 or HDq24 regimen. • Within 24 weeks of starting treatment, a change in central retinal thickness of approximately -158 or -158.1 micrometers (±17, 18, or 19 micrometers) if receiving the HDq12 or HDq24 regimen, or approximately -103 or -104 or -103.8 or -104.3 micrometers (±17, 18, or 19 micrometers) if receiving the HDq16 or HDq24 regimen. • Within 28 weeks of the start of treatment, a change in central retinal thickness of approximately -146, -147, or -146.7 micrometers (±17, 18, or 19 micrometers) if receiving the HDq12 or HDq24 regimen, or approximately -162 or -162.3 micrometers (±17, 18, or 19 micrometers) if receiving the HDq16 or HDq24 regimen. • Within 32 weeks of starting treatment, a change in central retinal thickness of approximately -132 micrometers (±17, 18, or 19 micrometers) if receiving the HDq12 or HDq24 regimen, or approximately -145, -146, or -145.8 micrometers (±17, 18, or 19 micrometers) if receiving the HDq16 or HDq24 regimen. • Within 36 weeks of the start of treatment, a change in central retinal thickness of approximately -168 or -168.1 micrometers (±17, 18, or 19 micrometers) if receiving the HDq12 or HDq24 regimen, or approximately -124 or -125 or -124.7 or -125.2 micrometers (±17, 18, o...

Claims

1. - In subjects requiring treatment or prevention of intraocular neovascular disease, age-related macular degeneration with neovascularization (nAMD), diabetic retinopathy (DR), and / or diabetic macular edema (DME), for the purpose of providing said treatment or prevention, - In subjects with nAMD, DR, and / or DME who require improvement of their best corrected visual acuity, for the purpose of performing such improvement, - A method for promoting retinal dryness in subjects with intraocular neovascular disease, nAMD, DR and / or DME, which require such promotion. A method comprising administering to the aforementioned target eye at least once every 8 to 24, 12 to 24, 16 to 24, 20 to 24, 21 to 24, 21, 22, 23, or 24 weeks a year, using a VEGF receptor fusion protein.

2. - A method for providing treatment or prevention to subjects in need of treatment or prevention of intraocular neovascular disease, age-related macular degeneration with neovascularization (nAMD), diabetic retinopathy (DR), and / or diabetic macular edema (DME), wherein the eye of the subject A single initial dose of approximately 8 mg (±0.8 mg) or more of VEGF receptor fusion protein, followed by One or more secondary doses of approximately 8 mg or more of VEGF receptor fusion protein, followed by This includes administering approximately 8 mg or more of VEGF receptor fusion protein as a third dose, Each secondary dose is administered approximately 2, 3, 4, or 2-4 weeks after the immediately preceding dose. The method according to claim 1, wherein each third dose is administered approximately 8 to 24, 12 to 24, 16 to 24, 20 to 24, 21 to 24, 21, 22, 23, or 24 weeks after the most recent dose.

3. A method for providing treatment or prevention to a subject in need of treatment or prevention of intraocular neovascular disease, age-related macular degeneration with neovascularization (nAMD), diabetic retinopathy (DR), and / or diabetic macular edema (DME), wherein the eye of the subject A single initial dose of approximately 8 mg (±0.8 mg) or more of VEGF receptor fusion protein, followed by Two secondary doses of approximately 8 mg (±0.8 mg) or more of VEGF receptor fusion protein, followed by This includes administering approximately 8 mg (±0.8 mg) or more of VEGF receptor fusion protein as a third-line dose, Each secondary dose is administered approximately four weeks after the previous dose. The method according to any one of claims 1 to 2, wherein each third dose is administered approximately 8 to 24, 12 to 24, 16 to 24, 20 to 24, 21 to 24, 21, 22, 23, or 24 weeks after the most recent dose.

4. A method for treating or preventing intraocular neovascular disease, age-related macular degeneration with neovascularization (nAMD), diabetic retinopathy and / or diabetic macular edema in subjects requiring such treatment or prevention, comprising administering a formulation containing approximately 114.3 mg / ml of VEGF receptor fusion protein to the eye of the subject, approximately three doses of approximately 8 mg (±0.8 mg) of VEGF receptor fusion protein, at intervals of approximately four weeks, and, after the three doses, administering one or more doses of VEGF receptor fusion protein at intervals extended up to approximately 24 weeks.

