Extended, high dose VEGF antagonist regimens for treatment of angiogenic eye disorders secondary to retinal vein occlusion

Abstract

The present invention relates to regimens for the treatment of angiogenic eye disorders secondary to retinal vein occlusion, such as vascular permeability, macular edema, retinal hemorrhage, and neovascularization, and for treatment of retinal vein occlusion, characterized by high doses of aflibercept and lengthening intervals between doses.

Description

Extended, High Dose VEGF Antagonist Regimens for Treatment of Angiogenic Eye Disorders Secondary to Retinal Vein Occlusion

[0001] This application claims the benefit of U. S. Provisional Patent Application No.63 / 733,920, filed on December 13, 2024; U. S. Provisional Patent Application No. 63 / 734,645, filed on December 16, 2024; U. S. Provisional Patent Application No. 63 / 749,365, filed on January 24, 2025; U. S. Provisional Patent Application No. 63 / 750,038, filed on January 27, 2025; U. S. Provisional Patent Application No. 63 / 773,224, filed on March 17, 2025; U. S.Provisional Patent Application No. 63 / 783,889, filed on April 4, 2025; U. S. Provisional Patent Application No. 63 / 786,626, filed on April 10, 2025; U. S. Provisional Patent Application No. 63 / 820,351, filed on June 9, 2025; U. S. Provisional Patent Application No. 63 / 822,119, filed on June 11, 2025; U. S. Provisional Patent Application No. 63 / 831,016, filed on June 26, 2025; U. S. Provisional Patent Application No. 63 / 837,714, filed on July 2, 2025; U. S. Provisional Patent Application No. 63 / 844,396, filed on July 15, 2025; U. S. Provisional Patent Application No. 63 / 848,102, filed on July 21, 2025; U. S. Provisional Patent Application No. 63 / 852,134, filed on July 28, 2025; U. S. Provisional Patent Application No. 63 / 853,117, filed on July 29, 2025; U. S. Provisional Patent Application No. 63 / 874,347, filed on September 2, 2025; U. S. Provisional Patent Application No. 63 / 886,606, filed on September 23, 2025; U. S. Provisional Patent Application No. 63 / 897,539, filed on October 10, 2025; U. S. Provisional Patent Application No.63 / 928,293, filed on December 1, 2025; and Canadian Patent Application No. 3291163, filed on November 3, 2025; each of which is herein incorporated by reference in its entirety.REFERENCE TO A SEQUENCE LISTING

[0002] This application incorporates by reference a computer readable Sequence Listing in ST.26 XML format, titled 11876WO01 Sequence, created on December 12, 2025, and containing 5,501 bytes.FIELD OF THE INVENTION

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

[0004] Retinal vein occlusion (RVO) is one of the most frequent causes of visual loss from diseases affecting the retinal vessels of the eye (Rogers et al., Ophthamology, 117(2):313-319, 2010). The 2 major RVO categories are central RVO (CRVO), with blockage of the single,central vein draining blood from the retina, and branch RVO (BRVO), where one or more of the branches of the central retinal vein are occluded. A less frequent subtype is hemiretinal vein occlusion (HRVO), where branches from the superior or inferior hemisphere are occluded, sharing characteristics with both CRVO and BRVO. All subtypes result in impaired venous drainage from the eye, which may lead to increased venous pressure, reduced arterial perfusion, and retinal ischemia (Brown et al., Investigate Ophthamology & Visual Science, 53(14):936, 2012; Korobelnik et al., Ophthamology, 121 (1 ):202-208, 2014; and Ogura etal., Am J Ophthalmol., 158(5):1032-1038, 2014). One result of retinal non-perfusion is an increase in the production of vascular endothelial growth factor (VEGF) (Aiello et al., N Engl J Med., 331 (22):1480-1487, 1994). The VEGF levels in aqueous humor from eyes with RVO can be more than 100 times higher than normal (Noma et al., Gurr Eye Res., 36(3):256-263, 2011 ). Increased expression of VEGF can lead to vascular permeability, macular edema, retinal hemorrhage, and neovascularization. Patients with central macular edema secondary to RVO lose visual acuity, and the visual prognosis, if untreated, is often poor (Holz etal., Br J Ophthalmol., 97(3):278-284, 2013).

[0005] Vascular endothelial growth factor mediates endothelial cell hypertrophy which leads to a reduction of capillary luminal diameter. This, in turn, results in an increase of intravascular pressure over the length of a retinal vessel. The resulting decrease in the blood flow in the retinal capillary augments ischemia and hypoxia, thereby increasing the expression of VEGF which maintains this pathogenic cycle (Aiello, supra).SUMMARY OF THE INVENTION

[0006] The present invention provides a method (i) for treating or preventing an angiogenic eye disorder, (ii) for treating or preventing an angiogenic eye disorder secondary to retinal vein occlusion in a subject in need thereof, (iii) for improving best corrected visual acuity with an angiogenic eye disorder secondary to retinal vein occlusion in a subject in need thereof, (iv) for treating or preventing retinal vein occlusion in a subject in need thereof, and / or (v) for treating or preventing macular edema secondary to retinal vein occlusion; including administering to an eye of the subject (e.g., by intravitreal injection), one or more doses of about 8 mg (±0.8 mg) of a VEGF receptor fusion protein (preferably aflibercept) about once every 4-8, 4-12 or 8-12 weeks (± 7 days), 4 weeks (± 7 days) or 8 weeks (± 7 days) or 12 weeks (± 7 days). In one embodiment, the method is for treating or preventing macular edema secondary to retinal vein occlusion. In another embodiment, the method is for treating or preventing retinal vein occlusion in a subject in need thereof. For example, in an embodiment of the invention, the subject is administered one or more doses of about 8 mg (±0.8 mg) of a VEGF receptor fusion protein(preferably aflibercept) about once every 4 weeks (± 7 days). In an embodiment of the invention, the method includes administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept), followed by one or more secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept), followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept); wherein each secondary dose is administered about 2 to 4 weeks (preferably about 4 weeks; (± 7 days)) after the immediately preceding dose; and wherein each tertiary dose is administered about 8 weeks (± 7 days) after the immediately preceding dose. In one such embodiment, each secondary dose is administered about 4 weeks; (± 7 days) after the immediately preceding dose. In an embodiment of the invention, the method includes administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept), followed by 2 secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept), followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept); wherein each secondary dose is administered about 2 to 4 weeks (preferably about 4 weeks; (± 7 days)) after the immediately preceding dose; and wherein each tertiary dose is administered about 8 weeks after the immediately preceding dose. In one such embodiment, each secondary dose is administered about 4 weeks; (± 7 days) after the immediately preceding dose. In an embodiment of the invention, the method includes administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept), followed by 4 secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept), followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept); wherein each secondary dose is administered about 2 to 4 weeks (preferably about 4 weeks; (± 7 days)) after the immediately preceding dose; and wherein each tertiary dose is administered about 8 weeks (± 7 days) after the immediately preceding dose. In one such embodiment, each secondary dose is administered about 4 weeks; (± 7 days) after the immediately preceding dose. For example, the method includes administering to the eye of the subject, 3 doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept) in a formulation that comprises about 114.3 mg / ml VEGF receptor fusion protein (preferably aflibercept) at an interval of once every 4 weeks (± 7 days); wherein after said 3 doses, administering one or more doses of the VEGF receptor fusion protein (preferably aflibercept) at an interval which is lengthened up to about 8 or more weeks (± 7 days). In another example, the method includes administering to the eye ofthe subject, 5 doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept) in a formulation that comprises about 114.3 mg / ml VEGF receptor fusion protein (preferably aflibercept) at an interval of once every 4 weeks (± 7 days); wherein after said 5 doses, administering one or more doses of the VEGF receptor fusion protein (preferably aflibercept) at an interval which is lengthened up to about 8 or more weeks (± 7 days). In any of the methods of the invention administration may be via intravitreal administration. In any of the embodiments of the invention, the VEGF receptor fusion protein is aflibercept which is administered intravitreally. For instance, for any of the methods discussed in this paragraph, the VEGF receptor fusion protein may be aflibercept which is administered intravitreally to treat macular edema secondary to retinal vein occlusion.

[0007] In an embodiment of the invention, the method is for treating or preventing macular edema secondary to retinal vein occlusion in an subject; wherein the method comprises administering to an eye of the subject an intravitreal injection of 8 mg aflibercept in a volume of 70 pL every month or every 4 weeks + / - 1 week for the first 3 consecutive doses followed by one or more doses of 8 mg aflibercept administered 8 weeks (2 month) or 12 weeks (3 month) after the immediately preceding dose.

[0008] In an embodiment of the invention, the method is for treating or preventing macular edema secondary to retinal vein occlusion in an subject; wherein the method comprises administering to the eye of the subject, a single initial dose of 8 mg aflibercept, followed by two secondary doses of 8 mg aflibercept, followed by one or more tertiary doses of 8 mg aflibercept; wherein each secondary dose is administered 4 weeks or one month after the immediately preceding dose; and wherein one tertiary dose is administered 8 weeks (2 month) after the immediately preceding dose and wherein further tertiary doses are administered 8 weeks (2 month) or 12 weeks (3 month) after the immediately preceding dose.

[0009] In one embodiment each dose of 8 mg aflibercept is administered intravitreally.

[0010] In one embodiment each dose of 8 mg aflibercept is administered in a volume of 70 pL.

[0011] The present invention provides a method that includes administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks (preferably 4 weeks; (± 7 days)) after the immediately preceding dose; and wherein each tertiary dose is administered about 12 weeks after the immediately preceding dose. In one such embodiment,each secondary dose is administered about 4 weeks; (± 7 days) after the immediately preceding dose. In an embodiment of the invention, the method includes administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by 5 secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks (± 7 days) after the immediately preceding dose; and wherein each tertiary dose is administered at least 8 weeks after the immediately preceding dose. In one such embodiment the tertiary doses are administered 8 to 12 weeks after the preceding dose. In one such embodiment, the administration is via intravitreal injection and the VEGF receptor fusion protein is aflibercept. In an embodiment of the invention, the method includes administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by 5 secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks (± 7 days) after the immediately preceding dose; and wherein each tertiary dose is administered about 12 weeks (± 7 days) after the immediately preceding dose. In one such embodiment the secondary doses are administered about 4 weeks (± 7 days) after each other. In one such embodiment, the administration is via intravitreal injection and the VEGF receptor fusion protein is aflibercept.

[0012] In one embodiment, a method of the present invention may employ the same interval between tertiary doses throughout the administration of tertiary doses. In one embodiment, a method of the present invention may comprise monitoring to determine whether to shorten, maintain, or lengthen the interval between tertiary doses. The interval between doses, e.g., tertiary doses may be shortened (e.g., from about 8 weeks to about 4 weeks) if, in the judgment of the treating physician, a sufficient response to 8 mg aflibercept treatment is not maintained, e.g., based on visual or anatomical outcomes, e.g., BCVA or CST.

[0013] In an embodiment of the invention, the tertiary dosing interval of a method of the present invention is shortened from about 12 weeks (± 7 days) to about 8 week (± 7 days)s or about 4 weeks (± 7 days) or about 4-8 weeks (± 7 days); or wherein the tertiary dosing interval is shortened from about 8 weeks (± 7 days) to about 4 weeks (± 7 days); and / or lengthened from about 4 weeks (± 7 days) to about 8 weeks (± 7 days) or about 12 weeks (± 7 days) or from about 8 weeks (± 7 days) to about 12 weeks (± 7 days). In an embodiment of the invention, the tertiary dosing interval is shortened if the subject exhibits any one or more of: >5 letters loss of BCVA from best previous BCVA; >5 letters loss of BCVA from best previous BCVA withpersistent or worsening macular edema; and / or >50 pm increase in CST (central subfield thickness) relative to CST measured at any previous time. In an embodiment of the invention, the tertiary dosing interval is lengthened if the subject exhibits any one or more of: Best-corrected visual acuity loss <5 letters relative to BCVA measured at any previous time; and / or CST thickness of <325 pm or <315 pm (e.g., wherein CST thickness of <325 pm or <315 pm is as measured by the Heidelberg Spectralis platform or by Cirrus or Topcon SD-OCT) and / or Central retinal thickness (CRT) of <320 pm or <300 pm (e.g., wherein CST thickness of <320 pm or <300 pm is as measured by the Heidelberg Spectralis platform or by Cirrus or Topcon SD-OCT). In one embodiment, a method of the invention may comprise such monitoring to determine whether to shorten, maintain, or lengthen the tertiary dosing interval. CRT (central retinal thickness) and CST (center subfield thickness) can be used, herein, interchangeably.

