Extended high-dose vega antagonist regimen for treating angiogenic eye disease

Abstract

This invention relates to a treatment regimen for angiogenic eye diseases such as nAMD, characterized by high doses of aflibercept and prolonged dosing intervals.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202380025712.6, filed on March 14, 2023, entitled "Prolonged High-Dose VEGF Antagonist Regimen for the Treatment of Angiogenic Ophthalmopathy".

[0002] This application is related to U.S. Provisional Patent Application No. 63 / 319,869, filed March 15, 2022; U.S. Provisional Patent Application No. 63 / 404,512, filed September 7, 2022; U.S. Provisional Patent Application No. 63 / 404,893, filed September 8, 2022; U.S. Provisional Patent Application No. 63 / 411,594, filed September 29, 2022; U.S. Provisional Patent Application No. 63 / 412,165, filed September 30, 2022; and November 1, 2022. The following U.S. Provisional Patent Application No. 63 / 421,298, filed on December 22, 2022; U.S. Provisional Patent Application No. 63 / 434,920, filed on December 22, 2022; U.S. Provisional Patent Application No. 63 / 444,480, filed on February 9, 2023; and U.S. Provisional Patent Application No. 63 / 447,582, filed on February 22, 2023 and Canadian Patent Application No. 3,190,733, filed on February 22, 2023 are related to this document; each of these patent applications is incorporated herein by reference in its entirety.

[0003] References to sequence listings

[0004] This application is incorporated by reference to a computer-readable sequence list in ST.26 XML format, named 11193WO01_Sequence, created on March 13, 2023, and containing 5,464 bytes. Technical Field

[0005] The field of this invention relates to methods for treating or preventing angiogenic eye diseases by administering VEGF antagonists. Background Technology

[0006] Neovascular (wet) AMD (nAMD) is a major health problem in the global aging population. Vision loss in nAMD is caused by abnormal growth and leakage of blood vessels in the macula. Vision loss tends to have a greater impact in older subjects with nAMD because it significantly reduces visual compensation for functional impairment caused by other age-related comorbidities such as arthritis and osteoporosis.

[0007] Intravitreal (IVT) administration of anti-vascular endothelial growth factor (VEGF) therapies (such as EYLEA®) inhibits the growth and leakage of new blood vessels in the retina and is currently the standard treatment for subjects with nAMD. They not only maintain visual function but also provide clinically meaningful visual gains. For most subjects, treatment for nAMD is long-term and lifelong to suppress retinal edema and recurrence of choroidal neovascularization (CNV). Although currently approved IVT anti-VEGF therapies are effective and well-tolerated, the need for IVT injections every 4 to 8 weeks, especially during the initial and maintenance phases of treatment, is a significant burden on physicians, subjects, and caregivers. While the procedure is simple and relatively easy to implement, ensuring the appropriate injection frequency to achieve subject outcomes similar to those seen in pivotal studies presents an increasing challenge for individual practice and the healthcare system as a whole. Furthermore, high-frequency dosing leads to complications for subjects. For example The burden of finding transportation and missing work increases. A second effect of this burden is that it reduces the likelihood of non-adherence to prescribed treatment plans.

[0008] While the efficacy and safety of currently approved VEGF antagonist therapies in treating nAMD have been proven, there remains an unmet medical need to develop therapies with the potential to reduce the treatment burden while providing visual outcomes that are at least similar to or even better than the currently available standard of care.

[0009] Increasing the molar concentration of the therapeutic protein of the VEGF antagonist in the dosing formulation is a potential approach to provide further benefit to subjects with choroidal retinal vascular diseases, including nAMD. Higher doses of aflibercept administered via IVT have the potential to prolong the therapeutic effect of the drug. Extending the treatment interval to every 12 or 16 weeks early after treatment initiation will reduce the number of injections in the first year of treatment. The potential reduction in injection-related treatment burden and safety events through fewer injections could be a significant contribution to patient / subject care and healthcare services. EYLEA (2 mg dose, administered at a concentration of 40 mg / mL, also known as intravitreal aflibercept [IAI]) is currently approved in the United States (US) for the treatment of nAMD and is also approved for the treatment of post-retinal vein occlusion macular edema (RVO), diabetic macular edema (DME), and diabetic retinopathy (DR). Summary of the Invention

[0010] This invention provides a method for treating or preventing neovascular age-related macular degeneration, the method comprising administering one or more doses (e.g., >Aflibercept (8 mg) is administered such that, following intravitreal injection, the clearance of free aflibercept from the ocular ventricle is approximately 0.367–0.458 mL / day (e.g., 0.41 mL / day), and the time to reach the lower limit of quantitation (LLOQ) of free aflibercept in the subject's ocular ventricle following said intravitreal injection is approximately 15 weeks; and the time to reach the lower limit of quantitation (LLOQ) (e.g., approximately 0.0156 mg / L) of free aflibercept in the subject's plasma following said intravitreal injection is approximately 3.5 weeks; for example, wherein aflibercept is administered in the form of an aqueous pharmaceutical formulation, wherein aflibercept immediately after production and purification has less than approximately 3.5% of high molecular weight material and / or less than or equal to approximately 6% of high molecular weight material after storage at approximately 2°C–8°C for approximately 24 months. In one embodiment of the invention, the aqueous pharmaceutical formulation comprises an aqueous pharmaceutical formulation containing: at least about 100 mg / ml of a VEGF receptor fusion protein, the fusion protein comprising two polypeptides, each polypeptide comprising an immunoglobulin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of VEGFR2, and a polymerized component; about 10 mM-100 mM L-arginine; sucrose; a histidine-based buffer; and a surfactant; wherein the pH of the formulation is about 5.0 to about 6.8; wherein the VEGF receptor fusion protein immediately after production and purification has less than about 3.5% of high molecular weight material and / or less than or equal to about 6% of high molecular weight material after storage at about 2°C-8°C for about 24 months. In one embodiment of the invention, the method includes administering a single initial dose of about 8 mg or more of aflibercept, followed by one or more administrations of a second dose of about 8 mg or more of aflibercept, followed by one or more administrations of a third dose of about 8 mg or more of aflibercept; wherein each second dose is administered about 2 to 4 weeks (preferably 4 weeks) immediately following the preceding dose; and wherein each third dose is administered about 12 to 20 weeks (preferably 12, 16 or 20 weeks) immediately following the preceding dose.

[0011] This invention provides a method for achieving a clearance rate of free aflibercept from the ocular ventricle after intravitreal injection relative to intravitreal injection. < A method for slowing the clearance rate of aflibercept from the ocular ventricle after 4 mg aflibercept, comprising intravitreal injection of about 8 mg or more of a single initial dose of aflibercept into the eye of a subject in need, followed by one or more second doses of about 8 mg or more of aflibercept, followed by one or more third doses of about 8 mg or more of aflibercept; wherein each second dose is administered about 2 to 4 weeks after the immediate preceding dose; and wherein each third dose is administered about 12 to 20 weeks after the immediate preceding dose. In one embodiment of the invention, the clearance rate of free aflibercept from the ocular ventricle is higher than that after intravitreal injection.< The clearance rate from the ocular ventricle after 4 mg aflibercept is slow, approximately 34%, for example, when injected intravitreal. > Following an 8 mg dose of aflibercept, the clearance of free aflibercept from the ocular ventricle was approximately 0.367–0.458 mL / day or 0.41 mL / day.

[0012] The present invention also provides a method for increasing the time to reach the lower limit of quantitation (LLOQ) of free aflibercept in the ventricle of a subject after intravitreal injection of aflibercept relative to the time to reach the LLOQ after intravitreal injection of about 2 mg of aflibercept, for example, by more than 1.3 weeks, for example, by more than 6 to 10 weeks, for example, by about 15 weeks, the method comprising intravitreal injection of a single initial dose of about 8 mg or more of aflibercept into the eye of a subject in need, followed by one or more second doses of about 8 mg or more of aflibercept, followed by one or more third doses of about 8 mg or more of aflibercept; wherein each second dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each third dose is administered about 12 to 20 weeks after the immediately preceding dose.

[0013] The present invention also provides a method for increasing the time to reach the lower limit of quantitation (LLOQ) (e.g., about 0.0156 mg / L) of free aflibercept in the plasma of a subject after intravitreal injection of aflibercept relative to the time to reach the LLOQ of free aflibercept in the plasma of a subject after intravitreal injection of about 2 mg of aflibercept, for example, by more than 1.5 weeks, for example by increasing it by about 2 weeks to about 3.5 weeks. The method comprises intravitreal injection of about 8 mg or more of a single initial dose of aflibercept into the eye of a subject in need, followed by one or more second doses of about 8 mg or more of aflibercept, followed by one or more third doses of about 8 mg or more of aflibercept; wherein each second dose is administered about 2 to 4 weeks immediately following the preceding dose; and wherein each third dose is administered about 12 to 20 weeks immediately following the preceding dose. In one embodiment of the invention, > 8 mg of aflibercept is administered in the form of an aqueous pharmaceutical formulation comprising one or more of the following: a histidine-based buffer, arginine (e.g., L-arginine, such as L-arginine HCl), a sugar or polyol (such as sucrose), and a pH of about 5.8. In one embodiment of the invention, aflibercept immediately after production and purification has less than about 3.5% of high molecular weight material and / or less than or equal to about 6% of high molecular weight material after storage at about 2°C–8°C for about 24 months; for example, wherein... >8 mg of aflibercept is contained in an aqueous pharmaceutical formulation comprising the following: at least about 100 mg / ml of a VEGF receptor fusion protein comprising two polypeptides, each containing an immunoglobulin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of VEGFR2, and a polymerized component; about 10 mM–100 mM L-arginine; sucrose; a histidine-based buffer; and a surfactant; wherein the pH of the formulation is about 5.0 to about 6.8; wherein the VEGF receptor fusion protein immediately after production and purification has less than about 3.5% of high molecular weight material and / or less than or equal to about 6% of high molecular weight material after storage at about 2°C–8°C for about 24 months.

[0014] This invention provides a method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject of need, for improving best-corrected visual acuity in a subject of need with nAMD, or for promoting retinal dryness in a subject of need with nAMD; the method comprising administering a dose of about 8 mg or more of VEGF receptor fusion protein once or multiple times to the eye of the subject every 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks, or 12-20 weeks, or 12-16 weeks, or 16-20 weeks.

[0015] The present invention provides a method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject of need, the method comprising administering to the eye of the subject a single initial dose of about 8 mg or more of VEGF receptor fusion protein (preferably aflibercept), followed by one or more administrations of a second dose of about 8 mg or more of VEGF receptor fusion protein, followed by one or more administrations of a third dose of about 8 mg or more of VEGF receptor fusion protein; wherein each second dose is administered about 2 to 4 weeks (preferably 4 weeks) immediately following the preceding dose; and wherein each third dose is administered about 12 to 20 weeks immediately following the preceding dose.

[0016] The present invention provides a method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject of need, the method comprising administering to the eye of the subject a single initial dose of about 8 mg or more of VEGF receptor fusion protein (preferably aflibercept), followed by one or more administrations of a second dose of about 8 mg or more of VEGF receptor fusion protein, followed by one or more administrations of a third dose of about 8 mg or more of VEGF receptor fusion protein; wherein each second dose is administered about 2 to 4 weeks (preferably 4 weeks) immediately following the preceding dose; and wherein each third dose is administered about 12 weeks immediately following the preceding dose.

[0017] The present invention provides a method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject of need, the method comprising administering to the eye of the subject a single initial dose of about 8 mg or more of VEGF receptor fusion protein (preferably aflibercept), followed by one or more administrations of a second dose of about 8 mg or more of VEGF receptor fusion protein, followed by one or more administrations of a third dose of about 8 mg or more of VEGF receptor fusion protein; wherein each second dose is administered about 2 to 4 weeks (preferably 4 weeks) immediately following the preceding dose; and wherein each third dose is administered about 16 weeks immediately following the preceding dose.

[0018] The present invention provides a method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject of need, the method comprising administering to the eye of the subject a single initial dose of about 8 mg or more of VEGF receptor fusion protein (preferably aflibercept), followed by one or more administrations of a second dose of about 8 mg or more of VEGF receptor fusion protein, followed by one or more administrations of a third dose of about 8 mg or more of VEGF receptor fusion protein; wherein each second dose is administered about 2 to 4 weeks after the immediate preceding dose; and wherein each third dose is administered about 20 weeks after the immediate preceding dose.

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

[0020] The present invention provides a method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject of need, comprising administering 8 mg of VEGF receptor fusion protein, preferably aflibercept (0.07 mL or 70 μL), via intravitreal injection for the first three doses every 4 weeks (approximately every 28 days + / - 7 days, once a month), and thereafter every 12 weeks (2-4 months + / - 7 days) via intravitreal injection of 8 mg of VEGF receptor fusion protein (0.07 mL).

[0021] The present invention provides a method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject of need, comprising administering 8 mg of VEGF receptor fusion protein, preferably aflibercept (0.07 mL or 70 μL), via intravitreal injection for the first three doses every 4 weeks (approximately every 28 days + / - 7 days, once a month), and thereafter every 16 weeks (2-4 months + / - 7 days) via intravitreal injection of 8 mg of VEGF receptor fusion protein (0.07 mL).

[0022] The present invention provides a method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject of need, comprising administering 8 mg of VEGF receptor fusion protein, preferably aflibercept (0.07 mL or 70 μL), via intravitreal injection for the first three doses every 4 weeks (approximately every 28 days + / - 7 days, once a month), and thereafter via intravitreal injection of 8 mg of VEGF receptor fusion protein (0.07 mL) every 20 weeks (+ / - 7 days).

[0023] The present invention provides a method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject of need, wherein: (1) the subject has received an initial 2 mg dose of VEGF receptor fusion protein, and the method comprises administering the initial 8 mg dose of VEGF receptor fusion protein to the subject after 1 month, followed by a first 8 mg dose of VEGF receptor fusion protein after 1 month thereafter; and a second 8 mg dose of VEGF receptor fusion protein after 1 month thereafter; and then, a maintenance dose of 8 mg of VEGF receptor fusion protein is administered once or multiple times every 12, 16, or 20 weeks according to the HDq12, HDq16, or HDq20 dosing regimen; (2) the subject has received an initial 2 mg dose of VEGF receptor fusion protein, and the method comprises administering the first 8 mg dose of VEGF receptor fusion protein to the subject after 1 month, followed by a second 8 mg dose of VEGF receptor fusion protein after 1 month thereafter. (2) The subject has received an initial 2 mg dose of VEGF receptor fusion protein; then, thereafter every 12, 16, or 20 weeks, one or more doses of 8 mg maintenance VEGF receptor fusion protein are administered according to the HDq12, HDq16, or HDq20 dosing regimen; (3) The subject has received an initial 2 mg dose of VEGF receptor fusion protein, and then the method includes administering a second 8 mg dose of VEGF receptor fusion protein to the subject after 1 month, and then, thereafter every 12, 16, or 20 weeks, one or more doses of 8 mg maintenance VEGF receptor fusion protein are administered according to the HDq12, HDq16, or HDq20 dosing regimen; (4) The subject has received an initial 2 mg dose of VEGF receptor fusion protein, and then the method includes administering a first 8 mg maintenance VEGF receptor fusion protein to the subject after 1 month, and all other 8 mg maintenance VEGF receptor fusion protein doses are administered according to the HDq12, HDq16, or HDq20 dosing regimen every 12, 16, or 20 weeks; (5) The subject has received an initial 2 mg dose of VEGF receptor fusion protein, and then the method includes administering a first 8 mg maintenance VEGF receptor fusion protein to the subject after 1 month, and all other 8 mg maintenance VEGF receptor fusion protein doses are administered according to the HDq12, HDq16, or HDq20 dosing regimen every 12, 16, or 20 weeks; The method involves administering an initial 8 mg dose of VEGF receptor fusion protein to the subject one month later, followed by a first 2 mg dose of VEGF receptor fusion protein, and then administering the initial 8 mg dose of VEGF receptor fusion protein to the subject one month later, followed by a first 8 mg dose of VEGF receptor fusion protein one month later; and administering a second 8 mg dose of VEGF receptor fusion protein one month later; and then administering one or more 8 mg maintenance doses of VEGF receptor fusion protein every 12, 16, or 20 weeks according to the HDq12, HDq16, or HDq20 dosing regimen.(6) The subject has received an initial 2 mg dose of VEGF receptor fusion protein and a first 2 mg dose of VEGF receptor fusion protein one month later. The method then includes administering a first 8 mg dose of VEGF receptor fusion protein one month later, followed by a second 8 mg dose of VEGF receptor fusion protein one month thereafter; then, every 12, 16, or 20 weeks thereafter, a maintenance dose of 8 mg of VEGF receptor fusion protein is administered once or multiple times according to the HDq12, HDq16, or HDq20 dosing regimen. (7) The subject has received an initial 2 mg dose of VEGF receptor fusion protein and a first 2 mg dose of VEGF receptor fusion protein one month later. The method then includes administering a second 8 mg dose of VEGF receptor fusion protein one month later, followed by every 12, 16, or 20 weeks thereafter, a maintenance dose of 8 mg of VEGF receptor fusion protein is administered once or multiple times according to the HDq12, HDq16, or HDq20 dosing regimen. (8) The subject has received an initial 2 mg dose of VEGF receptor fusion protein and received a first 2 mg dose of VEGF receptor fusion protein one month later, and the method then includes administering the subject a first 8 mg maintenance dose of VEGF receptor fusion protein one month later, and administering all other 8 mg maintenance doses of VEGF receptor fusion protein every 12, 16, or 20 weeks according to the HDq12, HDq16, or HDq20 dosing regimen; (9) The subject has received an initial 2 mg dose of VEGF receptor fusion protein and received a first 2 mg dose of VEGF receptor fusion protein one month later, and received a second 2 mg dose of VEGF receptor fusion protein one month later, and the method then includes administering the initial 8 mg dose of VEGF receptor fusion protein one month later, and administering a first 8 mg dose of VEGF receptor fusion protein one month later; and administering a second 8 mg dose of VEGF receptor fusion protein one month later. The method comprises administering a second dose of VEGF receptor fusion protein in mg; then, every 12, 16, or 20 weeks thereafter, a maintenance dose of 8 mg of VEGF receptor fusion protein is administered once or multiple times according to the HDq12, HDq16, or HDq20 dosing regimen; (10) the subject has received an initial 2 mg dose of VEGF receptor fusion protein and received a first 2 mg dose of VEGF receptor fusion protein 1 month later and a second 2 mg dose of VEGF receptor fusion protein 1 month later, and then the method comprises administering a first 8 mg dose of VEGF receptor fusion protein 1 month later to the subject and a second 8 mg dose of VEGF receptor fusion protein 1 month thereafter;Then, every 12, 16, or 20 weeks thereafter, a maintenance dose of 8 mg of VEGF receptor fusion protein is administered once or multiple times according to the HDq12, HDq16, or HDq20 dosing regimen; (11) the subject has received an initial 2 mg dose of VEGF receptor fusion protein and received a first 2 mg dose of VEGF receptor fusion protein one month later and a second 2 mg dose of VEGF receptor fusion protein one month later, then the method includes administering a second 8 mg dose of VEGF receptor fusion protein to the subject one month later, and then, every 12, 16, or 20 weeks thereafter, a maintenance dose of 8 mg of VEGF receptor fusion protein is administered once or multiple times according to the HDq12, HDq16, or HDq20 dosing regimen; (12) the subject has received an initial 2 mg dose of VEGF receptor fusion protein and received a first 2 mg dose of VEGF receptor fusion protein one month later and a second 2 mg dose of VEGF receptor fusion protein one month later. The method includes administering a second dose of VEGF receptor fusion protein at 2 mg after 2 months, followed by the administration of a first 8 mg maintenance dose of VEGF receptor fusion protein every 12, 16, or 20 weeks according to the HDq12, HDq16, or HDq20 dosing regimen; (13) the subject has received an initial 2 mg dose of VEGF receptor fusion protein and received a first 2 mg second dose of VEGF receptor fusion protein after 1 month, and received a second 2 mg second dose of VEGF receptor fusion protein after 1 month, and received a first 2 mg maintenance dose of VEGF receptor fusion protein after 8 weeks, followed by the administration of the initial 8 mg dose of VEGF receptor fusion protein to the subject at most 2 months after the last dose of VEGF receptor fusion protein, followed by the administration of a first 8 mg second dose of VEGF receptor fusion protein after 1 month thereafter; and after 1 month thereafter, administering a second 8 mg second dose of VEGF receptor fusion protein. The second dose of VEGF receptor fusion protein was administered in mg; thereafter, every 12, 16, or 20 weeks thereafter, a maintenance dose of 8 mg of VEGF receptor fusion protein was administered once or multiple times according to the HDq12, HDq16, or HDq20 dosing regimen.(14) The subject has received an initial 2 mg dose of VEGF receptor fusion protein and a first 2 mg dose of VEGF receptor fusion protein one month later, and a second 2 mg dose of VEGF receptor fusion protein one month later, and a first 2 mg maintenance dose of VEGF receptor fusion protein eight weeks later. The method then includes administering a first 8 mg dose of VEGF receptor fusion protein to the subject up to two months after the last dose, and a second 8 mg dose of VEGF receptor fusion protein one month thereafter, and then, thereafter, one or more 8 mg maintenance doses of VEGF receptor fusion protein every 12, 16, or 20 weeks according to the HDq12, HDq16, or HDq20 dosing regimen; (15) The subject has received an initial 2 mg dose of VEGF receptor fusion protein and a first 2 mg dose of VEGF receptor fusion protein one month later, and a second 2 mg dose of VEGF receptor fusion protein one month later, and a first 2 mg dose of VEGF receptor fusion protein eight weeks later. The method comprises administering a second 8 mg dose of VEGF receptor fusion protein to the subject up to 2 months after the last dose of VEGF receptor fusion protein, and then administering one or more doses of 8 mg maintenance VEGF receptor fusion protein every 12, 16, or 20 weeks thereafter, according to the HDq12, HDq16, or HDq20 dosing regimen; (16) the subject has received an initial 2 mg dose of VEGF receptor fusion protein and received a first 2 mg dose of VEGF receptor fusion protein 1 month later and a second 2 mg dose of VEGF receptor fusion protein 1 month later and a first 2 mg maintenance dose of VEGF receptor fusion protein 8 weeks later, and then administering one first 8 mg maintenance dose of VEGF receptor fusion protein to the subject up to 2 months after the last dose of VEGF receptor fusion protein, and administering all other 8 mg doses of VEGF receptor fusion protein every 12, 16, or 20 weeks according to the HDq12, HDq16, or HDq20 dosing regimen. The HDq12 dosing regimen comprises: a single initial dose of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more second doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more third doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each second dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each third dose is administered about 12 weeks after the immediately preceding dose.(ii) The HDq16 dosing regimen comprises: a single initial dose of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more second doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more third doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each second dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each third dose is administered about 16 weeks after the immediately preceding dose; and (iii) The HDq20 dosing regimen comprises: a single initial dose of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more second doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more third doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each second dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each third dose is administered about 20 weeks after the immediately preceding dose—preferably, the VEGF receptor fusion protein is aflibercept, and 2 to 4 weeks is preferably 4 weeks.

[0024] The present invention also provides a method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject of need, wherein: (a) the subject has received an initial 8 mg dose of VEGF receptor fusion protein; the method then includes administering a first 8 mg second dose of VEGF receptor fusion protein to the subject one month later, followed by a second 8 mg second dose of VEGF receptor fusion protein one month thereafter; then, thereafter, administering one or more 8 mg maintenance doses of VEGF receptor fusion protein every 12, 16, or 20 weeks according to an HDq12, HDq16, or HDq20 dosing regimen; (b) the subject has received an initial 8 mg dose of VEGF receptor fusion protein and received a first 8 mg second dose of VEGF receptor fusion protein one month later, the method then includes administering a second 8 mg second dose of VEGF receptor fusion protein to the subject one month later, followed by one or more 8 mg maintenance doses of VEGF receptor fusion protein every 12, 16, or 20 weeks according to an HDq12, HDq16, or HDq20 dosing regimen. (c) The subject has received an initial 8 mg dose of VEGF receptor fusion protein and received a first 8 mg dose of VEGF receptor fusion protein one month later, and a second 8 mg dose of VEGF receptor fusion protein one month later; the method then includes administering the first 8 mg maintenance dose of VEGF receptor fusion protein to the subject after 12, 16, or 20 weeks, and administering all other 8 mg maintenance doses of VEGF receptor fusion protein every 12, 16, or 20 weeks according to the HDq12, HDq16, or HDq20 dosing regimen; or (d) Where the subject has received an initial 8 mg dose of VEGF receptor fusion protein and received a first 8 mg dose of VEGF receptor fusion protein one month later, and a second 8 mg dose of VEGF receptor fusion protein one month later, and thereafter, every 12, 16, or 20 weeks, the subject has received one or more 8 mg maintenance doses of VEGF receptor fusion protein. The method comprises administering one or more 8 mg maintenance doses of VEGF receptor fusion protein to the subject 12, 16, or 20 weeks after the last maintenance dose of VEGF receptor fusion protein and administering all other 8 mg maintenance doses of VEGF receptor fusion protein every 12, 16, or 20 weeks according to the HDq12, HDq16, or HDq20 dosing regimen.The HDq12 dosing regimen comprises: a single initial dose of about 8 mg or more of VEGF receptor fusion protein, followed by one or more second doses of about 8 mg or more of VEGF receptor fusion protein, followed by one or more third doses of about 8 mg or more of VEGF receptor fusion protein; wherein each second dose is administered about 2 to 4 weeks after the preceding dose; and wherein each third dose is administered about 12 weeks after the preceding dose; (ii) the HDq16 dosing regimen comprises: a single initial dose of about 8 mg or more of VEGF receptor fusion protein, followed by one or more second doses of about 8 mg or more of VEGF receptor fusion protein, followed by one or more third doses of about 8 mg or more of VEGF receptor fusion protein; wherein each second dose is administered about 2 to 4 weeks after the preceding dose; and wherein each third dose is administered about 16 weeks after the preceding dose; and (iii) the HDq20 ..., followed by one or more third doses of about 8 mg or more of VEGF receptor fusion protein, followed by one or more third doses of about 8 mg or more of VEGF receptor fusion protein; wherein each second dose is administered about 2 to 4 weeks after the preceding dose; and wherein each third dose is administered about 16 weeks after A second dose of VEGF receptor fusion protein of 1 mg or more, followed by one or more doses of a third dose of VEGF receptor fusion protein of about 8 mg or more; wherein each second dose is administered about 2 to 4 weeks after the immediate preceding dose; and wherein each third dose is administered about 20 weeks after the immediate preceding dose - preferably, the VEGF receptor fusion protein is aflibercept, and 2 to 4 weeks is preferably 4 weeks.

[0025] The present invention also provides a method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject who has received a dosing regimen for the treatment or prevention of nAMD, the dosing regimen comprising: a single initial dose of about 2 mg of VEGF receptor fusion protein (preferably aflibercept), followed by one or more second doses of about 2 mg of VEGF receptor fusion protein, followed by one or more third doses of about 2 mg of VEGF receptor fusion protein; wherein each second dose is administered approximately 4 weeks after the immediately preceding dose; and wherein each third dose is administered approximately 8 weeks after the immediately preceding dose; and wherein the subject is at any stage of the 2 mg VEGF receptor fusion protein dosing regimen, the method comprising administering an 8 mg dose of VEGF receptor fusion protein to the eye of the subject, evaluating the subject approximately 8, 10, or 12 weeks after said administration, and continuing to administer 8 mg every 12 or 16 weeks to the subject if the treating physician determines that dosing every 12 or 16 weeks is appropriate. VEGF receptor fusion protein; or evaluate the subject approximately 8, 10, or 12 weeks after administration, and if the treating physician determines that administration every 12 weeks is appropriate, administer another 8 mg dose of VEGF receptor fusion protein, re-evaluate the subject approximately 12 weeks later, and if the treating physician determines that administration every 16 weeks is appropriate, continue administering 8 mg of VEGF receptor fusion protein to the subject every 16 weeks.

[0026] In one embodiment of the invention, the subject has received a dosing regimen for the treatment or prevention of neovascular age-related macular degeneration: a single initial dose of about 2 mg of VEGF receptor fusion protein (preferably aflibercept), followed by two second doses of about 2 mg of VEGF receptor fusion protein, followed by one or more third doses of about 2 mg of VEGF receptor fusion protein; wherein each second dose is administered about 4 weeks after the immediately preceding dose; and wherein each third dose is administered about 8 weeks after the immediately preceding dose.

[0027] The present invention provides a method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject of need, the method comprising administering to the eye of the subject a single initial dose of about 8 mg or more of VEGF receptor fusion protein (preferably aflibercept), followed by one or more administrations of a second dose of about 8 mg or more of VEGF receptor fusion protein, followed by one or more administrations of a third dose of about 8 mg or more of VEGF receptor fusion protein; wherein each second dose is administered about 2 to 4 weeks (preferably 4 weeks) immediately following the preceding dose; and wherein each third dose is administered about 12 or 16 weeks immediately following the preceding dose; the method further comprising, after receiving one or more of the third doses about 12 or 16 weeks after the preceding dose, extending the third dose interval from 12 weeks to 16 weeks; from 12 weeks to 20 weeks; or from 16 weeks to 20 weeks; for example, wherein the third dose interval is adjusted about 48 or 60 weeks after the start of treatment. In one embodiment of the invention, prior to the extension, the subject exhibits (a) BCVA impairment <5 letters; and / or (b) CRT <300 or 320 µm. In another embodiment of the invention, the method further includes evaluating the subject's BVCA and / or CRT, and extending the third dose interval if the subject exhibits (a) BCVA loss <5 letters; and / or (b) CRT <300 or 320 µm.

[0028] The present invention provides a method for treating or preventing nAMD in a subject in need, the method comprising administering to the eye of the subject a single initial dose of about >8 mg or more of VEGF receptor fusion protein (preferably aflibercept), followed by one or more administrations of a second dose of about 8 mg or more of VEGF receptor fusion protein, followed by one or more administrations of a third dose of about 8 mg or more of VEGF receptor fusion protein; wherein each second dose is administered about 2 to 4 weeks (preferably 4 weeks) immediately following the preceding dose; and wherein each third dose is administered about 12, 16, or 20 weeks immediately following the preceding dose; the method further comprising, after receiving one or more of the third doses about 12, 16, or 20 weeks immediately following the preceding dose, shortening the third dose interval from 12 weeks to 8 weeks; from 16 weeks to 12 weeks; from 16 weeks to 8 weeks; from 20 weeks to 8 weeks; from 20 weeks to 12 weeks; or from 20 weeks to 16 weeks. In one embodiment of the invention, prior to the shortening, the subject exhibits (a) a BCVA loss of >10 letters relative to baseline; and / or (b) a CRT increase of >50 µm relative to baseline. In another embodiment of the invention, the method further includes evaluating the subject's BVCA and / or CRT, and shortening the third dosing interval if the subject exhibits (a) a BCVA loss of >10 letters relative to baseline; and / or (b) a CRT increase of >50 µm relative to baseline.

[0029] In one embodiment of the invention, if (a) the BCVA (ETDRS) loss is greater than 5 letters relative to the BCVA observed approximately 12 weeks after treatment initiation; (b) the CRT increase is greater than 25 micrometers relative to the CRT observed approximately 12 weeks after treatment initiation; and / or (c) there is new foveal neovascularization or foveal hemorrhage; for example, at week 16 or week 20 after treatment initiation, the interval between the third doses is shortened from 12 or 16 weeks to 8 weeks; or if (a) the BCVA (ETDRS) loss is greater than 5 letters relative to the BCVA observed approximately 12 weeks after treatment initiation; (b) the CRT increase is greater than 25 micrometers relative to the CRT observed approximately 12 weeks after treatment initiation; and / or (c) there is new foveal neovascularization or foveal hemorrhage; for example, at week 24 after treatment initiation, the interval between the third doses is shortened from 16 weeks to 12 weeks.

[0030] The present invention provides a method for treating or preventing neovascular age-related macular degeneration in a subject of need, the method comprising administering three doses of approximately 8 mg of VEGF receptor fusion protein (preferably aflibercept) to the eye of the subject at 4-week intervals in the form of a formulation containing approximately 114.3 mg / ml of VEGF receptor fusion protein; and after said three doses, administering one or more doses of VEGF receptor fusion protein at intervals extended to 12 weeks, 16 weeks, or 20 weeks.

[0031] This invention provides a method for treating or preventing nAMD in a subject of need, comprising administering to the subject's eye a single initial dose of about 8 mg or more of VEGF receptor fusion protein (preferably aflibercept), followed by two second doses of about 8 mg or more of VEGF receptor fusion protein, wherein each second dose is administered about 2 to 4 weeks (preferably 4 weeks) immediately following the preceding dose; and, after said doses, (a) determining whether the subject meets at least one criterion for reducing or extending (extending) one or more intervals between VEGF receptor fusion protein doses by 2, 3, 4, or 2-4 weeks; and (b) if said determination is made, administering an additional dose of VEGF receptor fusion protein at said reduced or extended dose intervals, wherein the criteria for reducing the interval include: 1. BCVA loss > 5 letters; 2. Central retinal thickness (CRT) increase > 25 micrometers; 3. New foveal hemorrhage; and / or 4. New foveal neovascularization, wherein the criteria for extending the interval include: 1. BCVA loss < 5 letters; 2. No fluid in the central region; 3. No new foveal hemorrhage; and / or 4. No foveal neovascularization. In one embodiment of the invention, the criteria for extending the interval include: 1. BCVA loss <5 letters from week 12; 2. No fluid in the central region on the OCT; and 3. No new foveal hemorrhage or foveal neovascularization; and / or the criteria for reducing the interval include two of the following: 1. BCVA loss >5 letters from week 12; and 2. Increase in central retinal thickness (CRT) >25 micrometers or new foveal hemorrhage or new foveal neovascularization from week 12. In one embodiment of the invention, if the criteria are met, the interval is extended to 12 weeks, 16 weeks, or 20 weeks.

[0032] This invention provides a method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject who has been pretreated with one or more 2 mg doses of VEGF receptor fusion protein (preferably aflibercept). The method comprises administering a single initial dose of about 8 mg or more of VEGF receptor fusion protein to the subject's eye, followed by one or more administrations of a second dose of about 8 mg or more of VEGF receptor fusion protein, followed by one or more administrations of a third dose of about 8 mg or more of VEGF receptor fusion protein; wherein each second dose is administered about 2 to 4 weeks (preferably 4 weeks) immediately following the preceding dose; and wherein each third dose is administered about 12-20 minutes after the preceding dose. For example Apply at 12, 16 or 20 weeks.