5. A method for slowing the clearance of free aflibercept from the ocular compartment after intravitreal injection of 2 mg or ≤4 mg of aflibercept, compared to the rate of clearance of aflibercept from the ocular compartment after intravitreal injection of aflibercept, To the eyes of the target that needs it, A single initial dose of aflibercept of approximately 8 mg (±0.8 mg) or more, followed by Aflibercept administered as a secondary dose of approximately 8 mg (±0.8 mg) or more, followed by This includes intravitreal injection of approximately 8 mg (±0.8 mg) or more of aflibercept as a third-line dose, Each secondary dose is administered approximately 2 to 4 weeks after the previous dose. Each third dose is administered approximately 8–24, 12–24, 16–24, 20–24, 21–24, 21, 22, 23, or 24 weeks after the most recent dose.

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

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

8. A method for increasing the duration of efficacy and / or the time it takes for the amount of free aflibercept to reach the lower limit of quantification (LLOQ) in the target ocular compartment after intravitreal injection of aflibercept, compared to the time it takes for the amount of free aflibercept in the target ocular compartment to reach the LLOQ after intravitreal injection of aflibercept, wherein the method is administered to the target eye as required. A single initial dose of aflibercept of approximately 8 mg (±0.8 mg) or more, followed by Aflibercept administered as a secondary dose of approximately 8 mg (±0.8 mg) or more, followed by This includes intravitreal injection of approximately 8 mg (±0.8 mg) or more of aflibercept as a third-line dose, Each secondary dose is administered approximately 2 to 4 weeks after the previous dose. Each third dose is administered approximately 8–24, 12–24, 16–24, 20–24, 21–24, 21, 22, 23, or 24 weeks after the most recent dose.

9. The method according to any one of claims 1 to 8, wherein the duration of efficacy and / or the time it takes for the amount of free aflibercept to reach the lower limit of quantification (LLOQ) in the target ocular compartment after intravitreal injection of aflibercept is increased by about 5 or 6 weeks compared to the time it takes for the amount of free aflibercept in the target ocular compartment to reach LLOQ after intravitreal injection of about 2 mg or ≤4 mg of aflibercept.

10. The method according to any one of claims 1 to 9, wherein the time it takes for the amount of free aflibercept in the target ocular compartment to reach the lower limit of quantification (LLOQ) after intravitreal injection of aflibercept is increased by approximately 1, 2, 1.2, or 1.3 weeks or more compared to the time it takes for the amount of free aflibercept in the target ocular compartment to reach LLOQ after intravitreal injection of approximately 2 mg or ≤4 mg of aflibercept.

11. The method according to any one of claims 1 to 10, wherein the time it takes for the amount of free aflibercept in the target ocular compartment to reach the lower limit of quantification (LLOQ) after intravitreal injection of ≥8 mg (±0.8 mg) of aflibercept is approximately 15 weeks.

12. The method according to any one of claims 1 to 11, wherein the time to reach the lower limit of quantification (LLOQ) of the amount of free aflibercept in the target ocular compartment after intravitreal injection of ≥8 mg (±0.8 mg) of aflibercept is longer than approximately 8, 8.7, 8.71, 9, 9.2, 9.21, or 10 weeks.

13. A method for increasing the time it takes for free aflibercept in the target plasma to reach the lower limit of quantification (LLOQ) after intravitreal injection of aflibercept, compared to the time it takes for free aflibercept in the target plasma to reach LLOQ after intravitreal injection of approximately 2 mg or ≤4 mg of aflibercept, wherein the method is applied to the eye of the target in question. A single initial dose of aflibercept of approximately 8 mg (±0.8 mg) or more, followed by Aflibercept administered as a secondary dose of approximately 8 mg (±0.8 mg) or more, followed by This includes intravitreal injection of approximately 8 mg (±0.8 mg) or more of aflibercept as a third-line dose, Each secondary dose is administered approximately 2 to 4 weeks after the previous dose. Each third dose is administered approximately 8–24, 12–24, 16–24, 20–24, 21–24, 21, 22, 23, or 24 weeks after the most recent dose.