[0014] For example, in an embodiment of the invention, the method includes administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept), followed by one or more secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks (preferably 4 weeks; (± 7 days)) after the immediately preceding dose; and wherein each tertiary dose is administered about 12 weeks after the immediately preceding dose; wherein said tertiary interval is shortened if the subject exhibits any one or more of: >5 letters loss of BCVA from best previous BCVA; and >5 letters loss of BCVA from best previous BCVA with persistent or worsening macular edema. In one such embodiment, the interval between each immediately preceding secondary dose and the next is about 4 weeks (± 7 days).

[0015] In an embodiment of the invention, the method includes administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept), followed by one or more secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept), followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept); wherein each secondary dose is administered about 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 8 weeks after the immediately preceding dose; wherein said tertiary interval is shortened if the subject exhibits any one or more of: >5 letters loss of BCVA from best previous BCVA; >5 letters loss of BCVA from best previous BCVA with persistent or worsening macular edema; and / or >50 pm increase in CST relative to CST measured at any previous time.

[0016] In an embodiment of the invention, the method includes administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept), followed by 2 or 4 secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept), followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein (preferably aflibercept); wherein each secondary dose is administered about 4 weeks (± 7 days) after the immediately preceding dose; and wherein each tertiary dose is administered about 8 weeks (± 7 days) after the immediately preceding dose; wherein said tertiary interval is lengthened if the subject exhibits any one or more of: Best-corrected visual acuity loss <5 letters relative to BCVA measured at any previous time; and / or GST thickness of <325 pm or <315 pm.

[0017] In an embodiment of the invention, a subject discussed herein suffers from macular edema secondary to retinal vein occlusion, e.g., wherein the retinal vein occlusion is central retinal vein occlusion, branch retinal vein occlusion, or hemiretinal vein occlusion. In one embodiment, the occlusion is central retinal vein occlusion and / or branch retinal vein occlusion.

[0018] In an embodiment of the invention, the lengthening of an interval between tertiary doses is lengthened or shortened by one or more 4-week increments. In an embodiment of the invention, the interval between tertiary doses was lengthened one or more time prior. In an embodiment of the invention, the interval between tertiary doses has been lengthened one or more times prior from: about 8 weeks (± 7 days) to about 12 weeks (± 7 days), about 16 weeks (± 7 days) or about 20 weeks (± 7 days); about 12 weeks (± 7 days) to about 16 weeks (± 7 days)or about 20 weeks (± 7 days); and / or about 16 weeks (± 7 days) to about 20 weeks (± 7 days). In an embodiment of the invention, about 8 weeks is 8 weeks or about 8 weeks ± about 1 or 2 or 3 or 4 or 5 days; or is 2 months. In an embodiment of the invention, about 12 weeks is 12 weeks or about 12 weeks ± about 1 or 2 or 3 or 4 or 5 days or is 3 months. In an embodiment of the invention, about 16 weeks is 16 weeks or 12 weeks ± 1 or 2 or 3 or 4 or 5 days or 4 months. In an embodiment of the invention, about 20 weeks is 20 weeks or 20 weeks ± 1 or 2 or 3 or 4 or 5 days or 5 months. In one embodiment, the adjustment of the tertiary dose interval is to increase or decrease the interval by about 1 week ± about 1 day, provided that the new interval is at least about 4 weeks ± 1 week. In one embodiment, the adjustment of the tertiary dose interval is to increase or decrease the interval by about 4 weeks ± about 1 weeks, provided that the new interval is at least about 4 weeks ± 1 week. In one embodiment, the adjustment of the tertiary dose interval is to increase or decrease the interval by about 2 weeks ± about 1 day, provided that the new interval is at least about 4 weeks ± 1 week.

[0019] In an embodiment of the invention, the <325 m or <315 pm is measured by spectral domain optical coherence tomography (SD-OCT).

[0020] In any of the embodiments describe herein, it may be that the subject is treatment naive. In one embodiment the subject is treatment- naive macular and has edema secondary to retinal vein occlusion (RVO). In an embodiment of the invention, the subject exhibits one or more of: Treatment-naive macular edema; Treatment-naive macular edema involving the foveal center secondary to RVO (BRVO, HRVO, or CRVO); a mean CST >300 pm on OCT (or >320 pm on Heidelberg Spectralis platform); and / or macular edema following RVO (e.g., CRVO, BRVO, or HRVO) involving the foveal center.

[0021] In an embodiment of the invention, the subject does not exhibit one or more of:Evidence of macular edema due to any cause other than RVO; Diabetic retinopathy; Diabetic macular edema; Advanced age-related macular degeneration (neovascular AMD or geographic atrophy); Use of any intravitreal implantable agent in an eye; Prior treatment with ocriplasmin at any time in an eye; Prior treatment with pegcetacoplan injection or avacincaptad pegol injection in an eye; Prior treatment with retinal laser photocoagulation in an eye; Prior treatment with gene therapy and / or cell therapy in an eye; History of vitreoretinal surgery (including scleral buckle) in an eye; Any intraocular surgery, including cataract surgery, within 12 weeks (84 days) of treatment in an eye; YAG (Yttrium-aluminum-garnet) capsulotomy in an eye within 4 weeks (28 days) of treatment; IOP > 25 mm Hg in an eye; Uncontrolled glaucoma in an eye; Infectious blepharitis, keratitis, scleritis, or conjunctivitis in an eye; Any intraocular inflammation / infection (including trace, or above, cells in the anterior chamber and / or vitreous) within 12 weeks (84 days) of treatment in an eye; History of idiopathic or autoimmune uveitis in an eye;Vitreomacular traction or epiretinal membrane in an eye evident on biomicroscopy or OCT that is affects central vision; Myopia of a spherical equivalent of 8 diopters or greater in an eye (prior to any refractive or cataract surgery, if applicable); History of corneal transplant in an eye; Any corneal dystrophy affecting the visual axis in an eye; Aphakia, or pseudophakia with absence of posterior capsule (unless it occurred as a result of a YAG posterior capsulotomy performed more than 28 days before treatment in an eye; Any history of macular hole of stage 2 and above in an eye; Current anterior segment neovascularization, vitreous hemorrhage, or tractional retinal detachment visible in an eye; Structural damage in an eye that is likely to preclude improvement in BCVA following resolution of macular edema (including atrophy of the retinal pigment epithelium, preretinal fibrosis, subretinal fibrosis or scar, significant macular ischemia, or organized hard exudates); Uncontrolled blood pressure (systolic > 160 mm Hg or diastolic > 95 mm Hg); Uncontrolled diabetes mellitus (DM), defined by hemoglobin A1c (HbA1c) >12% attreatment; History of cerebrovascular accident / transient ischemic attack or myocardial infarction / acute coronary syndrome within 6 months (180 days) of treatment; Renal failure, dialysis, or history of renal transplant; Known sensitivity to the VEGF receptor fusion protein (e.g., aflibercept), histidine, arginine, polysorbate or sucrose; Presence of systemic infection or treatment for suspected or active systemic infection; Subject is pregnant or is a breastfeeding woman; and / or Subject is a man or woman of child bearing potential who is not practicing a highly effective contraception prior to treatment or at least 4 months after cessation of treatment; wherein said highly effective contraception comprises stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal, contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to treatment;, intrauterine device; or intrauterine hormone-releasing system; bilateral tubal occlusion / ligation; vasectomy; condom plus contraceptive sponge, foam, or jelly, or diaphragm plus contraceptive sponge, foam, or jelly; and / or sexual abstinence. In an embodiment of the invention, an eye is the eye to which said VEGF receptor fusion protein is administered and / or the fellow eye.

[0022] In an embodiment of the invention, the VEGF receptor fusion protein (preferably aflibercept) is in an aqueous pharmaceutical formulation (e.g., at a concentration of about IOS-126 mg / ml), for example, including a histidine-based buffer and / or arginine (e.g., L-arginine) and / or a sugar and / or a polyol (e.g., sucrose); and / or a non-ionic surfactant such as polysorbate (e.g., polysorbate 20 or polysorbate 80); e.g., with a pH of about 5.8. In an embodiment of the invention, the VEGF receptor fusion protein (preferably aflibercept) is in an aqueous pharmaceutical formulation including: at least about 100 mg / ml of a VEGF receptor fusion protein comprising two polypeptides that each comprises an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of VEGFR2, and a multimerizing component; about 10-100 mM L-arginine; sucrose; a histidine-based buffer; and a surfactant; wherein the formulation has a pH of about 5.0 to about 6.8; wherein the VEGF receptor fusion protein has less than about 3.5% high molecular weight species immediately after manufacture and purification and / or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C. In an embodiment of the invention, the VEGF receptor fusion protein (preferably aflibercept) is in an aqueous pharmaceutical formulation including about the VEGF receptor fusion protein (e.g., at about 103-126 mg / ml, for example, 114.3 mg / ml), a histidine-based buffer and arginine. In an embodiment of the invention, the VEGF receptor fusion protein is an aqueous pharmaceutical formulation comprising about 114.3 mg / ml VEGF receptor fusion protein, histidine-based buffer and arginine. In an embodiment of the invention, the VEGFreceptor fusion protein is aflibercept which is in an aqueous pharmaceutical formulation, wherein the aflibercept has less than about 3.5% high molecular weight species immediately after manufacture and purification and / or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8° C. In an embodiment of the invention, the VEGF receptor fusion protein (preferably aflibercept) is in an aqueous pharmaceutical formulation comprising: at least about 100 mg / ml of a VEGF receptor fusion protein; about 10-100 mM L-arginine; sucrose; a histidine-based buffer; and a surfactant (e.g., a non-ionic surfactant); wherein the formulation has a pH of about 5.0 to about 6.8; wherein the VEGF receptor fusion protein has less than about 3.5% high molecular weight species immediately after manufacture and purification and / or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C. In an embodiment of the invention, the VEGF receptor fusion protein (preferably aflibercept) is in an aqueous pharmaceutical formulation comprising: >100 mg / ml VEGF receptor fusion protein, histidine-based buffer and L-arginine; 140 mg / ml aflibercept; 20 mM histidine-based buffer; 5 % sucrose; 0.03 % polysorbate 20; 10 mM L-arginine; pH 5.8; 150 ± 15 mg / ml aflibercept, 10 mM phosphate-based buffer, 8 ± 0.8% (w / v) sucrose, 0.02-0.04% (w / v) polysorbate 20 and 50 mM L-arginine, pH 5.9-6.5; 103-126 mg / ml aflibercept, 10 ± 1 mM histidine-based buffer, 5 ± 0.5% (w / v) sucrose, 0.02-0.04% (w / v) polysorbate 20, and 50 ± 5 mM L-arginine, pH 5.5-6.1; 140 mg / ml aflibercept, 10 mM histidine-based buffer, 2.5 % (w / v) sucrose, 2.0 % (w / v) proline, 0.03 % (w / v) polysorbate 20 and 50 mM L-arginine, pH 5.8; 114.3 mg / ml aflibercept, 10 mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20 and 50 mM L-arginine, pH 5.8; >100 mg / ml aflibercept, histidine-based buffer and L-arginine; >100 mg / ml aflibercept at about pH 5.8, wherein the formulation forms <3% HMW aggregates after incubation at 5°C for 2 months; about 114.3 mg / mL aflibercept; 10 mM -50 mM histidine-based buffer, sugar, non-ionic surfactant, L-Arginine, pH 5.8; or about 114.3 mg / mL aflibercept; 10 mM His / His-HCl-based buffer, 5% sucrose, 0.03% polysorbate-20, 50 mM L-Arginine, pH 5.8. 41. In an embodiment of the invention, the VEGF receptor fusion protein is in an aqueous pharmaceutical formulation selected from the group consisting of formulations A to KKKK. In any of the embodiments set out herein, unless otherwise stated, the VEGF receptor fusion protein may be aflibercept which is present in the aqueous pharmaceutical formulation GGGG.

[0023] In an embodiment of the invention, a subject in a method as set forth herein having any one or more of: ocular or periocular infection; active intraocular inflammation; and / or hypersensitivity; is excluded from administration of the VEGF receptor fusion protein to the eye. In an embodiment of the invention, a method of the present invention further includes a step ofevaluating the subject for: ocular or periocular infection; active intraocular inflammation; and / or hypersensitivity; and excluding the subject from said administration if any one or more if found in the subject. In an embodiment of the invention, a method of the present invention further includes monitoring the subject during said treatment or prevention for conjunctival hemorrhage, cataract, vitreous detachment, vitreous floaters, corneal epithelium defect and / or increased intraocular pressure.