[0033] The present invention provides a method for treating or preventing angiogenic eye disease (preferably nAMD) in a subject of need, the method comprising administering to the eye of the subject (1) a single initial dose of about 8 mg or more of a VEGF receptor fusion protein (preferably aflibercept), followed by one or more subsequent doses. For example (1) A second dose of VEGF receptor fusion protein of about 8 mg or more, administered 2, 3 or 4 times, followed by a third dose of about 8 mg or more, administered once or more; wherein each second dose is administered about 2 to 4 weeks (preferably 4 weeks) immediately following the preceding dose; and wherein each third dose is administered about 8 weeks immediately following the preceding dose; or (2) a dose of VEGF receptor fusion protein of about 8 mg or more is administered once or more every 4 weeks.

[0034] In one embodiment of the invention, a subject having any one or more of the following: ocular or periocular infection; active intraocular inflammation; and / or hypersensitivity reaction is excluded from treatment or prevention. It is not necessary to exclude subjects lacking this criterion. In one embodiment of the invention, the method herein further includes the step of evaluating the subject for: ocular or periocular infection; active intraocular inflammation; and / or hypersensitivity reaction; and if any one or more of these are found in the subject, the subject is excluded from treatment or prevention.

[0035] In one embodiment of the invention, adverse events in the subject are monitored, such as conjunctival hemorrhage, cataract, vitreous detachment, vitreous floaters, corneal epithelial defects, and / or increased intraocular pressure. If such adverse events (AEs) are identified, the identified AEs can be treated and / or such treatment can be discontinued or prevented.

[0036] In one embodiment of the invention, the method includes preparation prior to administration of the VEGF receptor fusion protein (preferably aflibercept). For example, the method includes, prior to each administration, providing or preparing: a single-dose glass vial with a protective plastic cap and stopper, containing approximately 70 microliters of an aqueous formulation containing 8 mg of VEGF receptor fusion protein; a filter needle, such as an 18-gauge x 1.5-inch, 5-micron filter needle, including a tip and bevel; an inventive needle, such as a 30-gauge x 0.5-inch injection needle; and a syringe, such as a 1-mL Luer lock syringe with a graduation marking for a 70-microliter capacity; packaged together; then (1) visually inspecting the aqueous formulation in the vial, and if particles, turbidity, or discoloration are visible, using another vial containing an aqueous formulation of VEGF receptor fusion protein; (2) removing the protective plastic cap from the vial; and (3) cleaning the top of the vial with an alcohol swab; then using aseptic technique: (4) removing the 18-gauge x 1.5-inch, 5-micron filter needle and the 1-mL Luer lock syringe from their packaging. (5) Attach the filter needle to the syringe by screwing it onto the tip of the Luer lock syringe; (6) Push the filter needle into the center of the stopper until the needle is fully inserted into the vial and the tip touches the bottom or bottom edge of the vial; (7) Draw all the contents of the VEGF receptor fusion protein vial into the syringe, keeping the vial upright and slightly tilted, while ensuring that the bevel of the filter needle is submerged in the liquid; (8) Continue to tilt the vial during the drawing process, keeping the bevel of the filter needle submerged in the preparation; (9) When the vial is emptied, pull the plunger back fully to completely empty the filter needle; (10) Remove the filter needle from the syringe and dispose of it; (11) Remove the No. 30 x from its packaging. (12) Attach the 1 / 2-inch injection needle to the syringe by firmly screwing the injection needle onto the tip of the Luer lock syringe; (13) Hold the syringe with the needle facing upward and check the syringe for air bubbles, if any are present, gently tap the syringe with your fingers until the air bubble rises to the top; and (14) Slowly press down the plunger so that the plunger tip aligns with the 70 microliter mark on the syringe. In one embodiment of the invention, the injection of the VEGF receptor fusion protein is performed under controlled aseptic conditions, including surgical hand disinfection and the use of sterile gloves, sterile drapes, and sterile eyelid speculum (or equivalent), and prior to injection, an anesthetic and a topical broad-spectrum antimicrobial agent are administered.

[0037] In one embodiment of the invention, the subject is receiving a dosing regimen for the treatment or prevention of nAMD, which includes: a single initial dose of about 2 mg of VEGF receptor fusion protein (preferably aflibercept), followed by two second doses of about 2 mg of VEGF receptor fusion protein, followed by one or more third doses of about 2 mg of VEGF receptor fusion protein; wherein each second dose is administered approximately 4 weeks after the preceding dose; and wherein each third dose is administered approximately 8 weeks after the preceding dose; wherein the subject is at any stage of the 2 mg VEGF receptor fusion protein dosing regimen (initial dose, second dose, or third dose).

[0038] In one embodiment of the invention, one or more second doses constitute two second doses; 2 to 4 weeks is about 4 weeks; 12-20 weeks is about 12 weeks; 12-20 weeks is about 16 weeks; 12-20 weeks is about 20 weeks; 12-20 weeks is about 12-16 weeks; 8-16 weeks is about 12 weeks; 8-16 weeks is about 16 weeks; 8-16 weeks is about 12-16 weeks; 2 to 4 weeks is about 4 weeks and one or more second doses constitute two second doses; 12-20 weeks is about 12 weeks and one or more second doses constitute two doses; 12-20 weeks is about 16 weeks and one or more second doses constitute two second doses; 12-20 weeks is about 20 weeks and one or more second doses constitute two doses; 12-20 weeks is about 12-16 weeks and one... Or multiple second doses are two second doses; 2 to 4 weeks is about 4 weeks and one or more second doses are two second doses and the VEGF receptor fusion protein is aflibercept; 12-20 weeks is about 12 weeks and one or more second doses are two second doses and the VEGF receptor fusion protein is aflibercept; 12-20 weeks is about 16 weeks and one or more second doses are two second doses and the VEGF receptor fusion protein is aflibercept; 12-20 weeks is about 20 weeks and one or more second doses are two second doses and the VEGF receptor fusion protein is aflibercept; and / or 12-20 weeks is about 12-16 weeks and one or more second doses are two second doses and the VEGF receptor fusion protein is aflibercept.

[0039] In one embodiment of the present invention, the VEGF receptor fusion protein: (i) 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 130-231 of SEQ ID NO: 2; and (3) a polymerized component comprising amino acids 232-457 of SEQ ID NO: 2; (ii) comprises two polypeptides comprising an immunoglobulin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of VEGFR2, and a polymerized component; (iii) comprises two polypeptides comprising an immunoglobulin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of VEGFR2, an Ig domain 4 of VEGFR2, and a polymerized component; (iv) comprises a component comprising amino acids 27 to 129 of SEQ ID NO: 2; (iii) comprises a component comprising amino acids 27 to 129 of SEQ ID NO: 2 ... amino acids 27 to 129 of SEQ ID NO: 2; (iii) comprises amino acids 27 to 129 of SEQ ID NO: 2; (iv) comprises amino acids 27 to 129 of SEQ ID NO: 2; (iii) comprises amino acids 27 to 129 of SEQ ID NO: 2; (iv) comprises amino acids 27 to 129 of SEQ ID NO: 2; (iii) comprises amino acids 27 to 129 of SEQ ID NO: 2; (iv The nucleic acid sequence of SEQ ID NO: 2 encodes two VEGFR1R2-FcΔC1(a) polypeptides; or (v) selected from the group consisting of aflibercept and conbercept. In one embodiment of the invention, the VEGF receptor fusion protein comprises or consists of amino acids 27-457 of the amino acid sequence shown in SEQ ID NO: 2.

[0040] In one embodiment of the invention, 8 mg of VEGF receptor fusion protein (preferably aflibercept) is contained in an aqueous pharmaceutical formulation selected from the group consisting of A-KKKK.

[0041] In one embodiment of the invention, 8 mg of VEGF receptor fusion protein (preferably aflibercept) is administered in the form of an aqueous pharmaceutical formulation containing about 114.3 mg / ml of VEGF receptor fusion protein.

[0042] In one embodiment of the invention, the VEGF receptor fusion protein (preferably aflibercept) is administered intravitreally from a syringe or pre-filled syringe, which is, for example, glass or plastic, and / or sterile. In another embodiment of the invention, the VEGF receptor fusion protein is injected intravitreally using a 30-gauge × ½-inch sterile injection needle.

[0043] In one embodiment of the invention, the subject has previously received one or more doses of 2 mg VEGF receptor fusion protein (preferably aflibercept), such as Eylea.

[0044] In one embodiment of the invention, the method described herein further includes administering one or more additional doses.

[0045] In one embodiment of the invention, 2 mg of VEGF receptor fusion protein (preferably aflibercept) is in an aqueous pharmaceutical formulation containing 40 mg / ml of VEGF receptor fusion protein, for example containing 40 mg / ml of VEGF receptor fusion protein, 10 mM sodium phosphate, 40 mM NaCl, 0.03% polysorbate 20 and 5% sucrose, at a pH of 6.2.

[0046] In one embodiment of the invention, 8 mg of VEGF receptor fusion protein is contained in an aqueous pharmaceutical formulation, which includes... > 100 mg / ml VEGF receptor fusion protein (preferably aflibercept), histidine-based buffer, and arginine (e.g., L-arginine). In one embodiment of the invention, 8 mg of VEGF receptor fusion protein is contained in an aqueous pharmaceutical formulation comprising a sugar or polyol, such as sucrose. In one embodiment of the invention, 8 mg of VEGF receptor fusion protein is contained in an aqueous pharmaceutical formulation having a pH of about 5.8. In one embodiment of the invention, 8 mg of VEGF receptor fusion protein is contained in an aqueous pharmaceutical formulation comprising about 103-126 mg / ml VEGF receptor fusion protein, a histidine-based buffer, and arginine, for example, comprising about 114.3 mg / ml VEGF receptor fusion protein, a histidine-based buffer, and arginine.

[0047] In embodiments of the present invention, 8 mg of the VEGF antagonist is administered in the following doses: about 100 μl or less; about 75 μl or less; about 70 μl or less; or about 50 μl; 51 μl; 52 μl; 53 μl; 54 μl; 55 μl; 56 μl; 57 μl; 58 μl; 59 μl; 60 μl; 61 μl; 62 μl; 63 μl; 64 μl; 65 μl; 66 μl; 67 μl; 68 μl; 69 μl; 70 μl; 71 μl; 72 μl; 73 μl; 74 μl; 75 μl; 76 μl; 77 μl; 78 μl; 79 μl; 80 μl; 81 μl; 82 μl; 83 μl; 84 μl; 85 μl; 86 μl; 87 μl; 88 μl; 89 μl; 90 μl; 10 ... μl; 91 μl; 92 μl; 93 μl; 94 μl; 95 μl; 96 μl; 97 μl; 98 μl; 99 μl; or 100 μl; for example, about 70 + 4 or 5 microliters.

[0048] In one embodiment of the invention, the method herein includes the step of administering a VEGF receptor fusion protein (preferably aflibercept) to the eyes of a subject, for example, via intravitreal administration.

[0049] In one embodiment of the invention, the subject achieves and / or maintains one or more of the following: improved best-corrected visual acuity (BCVA). > 5. > 10. > 15 or > 20 letters; no decrease in best-corrected visual acuity (BCVA); elimination of retinal fluid; elimination of intraretinal fluid (IRF) and / or subretinal fluid; reduction in total damaged choroidal neovascularization (CNV) area; loss or reduction of intraretinal fluid; loss or reduction of subretinal fluid; reduction in central retinal thickness (CST); improvement in vision-related quality of life; absence of treatment-related adverse events (AEs) and / or serious AEs (SAEs); ETDRS letter score of at least 69 (approximately 20 / 40 Snellen equivalents); increase in BCVA as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart. > 5. > 10. > 15 or >20 letters, or no loss during the course of treatment; increase in mean BCVA over a 12-week period; no intraretinal fluid (IRF) or subretinal fluid; reduced choroidal neovascularization (CNV) size; reduced total damaged CNV area compared to baseline; loss of IRF and / or SRF; reduced central retinal zone thickness (CST); improvement in vision-related quality of life as measured by the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25); absence of adverse events (AEs) and / or serious AEs (SAEs) occurring during the treatment period; efficacy and / or safety in subjects with nAMD, with intravitreal administration of 2 mg approximately every 4 weeks for the first 3 months, followed by approximately every 8 weeks or every 2 months. Similar to aflibercept administered intravitreal at mg / dL, where efficacy is measured as an increase in BCVA and / or a decrease in central retinal thickness, and where safety is measured by the incidence of adverse events such as increased blood pressure, increased intraocular pressure, visual disturbances, vitreous floaters, vitreous detachment, iris neovascularization, and / or vitreous hemorrhage; no anti-drug antibodies detected during treatment; improvement in best-corrected visual acuity (BVCA) from treatment start (baseline) to weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, or 60; and an increase in BCVA ≥2 letters, ≥3 letters, ≥4 letters, ≥5 letters, ≥6 letters, or ≥5 letters as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart or Snellen equivalent. >7 letters; BCVA improvement at 4 weeks after treatment initiation is approximately 2 or 3 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 3 letters (ETDRS or Snellen equivalent) with the HDq16 regimen; BCVA improvement at 8 weeks after treatment initiation is approximately 5 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 4 or 5 letters (ETDRS or Snellen equivalent) with the HDq16 regimen; BCVA improvement at 12 weeks after treatment initiation is approximately 5 or 6 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 6 letters (ETDRS or Snellen equivalent) with the HDq16 regimen. The improvement in BCVA at 16 weeks after treatment initiation is approximately 5 or 6 letters (ETDRS or Snellen equivalent); or approximately 6 or 7 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; the improvement in BCVA at 20 weeks after treatment initiation is approximately 6 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 6 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen; the improvement in BCVA at 24 weeks after treatment initiation is approximately 5 or 6 letters (ETDRS or Sn) when using the HDq12 regimen. Snellen equivalent); or approximately 5 or 6 letters when using the HDq16 regimen (ETDRS or Snellen equivalent); BCVA improvement at 28 weeks after treatment initiation is approximately 7 letters when using the HDq12 regimen (ETDRS or Snellen equivalent); or approximately 6 letters when using the HDq16 regimen (ETDRS or Snellen equivalent); BCVA improvement at 32 weeks after treatment initiation is approximately 6 or 7 letters when using the HDq12 regimen (ETDRS or Snellen equivalent); or approximately 7 letters when using the HDq16 regimen (ETDRS or Snellen equivalent); BCVA improvement at 36 weeks after treatment initiation is approximately 7 letters when using the HDq12 regimen (ETDRS or Snellen equivalent); The BCVA improvement at 40 weeks after treatment initiation is approximately 6 or 7 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 5 or 6 letters (ETDRS or Snellen equivalent) with the HDq16 regimen; and approximately 7 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 5 or 6 letters (ETDRS or Snellen equivalent) with the HDq16 regimen.The improvement in BCVA at 48 weeks after treatment initiation was approximately 6 or 7 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 6 letters (ETDRS or Snellen equivalent) with the HDq16 regimen; the improvement in BCVA at 52 weeks after treatment initiation was approximately 7 or 8 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 6 or 7 letters (ETDRS or Snellen equivalent) with the HDq16 regimen; the improvement in BCVA at 56 weeks after treatment initiation was approximately 6 or 7 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 6 or 7 letters (ETDRS or Snellen equivalent) with the HDq16 regimen; and the improvement in BCVA at 60 weeks after treatment initiation was... Improvement in BCVA was approximately 6 or 7 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 6 or 7 letters (ETDRS or Snellen equivalent) with the HDq16 regimen; improvement in BCVA at approximately 48 to 60 weeks after treatment initiation was approximately 6 or 7 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 6 or 7 letters (ETDRS or Snellen equivalent) with the HDq16 regimen; improvement in BCVA at 60 weeks after treatment initiation was approximately 5, 10, or 15 letters (ETDRS or Snellen equivalent) with either the HDq12 or HDq16 regimen; improvement in BCVA was observed at approximately 8, 9, 10, 11, or 12 weeks after treatment initiation and maintained thereafter during the treatment regimen (at approximately; + 1 or +The BCVA at 4 weeks after treatment initiation is approximately 63 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 63 letters (ETDRS or Snellen equivalent) with the HDq16 regimen; approximately 65 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 65 letters (ETDRS or Snellen equivalent) with the HDq16 regimen; and approximately 66 letters (ETDRS or Snellen equivalent) with the HDq12 regimen at 12 weeks after treatment initiation. The BCVA at 16 weeks after treatment initiation is approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen; or approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or ... The BCVA is approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen; the BCVA at 28 weeks after treatment initiation is approximately 67 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen; the BCVA at 32 weeks after treatment initiation is approximately 67 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 67 letters (ETD) when using the HDq16 regimen. RS or Snellen equivalent); BCVA at 36 weeks after treatment initiation is approximately 67 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 66 letters (ETDRS or Snellen equivalent) with the HDq16 regimen; BCVA at 40 weeks after treatment initiation is approximately 67 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 66 letters (ETDRS or Snellen equivalent) with the HDq16 regimen; BCVA at 44 weeks after treatment initiation is approximately 68 letters (ETDRS or Snellen equivalent) with the HDq12 regimen.Alternatively, the BCVA may be approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen; the BCVA at 48 weeks post-treatment initiation may be approximately 67 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or the BCVA may be approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen; the BCVA at 52 weeks post-treatment initiation may be approximately 67 or 68 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen. The BCVA at 56 weeks post-treatment with the HDq16 regimen is approximately 66 or 67 letters (ETDRS or Snellen equivalent); the BCVA at 60 weeks post-treatment with the HDq12 regimen is approximately 66 or 67 letters (ETDRS or Snellen equivalent); or the BCVA at 60 weeks post-treatment with the HDq12 regimen is approximately 66 or 67 letters (ETDRS or Snellen equivalent). Snellen equivalent); or with the HDq16 regimen, the BCVA is approximately 66 or 67 letters (ETDRS or Snellen equivalent); the BCVA between approximately 48 and 60 weeks after treatment initiation is approximately 66 to approximately 72 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or with the HDq16 regimen, the BCVA is approximately 66 to approximately 70 letters (ETDRS or Snellen equivalent); the retina has no fluid in the central region (total fluid, intraretinal fluid [IR]). [F] and / or subretinal fluid [SRF]); no subretinal pigment epithelial fluid; no fluid leakage during fluorescein angiography (FA); a reduction in central retinal thickness (CRT) of at least approximately 100, 125, 130, 135, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, or 150 micrometers; a change in central retinal thickness over 4 weeks after treatment initiation of approximately -120, -121, -122, -122.4, or -120.2 micrometers when using this HDq12 regimen; + Approximately 10, 11, or 12 micrometers); or approximately -126, -127, -126.6, or -126.3 micrometers when using the HDq16 scheme. + Approximately 10, 11, or 12 micrometers); the change in central retinal thickness 8 weeks after treatment initiation using the HDq12 regimen was approximately -132, -133, -134, -135, -136, -136.2, or -132.8 micrometers. + Approximately 10, 11, or 12 micrometers); or approximately -139, -140, -139.5, or -139.6 micrometers when using the HDq16 scheme. +Approximately 10, 11, or 12 micrometers); the change in central retinal thickness 12 weeks after treatment initiation using the HDq12 regimen was approximately -136, -137, -138, -139, -140, -141, -140.9, or -136.6 micrometers. + Approximately 10, 11, or 12 micrometers); or approximately -144, -143, or -143.5 micrometers when using the HDq16 scheme. + Approximately 10, 11, or 12 micrometers); the change in central retinal thickness 16 weeks after treatment initiation using the HDq12 regimen was approximately -120, -121, -122, -123, -124, -123.4, or -120.1 micrometers. + Approximately 10, 11, or 12 micrometers); or approximately -132, -133, -132.1, or -133.1 micrometers when using the HDq16 scheme. + Approximately 10, 11, or 12 micrometers); the change in central retinal thickness 20 weeks after treatment initiation using the HDq12 regimen was approximately -110, -111, -112, -113, -114, -113.6, or -110.9 micrometers. + Approximately 10, 11, or 12 micrometers); or approximately -115, -116, -117, -118, -115.8, or -117.7 micrometers when using the HDq16 scheme. + Approximately 10, 11, or 12 micrometers); the change in central retinal thickness 24 weeks after treatment initiation using the HDq12 regimen was approximately -134, -135, -136, -137, -138, -137.6, or -134.9 micrometers. + Approximately 10, 11, or 12 micrometers); or approximately -105, -106, -107, -108, -105.3, or -107.8 micrometers when using the HDq16 scheme. + Approximately 10, 11, or 12 micrometers); the change in central retinal thickness 28 weeks after treatment initiation using the HDq12 regimen was approximately -130, -131, -132, -133, -134, -133.7, or -130.7 micrometers. + Approximately 10, 11, or 12 micrometers); or approximately -144, -145, -146, -147, -148, -144.7, or -147.2 micrometers when using the HDq16 scheme. + Approximately 10, 11, or 12 micrometers); the change in central retinal thickness 32 weeks after treatment initiation using the HDq12 regimen was approximately -118, -19, -120, -121, -120.4, or -118.1 micrometers. +Approximately 10, 11, or 12 micrometers); or approximately -141, -142, -143, -144, -141.5, or -144 micrometers when using the HDq16 scheme. + Approximately 10, 11, or 12 micrometers); the change in central retinal thickness 36 weeks after treatment initiation was approximately -142, -143, -144, -144.2, or -142.2 micrometers when using the HDq12 regimen. + Approximately 10, 11, or 12 micrometers); or approximately -126, -127, -128, -129, -130, -131, -126.4, or -130.5 micrometers when using the HDq16 scheme. + Approximately 10, 11, or 12 micrometers); the change in central retinal thickness 40 weeks after treatment initiation was approximately -131, -132, -133, -134, -133.8, or -131.2 micrometers with the HDq12 regimen. + Approximately 10, 11, or 12 micrometers); or approximately -127, -128, or -127.5 micrometers when using the HDq16 scheme. + Approximately 10, 11, or 12 micrometers); the change in central retinal thickness 44 weeks after treatment initiation using the HDq12 regimen was approximately -120, -121, -122, -123, -124, -125, -124.7, or -120.3 micrometers. + Approximately 10, 11, or 12 micrometers); or approximately -143, -144, -145, or -144.8 micrometers when using the HDq16 scheme. + Approximately 10, 11, or 12 micrometers); the change in central retinal thickness 48 weeks after treatment initiation was approximately -142, -143, -144, -144.4, or -142.3 micrometers when using the HDq12 regimen. + Approximately 10, 11, or 12 micrometers); or approximately -143, -144, -145, -146, -147, -148, -143.8, or -147.1 micrometers when using the HDq16 scheme. + Approximately 10, 11, or 12 micrometers); the change in central retinal thickness 52 weeks after treatment initiation was approximately -143.2 micrometers with the HDq12 regimen. + Approximately 10, 11, or 12 micrometers); or approximately -139.6 micrometers when using the HDq16 scheme. + Approximately 10, 11, or 12 micrometers); the change in central retinal thickness 56 weeks after treatment initiation was approximately -136.3 micrometers with the HDq12 regimen. + Approximately 10, 11, or 12 micrometers); or approximately -137.5 micrometers when using the HDq16 scheme. +Approximately 10, 11, or 12 micrometers); the change in central retinal thickness 60 weeks after treatment initiation was approximately -151.8 micrometers with the HDq12 regimen. + Approximately 10, 11, or 12 micrometers); or approximately -148.8 micrometers when using the HDq16 scheme. +(Approximately 10, 11, or 12 micrometers); the central retinal thickness at week 4 after treatment initiation was approximately 248.2 micrometers with the HDq12 regimen; or approximately 244.1 micrometers with the HDq16 regimen; the central retinal thickness at week 8 after treatment initiation was approximately 234.4 micrometers with the HDq12 regimen; or approximately 231.2 micrometers with the HDq16 regimen; the central retinal thickness at week 12 after treatment initiation was approximately 229.7 micrometers with the HDq12 regimen; or approximately 226.7 micrometers with the HDq16 regimen; the central retinal thickness at week 16 after treatment initiation was approximately 247.2 micrometers with the HDq12 regimen; or approximately 10, 11, or 12 micrometers with the HDq16 regimen. The central retinal thickness at week 20 after treatment initiation was approximately 238.6 micrometers with the HDq12 regimen; or approximately 254.9 micrometers with the HDq16 regimen; the central retinal thickness at week 24 after treatment initiation was approximately 233 micrometers with the HDq12 regimen; or approximately 265.4 micrometers with the HDq16 regimen; the central retinal thickness at week 28 after treatment initiation was approximately 236.9 micrometers with the HDq12 regimen; or approximately 226 micrometers with the HDq16 regimen; the central retinal thickness at week 32 after treatment initiation was approximately 250.2 micrometers with the HDq12 regimen; or approximately 229 micrometers with the HDq16 regimen. The central retinal thickness at week 36 after treatment initiation was approximately 226.4 micrometers with the HDq12 regimen; or approximately 244.3 micrometers with the HDq16 regimen; the central retinal thickness at week 40 after treatment initiation was approximately 236.8 micrometers with the HDq12 regimen; or approximately 243.7 micrometers with the HDq16 regimen; the central retinal thickness at week 44 after treatment initiation was approximately 245.9 micrometers with the HDq12 regimen; or approximately 227.7 micrometers with the HDq16 regimen; the central retinal thickness at week 48 after treatment initiation was approximately 226.2 micrometers with the HDq12 regimen; or approximately 226. 9 micrometers; the central retinal thickness at week 52 after treatment initiation was approximately 227.4 micrometers with the HDq12 regimen; or approximately 231.1 micrometers with the HDq16 regimen; the central retinal thickness at week 56 after treatment initiation was approximately 234.3 micrometers with the HDq12 regimen; or approximately 233.2 micrometers with the HDq16 regimen; the central retinal thickness at week 60 after treatment initiation was approximately 218.8 micrometers with the HDq12 regimen; or approximately 221.9 micrometers with the HDq16 regimen; the CRT decreased at approximately weeks 4, 5, 6, 7, or 8 after treatment initiation and remained thereafter during the treatment regimen (within approximately...).+ 10. + 11 or + Within 12 micrometers); approximately 4 hours after the initiation of HDq12 or HDq16 treatment, the plasma concentration of free aflibercept was approximately 0.0409 g (12 micrometers); + 0.0605 mg / L or 0 mg / L (or <0.0156 mg / L); approximately 8 hours after the initiation of HDq12 or HDq16 treatment, the plasma concentration of free aflibercept is approximately 0.05 mg / L. + 3.78), 0.0973 ( + 0.102) or 0.0672 mg / L; approximately day 2 after the initiation of HDq12 or HDq16 treatment, the plasma concentration of free aflibercept was approximately 0.11 ( + 2.21), 0.146 + 0.110) or 0.0903 mg / L; around day 3 after the initiation of HDq12 or HDq16 treatment, the plasma concentration of free aflibercept was approximately 0.11 ( + 2.06), 0.137 ( + 0.0947 mg / L or 0.112 mg / L; approximately day 5 after the initiation of HDq12 or HDq16 treatment, the plasma concentration of free aflibercept was approximately 0.08 mg / L. + 1.86), 0.0933 ( + 0.0481 mg / L or 0.0854 mg / L; approximately day 8 after the initiation of HDq12 or HDq16 treatment, the plasma concentration of free aflibercept was approximately 0.07 mg / L. + 1.75), 0.0794 + 0.0413 mg / L or 0.0682 mg / L; approximately day 15 after the initiation of HDq12 or HDq16 treatment, the plasma concentration of free aflibercept was approximately 0.04 mg / L. + 1.76), 0.0435 ( + 0.0199 mg / L or 0.0385 mg / L; around day 22 after the initiation of HDq12 or HDq16 treatment, the plasma concentration of free aflibercept was approximately 0.02 mg / L. + 1.76), 0.0213 ( + 0.0148) or 0.0232 mg / L; around day 29 after the initiation of HDq12 or HDq16 treatment, the plasma concentration of free aflibercept was approximately 0.00766 ( ). +0.00958 mg / L or 0 mg / L (or <0.0156 mg / L); approximately 4 hours after administration following the initiation of HDq12 or HDq16 treatment, the adjusted plasma concentration of bound aflibercept was approximately 0.00 mg / L; approximately 8 hours after administration following the initiation of HDq12 or HDq16 treatment, the adjusted plasma concentration of bound aflibercept was approximately 0.00 mg / L; approximately day 2 after the initiation of HDq12 or HDq16 treatment, the adjusted plasma concentration of bound aflibercept was approximately 0.06 mg / L. + 3.50) or 0.124 ( + 0.186) mg / L; approximately day 3 after the initiation of HDq12 or HDq16 treatment, the adjusted plasma concentration of bound aflibercept was approximately 0.13 ( + 2.07) or 0.173 ( + 0.155) mg / L; approximately day 5 after initiation of HDq12 or HDq16 treatment, the adjusted plasma concentration of bound aflibercept was approximately 0.18 ( + 1.88) or 0.223 ( + 0.157) mg / L; approximately day 8 after initiation of HDq12 or HDq16 treatment, the adjusted plasma concentration of bound aflibercept was approximately 0.31 ( + 1.56) or 0.334 ( + 0.135) mg / L; approximately day 15 after initiation of HDq12 or HDq16 treatment, the adjusted plasma concentration of bound aflibercept was approximately 0.37 ( + 1.50) or 0.393 ( + 0.130) mg / L; on approximately day 22 following the initiation of HDq12 or HDq16 treatment, the adjusted plasma concentration of bound aflibercept was approximately 0.25 ( + 3.00) or 0.335 ( + 0.155) mg / L; on approximately day 29 following the initiation of HDq12 or HDq16 treatment, the adjusted plasma concentration of bound aflibercept was approximately 0.32 ( + 1.39) or 0.331 ( +0.0953) mg / L; non-inferiority of BVCA compared to aflibercept administered intravitreally at approximately 2 mg every 4 weeks for the first 3, 4, or 5 injections, followed by approximately 2 mg every 8 weeks or every 2 months; ocular and non-ocular safety or mortality in subjects with DME compared to 5 injections of approximately 2 mg intravitreally at approximately 2 mg every 4 weeks, followed by approximately 2 mg every 8 weeks or every 2 months. Similar to aflibercept administered intravitreal at mg; improvement in best-corrected visual acuity from the start of treatment to weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48; improvement in best-corrected visual acuity of ≥2 letters, ≥3 letters, ≥4 letters, ≥5 letters, ≥6 letters, or ≥7 letters as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart or Snellen equivalent from the start of treatment to weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, or 60. > 7 letters; from the start of treatment to weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, or 60, the retina has no fluid in the central region (total fluid, intraretinal fluid [IRF], and / or subretinal fluid [SRF]); and / or from the start of treatment to weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, or 60, the central retinal thickness (CRT) is reduced by at least 100, 125, 130, 135, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, or 150 micrometers. In one embodiment of the invention, a dry retina lacks intraretinal fluid and / or subretinal fluid; or a dry retina is characterized by the absence of intraretinal fluid (IRF) and subretinal fluid (SRF) in the subject's eye. In another embodiment of the invention, a dry retina is characterized by the absence of intraretinal fluid (IRF) and subretinal fluid (SRF) in the subject's eye after the subject has received a three-month dose of VEGF receptor fusion protein.

[0050] In one embodiment of the invention, the subject is given one initial dose, two second doses, and three third doses in the first year; or the subject is given one initial dose, two second doses, and two third doses in the first year; or the subject is given one initial dose, two second doses, and three third doses in the first year, followed by two to four third doses in the second year.

[0051] In one embodiment of the invention, based on visual and / or anatomical results, such as according to Figure 3 and / or Figure 4Adjust (increase / maintain / decrease) the dose interval according to the standard shown.

[0052] In one embodiment of the invention, 12-20 weeks refers to 12, 13, 14, 15, 16, 17, 18, 19 or 20 weeks; while 2-4 weeks refers to 2, 3, 4 or 5 weeks.

[0053] Preferably, the VEGF receptor fusion protein in this article is aflibercept.

[0054] This invention provides a kit comprising: a container containing a VEGF receptor fusion protein (preferably aflibercept); and instructions for use of the VEGF receptor fusion protein, wherein the container is a vial or a pre-filled syringe, wherein the container contains... > 100 mg / mL VEGF receptor fusion protein, wherein the container contains > 114.3 mg / mL VEGF receptor fusion protein, wherein the instruction manual includes instructions for administering VEGF receptor fusion protein to patients with DME / AMD, wherein the instruction manual includes instructions for starting treatment with 8 mg of VEGF receptor fusion protein once a month (once every 4 weeks) for 3 consecutive doses, wherein the instruction manual includes instructions for extending the injection interval to every 16 weeks or every 20 weeks after the initial 3 consecutive doses, and wherein the instruction manual includes instructions for adjusting the treatment interval based on the physician's judgment of visual and / or anatomical results.

[0055] This invention provides aflibercept for use in the treatment or prevention of neovascular age-related macular degeneration (nAMD) in subjects in need, the treatment or prevention comprising administering one or more doses of aflibercept at intervals and in quantities such that, following intravitreal injection of aflibercept, the clearance of free aflibercept from the ocular ventricle is approximately 0.37-0.46 mL / day, the time to reach the lower limit of quantitation (LLOQ) of free aflibercept in the subject's ocular ventricle following the intravitreal injection is approximately 15 weeks, and the time to reach the lower limit of quantitation (LLOQ) of free aflibercept in the subject's plasma following the intravitreal injection is approximately 3.5 weeks.

[0056] This invention provides aflibercept for use in a method for slowing the clearance rate of free aflibercept from the ocular ventricle after intravitreal injection relative to the rate of clearance of aflibercept from the ocular ventricle after intravitreal injection of <4 mg aflibercept, wherein the method comprises intravitreal injection of a single initial dose of about 8 mg or more of aflibercept into the eye of a subject in need, followed by one or more second doses of about 8 mg or more of aflibercept, followed by one or more third doses of about 8 mg or more of aflibercept; wherein each second dose is administered about 2 to 4 weeks after the immediate preceding dose; and wherein each third dose is administered about 12 to 20 weeks after the immediate preceding dose.

[0057] This invention provides aflibercept used in a method for increasing the time to reach the lower limit of quantitation (LLOQ) of free aflibercept in the eye chamber of a subject after intravitreal injection of aflibercept relative to the time to reach the LLOQ after intravitreal injection of about 2 mg of aflibercept, wherein the method comprises intravitreal injection of about 8 mg or more of a single initial dose of aflibercept into the eye of a subject in need, followed by one or more second doses of about 8 mg or more of aflibercept, followed by one or more third doses of about 8 mg or more of aflibercept; wherein each second dose is administered about 2 to 4 weeks immediately following the preceding dose; and

[0058] Each third dose is administered approximately 12-20 weeks after the preceding dose.