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

15. The method according to any one of claims 1 to 14, wherein the time it takes for free aflibercept in the plasma of a subject to reach the lower limit of quantification (LLOQ) after intravitreal injection of aflibercept is increased by about two weeks compared to the time it takes for free aflibercept in the plasma of a subject to reach LLOQ after intravitreal injection of about 2 mg of aflibercept.

16. The method according to any one of claims 1 to 15, wherein the time it takes for free aflibercept in the target plasma to reach the lower limit of quantification (LLOQ) after intravitreal injection of ≥8 mg (±0.8 mg) of aflibercept is approximately 3, 3.5, 3.8, or 4 weeks.

17. The method according to any one of claims 1 to 16, wherein the time it takes for free aflibercept in the target plasma to reach the lower limit of quantification (LLOQ) after intravitreal injection of ≥8 mg (±0.8 mg) of aflibercept is longer than approximately 1.5 or 1.6 weeks.

18. The method according to any one of claims 5 to 17, wherein ≤4 mg is approximately 2 mg or 2 to 4 mg.

19. The method according to any one of claims 13 to 18, wherein the subject suffers from an intraocular neovascular disease, age-related macular degeneration with neovascularization, diabetic retinopathy, and / or diabetic macular edema.

20. The method according to any one of claims 1 to 19, wherein ≥ 8 mg (±0.8 mg) of aflibercept is present in an aqueous pharmaceutical preparation containing a histidine buffer.

21. The method according to any one of claims 1 to 20, wherein ≥ 8 mg (±0.8 mg) of aflibercept is present in an aqueous pharmaceutical preparation containing arginine.

22. The method according to any one of claims 1 to 21, wherein ≥ 8 mg (±0.8 mg) of aflibercept is present in an aqueous pharmaceutical preparation having a pH of approximately 5.

8.

23. The method according to any one of claims 1 to 22, wherein ≥ 8 mg (±0.8 mg) of aflibercept is present in an aqueous pharmaceutical preparation containing a sugar or a polyol.

24. The method according to any one of claims 1 to 23, wherein ≥ 8 mg (±0.8 mg) of aflibercept is present in an aqueous pharmaceutical preparation containing sucrose.

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

26. The method according to any one of claims 1 to 25, wherein ≥8 mg (±0.8 mg) of aflibercept is present in an aqueous pharmaceutical preparation comprising an aqueous pharmaceutical preparation, the aqueous pharmaceutical preparation comprising at least about 100 mg / ml of a VEGF receptor fusion protein containing two polypeptides each comprising the second immunoglobin-like (Ig) domain of VEGFR1, the third Ig domain of VEGFR2, and a polymer-forming component, about 10 to 100 mM of L-arginine, sucrose, a histidine-based buffer, and a surfactant, the aqueous pharmaceutical preparation having a pH of about 5.0 to about 6.8, and the VEGF receptor fusion protein having less than about 3.5% of high molecular weight molecular species immediately after production and purification, and / or about 6% or less of high molecular weight molecular species after storage at about 2 to 8°C for about 24 months.

27. - In subjects requiring treatment or prevention of intraocular neovascular disease, age-related macular degeneration with neovascularization (nAMD), diabetic retinopathy (DR), and / or diabetic macular edema (DME), for the purpose of providing said treatment or prevention, - In subjects with nAMD, DR, and / or DME who require improvement of their best corrected visual acuity, for the purpose of performing such improvement, - A method for promoting retinal dryness in subjects with intraocular neovascular disease, nAMD, DR and / or DME, which require such promotion. In the eye of the aforementioned subject, A single initial dose of approximately 8 mg (±0.8 mg) or more of VEGF receptor fusion protein, followed by One or more secondary doses of approximately 8 mg (±0.8 mg) or more of VEGF receptor fusion protein, followed by This involves administering approximately 8 mg (±0.8 mg) or more of VEGF receptor fusion protein as a third dose, Each secondary dose is administered approximately 2, 3, 4, or 2-4 weeks after the immediately preceding dose. Each third dose is administered approximately 8 to 23, 20, 21, 22, or 23 weeks after the most recent dose, and the subject is:

1. Loss of 5 letters in BCVA, 2. CRT is <300 μm or <320 μm, 3. The OCT shows no liquid in the central subfield, and / or 4. If there is no new onset of foveal hemorrhage or foveal neovascularization, A method that includes extending the interval between third doses by more than one week.