[0024] In an embodiment of the invention, prior to each administration in a method of the present invention includes, providing: one single-dose glass vial having a protective plastic cap and a stopper containing an aqueous formulation comprising 8 mg (±0.8 mg) VEGF receptor fusion protein in about 70 microliters; one 18-gauge x 11 / z-inch, 5-micron, filter needle that includes a tip and a bevel; one 30-gauge x1 / z-inch injection needle; and one 1-mL Luer lock syringe having a graduation line marking for 70 microliters of volume, packaged together; then (1) visually inspecting the aqueous formulation in the vial and, if particulates, cloudiness, or discoloration are visible, then using another vial of aqueous formulation containing the VEGF receptor fusion protein; (2) removing the protective plastic cap from the vial; and (3) cleaning the top of the vial with an alcohol wipe; then using aseptic technique: (4) removing the 18-gauge x 11 / 2-inch, 5-micron, filter needle and the 1 mL syringe from their packaging; (5) attaching the filter needle to the syringe by twisting it onto the Luer lock syringe tip; (6) pushing the filter needle into the center of the vial stopper until the needle is completely inserted into the vial and the tip touches the bottom or a bottom edge of the vial; (7) withdrawing all of the VEGF receptor fusion protein vial contents into the syringe, keeping the vial in an upright position, slightly inclined, while ensuring the bevel of the filter needle is submerged into the liquid; (8) continuing to tilt the vial during withdrawal keeping the bevel of the filter needle submerged in the formulation; (9) drawing the plunger rod sufficiently back when emptying the vial in order to completely empty the filter needle; (10) removing the filter needle from the syringe and disposing of the filter needle; (11) removing the 30-gauge x1 / z-inch injection needle from its packaging and attaching the injection needle to the syringe by firmly twisting the injection needle onto the Luer lock syringe tip; (12) holding the syringe with the needle pointing up, and checking the syringe for bubbles, wherein if there are bubbles, gently tapping the syringe with a finger until the bubbles rise to the top; and (13) slowly depressing the plunger so that the plunger tip aligns with the graduation line that marks 70 microliters on the syringe. In an embodiment of the invention, administration of the VEGF receptor fusion protein is performed by intravitreal injection under controlled aseptic conditions, which comprise surgical hand disinfection and the11876WO01use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent) and anesthesia and a topical broad-spectrum microbicide are administered prior to the injection.

[0025] In an embodiment of the invention, the VEGF receptor fusion protein includes amino acids 27-457 of the amino acid sequence set forth in SEQ ID NO: 2; or is aflibercept or conbercept. In an embodiment of the invention, the VEGF receptor fusion protein: (i) includes two polypeptides that comprise (1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO: 2; (2) a VEGFR2 component comprising amino acids 130-231 of SEQ ID NO: 2; and (3) a multimerization component comprising amino acids 232-457 of SEQ ID NO: 2; (ii) includes two polypeptides that comprise an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of a VEGFR2, and a multimerizing component; (iii) includes two polypeptides that comprise an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of VEGFR2, an Ig domain 4 of VEGFR2 and a multimerizing component; or (iv) includes two VEGFR1R2-FcAC1 (a) polypeptides encoded by the nucleic acid sequence of SEQ ID NO: 1. In an embodiment of the invention, the VEGF receptor fusion protein includes two polypeptides that include an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of a VEGFR2, and a multimerizing component. In any of the embodiments set out herein, unless otherwise stated, the VEGF receptor fusion protein may be aflibercept. Alternatively, in any of the embodiments set out herein, unless otherwise stated, the VEGF receptor fusion protein may be conbercept.

[0026] In an embodiment of the invention, the VEGF receptor fusion protein (preferably aflibercept) is administered to both eyes of the subject. In the alternative, the VEGF receptor fusion protein (preferably aflibercept) is administered to one eye of the subject.

[0027] In any of the embodiments set out herein, unless otherwise stated, it may be that the VEGF receptor fusion protein is present in a prefilled syringe that is then used to administered the VEGF receptor fusion protein. In an embodiment of the invention, the VEGF receptor fusion protein is administered from a syringe or a pre-filled syringe (e.g., which is glass or plastic, and / or sterile); for example, including a 30 gauge x1 / 2-inch sterile injection needle. In some cases the pre-filled syringe is glass and sterile.

[0028] In an embodiment of the invention, a subject has previously received one or more doses of 2 mg VEGF receptor fusion protein, for example, which is in an aqueous pharmaceutical formulation, e.g., including about 40 mg / ml VEGF receptor fusion protein; e.g., including 40 mg / ml VEGF receptor fusion protein, 10 mM sodium phosphate, 40 mM NaCI, 0.03% polysorbate 20 and 5% sucrose, with a pH of 6.2. In another embodiment, a subject has not previously received VEGF receptor fusion protein.

[0029] In an embodiment of the invention, the subject is administered one or more further doses of VEGF receptor fusion protein (preferably aflibercept); and / or the method further includes one or more periods of treat and extend (T& E) and / or pro re nata dosing.

[0030] In an embodiment of the invention, the VEGF receptor fusion protein (preferably aflibercept) is administered in a volume of about 100 pl or less, about 75 pl or less; about 70 pl or less; or about 50 pl; 51 pl; 52 pl; 53 pl; 54 pl; 55 pl; 56 pl; 57 pl; 58 pl; 59 pl; 60 pl; 61 pl; 62 pl; 63 pl; 64 pl; 65 pl; 66 pl; 67 pl; 68 pl; 69 pl; 70 pl (e.g., 70 ± 4 or 5 microliters); 71 pl; 72 pl; 73 pl; 74 pl; 75 pl; 76 pl; 77 pl; 78 pl; 79 pl; 80 pl; 81 pl; 82 pl; 83 pl; 84 pl; 85 pl; 86 pl; 87 pl; 88 pl; 89 pl; 90 pl; 91 pl; 92 pl; 93 pl; 94 pl; 95 pl; 96 pl; 97 pl; 98 pl; 99 pl; or 100 pl, e.g., by intravitreal injection.

[0031] In any of the embodiments set out herein, unless otherwise stated, the VEGF receptor fusion protein (preferably aflibercept) may be administered in a volume of about 100 pl or less. In any of the embodiments set out herein, unless otherwise stated, the VEGF receptor fusion protein (preferably aflibercept) may be administered in a volume of about 50pl to about 100 pl. In any of the embodiments set out herein, unless otherwise stated, the VEGF receptor fusion protein (preferably aflibercept) may be administered in a volume of about 60pl to about 80 pl.

[0032] In an embodiment of the invention, the interval between doses are adjusted (shortened, maintained or lengthened) based on visual and / or anatomic outcomes.

[0033] Preferably, herein, a VEGF receptor fusion protein is aflibercept; and / or the VEGF receptor fusion protein is administered by intravitreal injection.

[0034] In any of the embodiments set out herein, unless otherwise stated, it may be that the VEGF receptor fusion protein is aflibercept, administration is via intravitreal administration, and the injection volume is about 100 pl or less. In one such embodiment, the method is to treat or prevent or preventing macular edema secondary to retinal vein occlusion.

[0035] The present invention also provides a kit comprising a container comprising VEGF receptor fusion protein; and instructions for use of VEGF receptor fusion protein, wherein the container is a vial or a pre-filled syringe, wherein the container comprises >100 mg / mL VEGF receptor fusion protein, wherein the container comprises >114.3 mg / mL VEGF receptor fusion protein, wherein the instructions comprise instructions for the administration of aflibercept to patients with an angiogenic eye disorder secondary to RVO, wherein the instructions comprise instructions that aflibercept 8 mg (±0.8 mg) treatment is initiated with 1 injection per month (every 4 weeks) for 3 or 5 consecutive doses, wherein the instructions comprise instructions that after the initial 3 or 5 consecutive doses the injection interval may be lengthened up to every 8, 12, 16, 20 or 24 weeks, and wherein the instructions comprise instructions that the treatmentinterval may be adjusted based on the physician’s judgement of visual and / or anatomic outcomes. In some embodiments of the invention, the kit comprises a pre-filled syringe and instructions for use, wherein the pre-filled syringe comprises 114.3 mg / mL aflibercept and wherein the instructions for use comprise instructions for administration of 8 mg (±0.8 mg) aflibercept to patients with an angiogenic eye disorder, e.g., an angiogenic eye disorder secondary to RVO comprising: (i) that the recommended dose is 8 mg (±0.8 mg) aflibercept (equivalent to 70 microliters solution for injection), (ii) that treatment is initiated with 1 injection of 8 mg (±0.8 mg) aflibercept per month (every 4 weeks) for 3 consecutive doses, and (iii) that based on the physician’s judgement of visual and / or anatomic outcomes injection intervals may then be extended. In some embodiments of the invention the kit comprises a pre-filled syringe and instructions for use, wherein the pre-filled syringe comprises 114.3 mg / mL aflibercept and wherein the instructions for use comprise instructions for administration of 8 mg (±0.8 mg) aflibercept to patients with an angiogenic eye disorder, e.g., an angiogenic eye disorder secondary to RVO comprising (i) that the recommended dose is 8 mg (±0.8 mg) aflibercept (equivalent to 70 microliters solution for injection), (ii) that treatment is initiated with 1 injection of 8 mg (±0.8 mg) aflibercept per month (every 4 weeks) for 3 consecutive doses, (iii) that based on the physician’s judgement of visual and / or anatomic outcomes injection intervals may then be extended, (iv) if visual and / or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly, (v) the interval between two doses should not be shorter than 1 month (4 weeks), and (vi) the frequency of monitoring visits should be based on the patient's status and at the physician's discretion.

[0036] The present invention provides a method for treating or preventing macular edema following retinal vein occlusion (RVO) comprising administering 8 mg (±0.8 mg) aflibercept by intravitreal injection every 4 weeks (+ / - 7 days) for the first three to five doses (e.g., 3 or 4 or 7 days), followed by 8 mg (±0.8 mg) aflibercept via intravitreal injection once every 4 to 8 weeks (+ / - 1 week).

[0037] The present invention provides a method for treating or preventing macular edema following retinal vein occlusion (RVO) comprising administering 8 mg (±0.8 mg) of aflibercept in a pharmaceutical formulation comprising 114.3 mg / ml aflibercept in a volume of 0.07 mL by intravitreal injection every 4 weeks or approximately every 28 days (+ / - 7 days) for the first three to five doses, followed by 8 mg (±0.8 mg) of aflibercept in a pharmaceutical formulation comprising 114.3 mg / ml aflibercept in a volume of 0.07 mL via intravitreal injection once every 4 to 8 weeks (+ / - 1 week).

[0038] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in an subject; wherein the methods comprise(i) administering to the eye of the subject an intravitreal injection of 8 mg aflibercept every month or every 4 weeks for the first 3 consecutive injections and (ii) one or more further injections of 8 mg aflibercept after said first 3 consecutive injections wherein the injection interval between two consecutive injections is adjusted based on the physician’s judgement of visual and / or anatomic outcomes.

[0039] In one embodiment of the invention the method for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise (i) administering to the eye of the subject an intravitreal injection of 8 mg aflibercept every month or every 4 weeks for the first 3 consecutive injections and (ii) one or more further injections of 8 mg aflibercept after said first 3 consecutive injections wherein the injection interval between two consecutive injections is first extended to 8 weeks or 2 months for one or more injections and then adjusted based on the physicians judgement of visual and / or anatomic outcomes, wherein the treatment interval between two consecutive injections is between 4 weeks (1 month) and 20 weeks (5 months).

[0040] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in an subject in an subject; wherein the method comprises administering to the eye of the subject, a single initial dose of 8 mg aflibercept, followed by two secondary doses of said 8 mg aflibercept, followed by one or more tertiary doses of 8 mg aflibercept; wherein each secondary dose is administered 4 weeks or one month after the immediately preceding dose; and wherein the treatment interval between two consecutive tertiary doses is adjusted based on the physicians judgement of visual and / or anatomic outcomes.

[0041] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,a single initial dose of 8 mg aflibercept, followed by;one or more tertiary doses of 8 mg aflibercept;wherein the treatment interval between two consecutive tertiary closes is adjusted based on the physician’s judgement of visual and / or anatomic outcomes and wherein the subject has been treated with a different anti-angiogenic treatment prior to said single initial dose of 8 mg aflibercept. Such anti-angiogenic treatment is for example an anti-VEGF treatment using for e.g.2 mg aflibercept, faricimab, ranibizumab or bevacizumab. In one embodiment of the invention the subject was treated with 2 mg aflibercept or faricimab prior to said single initial dose of 8 mg aflibercept. In one embodiment of the invention, the subject was treated with ranibizumab or bevacizumab prior to said single initial dose of 8 mg aflibercept.