[0059] This invention provides a method for increasing the time to reach the lower limit of quantitation (LLOQ) of free aflibercept in a subject's plasma after intravitreal injection of aflibercept relative to the time to reach the LLOQ of free aflibercept in a subject's plasma after intravitreal injection of approximately 2 mg of aflibercept. This method involves injecting the vitreous humor into the eye of the recipient. A single initial dose of approximately 8 mg or more of aflibercept, followed by A second dose of aflibercept, once or multiple times, approximately 8 mg or more, followed by A third dose of aflibercept, once or multiple times, approximately 8 mg or more; Each second dose is administered approximately 2 to 4 weeks after the preceding dose; and each third dose is administered approximately 12 to 20 weeks after the preceding dose. This invention provides a VEGF receptor fusion protein for use in the following method, which is used for - For the treatment or prevention of neovascular age-related macular degeneration (nAMD) in subjects of need. - Used to improve the best corrected visual acuity of subjects in need with nAMD; or - Used to promote retinal dryness in subjects in need who have nAMD; The method involves administering one or more doses of approximately 8 mg or more of the VEGF receptor fusion protein to the eye of the subject every 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks, or 12-20 weeks, or 12-16 weeks, or 16-20 weeks.

[0060] This invention provides aflibercept for use in the treatment or prevention of neovascular age-related macular degeneration (nAMD) in subjects of need, wherein the treatment or prevention comprises initiating treatment with an 8 mg aflibercept injection once monthly (every 4 weeks) for three consecutive doses, followed by one or more injections every 8-16 weeks or 8-20 weeks, wherein the concentration of aflibercept at each dose is 114.3 mg / mL or wherein the application volume of each dose is 70 µL. In one embodiment of the invention, adjustments (increase / maintain / decrease) are made based on visual and / or anatomical results, such as, but not limited to, an increase or loss of letters in BCVA; an increase or decrease in CRT; the presence of subretinal fluid; or the presence of hemorrhage. > The treatment interval between two subsequent administrations of 8 mg aflibercept. In one embodiment of the invention, if the subject has been identified as meeting at least one of the following criteria for reducing the treatment interval, the treatment interval is reduced by 2-4 weeks, 2 weeks, 3 weeks, or 4 weeks compared to the previous treatment interval: BCVA loss > 5 letters; central retinal thickness (CRT) increase > 25 micrometers; new foveal hemorrhage; or new foveal neovascularization. In one embodiment of the invention, if the subject has been identified as meeting at least one of the following criteria for extending the treatment interval, the treatment interval is extended by 2-4 weeks, 2 weeks, 3 weeks, or 4 weeks compared to the previous treatment interval: BCVA loss < 5 letters; no fluid in the central region; no new foveal hemorrhage; or no foveal neovascularization.

[0061] This invention provides a VEGF receptor fusion protein for use in the treatment or prevention of neovascular age-related macular degeneration (nAMD) in subjects of need, wherein the method comprises administering 8 mg of VEGF receptor fusion protein (0.07 mL or 70 μL) via intravitreal injection for the first three doses every 4 weeks (approximately every 28 days + / - 7 days, once a month), followed by intravitreal injection of 8 mg of VEGF receptor fusion protein (0.07 mL) every 8–16 weeks (2–4 months + / - 7 days) or every 8–20 weeks (2–5 months + / - 7 days).

[0062] This invention provides a VEGF receptor fusion protein for use in the treatment or prevention of neovascular age-related macular degeneration (nAMD) in subjects of need, wherein the method comprises administering 8 mg of VEGF receptor fusion protein (0.07 mL or 70 μL) via intravitreal injection for the first three doses every 4 weeks (approximately every 28 days + / - 7 days, once a month), and thereafter every 12 weeks (2-4 months + / - 7 days) via intravitreal injection of 8 mg of VEGF receptor fusion protein (0.07 mL).

[0063] This invention provides a VEGF receptor fusion protein for use in the treatment or prevention of neovascular age-related macular degeneration (nAMD) in subjects in need, wherein the method comprises administering 8 mg of VEGF receptor fusion protein (0.07 mL or 70 μL) via intravitreal injection for the first three doses every 4 weeks (approximately every 28 days + / - 7 days, once a month), and thereafter every 16 weeks (2-4 months + / - 7 days) via intravitreal injection of 8 mg of VEGF receptor fusion protein (0.07 mL).

[0064] This invention provides a VEGF receptor fusion protein for use in the treatment or prevention of disease in subjects in need, wherein the method comprises administering 8 mg of VEGF neovascular age-related macular degeneration (nAMD) receptor fusion protein (0.07 mL or 70 μL) via intravitreal injection for the first three doses every 4 weeks (approximately every 28 days + / - 7 days, once a month), and thereafter every 20 weeks (2-4 months + / - 7 days) via intravitreal injection of 8 mg of VEGF receptor fusion protein (0.07 mL).

[0065] This invention provides a VEGF receptor fusion protein for use in the treatment or prevention of neovascular age-related macular degeneration (nAMD) in subjects of need, wherein: (1) The subject had received an initial 2 mg dose of VEGF receptor fusion protein, and the method then included administering the initial dose to the subject one month later. > 8 mg dose of VEGF receptor fusion protein, followed by the first administration 1 month later. > A second dose of 8 mg of VEGF receptor fusion protein; and a second dose one month thereafter. > A second dose of 8 mg of the VEGF receptor fusion protein; then, once or multiple times every 12, 16, or 20 weeks, according to the HDq12, HDq16, or HDq20 dosing regimen. > 8 mg maintenance dose of VEGF receptor fusion protein; (2) The subject had received an initial 2 mg dose of VEGF receptor fusion protein, and then the method included administering the first dose to the subject 1 month later. > A second dose of 8 mg of VEGF receptor fusion protein was administered, followed by a second dose one month later. > 8 mg of VEGF receptor fusion protein as a second dose; then, once or multiple times every 12, 16, or 20 weeks, according to the HDq12, HDq16, or HDq20 dosing regimen. > 8 mg maintenance dose of VEGF receptor fusion protein; (3) The subject had received an initial 2 mg dose of VEGF receptor fusion protein, and the method then included administering a second dose to the subject one month later. > A second dose of 8 mg of VEGF receptor fusion protein, followed by one or more administrations every 12, 16, or 20 weeks according to the stated HDq12, HDq16, or HDq20 dosing regimen. > 8 mg maintenance dose of VEGF receptor fusion protein; (4) The subject had received an initial 2 mg dose of VEGF receptor fusion protein, and the method then included administering the first dose to the subject 1 month later. > 8 mg maintenance dose of VEGF receptor fusion protein, and all other medications administered every 12, 16, or 20 weeks according to the HDq12, HDq16, or HDq20 dosing regimen. > 8 mg maintenance dose of VEGF receptor fusion protein; (5) The subject has received an initial 2 mg dose of VEGF receptor fusion protein and received a first 2 mg second dose of VEGF receptor fusion protein one month later, and the method then includes administering the initial dose to the subject one month later. > 8 mg dose of VEGF receptor fusion protein, followed by the first administration 1 month later. > A second dose of 8 mg of VEGF receptor fusion protein; and a second dose one month thereafter. > A second dose of 8 mg of the VEGF receptor fusion protein; then, once or multiple times every 12, 16, or 20 weeks, according to the HDq12, HDq16, or HDq20 dosing regimen. > 8 mg maintenance dose of VEGF receptor fusion protein; (6) The subject had received an initial 2 mg dose of VEGF receptor fusion protein and received a first 2 mg dose of VEGF receptor fusion protein one month later, and the method then included administering the first dose of VEGF receptor fusion protein to the subject one month later.> A second dose of 8 mg of VEGF receptor fusion protein was administered, followed by a second dose one month later. > 8 mg of VEGF receptor fusion protein as a second dose; then, once or multiple times every 12, 16, or 20 weeks, according to the HDq12, HDq16, or HDq20 dosing regimen. > 8 mg maintenance dose of VEGF receptor fusion protein; (7) The subject had received an initial 2 mg dose of VEGF receptor fusion protein and received a first 2 mg second dose of VEGF receptor fusion protein one month later, and the method then included administering a second dose to the subject one month later. > A second dose of 8 mg of VEGF receptor fusion protein, followed by one or more administrations every 12, 16, or 20 weeks according to the stated HDq12, HDq16, or HDq20 dosing regimen. > 8 mg maintenance dose of VEGF receptor fusion protein; (8) The subject had received an initial 2 mg dose of VEGF receptor fusion protein and received a first 2 mg dose of VEGF receptor fusion protein one month later, and the method then included administering the first dose to the subject one month later. > 8 mg maintenance dose of VEGF receptor fusion protein, and all other medications administered every 12, 16, or 20 weeks according to the HDq12, HDq16, or HDq20 dosing regimen. > 8 mg maintenance dose of VEGF receptor fusion protein; (9) The subject has received an initial 2 mg dose of VEGF receptor fusion protein, and one month later received a first 2 mg dose of VEGF receptor fusion protein, and one month later received a second 2 mg dose of VEGF receptor fusion protein. The method then includes administering the initial dose to the subject one month later. > 8 mg dose of VEGF receptor fusion protein, followed by the first administration 1 month later. > A second dose of 8 mg of VEGF receptor fusion protein; and a second dose one month thereafter. > A second dose of 8 mg of the VEGF receptor fusion protein; then, once or multiple times every 12, 16, or 20 weeks, according to the HDq12, HDq16, or HDq20 dosing regimen. > 8 mg maintenance dose of VEGF receptor fusion protein; (10) The subject had received an initial 2 mg dose of VEGF receptor fusion protein and, one month later, a first 2 mg dose of VEGF receptor fusion protein and, one month after that, a second 2 mg dose of VEGF receptor fusion protein. The method then includes administering the first dose of VEGF receptor fusion protein to the subject one month later. > A second dose of 8 mg of VEGF receptor fusion protein was administered, followed by a second dose one month later. > 8 mg of VEGF receptor fusion protein as a second dose; then, once or multiple times every 12, 16, or 20 weeks, according to the HDq12, HDq16, or HDq20 dosing regimen. > 8 mg maintenance dose of VEGF receptor fusion protein; (11) The subject had received an initial 2 mg dose of VEGF receptor fusion protein, and one month later received a first 2 mg dose of VEGF receptor fusion protein, and one month later received a second 2 mg dose of VEGF receptor fusion protein. The method then includes administering the second dose to the subject one month later. > A second dose of 8 mg of VEGF receptor fusion protein, followed by one or more administrations every 12, 16, or 20 weeks according to the stated HDq12, HDq16, or HDq20 dosing regimen. > 8 mg maintenance dose of VEGF receptor fusion protein; (12) The subject had received an initial 2 mg dose of VEGF receptor fusion protein, received a first 2 mg dose of VEGF receptor fusion protein one month later, and received a second 2 mg dose of VEGF receptor fusion protein one month later. The method then includes administering the first dose to the subject two months later. > 8 mg maintenance dose of VEGF receptor fusion protein, and all other medications administered every 12, 16, or 20 weeks according to the HDq12, HDq16, or HDq20 dosing regimen. > 8 mg maintenance dose of VEGF receptor fusion protein; (13) The subject had received an initial 2 mg dose of VEGF receptor fusion protein, received a first 2 mg dose of VEGF receptor fusion protein one month later, received a second 2 mg dose of VEGF receptor fusion protein one month later, and received a first 2 mg maintenance dose of VEGF receptor fusion protein eight weeks later. The method then includes administering the initial dose of VEGF receptor fusion protein to the subject up to two months after the last dose. >8 mg dose of VEGF receptor fusion protein, followed by the first administration 1 month later. > A second dose of 8 mg of VEGF receptor fusion protein; and a second dose one month thereafter. > A second dose of 8 mg of the VEGF receptor fusion protein; then, once or multiple times every 12, 16, or 20 weeks, according to the HDq12, HDq16, or HDq20 dosing regimen. > 8 mg maintenance dose of VEGF receptor fusion protein; (14) The subject had received an initial 2 mg dose of VEGF receptor fusion protein, and one month later received a first 2 mg dose of VEGF receptor fusion protein, and one month later received a second 2 mg dose of VEGF receptor fusion protein, and eight weeks later received a first 2 mg maintenance dose of VEGF receptor fusion protein, and then the method included administering the first dose of VEGF receptor fusion protein to the subject up to two months after the last dose. > A second dose of 8 mg of VEGF receptor fusion protein, followed by a second dose one month thereafter. > A second dose of 8 mg of VEGF receptor fusion protein, followed by one or more administrations every 12, 16, or 20 weeks according to the HDq12, HDq16, or HDq20 dosing regimen. > 8 mg maintenance dose of VEGF receptor fusion protein; (15) The subject had received an initial 2 mg dose of VEGF receptor fusion protein, received a first 2 mg dose of VEGF receptor fusion protein one month later, received a second 2 mg dose of VEGF receptor fusion protein one month later, and received a first 2 mg maintenance dose of VEGF receptor fusion protein eight weeks later. The method then includes administering a second dose of VEGF receptor fusion protein to the subject up to two months after the last dose. > A second dose of 8 mg of VEGF receptor fusion protein, followed by one or more administrations every 12, 16, or 20 weeks according to the HDq12, HDq16, or HDq20 dosing regimen. > 8 mg maintenance dose of VEGF receptor fusion protein; (16) The subject had received an initial 2 mg dose of VEGF receptor fusion protein, received a first 2 mg dose of VEGF receptor fusion protein one month later, received a second 2 mg dose of VEGF receptor fusion protein one month later, and received a first 2 mg maintenance dose of VEGF receptor fusion protein eight weeks later. The method then includes administering the first dose of VEGF receptor fusion protein to the subject up to two months after the last dose. > 8 mg maintenance dose of VEGF receptor fusion protein, and all other medications administered every 12, 16, or 20 weeks according to the HDq12, HDq16, or HDq20 dosing regimen. > 8 mg maintenance dose of VEGF receptor fusion protein; in, (i) The HDq12 dosing regimen includes: A single initial dose of approximately 8 mg or more of the VEGF receptor fusion protein, followed by... One or more second doses of the VEGF receptor fusion protein, approximately 8 mg or more, followed by One or more doses of approximately 8 mg or more of the VEGF receptor fusion protein; Each second dose is administered approximately 2 to 4 weeks after the preceding dose; and Each third dose is administered approximately 12 weeks after the preceding dose. (ii) The HDq16 dosing regimen includes: A single initial dose of approximately 8 mg or more of the VEGF receptor fusion protein, followed by... One or more second doses of the VEGF receptor fusion protein, approximately 8 mg or more, followed by One or more doses of approximately 8 mg or more of the VEGF receptor fusion protein; Each second dose is administered approximately 2 to 4 weeks after the preceding dose; and Each third dose is administered approximately 16 weeks after the preceding dose. and (iii) The HDq20 dosing regimen includes: A single initial dose of approximately 8 mg or more of the VEGF receptor fusion protein, followed by... One or more second doses of the VEGF receptor fusion protein, approximately 8 mg or more, followed by One or more doses of approximately 8 mg or more of the VEGF receptor fusion protein; Each second dose is administered approximately 2 to 4 weeks after the preceding dose; and Each third dose is administered approximately 20 weeks after the preceding dose.

[0066] This invention provides aflibercept for use in the treatment or prevention of neovascular age-related macular degeneration (nAMD) in subjects in need, the treatment or prevention comprising administration to the subject's eye. > A single initial dose of 8 mg aflibercept, followed by one or more administrations approximately > A third dose of aflibercept, 8 mg; wherein each third dose is administered approximately 8, 12, 16, or 20 weeks after the immediately preceding dose. In one embodiment of the invention, the subject is not a treatment-naïve subject, or the subject has been pretreated with a VEGF antagonist, or preferably the subject has been pretreated with 8 mg or 2 mg of aflibercept.

[0067] This invention provides aflibercept for use in the treatment or prevention of neovascular age-related macular degeneration (nAMD) in a subject who has been pretreated with 2 mg of aflibercept, the treatment or prevention comprising administering approximately [amount missing] mg of aflibercept to the subject's eye. > A single initial dose of 8 mg aflibercept, followed by one or more administrations approximately > A second dose of 8 mg aflibercept, followed by one or more administrations of a third dose of approximately 8 mg aflibercept, wherein each second dose is administered approximately 4 weeks after the immediate preceding dose and each third dose is administered approximately 8, 10, 12, 14, 16, 18, or 20 weeks after the immediate preceding dose. In one embodiment of the invention, one or more doses of 8 mg aflibercept are administered to the eye of the subject according to HDq12, HDq16, HDq20, or a treatment and extended dosing regimen.

[0068] This invention provides a VEGF receptor fusion protein for use in the treatment or prevention of neovascular age-related macular degeneration (nAMD) in subjects who have received a dosing regimen for the treatment or prevention of said condition, wherein: (a) The subject has received initial treatment > The method involves administering an 8 mg dose of VEGF receptor fusion protein to the subject, followed by the first administration of the protein one month later. > A second dose of 8 mg of VEGF receptor fusion protein was administered, followed by a second dose one month later. > 8 mg of VEGF receptor fusion protein as a second dose; then, once or multiple times every 12, 16, or 20 weeks, according to the HDq12, HDq16, or HDq20 dosing regimen. >8 mg maintenance dose of VEGF receptor fusion protein; or (b) The subject has received initial > 8 mg dose of VEGF receptor fusion protein and the first dose was administered 1 month later. > The method involves administering a second dose of 8 mg of VEGF receptor fusion protein to the subject, followed by a second dose one month later. > A second dose of 8 mg of VEGF receptor fusion protein, followed by one or more administrations every 12, 16, or 20 weeks according to the stated HDq12, HDq16, or HDq20 dosing regimen. > 8 mg maintenance dose of VEGF receptor fusion protein; or (c) The subject has received initial > 8 mg dose of VEGF receptor fusion protein and the first dose was administered 1 month later. > A second dose of 8 mg of VEGF receptor fusion protein was administered, followed by a second dose one month later. > The method involves administering a second dose of 8 mg of VEGF receptor fusion protein to the subject after 12, 16, or 20 weeks following the administration of the first dose. > 8 mg maintenance dose of VEGF receptor fusion protein, and all other medications administered every 12, 16, or 20 weeks according to the HDq12, HDq16, or HDq20 dosing regimen. > 8 mg maintenance dose of VEGF receptor fusion protein; or (d) wherein the subject has received initial > 8 mg dose of VEGF receptor fusion protein and the first dose was administered 1 month later. > 8 mg of VEGF receptor fusion protein as a second dose, followed by a second dose one month later. > The subject received a second dose of 8 mg of VEGF receptor fusion protein, followed by one or more doses every 12, 16, or 20 weeks thereafter. > The method then comprises administering one or more doses of VEGF receptor fusion protein to the subject 12, 16, or 20 weeks after the last maintenance dose of VEGF receptor fusion protein. > 8 mg maintenance dose of VEGF receptor fusion protein and all other medications administered every 12, 16, or 20 weeks according to the HDq12, HDq16, or HDq20 dosing regimen. > 8 mg maintenance dose of VEGF receptor fusion protein; in, (i) The HDq12 dosing regimen includes: about > A single initial dose of 8 mg or more of VEGF receptor fusion protein, followed by One or more appointments > A second dose of 8 mg or more of the VEGF receptor fusion protein, followed by One or more appointments > A third dose of the VEGF receptor fusion protein of 8 mg or more; Each second dose is administered approximately 2 to 4 weeks after the preceding dose; and Each third dose is administered approximately 12 weeks after the preceding dose. (ii) The HDq16 dosing regimen includes: A single initial dose of approximately 8 mg or more of the VEGF receptor fusion protein, followed by... One or more second doses of the VEGF receptor fusion protein, approximately 8 mg or more, followed by One or more doses of approximately 8 mg or more of the VEGF receptor fusion protein; Each second dose is administered approximately 2 to 4 weeks after the preceding dose; and Each third dose is administered approximately 16 weeks after the preceding dose. and (iii) The HDq20 dosing regimen includes: A single initial dose of approximately 8 mg or more of the VEGF receptor fusion protein, followed by... One or more second doses of the VEGF receptor fusion protein, approximately 8 mg or more, followed by One or more doses of approximately 8 mg or more of the VEGF receptor fusion protein; Each second dose is administered approximately 2 to 4 weeks after the preceding dose; and Each third dose is administered approximately 20 weeks after the preceding dose.

[0069] This invention provides a VEGF receptor fusion protein for use in the treatment or prevention of neovascular age-related macular degeneration (nAMD) in a subject who has received a dosing regimen for the treatment or prevention of nAMD, the dosing regimen comprising: a single initial dose of about 2 mg of the VEGF receptor fusion protein, followed by one or more second doses of about 2 mg of the VEGF receptor fusion protein, followed by one or more third doses of about 2 mg of the VEGF receptor fusion protein; wherein each second dose is administered approximately 4 weeks after the immediately preceding dose; and wherein each third dose is administered approximately 8 weeks after the immediately preceding dose; and wherein the subject is at any stage of the 2 mg VEGF receptor fusion protein dosing regimen, the method comprising administration to the subject's eye. > The subject was evaluated approximately 8, 10, or 12 weeks after administration of an 8 mg dose of VEGF receptor fusion protein, and if the treating physician determined that administration every 12 or 16 weeks was appropriate, the subject was continued to receive administration every 12 or 16 weeks. > 8 mg VEGF receptor fusion protein; or evaluate the subject approximately 8, 10, or 12 weeks after administration, and administer another dose if the treating physician determines that dosing every 12 weeks is appropriate. > The subject was given an 8 mg dose of VEGF receptor fusion protein and re-evaluated at approximately 12 weeks. If the treating physician determined that administration every 16 weeks was appropriate, the subject was continued to receive 8 mg of VEGF receptor fusion protein every 16 weeks.

[0070] This invention provides a VEGF receptor fusion protein for use in the treatment or prevention of neovascular age-related macular degeneration (nAMD) in subjects in need, wherein the treatment or prevention comprises administering a single initial dose of about 8 mg or more of the VEGF receptor fusion protein to the subject's eye, followed by one or more administrations of a second dose (preferably two doses) of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more administrations of a third dose of about 8 mg or more of the VEGF receptor fusion protein; wherein each second dose is administered about 2 to 4 weeks immediately following the preceding dose; and wherein each third dose is administered about 12 or 16 weeks immediately following the preceding dose; The method further includes extending the third dose interval after receiving one or more third doses approximately 12 or 16 weeks after the preceding dose. The duration has been extended from 12 weeks to 16 weeks. Extend from 12 weeks to 20 weeks; or The duration has been extended from 16 weeks to 20 weeks. This is immediately after the previous dose.

[0071] This invention provides a VEGF receptor fusion protein for use in the treatment or prevention of neovascular age-related macular degeneration (nAMD) in subjects of need, the treatment and prevention comprising administering a single initial dose of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more administrations of a second dose of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more administrations of a third dose of about 8 mg or more of the VEGF receptor fusion protein; wherein each second dose is administered about 2 to 4 weeks immediately following the preceding dose; and wherein each third dose is administered about 12, 16, or 20 weeks immediately following the preceding dose; The method further includes shortening the third dose interval after receiving one or more third doses approximately 12, 16, or 20 weeks immediately following the previous dose. Shortened from 12 weeks to 8 weeks; The duration has been shortened from 16 weeks to 12 weeks. Shortened from 16 weeks to 8 weeks Shortened from 20 weeks to 8 weeks Shortened from 20 weeks to 12 weeks, or The duration has been shortened from 20 weeks to 16 weeks.

[0072] This invention provides a VEGF receptor fusion protein for use in the treatment or prevention of neovascular age-related macular degeneration (nAMD) in subjects in need, the treatment and prevention comprising administering three doses to the subject's eye at 4-week intervals in the form of a formulation containing approximately 114.3 mg / ml of VEGF receptor fusion protein. > 8 mg of VEGF receptor fusion protein; wherein, after the three doses, one or more doses of VEGF receptor fusion protein are administered at intervals of extended 12, 16 or 20 weeks.

[0073] This invention provides a VEGF receptor fusion protein for use in the treatment and prevention of neovascular age-related macular degeneration (nAMD) in subjects of need, the treatment and prevention comprising administering a single initial dose of about 8 mg or more of the VEGF receptor fusion protein to the eye of the subject, followed by two second doses of about 8 mg or more of the VEGF receptor fusion protein. Each second dose is administered approximately 2 to 4 weeks after the preceding dose; and, after said dose... a) Determine whether the subject meets at least one criterion for reducing or extending one or more intervals between VEGF receptor fusion protein doses by 2 weeks, 3 weeks, 4 weeks, or 2–4 weeks; and b) If the determination is made, administer a higher dose of the VEGF receptor fusion protein at the reduced or extended dose interval. The criteria for extending the interval include: 1. BCVA loss > 5 letters; 2. Increase in central retinal thickness (CRT) > 25 micrometers; 3. New central fossa hemorrhage; and / or 4. New vascularization in the central fovea Furthermore, the criteria for reducing the interval include: 1. BCVA loss < 5 letters, 2. There is no liquid in the central compartment; 3. No new central foveal hemorrhage; and / or 4. No new blood vessels formed in the central fovea.

[0074] This invention provides a VEGF receptor fusion protein for use in the treatment and prevention of neovascular age-related macular degeneration (nAMD) in subjects who have been pretreated with one or more 2 mg doses of the VEGF receptor fusion protein, the method comprising administering to the eye of the subject a single initial dose of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more administrations of a second dose of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more administrations of a third dose of about 8 mg or more of the VEGF receptor fusion protein; Each second dose is administered approximately 2 to 4 weeks after the preceding dose; and each third dose is administered approximately 12 to 20 weeks after the preceding dose. This invention provides a VEGF receptor fusion protein for use in the treatment and prevention of angiogenic eye disease in subjects in need, the treatment and prevention comprising administration to the subject's eye. (1) A single initial dose of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more second doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more third doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each second dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each third dose is administered about 8 weeks after the immediately preceding dose; or (2) VEGF receptor fusion protein is administered once or more every 4 weeks at a dose of 8 mg or more.

[0075] A VEGF receptor fusion protein for use in the treatment and prevention of angiogenic eye diseases, wherein the treatment or prevention includes providing [the protein] before each administration. A single-dose glass vial with a protective plastic cap and stopper contains approximately 70 microliters of an aqueous formulation containing 8 mg of VEGF receptor fusion protein; A 18-gauge x 1.5-inch, 5-micron filter needle, including a tip and bevel; Packaged together; then (1) Visually inspect the aqueous formulation in the vial, and if particles, turbidity or discoloration are visible, use another vial containing the aqueous formulation of the 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; then Use aseptic techniques: (4) Remove the 18-gauge x 1.5-inch, 5-micron filter needle and the 1 mL syringe from their packaging; (5) The filter needle is attached to the syringe by screwing it onto the tip of the Luer lock syringe; (6) Push the filter needle into the center of the stopper until the needle is fully inserted into the vial and the tip touches the bottom or bottom edge of the vial; (7) Draw all the contents of the VEGF receptor fusion protein vial into the syringe, keep the vial upright and slightly tilted, and ensure that the bevel of the filter needle is submerged in the liquid; (8) Continue to tilt the vial during extraction, keeping the bevel of the filter needle submerged in the formulation; (9) When the vial is emptied, pull the plunger rod back fully to completely empty the filter needle; (10) Remove the filter needle from the syringe and dispose of the filter needle; (11) Remove the 30 x ½ inch injection needle from its packaging and attach the injection needle to the syringe by firmly screwing the injection needle onto the tip of the Luer lock syringe; (12) Hold the syringe with the needle facing upwards and check for air bubbles in the syringe. If air bubbles are present, gently tap the syringe with your finger until the air bubbles rise to the top; and (13) Slowly press down the plunger so that the tip of the plunger is aligned with the 70 microliter mark on the syringe.

[0076] This invention provides a VEGF receptor fusion protein for use in the treatment and prevention of neovascular age-related macular degeneration (nAMD) in subjects of need, wherein... > 8 mg of VEGF receptor fusion protein is contained in an aqueous pharmaceutical formulation comprising approximately 103-126 mg / ml of VEGF receptor fusion protein, histidine-based buffer, and arginine.

[0077] This invention provides a VEGF receptor fusion protein for use in the treatment and prevention of neovascular age-related macular degeneration (nAMD) in subjects of need, wherein... > The 8 mg VEGF receptor fusion protein is an aqueous pharmaceutical formulation containing approximately 114.3 mg / ml VEGF receptor fusion protein, histidine-based buffer, and arginine.

[0078] This invention provides aflibercept for use in the treatment or prevention of neovascular age-related macular degeneration (nAMD) in subjects of need, wherein... > 8 mg of aflibercept is contained in an aqueous pharmaceutical formulation, wherein the aflibercept immediately after production and purification has less than about 3.5% of high molecular weight material and / or less than or equal to about 6% of high molecular weight material after storage at about 2°C to 8°C for about 24 months.

[0079] This invention provides a VEGF receptor fusion protein for use in the treatment and prevention of neovascular age-related macular degeneration (nAMD) in subjects of need, wherein... > 8 mg of VEGF receptor fusion protein is contained in an aqueous pharmaceutical formulation, which comprises: At least approximately 100 mg / ml of VEGF receptor fusion protein; Approximately 10 mM-100 mM L-arginine; sucrose; Histidine-based buffer solutions; and Surfactants; The pH of the formulation is approximately 5.0 to approximately 6.8; the VEGF receptor fusion protein immediately after production and purification contains less than approximately 3.5% high molecular weight material and / or less than or equal to approximately 6% high molecular weight material after storage at approximately 2°C to 8°C for approximately 24 months.

[0080] This invention provides a VEGF receptor fusion protein for use in the treatment and prevention of neovascular age-related macular degeneration (nAMD) in subjects of need, wherein...> 8 mg of VEGF receptor fusion protein is contained in an aqueous pharmaceutical formulation, the aqueous pharmaceutical formulation comprising: >100 mg / ml VEGF receptor fusion protein, histidine-based buffer, and L-arginine; 140 mg / ml aflibercept; 20 mM histidine-based buffer; 5% sucrose; 0.03% polysorbate 20; 10 mM L-arginine; pH 5.8; 150 + 15 mg / ml aflibercept, 10 mM phosphate buffer, 8 + 0.8% (w / v) sucrose, 0.02-0.04% (w / v) polysorbate 20 and 50 mM L-arginine, pH 5.9-6.5; 103-126 mg / ml aflibercept, 10+1 mM histidine-based buffer, 5+0.5% (w / v) sucrose, 0.02%-0.04% (w / v) polysorbate 20 and 50+5 mM L-arginine, pH 5.5-6.1; 140 mg / ml aflibercept, 10 mM histidine-based buffer, 2.5% (w / v) sucrose, 2.0% (w / v) proline, 0.03% (w / v) polysorbate 20 and 50 mM L-arginine, pH 5.8; 114.3 mg / ml aflibercept, 10 mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20 and 50 mM L-arginine, pH 5.8; >100 mg / ml aflibercept, histidine-based buffer, and L-arginine; >100 mg / ml aflibercept, approximately pH 5.8, wherein the formulation forms <3% HMW aggregates after incubation at 5°C for 2 months; Approximately 114.3 mg / mL aflibercept; 10 mM-50 mM histidine-based buffer, sugar, nonionic surfactant, L-arginine, pH 5.8; Approximately 114.3 mg / mL aflibercept; 10 mM His / His-HCl-based buffer, 5% sucrose, 0.03% polysorbate-20, 50 mM L-arginine, pH 5.8; or Approximately 114.3 mg / mL aflibercept; arginine hydrochloride; histidine; histidine hydrochloride hydrate; polysorbate 20; sucrose and water for injection.