28. The method according to claim 27, wherein the interval between the third doses has been extended at least once so far.

29. The interval between the aforementioned third doses has occurred at least once so far. Over 24 weeks, Or, From 8 weeks to 12, 16, or 20 weeks, 12 weeks to 16 or 20 weeks, and / or The method according to claims 27-28, extended to 16 to 20 weeks.

30. The method according to any one of claims 27 to 29, wherein extending the interval between the third doses by one week or more means extending the interval between the third doses by one or more increments of four weeks.

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

32. The method according to claim 31, wherein the aforementioned 8 to 23 weeks is 20 weeks.

33. The interval between the third doses is such that the subject is 1. Loss of the first 5 letters of BCVA, and 2. The method according to any one of claims 27 to 32, which is extended when the CRT exhibits a width of <300 μm or <320 μm.

34. The method according to claim 33, wherein the subject has DR and / or DME.

35. The interval between the third doses is such that the subject is 1. Loss of the first 5 letters of BCVA, and 2. There is no liquid in the central subfield, and 3. The method according to any one of claims 27 to 32, which is extended in cases where there is no newly occurring foveal hemorrhage or foveal neovascularization.

36. The method according to claim 35, wherein the subject has nAMD.

37. - Loss of <5 letters in BCVA refers to the loss of <5 letters in BCVA starting from week 12 of treatment. • CRTs with a diameter of <300 μm or <320 μm are derived from SD-OCT. • The <300 μm CRT is from Cirrus SD-OCT. • CRTs <320 μm are from Spectralis SD-OCT and / or The method according to any one of claims 27 to 36, wherein the absence of liquid in the central subfield is on the OCT.

38. - In subjects requiring treatment or prevention of intraocular neovascular disease, age-related macular degeneration with neovascularization (nAMD), diabetic retinopathy (DR), and / or diabetic macular edema (DME), for the purpose of providing said treatment or prevention, - In subjects with nAMD, DR, and / or DME who require improvement of their best corrected visual acuity, for the purpose of performing such improvement, - A method for promoting retinal dryness in subjects with intraocular neovascular disease, nAMD, DR and / or DME, which require such promotion. In the eye of the aforementioned subject, A single initial dose of approximately 8 mg (±0.8 mg) or more of VEGF receptor fusion protein, followed by One or more secondary doses of approximately 8 mg (±0.8 mg) or more of VEGF receptor fusion protein, followed by This includes administering approximately 8 mg (±0.8 mg) or more of VEGF receptor fusion protein as a third-line dose, Each secondary dose is administered approximately 2 to 4 weeks after the previous dose. Each third dose is administered approximately 8–24, 12–24, 16–24, 20–24, 21–24, 21, 22, 23, or 24 weeks after the most recent dose, and the subject is 1. Loss of >5 or >10 characters in BCVA, 2. An increase of >25 μm or >50 μm in central retinal thickness (CRT), 3. Novel foveal hemorrhage, 4. Novel foveal neovascularization, and / or 5. If DME persists or worsens, A method that includes shortening the interval between third doses by more than one week.

39. The method according to claim 38, wherein shortening the interval between the third doses by one week or more means shortening the interval between the third doses by one or more increments of four weeks.

40. The interval between the third doses is such that the subject is 1. In association with the persistence or worsening of DME, BCVA is >10 letter loss, and 2. The method according to any one of claims 38 to 39, wherein if the CRT shows an increase of >50 μm, the CRT is shortened.

41. The method according to claim 40, wherein the subject has DR and / or DME.

42. The interval between the third doses is such that the subject is 1. Loss of >5 letters in BCVA, and 2. The method according to any one of claims 38 to 39, which extends the central retinal thickness (CRT) when it is increased by >25 μm, or when there is a new foveal hemorrhage or new foveal neovascularization.