[0042] Adjustment of treatment interval means that the interval between two consecutive administrations of 8 mg aflibercept is extended or shortened based on the physician’s judgement of visual and / or anatomic outcomes.

[0043] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise(i) administering to the eye of the subject an intravitreal injection of 8 mg aflibercept every month or every 4 weeks for the first 3 consecutive injections and(ii) one or more further injections of 8 mg aflibercept after said first 3 consecutive injections wherein the injection interval between two consecutive injections is extended based on the physician’s judgement of visual and / or anatomic outcomes.

[0044] In one embodiment of the invention the method for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise (i) administering to the eye of the subject an intravitreal injection of 8 mg aflibercept every month or every 4 weeks for the first 3 consecutive injections and (ii) one or more further injections of 8 mg aflibercept after said first 3 consecutive injections wherein the injection interval between two consecutive injections is first extended to 8 weeks or 2 months for one or more injections and then further extended to up to 16 weeks (4 months) or 20 weeks (5 months) based on the physicians judgement of visual and / or anatomic outcomes.

[0045] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in an subject in ansubject; wherein the method comprises administering to the eye of the subject, a single initial dose of 8 mg aflibercept, followed by two secondary doses of said 8 mg aflibercept, followed by one or more tertiary doses of 8 mg aflibercept; wherein each secondary dose is administered 4 weeks or one month after the immediately preceding dose; and wherein the treatment interval between two consecutive tertiary doses is extended based on the physicians judgement of visual and / or anatomic outcomes.

[0046] In one embodiment of the invention, the first tertiary dose is administered 8 weeks (2 months) after the immediately preceding dose and one or more further tertiary doses are administered 8 weeks (2 months), or 12 weeks (3 months), or 16 weeks (4 months), or 20 weeks (5 months) after the immediately preceding dose. In one embodiment of the invention, the first tertiary dose is administered 8 weeks (2 months) after the immediately preceding dose and then the treatment interval between two consecutive injections is extended to up to 16 weeks (4 months) or 20 weeks (5 months) based on the physician’s judgement of visual and / or anatomic outcomes.

[0047] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,a single initial dose of 8 mg aflibercept, followed by;one or more tertiary doses of 8 mg aflibercept;wherein the treatment interval between two consecutive tertiary doses is extended based on the physician’s judgement of visual and / or anatomic outcomes andwherein the subject has been treated with a different anti-angiogenic treatment prior to said single initial dose of 8 mg aflibercept. Such anti-angiogennic treatment is for example an anti-VEGF treatment using for e.g., 2 mg aflibercept, faricimab, ranibizumab or bevacizumab. In one embodiment of the invention the subject was treated with 2 mg aflibercept or faricimab prior to said single initial dose of 8 mg aflibercept. In one embodiment of the invention, the subject was treated with ranibizumab or bevacizumab prior to said single initial dose of 8 mg aflibercept.

[0048] In various embodiments, any of the features or components of embodiments discussed above or herein may be combined, and such combinations are encompassed within the scope of the present disclosure. Any specific value discussed above or herein may be combined with another related value discussed above or herein to recite a range with the values representing the upper and lower ends of the range, and such ranges are encompassed within the scope of the present disclosure.11876WO01BRIEF DESCRIPTION OF THE FIGURES

[0049] Figure 1 shows an exemplary dosing schedule as discussed in Example 1. Note: Regimens including the dosing intervals embodied in the table herein for the AFL 8mg / 3 and AFL 8mg / 5 regimens, preferably as represented by the “X” and “T& E” marks, form part of the present invention. AFL=aflibercept, BCVA=best-corrected visual acuity, CST=central subfield thickness, DRM=dose regimen modification, KSE=key secondary endpoint, SD-OCT=spectral domain optical coherence tomography, T& E=treat and extend, Wk=week, X=active injection visit, -=no injection, 8 mg / 3=8 mg Q8W after 3 initial Q4W doses, 8 mg / 5=8 mg Q8W after 5 initial Q4W doses.1=Participants meeting rescue at Week 16 or Week 24 are thereafter dosed Q4W. Interval extension is possible from Week 32 depending on DRM.2=Participants meeting rescue at any visit from Week 20 to Week 36 receive an active dose at that same visit and are thereafter dosed Q4W. Interval extension is possible from Week 32 depending on DRM. For participants who do not meet both criteria for shortening or extension of the interval, the dosing interval of Q8W will be maintained.

[0050] Figure 2 shows an exemplary study design as discussed in Example 1. BCVA=Best-corrected Visual Acuity, ETDRS=Early Treatment of Diabetic Retinopathy Study, Nl=non-inferiority, Q4W=every 4 weeks, Q8W=every 8 weeks, RVO=retinal vein occlusion, T& E=treat and extend.

[0051] Figure 3 shows a Study Flow Diagram for the QUANTUM study as discussed in Example 2.

[0052] Figure 4 shows a Dosing Schedule for the QUANTUM study as discussed in Example 2. Note: Regimens including the dosing intervals embodied in the table herein for the 8Q4 regimen, preferably as represented by the “X” marks, form part of the present invention.X=scheduled injection visit; O=injection only if DRM Criteria have been met.1Participant assessed for DRM Criteria at weeks 28 and 32; if DRM Criteria met at week 28 dosing interval will be shortened to q4 weeks. If DRM Criteria met at week 32, dosing interval will be shortened to q8 weeks - if met again at week 40, dosing interval will be shortened further to q4 weeks;2no injection at week 44 if DRM Criteria not met at week 40, dosing interval will remain q8 weeks. PE=primary endpoint.

[0053] Figure 5 shows the study design of the ELARA study set forth in Example 3. Q4=once every 4 weeks, DME=diabetic macular edema, DRM=dose regimen modification, nAMD=neovascular age-related macular degeneration.

[0054] Figure 6 shows the dosing plan for patients in the ELARA study. ‘Participants will be evaluated for interval modification based on DRM criteria beginning at week 24. EOS=end of study, Mand=mandatory, *= primary safety assessment, wk(s)=weeks.

[0055] Figure 7 shows free and adjusted bound aflibercept concentration versus time since first dose observed in the quasar study, stratified by dosing regimen. IVT, Intravitreal; LLOQ, Lower limit of quantitation; QxW, Every X weeks; Q4Wx3, 3 initial monthly doses; Q4Wx5, 5 initial monthly doses Blue lines represent the median of observed data at specific visits. Dashed lines represent the LLOQ.

[0056] Figure 8 shows free and adjusted bound aflibercept concentration versus time since first dose observed between weeks 4 and 18 in the participants enrolled in the CANDELA, PULSAR, PHOTON, and QUASAR studies who received high dose. IVT, intravitreal; LLOQ, Lower limit of quantitation; QxW, Every X weeks, The solid and dashed lines represent the medians of observed data and LLOQ. Numbers shown in each panel represent the medians of observed post-dose data around week 9 for CANDELA, PULSAR, and PHOTON and around week 16 for QUASAR

[0057] Figure 9 shows the distribution of ocular distribution clearance corrected for age effect in participants who received intravitreal administration of aflibercept, stratified by disease and drug product. DME, Diabetic macular edema; IVT, Intravitreal; MEfRVO, Macular edema following retinal vein occlusion; nAMD, Neovascular age-related macular degeneration; QE, Ocular distribution clearance, The boxes and whiskers delimit the interquartile and 5thto 95thpercentile ranges. The lines within boxes represent the medians of the data. The number of records used for statistic calculations is shown above each box.

[0058] Figure 10 shows Forest plots of geometric mean ratios (90% confidence interval) of Bayesian model-based predictions of exposure metrics of free and adjusted bound aflibercept in participants from the CANDELA, PULSAR, PHOTON, and QUASAR studies, stratified by grouped disease population. AUCweek56-64, Area under the concentration curve from weeks 56 Io 64; Cmax,week8-12, Maximum concentration from weeks 8 to 12; Cmax, week56-64, Maximum concentration from weeks 56 to 64; DME, Diabetic macular edema; MEfRVO, Macular edema following retinal vein occlusion; n, Number of participants in each group; nAMD, Neovascular age-related macular degeneration; QxW, Every X weeks [or] indicates that the respective limit is included in the interval.

[0059] Figures 11 A, 11 B, 11C and 11D correspond to a case study patient’s angiograms at (Fig. 11 A) baseline, (Fig. 11 B) up to week 4 (4 weeks after aflibercept 8 mg injection #1), (Fig.11 C) week 12, and (Fig. 11 D) up to week 36 (4 weeks after aflibercept 8 mg injection #6).

[0060] Figure 12 summarizes BCVA gains in 8 mg aflibercept groups compared to aflibercept 2 mg groups at week 36 across RVO subtypes. Full analysis set. LS means were generated using a mixed model for repeated measures with baseline BCVA as a covariate. The fixed factors were treatment group (aflibercept 8q8 / 3, 8q8 / 5, 2q4); visit; and stratification variables: geographic region (Japan, Asia-Pacific, Europe, America), BL BCVA (<60 vs >60 letters), and, for the overall RVO population analysis only, RVO type (CRVO / HRVO vs BRVO). The model also included terms for the interactions between baseline BCVA and visit, and between treatment and visit.aObserved values (censoring data post intercurrent event).bMissing endpoint values imputed using a multiple imputation procedure. Estimates based on a linear regression model, within the multiple imputation procedure, adjusted for BL BCVA, BL CRT, and stratification variables (geographic region [Japan vs Asia-Pacific vs Europe vs America], BCVA score [>60 vs >60], RVO type [CRVO / HRVO vs BRVO]).cNominal p-values. BL, baseline; BRVO, branched retinal vein occlusion; Cl, confidence interval; CRVO, central retinal vein occlusion; ETDRS, Early Treatment Diabetic Retinopathy Study; HRVO, hemiretinal vein occlusion; LS, least squares. Both aflibercept 8 mg groups achieved non-inferior BCVA gains compared to aflibercept 2 mg at week 36, with fewer injections overall and consistent results across RVO subtypes.

[0061] Figure 13 summarizes CRT reductions in 8 mg aflibercept groups compared to aflibercept 2 mg groups at week 36, across RVO Subtypes. Full analysis set. LS means were generated using a mixed model for repeated measures with baseline CRT as a covariate. The fixed factors were treatment group (aflibercept 8q8 / 3, 8q8 / 5, 2q4), visit; and stratification variables: geographic region (Japan, Asian-Pacific, Europe, America), BL BCVA (<60 vs >60 letters), and, for the overall RVO population analysis only, RVO type (CRVO / HRVO vs BRVO). The model also included terms for the interaction between baseline CRT and visit, and treatment and visit.aMissing endpoint values imputed using a multiple imputation procedure. Based on a linear regression model. Non-parametric rank analysis of covariance, adjusted for BL BCVA, BL CRT, and stratification variables (geographic region [Japan vs Asian-Pacific vs Europe vs America], BCVA score [>60 vs >60], RVO type [CRVO / HRVO vs BRVO], within the multiple imputation procedure. Both aflibercept 8 mg groups achieved robust CRT reductions compared to aflibercept 2 mg at week 36, with fewer injections overall and across RVO subtypes.

[0062] Figure14 summarizes BCVA gains across CRT tertiles by RVO subtypes at week 36. Full analysis set. Observed cases excluding values after intercurrent event: Observations after the occurrence of an intercurrent event are excluded in line with the primary estimand strategy.CRT tertiles for BRVO were <452 pm, >452-<586 pm, and >586 pm and for CRVO / HRVO were <576 pm, >576-<798 pm, and >798 pm. a Safety analysis set. Patients completing Week 36. Both aflibercept 8 mg groups achieved comparable BCVA gains compared with aflibercept 2 mg at week 36, with fewer injections across baseline CRT tertiles by RVO subtypes.

[0063] Figure 15 summarizes CRT reductions across CRT tertiles by RVO subtypes at week 36. Full analysis set. Observed cases excluding values after intercurrent event: Observations after the occurrence of an intercurrent event are excluded in line with the primary estimand strategy. CRT tertiles for BRVO were <452 pm, >452-<586 pm, and >586 pm and for CRVO / HRVO were <576 pm, >576-<798 pm, and >798 pm.aSafety analysis set. Patients completing Week 36. Both aflibercept 8 mg groups achieved robust CRT improvements compared with aflibercept 2 mg at week 36, with fewer injections across baseline CRT tertiles by RVO subtypes.