[0081] Best-corrected visual acuity (BCVA) improved; Best corrected visual acuity (BCVA) improved > 5. > 10. > 15 or > 20 letters; Best corrected visual acuity (BCVA) did not decrease; Eliminate retinal fluid; According to fluorescein angiography, there was no retinal fluid leakage. Reduced size of choroidal neovascularization There is no intraretinal fluid (IRF) and / or subretinal fluid in the central region; The total damaged choroidal neovascularization (CNV) area is reduced; Loss or reduction of intraretinal fluid; Loss or reduction of subretinal fluid; Central retinal thickness (CST) is reduced; Improvement in vision-related quality of life (e.g., measured by the NEI-VFQ-25 total score); The treatment period lacks adverse events (AEs) and / or serious AEs (SAEs); The ETDRS letter score is at least 69 (approximately 20 / 40 Snellen equivalent); An increase of >5, >10, >15, or >20 letters in BCVA as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart, or no loss during the course of treatment; The increase in average BCVA over a 12-week period; No intraretinal fluid (IRF) or subretinal fluid; The size of choroidal neovascularization (CNV) is reduced; The total damage CNV area decreased compared to baseline; Loss of IRF and / or SRF; Central retinal thickness (CST) is reduced; Improvements in vision-related quality of life as measured by the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25); The treatment period lacks adverse events (AEs) and / or serious AEs (SAEs); The efficacy and / or safety in subjects with nAMD were similar to those of aflibercept administered intravitreally at approximately 2 mg every 4 weeks for the first 3 months, followed by approximately 2 mg intravitreally every 8 weeks or every 2 months, wherein efficacy was measured as an increase in BCVA and / or a decrease in central retinal thickness, and wherein safety was measured as the incidence of adverse events such as increased blood pressure, increased intraocular pressure, visual disturbances, vitreous floaters, vitreous detachment, iris neovascularization, and / or vitreous hemorrhage. No anti-drug antibodies were detected during treatment; From the start of treatment (baseline) to weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56 or 60, the best corrected visual acuity (BVCA) improved; An increase of ≥2 letters, ≥3 letters, ≥4 letters, ≥5 letters, ≥6 letters, or >7 letters in BCVA as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart or Snellen equivalent. The improvement in BCVA 4 weeks after the start of treatment was approximately 2 or 3 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 3 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. The improvement in BCVA at 8 weeks after treatment initiation was approximately 5 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 4 or 5 letters (ETDRS or Snellen equivalent) with the HDq16 regimen. The improvement in BCVA at 12 weeks after treatment initiation was approximately 5 or 6 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 5 or 6 letters (ETDRS or Snellen equivalent) with the HDq16 regimen. The improvement in BCVA at 16 weeks after treatment initiation was approximately 6 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 6 or 7 letters (ETDRS or Snellen equivalent) with the HDq16 regimen. The improvement in BCVA at 20 weeks after treatment initiation was approximately 6 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 6 letters (ETDRS or Snellen equivalent) with the HDq16 regimen. The improvement in BCVA at 24 weeks after treatment initiation was approximately 5 or 6 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 5 or 6 letters (ETDRS or Snellen equivalent) with the HDq16 regimen. The improvement in BCVA at 28 weeks after treatment initiation was approximately 7 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 6 letters (ETDRS or Snellen equivalent) with the HDq16 regimen. The improvement in BCVA at 32 weeks after treatment initiation was approximately 6 or 7 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 7 letters (ETDRS or Snellen equivalent) with the HDq16 regimen. The improvement in BCVA at 36 weeks after the start of treatment was approximately 6 or 7 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 6 letters (ETDRS or Snellen equivalent) with the HDq16 regimen. The improvement in BCVA at 40 weeks after treatment initiation was approximately 6 or 7 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 5 or 6 letters (ETDRS or Snellen equivalent) with the HDq16 regimen. The improvement in BCVA at 44 weeks after treatment initiation was approximately 7 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 5 or 6 letters (ETDRS or Snellen equivalent) with the HDq16 regimen. The improvement in BCVA at 48 weeks after treatment initiation was approximately 6 or 7 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 6 letters (ETDRS or Snellen equivalent) with the HDq16 regimen. The improvement in BCVA at 52 weeks after treatment initiation was approximately 7 or 8 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 6 or 7 letters (ETDRS or Snellen equivalent) with the HDq16 regimen. The improvement in BCVA at 56 weeks after treatment initiation was approximately 6 or 7 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 6 or 7 letters (ETDRS or Snellen equivalent) with the HDq16 regimen. The improvement in BCVA at 60 weeks after treatment initiation was approximately 6 or 7 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 6 or 7 letters (ETDRS or Snellen equivalent) with the HDq16 regimen. The improvement in BCVA at approximately 48 to 60 weeks after the start of treatment was approximately 6 or 7 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 6 or 7 letters (ETDRS or Snellen equivalent) with the HDq16 regimen. The improvement in BCVA at 60 weeks after treatment initiation was approximately 5, 10, or 15 letters (ETDRS or Snellen equivalent) when using the HDq12 or HDq16 regimens. BCVA improves around week 8, 9, 10, 11 or 12 after treatment initiation and is maintained during the treatment regimen (within approximately 1 or 2 ETDRS letters or Snellen equivalents). The BCVA at 4 weeks after treatment initiation was approximately 63 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 63 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. The BCVA at 8 weeks after treatment initiation is approximately 65 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 65 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. The BCVA at 12 weeks after treatment initiation is approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. The BCVA at 16 weeks after treatment initiation is approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. The BCVA at 20 weeks after treatment initiation is approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. The BCVA at 24 weeks after treatment initiation is approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. The BCVA at 28 weeks after treatment initiation was approximately 67 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. The BCVA at 32 weeks after treatment initiation is approximately 67 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 67 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. The BCVA at 36 weeks after treatment initiation was approximately 67 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. The BCVA at 40 weeks after treatment initiation was approximately 67 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. The BCVA at 44 weeks after treatment initiation was approximately 68 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. The BCVA at 48 weeks after treatment initiation was approximately 67 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. The BCVA at 52 weeks after treatment initiation is approximately 67 or 68 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 or 67 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. The BCVA at 56 weeks after treatment initiation is approximately 66 or 67 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 or 67 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. The BCVA at 60 weeks after treatment initiation is approximately 66 or 67 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 or 67 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. The BCVA between approximately 48 and 60 weeks after the start of treatment is approximately 66 to approximately 72 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 to approximately 70 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. The retina has no fluid (total fluid, intraretinal fluid [IRF], and / or subretinal fluid [SRF]) in the central region; No subretinal pigment epithelial fluid; According to fluorescein angiography (FA), there was no fluid leakage; The central retinal thickness (CRT) is reduced by at least approximately 100, 125, 130, 135, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, or 150 micrometers; The change in central retinal thickness 4 weeks after treatment initiation was approximately -120, -121, -122, -122.4, or -120.2 micrometers when using the HDq12 regimen. + Approximately 10, 11, or 12 micrometers); or approximately -126, -127, -126.6, or -126.3 micrometers when using the HDq16 scheme. + (Approximately 10, 11, or 12 micrometers); The change in central retinal thickness 8 weeks after treatment initiation was approximately -132, -133, -134, -135, -136, -136.2, or -132.8 micrometers when using the HDq12 regimen. + Approximately 10, 11, or 12 micrometers); or approximately -139, -140, -139.5, or -139.6 micrometers when using the HDq16 scheme. + (Approximately 10, 11, or 12 micrometers); The change in central retinal thickness 12 weeks after treatment initiation was approximately -136, -137, -138, -139, -140, -141, -140.9, or -136.6 micrometers when using the HDq12 regimen. + Approximately 10, 11, or 12 micrometers); or approximately -144, -143, or -143.5 micrometers when using the HDq16 scheme. + (Approximately 10, 11, or 12 micrometers); The change in central retinal thickness 16 weeks after treatment initiation was approximately -120, -121, -122, -123, -124, -123.4, or -120.1 micrometers when using the HDq12 regimen. + Approximately 10, 11, or 12 micrometers); or approximately -132, -133, -132.1, or -133.1 micrometers when using the HDq16 scheme. + (Approximately 10, 11, or 12 micrometers); The change in central retinal thickness 20 weeks after treatment initiation was approximately -110, -111, -112, -113, -114, -113.6, or -110.9 micrometers when using the HDq12 regimen. +Approximately 10, 11, or 12 micrometers); or approximately -115, -116, -117, -118, -115.8, or -117.7 micrometers when using the HDq16 scheme. + (Approximately 10, 11, or 12 micrometers); The change in central retinal thickness 24 weeks after treatment initiation was approximately -134, -135, -136, -137, -138, -137.6, or -134.9 micrometers when using the HDq12 regimen. + Approximately 10, 11, or 12 micrometers); or approximately -105, -106, -107, -108, -105.3, or -107.8 micrometers when using the HDq16 scheme. + (Approximately 10, 11, or 12 micrometers); The change in central retinal thickness 28 weeks after treatment initiation was approximately -130, -131, -132, -133, -134, -133.7, or -130.7 micrometers when using the HDq12 regimen. + Approximately 10, 11, or 12 micrometers); or approximately -144, -145, -146, -147, -148, -144.7, or -147.2 micrometers when using the HDq16 scheme. + (Approximately 10, 11, or 12 micrometers); The change in central retinal thickness 32 weeks after treatment initiation was approximately -118, -19, -120, -121, -120.4, or -118.1 micrometers when using the HDq12 regimen. + Approximately 10, 11, or 12 micrometers); or approximately -141, -142, -143, -144, -141.5, or -144 micrometers when using the HDq16 scheme described above. + (Approximately 10, 11, or 12 micrometers); The change in central retinal thickness 36 weeks after treatment initiation was approximately -142 or -143 or -144 or -144.2 or -142.2 micrometers when using the HDq12 regimen. + Approximately 10, 11, or 12 micrometers); or approximately -126, -127, -128, -129, -130, -131, -126.4, or -130.5 micrometers when using the HDq16 scheme. + (Approximately 10, 11, or 12 micrometers); The change in central retinal thickness 40 weeks after treatment initiation was approximately -131, -132, -133, -134, -133.8, or -131.2 micrometers when using the HDq12 regimen.+ Approximately 10, 11, or 12 micrometers); or approximately -127, -128, or -127.5 micrometers when using the HDq16 scheme. + (Approximately 10, 11, or 12 micrometers); The change in central retinal thickness 44 weeks after treatment initiation was approximately -120, -121, -122, -123, -124, -125, -124.7, or -120.3 micrometers when using the HDq12 regimen. + Approximately 10, 11, or 12 micrometers); or approximately -143, -144, -145, or -144.8 micrometers when using the HDq16 scheme. + (Approximately 10, 11, or 12 micrometers); The change in central retinal thickness 48 weeks after treatment initiation was approximately -142, -143, -144, -144.4, or -142.3 micrometers when using the HDq12 regimen. + Approximately 10, 11, or 12 micrometers); or approximately -143, -144, -145, -146, -147, -148, -143.8, or -147.1 micrometers when using the HDq16 scheme. + (Approximately 10, 11, or 12 micrometers); The change in central retinal thickness 52 weeks after treatment initiation was approximately -143.2 micrometers with the HDq12 regimen. + Approximately 10, 11, or 12 micrometers); or approximately -139.6 micrometers when using the HDq16 scheme. + (Approximately 10, 11, or 12 micrometers); The change in central retinal thickness 56 weeks after treatment initiation was approximately -136.3 micrometers with the HDq12 regimen. + Approximately 10, 11, or 12 micrometers); or approximately -137.5 micrometers when using the HDq16 scheme. + (Approximately 10, 11, or 12 micrometers); The change in central retinal thickness 60 weeks after treatment initiation was approximately -151.8 micrometers with the HDq12 regimen. + Approximately 10, 11, or 12 micrometers); or approximately -148.8 micrometers when using the HDq16 scheme. + (Approximately 10, 11, or 12 micrometers); The central retinal thickness at week 4 after treatment initiation was approximately 248.2 micrometers with the HDq12 protocol and approximately 244.1 micrometers with the HDq16 protocol. At week 8 after treatment initiation, the central retinal thickness was approximately 234.4 micrometers with the HDq12 protocol and approximately 231.2 micrometers with the HDq16 protocol. The central retinal thickness at week 12 after treatment initiation was approximately 229.7 micrometers with the HDq12 protocol and approximately 226.7 micrometers with the HDq16 protocol. At week 16 after treatment initiation, the central retinal thickness was approximately 247.2 micrometers with the HDq12 protocol and approximately 238.6 micrometers with the HDq16 protocol. At week 20 after treatment initiation, the central retinal thickness was approximately 257 micrometers with the HDq12 protocol and approximately 254.9 micrometers with the HDq16 protocol. At week 24 after treatment initiation, the central retinal thickness was approximately 233 micrometers with the HDq12 protocol and approximately 265.4 micrometers with the HDq16 protocol. At week 28 after treatment initiation, the central retinal thickness was approximately 236.9 micrometers with the HDq12 protocol and approximately 226 micrometers with the HDq16 protocol. At week 32 after treatment initiation, the central retinal thickness was approximately 250.2 micrometers with the HDq12 protocol and approximately 229.2 micrometers with the HDq16 protocol. At week 36 after treatment initiation, the central retinal thickness was approximately 226.4 micrometers with the HDq12 protocol and approximately 244.3 micrometers with the HDq16 protocol. At week 40 after treatment initiation, the central retinal thickness was approximately 236.8 micrometers with the HDq12 protocol and approximately 243.7 micrometers with the HDq16 protocol. At week 44 after treatment initiation, the central retinal thickness was approximately 245.9 micrometers with the HDq12 protocol and approximately 227.7 micrometers with the HDq16 protocol. At week 48 after treatment initiation, the central retinal thickness was approximately 226.2 micrometers with the HDq12 protocol and approximately 226.9 micrometers with the HDq16 protocol. At week 52 after treatment initiation, the central retinal thickness was approximately 227.4 micrometers with the HDq12 protocol and approximately 231.1 micrometers with the HDq16 protocol. At week 56 after treatment initiation, the central retinal thickness was approximately 234.3 micrometers with the HDq12 protocol and approximately 233.2 micrometers with the HDq16 protocol. At week 60 after treatment initiation, the central retinal thickness was approximately 218.8 micrometers with the HDq12 protocol and approximately 221.9 micrometers with the HDq16 protocol. CRT decreased at approximately 4, 5, 6, 7, or 8 weeks after treatment initiation, and was maintained thereafter during the treatment regimen (within approximately...). + 10. + 11 or + (within 12 micrometers); Approximately 4 hours after the initiation of HDq12 or HDq16 treatment, the plasma concentration of free aflibercept was approximately 0.0409 g / L. + 0.0605 mg / L or 0 mg / L (or <0.0156 mg / L); Approximately 8 hours after the initiation of HDq12 or HDq16 treatment, the plasma concentration of free aflibercept was approximately 0.05 ( + 3.78), 0.0973 ( + 0.102) or 0.0672 mg / L; Approximately day 2 after the initiation of HDq12 or HDq16 treatment, the plasma concentration of free aflibercept was approximately 0.11 ( + 2.21), 0.146 ( + 0.110) or 0.0903 mg / L; Approximately day 3 after the initiation of HDq12 or HDq16 treatment, the plasma concentration of free aflibercept was approximately 0.11 ( + 2.06), 0.137 ( + 0.0947) or 0.112 mg / L; Approximately day 5 after the initiation of HDq12 or HDq16 treatment, the plasma concentration of free aflibercept was approximately 0.08 ( + 1.86), 0.0933 ( +0.0481) or 0.0854 mg / L; Approximately day 8 after the initiation of HDq12 or HDq16 treatment, the plasma concentration of free aflibercept was approximately 0.07 ( + 1.75), 0.0794 ( + 0.0413) or 0.0682 mg / L; Approximately day 15 after the initiation of HDq12 or HDq16 treatment, the plasma concentration of free aflibercept was approximately 0.04 ( + 1.76), 0.0435 ( + 0.0199) or 0.0385 mg / L; Approximately day 22 after the initiation of HDq12 or HDq16 treatment, the plasma concentration of free aflibercept was approximately 0.02 ( + 1.76), 0.0213 ( + 0.0148) or 0.0232 mg / L; Approximately day 29 after the initiation of HDq12 or HDq16 treatment, the plasma concentration of free aflibercept was approximately 0.00766 (mg / L). + 0.00958) or 0 mg / L (or <0.0156 mg / L); Approximately 4 hours after administration of HDq12 or HDq16 treatment, the adjusted plasma concentration of bound aflibercept was approximately 0.00 mg / L. Approximately 8 hours after administration of HDq12 or HDq16 treatment, the adjusted plasma concentration of bound aflibercept was approximately 0.00 mg / L. Approximately day 2 after initiation of HDq12 or HDq16 treatment, the adjusted plasma concentration of bound aflibercept was approximately 0.06 ( + 3.50) or 0.124 ( + 0.186) mg / L; Approximately day 3 after initiation of HDq12 or HDq16 treatment, the adjusted plasma concentration of bound aflibercept was approximately 0.13 ( + 2.07) or 0.173 ( + 0.155) mg / L; Approximately day 5 after initiation of HDq12 or HDq16 treatment, the adjusted plasma concentration of bound aflibercept was approximately 0.18 ( + 1.88) or 0.223 ( + 0.157) mg / L; Approximately day 8 after initiation of HDq12 or HDq16 treatment, the adjusted plasma concentration of bound aflibercept was approximately 0.31 ( + 1.56) or 0.334 ( + 0.135) mg / L; Approximately day 15 after initiation of HDq12 or HDq16 treatment, the adjusted plasma concentration of bound aflibercept was approximately 0.37 ( + 1.50) or 0.393 ( + 0.130) mg / L; Approximately day 22 after initiation of HDq12 or HDq16 treatment, the adjusted plasma concentration of bound aflibercept was approximately 0.25 ( + 3.00) or 0.335 ( + 0.155) mg / L; Approximately day 29 after initiation of HDq12 or HDq16 treatment, the adjusted plasma concentration of bound aflibercept was approximately 0.32 ( + 1.39) or 0.331 ( + 0.0953) mg / L; BVCA was non-inferior to aflibercept administered intravitreally at 2 mg every 4 weeks for the first 5 injections, followed by 2 mg every 8 weeks or every 2 months. The ocular and nonocular safety or mortality rates in subjects with DME were similar to those of aflibercept administered intravitreally at approximately 2 mg every 4 weeks for the first 3 or 4 or 5 injections, followed by intravitreal administration at approximately 2 mg every 8 weeks or every 2 months. The best corrected visual acuity improvement from the start of treatment to weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 or 48; From the start of treatment to weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, or 60, the best corrected visual acuity increased by ≥2 letters, ≥3 letters, ≥4 letters, ≥5 letters, ≥6 letters, or >7 letters as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart or Snellen equivalent. From the start of treatment until weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, or 60, the retina showed no fluid (total fluid, intraretinal fluid [IRF], and / or subretinal fluid [SRF]) in the central region; and / or From the start of treatment until weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, or 60, the central retinal thickness (CRT) is reduced by at least 100, 125, 130, 135, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, or 150 micrometers.

[0082] This invention provides a VEGF receptor fusion protein for use in the treatment and prevention of neovascular age-related macular degeneration (nAMD) in subjects of need, wherein: The subjects were administered one initial dose, two second doses, and three third doses during the first year. > 8mg VEGF receptor fusion protein; The subjects were administered one initial dose, two second doses, and two third doses during the first year. > 8 mg VEGF receptor fusion protein; or The subjects were administered one initial dose, two second doses, and three third doses during the first year. > 8 mg of VEGF receptor fusion protein, followed by 2-4 third doses in the second year.

[0083] This invention provides a VEGF receptor fusion protein for use in the treatment and prevention of neovascular age-related macular degeneration (nAMD) in subjects of need, wherein adjustments (increases / maintains / decreases) are based on visual and / or anatomical outcomes. > Dosage intervals of 8 mg VEGF receptor fusion protein.

[0084] This invention provides VEGF receptor fusion proteins for use in the treatment and prevention of neovascular age-related macular degeneration (nAMD) in subjects of need, wherein these doses are administered according to a need-to-use (PRN), capped PRN, or treatment and extension (T&E) dosing regimen. > 8 mg VEGF receptor fusion protein.

[0085] 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 invention, the container is a vial or a pre-filled syringe, the vial being a type I glass vial containing a nominal fill volume of approximately 0.26 mL of intravitreal injection solution. In one embodiment of the invention, the container contains a VEGF receptor fusion protein at a concentration greater than or equal to 100 mg / mL, or the container contains aflibercept at a concentration of approximately 114.3 mg / mL. In one embodiment of the invention, the instructions for use include instructions for using the VEGF fusion protein or aflibercept to treat DME and / or AMD. In one embodiment of the invention, the instructions for use include the following information: i) the container contains... > ii) Aflibercept solution of 8 mg (114.3 mg / mL) for intravitreal injection; iii) Each single-dose vial provides a usable amount to deliver a single 70 μL dose containing 8 mg aflibercept to an adult patient; iv) The recommended dose is... > 8 mg aflibercept (equivalent to 70 μL injection solution), IV) > Treatment with 8 mg aflibercept begins with one injection per month (every 4 weeks) for three consecutive doses; v) the injection interval may then be increased to every 16 or 20 weeks; vi) the treatment interval may be adjusted based on the physician's judgment of visual and / or anatomical findings; and / or vii) > 8 mg aflibercept / 0.07 mL is provided as a sterile aqueous solution containing arginine monohydrochloride, histidine, histidine hydrochloride monohydrate, polysorbate 20, sucrose and water for injection. Attached Figure Description

[0086] Figure 1 Summary of PULSAR clinical trials.

[0087] Figure 2 Key eligibility criteria (inclusion and exclusion criteria) for PULSAR clinical trials.

[0088] Figure 3 Dosing schedule and dosage regimen modification (DRM) standards for PULSAR clinical trials.

[0089] Figure 4 Dosage regimen modification (DRM) criteria for PULSAR clinical trials.

[0090] Figure 5 Patient management at week 48 of the PULSAR clinical trial.

[0091] Figure 6 Baseline demographic data of participants in the PULSAR clinical trial.

[0092] Figure 7 The baseline characteristics of the eyes of subjects were studied in the PULSAR clinical trial.

[0093] Figure 8 The average number of injections by week 48 in the PULSAR clinical trial.

[0094] Figure 9 The mean change in best corrected visual acuity (BCVA) at week 48 in the PULSAR clinical trial is shown. The least squares mean change from baseline at week 48 is shown (see data below).

[0095] The present invention includes a method for achieving a specified improvement in BVCA approximately at a specified time point when receiving a specified treatment regimen for treating wet AMD.

[0096] Figure 10 The percentage of subjects who maintained the Q12 and Q16 intervals through week 48 in the PULSAR clinical trial.

[0097] Figure 11 The key secondary endpoint in the PULSAR clinical trial was the percentage of participants without retinal fluid in the central region at week 16.

[0098] Figure 12 The percentage of subjects without retinal fluid in the central region at week 48 in the PULSAR clinical trial.

[0099] Figure 13A and Figure 13B : The average change in central retinal thickness from baseline by week 48 ( Figure 13A ) The present invention includes a method for achieving approximately a specified reduction in central retinal thickness at a specified time point when receiving a specified treatment regimen for treating wet AMD.

[0100] ; and the central retinal thickness up to week 48 ( Figure 13B(See data below).

[0101] The present invention includes a method for achieving approximately a specified central retinal thickness at a specified time point when receiving a specified treatment regimen for treating wet AMD.

[0102] Figure 14A and 14B Serious treatment-emergent adverse events (TEAEs) in the eye at week 48 of the PULSAR clinical trial. Figure 14A The most common ocular adverse events (AEs) by week 48 were... Figure 14B ).

[0103] Figure 15 Intraocular inflammation occurred during the 48th week of treatment in the PULSAR clinical trial.

[0104] Figure 16 The average change in intraocular pressure from baseline at week 48 of the PULSAR clinical trial.

[0105] Figure 17 The percentage of subjects who met the intraocular pressure criteria in the PULSAR clinical trial.

[0106] Figure 18 In the PULSAR clinical trial, the percentage of non-ocular severe TEAEs at week 48 was ≥0.5%.

[0107] Figure 19A and 19B Antiplatelet trial participant collaboration (APTC) events that occurred during the 48th week of treatment in the PULSAR clinical trial. Figure 19A Non-ocular safety at week 48 Figure 19B ).

[0108] Figure 20 Hypertensive events that occurred during the treatment period up to week 48 of the PULSAR clinical trial.

[0109] Figure 21 Potentially clinically significant values ​​(PCSV) of blood pressure at week 48 in the PULSAR clinical trial.

[0110] Figure 22 The mean change in systolic blood pressure from baseline to week 48 in the PULSAR clinical trial is shown in the inset. The inset plot shows the mean change from baseline to week 9 and the mean baseline blood pressure.

[0111] Figure 23The mean change in diastolic blood pressure from baseline to week 48 in the PULSAR clinical trial is shown in the inset. The inset plot illustrates the mean change from baseline to week 9 and the mean baseline blood pressure.

[0112] Figure 24 The patient died at week 48 during the PULSAR clinical trial.

[0113] Figure 25 PULSAR dosing schedule up to week 60. Dosing regimen modifications are illustrated in the illustrations.

[0114] Figure 26 Absolute BCVA and BCVA variation (ETDRS letters) from baseline to week 60. The least squares mean change from baseline is shown at week 60.

[0115] Figure 27 The proportion of patients who maintained the HDq12 (8q12)- and HDq16 (8q16) intervals by week 60.

[0116] Figure 28 The average number of injections by week 60 in each group.

[0117] Figure 29A , Figure 29B and Figure 29C Central retinal thickness (CRT) and its change from baseline up to week 60. (A) Central retinal thickness (µm) over time (observations - review data after ICE); (B) Mean change from baseline of CST (central retinal thickness (convertible with CRT); µm) at week 60 visit in the full analysis set, prior to ICE in the OC; (C) CST (µm) at MMRM (mixed model for repeated measures) (up to week 48) at visit in the full analysis set, compared with baseline LS. mean (95% CI) change.

[0118] Figure 30A , Figure 30B , Figure 30C , Figure 30D , Figure 30E , Figure 30F and Figure 30G For PULSAR, security data summary: ( Figure 30A ) By week 60, ocular TEAE ≥ 2%, Figure 30B Severe TEAE of the eye at week 60, Figure 30C By week 60, non-ocular TEAE ≥2%, Figure 30D By week 60, the percentage of non-ocular severe TEAEs ≥0.5% Figure 30E Death at week 60, Figure 30FThe mean change in systolic blood pressure at week 60, and ( Figure 30G Mean change in diastolic blood pressure at week 60.

[0119] Figure 31 Changes in letters 5, 10, and 15 at week 60. Observation (OC) (Data review after ICE)

[0120] Figure 32 By the week 60 visit (weeks and timetable dosages shown), the percentage of subjects without retinal fluid in the central region was [percentage missing]. LOCF (Data review after ICE).

[0121] Figure 33 Structural representation of population pharmacokinetic models after aflibercept administration via IV, SC, and IVT. CMT = compartment, IV = intravenous, IVT = intravitreal, K20 = elimination rate constant of free aflibercept, K40 = adjusted elimination rate constant of bound aflibercept, K62 = absorption rate from subcutaneous reservoir compartment, K70 = elimination rate constant from tissue (platelet) compartment; QE = intercompartmental clearance of free aflibercept between the ocular ventricle and central compartment, QF1 and QF2 = intercompartmental clearance of free aflibercept, VMK24, KM = saturated Michaelis-Mententype binding of free aflibercept to VEGF; VMK27, KMK27 = saturated elimination from plasma compartment to tissue compartment (platelet), CMT 2 and CMT 4 are representative of plasma compartments and are assumed to be of equal volume.

[0122] Figure 34 In dense PK sub-studies (DPKS, log-scale), the mean free and adjusted bound aflibercept levels over 28 days were measured by single 2 mg and 8 mg IVT doses in nAMD or DME. SD) concentration (mg / L). LQ = below the limit of quantitation, DME = diabetic macular edema, DPKS = intensive pharmacokinetic sub-study, HDq12 = 8 mg aflibercept every 12 weeks after 3 initial monthly injections, HDq16 = 8 mg aflibercept every 16 weeks after 3 initial monthly injections, IVT = intravitreal, LLOQ = lower limit of quantitation, N = number of participants, nAMD = neovascular age-related macular degeneration, SD = standard deviation adjusted for combined aflibercept = 0.717 Note: A concentration below LLOQ (free aflibercept concentration of 0.0156 mg / L and adjusted bound aflibercept concentration of 0.0224 mg / L) is defined as LLOQ / 2. NoteData for the first 28 days of 8 mg HD aflibercept (obtained from PULSAR or PHOTON) are a combination of data from participants who received HDq12 or HDq16. One outlier free aflibercept concentration at day 28 in PULSAR was excluded. Records from the ipsilateral eye after treatment were excluded. Data source: Drug concentration data from the week 48 database locks of PULSAR and PHOTON and the final locks of CANDELA.

[0123] Figure 35 Stratified by dose and population, observed and model-predicted plasma concentrations (mg / L) of free aflibercept and adjusted bound aflibercept within 28 days after a single IVT injection in participants with nAMD or DME in intensive PK sub-studies (DPKS). DME = diabetic macular edema, IVT = intravitreal, LLOQ = lower limit of quantitation, nAMD = neovascular age-related macular degeneration, PK = observed pharmacokinetic concentration below the lower limit of quantitation (LLOQ; 0.0156 mg / L for free aflibercept and 0.0224 mg / L for adjusted bound aflibercept) were set as LLOQ / 2. Data source: Drug concentration data from intensive PK sub-studies in PHOTON, PULSAR, and CANDELA.

[0124] Figure 36 The sum of observed and model-predicted concentrations (mg / L) of free and adjusted bound aflibercept in the plasma of the nAMD and DME combined populations. 2q8 = 2 mg aflibercept every 8 weeks after 3 initial injections at 4-week intervals; 2q12 = 2 mg aflibercept every 12 weeks after 3 initial injections at 4-week intervals; DME = diabetic macular edema; HDq12 = 8 mg aflibercept every 12 weeks after 3 initial monthly injections; HDq16 = 8 mg aflibercept every 16 weeks after 3 initial monthly injections; IVT = intravitreal; LLOQ = lower limit of quantitation; nAMD = neovascular age-related macular degeneration; Observed concentrations below the lower limit of quantitation (LLOQ; 0.0156 mg / L for free aflibercept and 0.0224 mg / L for adjusted bound aflibercept) are set as LLOQ / 2. Data source: Drug concentration data from CANDELA, PHOTON, and PULSAR.

[0125] Figure 37In participants with a combination of nAMD and DME, the model predicted aflibercept exposure (mg) after a single IVT injection was stratified by dosing regimen. DME = diabetic macular edema, HD = aflibercept 8 mg, IVT = intravitreal, nAMD = neovascular age-related macular degeneration, PI = predicted interval, PK = pharmacokinetics, QE = intercompartmental clearance of free aflibercept between the ocular ventricle and central compartment. The adjusted LLOQ (0.0624 μg) was set as the LLOQ of the free aflibercept concentration in plasma (i.e., 0.0156 mg / L) multiplied by the assumed volume of the study ocular ventricle in the PK model (i.e., 4 mL). Since the concentration of intraocular (free or bound) aflibercept was not measured in the clinical studies included in the population PK analysis dataset, this target was arbitrarily chosen based on the LLOQ in plasma and used as a reference for comparisons between dosing regimens to assess the effect of HD aflibercept on QE.

[0126] Figure 38 In the Dense PK Sub-Study (DPKS, Log-Scale), the mean free and adjusted bound aflibercept levels over 28 days were measured by single 2 mg and 8 mg IVT doses in participants with nAMD. SD) Concentration (mg / L) - No outliers. DME = Diabetic macular edema, DPKS = Intensive pharmacokinetic sub-study, HDq12 = 8 mg aflibercept every 12 weeks after 3 initial monthly injections, HDq16 = 8 mg aflibercept every 16 weeks after 3 initial monthly injections, IVT = Intravitreal, LLOQ = Lower limit of quantitation, N = Number of participants, nAMD = Neovascular age-related macular degeneration, PK = Pharmacokinetics, SD = Standard deviation adjusted for combined aflibercept = 0.717 Conjugated aflibercept. Note: Concentrations below LLOQ (free aflibercept concentration of 0.0156 mg / L and adjusted conjugated aflibercept concentration of 0.0224 mg / L) are defined as LLOQ / 2. Note: 8 mg data for the first 28 days (obtained from PULSAR or PHOTON) are a combination of data from participants who received HDq12 or HDq16. Data source: Drug concentrations at week 48 from PULSAR and PHOTON and final locks from CANDELA. Records after ipsilateral eye treatment were excluded.

[0127] Figure 39 In the Dense PK Sub-Study (DPKS, Log-Scale), the mean free and adjusted bound aflibercept levels over 28 days were measured by single 2 mg and 8 mg IVT doses in participants with nAMD. SD) Concentration (mg / L) - including outliers. DME = Diabetic macular edema, DPKS = Intensive pharmacokinetic substudy, HDq12 = 8 mg aflibercept every 12 weeks after 3 initial monthly injections, HDq16 = 8 mg aflibercept every 16 weeks after 3 initial monthly injections, IVT = Intravitreal, LLOQ = Lower limit of quantitation, N = Number of participants, nAMD = Neovascular age-related macular degeneration, PK = Pharmacokinetics, SD = Standard deviation adjusted for combined aflibercept = 0.717 Conjugated aflibercept. Note: Concentrations below the lower limit of quantitation (LLOQ, free aflibercept concentration of 0.0156 mg / L, adjusted conjugated aflibercept concentration of 0.0224 mg / L) are defined as LLOQ / 2. Data source: Drug concentrations at week 48 of PULSAR and final lockouts of CANDELA. Data from VGFTOD-0702 are used as a reference (concentrations in the PK sub-study were subtracted from pre-dose concentrations when >LLOQ). Records after treatment in the ipsilateral eye were excluded.

[0128] Figure 40 In the Dense PK Sub-Study (DPKS, Log-Scale), the mean free and adjusted bound aflibercept levels over 28 days were measured by single 2 mg and 8 mg IVT doses in participants with DME. SD) concentration (mg / L). BLQ = below the limit of quantitation, DME = diabetic macular edema, DPKS = dense pharmacokinetic analysis set, HDq12 = 8 mg aflibercept every 12 weeks after 3 initial monthly injections, HDq16 = 8 mg aflibercept every 16 weeks after 3 initial monthly injections, IVT = intravitreal, LLOQ = lower limit of quantitation, N = number of participants, nAMD = neovascular age-related macular degeneration, SD = standard deviation. Note: Concentrations below LLOQ (free aflibercept concentration of 0.0156 mg / L, adjusted bound aflibercept concentration of 0.0224 mg / L) are defined as LLOQ / 2. Adjusted bound aflibercept = 0.717 Combined with aflibercept. Note: 8 mg data for the first 28 days (obtained from PULSAR or PHOTON) are a combination of data from participants who received HDq12 or HDq16. Note: If a participant took aflibercept before starting the study drug within 12 weeks and had a baseline concentration >BLQ, that concentration was subtracted from the baseline concentration. Data source: Drug concentration data from PHOTON at week 48. Drug concentration data from VGFT-OD-0706 (historical data) were included for reference. Records after treatment in the ipsilateral eye were excluded.

[0129] Figure 41The sum of observed and model-predicted concentrations (mg / L) of free and adjusted bound aflibercept in the plasma of participants with nAMD. 2q8 = 2 mg aflibercept every 8 weeks after 3 initial injections at 4-week intervals; 2q12 = 2 mg aflibercept every 12 weeks after 3 initial injections at 4-week intervals; DME = diabetic macular edema; HDq12 = 8 mg aflibercept every 12 weeks after 3 initial monthly injections; HDq16 = 8 mg aflibercept every 16 weeks after 3 initial monthly injections; IVT = intravitreal; LLOQ = lower limit of quantitation; nAMD = neovascular age-related macular degeneration; PK = pharmacokinetics, with observed concentrations below the lower limit of quantitation (LLOQ; 0.0156 mg / L for free aflibercept and 0.0224 mg / L for adjusted bound aflibercept) set as LLOQ / 2. Data from PULSAR and CANDELA.

[0130] Figure 42 This is the sum of observed and model-predicted concentrations (mg / L) of free and adjusted bound aflibercept in the plasma of participants with diabetic macular edema in the PHOTON study. 2q8 = 2 mg aflibercept every 8 weeks following 3 initial injections at 4-week intervals; HDq12 = 8 mg aflibercept every 12 weeks following 3 initial injections at 4-week intervals; HDq16 = 8 mg aflibercept every 16 weeks following 3 initial injections at 4-week intervals; IVT = intravitreal; LLOQ = lower limit of quantitation. Data from PHOTON. Detailed Implementation

[0131] This invention partially provides a safe and effective high-dose aflibercept IVT injection that extends the maintenance dosing interval to more than 8 weeks, with at least similar functionality and potentially improved anatomical outcomes. This regimen demonstrated a surprisingly high level of durability in subjects, exceeding the expected durability based solely on administering more aflibercept.

[0132] EYLEA has become the standard of care for nAMD. Eylea is used for nAMD at a dose of 2 mg once monthly for three months, followed by maintenance every 8 weeks. The dosing regimen of this invention has demonstrated that a substantial percentage of subjects can maintain the 12-week and 16-week dosing intervals. In trials testing these dosing regimens, nearly 90% of subjects with diabetic macular edema were able to maintain the 16-week dosing regimen. These durability data, coupled with a safety profile consistent with EYLEA, support high-dose aflibercept as a potential new standard of care for angiogenic eye diseases such as nAMD. The data presented here demonstrate that aflibercept 8 mg dosing regimens for 12 and 16 weeks achieved high levels of improvement in visual acuity and retinal fluid anatomy measurements in subjects with nAMD, maintaining these improvements over 48 weeks. These results were obtained in subjects who rapidly initiated the extended dosing intervals, the vast majority of whom did not require regimen modifications. In conclusion, the key data support that aflibercept 8 mg provides a longer duration of action while maintaining a similar safety profile to EYLEA.