43. The method according to claim 42, wherein the object has nAMD.

44. - Loss of >10 letters in BCVA in association with the persistence or worsening of DME means that the loss of >10 letters in BCVA occurs from week 12 of treatment initiation or 4 weeks after the last second dose in association with the persistence or worsening of DME. • The increase in CRT >50 μm occurred from the 12th week after the start of treatment. The loss of the >5 letters in BCVA occurred from the 12th week after the start of treatment. The method according to any one of claims 38 to 43, wherein the increase in central retinal thickness (CRT) by >25 μm, or a new foveal hemorrhage, or a new foveal neovascularization occurs from the 12th week after the start of treatment.

45. By the 96th week from the start of treatment, the aforementioned subjects - Improvement of BCVA of approximately 6, 7, 8, or 9 characters. - Improvement of BCVA with 39, 40, 41, 42, 43, 44, 45, 46, or 47 characters. - BCVA must not lose 5 or more characters, 10 or more characters, or 15 or more characters. - BCVA must be approximately 65, 66, 67, 68, 69, 70, 71, 72, or 73 characters long. - BCVA must have 5 or more characters, 10 or more characters, or 15 or more characters. - Improvement of DRSS by two or more levels. - A decrease of approximately 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, and 194 micrometers in CRT. - Between weeks 48 and 96 of treatment, further improvement or maintenance of BCVA improvement from baseline by ±1 or 2 letters. - Between weeks 48 and 96 of treatment, maintain BCVA or approximately 66±2 letters. - Maintenance of the fluid-free central retinal subfield between weeks 48 and 96 of treatment. CRTs of approximately 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 weeks 48 and 96 of treatment, a further decrease or maintenance of central subfield thickness from baseline of ±1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 micrometers, or a decrease in central retinal thickness, No IRF, - No SRF, - No IRF, and no SRF, - No significant change in intraocular pressure. - No significant change in systolic blood pressure, and / or The method according to any one of claims 1 to 44, wherein one or more of the following are observed: - No significant change in diastolic blood pressure.

46. The method according to claim 45, wherein the subject has DR and / or DME.

47. By the 96th week from the start of treatment, the aforementioned subjects - Improvement of BCVA of approximately 5, 6, or 7 characters. - Improvement of BCVA with 43, 44, 45, 46, 47, or 48 characters. ・BCVA must be 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 characters long. - BCVA must not lose 5 or more characters, 10 or more characters, or 15 or more characters. - BCVA must have 5 or more characters, 10 or more characters, or 15 or more characters. - Improvement of DRSS by two or more levels. • Approximately 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;9 4; 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;1 58; 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; 1 89; 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; 22 0; 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;A decrease in CRT of 283; 284; 285; 286; 287; 288; 289; 290; 291; 292; 293, or 294 micrometers; - CRT is approximately 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; 1 88; 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; 22 2;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;25 6;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. Approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mm ２ The decrease in choroidal neovascularization size, - Choroidal neovascularization size is approximately 0, 1, 2, or 3 mm. ２ Being - No leakage should be observed on fluorescein angiography. - Total lesion size is approximately 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 mm ２ Being Approximately 0, 0.1, 0.2, or 0.3 mm ２ Reduction in total lesion size, - The total score of the NEI-VFQ-25 is approximately 80. - The change in the total NEI-VFQ-25 score from baseline is approximately 2 or 3. No IRF, - No SRF, - No IRF, and no SRF, - No significant change in intraocular pressure before administration. - No significant change in systolic blood pressure, and / or The method according to any one of claims 1 to 46, wherein one or more of the following are observed: - No significant change in diastolic blood pressure.

48. The method according to claim 47, wherein the subject has nAMD.

49. Eye infection, or periorbital infection, Active intraocular inflammation, and / or Subjects who have one or more of the following hypersensitivity conditions: The method according to any one of claims 1 to 48, wherein administration of a VEGF receptor fusion protein to the eye is excluded.

50. The target is Eye infection, or periorbital infection, Active intraocular inflammation, and / or Steps for evaluating hypersensitivity, The method according to claim 49, further comprising the step of excluding any one or more of the subjects from the administration if any of the subjects are found.