[0064] Figure 16 summarizes patients maintaining > Q8 dosing intervals at week 36 across RVO subtypes. Safety analysis set. Patients completing Week 36. Q4, every 4 weeks; Q8, every 8 weeks. Most patients in the aflibercept 8 mg groups maintained > Q8 dosing intervals at week 36 across RVO subtypes.

[0065] Figure 17 summarizes patient last assigned dosing intervals at week 36 across RVO subtypes. Safety analysis set. Patients completing Week 36. Per study design, dosing interval extension was not possible in the 8q8 / 5 group until Week 40. Q12, every 12 weeks. Most patients eligible for dosing interval extension treated with aflibercept 8 mg were last assigned to Q8 or longer dosing intervals at week 36 across RVO subtypes.

[0066] Figure 18 is a comparison of ocular clearance estimates in patients assigned or not assigned to receive HD aflibercept Q4W, stratified by randomization group. HD=High dose; I VT=lntravitreal; Q4W=Every 4 weeks; Q4Wx3+Q8W=3 initial monthly doses followed by dosing every 8 weeks; Q4Wx5+Q8W=5 initial monthly doses followed by dosing every 8 weeks. The boxes and whiskers delimit the interquartile ranges and the 5th to 95th percentile ranges. The lines within boxes represent the medians of the data. The open circles represent the individual data outside the 5th to 95th percentile range. The numbers represent the number of data points within each data sub-group.

[0067] Figure 19 is a comparison of baseline central retinal thickness in patients assigned or not assigned to receive HD aflibercept Q4W, stratified by randomization group. HD=High dose; IVT=lntravitreal; Q4W=Every 4 weeks; Q4Wx3+Q8W=3 initial monthly doses followed by dosing every 8 weeks; Q4Wx5+Q8W=5 initial monthly doses followed by dosing every 8 weeks. The boxes and whiskers delimit the interquartile ranges and the 5th to 95th percentile ranges. Thelines within boxes represent the medians of the data. The open circles represent the individual data outside the 5th to 95th percentile range. The numbers represent the number of data points within each data sub-group.

[0068] Figure 20 is a comparison of baseline best corrected visual acuity in patients assigned or not assigned to receive HD aflibercept Q4W, stratified by randomization group. HD=High dose; I VT=lntravitreal; Q4W=Every 4 weeks; Q4Wx3+Q8W=3 initial monthly doses followed by dosing every 8 weeks; Q4Wx5+Q8W=5 initial monthly doses followed by dosing every 8 weeks. The boxes and whiskers delimit the interquartile ranges and the 5th to 95th percentile ranges. The lines within boxes represent the medians of the data. The open circles represent the individual data outside the 5th to 95th percentile range. The numbers represent the number of data points within each data sub-group.

[0069] Figure 21 summarizes the incidence of dosing interval shortening to every 4 weeks for patients with ocular clearance estimates and baseline central retinal thickness values above and below the respective medians. CRT=Central retinal thickness; IVT=lntravitreal; Q4W=Every 4 weeks; Q4Wx3+Q8W=3 initial monthly doses followed by dosing every 8 weeks; Q4Wx5+Q8W =5 initial monthly doses followed by dosing every 8 weeks; QE = Ocular distribution clearance; Open circle indicates proportion of patients assigned to Q4W for each randomization group independently of baseline CRT and QE.

[0070] Figure 22 is a schematic representation of the structural PK / PD model. BCVA, Best visual corrected acuity; CRT, Central retinal thickness; DRM, Dosing Interval Shortening; QE, Ocular clearance. Note: in this schematic representation of the PK / PD model, the relation between " DRM” and “Dose" indicates that, when performing simulations, dosing of HD aflibercept (yes / no) was determined at every visit (every 4 weeks) considering the randomization group, the time since the last dose, and the dosing interval shortenings that happened during the clinical trial simulation. DRM was determined by predictions of CRT and BCVA and the DRM criteria of the respective clinical trial.

[0071] Figure 23 summarizes the ocular clearance for patients who did and did not qualify to receive high dose aflibercept every 4 weeks in the PHOTON and PULSAR studies. IVT, Intravitreal; Q4W, Every 4 weeks. The boxes and whiskers delimit the interquartile ranges and the 5th to 95th percentile range. The lines within boxes represent the medians of the data. The open circles represent the individual data outside the 5thto 95thpercentile range. The numbers represent the number of data points within each data subgroup.

[0072] Figure 24 summarizes the baseline central retinal thickness for patients who did and did not qualify to receive high dose aflibercept every 4 weeks in the PHOTON and PULSAR11876WO01studies. IVT, Intravitreal; Q4W, Every 4 weeks. The boxes and whiskers delimit the interquartile ranges and the 5th to 95th percentile range. The lines within boxes represent the medians of the data. The open circles represent the individual data outside the 5thto 95thpercentile range. The numbers represent the number of data points within each data subgroup.

[0073] Figure 25 summarizes the incidence of dosing interval shortening to every 4 weeks for patients with ocular clearance estimates and baseline central retinal thickness values above and below the respective medians. CRT, Central retinal thickness; Q4W, Every 4 weeks; QE, Ocular clearance. One patient was excluded from this plot since the baseline central retinal thickness measurement was missing. Open circles represented the proportion of patients that qualified for dosing every 4 weeks in each of the trials irrespective of the baseline central retinal thickness and the ocular clearance estimate.

[0074] Figure 26 summarizes the mean best corrected visual acuity difference when allowing every 4 weeks dosing. BCVA, Best visual corrected acuity; HD, High dose; Q4W, Every 4 weeks. Points and error bars represent the predicted mean difference in BCVA and its corresponding 95% prediction interval when comparing the Q4W protocol vs the Q8W protocol. These were obtained by computing the median and the 2.5th and 97.5th quantiles of the 100 simulated mean differences produced through the 100 replicates of the simulated trials. In this plot, positive differences represent a benefit of dose interval reduction down to every 4 weeks as compared to down to every 8 weeks, in patients who would qualify to receive HD aflibercept every 4 weeks.

[0075] Figure 27 summarizes the mean change in BCVA through Week 64-AII RVO (QUASAR).

[0076] Figure 28 summarizes the mean absolute BCVA through Week 64-AII RVO (QUASAR)

[0077] Figure 29 summarizes the mean change in BCVA through Week 64-BRVO (QUASAR)

[0078] Figure 30 summarizes the mean absolute BCVA through Week 64-BRVO (QUASAR)

[0079] Figure 31 summarizes the mean change in BCVA through Week 64-CRVO / HRVO (QUASAR)

[0080] Figure 32 summarizes the mean absolute BCVA through Week 64-CRVO / HRVO (QUASAR)

[0081] Figure 33 summarizes the mean absolute CST through Week 64-RVO (QUASAR)

[0082] Figure 34 summarizes the mean change in CST through Week 64-RVO (QUASAR)

[0083] Figure 35 summarizes the mean absolute CST through Week 64-BRVO (QUASAR)

[0084] Figure 36 summarizes the mean change in CST through Week 64-BRVO (QUASAR)11876WO01

[0085] Figure 37 summarizes the mean absolute CST through Week 64-CRVO / HRVO (QUASAR)

[0086] Figure 38 summarizes the mean change in CST through Week 64-CRVO / HRVO (QUASAR)

[0087] Figure 39 summarizes the key-secondary endpoint-Number of active injections by Week 64 (QUASAR)

[0088] Figure 40 summarizes the key-secondary endpoint-Number of active injections by Week 64 by RVO type (QUASAR)

[0089] Figure 41 summarizes the patients maintaining Q8 through Week 64 (QUASAR)

[0090] Figure 42 summarizes the last assigned Interval at Week 64 (QUASAR)

[0091] Figure 43 summarizes the overview AEs through W64 (QUASAR)DETAILED DESCRIPTION OF THE INVENTION

[0092] The present invention provides surprisingly effective methods for treating patients with a relatively common cause of retinal vascular disease which is associated with devastating vision loss, macular edema secondary to retinal vein occlusion (MERVO). The current treatment paradigm of monthly eye injections, for example of 2 mg Eylea, can make it challenging for patients to maintain their treatment plan, potentially leading to poor adherence and vision loss. Based, in part, on the data presented herein, aflibercept 8 mg can offer the potential to halve the number of injections needed, as compared to standard-of-care aflibercept 2 mg and other anti-VEGF therapies.

[0093] With the results from the QUASAR clinical trial (NCT05850520) to study macular edema secondary to RVO, EYLEA HD (8 mg aflibercept), with extended dosing, met the high bar of vision gains and safety seen with standard-of-care EYLEA (2 mg aflibercept). Importantly, in the most difficult to treat macular edema secondary to CRVO and HRVO subtypes, vision was not compromised, with fewer injections of aflibercept 8 mg. The QUASAR clinical trial met its primary endpoint at 36 weeks, with both groups of EYLEA HD (8 mg aflibercept) patients dosed every 8 weeks achieving non-inferior visual acuity gains compared to those receiving EYLEA® (aflibercept) Injection 2 mg dosed every 4 weeks. The EYLEA HD results were consistent across patients with branch retinal vein occlusions, and thosewith central retinal or hemiretinal vein occlusions. The safety profile of EYLEA HD was similar to EYLEA in QUASAR and remained generally consistent with the known safety profile of EYLEA HD in its pivotal trials.

[0094] One of the key differences observed between QUASAR treatment arms was the ability to extend treatment intervals. At week 36, about 70% of patients in one arm had a last assigneddosing interval of every 12 weeks. By contrast, 25% of patients in the 2 mg group still required monthly injections compared with only 6% in an 8 mg arm. The number of patients who needed every-4-week dosing of aflibercept was about 3 times higher in 2 mg compared to 8 mg of aflibercept.

[0095] Standard methods in molecular biology are described Sambrook, Fritsch and Maniatis (1982 & 19892ndEdition, 2001 3rdEdition) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y.; Sambrook and Russell (2001) Molecular Cloning, 3rded., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y.; Wu (1993) Recombinant DNA, Vol. 217, Academic Press, San Diego, Calif.). Standard methods also appear in Ausbel, etal. (2001) Current Protocols in Molecular Biology, Vols. 1-4, John Wiley and Sons, Inc. New York, N. Y., which describes cloning in bacterial cells and DNA mutagenesis (Vol. 1), cloning in mammalian cells and yeast (Vol. 2), glycoconjugates and protein expression (Vol. 3), and bioinformatics (Vol. 4).

[0096] General methods for protein purification including immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization are described (Coligan et al. (2000) Current Protocols in Protein Science, Vol. 1, John Wiley and Sons, Inc., New York). Chemical analysis, chemical modification, post-translational modification, production of fusion proteins, glycosylation of proteins are described (see e.g., Coligan et al. (2000) Current Protocols in Protein Science, Vol. 2, John Wiley and Sons, Inc., New York; Ausubel, etal.(2001) Current Protocols in Molecular Biology, Vol. 3, John Wiley and Sons, Inc., NY, N. Y., pp.16.0.5-16.22.17; Sigma-Aldrich, Co. (2001) Products for Life Science Research, St. Louis, Mo.; pp. 45-89; Amersham Pharmacia Biotech (2001) BioDirectory, Piscataway, N. J., pp. 384-391). Production, purification, and fragmentation of polyclonal and monoclonal antibodies are described (Coligan etal. (2001) Current Protcols in Immunology, Vol. 1, John Wiley and Sons, Inc., New York; Harlow and Lane (1999) Using Antibodies, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y.; Harlow and Lane, supra). Standard techniques for characterizing ligand / receptor interactions are available (see, e.g., Coligan et al. (2001) Current Protocols in Immunology, Vol. 4, John Wiley, Inc., New York).

[0097] Methods for flow cytometry, including fluorescence activated cell sorting (FACS), are available (see, e.g., Owens et al. (1994) Flow Cytometry Principles for Clinical Laboratory Practice, John Wiley and Sons, Hoboken, N. J.; Givan (2001) Flow Cytometry, 2nded.; Wiley-Liss, Hoboken, N. J.; Shapiro (2003) Practical Flow Cytometry, John Wiley and Sons, Hoboken, N. J.). Fluorescent reagents suitable for modifying nucleic acids, including nucleic acid primers and probes, polypeptides, and antibodies, for use, e.g., as diagnostic reagents, are available(Molecular Probes (2003) Catalogue, Molecular Probes, Inc., Eugene, Oreg.; Sigma-Aldrich (2003) Catalogue, St. Louis, Mo.).