[0133] Prior to the initiation of the HD aflibercept clinical development program, pharmacokinetic simulations using a one-chamber eye model to model the concentration-time profile of free aflibercept in the human vitreous body predicted that an 8 mg IVT dose of aflibercept would extend the dosing interval by approximately 20 days (two half-lives) compared to a 2 mg IVT dose. The HDq12 and HDq16 regimens of aflibercept demonstrated a longer duration of efficacy in the HD clinical studies than predicted. Subsequent population pharmacokinetic analyses integrating data from the CANDELA PHOTON and PULSAR Phase 3 studies indicated that the intraocular clearance of free aflibercept in HD was 34% slower than that of 2 mg IVT aflibercept administered as Eylea. This slower intraocular clearance of HD aflibercept was expected to result in a longer persistence of free aflibercept in the eye and a duration of efficacy approximately 6 weeks longer compared to 2 mg. Compared to 2 mg Eylea, the reduction in ocular clearance with HD aflibercept was greater than expected and was attributed to the "HD aflibercept effect," a highly statistically significant effect in a population pharmacokinetic model that cannot be explained simply by increasing the dose from 2 mg to 8 mg.

[0134] Population pharmacokinetic (PK) estimates suggest a median time to reach the lower limit of quantitation (LLOQ) of free aflibercept in plasma after 2 mg IVT aflibercept, compared to 3.5 weeks for 8 mg HD aflibercept. The longer duration of systemic exposure to free aflibercept (representing the movement of free aflibercept from the eye) with the HD aflibercept regimen is attributed not only to the higher dose and nonlinear systemic targeting-mediated elimination, but also to a 34% slower ocular clearance of free aflibercept. The slower ocular clearance of HD aflibercept compared to 2 mg aflibercept is projected to provide a longer 6-week duration of efficacy because, for HD aflibercept, the population pharmacokinetic estimate of reaching the amount of free aflibercept in the ocular ventricle at the end of the 8-week dosing interval occurs after 6 weeks. Exposure-response analysis estimated that the slower ocular clearance of 8 mg aflibercept could be attributed to the effect of the HD drug, resulting in a dosing regimen modification (DRM) rate that was 20.6% lower than expected if the HD drug had the same ocular clearance as 2 mg aflibercept.

[0135] General methods for protein purification are described, including immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization (Coligan, et al. (2000), Current Protocols in Protein Science, Vol. 1, John Wiley & Sons, New York). Chemical analysis, chemical modification, post-translational modification, fusion protein generation, and protein glycosylation are also described (see [link to relevant documentation]). For example Coligan, et al. (2000) *The Latest Laboratory Guide to Protein Science*, Volume 2, John Wiley & Son, New York; Ausubel, et al. (2001) Modern Molecular Biology Experimental Techniques, Vol. 3, John Wiley & Sons, New York, NY, pp. 16.0.5-16.22.17; Sigma-Aldrich, Co. (2001) Products for LifeScience Research, St. Louis, Missouri, pp. 45-89; Amersham Pharmacia Biotech (2001) BioDirectory, Piscataway, NJ, pp. 384-391. Describes the generation, purification, and fragmentation of polyclonal and monoclonal antibodies (Coligan, et al.(2001) Current Protocols in Immunology, Vol. 1, John Wiley & Son, New York; Harlow and Lane (1999) Using Antibodies, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York; Harlow and Lane, ibid. Standard techniques for characterizing ligand / receptor interactions are available (see [reference needed]). For example Coligan et al. (2001) The Latest Protocols in Immunology, Volume 4, John Willie Company, New York.

[0136] Flow cytometry methods, including fluorescence activated cell sorting (FACS), are available (see, for example, Owens, et al. (1994), *Flow Cytometry Principles for Clinical Laboratory Practice*, John Wiley & Son Publishing, Hoboken, NJ; Givan (2001), *Flow Cytometry*, 2nd ed.; Wiley-Liss, Hoboken, NJ; Shapiro (2003), *Practical Flow Cytometry*, John Wiley & Son Publishing, Hoboken, NJ). Used as... For example Diagnostic reagents suitable for modifying nucleic acids, peptides, and antibodies, including nucleic acid primers and probes, are available as fluorescent reagents (Molecular Probes (2003) Catalog, Molecular Probes, Inc., Eugene, Oreg.; Sigma-Aldrich (2003) Catalog, St. Louis, Missouri).

[0137] Describe the standard immune system histological methods (see For example Muller-Harmelink (ed.) (1986), *Human Thymus: Histopathology and Pathology*, Springer Verlag, New York; Hiatt, et al.(2000) *Color Atlas of Histology*, Lippincott, Williams, and Wilkins, Philadelphia, Pennsylvania; Louis, et al. (2002) Basic Histology: Text and Atlas, McGraw-Hill, New York.

[0138] "Separated" VEGF antagonist and VEGF receptor fusion protein ( For example Aflibercept, peptides, polynucleotides, and carriers are at least partially free of other biomolecules from the cells or 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 materials such as cell debris and growth media. Isolated VEGF antagonists or VEGF receptor fusion proteins may further be at least partially free of expression system components, such as biomolecules from the host cell or its growth medium. Generally, the term "isolated" is not intended to mean the complete absence of such biomolecules. For example (May contain small or insignificant amounts of impurities), or may refer to the absence of water, buffer solution or salt, or may refer to components of a pharmaceutical formulation that include VEGF antagonists or VEGF receptor fusion proteins.

[0139] "Separated" VEGF antagonist and VEGF receptor fusion protein ( For example Aflibercept, peptides, polynucleotides, and carriers are at least partially free of other biomolecules from the cells or 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 materials such as cell debris and growth media. Isolated VEGF antagonists or VEGF receptor fusion proteins may further be at least partially free of expression system components, such as biomolecules from the host cell or its growth medium. Generally, the term "isolated" is not intended to mean the complete absence of such biomolecules. For example (May contain small or insignificant amounts of impurities), or may refer to the absence of water, buffer solution or salt, or may refer to components of a pharmaceutical formulation that include VEGF antagonists or VEGF receptor fusion proteins.

[0140] The dosages mentioned in this article (e.g., 8 mg) cover a range including specified amounts. + 10%, for example, 8 mg ( +The implementation scheme is 0.8 mg. The concentrations or amounts of excipients mentioned herein, such as those used in formulations, also include specified amounts. + A 10% implementation plan.

[0141] The terms "subject" and "patient" are used interchangeably herein. A subject or patient is a mammal, such as a human, mouse, rabbit, monkey, or non-human primate, preferably a human. It can be said that a subject or patient "suffers from" angiogenic eye disease, such as nAMD. Such a subject or patient has the disease in one or both eyes. In one embodiment of the invention, the subject or patient (preferably a human) has one or more of the following characteristics (currently or in the past): 1. ≥50 years old, for example, 61, 62, 63, 74 or 75 years old; 2. Having active subfoveal CNVs secondary to nAMD, for example, with a total area > 50% of the total lesion area, such as including lesions near the fovea that affect the fovea of ​​the eye; 3. Research on early treatment of diabetic retinopathy with best-corrected visual acuity (BCVA) (ETDRS) letter ratings are approximately 78 to 24, 73-78, <73, 58, 59, 60, 61, or 62 (Snellen equivalents are 20 / 40, 20 / 63, 20 / 50, 20 / 32, or 20 / 320), for example due to DME or nAMD; 4. Central retinal thickness > 300 micrometers or > 320 micrometers or approximately 367, 368, 369, 370, 450, 451, 452, 453, 454, or 455 micrometers; or and / or DME with central involvement in the eye, CRT ≥ 300 micrometers (or ≥ 320 micrometers as determined by Spectralis). 5. The total damaged area is approximately 6 or 7 mm. 2 For example, the damage types are predominantly occult or classical, or have the lowest classical type. 6. DRSS score is better than or equal to 43, 47 or worse; 7. Type 1 or type 2 diabetes; and / or 8. Intraretinal fluid and / or subretinal fluid are present in the central region of the eye as seen on an OCT scan; 9. Body mass index (BMI) of approximately 27 or 28 or higher; and / or 10. High blood pressure; and / or 11. History of any one or more of the following: cataracts, dry age-related macular degeneration, vitreous detachment, dry eye, nuclear cataracts, glaucoma, astigmatism, presbyopia, choroidal neovascularization, open-angle glaucoma, hyperopia, macular degeneration, myopia, posterior capsule opacification, epiretinal membrane, retinal degeneration, skin laxity, retinal hypertension, drusen, iridodialysis syndrome, vitreous floaters, cortical cataracts, ptosis, retinal tear, vitreous diseases, pterygium, vitreous degeneration, eye strain, cataract surgery, intraocular lens implantation, lens capsulotomy, blepharoplasty, keratomileusis, laser therapy, tumors (benign, malignant, and unexplained (including cysts and polyps)) or facial moles. And / or, It has or lacks any one or more of the following characteristics: 1. Subretinal hemorrhage in the eye with a total damaged area ≥50%; 2. Intraocular pressure ≥25 mmHg; 3. Signs of infectious blepharitis, keratitis, scleritis, or conjunctivitis in the eyes; 4. Any intraocular inflammation and / or eye infection; 5. A history of stage II or higher macular hole; 6. Examine the eye for current iris neovascularization, vitreous hemorrhage, or tractional retina visible during screening assessment. Detachment; 7. Blood pressure loss of control (defined as systolic blood pressure > 140 mm Hg or diastolic blood pressure > 90 mm Hg); 8. The change in BP measurements exceeds 10% across three measurements; 9. Cerebrovascular accident / transient ischemic attack or myocardial infarction / History of acute coronary syndrome; 10. History of kidney failure, dialysis, or kidney transplantation; 11. Known to be sensitive to aflibercept; 12. Pregnant or breastfeeding women; 13. Has fertility potential And unwilling to be efficient Women who use contraception; 14. Any intraocular surgery performed within 12 weeks (84 days); and / or 15. History of corneal transplantation or corneal dystrophy.

[0142] Therefore, the present invention includes a method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject of need.

[0143] 1. Age ≥ 50 years old; 2. It has an active central depression CNV derived from nAMD; 3. Study on Early Treatment of Diabetic Retinopathy Based on Best Corrected Visual Acuity (BCVA) The (ETDRS) letter score is approximately 78 to 24; 4. Central retinal thickness > 300 micrometers or > 320 micrometers; 5. The damaged area is approximately 6 or 7 mm. 2 ; 6. DRSS score of 43 or higher, 47 or lower; and / or 7. Have type 1 or type 2 diabetes; and / or 1. No subretinal hemorrhage covering ≥50% of the total damaged area in the eye; 2. No intraocular pressure ≥25 mmHg in the eye; 3. The eyes show no signs of infectious blepharitis, keratitis, scleritis, or conjunctivitis; 4. There is no intraocular inflammation and / or eye infection in the eyes; 5. No history of stage II or higher macular hole in the eye; 6. No visible neovascularization of the iris, vitreous hemorrhage, or tractional retinal detachment is observed in the eye; 7. There are no uncontrolled BPs; 8. No change exceeding 10% in the three BP measurements; 9. No history of cerebrovascular accident / transient ischemic attack or myocardial infarction / acute coronary syndrome; 10. No history of kidney failure, dialysis, and / or kidney transplantation; 11. No known sensitivity to aflibercept; 12. Women who are not pregnant or breastfeeding; 13. Lacking the ability to reproduce and unwilling to undergo efficient [fertilization / reproduction]. Women who use contraception; 14. No intraocular surgery was performed within 12 weeks (84 days); and / or 15. No history of corneal transplantation or corneal dystrophy in the eye; The method involves administering a single initial dose of about 8 mg or more of VEGF receptor fusion protein (preferably aflibercept) to the eye of a subject, followed by one or more second doses of about 8 mg or more of VEGF receptor fusion protein, followed by one or more third doses of about 8 mg or more of VEGF receptor fusion protein; wherein each second dose is administered about 2 to 4 weeks after the immediate preceding dose; and wherein each third dose is administered about 12 to 20 weeks after the immediate preceding dose.

[0144] VEGF antagonists

[0145] This invention includes methods for treating or preventing angiogenic eye diseases using VEGF antagonists. VEGF antagonists comprise molecules that interfere with the interaction between VEGF and its natural receptor. For example A molecule that binds to VEGF or VEGF receptors and prevents or inhibits the interaction between VEGF and VEGF receptors. Specific exemplary VEGF antagonists include anti-VEGF antibodies, anti-VEGF receptor antibodies, and VEGF receptor fusion proteins. Although VEGF receptor fusion proteins, such as aflibercept, are preferably used in conjunction with the methods described herein, the scope of the invention includes methods in which any of the VEGF antagonists described herein (e.g., scFv, DARPin, anti-VEGF antibodies) are used instead of such fusion proteins.

[0146] For the purposes of this article, "VEGF receptor fusion protein" refers to a molecule containing one or more VEGF receptors or their domains, which fuses with another polypeptide to interfere with the interaction between VEGF and the native VEGF receptor. For example Two such fusion peptides associate to form a homodimer or other multimer. Such VEGF receptor fusion proteins may be referred to as “VEGF-Trap” or “VEGF Trap”. VEGF receptor fusion proteins falling within the context of this disclosure as defined herein include chimeric peptides containing two or more immunoglobulin (Ig)-like domains of the VEGF receptor, such as VEGFR1 (also known as Flt1) and / or VEGFR2 (also known as Flk1 or KDR), and may also contain multimerizing domains (e.g., Fc domains).

[0147] 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 nucleotides 79 to 1374 or 79 to 1371 therein.

[0148] VEGF1R2-FcΔC1(a) contains three components: (1) VEGFR1 component, which contains amino acids 27 to 129 of SEQ ID NO:2; (2) The VEGFR2 component, comprising amino acids 130 to 231 of SEQ ID NO:2; and (3) The polymerized component ("FcΔC1(a)") contains amino acids 232 to 457 of SEQ ID NO: 2 (VEGF receptor fusion proteins may or may not include the C-terminal amino acid of SEQ ID NO: 2). Right now K458 (see U.S. Patent Nos. 7,396,664 or 7,354,579, which are incorporated herein for all purposes). Note that amino acids 1 through 26 of SEQ ID NO:2 are the signal sequence.

[0149] If the multipolymerized component (MC) of the VEGF receptor fusion protein originates from IgG ( For example If the IgG1)Fc domain is present, then the amino acid composition of MC is not less than amino acids 232 to 457 of SEQ ID NO:2. Therefore, the IgG in MC cannot be truncated to less than 226 amino acids.

[0150] In one embodiment of the invention, the VEGF receptor fusion protein comprises amino acids 27-458 or 27-457 of SEQ ID NO: 2 (e.g., in the form of a homodimer).

[0151]

[0152] (SEQ ID NO: 1)

[0153] MVSYWDTGVLLCALLSCLLLTGSSSG SDTGPFVEMYSEIPEIIHMTEGRELVIPCRVTS

[0154] PNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLT

[0155] HRQTNTIIDVVLSSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRD

[0156] LKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKDKTHTCPPC

[0157] PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT

[0158] KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY

[0159] TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK

[0160] LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0161] (SEQ ID NO: 2)

[0162] In embodiments of the present invention, the VEGF receptor fusion protein comprises

[0163] (1) Immunoglobulin-like (Ig) domain 2 of the first VEGF receptor ( For example VEGFR1), and

[0164] (2) Ig domain 3 of the second VEGF receptor For example VEGFR2), (3) and optionally, further comprising the Ig domain 4 of the second VEGF receptor. For example VEGFR2) and (4) Polymerized components ( For example The Fc domain of IgG includes the hinge, CH2, and CH3 domains.

[0165] For example, in an embodiment of the present invention, the VEGF receptor fusion protein has the following arrangement of domains: ● [VEGFR1 Ig domain 2]-[VEGFR2 Ig domain 3]-[MC]( For example Its homodimer) or ● [VEGFR1 Ig domain 2]-[VEGFR2 Ig domain 3]-[VEGFR2 Ig domain 4]-[MC]( For example Its homodimer).

[0166] Note that this disclosure also includes, within its scope, high-concentration formulations, including VEGF-binding molecules or anti-VEGF antibodies or their antigen-binding fragments or biopolymer conjugates. For example KSI-301 (excluding VEGF receptor fusion protein), For example

[0167] ● Bevacizumab ( For example (Concentration is approximately 80-90 or 88 mg / ml) ● Ranizumab ( For example The concentration is approximately 20-40 mg / ml. For example 21-35, 21 or 35 mg / ml) ● Anti-VEGF aptamers, such as piperacanib ( For example Pigastanib sodium), ● Single chain ( For example V L -V H Anti-VEGF antibodies, such as broxolizumab ( For example The concentration is approximately 200-400 mg / ml, or 200, 210, 400, or 420 mg / ml. ● Anti-VEGF DARPin, such as Abicipar Pegol DARPin ( For example Concentrations of approximately 70-140 mg / ml, or 70 or 140 mg / ml ● Bispecific anti-VEGF antibody, For example It also combines with ANG2, such as RG7716 (fareximab) ( For example The concentration is approximately 100-400, 100, 105, 400, or 420 mg / ml.

[0168] To minimize the reproducibility of the embodiments discussed herein, the scope of the invention is intended to include embodiments in which any formulation discussed herein comprises any concentration of anti-VEGF antibody or antibody fragment or other VEGF-binding molecule discussed herein. For example The VEGF receptor fusion protein is replaced with an anti-VEGF DARPin. For example, the present invention includes formulations containing 35 or 80 mg / ml ranizumab, buffer, heat stabilizer, viscosity reducer, and surfactant.

[0169] DARPin is a designed ankyrin repeat protein. DARPin typically contains three to four tightly packed repeat sequences of approximately 33 amino acid residues, each repeat containing one β-turn and two antiparallel α-helices. This rigid framework provides the protein with stability while enabling the presentation of variable regions, typically six amino acid residues per repeat, for target recognition.

[0170] "Anti-VEGF" antibodies or antigen-binding fragments of antibodies refer to antibodies or fragments that specifically bind to VEGF.

[0171] Exemplary VEGF receptor fusion proteins include aflibercept (EYLEA®, Regeneron Pharmaceuticals, Inc.) or conbercept (marketed by Chengdu Kanghong Biotechnology Co., Ltd.). See International Patent Application Publication Nos. WO2005 / 121176 or WO2007 / 112675. The terms “aflibercept” and “conbercept” include their biosimilars. Refer to the biosimilar version of the product ( For example Aflibercept typically refers to products containing the same amino acid sequence, but includes biosimilar products under the U.S. Biologics Price Competition and Innovation Act.

[0172] The present invention also includes embodiments in addition to VEGF antagonists, including administration of one or more other therapeutic agents, such as administration (in one or more doses) of a second VEGF antagonist, antibiotics, anesthetics (e.g., local anesthetics), nonsteroidal anti-inflammatory drugs (NSAIDs), steroids (e.g., corticosteroids, dexamethasone), triamcinolone (TA), methotrexate, rapamycin, antitumor necrosis factor α drugs (e.g., infliximab), daklizumab, and / or complement component (e.g., C3 or C5) inhibitors.

[0173] Drug formulation

[0174] This invention includes a method of administering a VEGF antagonist to the eye of a subject in a pharmaceutical formulation. The pharmaceutical formulation includes a VEGF antagonist and a pharmaceutically acceptable carrier. Other agents may be incorporated into the pharmaceutical formulation to provide improved transfer, delivery, tolerability, etc. The term "pharmaceuticalally acceptable" means approved by a federal or state regulatory agency or listed in the United States Pharmacopeia or other recognized pharmacopoeia for animal (more specifically, for human) use. The term "carrier" refers to a diluent, adjuvant, excipient, or medium administered with the VEGF antagonist. Numerous suitable formulations can be found in all formularies known to pharmaceutical chemists: Remington's Pharmaceutical Sciences (15th edition, ...). Mack Publishing Company, Easton, Pa., 1975), For example , Chapter 87 by Blaug, Seymour.

[0175] The pharmaceutical formulation used in the method of the present invention can be "high concentration". The high concentration pharmaceutical formulations of the present invention include VEGF antagonists with concentrations 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. ,For exampleVEGF receptor fusion protein. “High concentration” can refer to formulations comprising VEGF antagonists at concentrations from about 140 mg / ml to about 160 mg / ml, at least about 140 mg / ml but less than 160 mg / ml, from about 41 mg / ml to about 275 mg / ml, from about 70 mg / ml to about 75 mg / ml, or from about 80 mg / ml to about 250 mg / ml. In some respects, the concentration of the VEGF antagonist in the formulation is approximately any of the following: 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. mg / ml; 74 mg / ml; 75mg / ml; 76 mg / ml; 77 mg / ml; 78 mg / ml; 79 mg / ml; 80 mg / ml; 81 mg / ml; 82mg / ml; 83 mg / ml; 84 mg / ml; 90 mg / ml; 91 mg / ml; 92 mg / ml; 93 mg / ml; 94 mg / ml; 95mg / ml; 96 mg / ml; 97 mg / ml; 98mg / ml; 99 mg / ml; 100 mg / ml; 101 mg / ml; 102 mg / ml; 103 mg / ml; 104 mg / ml; 106mg / ml; 107 mg / ml; 108 mg / ml; 109 mg / ml; 110 mg / ml; 111 mg / ml; 112mg / ml; 113 mg / ml; 113.3 mg / ml; 114 mg / ml; 114.1 mg / ml; mg / ml;114.6 mg / ml, 114.7 mg / ml, 114.8 mg / ml; 114.9mg / ml; 115 mg / ml; 116 mg / ml; 117 mg / ml; 118 mg / ml; 119 mg / ml; 120 mg / ml; 121mg / ml; 122 mg / ml; 123 mg / ml; 124 mg / ml; 125 mg / ml; 126 mg / ml; 127mg / ml; 128mg / ml; 129 mg / ml; 130 mg / ml; 131 mg / ml; 132 mg / ml; 133 mg / ml; 133.3 mg / ml;133.4 mg / ml, 134 mg / ml; 135 mg / ml; 136 mg / ml; 137 mg / ml; 138 mg / ml; 139 mg / ml; 140 mg / ml; 141 mg / ml; 142 mg / ml; 143 mg / ml; 144 mg / ml; 145 mg / ml; 146 mg / ml; 147 mg / ml; 148 mg / ml; 149 mg / ml; 150 mg / ml; 151 mg / ml; 152 mg / ml; 153 mg / ml; 154mg / ml; 155 mg / ml; 156 mg / ml; 157mg / ml; 158 mg / ml; 159 mg / ml; 160 mg / ml; 161 mg / ml; 162 mg / ml; 163 mg / ml; 164 mg / ml; 165 mg / ml; 166 mg / ml; 167 mg / ml; 168 mg / ml; 169 mg / ml; 170 mg / ml; 171 mg / ml; 172 mg / ml; 173 mg / ml; 174 mg / ml; 175 mg / ml; 176 mg / ml; 177 mg / ml; 178 mg / ml; 179 mg / ml; 180 mg / ml; 181 mg / ml; 182 mg / ml; 183 mg / ml; 184 mg / ml; 185 mg / ml; 186 mg / ml; 187 mg / ml; 188 mg / ml; 189 mg / ml; 190 mg / ml; 191 mg / ml; 192 mg / ml; 193 mg / ml; 194 mg / ml; 195 mg / ml; 196 mg / ml; 197 mg / ml; 198 mg / ml;199 mg / ml; 200 mg / ml; 201 mg / ml; 202 mg / ml; 203 mg / ml; 204 mg / ml; 205 mg / ml; 206 mg / ml; 207 mg / ml; 208 mg / ml; 209 mg / ml; 210 mg / ml; 211 mg / ml; 212 mg / ml; 213 214 mg / ml 215 mg / ml 216 mg / ml 217 mg / ml 218 mg / ml 219 mg / ml 220 mg / ml 221 mg / ml 222 mg / ml 223 mg / ml 224 mg / ml 225 mg / ml 226 mg / ml 227 mg / ml 228 mg / ml; 229 mg / ml; 230 mg / ml; 231 mg / ml; 232 mg / ml; 233 mg / ml; 234 mg / ml; 235 mg / ml; 236 mg / ml; 237mg / ml; 238 mg / ml; 239 mg / ml; 240 mg / ml; 244 mg / ml; 245 mg / ml; 246 mg / ml; 247 mg / ml; 248 mg / ml; 249 mg / ml; 250 mg / ml; 251 mg / ml; 252 mg / ml; 253 mg / ml; 254 mg / ml; 255 mg / ml; 256 mg / ml; 257 mg / ml; 258 mg / ml; 259 mg / ml; 260 mg / ml; 261 mg / ml; 262 mg / ml; 263 mg / ml; 264 mg / ml; 265 mg / ml; 266 mg / ml; 267 mg / ml; 268 mg / ml; 269 mg / ml; 270 mg / ml; 271 mg / ml; 272 mg / ml; 273 mg / ml; 274 mg / ml; or 275 mg / ml. Other VEGF antagonist concentrations are considered, provided that the concentration is effective according to the embodiments described herein.

[0176] In embodiments of the present invention, the concentration of the pharmaceutical formulation used in the method of the present invention is approximately 4, 6, 8, 10, 12, 14, 16, 18, or 20 mg of VEGF receptor fusion protein. For exampleAflibercept, or any acceptable dose of such protein discussed 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; 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; 89μl; 90 μl; 91 μl; 92 μl; 93 μl; 94 μl; 95 μl; 96 μl; 97 μl; 98 μl; 99 μl; or 100 μl.

[0177] This invention includes the use of (as discussed herein) the term " Exemplary formulation "The method of any formulation described below, but in which the VEGF receptor fusion protein ( For example The concentration of aflibercept is replaced by the concentration described in this section (“VEGF receptor fusion proteins and other VEGF inhibitors”).

[0178] Buffer solutions used in pharmaceutical formulations herein that can be employed in the methods of this invention refer to solutions that resist pH changes by using acid-base conjugates. Buffer solutions are capable of maintaining a pH in the range of about 5.0 to about 6.8, more typically from about 5.8 to about 6.5, and most typically from about 6.0 to about 6.5. In some cases, the pH of the formulations of this 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 buffer solutions included in formulations herein include histidine-based buffer solutions, such as histidine with histidine hydrochloride or histidine acetate. The buffer solution included in the formulations herein may alternatively be a phosphate-based buffer (e.g., containing sodium phosphate), an acetate-based buffer (e.g., containing sodium acetate or acetic acid), or a citrate-based buffer (e.g., containing sodium citrate or citric acid). It is also recognized that the buffer solution may be a mixture of the above substances, provided that the buffer solution functions as a buffer for the formulation within the pH range described above. In some cases, the buffer solution is from about 5 mM to about 25 mM, or more typically, from about 5 mM to about 15 mM. The buffer solution 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.

[0179] In an embodiment of the present invention, histidine and histidine hydrochloride are used to prepare a histidine-based buffer solution.

[0180] The surfactants used in this article refer to components that protect high concentrations of VEGF antagonists from various surface and interface-induced stresses. For exampleVEGF receptor fusion protein. Therefore, surfactants can be used to limit or minimize the aggregation of VEGF receptor fusion proteins and promote protein dissolution. Suitable surfactants described herein are shown to be nonionic and may include surfactants having a polyoxyethylene moiety. Exemplary such surfactants include: polysorbate 20, polysorbate 80, poloxamer 188, polyethylene glycol 3350, and mixtures thereof. The surfactant in the formulation may be from about 0.02% to about 0.1% by weight / volume (w / v), and more typically, from about 0.02% to about 0.04% (w / v). In some cases, the surfactant is about 0.02% (w / v), about 0.03% (w / v), about 0.04% (w / v), about 0.05% (w / v), about 0.06% (w / v), about 0.07% (w / v), about 0.08% (w / v), about 0.09% (w / v), or about 0.1% (w / v).

[0181] Heat stabilizers used in pharmaceutical formulations that can be used in the methods described herein refer to those that provide resistance to VEGF antagonists ( For example The heat stabilizer is needed to prevent the thermal denaturation of VEGF receptor fusion proteins and to prevent the loss of their efficacy or activity. Suitable heat stabilizers include sugars, such as sucrose, trehalose, sorbitol, or mannitol, or amino acids such as L-proline or L-arginine. For example L-arginine hydrochloride, or taurine. In addition, heat stabilizers may include substituted acrylamide or propanesulfonic acid, or compounds such as glycerol.

[0182] In some cases, the pharmaceutical formulations used 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 amino acids and propanesulfonic acid. Additionally, formulations may include sugars, taurine and propanesulfonic acid, glycerol, taurine and propanesulfonic acid, and L-proline, taurine and propanesulfonic acid.

[0183] The embodiments described herein may have heat stabilizers present individually, each independently at a concentration of about 2% (w / v) to about 10% (w / v), or 4% (w / v) to about 10% (w / v), or about 4% (w / v) to about 9% (w / v), or about 5% (w / v) to about 8% (w / v), or in combination of the above total concentrations. The concentration of the heat stabilizer in the formulation may be 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).

[0184] Regarding taurine and propanesulfonic acid, in embodiments of the invention, these heat stabilizers may be present in the formulation in amounts of about 25 mM to about 100 mM, more typically about 50 mM to about 75 mM (compared to other heat stabilizers).

[0185] Viscosity reducers are commonly used to reduce or prevent protein aggregation. Viscosity reducers included in this article include: sodium chloride, magnesium chloride, D- or L-arginine (…). For example L-arginine hydrochloride), lysine, or mixtures thereof. When present herein, the viscosity reducer may be present in amounts from about 10 mM to about 100 mM, more typically from about 30 mM to about 75 mM, and even more typically from about 40 mM to about 70 mM. In some cases, the viscosity reducer is present in amounts of 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.

[0186] Drugs used in the methods described herein formulation It may also have a pharmaceutically acceptable viscosity for ocular application, such as intravitreal injection. Viscosity is generally a measure of the resistance of a fluid to deformation under shear or tensile stress (typically measured using techniques known in the art, such as a viscometer or rheometer). Typical viscosities of formulations used in the methods described herein are from about 5.0 cP (centipoise) to about 15 cP, from about 11 cP to about 14 cP, from about 12 cP to about 15 cP, or from about 11 cP to about 12 cP. Therefore, the viscosity of the formulations described herein can 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 20 o (When measuring C).

[0187] The various embodiments described herein do not require the inclusion of inorganic salts or other viscosity reducers to maintain these highly useful viscosities. Typically, high-concentration protein solutions require viscosity reducers to prevent protein aggregation and higher viscosity, which makes formulations difficult to inject intravitreal and reduces the potency of VEGF receptor fusion proteins. Therefore, the embodiments described herein include the use of substantially no or no sodium chloride (NaCl), magnesium chloride (MgCl2), D- or L-arginine (… For example Methods for formulating compounds containing D- or L-arginine hydrochloride, lysine, or other viscosity reducers.

[0188] Osmoregulation is a key property of injectable drug formulations used in the methods of this invention. It is desirable that the product conforms to physiological osmotic conditions. Furthermore, osmoregulation provides confirmation of the soluble content in the solution. In embodiments of this invention, the molar osmoregulation of the formulation used in the methods of this invention is less than or equal to about 506 mmol / Kg, or from about 250 to about 506 mmol / Kg. For example Approximately 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 embodiments of the invention, the osmotic pressure is below approximately 250 mmol / Kg.

[0189] Exemplary pharmaceutical formulations for use in the methods of the present invention include the following: Preparation A: 80 mg / ml aflibercept, 10 mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20 and 40 mM sodium chloride, pH 5.8 to 6.2.

[0190] Preparation B: 80 mg / ml aflibercept, 10 mM phosphate-buffered saline, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20 and 40 mM sodium chloride, pH 5.8 to 6.2.

[0191] Preparation 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 to 6.2.

[0192] Preparation D: 80 mg / ml aflibercept, 10 mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80 and 40 mM sodium chloride, pH 6.2.

[0193] Preparation E: 80 mg / ml aflibercept, 10 mM phosphate-buffered saline, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80 and 40 mM sodium chloride, pH 5.8 to 6.2.

[0194] Preparation F: 80 mg / ml aflibercept, 10 mM citrate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80 and 40 mM sodium chloride, pH 5.8 to 6.2.

[0195] Formulation G: 80 mg / ml aflibercept, 10 mM histidine-based buffer, 8% (w / v) sucrose and 0.03% (w / v) polysorbate 20, pH 5.8 to 6.2, and optionally, specifically, excluding viscosity reducers.

[0196] Formulation H: 80 mg / ml aflibercept, 10 mM phosphate-buffered saline, 8% (w / v) sucrose and 0.03% (w / v) polysorbate 20, pH 5.8 to 6.2, and optionally, specifically, excluding viscosity reducers.

[0197] 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 to 6.2, and optionally, specifically, excluding viscosity reducers.

[0198] 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 to 6.2, and optionally, specifically, excluding viscosity reducers.

[0199] Formulation K: 80 mg / ml aflibercept, 10 mM phosphate-buffered saline, 8% (w / v) sucrose and 0.03% (w / v) polysorbate 80, pH 5.8 to 6.2, and optionally, specifically, excluding viscosity reducers.

[0200] Formulation L: 80 mg / ml aflibercept, 10 mM citrate-based buffer, 8% (w / v) sucrose and 0.03% (w / v) polysorbate 80, pH 5.8 to 6.2, and optionally, specifically, excluding viscosity reducers.

[0201] Preparation M: 150 mg / ml aflibercept, 10 mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20 and 40 mM sodium chloride, pH 5.8 to 6.2.

[0202] Preparation N: 150 mg / ml aflibercept, 10 mM phosphate-buffered saline, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20 and 40 mM sodium chloride, pH 5.8 to 6.2.

[0203] Preparation O: 150 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 to 6.2.

[0204] Preparation P: 150 mg / ml aflibercept, 10 mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80 and 40 mM sodium chloride, pH 6.2.

[0205] Preparation Q: 150 mg / ml aflibercept, 10 mM phosphate-buffered saline, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80 and 40 mM sodium chloride, pH 5.8 to 6.2.

[0206] Preparation R: 150 mg / ml aflibercept, 10 mM citrate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80 and 40 mM sodium chloride, pH 5.8 to 6.2.

[0207] 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 to 6.2, and optionally, specifically, excluding viscosity reducers.

[0208] Preparation T: 150 mg / ml aflibercept, 10 mM phosphate-buffered saline, 8% (w / v) sucrose and 0.03% (w / v) polysorbate 20, pH 5.8 to 6.2. For example 6.2), and optionally, in particular, does not include viscosity reducers.

[0209] 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 to 6.2, and optionally, specifically, excluding viscosity reducers.

[0210] Formulation V: 150 mg / ml aflibercept, 10 mM histidine-based buffer, 8% (w / v) sucrose and 0.03% (w / v) polysorbate 80, pH 5.8 to 6.2, and optionally, specifically, excluding viscosity reducers.

[0211] The formulation W consists of 150 mg / ml aflibercept, 10 mM phosphate-buffered saline, 8% (w / v) sucrose and 0.03% (w / v) polysorbate 80, at pH 5.8 to 6.2, and optionally, specifically, excludes viscosity reducers.