51. The method according to any one of claims 49 to 50, further comprising monitoring the subject during the treatment or prevention of conjunctival hemorrhage, cataract, vitreous detachment, vitreous floaters, corneal epithelial defects, and / or elevated intraocular pressure.

52. Before each dose, packaged together, A single-dose glass vial with a protective plastic cap and stopper contains an aqueous formulation containing approximately 70 microliters of 8 mg (±0.8 mg) of VEGF receptor fusion protein, - A single 18-gauge x 1.5-inch, 5-micron filter needle including the tip and beveled end, - One 30 gauge x 0.5 inch hypodermic needle, To provide a 1-mL Luer lock syringe having a graduated line marking a volume of 70 microliters, Next, (1) Visually inspect the aqueous formulation in the vial, and if particles, turbidity, or discoloration are observed, then use another vial of the aqueous formulation containing the VEGF receptor fusion protein. (2) Remove the protective plastic cap from the vial, (3) Clean the top of the vial with an alcohol wipe, and then, By using aseptic techniques, (4) Remove the 18 gauge x 1.5 inch, 5 micron filter needle and the 1 mL syringe from their packaging, (5) Attaching the filter needle to the syringe by twisting it onto the tip of the Luer lock syringe, (6) Push the filter needle into the center of the vial stopper until the needle is fully inserted into the vial and the tip of the needle contacts the bottom or bottom edge of the vial, (7) With the vial upright and slightly tilted, while ensuring that the angled end of the filter needle is immersed in the liquid, the contents of the VEGF receptor fusion protein vial are drawn into the syringe, (8) During withdrawal, tilt the vial so that the angled end of the filter needle remains immersed in the formulation, (9) When emptying the vial to completely empty the filter needle, fully retract the plunger rod, (10) Remove the filter needle from the syringe and discard the filter needle, (11) Remove the 30 gauge x 0.5 inch injection needle from its packaging and attach the injection needle to the syringe by screwing it firmly onto the tip of the Luer lock syringe, (12) Hold the syringe with the needle pointing upwards and check for air bubbles in the syringe; if air bubbles are present, gently flick the syringe with your finger until the bubbles rise to the top. (13) The method according to any one of claims 1 to 51, comprising slowly pushing the plunger so that the tip of the plunger aligns with a mark on the syringe indicating 70 microliters.

53. The method according to any one of claims 1 to 52, wherein the injection of the VEGF receptor fusion protein is performed under controlled sterile conditions, which include surgical hand disinfection, as well as the use of sterile gloves, sterile drapes, and sterile eyelid retractors (or equivalents), and an anesthetic and a topical broad-spectrum antimicrobial eye drop is administered prior to the injection.

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

2.

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

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

2. (ii) comprising the second immunoglobin-like (Ig) domain of VEGFR1, the third Ig domain of VEGFR2, and two polypeptides containing a polymerizing component, (iii) comprising two polypeptides containing the second immunoglobin-like (Ig) domain of VEGFR1, the third Ig domain of VEGFR2, the fourth Ig domain of VEGFR2 and a polymerizing component, or (iv) The method according to any one of claims 1 to 53, comprising two VEGFR1R2-FcΔC1(a) polypeptides encoded by the nucleic acid sequence of Sequence ID No.

1.

57. The method according to claims 1 to 53, wherein the VEGF receptor fusion protein comprises a second immunoglobin-like (Ig) domain of VEGFR1, a third Ig domain of VEGFR2, and two polypeptides comprising a polymerizing component.

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

59. The method according to any one of claims 1 to 58, wherein the VEGF receptor fusion protein is present in an aqueous pharmaceutical formulation containing approximately 114.3 mg / ml of VEGF receptor fusion protein.

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

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

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

63. The method according to any one of claims 1 to 62, wherein the VEGF receptor fusion protein is injected intravitreously using a 30-gauge x 0.5-inch sterile injection needle.

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

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

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

67. 2 mg of VEGF receptor fusion protein, The method according to claims 5 to 26 or 64 to 66, wherein the aqueous pharmaceutical formulation contains 40 mg / ml of VEGF receptor fusion protein, 10 mM sodium phosphate, 40 mM NaCl, 0.03% polysorbate 20, and 5% sucrose, and has a pH of 6.