[0098] Standard methods of histology of the immune system are described (see e.g., Muller-Harmelink (ed.) (1986) Human Thymus: Histopathology and Pathology, Springer Verlag, New York, N. Y.; Hiatt et al. (2000) Color Atlas of Histology, Lippincott, Williams, and Wilkins, Phila, Pa.; Louis etal. (2002) Basic Histology: Text and Atlas, McGraw-Hill, New York, N. Y.).

[0099] Various concentrations, amounts, dosages and volumes as well as time intervals, for example between doses are mentioned herein. The scope of the present invention includes embodiments, including such concentration, amount, dosage, volume or time interval, ±10% thereof.

[0100] " Isolated" VEGF antagonists and VEGF receptor fusion proteins (e.g., aflibercept), polypeptides, polynucleotides and vectors, are at least partially free of other biological molecules from the cells or cell culture from which they are produced. Such biological molecules include nucleic acids, proteins, other VEGF antagonists and VEGF receptor fusion proteins, lipids, carbohydrates, or other material such as cellular debris and growth medium. An isolated VEGF antagonist or VEGF receptor fusion protein may further be at least partially free of expression system components such as biological molecules from a host cell or of the growth medium thereof. Generally, the term "isolated" is not intended to be limited to a complete absence of such biological molecules (e.g., minor or insignificant amounts of impurity may remain) or to an absence of water, buffers, or salts or to components of a pharmaceutical formulation that includes the VEGF antagonists or VEGF receptor fusion proteins.

[0101] “Subject” and “patient” are used interchangeably herein. A subject or patient is a mammal, for example a human, mouse, rabbit, monkey or non-human primate, preferably a human. In one embodiment the subject is human. A subject or patient may be said to be “suffering from” an angiogenic eye disorder such as macular edema secondary to retinal vein occlusion or visual impairment due to macular edema secondary to retinal vein occlusion. Retinal vein occlusion includes branch RVO (BRVO), central RVO (CRVO), and hemiretinal RVO (HRVO). Such a subject or patient has the disorder in one or both eyes. In an embodiment of the disclosure, a subject or patient (preferably, a human) has one or more of the following characteristics (presently or in the past):• Treatment-naive macular edema;• Treatment-naive macular edema involving the foveal center secondary to RVO (BRVO, HRVO, or CRVO);• A Mean central subfield thickness (CST) >300 pm on OCT e.g., measured by Cirrus or Topcon spectral domain optical coherence tomography (SD-OCT) (or >320 pm measured on Heidelberg Spectralis); and / or• Macular edema following RVO (CRVO, BRVO, or HRVO) involving the foveal center.

[0102] In any of the embodiments set out herein, unless otherwise stated, the method is for treating or preventing retinal vein occlusion (RVO) in an eye of a subject in need thereof.

[0103] In any of the embodiments set out herein, unless otherwise stated, the method is for treating or preventing macular edema secondary retinal vein occlusion (RVO) in an eye of a subject in need thereof.

[0104] In any of the embodiments set out herein, unless otherwise stated, the method is for improving visual impairment or best corrected visual acuity due to an angiogenic eye disorder macular edema secondary to retinal vein occlusion in an eye of a subject in need thereof.

[0105] In one embodiment of the invention subjects suffering from retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion have not been previously treated with anti-VEGF treatment.

[0106] In one embodiment of the invention, subjects suffering from retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion have been previously treated with anti-VEGF treatment.

[0107] Such anti-VEGF treatments include but are not limited to aflibercept at a dose of 2 mg, faricimab, ranibizumab or bevacizumab. In one embodiment of the invention, said subject has been previously treated with aflibercept at a dose of 2 mg. In one embodiment of the invention said subject has been previously treated with faricimab. In one embodiment of the invention said subject has been previously treated with 2 mg aflibercept.

[0108] In any of the embodiments set out herein, unless otherwise stated, a subject may have Macular Edema Secondary to Retinal Vein Occlusion (MERVO); Retinal vein occlusion includes, for example, branch RVO (BRVO), central RVO (CRVO), and hemiretinal RVO (HRVO).

[0109] In any of the embodiments set out herein, unless otherwise stated, the subject may be one that has treatment-naive macular edema. It may be that such subjects have treatment-naive macular edema involving the foveal center secondary to RVO (e.g., BRVO, HRVO, or CRVO).

[0110] In any of the embodiments set out herein, unless otherwise stated, the subject may be one that has macular edema secondary to RVO that has pre-treatment with an VEGF antagonist such as but not limited to 2 mg aflibercept, faricimab, ranibizumab or bevacizumab (e.g., >3 anti-VEGF ocular injections over the prior 5 months (-150 days). It may be that such subjects have pre-treated macular edema involving the foveal center secondary to RVO (e.g., BRVO, HRVO, or ORVO). In an embodiment of the invention, the subject is treatment-naive.

[0111] In an embodiment of the disclosure, a subject or patient (preferably, a human) does not have one or more of the following characteristics:• Evidence of macular edema due to any cause other than RVO;• Diabetic retinopathy;• Diabetic macular edema;• Advanced age-related macular degeneration (nAMD or geographic atrophy);• Use of any intravitreal implantable agent in an eye (e.g., the eye to receive the treatment);• Prior treatment with ocriplasmin at any time in an eye (e.g., the eye to receive the treatment);• Prior treatment with pegcetacoplan injection or avacincaptad pegol injection in an eye (e.g., the eye to receive the treatment);• Prior treatment with retinal laser photocoagulation in an eye (e.g., the eye to receive the treatment);• Prior treatment with gene therapy and / or cell therapy in an eye (e.g., the eye to receive the treatment);• History of vitreoretinal surgery (including scleral buckle) in an eye (e.g., the eye to receive the treatment);• Any intraocular surgery, including cataract surgery, e.g., within 12 weeks (84 days) of treatment, in an eye (e.g., the eye to receive the treatment);• YAG (Yttrium-aluminum-garnet) capsulotomy in an eye within 4 weeks (28 days) of treatment (e.g., the eye to receive the treatment);• IOP > 25 mm Hg in an eye (e.g., the eye to receive the treatment);• Uncontrolled glaucoma in an eye (e.g., the eye to receive the treatment);• Infectious blepharitis, keratitis, scleritis, or conjunctivitis in an eye (e.g., the eye to receive the treatment);• Any intraocular inflammation / infection (including trace, or above, cells in the anterior chamber and / or vitreous), e.g., within 12 weeks (84 days) of the treatment, in an eye (e.g., the eye to receive the treatment);• History of idiopathic or autoimmune uveitis in an eye (e.g., the eye to receive the treatment);• Vitreomacular traction or epiretinal membrane in an eye evident on biomicroscopy or OCT that is affects central vision (e.g., the eye to receive the treatment);• Myopia of a spherical equivalent of 8 diopters or greater in an eye (prior to any refractive or cataract surgery, if applicable) (e.g., the eye to receive the treatment);• History of corneal transplant in an eye (e.g., the eye to receive the treatment);• Any corneal dystrophy affecting the visual axis in an eye (e.g., the eye to receive the treatment);• Aphakia, or pseudophakia with absence of posterior capsule (unless it occurred as a result of a YAG posterior capsulotomy, e.g., performed more than 28 days before treatment in an eye (e.g., the eye to receive the treatment);• Any history of macular hole of stage 2 and above in an eye (e.g., the eye to receive the treatment);• Current anterior segment neovascularization, vitreous hemorrhage, or tractional retinal detachment visible in an eye (e.g., the eye to receive the treatment);• Structural damage in an eye (e.g., the eye to receive the treatment) that is likely to preclude improvement in BCVA following resolution of macular edema (including atrophy of the retinal pigment epithelium, preretinal fibrosis, subretinal fibrosis or scar, significant macular ischemia, or organized hard exudates);• Uncontrolled blood pressure (systolic > 160 mm Hg or diastolic > 95 mm Hg);• Uncontrolled diabetes mellitus (DM), defined by hemoglobin A1c (HbA1c) >12% at treatment;• History of cerebrovascular accident / transient ischemic attack or myocardial infarction / acute coronary syndrome, e.g., within 6 months (180 days) of treatment; • Renal failure, dialysis, or history of renal transplant;• Known sensitivity to any of the compounds administered to an eye (e.g., the eye to receive the treatment);• Presence of systemic infection or treatment for suspected or active systemic infection;• Subject is pregnant or is a breastfeeding woman;• Subject is a man or woman of child bearing potential who is not practicing a highly effective contraception prior to treatment or at least 4 months after cessation of treatment; wherein said highly effective contraception comprises stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal, contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to treatment;, intrauterine device; or intrauterine hormone-releasing system; bilateral tubal occlusion / ligation; vasectomy; condom plus contraceptive sponge, foam, or jelly, or diaphragm plus contraceptive sponge, foam, or jelly; and / or sexual abstinence.

[0112] Thus, the present disclosure includes a method for treating and / or preventing an angiogenic eye disorder, e.g., an angiogenic eye disorder secondary to retinal vein occlusion (e.g., MERVO), or treating retinal vein occlusion, in a subject in need thereof:• that is an adult >18 years of age (or country’s legal age of adulthood if the legal age is >18 years);• that has treatment-naive macular edema involving the foveal center secondary to RVO (e.g., BRVO, HRVO, or CRVO) diagnosed within 16 weeks (112 days) before beginning treatment;• that has a Early Treatment Diabetic Retinopathy Study BCVA letter score of 73 to 24 (20 / 40 to 20 / 320) in at least one eye;• that has experienced a decrease in BCVA determined to be primarily the result of RVO in at least one eye; or• that has a mean CST >300 pm on OCT (or >320 pm on Heidelberg Spectralis) in at least one eye,comprising administering to an eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of a VEGF receptor fusion protein, preferably aflibercept, followed by one or more (e.g., 2, 3 or 4) secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 4, 8, 12, 16, 20 or 24 weeks after the immediately preceding dose. In one such embodiment, the subject has macular edema secondary to retinal vein occlusion (MERVO).11876WO01VEGF Antagonists

[0113] The present invention includes methods for using a VEGF antagonist for treating or preventing angiogenic eye disorders (e.g., RVO or conditions secondary to RVO; e.g., MERVO). VEGF antagonists include molecules which interfere with the interaction between VEGF and a natural VEGF receptor, e.g., molecules which bind to VEGF or a VEGF receptor and prevent or otherwise hinder the interaction between VEGF and a VEGF receptor. Specific, exemplary VEGF antagonists include anti-VEGF antibodies, anti-VEGF receptor antibodies, and VEGF receptor fusion proteins. Though VEGF receptor fusion proteins, such as aflibercept, are preferred for use in connection with the methods set forth herein, the scope of the present invention includes such methods wherein any of the VEGF antagonists described herein (e.g., scFvs, DARPins, anti-VEGF antibodies) are used in place of such fusion proteins.

[0114] For purposes herein, a “VEGF receptor fusion protein” refers to a molecule that comprises one or more VEGF receptors or domains thereof, fused to another polypeptide, which interferes with the interaction between VEGF and a natural VEGF receptor, e.g., wherein two of such fusion polypeptides are associated thereby forming a homodimer or other multimer. Such VEGF receptor fusion proteins may be referred to as a " VEGF-Trap" or “VEGF Trap”. VEGF receptor fusion proteins within the context of the present disclosure that fall within this definition include chimeric polypeptides which comprise two or more immunoglobulin (Ig)-like domains of a VEGF receptor such as VEGFR1 (also known as Flt1 ) and / or VEGFR2 (also known as Flk1 or KDR), and may also contain a multimerizing domain (for example, an Fc domain).

[0115] An exemplary VEGF receptor fusion protein is a molecule referred to as VEGF1R2-FcAC1 (a) which is encoded by the nucleic acid sequence of SEQ ID NO:1 or nucleotides 79-1374 or 79-1371 thereof.

[0116] VEGF1R2-FcAC1(a) comprises or consists of three components:(1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO:2;(2) a VEGFR2 component comprising amino acids 130 to 231 of SEQ ID NO:2; and (3) a multimerization component (" FcAC1(a)") comprising amino acids 232 to 457 of SEQ ID NO:2 (with an optional lysine at the C-terminal end (K458); e.g., the C- terminal amino acids of SEQ ID NO:2, i.e., K458, may or may not be included in the VEGF receptor fusion proteins, see U. S. Patent No. 7,396,664 or 7,354,579, incorporated herein for all purposes). Note that amino acids 1 to 26 of SEQ ID NO:2 are the signal sequence.