[0212] 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 to 6.2, and optionally, specifically, excluding viscosity reducers.

[0213] Preparation Y: 80 mg / ml conbercept, 10 mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20 and 40 mM sodium chloride, pH 5.8 to 6.2.

[0214] Preparation Z: 80 mg / ml Conbercept, 10 mM phosphate-buffered saline, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20 and 40 mM sodium chloride, pH 5.8 to 6.2.

[0215] Preparation AA: 80 mg / ml Conbercept, 10 mM citrate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20 and 40 mM sodium chloride, pH 5.8 to 6.2.

[0216] Preparation BB: 80 mg / ml Conbercept, 10 mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80 and 40 mM sodium chloride, pH 6.2.

[0217] Preparation CC: 80 mg / ml Conbercept, 10 mM phosphate-buffered saline, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80 and 40 mM sodium chloride, pH 5.8 to 6.2.

[0218] Preparation DD: 80 mg / ml Conbercept, 10 mM citrate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80 and 40 mM sodium chloride, pH 5.8 to 6.2.

[0219] Formulation EE: 80 mg / ml conbercept, 10 mM histidine-based buffer, 8% (w / v) sucrose and 0.03% (w / v) polysorbate 20, pH 5.8 to 6.2, and optionally, specifically, excluding viscosity reducers.

[0220] Formulation FF: 80 mg / ml Conbercept, 10 mM phosphate-buffered saline, 8% (w / v) sucrose and 0.03% (w / v) polysorbate 20, pH 5.8 to 6.2, and optionally, specifically, excluding viscosity reducers.

[0221] Formulation GG: 80 mg / ml Conbercept, 10 mM citrate-based buffer, 8% (w / v) sucrose and 0.03% (w / v) polysorbate 20, pH 5.8 to 6.2, and optionally, specifically, excluding viscosity reducers.

[0222] Formulation HH: 80 mg / ml conbercept, 10 mM histidine-based buffer, 8% (w / v) sucrose and 0.03% (w / v) polysorbate 80, pH 5.8 to 6.2, and optionally, specifically, excluding viscosity reducers.

[0223] Formulation II: 80 mg / ml Conbercept, 10 mM phosphate-buffered saline, 8% (w / v) sucrose and 0.03% (w / v) polysorbate 80, pH 5.8 to 6.2, and optionally, specifically, excluding viscosity reducers.

[0224] Formulation JJ: 80 mg / ml Conbercept, 10 mM citrate-based buffer, 8% (w / v) sucrose and 0.03% (w / v) polysorbate 80, pH 5.8 to 6.2, and optionally, specifically, excluding viscosity reducers.

[0225] Preparation KK: 150 mg / ml conbercept, 10 mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20 and 40 mM sodium chloride, pH 5.8 to 6.2.

[0226] Preparation LL: 150 mg / ml Conbercept, 10 mM phosphate-buffered saline, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20 and 40 mM sodium chloride, pH 5.8 to 6.2.

[0227] Preparation MM: 150 mg / ml Conbercept, 10 mM citrate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20 and 40 mM sodium chloride, pH 5.8 to 6.2.

[0228] Preparation NN: 150 mg / ml Conbercept, 10 mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80 and 40 mM sodium chloride, pH 6.2.

[0229] Preparation OO: 150 mg / ml Conbercept, 10 mM phosphate-buffered saline, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80 and 40 mM sodium chloride, pH 5.8 to 6.2.

[0230] Preparation PP: 150 mg / ml Conbercept, 10 mM citrate buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 80 and 40 mM sodium chloride, pH 5.8 to 6.2.

[0231] Formulation QQ: 150 mg / ml Conbercept, 10 mM histidine-based buffer, 8% (w / v) sucrose and 0.03% (w / v) polysorbate 20, pH 5.8 to 6.2, and optionally, specifically, excluding viscosity reducers.

[0232] The formulation RR is: 150 mg / ml conbercept, 10 mM phosphate-buffered saline, 8% (w / v) sucrose and 0.03% (w / v) polysorbate 20, pH 5.8 to 6.2, and optionally, specifically, excludes viscosity reducers.

[0233] The formulation SS consists of 150 mg / ml conbercept, 10 mM citrate-based buffer, 8% (w / v) sucrose and 0.03% (w / v) polysorbate 20, at pH 5.8 to 6.2, and optionally, specifically, excludes viscosity reducers.

[0234] Formulation TT: 150 mg / ml Conbercept, 10 mM histidine-based buffer, 8% (w / v) sucrose and 0.03% (w / v) polysorbate 80, pH 5.8 to 6.2, and optionally, specifically, excluding viscosity reducers.

[0235] The formulation UU consists of 150 mg / ml conbercept, 10 mM phosphate-buffered saline, 8% (w / v) sucrose and 0.03% (w / v) polysorbate 80, at pH 5.8 to 6.2, and optionally, specifically, excludes viscosity reducers.

[0236] Formulation VV: 150 mg / ml Conbercept, 10 mM citrate-based buffer, 8% (w / v) sucrose and 0.03% (w / v) polysorbate 80, pH 5.8 to 6.2, and optionally, specifically, excluding viscosity reducers.

[0237] Formulation WW: 140 mg / ml VEGF receptor fusion protein ( For exampleAflibercept, 10 mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20 and 50 mM taurine, pH 5.8.

[0238] Formulation XX: 140 mg / ml VEGF receptor fusion protein ( For example Aflibercept, 20 mM histidine-based buffer, 4% (w / v) proline, 0.03% (w / v) polysorbate 20 and 50 mM arginine ( For example Arginine hydrochloride, pH 5.8.

[0239] Formulation YY: 140 mg / ml VEGF receptor fusion protein ( For example 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.

[0240] Formulation ZZ: 140 mg / ml VEGF receptor fusion protein ( For example 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 ( For example Arginine hydrochloride, pH 5.8.

[0241] Formulation AAA: 140 mg / ml VEGF receptor fusion protein ( For example Aflibercept, 20 mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20 and 50 mM PSA, pH 5.8.

[0242] Formulation BBB: 140 mg / ml VEGF receptor fusion protein ( For example 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.

[0243] Formulation CCC: 80, 100, 120 or 140 mg / ml VEGF receptor fusion protein ( For example Aflibercept, 20 mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20 and 50 mM arginine ( For example Arginine hydrochloride, pH 5.8.

[0244] Formulation DDD: 140 mg / ml VEGF receptor fusion protein ( For example Aflibercept, 10 mM histidine-based buffer, 4% (w / v) proline, 0.03% (w / v) polysorbate 20 and 50 mM PSA, pH 5.8.

[0245] Formulation EEE: 140 mg / ml VEGF receptor fusion protein ( For example Aflibercept, 20 mM histidine-based buffer, 5% (w / v) sucrose and 0.03% (w / v) polysorbate 20, and optionally without heat stabilizers, at pH 5.8.

[0246] Formulation FFF: 140 mg / ml VEGF receptor fusion protein ( For example Aflibercept, 10 mM sodium phosphate, 5% (w / v) sucrose and 0.03% polysorbate 20, pH 6.2.

[0247] Formulation GGG: 140 mg / ml VEGF receptor fusion protein ( For example Aflibercept; 20 mM histidine, pH 5.8; 5% sucrose; 0.03% polysorbate 20; 50 mM sodium sulfate

[0248] Formulation HHH: 140 mg / ml VEGF receptor fusion protein formulation ( For example Aflibercept; 20 mM histidine, pH 5.8; 5% sucrose; 0.03% polysorbate 20; 50 mM sodium thiocyanate

[0249] Formulation III: 140 mg / ml VEGF receptor fusion protein ( For example Aflibercept; 20 mM histidine, pH 5.8; 5% sucrose, 0.03% polysorbate; 40 mM sodium citrate

[0250] Formulation JJJ: 140 mg / ml VEGF receptor fusion protein ( For example Aflibercept; 20 mM histidine, pH 5.8; 5% sucrose, 0.03% polysorbate; 50 mM glycine

[0251] Formulation KKK: 140 mg / ml VEGF receptor fusion protein ( For example Aflibercept; 20 mM histidine, pH 5.8; 5% sucrose, 0.03% polysorbate; 50 mM sodium chloride

[0252] Formulation LLL: 140 mg / ml VEGF receptor fusion protein ( For example Aflibercept; 20 mM histidine, pH 5.8; 5% sucrose; 0.03% polysorbate 20; 50 mM lysine

[0253] Formulation MMM: 140 mg / ml VEGF receptor fusion protein formulation ( For example Aflibercept; 20 mM histidine, pH 5.8; 5% sucrose; 0.03% polysorbate 20; 50 mM sodium aspartate

[0254] Formulation NNN: 140 mg / ml VEGF receptor fusion protein formulation ( For example Aflibercept; 20 mM histidine, pH 5.8; 5% sucrose; 0.03% polysorbate 20; 50 mM sodium glutamate

[0255] Formulation OOO: 140 mg / ml VEGF receptor fusion protein ( For example Aflibercept; 20 mM histidine, pH 5.8; 5% sucrose; 0.03% polysorbate 20; 50 mM sodium citrate; 50 mM arginine ( For example Arginine hydrochloride)

[0256] Formulation PPP: 140 mg / ml VEGF receptor fusion protein ( For example Aflibercept; 20 mM histidine, pH 5.8; 5% sucrose, 0.03% polysorbate 20; 50 mM glycine; 50 mM arginine ( For example Arginine hydrochloride)

[0257] Formulation QQQ: 140 mg / ml VEGF receptor fusion protein formulation ( For example Aflibercept; 20 mM histidine, pH 5.8; 5% sucrose; 0.03% polysorbate 20; 50 mM sodium aspartate; 50 mM arginine ( For example Arginine hydrochloride)

[0258] Formulation RRR: 140 mg / ml VEGF receptor fusion protein ( For example Aflibercept; 20 mM histidine, pH 5.8; 5% sucrose; 0.03% polysorbate 20; 50 mM sodium glutamate; 50 mM arginine ( For example Arginine hydrochloride)

[0259] SSS formulation: 140 mg / ml 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).

[0260] Formulation TTT: 140 mg / ml VEGF receptor fusion protein ( For example Aflibercept; 20 mM histidine, pH 5.8; 5% sucrose, 0.03% polysorbate 20; 100 L-arginine (L-arginine hydrochloride)

[0261] Formulation UUU: 30 mg / ml VEGF receptor fusion protein ( For example Aflibercept; 10% sucrose, 10 mM phosphate, 0.03% polysorbate 20, pH 6.2

[0262] Formulation VVV: 30 mg / ml VEGF receptor fusion protein ( For example Aflibercept; 20% sucrose, 10 mM phosphate, 0.03% polysorbate 20, pH 6.2

[0263] Formulation WWW: 60 mg / ml VEGF receptor fusion protein ( For example Aflibercept; 10% sucrose, 10 mM phosphate, 0.03% polysorbate 20, pH 6.2

[0264] Formulation XXX: 60 mg / ml VEGF receptor fusion protein ( For example Aflibercept; 20% sucrose, 10 mM phosphate, 0.03% polysorbate 20, pH 6.2

[0265] Formulation YYY: 120 mg / ml VEGF receptor fusion protein ( For example Aflibercept; 10% sucrose, 10 mM phosphate, 0.03% polysorbate 20, pH 6.2

[0266] Formulation ZZZ: 120 mg / ml VEGF receptor fusion protein ( For example Aflibercept; 20% sucrose, 10 mM phosphate, 0.03% polysorbate 20, pH 6.2

[0267] Formulation AAAA: 120 mg / ml VEGF receptor fusion protein ( For example Aflibercept, 10% sucrose, 10 mM phosphate, 0.03% polysorbate 20, 50 mM NaCl, pH 6.2

[0268] Formulation BBBB: 120 mg / ml VEGF receptor fusion protein ( For example Aflibercept, 20% sucrose, 10 mM phosphate, 0.03% polysorbate, 50 mM NaCl, pH 6.2

[0269] Formulation CCCC: 140 mg / ml VEGF receptor fusion protein ( For example Aflibercept, 10 mM sodium phosphate, 5% sucrose, 40 mM sodium chloride, 0.03% PS20, pH 6.2

[0270] Formulation DDDD: 80 mg / ml VEGF receptor fusion protein ( For example 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-hydrochloride), pH 5.8.

[0271] Formulation EEEE: 120.0 mg / ml VEGF receptor fusion protein ( For example Abersipu)( For example + 12 mg / ml), 20 mM histidine-based buffer ( For example + 2 mM), 5% (w / v) sucrose ( For example + 0.5%), 0.03% (w / v) polysorbate 20 ( For example 0.02%-0.04%) and 50 mM L-arginine (e.g., L-arginine hydrochloride-hydrochloride) For example + 5 mM), pH 5.8 For example 5.6-6.0 or 5.5-6.1).

[0272] Formulation FFFF: 113.3 mg / ml VEGF receptor fusion protein ( For example Abersipu)( For example 102-125 mg / ml), 20 mM histidine-based buffer ( For example + 2 mM), 5% (w / v) sucrose ( For example + 0.5%), 0.03% (w / v) polysorbate 20 ( For example 0.02-0.04%) and 50 mM L-arginine (L-arginine monohydrochloride) For example +5 mM), pH 5.8 For example 5.6-6.0 or 5.5-6.1).

[0273] Formulation GGGG: 114.3 mg / ml VEGF receptor fusion protein ( For example Abersipu)( For example 103-126 mg / ml), 10 mM histidine-based buffer (e.g., including histidine and histidine-HCl). For example + 1 mM), 5% (w / v) sucrose ( For example + 0.5%), 0.03% (w / v) polysorbate 20 ( For example 0.02%-0.04%) and 50 mM L-arginine ( For example L-arginine hydrochloride) For example + 5 mM), pH 5.8 For example 5.6-6.0 or 5.5-6.1).

[0274] Formulation HHHH: 100.0 mg / ml VEGF receptor fusion protein ( For example Abersipu)( For example + 10 mg / ml), 20 mM histidine-based buffer ( For example + 2 mM), 5% (w / v) sucrose ( For example + 0.5%), 0.03% (w / v) polysorbate 20 ( For example 0.02%-0.04%) and 50 mM L-arginine (e.g., L-arginine hydrochloride-hydrochloride) For example + 5 mM), pH 5.8 For example 5.6-6.0 or 5.5-6.1).

[0275] Formulation IIII: 133.3 mg / ml VEGF receptor fusion protein ( For example Abersipu)( For example + 13 mg / ml), 20 mM histidine-based buffer ( For example + 2 mM), 5% (w / v) sucrose ( For example + 0.5%), 0.03% (w / v) polysorbate 20 ( For example0.02%-0.04%) and 50 mM L-arginine (e.g., L-arginine hydrochloride-hydrochloride) For example + 5 mM), pH 5.8 For example 5.6-6.0 or 5.5-6.1).

[0276] Preparation JJJJ: 150 mg / ml aflibercept ( For example Abersipu)( For example + 15 mg / ml), 10 mM sodium phosphate, 8% (w / v) sucrose ( For example + 0.8%), 0.03% (w / v) polysorbate 20 ( For example 0.02%-0.04%) and 50 mM L-arginine (L-arginine hydrochloride), pH 6.2 For example 6.0-6.4 or 5.9-6.5).

[0277] Formulation KKKK: 114.3 mg / ml VEGF receptor fusion protein ( For example Abersipu)( For example + 14 mg / ml), 20 mM histidine-based buffer ( For example + 2 mM), 5% (w / v) sucrose ( For example + 0.5%), 0.03% (w / v) polysorbate 20 ( For example 0.02%-0.04%) and 50 mM L-arginine (e.g., arginine monohydrochloride) For example + 5 mM), pH 5.8 For example (5.6-6.0 or 5.5-6.1); See International Patent Application Publication No. WO2019 / 217927.

[0278] In one embodiment of the present invention, > 8 mg of VEGF receptor fusion protein (preferably aflibercept) is administered in an aqueous pharmaceutical formulation comprising: a VEGF receptor fusion protein, the fusion protein comprising two polypeptides, each polypeptide comprising an immunoglobulin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of VEGFR2, and a polymerized component ( For example Containing amino acids 27-457 of SEQ ID NO: 2, at a concentration of at least about 100 mg / ml; about 5% sucrose; L-arginine ( For example L-arginine hydrochloride; histidine-based buffer ( For example The formulation contains histidine (HCl); and about 0.03% surfactant; wherein the pH of the formulation is about 5.0 to about 6.8 (e.g., 5.8 to 6.5, e.g., 5.8). Preferably, the formulation is suitable for intravitreal administration. Other components that may be included are sodium sulfate, sodium thiocyanate, glycine, NaCl, sodium aspartate, and / or monosodium glutamate. In one embodiment of the invention, the concentration of the VEGF receptor fusion protein is: about 100 mg / ml; about 111.5 mg / ml; about 112.0 mg / ml; about 113.3 mg / ml; about 114.3 mg / ml; about 115.6 mg / ml; about 116.3 mg / ml; about 120 mg / ml; about 133 mg / ml; about 140 mg / ml; about 150 mg / ml; about 200 mg / ml; or about 250 mg / ml. The formulation may be characterized by (i) a molar osmotic concentration of about 299 to about 506 mmol / Kg; and / or (ii) a viscosity of about 6-15 cP at 20°C. The surfactant may be a nonionic surfactant, such as polysorbate 20, polysorbate 80, poloxamer 188, polyethylene glycol 3350, or mixtures thereof. The concentration of the histidine-based buffer may be about 10 mM to 20 mM. In one embodiment of the invention, the VEGF receptor fusion protein immediately after production and purification has less than about 3.5% of high molecular weight material and / or less than or equal to about 6% of high molecular weight material after storage at about 2°C-8°C for about 24 months.

[0279] In one embodiment of the present invention, > 8 mg of VEGF receptor fusion protein is administered in an aqueous pharmaceutical formulation comprising: at least about 100 mg / ml of VEGF receptor fusion protein, the fusion protein comprising two polypeptides, each polypeptide comprising an immunoglobulin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of VEGFR2, and a polymerized component; about 10 mM-100 mM L-arginine; sucrose; a histidine-based buffer; and a surfactant; wherein the pH of the formulation is about 5.0 to about 6.8; wherein the VEGF receptor fusion protein immediately after production and purification has less than about 3.5% of high molecular weight material and / or less than or equal to about 6% of high molecular weight material after storage at about 2°C-8°C for about 24 months.

[0280] In one embodiment of the present invention, the aqueous formulation comprises: ● > Approximately 100 mg / ml VEGF receptor fusion protein ( For example (Aflibercept), histidine-based buffers, and L-arginine; ● Approximately 140 mg / ml aflibercept; 20 mM histidine-based buffer; 5% sucrose; 0.03% polysorbate 20; 10 mM L-arginine; pH 5.8; ● Approximately 150 + 15 mg / ml aflibercept, 10 mM phosphate buffer, 8 + 0.8% (w / v) sucrose, 0.02-0.04% (w / v) polysorbate 20 and 50 mM L-arginine, pH 5.9-6.5; ● Approximately 103-126 mg / ml aflibercept, 10 + 1 mM histidine-based buffer, 5 + 0.5% (w / v) sucrose, 0.02%-0.04% (w / v) polysorbate 20 and 50 + 5 mM L-arginine, pH 5.5-6.1; ● Approximately 140 mg / ml aflibercept, 10 mM histidine-based buffer, 2.5% (w / v) sucrose, 2.0% (w / v) proline, 0.03% (w / v) polysorbate 20 and 50 mM L-arginine, pH 5.8; ● Approximately 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; ● > Approximately 100 mg / ml aflibercept, histidine-based buffer, and L-arginine; ● > Approximately 100 mg / ml aflibercept, approximately pH 5.8, wherein this formulation forms <3% HMW aggregates after incubation at 5°C for 2 months; ● Approximately 114.3 mg / mL aflibercept; 10 mM-50 mM histidine-based buffer, sugar, nonionic surfactant, L-arginine, pH 5.8; or ● Approximately 114.3 mg / mL aflibercept; 10 mM His / His-HCl-based buffer, 5% sucrose, 0.03% polysorbate-20, 50 mM L-arginine, pH 5.8.

[0281] In one embodiment of the present invention, >8 mg of VEGF receptor fusion protein is administered in an aqueous pharmaceutical formulation containing...

[0282] 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); Heat stabilizers, which are sugars, amino acids, sucrose, mannitol, sorbitol, trehalose, L-proline, glycine, glycerol, taurine, or propanesulfonic acid. For example From approximately 2% (w / v) to approximately 10% (w / v), for example, 5% (w / v); Buffers, which are histidine-based buffers, phosphate-based buffers, acetate-based buffers (e.g., at a concentration of about 5-25 mM, such as 10 mM or 20 mM); or citrate-based buffers; Nonionic surfactants, such as polysorbate 20, polysorbate 80, poloxamer 188, or polyethylene glycol 3350 based on polyoxyethylene. For example The concentration is from about 0.02% to about 0.1% (w / v), for example 0.03% (w / v); and Viscosity reducers, such as NaCl, MgCl2, D-arginine, L-arginine, or lysine ( For example The concentration is approximately 10-100 mM, for example, 50 mM. The pH of this formulation is approximately 5.0 to approximately 6.8. For example 5.0-6.0 or 5.8).

[0283] In one embodiment of the present invention, the concentration of aflibercept in the 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.;

[0284] In one embodiment of the invention, the aqueous pharmaceutical formulation comprises aflibercept at a concentration of at least about 100 mg / ml; sucrose, mannitol, sorbitol, trehalose; a histidine-based buffer; polysorbate 20 or polysorbate 80; and L-arginine, with a pH of about 5.0 to about 6.8; wherein the aflibercept immediately after production and purification has less than about 3.5% of high molecular weight substances and / or about 2-8% of high molecular weight substances. o After being stored at C for approximately 24 months, it contains less than or equal to approximately 6% high molecular weight substances.

[0285] In one embodiment of the invention, the concentration of sucrose, mannitol, sorbitol, or trehalose is about 2-10% (w / v); the concentration of L-arginine is about 10-100 mM; the concentration of polysorbate 20 or polysorbate 80 is about 0.02-0.1% (w / v); and the concentration of the histidine-based buffer is about 5-25 mM; the pH is about 5.0 to about 6.8.

[0286] Treatment and application

[0287] This invention provides a method for treating angiogenic eye diseases, such as neovascular age-related macular degeneration (nAMD), by sequentially administering an initial loading dose (e.g., 2 mg or more, 4 mg or more, or preferably 8 mg or more of a VEGF antagonist or inhibitor, such as a VEGF receptor fusion protein like aflibercept) (e.g., about every 2-4 weeks or 3-5 weeks), followed by additional doses every 12-20 weeks, preferably 12-16 weeks, 12 weeks, 16 weeks, or 20 weeks. For example, this invention provides a method for treating or preventing angiogenic eye diseases such as neovascular age-related macular degeneration (nAMD) by administering an initial loading dose (e.g., 2 mg or more, 4 mg or more, or preferably 8 mg or more of a VEGF antagonist or inhibitor, such as a VEGF receptor fusion protein like aflibercept) every 2-4 weeks or 3-5 weeks, for example, monthly (or about every 28 days, 28 weeks). +A VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) may be administered once or more (e.g., 3, 4, or 5 times) every 5 days or approximately every 4 weeks, followed by one or more doses of approximately 8 mg or more every 12 weeks (or approximately every 3 months, or approximately every quarter, or approximately every 84 days), or every 16 weeks (or approximately every 4 months, or approximately every 1 / 3 year, or approximately every 112 days), or every 20 weeks. A dosing regimen including a 12-week third dosing interval may be referred to herein as a 12-week dosing regimen or 8q12 or HDq12; a dosing regimen including a 16-week third dosing interval may be referred to herein as a 16-week dosing regimen or 8q16 or HDq16; and a dosing regimen including a 20-week third dosing interval may be referred to herein as a 20-week dosing regimen or 8q20 or HDq20. The dosing regimen that includes a third dosing interval between 12 and 20 weeks may be referred to herein as the 12-20 week dosing regimen or 8q12-20 or HDq12-20.

[0288] Additionally, the present invention includes a method for treating angiogenic eye diseases (e.g., neovascular age-related macular degeneration (nAMD)) by administering the medication once or multiple times every 4 weeks, 8 weeks, 12-20 weeks, 12-16 weeks, 12 weeks, or 16 weeks. > 8 mg VEGF receptor fusion protein, preferably aflibercept; and the first 3, 4 or 5 doses every 4 weeks, followed by approximately every 8 weeks.

[0289] In one embodiment of the present invention, > After an 8 mg monthly loading dose, subjects begin receiving doses every 12, 16, or 20 weeks. > An 8 mg maintenance dose is administered, with no intermediate doses. Subjects rapidly / immediately transition to the maintenance dose phase after the loading dose phase. In one embodiment of the invention, the subject continues to receive... > 8 mg doses for 12 to 20 weeks, 12 weeks, 16 weeks, or 20 weeks, with no intermediate doses.

[0290] In one embodiment of the invention, the subject does not receive a dosing regimen modification (DRM) or discontinue treatment for at least 1, 2, 3, 4 or 5 years.

[0291] The terms “initial dose,” “second dose,” and “third dose” refer to the temporal sequence of administration of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept). Therefore, the “initial dose” is the dose administered at the start of the treatment regimen (also known as the “baseline dose”); the “second dose” is the dose administered after the initial dose; and the “third dose” is the dose administered after the second dose. The initial, second, and third doses may contain the same amount of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), but typically differ in their frequency of administration. However, in some embodiments, the amount of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) contained in the initial, second, and / or third doses differs from each other during treatment (e.g., adjusted upwards or downwards as appropriate).

[0292] Therefore, the dosing regimen of the present invention can be expressed as follows: A method for treating angiogenic eye disease (e.g., nAMD) in a subject of need, the method comprising administering (e.g., intravitreal administration) to the subject of need. A single initial dose is approximately > 5 mg 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 VEGF antagonists (e.g., VEGF receptor fusion proteins such as aflibercept) in μl; 93 μl; 94 μl; 95 μl; 96 μl; 97 μl; 98 μl; 99 μl; or 100 μl) were administered subsequently. One or more (e.g., 2, 3, or 4 times, preferably 2 times) of a second dose of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), followed by One or more third doses of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept); Each second dose is administered 2 to 4 weeks (preferably 4 weeks) immediately following the previous dose; and Each third dose is administered at least 12, 16, or 20 weeks after the immediately preceding dose (preferably 12-20, 12-16, 12, or 16 weeks).

[0293] This invention includes methods in which one or more additional, unpredictable doses of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) are administered to a subject, in addition to any predetermined initial, second, and / or third doses. Such doses are typically administered at the discretion of the treating physician based on the specific needs of the subject. This invention also provides a method for treating angiogenic ophthalmopathy by administering approximately [amount missing] doses to a subject in need based on PRN. > 8 mg (e.g., about 100 μl or less, about 75 μl or less, or about 70 μl or less, such as about 50 μl; 51 μl; 52 μl; 53 μl; 54 μl; 55 μl; 56 μl; 57 μl; 58 μl; 59 μl; 60 μl; 61 μl; 62 μl; 63 μl; 64 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 VEGF antagonists (e.g., VEGF receptor fusion proteins such as aflibercept) in the following amounts: 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.

[0294] On-demand (PRN) treatment regimens require physician visits to be kept at fixed intervals (e.g., every 2, 3, 4, 8, 12, 16, or 20 weeks), and the decision to administer VEGF receptor fusion protein injections is based on the anatomical findings at each visit. Capped PRN dosing regimens require subjects to be treated at a minimum frequency, such as at least every 2, 3, or 4 months.

[0295] Treatment and extension (T&E) protocols require adjustments to the intervals between physician visits based on the patient's clinical course—for example, if the subject shows no signs of active disease (e.g., the macula remains dry and there is no leakage), the next one or more intervals can be extended; if there is fluid accumulation, the next interval will be shortened. At each visit following T&E, an injection of VEGF receptor fusion protein will be administered; the current clinical status only affects the duration of the next injection interval.

[0296] This invention includes embodiments in which, at any point during an HDq12-20, HDq12, HDq16, or HDq20 treatment regimen, a patient can switch to a PRN, capped PRN, or T&E regimen. The PRN, capped PRN, and / or T&E can continue indefinitely or can be stopped at any point in time, and then the HDq12, HDq16, or HDq20 regimen can be restarted at any stage. A period of PRN, capped PRN, and / or T&E can occur before or after any HDq12-20, HDq12, HDq16, or HDq20 regimen.

[0297] The method included in this invention comprises administering a desired dose of HDq12-20, HDq12, HDq16, or HDq20, wherein each third dose is administered 12-20 weeks, 12 weeks, 16 weeks, or 20 weeks after the immediate preceding dose, wherein the treatment interval between two third doses is extended (e.g., from 12 weeks to 13, 14, 15, 16, or 20 weeks, or from 16 weeks to 17, 18, 19, or 20 weeks) until signs of disease activity or visual impairment worsen or relapse, and then administration continues at the last third interval used or the penultimate third interval used. In one embodiment of the invention, the subject receives an initial, second interval, then a 12 or 16-week third interval, and then, after approximately one year, the third interval is extended to approximately 20 weeks.

[0298] The method included in this invention comprises administering a desired dose of HDq12-20 or HDq12 or HDq16 or HDq20, wherein the treatment interval between any two third doses is reduced (e.g., from 20 weeks to 8, 12 or 16 weeks, from 16 weeks to 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3 or 2 weeks, or from 12 weeks to 11, 10, 9, 8, 7, 6, 5, 4, 3 or 2 weeks), for example, an improvement in signs of disease activity or visual impairment (e.g., stabilization or improvement of BCVA and / or stabilization or reduction of CRT), and thus, optionally, the dose interval may be extended, for example, extended back to a larger interval length.

[0299] For example, in one embodiment of the invention, the dosing interval, for example during a dosing phase of 12-20 weeks, 12 weeks, 16 weeks, or 20 weeks, can be shortened (e.g., shortened to 8 weeks) if: ● For example, a loss of more than 5 letters in BCVA (ETDRS or Snellen equivalent) (e.g., relative to BCVA observed approximately 12 weeks after treatment initiation), such as due to persistent or worsening AMD; and / or ● An increase in CRT greater than 25 micrometers is observed (e.g., relative to CRT observed approximately 12 weeks after treatment initiation), and / or if new foveal neovascularization or foveal hemorrhage is observed.

[0300] In one embodiment of the invention, if a subject receiving the HDq12 regimen meets the criteria for reducing the dose interval, the dose interval is reduced to 8 weeks at week 16 or 20.

[0301] In one embodiment of the invention, if a subject receiving the HDq16 regimen meets the criteria for reducing the dose interval, the dose interval is reduced to 8 weeks at week 16 or 20; and if a subject receiving the HDq16 regimen meets the criteria for reducing the dose interval, the dose interval is reduced to 12 weeks at week 24.

[0302] In one embodiment of the invention, the interval is not reduced to any interval shorter than 8 weeks.

[0303] For example, in one embodiment of the invention, the dosing interval, for example, during a dosing phase of 12-20 weeks, 12 weeks, 16 weeks, or 20 weeks, may be extended (e.g., increased by 4 weeks, for example, from 12 to 16 weeks, or 16 to 20 weeks), if: ● BCVA loss < 5 letters (e.g., from week 12 onwards); ● For example, there is no liquid in the central compartment of the OCT, and / or ● No new foveal hemorrhage or foveal neovascularization. (For example, if all three criteria are met) See Figure 3 or Figure 4 .

[0304] The present invention also provides a method for treating angiogenic eye diseases (e.g., nAMD) by administering the following: Approximately every 4, 5, 6, 7, 8, 12, 16, or 20 weeks. >8 mg (e.g., about 100 μl or less, about 75 μl or less, or about 70 μl or less, such as about 50 μl; 51 μl; 52 μl; 53 μl; 54 μl; 55 μl; 56 μl; 57 μl; 58 μl; 59 μl; 60 μl; 61 μl; 62 μl; 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; μl; 84 μl; 85 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); or (For example, about > 8 mg, such as about 100 μl or less, about 75 μl or less, or about 70 μl or less, such as about 50 μl; 51 μl; 52 μl; 53 μl; 54 μl; 55 μl; 56 μl; 57 μl; 58 μl; 59 μl; 60 μl; 61 μl; 62 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; μl; 85 μl; 86 A single initial dose of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) in the following doses: 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), followed by... One or more (e.g., 2, 3, or 4 times (preferably 2 or 4 times)) of a second dose of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), followed by One or more third doses of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept); Each second dose is administered 2 to 4 weeks (preferably 4 weeks) immediately following the previous dose; and Each third dose is administered approximately 4, 5, 6, 7, or 8 weeks (e.g., 8 weeks) after the preceding dose. or Approximately once every 4 weeks (q4w) > 8 mg (e.g., about 100 μl or less, about 75 μl or less, or about 70 μl or less, such as about 50 μl; 51 μl; 52 μl; 53 μl; 54 μl; 55 μl; 56 μl; 57 μl; 58 μl; 59 μl; 60 μl; 61 μl; 62 μl; 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; μl; 84 μl; 85 VEGF antagonists (e.g., VEGF receptor fusion proteins such as aflibercept) in the following amounts: 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. or Less than about 8 doses (e.g., about 5 or 6 doses) over a period of approximately 48 weeks. >8 mg (e.g., about 100 μl or less, about 75 μl or less, or about 70 μl or less, such as about 50 μl; 51 μl; 52 μl; 53 μl; 54 μl; 55 μl; 56 μl; 57 μl; 58 μl; 59 μl; 60 μl; 61 μl; 62 μl; 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; VEGF antagonists (e.g., VEGF receptor fusion proteins such as aflibercept) in doses of 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.

[0305] "Monthly" dosing or "dosing after one month" refers to administration approximately 28 days, 4 weeks, or 28 (months) after the last dose. + Dosage can be administered after 5 days and may cover up to 5 weeks. + (5 days).

[0306] Dosing every "4 weeks" or after "4 weeks" refers to approximately 28 days ( + 5 days), about one month or about 28 days + Dosage can be administered after 5 days and can cover up to every 5 weeks. + Dosage is administered over 5 days.

[0307] Dosing every "2-4 weeks" or after "2-4 weeks" means approximately 2 weeks later. + 5 days), 3 weeks + 5 days) or 4 weeks + Administer the medication 5 days later.

[0308] Dosing every "8 weeks" or after "8 weeks" refers to approximately 2 months ( + 5 days) or about 56 ( + Administer the medication 5 days later.

[0309] Dosing every "12 weeks" or after "12 weeks" refers to administration approximately 3 months, or approximately 84 days later. + 5 days), approximately 90 days + 5 days) or about 84 ( + Administer the medication 5 days later.

[0310] Dosing every "16 weeks" or after "16 weeks" refers to administration approximately 4 months or approximately 112 days later. + Administer the medication 5 days later.