2.

68. The method according to any one of claims 1 to 67, wherein ≥8 mg (±0.8 mg) of VEGF receptor fusion protein is present in an aqueous pharmaceutical formulation containing a sugar or a polyol.

69. The method according to any one of claims 1 to 68, wherein ≥8 mg (±0.8 mg) of VEGF receptor fusion protein is present in an aqueous pharmaceutical formulation containing sucrose.

70. The method according to any one of claims 1 to 69, wherein ≥8 mg (±0.8 mg) of VEGF receptor fusion protein is present in an aqueous pharmaceutical formulation having a pH of approximately 5.

8.

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

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

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

74. ≥8 mg of VEGF receptor fusion protein, At least approximately 100 mg / ml of VEGF receptor fusion protein, Approximately 10-100 mM L-arginine, Sucrose and, Histidine-based buffer and It is contained in an aqueous pharmaceutical formulation containing a surfactant, The method according to any one of claims 1 to 73, wherein the aqueous pharmaceutical preparation has a pH of about 5.0 to about 6.8, and the VEGF receptor fusion protein has less than 3.5% of high molecular weight molecular species immediately after production and purification, and / or less than 6% of high molecular weight molecular species after storage at about 2 to 8°C for about 24 months.

75. The aqueous pharmaceutical preparation contains approximately ≥8 mg (±0.8 mg) of VEGF receptor fusion protein, and the aqueous pharmaceutical preparation is • Contains ≥100 mg / ml of VEGF receptor fusion protein, histidine-based buffer, and L-arginine, - Contains 140 mg / ml aflibercept, 20 mM histidine buffer, 5% sucrose, 0.03% polysorbate 20, 10 mM L-arginine, pH 5.8, - Contains 150 ± 15 mg / ml aflibercept, 10 mM phosphate buffer, 8 ± 0.8% (w / v) sucrose, 0.02–0.04% (w / v) polysorbate 20 and 50 mM L-arginine, pH 5.9–6.5, - Contains 103-126 mg / ml of 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, - Contains 140 mg / ml aflibercept, 10 mM histidine buffer, 2.5% (w / v) sucrose, 2.0% (w / v) proline, 0.03% (w / v) polysorbate 20, and 50 mM L-arginine, pH 5.8, - Contains 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, • Contains aflibercept, histidine-based buffer, and L-arginine at a concentration of ≥100 mg / ml, - Aflibercept in an aqueous pharmaceutical formulation having a pH of approximately 5.8 and containing ≥100 mg / ml of aflibercept, wherein the aqueous pharmaceutical formulation forms <3% HMW aggregates after incubation at 5°C for 2 months, - Contains approximately 114.3 mg / mL of aflibercept, 10 mM to 50 mM histidine-based buffer, sugar, nonionic surfactant, L-arginine, and pH 5.8, or The method according to claims 1 to 74, comprising approximately 114.3 mg / mL of aflibercept; 10 mM His / His-HCl buffer, 5% sucrose, 0.03% polysorbate-20, 50 mM L-arginine, and pH 5.

8.

76. ≥8 mg (±0.8 mg) of VEGF receptor fusion protein in approximately 100 μl or less, approximately 75 μl or less, approximately 70 μl or less, or approximately 50 μl, 51 μl, 52 μl, 53 μl, 54 μl, 55 μl, 56 μl, 57 μl, 58 μl, 59 μl, 60 μl, 61 μl, 62 μl, 63 μl, 64 μl, 65 μl, 66 μl, 67 μl, 68 μl, 69 μl, 70 μl, 71 μl, 72 μl, 7 The method according to any one of claims 1 to 75, administered in a volume of 3 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 according to claim 76, wherein the VEGF receptor fusion protein is administered in a volume of about 70 ± 4 or 5 microliters.

78. The method according to any one of claims 1 to 77, wherein the interval between administrations is adjusted (increased / maintained / decreased) based on visual outcomes and / or anatomical outcomes.

79. The method according to any one of claims 1 to 78, further comprising, if necessary, one or more periods of administration of (pro re nata) (PRN), capped PRN, or Treat and Extended (T&E) as needed.

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

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

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

Images