[0117] If the multimerizing component (MO) of a VEGF receptor fusion protein is derived from an IgG (e.g., lgG1 ) Fc domain, then the MO has no fewer amino acids than are in amino acids 232 to 457 of SEQ ID NO:2. Thus, the IgG of the MC cannot be truncated to be shorter than 226 amino acids.

[0118] In an embodiment of the invention, the VEGF receptor fusion protein consists of amino acids 27-458 or 27-457 of SEQ ID NO: 2, e.g., with an optional lysine at the C-terminal end (K458). Said VEGF receptor fusion protein can form a homodimer.atggtcagctactgggacaccggggtcctgctgtgcgcgctgctcagctgtctgcttctcacaggatctagttccgg aagtgataccggtagacctttcgtagagatgtacagtgaaatccccgaaattatacacatgactgaaggaagggagc tcgtcattccctgccgggttacgtcacctaacatcactgttactttaaaaaagtttccacttgacactttgatccct gatggaaaacgcataatctgggacagtagaaagggcttcatcatatcaaatgcaacgtacaaagaaatagggcttct gacctgtgaagcaacagtcaatgggcatttgtataagacaaactatctcacacatcgacaaaccaatacaatcatag atgtggttct agtccgtctcat gaattgaactatctgttggagaaaagcttgtcttaaattgt cagcaagaact gaact aatgtggggattgacttcaactgggaatacccttcttcgaagcatcagcataagaaacttgt aaccgaga cctaaaaacccagtctgggagtgagatgaagaaatttttgagcaccttaactatagatggtgtaacccggagtgacc aaggattgtacacctgtgcagcatccagtgggctgatgaccaagaagaacagcacatttgtcagggtccatgaaaag gacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaa acccaaggacaccctcatgatctcccggacccctgaggtcacat cgtggtggtggacgtgagccacgaagaccctg aggtcaagttcaactggtacgtggacggcgtggaggtgcataat ccaagacaaagccgcgggaggagcagtacaac agcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggt ctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgt acaccctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacct cctggtcaaaggcttctatccc agcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactc cgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgct ccgtgat catgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaatga(SEQ ID NO: 1)MVSYWDTGVLLCALLSCLLLTGSSSGSDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTS PNITVTLKKFPLDTLIPDGKRI IWDSRKGFI I SNATYKEIGLLTCEATVNGHLYKTNYLT HRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRD LKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO: 2; signal sequence underscored; optionally lacking C-terminal K residue)

[0119] In an embodiment of the invention, the VEGF receptor fusion protein comprises (1 ) an immunoglobin-like (Ig) domain 2 of a first VEGF receptor (e.g., VEGFR1 ), and(2) an Ig domain 3 of a second VEGF receptor (e.g., VEGFR2),(3) and, optionally, further including an Ig domain 4 of the second VEGF receptor (e.g., VEGFR2) and(4) a multimerizing component (e.g., Fc domain of IgG including the hinge, CH2 and CH3 domains).

[0120] For example, in an embodiment of the invention, the VEGF receptor fusion protein has the following arrangement of said domains:• [VEGFR1 Ig domain 2]-[VEGFR2 Ig domain 3]-[MC] (e.g., a homodimer thereof) or • [VEGFR1 Ig domain 2]-[VEGFR2 Ig domain 3]-[VEGFR2 Ig domain 4]-[MC] (e.g., a homodimer thereof).

[0121] In any of the embodiments set out herein, unless otherwise stated, the VEGF receptor fusion protein may, preferably, be aflibercept. In an alternative embodiment it may be conbercept.

[0122] Note that the present disclosure also includes, within its scope, high concentration formulations including, instead of a VEGF receptor fusion protein, a VEGF binding molecule or anti-VEGF antibody or antigen-binding fragments thereof or biopolymer conjugate thereof (e.g., KSI-301), e.g.,• bevacizumab (e.g., at a concentration of about 80-90 or 88 mg / ml),• ranibizumab (e.g., at a concentration of about 20-40 mg / ml, e.g., 21-35, 21 or 35 mg / ml), • an anti-VEGF aptamer such as pegaptanib (e.g., pegaptanib sodium),• a single chain (e.g., VL-V ) anti-VEGF antibody such as brolucizumab (e.g., at a concentration of about 200-400 or 200, 210, 400 or 420 mg / ml),• an anti-VEGF DARPin such as the Abicipar Pegol DARPin (e.g., at a concentration of about 70-140, 70 or 140 mg / ml), or• a bispecific anti-VEGF antibody, e.g., which also binds to ANG2, such as RG7716 (faricimab) (e.g., at a concentration of about 100-400, 100, 105, 400 or 420 mg / ml).

[0123] In order to minimize the repetitiveness of the embodiments discussed herein, it is contemplated that the scope of the present invention includes embodiments wherein any of the formulations discussed herein include, in place of a VEGF receptor fusion protein, an anti-VEGF antibody or antibody fragment or other VEGF binding molecule as discussed herein (e.g., substituted with an anti-VEGF DARPin) at any of the concentrations discussed herein. Forexample, the present invention includes a formulation having 35 or 80 mg / ml ranibizumab, a buffer, a thermal stabilizer, a viscosity reducing agent and a surfactant.

[0124] DARPins are Designed Ankyrin Repeat Proteins. DARPins generally contain three to four tightly packed repeats of approximately 33 amino acid residues, with each repeat containing a [3-turn and two anti-parallel a-helices. This rigid framework provides protein stability whilst enabling the presentation of variable regions, normally comprising six amino acid residues per repeat, for target recognition.

[0125] An “anti-VEGF” antibody or antigen-binding fragment of an antibody refers to an antibody or fragment that specifically binds to VEGF.

[0126] Illustrative VEGF receptor fusion proteins include aflibercept (sold as EYLEA or EYLEA HD, Regeneron Pharmaceuticals, Inc.) or conbercept (sold commercially by Chengdu Kanghong Biotechnology Co., Ltd.). See International patent application publication no.W02005 / 121176 or W02007 / 112675. The terms “aflibercept” and “conbercept” include biosimilar versions thereof. A biosimilar version of a reference product (e.g., aflibercept) generally refers to a product comprising the identical amino acid sequence, but includes products which are biosimilar under the U. S. Biologies Price Competition and Innovation Act. In one embodiment, the VEGF receptor fusion protein is aflibercept or a bioequivalent thereof. In an embodiment of the invention the VEGF receptor fusion protein is aflibercept.

[0127] The present invention also includes embodiments including administering one or more further therapeutic agents in addition to VEGF antagonist, for example, administering (one or more doses of) a second VEGF antagonist, an antibiotic, anesthetic (e.g., local anesthetic) to the eye receiving an injection, a non-steroidal anti-inflammatory drug (NSAID), a steroid (e.g., a corticosteroid, dexamethasone), triamcinolone acetonide (TA), methotrexate, rapamycin, an anti-tumor necrosis factor alpha drug (e.g., infliximab), daclizumab, and / or a complement component (e.g., C3 or C5) inhibitor, e.g., systemically or intraocularly or intravitreally. In any of the embodiments where a further therapeutic agent is administered, it may be that both the VEGF antagonist and further therapeutic agent are administered in the same pharmaceutical composition. Alternatively, it may be that they are administered in separate pharmaceutical compositions. In one embodiment, it may be that the VEGF antagonist and further therapeutic agent are in separate compositions that are administered simultaneously, separately, or sequentially.

[0128] In an embodiment of the invention, a VEGF antagonist such as a VEGF receptor fusion protein, e.g., aflibercept, was expressed in a chemically defined medium (CDM). In an embodiment of the invention, one or more histidines in the VEGF antagonist (e.g., aflibercept) isa 2-oxo-histidine (e.g., orPharmaceutical Formulations

[0129] The present invention includes methods in which the VEGF antagonist that is administered to the subject’s eye is contained within an aqueous pharmaceutical formulation that includes a pharmaceutically acceptable carrier. The present invention also includes a pharmaceutical formulation as set out herein for use in a method as set out herein. The pharmaceutical formulation includes a VEGF antagonist, which is preferably aflibercept, along with a pharmaceutically acceptable carrier. Other agents may be incorporated into the pharmaceutical formulation to provide improved transfer, delivery, tolerance, and the like. The term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U. S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly, in humans, preferably by intravitreal injection. The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the VEGF antagonist is administered. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences (15thed, Mack Publishing Company, Easton, Pa., 1975), e.g., Chapter 87 by Blaug, Seymour, therein.

[0130] Pharmaceutical formulations for use in a method of the present invention can be “high concentration”. High concentration pharmaceutical formulations of the present invention include a VEGF antagonist, e.g., VEGF receptor fusion protein, at a concentration of at least 41 mg / ml, of at least 80 mg / ml, of at least 100 mg / ml, greater than about 100 mg / ml, of at least 125 mg / ml, of at least 140 mg / ml, of at least 150 mg / ml, of at least 175 mg / ml, of at least 200 mg / ml, of atleast 225 mg / ml, of at least 250 mg / ml, or of at least 275 mg / ml. " High concentration” can refer to formulations that include a concentration of VEGF antagonist of from about 140 mg / ml to about 160 mg / ml, at least about 140 mg / ml but less than 160 mg / ml, from about 41 mg / ml to about 275 mg / ml, from about 70 mg / ml to about 75 mg / ml or from about 80 mg / ml to about 250 mg / ml. In some aspects, the VEGF antagonist concentration in the formulation is about any of the following concentrations: 41 mg / ml; 42 mg / ml; 43 mg / ml; 44 mg / ml; 45 mg / ml; 46 mg / ml; 47 mg / ml; 48 mg / ml; 49 mg / ml; 50mg / ml; 51 mg / ml; 52 mg / ml; 53 mg / ml; 54 mg / ml; 55 mg / ml; 56 mg / ml; 57 mg / ml; 58 mg / ml; 59 mg / ml; 60 mg / ml; 61 mg / ml; 62 mg / ml; 63 mg / ml; 64 mg / ml; 65 mg / ml; 66 mg / ml; 67 mg / ml; 68 mg / ml; 69 mg / ml; 70 mg / ml; 71 mg / ml; 72 mg / ml; 73 mg / ml; 74 mg / ml; 75 mg / ml; 76 mg / ml; 77 mg / ml; 78 mg / ml; 79 mg / ml; 80 mg / ml; 81 mg / ml; 82mg / ml; 83 mg / ml; 84 mg / ml; 85 mg / ml; 86 mg / ml; 87mg / ml; 88 mg / ml; 89 mg / ml; 90 mg / ml; 91 mg / ml; 92 mg / ml; 93 mg / ml; 94 mg / ml; 95mg / ml; 96 mg / ml; 97 mg / ml; 98 mg / ml; 99 mg / ml; 100 mg / ml; 101 mg / ml; 102 mg / ml; 103 mg / ml; 104 mg / ml; 105 mg / ml; 106mg / ml; 107 mg / ml; 108 mg / ml; 109 mg / ml; 110 mg / ml; 111 mg / ml; 112 mg / ml; 113 mg / ml; 113.3 mg / ml; 114 mg / ml; 114.1 mg / ml; 114.2 mg / ml; 114.3 mg / ml; 114.4 mg / ml; 114.5 mg / ml; 114.6 mg / ml; 114.7 mg / ml; 114.8 mg / ml; 114.9 mg / ml; 115 mg / ml; 116 mg / ml; 117 mg / ml; 118 mg / ml; 119 mg / ml; 120 mg / ml; 121 mg / ml; 122 mg / ml; 123 mg / ml; 124 mg / ml; 125 mg / ml; 126 mg / ml; 127mg / ml; 128 mg / ml; 129 mg / ml; 130 mg / ml; 131 mg / ml; 132 mg / ml; 133 mg / ml; 133.3 mg / ml; 133.4 mg / ml; 134 mg / ml; 135 mg / ml; 136 mg / ml; 137 mg / ml; 138 mg / ml; 139 mg / ml; 140 mg / ml; 141 mg / ml; 142 mg / ml; 143 mg / ml; 144 mg / ml; 145 mg / ml; 146 mg / ml; 147 mg / ml; 148 mg / ml; 149 mg / ml; 150 mg / ml; 151 mg / ml; 152 mg / ml; 153 mg / ml; 154mg / ml; 155 mg / ml; 156 mg / ml; 157mg / ml; 158 mg / ml; 159 mg / ml; 160 mg / ml; 161 mg / ml; 162 mg / ml; 163 mg / ml; 164 mg / ml; 165 mg / ml; 166 mg / ml; 167 mg / ml; 168 mg / ml; 169 mg / ml; 170 mg / ml; 171 mg / ml; 172 mg / ml; 173 mg / ml; 174 mg / ml; 175 mg / ml; 176 mg / ml; 177 mg / ml; 178 mg / ml; 179 mg / ml; 180 mg / ml; 181 mg / ml; 182 mg / ml;183 mg / ml; 184 mg / ml; 185 mg / ml; 186 mg / ml; 187 mg / ml; 188 mg / ml; 189 mg / ml; 190 mg / ml; 191 mg / ml; 192 mg / ml; 193 mg / ml; 194 mg / ml; 195 mg / ml; 196 mg / ml; 197 mg / ml; 198 mg / ml; 199 mg / ml; 200 mg / ml; 201 mg / ml; 202 mg / ml; 203 mg / ml; 204 mg / ml; 205 mg / ml; 206 mg / ml; 207 mg / ml; 208 mg / ml; 209 mg / ml; 210 mg / ml; 211 mg / ml; 212 mg / ml; 213 mg / ml; 214 mg / ml; 215 mg / ml; 216 mg / ml; 217 mg / ml; 218 mg / ml; 219 mg / ml; 220 mg / ml; 221 mg / ml; 222 mg / ml; 223 mg / ml; 224 mg / ml; 225 mg / ml; 226 mg / ml; 227 mg / ml; 228 mg / ml; 229 mg / ml; 230 mg / ml; 231 mg / ml; 232 mg / ml; 233 mg / ml; 234 mg / ml; 235 mg / ml; 236 mg / ml; 237mg / ml; 238 mg / ml; 239 mg / ml; 240 mg / ml; 241 mg / ml; 242 mg / ml; 243 mg / ml; 244 mg / ml; 245 mg / ml; 246 mg / ml; 247 mg / ml; 248 mg / ml; 249 mg / ml; 250 mg / ml; 251 mg / ml; 252 mg / ml; 253 mg / ml; 254 mg / ml; 255 mg / ml; 256 mg / ml; 257 mg / ml; 258 mg / ml; 259 mg / ml; 260 mg / ml; 261 mg / ml; 262mg / ml; 263 mg / ml; 264 mg / ml; 265 mg / ml; 266 mg / ml; 267 mg / ml; 268 mg / ml; 269 mg / ml; 270 mg / ml; 271 mg / ml; 272 mg / ml; 273 mg / ml; 274 mg / ml; or 275 mg / ml. Other VEGF antagonist concentrations are contemplated herein, as long as the concentration functions in accordance with embodiments herein. In an embodiment of the invention, the VEGF antagonist concentration in a pharmaceutical formulation is about 100 mg / l to about 120 mg / ml aflibercept. In an embodiment of the invention, the VEGF antagonist concentration in a pharmaceutical formulation is about 110 mg / l to about 120 mg / ml aflibercept. In an embodiment of the invention, the VEGF antagonist concentration in a pharmaceutical formulation is about 114.3 mg / mL aflibercept.