[0311] Dosing every “12–20 weeks” or after “12–20 weeks” means at approximately 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks. + Dosage is administered after 5 days, preferably approximately 12-16 weeks. + 5 days), approximately 12 weeks + 5 days), approximately 16 weeks + 5 days) or about 20 weeks + Administer the medication 5 days later.

[0312] Dosing every "12-20 weeks" refers to administration at approximately weeks 12, 13, 14, 15, 16, 17, 18, 19, or 20. + Dosage is administered after 5 days, preferably approximately 12-16 weeks. + 5 days), approximately 12 weeks + 5 days), approximately 16 weeks + 5 days) or about 20 weeks + Administer the medication 5 days later.

[0313] > The 8 mg dose covers doses of approximately 8 mg or more, such as approximately 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg.

[0314] In embodiments of the present invention, any dosing frequency specified herein may be expressed as a specific frequency. + 5 days For example The invention also includes terms such as "4 weeks" as stated therein. + (5-day implementation plan). Terminology + 5 days including + 1. + 2. + 3. + 4 and / or + 5 days.

[0315] "Sequential administration" means administering each dose of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) to the eye of a subject at different times, such as on different dates at predetermined time intervals (e.g., hours, days, weeks, or months). The present invention includes a method comprising sequentially administering a single initial dose of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) to the eye of a subject, followed by one or more administrations of a second dose of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), followed by one or more administrations of a third dose of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept).

[0316] An effective or therapeutically effective dose of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) for the treatment or prevention of angiogenic eye diseases refers to an amount of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) sufficient to reduce one or more signs and / or symptoms of the disease or condition in the treated subject, whether by inducing the regression or elimination of such signs and / or symptoms or by inhibiting the progression of such signs and / or symptoms. In one embodiment of the invention, the effective or therapeutically effective dose of the VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) is approximately [amount missing] per month. > 8 mg, 3 times a day, then every 12-20 weeks. In one embodiment of the invention, vital signs and / or... Or symptom relief is, for example, achieving an increase of ≥5, 10, or 15 letters in BCVA (relative to baseline) by 1 year (e.g., in nAMD). Improvement in subjects > 5 letters and / or 8-14 letters improved in DME patients / subjects); achieving BCVA ≥ 69 letters. Mother; achieving the absence of fluid at the center of the fovea; reducing the central retinal thickness (CRT) by approximately 150 micrometers or more (e.g., in (less than 300 micrometers in nAMD subjects / patients; and / or reduced by at least approximately 200 micrometers in DR or RVO patients / subjects) or Achieve normal CRT (e.g., approximately 300 micrometers or smaller); and / or achieve leak-free fluorescein angiography.

[0317] In one embodiment of the invention, subjects receiving HDq12-20, HDq16, or HDq16 received fewer injections per month or quarter compared to subjects receiving the 2q8 regimen. For example From the start of treatment until week 60. For example, subjects receiving HDq12 received approximately 7 injections over 60 weeks and / or subjects receiving the HDq16 regimen received approximately 6 injections over 60 weeks.

[0318] "Angiogenic eye disease" refers to any eye disease caused by or related to blood vessel growth or proliferation or vascular leakage. Non-limiting examples of angiogenic eye diseases that can be treated or prevented using the methods of the present invention include: ● Age-related macular degeneration (neovascular (nAMD)) ● Macular edema (ME) ● Macular edema following retinal vein occlusion (ME-RVO) ● Retinal vein occlusion (RVO) ● Central retinal vein occlusion (CRVO) ● Branch retinal vein occlusion (BRVO) ● Diabetic macular edema (DME) ● Choroidal neovascularization (CNV) ● Iris neovascularization, ● Neovascular glaucoma ● Postoperative fibrosis in glaucoma patients ● Proliferative vitreoretinopathy (PVR) ● Optic disc neovascularization, ● Corneal neovascularization, ● Retinal neovascularization, ● Vitreous neovascularization, ● vascular pterygium ● Polypoid choroidal vascular lesions (PCV), optionally, in which the subject also has nAMD. ● Pterygium ● Vascular retinopathy ● Diabetic retinopathy (DR) For example Nonproliferative diabetic retinopathy ( For example The characteristic feature is a diabetic retinopathy severity scale (DRSS) level of approximately 47 or 53) or proliferative diabetic retinopathy; ,example like In subjects who did not have DME, and ● Diabetic retinopathy in subjects with diabetic macular edema (DME).

[0319] This invention provides a method for treating angiogenic eye disease (e.g., nAMD) in subjects of need, comprising sequentially 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 such as aflibercept) (e.g., about every 2-4 weeks or 3-5 weeks, preferably every 4 weeks; preferably three initial loading doses), followed by additional doses every 12-20 weeks, preferably 12-16 weeks, 12 weeks, 16 weeks, or 20 weeks, wherein the subject achieves and / or maintains this status after treatment initiation, for example at 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: ● During the treatment process, BCVA adds, for example, the letters 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or＞ 5. ＞ 10. ＞ 15 or ＞ 20 letters, or the absence of their loss, for example, as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart (e.g., at 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); ● No dosage regimen modifications were accepted, for example, where the dosing interval (e.g., the interval between the third dose) was reduced from the HDq12-20 or HDq12 or HDq16 or HDq20 treatment regimen once started, for example, for at least 48, 60 or 96 weeks. ● Receive 100% of all predetermined doses, for example, for at least 48, 60, or 96 weeks; ● The average BCVA increases over a 12-week period, for example, by week 36 or week 48; ● Absence of intraretinal fluid (IRF) and / or absence of subretinal fluid and / or subretinal epithelial fluid (e.g., at 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), for example, where the subject had nAMD and PCV; ● The retina has no fluid in the central region (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF] and / or subretinal epithelial fluid) (e.g., from the start of treatment to approximately 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); for example, where the subject has nAMD and PCV; ● No subretinal pigment epithelial fluid (e.g., from the start of treatment to approximately 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); ● Fluorescein angiography (FA) without fluid leakage (e.g., approximately 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92 or 96 weeks from the start of treatment); ● The size of choroidal neovascularization (CNV) is reduced, for example, by approximately 2.9, 3, 3.5, 3.65, or 4 mm. 2(For example, from the start of treatment to 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), where the baseline size is approximately 6 or 6.5 mm. 2 ; ● The total damaged CNV area is reduced compared to baseline (e.g., from the start of treatment to 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). ●Loss of IRF and / or SRF, for example in the central partition (e.g., from the start of treatment to 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); ● Reduction in central retinal thickness (CST) (e.g., from the start of treatment to 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); for example, a reduction of approximately 125, 150, 175, or 200 micrometers; ● Improvements in vision-related quality of life, such as an improvement of approximately 3 or 4 points. For example Measurements were taken using the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) (e.g., from the start of treatment to 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). For example The baseline score was approximately 76 or 77. ● Lack of adverse events (AEs) and / or serious AEs (SAEs) occurring during the treatment period, such as adverse events occurring during the treatment period that occur at any time within 30 days of any injection, such as increased blood pressure, increased intraocular pressure, visual impairment, vitreous floaters, vitreous detachment, iris neovascularization and / or vitreous hemorrhage (e.g. from the start of treatment to 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); ● An ETDRS letter score of at least 69 (approximately 20 / 40 Snellen equivalents) (e.g., from the start of treatment to 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); and / or ● Efficacy and / or safety in subjects with nAMD were similar to those of aflibercept administered intravitreally at approximately 2 mg every 4 weeks for the first 3 months, followed by approximately 2 mg intravitreally every 8 weeks or every 2 months, for example, where efficacy was measured as an increase in BCVA and / or a decrease in central retinal thickness, and where safety was measured as the incidence of adverse events (adverse events occurring at any time within 30 days of any injection during the treatment period), such as increased blood pressure, increased intraocular pressure, visual disturbances, vitreous floaters, vitreous detachment, iris neovascularization, and / or vitreous hemorrhage.

[0320] This invention provides a method for treating angiogenic eye disease (e.g., nAMD) in subjects of need, comprising sequentially 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 such as aflibercept) (e.g., about every 2-4 weeks or 3-5 weeks, preferably every 4 weeks; preferably three initial loading doses), followed by additional doses every 12-20 weeks, preferably 12-16 weeks, 12 weeks, 16 weeks, or 20 weeks, wherein the subject achieves and / or maintains this status after treatment initiation, for example at 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: ● No anti-drug antibodies (e.g., anti-aflibercept) were detected during treatment; ●From the start of treatment to 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, best corrected visual acuity (BVCA) improves; ● For example, an increase in BCVA measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart or Snellen equivalent (e.g., from the start of treatment to 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) ≥2 letters, ≥3 letters, ≥4 letters, ≥5 letters, ≥6 letters, or > 7 letters; ● The improvement in BCVA 4 weeks after the start of treatment is approximately 2 or 3 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 3 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The improvement in BCVA at 8 weeks after the start of treatment is approximately 5 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 4 or 5 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The improvement in BCVA 12 weeks after the start of treatment is approximately 5 or 6 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 5 or 6 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The improvement in BCVA at 16 weeks after the start of treatment is approximately 6 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 6 or 7 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The improvement in BCVA at 20 weeks after the start of treatment is approximately 6 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 6 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The improvement in BCVA at 24 weeks after the start of treatment is approximately 5 or 6 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 5 or 6 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The improvement in BCVA at 28 weeks after the start of treatment is approximately 7 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 6 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The improvement in BCVA at 32 weeks after the start of treatment is approximately 6 or 7 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 7 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The improvement in BCVA at 36 weeks after the start of treatment is approximately 6 or 7 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 6 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The improvement in BCVA at 40 weeks after the start of treatment is approximately 6 or 7 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 5 or 6 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The improvement in BCVA at 44 weeks after the start of treatment is approximately 7 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 5 or 6 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The improvement in BCVA at 48 weeks after the start of treatment is approximately 6 or 7 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 6 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The improvement in BCVA at 52 weeks after the start of treatment is approximately 7 or 8 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 6 or 7 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The improvement in BCVA at 56 weeks after the start of treatment is approximately 6 or 7 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 6 or 7 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The improvement in BCVA at 60 weeks after the start of treatment is approximately 6 or 7 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 6 or 7 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● BCVA improvement at approximately 36 to 48 weeks after treatment initiation is approximately 6 or 7 letters, or up to 46 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 6 or 7 letters, or up to 40 letters (ETDRS or Snellen equivalent) with the HDq16 regimen. ● BCVA improvement at approximately 48 to 60 weeks after treatment initiation is approximately 6 or 7 letters, or up to 46 letters (ETDRS or Snellen equivalent) with the HDq12 regimen; or approximately 6 or 7 letters, or up to 40 letters (ETDRS or Snellen equivalent) with the HDq16 regimen. ● BCVA improvement at 48 or 60 weeks after treatment initiation is at least about 5, 10, or 15 letters (ETDRS or Snellen equivalent) when using the HDq12 or HDq16 regimen. ● BCVA patients who were 48, 60, or 96 weeks after the start of treatment did not lose 5, 10, or 15 letters (ETDRS letters or Snellen equivalents) when using the HDq12 or HDq16 regimens. ● BCVA improves around weeks 8, 9, 10, 11, or 12 after treatment initiation and is maintained during the treatment regimen thereafter (e.g., around...). + 1 or + (within the range of 2 ETDRS letters or Snellen equivalent), for example, until at least week 48.

[0321] ●By approximately week 48 or 60, the BCVA should have at least 69 letters (ETDRS letters or Snellen equivalent) when receiving the HDq12 or HDq16 protocol; ● The BCVA at 4 weeks after treatment initiation is approximately 63 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 63 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The BCVA at 8 weeks after treatment initiation is approximately 65 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 65 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The BCVA at 12 weeks after treatment initiation is approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The BCVA at 16 weeks after treatment initiation is approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The BCVA at 20 weeks after treatment initiation is approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The BCVA at 24 weeks after treatment initiation is approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The BCVA at 28 weeks after treatment initiation is approximately 67 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The BCVA at 32 weeks after treatment initiation is approximately 67 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 67 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The BCVA at 36 weeks after treatment initiation is approximately 67 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The BCVA at 40 weeks after treatment initiation is approximately 67 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The BCVA at 44 weeks after treatment initiation is approximately 68 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The BCVA at 48 weeks after treatment initiation is approximately 67 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The BCVA between weeks 36 and 48 after the start of treatment is approximately 66, 67, 68, 69, 70, 71, or 72 letters or up to 91 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen. ● The BCVA between weeks 36 and 48 after the start of treatment is approximately 66, 67, 68, 69, or 70 letters or up to 94 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The BCVA between weeks 48 and 60 after the start of treatment is approximately 66, 67, 68, 69, 70, 71, or 72 letters or up to 91 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen. ● The BCVA between weeks 48 and 60 after the start of treatment is approximately 66, 67, 68, 69, or 70 letters or up to 94 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● By approximately week 48, the BCVA improvement is approximately 7, 8, 9, 10, or 11 letters (ETDRS or Snellen equivalent), for example, where the baseline BCVA... < 54 letters; ● By approximately week 48, the BCVA has improved by about 5, 6, or 7 letters (ETDRS or Snellen equivalent), for example, where the baseline BCVA is about 55-73 letters; ● By approximately week 48, the BCVA has improved by about one, two, or three letters (ETDRS or Snellen equivalent), for example, where the baseline BCVA is approximately > 74 letters; ● By approximately week 48, the BCVA has improved by about 4, 5, or 6 letters (ETDRS or Snellen equivalent), for example, where the baseline BCVA is about 63 letters and the baseline CRT is <400 micrometers; ● By approximately week 48, the BCVA has improved by about 5, 6, 7, 8, or 9 letters (ETDRS or Snellen equivalent), for example, where the baseline BCVA is about 52 or 53 letters and the baseline CRT is... > 400 micrometers; ●By approximately week 48, the BCVA improves by about 2, 3, 4, 5, or 6 letters (ETDRS or Snellen equivalent), for example, where the baseline BCVA is about 56, 57, or 58 letters and the subject has classic minimum CNV; ●By approximately week 48, the BCVA improved by about 5 letters (ETDRS or Snellen equivalent), for example, where the baseline BCVA was about 62, 63, or 64 letters and the subject had only occult CNV; ● By approximately week 48, the BCVA improved by about 6, 7, 8, 9, or 10 letters (ETDRS or Snellen equivalent), for example, where the baseline BCVA was about 53 or 54 letters and the subject had a classic-dominant CNV. ● The BCVA at 52 weeks after treatment initiation is approximately 67 or 68 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 or 67 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The BCVA at 56 weeks after treatment initiation is approximately 66 or 67 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 or 67 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The BCVA at 60 weeks after treatment initiation is approximately 66 or 67 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 or 67 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● The BCVA between approximately 48 and 60 weeks after the start of treatment is approximately 66 to approximately 72 letters (ETDRS or Snellen equivalent) when using the HDq12 regimen; or approximately 66 to approximately 70 letters (ETDRS or Snellen equivalent) when using the HDq16 regimen. ● In subjects with polypoid choroidal vascular disease (PCV) and neovascular age-related macular degeneration (nAMD), the BCVA at approximately week 4 after treatment initiation was approximately 59 letters (ETDRS) when receiving the HDq12 regimen (e.g., where the baseline BCVA was approximately 57 letters); and / or the BCVA was approximately 64 letters (ETDRS) when receiving the HDq16 regimen (e.g., where the baseline BCVA was approximately 60 letters). ● In subjects with polypoid choroidal vascular disease (PCV) and neovascular age-related macular degeneration (nAMD), the BCVA at approximately week 8 after treatment initiation was approximately 63 letters (ETDRS) when receiving the HDq12 regimen (e.g., where the baseline BCVA was approximately 57 letters); and / or the BCVA was approximately 65 letters (ETDRS) when receiving the HDq16 regimen (e.g., where the baseline BCVA was approximately 60 letters). ● In subjects with polypoid choroidal vascular disease (PCV) and neovascular age-related macular degeneration (nAMD), the BCVA at approximately week 12 after treatment initiation was approximately 63 letters (ETDRS) when receiving the HDq12 regimen (e.g., where the baseline BCVA was approximately 57 letters); and / or the BCVA was approximately 66 letters (ETDRS) when receiving the HDq16 regimen (e.g., where the baseline BCVA was approximately 60 letters). ● In subjects with polypoid choroidal vascular disease (PCV) and neovascular age-related macular degeneration (nAMD), the BCVA at approximately week 16 after treatment initiation was approximately 64 letters (ETDRS) when receiving the HDq12 regimen (e.g., where the baseline BCVA was approximately 57 letters); and / or the BCVA at approximately 67 letters (ETDRS) when receiving the HDq16 regimen (e.g., where the baseline BCVA was approximately 60 letters). ● In subjects with polypoid choroidal vascular disease (PCV) and neovascular age-related macular degeneration (nAMD), the BCVA at approximately week 20 after treatment initiation was approximately 64 letters (ETDRS) when receiving the HDq12 regimen (e.g., where the baseline BCVA was approximately 57 letters); and / or the BCVA was approximately 68 letters (ETDRS) when receiving the HDq16 regimen (e.g., where the baseline BCVA was approximately 60 letters). ● In subjects with polypoid choroidal vascular disease (PCV) and neovascular age-related macular degeneration (nAMD), the BCVA at approximately week 24 after treatment initiation was approximately 64 letters (ETDRS) when receiving the HDq12 regimen (e.g., where the baseline BCVA was approximately 57 letters); and / or the BCVA was approximately 67 letters (ETDRS) when receiving the HDq16 regimen (e.g., where the baseline BCVA was approximately 60 letters). ● In subjects with polypoid choroidal vascular disease (PCV) and neovascular age-related macular degeneration (nAMD), the BCVA at approximately week 28 after treatment initiation was approximately 65 letters (ETDRS) when receiving the HDq12 regimen (e.g., where the baseline BCVA was approximately 57 letters); and / or the BCVA was approximately 68 letters (ETDRS) when receiving the HDq16 regimen (e.g., where the baseline BCVA was approximately 60 letters). ● In subjects with polypoid choroidal vascular disease (PCV) and neovascular age-related macular degeneration (nAMD), the BCVA at approximately week 32 after treatment initiation was approximately 64 letters (ETDRS) when receiving the HDq12 regimen (e.g., where the baseline BCVA was approximately 57 letters); and / or the BCVA was approximately 71 letters (ETDRS) when receiving the HDq16 regimen (e.g., where the baseline BCVA was approximately 60 letters). ● In subjects with polypoid choroidal vascular disease (PCV) and neovascular age-related macular degeneration (nAMD), the BCVA at approximately week 36 after treatment initiation was approximately 64 letters (ETDRS) when receiving the HDq12 regimen (e.g., where the baseline BCVA was approximately 57 letters); and / or the BCVA was approximately 71 letters (ETDRS) when receiving the HDq16 regimen (e.g., where the baseline BCVA was approximately 60 letters). ● In subjects with polypoid choroidal vascular disease (PCV) and neovascular age-related macular degeneration (nAMD), the BCVA at approximately week 40 after treatment initiation was approximately 65 letters (ETDRS) when receiving the HDq12 regimen (e.g., where the baseline BCVA was approximately 57 letters); and / or the BCVA was approximately 69 letters (ETDRS) when receiving the HDq16 regimen (e.g., where the baseline BCVA was approximately 60 letters). ● In subjects with polypoid choroidal vascular disease (PCV) and neovascular age-related macular degeneration (nAMD), the BCVA at approximately week 44 after treatment initiation was approximately 65 letters (ETDRS) when receiving the HDq12 regimen (e.g., where the baseline BCVA was approximately 57 letters); and / or the BCVA was approximately 68 letters (ETDRS) when receiving the HDq16 regimen (e.g., where the baseline BCVA was approximately 60 letters). ● In subjects with PCV and nAMD, BCVA increased by approximately 3.0 letters (ETDRS) at approximately week 4 after treatment initiation with the HDq12 regimen; and / or by approximately 3.0 letters with the HDq16 regimen; ● In subjects with PCV and nAMD, BCVA at approximately week 8 after treatment initiation increased by approximately 6.0 letters (ETDRS) when receiving the HDq12 regimen; and / or by approximately 5.0 letters when receiving the HDq16 regimen; ● In subjects with PCV and nAMD, BCVA at approximately week 12 after treatment initiation increased by approximately 7.0 letters (ETDRS) when receiving the HDq12 regimen; and / or by approximately 6.0 letters when receiving the HDq16 regimen; ● In subjects with PCV and nAMD, BCVA increased by approximately 7.0 letters (ETDRS) at approximately 16 weeks after treatment initiation with the HDq12 regimen; and / or by approximately 7.0 letters with the HDq16 regimen; ● In subjects with PCV and nAMD, BCVA at approximately week 20 after treatment initiation increased by approximately 7.0 letters (ETDRS) when receiving the HDq12 regimen; and / or increased by approximately 7.0 letters when receiving the HDq16 regimen; ● In subjects with PCV and nAMD, BCVA at approximately week 24 after treatment initiation increased by approximately 7.0 letters (ETDRS) when receiving the HDq12 regimen; and / or by approximately 5.0 letters when receiving the HDq16 regimen; ● In subjects with PCV and nAMD, BCVA at approximately week 28 after treatment initiation increased by approximately 9.0 letters (ETDRS) when receiving the HDq12 regimen; and / or by approximately 7.0 letters when receiving the HDq16 regimen; ● In subjects with PCV and nAMD, BCVA at approximately week 32 after treatment initiation increased by approximately 8.0 letters (ETDRS) when receiving the HDq12 regimen; and / or by approximately 10.0 letters when receiving the HDq16 regimen; ● In subjects with PCV and nAMD, BCVA at approximately week 36 after treatment initiation increased by approximately 8.0 letters (ETDRS) when receiving the HDq12 regimen; and / or by approximately 10.0 letters when receiving the HDq16 regimen; ● In subjects with PCV and nAMD, BCVA at approximately week 40 after treatment initiation increased by approximately 9.0 letters (ETDRS) when receiving the HDq12 regimen; and / or by approximately 8.0 letters when receiving the HDq16 regimen; ● In subjects with PCV and nAMD, BCVA at approximately week 44 after treatment initiation increased by approximately 9.0 letters (ETDRS) when receiving the HDq12 regimen; and / or by approximately 8.0 letters when receiving the HDq16 regimen; ● In subjects with PCV and nAMD, BCVA at approximately week 48 after treatment initiation increased by approximately 9.0 letters when receiving the HDq12 regimen (ETDRS); and / or increased by approximately 9.0 letters when receiving the HDq16 regimen; ● In subjects with polypoid choroidal vascular disease (PCV) and neovascular age-related macular degeneration (nAMD), the BCVA at approximately week 48 after treatment initiation was approximately 65 letters (ETDRS) when receiving the HDq12 regimen (e.g., where the baseline BCVA was approximately 57 letters); and / or the BCVA was approximately 69 letters (ETDRS) when receiving the HDq16 regimen (e.g., where the baseline BCVA was approximately 60 letters). ● The reduction in total lesion size at approximately week 12 after treatment initiation was approximately 0.45% when receiving the HDq12 regimen. + 2.3) or 0.5 ( + 2.3) or 0.23 mm 2 or at most 11 mm 2 Or approximately 0.40 when accepting the HDq16 scheme. + 2.6) or 0.13 mm 2 or at most 17 mm 2 For example, the baseline total lesion area is approximately 5, 6, or 7 mm. 2 ; ● The reduction in total lesion size at approximately week 48 after treatment initiation was approximately 0.36, 0.4, 0.46, or 0.26 when receiving the HDq12 regimen. + 2.9 or + 0.19) mm 2 Or, when accepting the HDq16 scheme, approximately 0.2, 0.2856, 0.3, or 0.04 ( + 3.2 or + 0.2) mm 2 or at most 16 mm 2 For example, the baseline total lesion area is approximately 5, 6, or 7 mm. 2 ; ● The reduction in total lesion size at approximately week 60 after treatment initiation was approximately 0.52, 0.6, or 0.32 when receiving the HDq12 regimen. + 2.8) mm 2 or at most 14 mm 2 Or, when accepting the HDq16 scheme, approximately 0.35, 0.4, or 0.14 ( + 3.2) mm 2 or at most 17 mm 2 For example, the baseline total lesion area is approximately 5, 6, or 7 mm. 2 ; ● A reduction in central retinal thickness (CRT) of at least approximately 100, 125, 130, 135, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, or 150 micrometers (e.g., from the start of treatment to weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48); ●The change in central retinal thickness 4 weeks after the start of treatment is approximately -120, -121, -122, -122.4, or -120.2 micrometers when using the HDq12 protocol; or approximately -126, -127, -126.6, or -126.3 micrometers when using the HDq16 protocol; ● The change in central retinal thickness 8 weeks after the start of treatment is approximately -132, -133, -134, -135, -136, -136.2, or -132.8 micrometers when using the HDq12 protocol; or approximately -139, -140, -139.5, or -139.6 micrometers when using the HDq16 protocol; ● The change in central retinal thickness 12 weeks after the start of treatment is approximately -136, -137, -138, -139, -140, -141, -140.9, or -136.6 micrometers when using the HDq12 protocol; or approximately -144, -143, or -143.5 micrometers when using the HDq16 protocol; ● The change in central retinal thickness 16 weeks after the start of treatment is approximately -120 or -121 or -122 or -123 or -124 or -123.4 or -120.1 micrometers when using the HDq12 protocol; or approximately -132 or -133 or -132.1 or -133.1 micrometers when using the HDq16 protocol; ● The change in central retinal thickness 20 weeks after the start of treatment is approximately -110, -111, -112, -113, -114, -113.6, or -110.9 micrometers when using the HDq12 protocol; or approximately -115, -116, -117, -118, -115.8, or -117.7 micrometers when using the HDq16 protocol; ● The change in central retinal thickness 24 weeks after the start of treatment was approximately -134, -135, -136, -137, -138, -137.6, or -134.9 micrometers when using the HDq12 protocol; or approximately -105, -106, -107, -108, -105.3, or -107.8 micrometers when using the HDq16 protocol; ● The change in central retinal thickness 28 weeks after the start of treatment is approximately -130, -131, -132, -133, -134, -133.7, or -130.7 micrometers when using the HDq12 protocol; or approximately -144, -145, -146, -147, -148, -144.7, or -147.2 micrometers when using the HDq16 protocol; ●The change in central retinal thickness 32 weeks after the start of treatment is approximately -118 or -19 or -120 or -121 or -120.4 or -118.1 micrometers when using the HDq12 protocol; or approximately -141 or -142 or -143 or -144 or -141.5 or -144 micrometers when using the HDq16 protocol; ●The change in central retinal thickness 36 weeks after the start of treatment is approximately -142 or -143 or -144 or -144.2 or -142.2 micrometers when using the HDq12 protocol; or approximately -126 or -127 or -128 or -129 or -130 or -131 or -126.4 or -130.5 micrometers when using the HDq16 protocol; ● The change in central retinal thickness 40 weeks after the start of treatment is approximately -131, -132, -133, -134, -133.8, or -131.2 micrometers when using the HDq12 protocol; or approximately -127, -128, or -127.5 micrometers when using the HDq16 protocol; ● The change in central retinal thickness 44 weeks after the start of treatment is approximately -120, -121, -122, -123, -124, -125, -124.7, or -120.3 micrometers when using the HDq12 protocol; or approximately -143, -144, -145, or -144.8 micrometers when using the HDq16 protocol; ● Changes in central retinal thickness at 48 weeks after treatment initiation were approximately -141, -141.9, -142, -142.3, -143, -144, -144.4, -145, -146, -147, -147.37, or -148 micrometers with the HDq12 regimen (e.g., where the baseline CRT is approximately 370 micrometers); or approximately -143, -144, -145, -146, -146.76, -147, -147.1, -148, -143.8, or -147.1 micrometers with the HDq16 regimen (e.g., where the baseline CRT is approximately 370 micrometers). ●The change in central retinal thickness 60 weeks after the start of treatment was approximately -153 micrometers when using the HDq16 regimen described above; ● The central retinal thickness at week 4 after treatment initiation was approximately 248.2 micrometers with the HDq12 protocol; or approximately 244.1 micrometers with the HDq16 protocol (e.g., where the initial CRT was approximately 370 micrometers); ● The central retinal thickness at week 8 after treatment initiation was approximately 234.4 micrometers with the HDq12 protocol; or approximately 231.2 micrometers with the HDq16 protocol (e.g., where the initial CRT was approximately 370 micrometers); ● The central retinal thickness at week 12 after treatment initiation was approximately 229.7 micrometers with the HDq12 protocol; or approximately 226.7 micrometers with the HDq16 protocol (e.g., where the initial CRT was approximately 370 micrometers); ● The central retinal thickness at week 16 after treatment initiation was approximately 247.2 micrometers with the HDq12 protocol; or approximately 238.6 micrometers with the HDq16 protocol (e.g., where the initial CRT was approximately 370 micrometers); ● The central retinal thickness at week 20 after treatment initiation was approximately 257 micrometers with the HDq12 protocol; or approximately 254.9 micrometers with the HDq16 protocol (e.g., where the initial CRT was approximately 370 micrometers). ● The central retinal thickness at week 24 after treatment initiation was approximately 233 micrometers with the HDq12 protocol; or approximately 265.4 micrometers with the HDq16 protocol (e.g., where the initial CRT was approximately 370 micrometers). ● The central retinal thickness at week 28 after treatment initiation was approximately 236.9 micrometers with the HDq12 protocol; or approximately 226 micrometers with the HDq16 protocol (e.g., where the initial CRT was approximately 370 micrometers); ● The central retinal thickness at week 32 after treatment initiation was approximately 250.2 micrometers with the HDq12 protocol; or approximately 229.2 micrometers with the HDq16 protocol (e.g., where the initial CRT was approximately 370 micrometers); ● The central retinal thickness at week 36 after treatment initiation was approximately 226.4 micrometers with the HDq12 protocol; or approximately 244.3 micrometers with the HDq16 protocol (e.g., where the initial CRT was approximately 370 micrometers); ● The central retinal thickness at week 40 after treatment initiation was approximately 236.8 micrometers with the HDq12 protocol; or approximately 243.7 micrometers with the HDq16 protocol (e.g., where the initial CRT was approximately 370 micrometers). ● The central retinal thickness at week 44 after treatment initiation was approximately 245.9 micrometers with the HDq12 protocol; or approximately 227.7 micrometers with the HDq16 protocol (e.g., where the initial CRT was approximately 370 micrometers). ● The central retinal thickness at week 48 after treatment initiation was approximately 226 micrometers with the HDq12 protocol; or approximately 226.9 micrometers with the HDq16 protocol (e.g., where the initial CRT was approximately 370 micrometers); ● The central retinal thickness at week 52 after treatment initiation was approximately 227.4 micrometers with the HDq12 protocol; or approximately 231.1 micrometers with the HDq16 protocol (e.g., where the initial CRT was approximately 370 micrometers); ● The central retinal thickness at week 56 after treatment initiation was approximately 234.3 micrometers with the HDq12 protocol; or approximately 233.2 micrometers with the HDq16 protocol (e.g., where the initial CRT was approximately 370 micrometers); ● The central retinal thickness at week 60 after treatment initiation was approximately 218.8 micrometers with the HDq12 protocol; or approximately 221.9 micrometers with the HDq16 protocol (e.g., where the initial CRT was approximately 370 micrometers). ● When using the HDq12 regimen, the central retinal thickness changed by approximately -112, -113, or -112.4 micrometers from week 0 (treatment start) to week 4; ● When using the HDq12 protocol, the central retinal thickness changed by approximately -13, -14, or -13.8 micrometers between weeks 4 and 8; ● When using the HDq12 protocol, the central retinal thickness variation between week 8 and week 12 was approximately -4, -5, or -4.7 micrometers; ● When using the HDq12 protocol, the central retinal thickness change was approximately -24 or -25 micrometers between weeks 20 and 24; ● When using the HDq12 protocol, the central retinal thickness changed by approximately -23, -24, or -23.8 micrometers between weeks 32 and 36; ● When using the HDq12 protocol, the central retinal thickness changed by approximately -19, -20, or -19.7 micrometers between weeks 44 and 48; ● When using the HDq16 protocol, the central retinal thickness varies by approximately -126, -127, or -126.6 micrometers between week 0 and week 4; ● When using the HDq16 protocol, the central retinal thickness varied by approximately -12, -13, or -12.9 micrometers between weeks 4 and 8; ● When using the HDq16 protocol, the central retinal thickness variation was approximately -4, -5, or -4.5 micrometers between weeks 8 and 12; ● When using the HDq16 protocol, the central retinal thickness varied by approximately -39, -40, or -39.4 micrometers between weeks 24 and 28; ● When using the HDq16 protocol, the central retinal thickness variation was approximately 0, -1, or -0.6 micrometers between weeks 36 and 40; ● When using the HDq16 protocol, the central retinal thickness change was approximately -15 or -16 micrometers between weeks 40 and 44; ● When using the HDq16 protocol, the central retinal thickness variation was approximately 0 or -1 or -0.8 micrometers between weeks 44 and 48; ● When using the HDq16 protocol, the central retinal thickness varied by approximately -11, -12, or -11.3 micrometers between weeks 56 and 60; ● The CRT decreases approximately at week 4, 5, 6, 7, or 8 after treatment initiation, and is subsequently maintained throughout the treatment regimen (e.g., at approximately...). + 10. + 11 or + Within 12 micrometers), for example, until at least week 48; ● In subjects with PCV and nAMD, the change in central retinal thickness (CRT) at approximately week 4 after treatment initiation was approximately -130.2 micrometers when receiving the HDq12 regimen; and / or approximately -111.6 micrometers when receiving the HDq16 regimen; ● In subjects with PCV and nAMD, the change in central retinal thickness (CRT) at approximately week 8 after treatment initiation was approximately -152.5 micrometers when receiving the HDq12 regimen; and / or approximately -134.5 micrometers when receiving the HDq16 regimen; ● In subjects with PCV and nAMD, the change in central retinal thickness (CRT) at approximately 12 weeks after treatment initiation was approximately -160.9 micrometers when receiving the HDq12 regimen; and / or approximately -147.7 micrometers when receiving the HDq16 regimen; ● In subjects with PCV and nAMD, the change in central retinal thickness (CRT) at approximately 16 weeks after treatment initiation was approximately -150 micrometers when receiving the HDq12 regimen; and / or approximately -141.1 micrometers when receiving the HDq16 regimen; ● In subjects with PCV and nAMD, the change in central retinal thickness (CRT) at approximately 20 weeks after treatment initiation was approximately -135.9 micrometers when receiving the HDq12 regimen; and / or approximately -128 micrometers when receiving the HDq16 regimen; ● In subjects with PCV and nAMD, the change in central retinal thickness (CRT) at approximately 24 weeks after treatment initiation was approximately -162.7 micrometers when receiving the HDq12 regimen; and / or approximately -115.7 micrometers when receiving the HDq16 regimen; ● In subjects with PCV and nAMD, the change in central retinal thickness (CRT) at approximately 28 weeks after treatment initiation was approximately -163.4 micrometers when receiving the HDq12 regimen; and / or approximately -147.9 micrometers when receiving the HDq16 regimen; ● In subjects with PCV and nAMD, the change in central retinal thickness (CRT) at approximately 32 weeks after treatment initiation was approximately -148.2 micrometers when receiving the HDq12 regimen; and / or approximately -142.3 micrometers when receiving the HDq16 regimen; ● In subjects with PCV and nAMD, the change in central retinal thickness (CRT) at approximately 36 weeks after treatment initiation was approximately -167.4 micrometers when receiving the HDq12 regimen; and / or approximately -132.6 micrometers when receiving the HDq16 regimen; ● In subjects with PCV and nAMD, the change in central retinal thickness (CRT) at approximately 40 weeks after treatment initiation was approximately -159.2 micrometers when receiving the HDq12 regimen; and / or approximately -121.1 micrometers when receiving the HDq16 regimen; ● In subjects with PCV and nAMD, the change in central retinal thickness (CRT) at approximately week 44 after treatment initiation was approximately -146.7 micrometers when receiving the HDq12 regimen; and / or approximately -143.9 micrometers when receiving the HDq16 regimen; ● In subjects with PCV and nAMD, the change in central retinal thickness (CRT) at approximately 48 weeks after treatment initiation was approximately -170.6 micrometers when receiving the HDq12 regimen; and / or approximately -146.1 micrometers when receiving the HDq16 regimen; ● In subjects with PCV and nAMD, the central retinal thickness (CRT) at approximately week 4 after treatment initiation was approximately 260.2 micrometers when receiving the HDq12 regimen (e.g., where the baseline CRT was approximately 390.4 micrometers); and / or approximately 263.6 micrometers when receiving the HDq16 regimen (e.g., when the baseline CRT was approximately 375.2 micrometers); ● In subjects with PCV and nAMD, the central retinal thickness (CRT) at approximately week 8 after treatment initiation was approximately 237.9 micrometers when receiving the HDq12 regimen (e.g., where the baseline CRT was approximately 390.4 micrometers); and / or approximately 240.7 micrometers when receiving the HDq16 regimen (e.g., when the baseline CRT was approximately 375.2 micrometers); ● In subjects with PCV and nAMD, the central retinal thickness (CRT) at approximately 12 weeks after treatment initiation was approximately 229.5 micrometers when receiving the HDq12 regimen (e.g., where the baseline CRT was approximately 390.4 micrometers); and / or approximately 227.5 micrometers when receiving the HDq16 regimen (e.g., when the baseline CRT was approximately 375.2 micrometers); ● In subjects with PCV and nAMD, the central retinal thickness (CRT) at approximately 16 weeks after treatment initiation was approximately 240.4 micrometers when receiving the HDq12 regimen (e.g., where the baseline CRT was approximately 390.4 micrometers); and / or approximately 234.1 micrometers when receiving the HDq16 regimen (e.g., when the baseline CRT was approximately 375.2 micrometers); ● In subjects with PCV and nAMD, the central retinal thickness (CRT) at approximately 20 weeks after treatment initiation was approximately 254.5 micrometers when receiving the HDq12 regimen (e.g., where the baseline CRT was approximately 390.4 micrometers); and / or approximately 247.2 micrometers when receiving the HDq16 regimen (e.g., when the baseline CRT was approximately 375.2 micrometers); ● In subjects with PCV and nAMD, the central retinal thickness (CRT) at approximately 24 weeks after treatment initiation was approximately 227.7 micrometers when receiving the HDq12 regimen (e.g., where the baseline CRT was approximately 390.4 micrometers); and / or approximately 259.5 micrometers when receiving the HDq16 regimen (e.g., when the baseline CRT was approximately 375.2 micrometers); ● In subjects with PCV and nAMD, the central retinal thickness (CRT) at approximately 28 weeks after treatment initiation was approximately 227 micrometers when receiving the HDq12 regimen (e.g., where the baseline CRT was approximately 390.4 micrometers); and / or approximately 227.3 micrometers when receiving the HDq16 regimen (e.g., when the baseline CRT was approximately 375.2 micrometers); ● In subjects with PCV and nAMD, the central retinal thickness (CRT) at approximately 32 weeks after treatment initiation was approximately 242.2 micrometers when receiving the HDq12 regimen (e.g., where the baseline CRT was approximately 390.4 micrometers); and / or approximately 232.9 micrometers when receiving the HDq16 regimen (e.g., when the baseline CRT was approximately 375.2 micrometers); ● In subjects with PCV and nAMD, the central retinal thickness (CRT) at approximately 36 weeks after treatment initiation was approximately 223 micrometers when receiving the HDq12 regimen (e.g., where the baseline CRT was approximately 390.4 micrometers); and / or approximately 242.6 micrometers when receiving the HDq16 regimen (e.g., when the baseline CRT was approximately 375.2 micrometers); ● In subjects with PCV and nAMD, the central retinal thickness (CRT) at approximately 40 weeks after treatment initiation was approximately 231.2 micrometers when receiving the HDq12 regimen (e.g., where the baseline CRT was approximately 390.4 micrometers); and / or approximately 254.1 micrometers when receiving the HDq16 regimen (e.g., when the baseline CRT was approximately 375.2 micrometers); ● In subjects with PCV and nAMD, the central retinal thickness (CRT) at approximately 44 weeks after treatment initiation was approximately 243.7 micrometers when receiving the HDq12 regimen (e.g., where the baseline CRT was approximately 390.4 micrometers); and / or approximately 231.3 micrometers when receiving the HDq16 regimen (e.g., when the baseline CRT was approximately 375.2 micrometers); ● In subjects with PCV and nAMD, the central retinal thickness (CRT) at approximately 48 weeks after treatment initiation was approximately 219.8 micrometers when receiving the HDq12 regimen (e.g., where the baseline CRT was approximately 390.4 micrometers); and / or approximately 229.1 micrometers when receiving the HDq16 regimen (e.g., when the baseline CRT was approximately 375.2 micrometers); ●The reduction in choroidal neovascularization size at week 12 was approximately 0.6, 1.5, 1, or 2 mm when receiving the HDq12 protocol. 2 (±3.7 mm 2 ), or at most about 11 or 12 mm 2 (For example, when the baseline size at the start of treatment is approximately 4, 5, or 6 mm) 2 hour); ●The reduction in choroidal neovascularization size at week 48 was approximately 2, 3, 4, 3.5, or 2.5 mm when receiving the HDq12 regimen. 2 (±5 mm 2 ), or at most about 15 or 16 mm2 (For example, when the baseline size at the start of treatment is approximately 4, 5, or 6 mm) 2 hour); ●The reduction in choroidal neovascularization size at week 60 was approximately 2, 3, 4, 3.8, and 2.8 mm when receiving the HDq12 regimen. 2 (±5 mm 2 ), or at most 13 mm 2 (For example, when the baseline size at the start of treatment is approximately 4, 5, or 6 mm) 2 hour); ●The reduction in choroidal neovascularization size at week 12 was approximately 1, 2, 0.5, or 1.5 mm when receiving the HDq16 regimen. 2 (±4.2 mm 2 ), or at most 17 mm 2 (For example, when the baseline size at the start of treatment is approximately 4, 4.5, 5, 6, 6.5, or 7 mm) 2 hour); ● Choroidal neovascularization size at week 48 (mm) 2 The reduction in () is approximately 1, 2, 1.4, or 3 mm when the HDq16 scheme is accepted. 2 (±5 mm 2 ), or at most 16 mm 2 (For example, when the baseline size at the start of treatment is approximately 4, 4.5, 5, 6, 6.5, or 7 mm) 2 hour); ●The reduction in choroidal neovascularization size at week 60 was approximately 2, 3, 4, or 3.7 mm when receiving the HDq16 regimen. 2 (±5.7 mm 2 ), or at most 17 mm 2 (For example, when the baseline size at the start of treatment is approximately 4, 4.5, 5, 6, 6.5, or 7 mm) 2 hour); ● At baseline, the concentration of free aflibercept in plasma is approximately 0 mg / L (or <0.0156 mg / L); ●Approximately 4 hours after the initiation of HDq12 or HDq16 treatment, the plasma concentration of free aflibercept is approximately 0.04 ( + 0.06 mg / L or 0 mg / L (or <0.0156 mg / L); ●Approximately 8 hours after the initiation of HDq12 or HDq16 treatment, the plasma concentration of free aflibercept is approximately 0.05 ( + 3.8), 0.1 ( + 0.102) or 0.067 mg / L; ●Approximately day 2 after the initiation of HDq12 or HDq16 treatment, the plasma concentration of free aflibercept is approximately 0.11 ( + 2.21), 0.146 ( + 0.110) or 0.0903 mg / L; ●Approximately day 3 after the initiation of HDq12 or HDq16 treatment, the plasma concentration of free aflibercept is approximately 0.11 ( + 2.06), 0.137 ( + 0.0947) or 0.112 mg / L; ●Approximately day 5 after the initiation of HDq12 or HDq16 treatment, the plasma concentration of free aflibercept is approximately 0.08 ( + 1.86), 0.09 ( + 0.048) or 0.085 mg / L; ●Approximately day 8 after the initiation of HDq12 or HDq16 treatment, the plasma concentration of free aflibercept is approximately 0.07 ( + 1.75), 0.0794 ( + 0.041) or 0.068 mg / L; ● Approximately day 15 after the initiation of HDq12 or HDq16 treatment, the plasma concentration of free aflibercept is approximately 0.04 ( + 1.76), 0.044 ( + 0.0199) or 0.039 mg / L; ● Approximately day 22 after the initiation of HDq12 or HDq16 treatment, the plasma concentration of free aflibercept was approximately 0.02 ( + 1.76), 0.021 ( + 0.0148) or 0.023 mg / L; ● On approximately day 29 following the initiation of HDq12 or HDq16 treatment, the plasma concentration of free aflibercept was approximately 0.0077 (mg / L). + 0.0096 mg / L or 0 mg / L (or <0.0156 mg / L); ● Approximately 48 weeks after the initiation of HDq12 treatment, the plasma concentration of free aflibercept was approximately 0.014 mg / L. + 0.018); ● Approximately 48 weeks after the initiation of HDq16 treatment, the plasma concentration of free aflibercept was approximately 0.00056 mg / L. + 0.0038); ●Approximately 28 weeks after the initiation of HDq12 treatment, the plasma concentration of free aflibercept was approximately 0.00088 mg / L. +0.0053); ●Approximately 28 weeks after the initiation of HDq16 treatment, the plasma concentration of free aflibercept was approximately 0.015 mg / L. + 0.016); ●Approximately 12 weeks after the initiation of HDq12 treatment, the plasma concentration of free aflibercept was approximately 0.02 mg / L. + 2) or approximately 0.028 mg / L ( + 0.023); ● Approximately 12 weeks after the initiation of HDq16 treatment, the plasma concentration of free aflibercept was approximately 0.02 mg / L. + 2) or approximately 0.029 mg / L ( + 0.023); ●Approximately 4 weeks after the initiation of HDq12 treatment, the plasma concentration of free aflibercept was approximately 0.017 mg / L. + 0.016); ●Approximately 4 weeks after the initiation of HDq16 treatment, the plasma concentration of free aflibercept was approximately 0.017 mg / L. + 0.016); ● Approximately 4 hours after administration of HDq12 or HDq16 treatment, the adjusted plasma concentration of bound aflibercept is approximately 0.00 mg / L. ● Approximately 8 hours after administration of HDq12 or HDq16 treatment, the adjusted plasma concentration of bound aflibercept is approximately 0.00 mg / L. ●Approximately day 2 after initiation of HDq12 or HDq16 treatment, the adjusted plasma concentration of bound aflibercept is approximately 0.06 ( + 3.50) or 0.12 ( + 0.19) mg / L; ● Approximately day 3 after initiation of HDq12 or HDq16 treatment, the adjusted plasma concentration of bound aflibercept is approximately 0.13 ( + 2.07) or 0.17 ( + 0.155) mg / L; ●Approximately day 5 after initiation of HDq12 or HDq16 treatment, the adjusted plasma concentration of bound aflibercept is approximately 0.18 ( + 1.9) or 0.22 ( + 0.157) mg / L; ●Approximately day 8 after initiation of HDq12 or HDq16 treatment, the adjusted plasma concentration of bound aflibercept is approximately 0.31 ( + 1.56) or 0.33 (+ 0.135) mg / L; ● Approximately day 15 after initiation of HDq12 or HDq16 treatment, the adjusted plasma concentration of bound aflibercept was approximately 0.37 ( + 1.50) or 0.39 ( + 0.130) mg / L; ● Approximately day 22 after initiation of HDq12 or HDq16 treatment, the adjusted plasma concentration of bound aflibercept is approximately 0.25 ( + 3.00) or 0.34 ( + 0.155) mg / L; ● On approximately day 29 following the initiation of HDq12 or HDq16 treatment, the adjusted plasma concentration of bound aflibercept was approximately 0.32 ( + 1.39)...

Claims

1. A method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject of need, said method comprising administering one or more doses of aflibercept at predetermined intervals and amounts, thereby Following intravitreal injection of aflibercept, the clearance rate of free aflibercept from the ocular ventricle was approximately 0.3 mL / day, 0.4 mL / day, 0.41 mL / day, or 0.37–0.46 mL / day. Following intravitreal injection of aflibercept, the time to reach the lower limit of quantitation (LLOQ) of free aflibercept in the subject's ocular ventricle was approximately 15 weeks; and / or Following intravitreal injection of aflibercept, the time to reach the lower limit of quantitation (LLOQ) of free aflibercept in the plasma of the subjects was approximately 3.8 weeks, 3.5 weeks, or 3.5–3.8 weeks.

2. A method for achieving clearance of free aflibercept from the ocular ventricle after intravitreal injection relative to intravitreal injection of 2 mg or... < A method for slowing the clearance rate of aflibercept from the ocular ventricle after 4 mg aflibercept, the method comprising: Injected into the vitreous humor of the eyes of subjects who require it. A single initial dose of approximately 8 mg or more of aflibercept, followed by A second dose of aflibercept, once or multiple times, approximately 8 mg or more, followed by A third dose of aflibercept, once or multiple times, approximately 8 mg or more; Each second dose is administered approximately 2 to 4 weeks after the preceding dose; and Each third dose is administered approximately 12-20 weeks after the preceding dose.

3. A method for determining the duration of efficacy of free aflibercept in the ocular ventricle of a subject following intravitreal injection and / or the time to reach the lower limit of quantitation (LLOQ) of free aflibercept relative to an intravitreal injection of approximately 2 mg or < A method for increasing the time to reach the LLOQ (Limited-Like Quantity) of free aflibercept in the ocular ventricle of a subject after 4 mg aflibercept, the method comprising intravitreal injection into the eye of a subject in need. A single initial dose of approximately 8 mg or more of aflibercept, followed by A second dose of aflibercept, once or multiple times, approximately 8 mg or more, followed by A third dose of aflibercept, once or multiple times, approximately 8 mg or more; Each second dose is administered approximately 2 to 4 weeks after the preceding dose; and Each third dose is administered approximately 12-20 weeks after the preceding dose.

4. A method for determining the time to reach the lower limit of quantitation (LLOQ) of free aflibercept in a subject's plasma after intravitreal injection of approximately 2 mg or more. < A method for increasing the time to LLOQ of free aflibercept in the plasma of a subject after 4 mg aflibercept, the method comprising intravitreal injection into the eye of a subject in need. A single initial dose of approximately 8 mg or more of aflibercept, followed by A second dose of aflibercept, once or multiple times, approximately 8 mg or more, followed by A third dose of aflibercept, once or multiple times, approximately 8 mg or more; Each second dose is administered approximately 2 to 4 weeks after the preceding dose; and Each third dose is administered approximately 12-20 weeks after the preceding dose.

5. A method, said method for - For the treatment or prevention of neovascular age-related macular degeneration (nAMD) in subjects of need. - Used to improve the best corrected visual acuity of subjects in need with nAMD; or - Used to promote retinal dryness in subjects in need who have nAMD; The method comprises administering one or more doses of approximately 8 mg or more of VEGF receptor fusion protein to the eye of the subject every 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks, or 12-20 weeks, or 12-16 weeks, or 16-20 weeks.

6. A method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject of need, the method comprising administering 8 mg of VEGF receptor fusion protein (0.07 mL or 70 μL) via intravitreal injection every 4 weeks (approximately every 28 days + / - 7 days, once a month) for the first three doses, followed by intravitreal injection of 8 mg aflibercept (0.07 mL) every 8 to 16 weeks (2 to 4 months + / - 7 days), for example, every 12 weeks (2 to 4 months + / - 7 days), for example, every 16 weeks (2 to 4 months + / - 7 days), for example, every 20 weeks (+ / - 7 days).

7. A method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject of need at a dose of 8 mg aflibercept (equivalent to 70 μL of injection), the method comprising administering the 8 mg aflibercept once a month (every 4 weeks) for 3 consecutive times, wherein the injection interval can then be extended to every 16 weeks based on the physician’s judgment of visual and / or anatomical outcomes.

8. A method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject of need, wherein: (1) The subject has received an initial 2 mg dose of VEGF receptor fusion protein, and the method includes administering the initial 8 mg dose of VEGF receptor fusion protein to the subject after 1 month, and administering a first 8 mg dose of VEGF receptor fusion protein after 1 month thereafter; and administering a second 8 mg dose of VEGF receptor fusion protein after 1 month thereafter; and then administering one or more 8 mg maintenance doses of VEGF receptor fusion protein every 12, 16 or 20 weeks thereafter, according to the HDq12 or HDq16 or HDq20 dosing regimen. (2) The subject has received an initial 2 mg dose of VEGF receptor fusion protein, and the method includes administering a first 8 mg second dose of VEGF receptor fusion protein to the subject after 1 month, and administering a second 8 mg second dose of VEGF receptor fusion protein after 1 month thereafter; and then, every 12, 16 or 20 weeks thereafter, administering one or more 8 mg maintenance doses of VEGF receptor fusion protein according to the HDq12 or HDq16 or HDq20 dosing regimen. (3) The subject has received an initial 2 mg dose of VEGF receptor fusion protein, and then the method includes administering a second 8 mg dose of VEGF receptor fusion protein to the subject after 1 month, and then administering one or more 8 mg maintenance doses of VEGF receptor fusion protein every 12, 16 or 20 weeks thereafter, according to the HDq12 or HDq16 or HDq20 dosing regimen. (4) The subject has received an initial 2 mg dose of VEGF receptor fusion protein, and then the method includes administering the subject a first 8 mg maintenance dose of VEGF receptor fusion protein after 1 month, and administering all other 8 mg maintenance doses of VEGF receptor fusion protein every 12, 16 or 20 weeks according to the HDq12 or HDq16 or HDq20 dosing regimen. (5) The subject has received an initial 2 mg dose of VEGF receptor fusion protein and a first 2 mg second dose of VEGF receptor fusion protein one month later. The method then includes administering the initial 8 mg dose of VEGF receptor fusion protein to the subject one month later, followed by a first 8 mg second dose of VEGF receptor fusion protein one month thereafter; and administering a second 8 mg dose of VEGF receptor fusion protein one month thereafter; and then, every 12, 16, or 20 weeks thereafter, administering one or more 8 mg maintenance doses of VEGF receptor fusion protein according to the HDq12, HDq16, or HDq20 dosing regimen. (6) The subject has received an initial 2 mg dose of VEGF receptor fusion protein and a first 2 mg dose of VEGF receptor fusion protein one month later. The method then includes administering a first 8 mg dose of VEGF receptor fusion protein to the subject one month later, followed by a second 8 mg dose of VEGF receptor fusion protein one month thereafter; and then, every 12, 16, or 20 weeks thereafter, administering one or more 8 mg maintenance doses of VEGF receptor fusion protein according to the HDq12, HDq16, or HDq20 dosing regimen. (7) The subject has received an initial 2 mg dose of VEGF receptor fusion protein and received a first 2 mg second dose of VEGF receptor fusion protein one month later. The method then includes administering a second 8 mg dose of VEGF receptor fusion protein to the subject one month later, and then administering one or more 8 mg maintenance doses of VEGF receptor fusion protein every 12, 16 or 20 weeks thereafter, according to the HDq12 or HDq16 or HDq20 dosing regimen. (8) The subject has received an initial 2 mg dose of VEGF receptor fusion protein and a first 2 mg second dose of VEGF receptor fusion protein one month later. The method then includes administering the subject a first 8 mg maintenance dose of VEGF receptor fusion protein one month later, and administering all other 8 mg maintenance doses of VEGF receptor fusion protein every 12, 16, or 20 weeks according to the HDq12, HDq16, or HDq20 dosing regimen. (9) The subject has received an initial 2 mg dose of VEGF receptor fusion protein and received a first 2 mg second dose of VEGF receptor fusion protein one month later and a second 2 mg second dose of VEGF receptor fusion protein one month later. The method then includes administering the initial 8 mg dose of VEGF receptor fusion protein to the subject one month later, and administering a first 8 mg second dose of VEGF receptor fusion protein one month thereafter; and administering a second 8 mg second dose of VEGF receptor fusion protein one month thereafter; and then administering one or more 8 mg maintenance doses of VEGF receptor fusion protein every 12, 16, or 20 weeks according to the HDq12, HDq16, or HDq20 dosing regimen. (10) The subject has received an initial 2 mg dose of VEGF receptor fusion protein and a first 2 mg dose of VEGF receptor fusion protein one month later and a second 2 mg dose of VEGF receptor fusion protein one month later. The method then includes administering a first 8 mg dose of VEGF receptor fusion protein to the subject one month later, and administering a second 8 mg dose of VEGF receptor fusion protein one month thereafter; then, every 12, 16, or 20 weeks thereafter, administering one or more 8 mg maintenance doses of VEGF receptor fusion protein according to the HDq12, HDq16, or HDq20 dosing regimen. (11) The subject has received an initial 2 mg dose of VEGF receptor fusion protein and received a first 2 mg second dose of VEGF receptor fusion protein one month later and a second 2 mg second dose of VEGF receptor fusion protein one month later. The method then includes administering a second 8 mg second dose of VEGF receptor fusion protein to the subject one month later, and then administering one or more 8 mg maintenance doses of VEGF receptor fusion protein every 12, 16 or 20 weeks thereafter, according to the HDq12 or HDq16 or HDq20 dosing regimen. (12) The subject has received an initial 2 mg dose of VEGF receptor fusion protein and a first 2 mg dose of VEGF receptor fusion protein one month later and a second 2 mg dose of VEGF receptor fusion protein one month later. The method then includes administering the subject a first 8 mg maintenance dose of VEGF receptor fusion protein two months later, and administering all other 8 mg maintenance doses of VEGF receptor fusion protein every 12, 16, or 20 weeks according to the HDq12, HDq16, or HDq20 dosing regimen. (13) The subject has received an initial 2 mg dose of VEGF receptor fusion protein and a first 2 mg dose of VEGF receptor fusion protein one month later, and a second 2 mg dose of VEGF receptor fusion protein one month later, and a first 2 mg maintenance dose of VEGF receptor fusion protein eight weeks later. The method then includes administering the initial 8 mg dose of VEGF receptor fusion protein to the subject up to two months after the last dose of VEGF receptor fusion protein, and administering a first 8 mg dose of VEGF receptor fusion protein one month thereafter; and administering a second 8 mg dose of VEGF receptor fusion protein one month thereafter; and then administering one or more 8 mg maintenance doses of VEGF receptor fusion protein every 12, 16, or 20 weeks according to the HDq12, HDq16, or HDq20 dosing regimen. (14) The subject has received an initial 2 mg dose of VEGF receptor fusion protein and a first 2 mg dose of VEGF receptor fusion protein one month later, and a second 2 mg dose of VEGF receptor fusion protein one month later, and a first 2 mg maintenance dose of VEGF receptor fusion protein eight weeks later. The method then includes administering the subject a first 8 mg dose of VEGF receptor fusion protein up to two months after the last dose of VEGF receptor fusion protein, and a second 8 mg dose of VEGF receptor fusion protein one month thereafter, and then administering one or more 8 mg maintenance doses of VEGF receptor fusion protein every 12, 16 or 20 weeks thereafter, according to the HDq12 or HDq16 or HDq20 dosing regimen. (15) The subject has received an initial 2 mg dose of VEGF receptor fusion protein and a first 2 mg second dose of VEGF receptor fusion protein after 1 month and a second 2 mg second dose of VEGF receptor fusion protein after 1 month and a first 2 mg maintenance dose of VEGF receptor fusion protein after 8 weeks. The method then includes administering a second 8 mg dose of VEGF receptor fusion protein to the subject up to 2 months after the last dose of VEGF receptor fusion protein, and then, thereafter, administering one or more 8 mg maintenance doses of VEGF receptor fusion protein every 12, 16 or 20 weeks according to the HDq12 or HDq16 or HDq20 dosing regimen. (16) The subject has received an initial 2 mg dose of VEGF receptor fusion protein and a first 2 mg dose of VEGF receptor fusion protein one month later, and a second 2 mg dose of VEGF receptor fusion protein one month later, and a first 2 mg maintenance dose of VEGF receptor fusion protein eight weeks later, and then the method includes administering the subject a first 8 mg maintenance dose of VEGF receptor fusion protein up to two months after the last dose of VEGF receptor fusion protein, and administering all other 8 mg maintenance doses of VEGF receptor fusion protein every 12, 16, or 20 weeks according to the HDq12, HDq16, or HDq20 dosing regimen; in, (i) The HDq12 dosing regimen includes: A single initial dose of approximately 8 mg or more of the VEGF receptor fusion protein, followed by... One or more second doses of the VEGF receptor fusion protein, approximately 8 mg or more, followed by One or more doses of approximately 8 mg or more of the VEGF receptor fusion protein; Each second dose is administered approximately 2 to 4 weeks after the preceding dose; and Each third dose is administered approximately 12 weeks after the preceding dose. (ii) The HDq16 dosing regimen includes: A single initial dose of approximately 8 mg or more of the VEGF receptor fusion protein, followed by... One or more second doses of the VEGF receptor fusion protein, approximately 8 mg or more, followed by One or more doses of approximately 8 mg or more of the VEGF receptor fusion protein; Each second dose is administered approximately 2 to 4 weeks after the preceding dose; and Each third dose is administered approximately 16 weeks after the preceding dose. and (iii) The HDq20 dosing regimen includes: A single initial dose of approximately 8 mg or more of the VEGF receptor fusion protein, followed by... One or more second doses of the VEGF receptor fusion protein, approximately 8 mg or more, followed by One or more doses of approximately 8 mg or more of the VEGF receptor fusion protein; Each second dose is administered approximately 2 to 4 weeks after the preceding dose; and Each third dose is administered approximately 20 weeks after the preceding dose.

9. A method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject of need, wherein: (a) The subject has received an initial 8 mg dose of VEGF receptor fusion protein, and the method includes administering a first 8 mg second dose of VEGF receptor fusion protein to the subject after 1 month and administering a second 8 mg second dose of VEGF receptor fusion protein after 1 month thereafter; and then, thereafter, administering one or more 8 mg maintenance doses of VEGF receptor fusion protein every 12, 16 or 20 weeks according to the HDq12 or HDq16 or HDq20 dosing regimen. (b) The subject has received an initial 8 mg dose of VEGF receptor fusion protein and received a first 8 mg second dose of VEGF receptor fusion protein one month later. The method then includes administering a second 8 mg dose of VEGF receptor fusion protein to the subject one month later, and then administering one or more 8 mg maintenance doses of VEGF receptor fusion protein every 12, 16 or 20 weeks thereafter, according to the HDq12 or HDq16 or HDq20 dosing regimen. (c) The subject has received an initial 8 mg dose of VEGF receptor fusion protein and received a first 8 mg second dose of VEGF receptor fusion protein one month later and a second 8 mg second dose of VEGF receptor fusion protein one month later. The method then includes administering the subject a first 8 mg maintenance dose of VEGF receptor fusion protein after 12, 16, or 20 weeks, and administering all other 8 mg maintenance doses of VEGF receptor fusion protein every 12, 16, or 20 weeks according to the HDq12, HDq16, or HDq20 dosing regimen. or (d) The subject has received an initial 8 mg dose of VEGF receptor fusion protein and a first 8 mg dose of VEGF receptor fusion protein one month later, followed by a second 8 mg dose of VEGF receptor fusion protein one month later, and thereafter, every 12, 16, or 20 weeks, the subject has received one or more 8 mg maintenance doses of VEGF receptor fusion protein; and then the method comprises administering one or more 8 mg maintenance doses of VEGF receptor fusion protein to the subject 12, 16, or 20 weeks after the last maintenance dose of VEGF receptor fusion protein, and administering all other 8 mg maintenance doses of VEGF receptor fusion protein every 12, 16, or 20 weeks according to the HDq12, HDq16, or HDq20 dosing regimen; in, (i) The HDq12 dosing regimen includes: A single initial dose of approximately 8 mg or more of the VEGF receptor fusion protein, followed by... One or more second doses of the VEGF receptor fusion protein, approximately 8 mg or more, followed by One or more doses of approximately 8 mg or more of the VEGF receptor fusion protein; Each second dose is administered approximately 2 to 4 weeks after the preceding dose; and Each third dose is administered approximately 12 weeks after the preceding dose. (ii) The HDq16 dosing regimen includes: A single initial dose of approximately 8 mg or more of the VEGF receptor fusion protein, followed by... One or more second doses of the VEGF receptor fusion protein, approximately 8 mg or more, followed by One or more doses of approximately 8 mg or more of the VEGF receptor fusion protein; Each second dose is administered approximately 2 to 4 weeks after the preceding dose; and Each third dose is administered approximately 16 weeks after the preceding dose. and (iii) The HDq20 dosing regimen includes: A single initial dose of approximately 8 mg or more of the VEGF receptor fusion protein, followed by... One or more second doses of the VEGF receptor fusion protein, approximately 8 mg or more, followed by One or more doses of approximately 8 mg or more of the VEGF receptor fusion protein; Each second dose is administered approximately 2 to 4 weeks after the preceding dose; and Each third dose is administered approximately 20 weeks after the preceding dose.

10. A method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject of need, said subject having received a dosing regimen for treating or preventing said nAMD, said dosing regimen requiring A single initial dose of approximately 2 mg of the VEGF receptor fusion protein, followed by one or more second doses of approximately 2 mg of the VEGF receptor fusion protein, followed by one or more third doses of approximately 2 mg of the VEGF receptor fusion protein. Each second dose is administered approximately 4 weeks after the preceding dose; and each third dose is administered approximately 8 weeks after the preceding dose; and wherein the subject is at any stage of the 2 mg VEGF receptor fusion protein dosing regimen. The method includes applying [something] to the subject's eyes. 8 mg dose of VEGF receptor fusion protein, The subjects were evaluated approximately 8, 10, or 12 weeks after administration, and if the treating physician determined that administration every 12 or 16 weeks was appropriate, the subjects were continued to receive 8 mg of VEGF receptor fusion protein every 12 or 16 weeks. or The subject is evaluated approximately 8, 10, or 12 weeks after administration, and if the treating physician determines that administration every 12 weeks is appropriate, another 8 mg dose of VEGF receptor fusion protein is administered, the subject is re-evaluated approximately 12 weeks later, and if the treating physician determines that administration every 16 weeks is appropriate, the subject continues to be administered 8 mg of VEGF receptor fusion protein every 16 weeks.

11. A method for treating or preventing nAMD in a subject in need, the method comprising administering to the subject's eye... A single initial dose of approximately 8 mg or more of the VEGF receptor fusion protein, followed by... Two doses of approximately 8 mg or more of the VEGF receptor fusion protein were administered. Each second dose is administered approximately 2 to 4 weeks after the preceding dose; and, after said dose... a) Determine whether the subject meets at least one criterion for reducing or extending one or more intervals between VEGF receptor fusion protein doses by 2 weeks, 3 weeks, 4 weeks, or 2–4 weeks; and b) If the determination is made, administer a higher dose of the VEGF receptor fusion protein at the reduced or extended dose interval. The criteria for reducing the interval include:

1. BCVA loss > 5 letters; 2. Increase in central retinal thickness (CRT) > 25 micrometers; 3. New central fossa hemorrhage; and / or 4. New blood vessels form in the central fovea. The criteria for extending the interval include:

1. BCVA loss < 5 letters, 2. There is no liquid in the central compartment; 3. No new central foveal hemorrhage; and / or 4. No new blood vessels formed in the central fovea.

12. A method for treating or preventing angiogenic eye disease in a subject of need, the method comprising administering to the eye of the subject... (1) A single initial dose of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more second doses of about 8 mg or more of the VEGF receptor fusion protein, followed by one or more third doses of about 8 mg or more of the VEGF receptor fusion protein; wherein each second dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each third dose is administered about 8 weeks after the immediately preceding dose; or (2) Administer VEGF receptor fusion protein at doses of 8 mg or more once or multiple times approximately every 4 weeks; For example, the angiogenic ophthalmopathy mentioned above is nAMD; For example, one or more second doses are 2, 3 or 4 second doses and / or about 2-4 weeks is about 4 weeks.

13. A method for treating or preventing neovascular age-related macular degeneration (nAMD) in a subject of need, the method comprising: Approximately > A single initial dose of 8 mg or more of VEGF receptor fusion protein, This is followed by one or more administrations of a second dose of approximately 8 mg or more of the VEGF receptor fusion protein. Subsequently, a third dose of approximately 8 mg or more of the VEGF receptor fusion protein was administered once or multiple times. Each second dose is administered approximately 2 to 4 weeks after the preceding dose; and Each third dose is administered approximately 12-16 weeks after the preceding dose, and The VEGF receptor fusion protein mentioned therein is aflibercept, and The vitreous half-life of aflibercept was increased compared to that of aflibercept administered intravitreally with 40 mg / mL aflibercept, 10 mM phosphate buffer, 5% sucrose, 0.03% polysorbate 20, 40 mM NaCl, and pH 6.2-6.

3.

14. A kit comprising: A container containing a VEGF receptor fusion protein; and Instructions for use of VEGF receptor fusion protein The container mentioned is a vial or a pre-filled syringe. The container contains > 100 mg / mL VEGF receptor fusion protein, or the container described herein contains > 114.3 mg / mL VEGF receptor fusion protein The instructions mentioned therein include instructions for administering the VEGF receptor fusion protein to patients with nAMD. The instructions stated that treatment with VEGF receptor fusion protein 8 mg should be initiated with one injection per month (once every 4 weeks) for a total of 3 consecutive doses. The instructions mentioned include that the injection interval can be extended to every 16 weeks or every 20 weeks after the initial 3 consecutive doses, and The instruction manual includes instructions that allow for adjustments to the treatment intervals based on the physician's assessment of visual and / or anatomical results.

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