[0131] In an embodiment of the invention, a pharmaceutical formulation for use in a method of the present invention is of such a concentration as to contain about 4, 6, 8, 10, 12, 14, 16, 18 or 20 mg VEGF receptor fusion protein (e.g., aflibercept), or the amount of such protein in any of the acceptable doses thereof which are discussed herein, in about 100 pl or less, about 75 pl or less or about 70 pl or less, e.g., about 50 pl; 51 pl; 52 pl; 53 pl; 54 pl; 55 pl; 56 pl; 57 pl; 58 pl; 59 pl; 60 pl; 61 pl; 62 pl; 63 pl; 64 pl; 65 pl; 66 pl; 67 pl; 68 pl; 69 pl; 70 pl; 71 pl; 72 pl; 73 pl; 74 pl; 75 pl; 76 pl; 77 pl; 78 pl; 79 pl; 80 pl; 81 pl; 82 pl; 83 pl; 84 pl; 85 pl; 86 pl; 87 pl; 88 pl; 89 pl; 90 pl; 91 pl; 92 pl; 93 pl; 94 pl; 95 pl; 96 pl; 97 pl; 98 pl; 99 pl; or 100 pl. In an embodiment of the invention, the VEGF antagonist concentration in a pharmaceutical formulation is about 8 mg (±0.8 mg) aflibercept in about 70 pl.

[0132] The present invention includes methods of using (as discussed herein) any of the formulations set forth under “Illustrative pharmaceutical formulations" herein, but wherein the concentration of the VEGF receptor fusion protein (e.g., aflibercept) is substituted with a concentration which is set forth in this section.

[0133] Buffers for use in pharmaceutical formulations herein that may be used in a method of the present invention refer to solutions that resist pH change by use of acid-base conjugates. Buffers are capable of maintaining pH in the range of from about 5.0 to about 6.8, and more typically, from about 5.8 to about 6.5, and most typically, from about 6.0 to about 6.5. In some cases, the pH of the formulation of the present invention is about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, or about 6.8. Example buffers for inclusion in formulations herein include histidine-based buffers, for example, histidine and histidine hydrochloride or histidine acetate. Buffers for inclusion in formulations herein can alternatively be phosphate-based buffers, for example, sodium phosphate, tris-based, acetate-based buffers, for example, sodium acetate or acetic acid, or can be citrate-based, for example,sodium citrate or citric acid. It is also recognized that buffers can be a mix of the above, as long as the buffer functions to buffer the formulations in the above described pH ranges. In some cases, the buffer is from about 5 mM to about 25 mM, or more typically, about 5 mM to about 15 mM. Buffers can be about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM, about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM, about 20 mM, about 21 mM, about 22 mM, about 23 mM, about 24 mM, or about 25 mM.

[0134] In an embodiment of the invention, a histidine-based buffer is prepared using histidine and histidine monohydrochloride.

[0135] In one embodiment of the invention the pharmaceutical formulation has a pH of 5.8.

[0136] In one embodiment of the invention the pharmaceutical formulation comprises a histidine-based buffer or a phosphate-based buffer.

[0137] In one embodiment of the invention the pharmaceutical formulation does not include a buffer. In this embodiment, the anti-VEGF antagonist (e.g. aflibercept) functions, itself, as a buffer.

[0138] In one embodiment of the invention the pharmaceutical formulation comprises 10 -50 mM buffer.

[0139] In one embodiment of the invention the pharmaceutical formulation comprises 10 -50 mM histidine-based buffer (e.g., 10 mM histidine-based buffer).

[0140] In one embodiment of the invention the pharmaceutical formulation comprises 10 -50 mM phosphate-based buffer.

[0141] Surfactant for use herein refers to ingredients that protect the higher concentration of VEGF antagonist, e.g., VEGF receptor fusion protein, from various surface and interfacial induced stresses. As such, surfactants can be used to limit or minimize VEGF receptor fusion protein aggregation, and promote protein solubility. Suitable surfactants herein have been shown to be non-ionic, and can include surfactants that have a polyoxyethylene moiety.Illustrative surfactants in this category include: polysorbate 20, polysorbate 80, poloxamer 188, polyethylene glycol 3350, and mixtures thereof. Surfactants in the formulations can be present at from about 0.02% to about 0.1% weight per volume (w / v), and more typically, about 0.02% to about 0.04% (w / v). In some cases, the surfactant is about 0.02% (w / v), about 0.03% (w / v), about 0.04% (w / v), about 0.05% (w / v), about 0.06% (w / v), about 0.07% (w / v), about 0.08% (w / v), about 0.09% (w / v), or about 0.1% (w / v).

[0142] In one embodiment of the invention the pharmaceutical formulation comprises a surfactant.

[0143] In one embodiment of the invention the pharmaceutical formulation comprises 0.01% to 0.04% (w / v) (e.g. 0.03% (w / v) surfactant.

[0144] In one embodiment of the invention the pharmaceutical formulation comprises 0.01% (w / v) - 0.03% (w / v) polysorbate 20 or polysorbate 80.

[0145] Thermal stabilizers for use in pharmaceutical formulations that may be used in methods set forth herein refers to ingredients that provide thermal stability against thermal denaturation of the VEGF antagonist, e.g., VEGF receptor fusion protein, as well as protect against loss of VEGF receptor fusion protein potency or activity. Suitable thermal stabilizers include sugars, and can be sucrose, trehalose, sorbitol or mannitol, or can be amino acids, for example L-proline, L-arginine (e.g., L-arginine monohydrochloride), or taurine. Additionally, thermal stabilizers may also include substituted acrylamides or propane sulfonic acid, or may be compounds like glycerol.

[0146] In one embodiment of the invention the pharmaceutical formulation comprises a sugar and / or an amino acid (e.g., L-arginine).

[0147] In one embodiment of the invention the pharmaceutical formulation comprises 2% (w / v) - 10% (w / v) sugar.

[0148] In one embodiment of the invention the pharmaceutical formulation comprises 2% (w / v) - 10% (w / v) sucrose, trehalose, sorbitol or mannitol.

[0149] In one embodiment of the invention the pharmaceutical formulation comprises 2% (w / v) - 10% (w / v) sucrose or trehalose.

[0150] In one embodiment of the invention the pharmaceutical formulation comprises 5% (w / v) sucrose.

[0151] In one embodiment of the invention the pharmaceutical formulation comprises 10 mM - 100 mM amino acid.

[0152] In one embodiment of the invention the pharmaceutical formulation comprises 10 mM - 100 mM (e.g. 10 mM -50 mM) proline, arginine (e.g., arginine monohydrochloride), or taurine.

[0153] In one embodiment of the invention the pharmaceutical formulation comprises 10 mM - 100 mM (e.g. 10 - 50 mM) arginine (e.g., arginine monohydrochloride).

[0154] In one embodiment of the invention the pharmaceutical formulation comprises 50 mM L-arginine, e.g., L-arginine monohydrochloride.

[0155] In an embodiment of the invention, a pharmaceutical formulation of the present invention includes aflibercept, e.g., greater than 100 mg / ml aflibercept, L-arginine and a histidine-based buffer.

[0156] In some cases, the pharmaceutical formulations for use in a method herein include both a sugar and taurine, a sugar and an amino acid, a sugar and propane sulfonic acid, a sugar and taurine, glycerol and taurine, glycerol and propane sulfonic acid, an amino acid and taurine, or an amino acid and propane sulfonic acid. In addition, formulations can include a sugar, taurine and propane sulfonic acid, glycerol, taurine and propane sulfonic acid, as well as L-proline, taurine and propane sulfonic acid.

[0157] Embodiments herein may have thermal stabilizers present alone, each independently present at a concentration of, or present in combination at a total concentration of, from about 2% (w / v) to about 10% (w / v) or 4% (w / v) to about 10% (w / v), or about 4% (w / v) to about 9% (w / v), or about 5% (w / v) to about 8% (w / v). Thermal stabilizers in the formulation can be at a concentration of about 2% (w / v), about 2.5% (w / v), about 3% (w / v), about 4% (w / v), about 5% (w / v), about 6% (w / v), about 7% (w / v), about 8% (w / v), about 9% (w / v), about 10% (w / v) or about 20% (w / v). In an embodiment of the invention, the stabilizer is L-arginine, e.g., L-arginine monohydrochloride.

[0158] With respect to taurine and propane sulfonic acid, in an embodiment of the invention, these thermal stabilizers can be present in the formulations at about from 25 mM to about 100 mM, and more typically from about 50 mM to about 75 mM (as compared to the other thermal stabilizers).

[0159] Viscosity reducing agents typically are used to reduce or prevent protein aggregation. Viscosity reducing agents for inclusion herein include: sodium chloride, magnesium chloride, D-or L-arginine (e.g., L-arginine monohydrochloride), lysine, or mixtures thereof. When present herein, viscosity reducing agents can be present at from about 10 mM to about 100 mM, and more typically from about 30 mM to about 75 mM, and even more typically from about 40 mM to about 70 mM. In some cases, the viscosity reducing agent is present at about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM, about 95 mM or about 100 mM.

[0160] In one embodiment of the invention the pharmaceutical formulation comprises 10 mM - 100 mM amino acid or / and an inorganic salt (e.g. sodium chloride, magnesium chloride).

[0161] In one embodiment of the invention the pharmaceutical formulation comprises 10 mM - 100 mM (e.g. 10 mM -50 mM) L-arginine (e.g., L-arginine monohydrochloride).

[0162] In one embodiment of the invention the pharmaceutical formulation comprises 10 mM - 100 mM (e.g. 10 - 50 mM) arginine (e.g., L-arginine monohydrochloride).

[0163] In one embodiment of the invention the pharmaceutical formulation comprises 50 mM L-arginine monohydrochloride.

[0164] In one embodiment of the invention the pharmaceutical formulation comprises 10 mM - 100 mM sodium chloride or magnesium chloride.

[0165] In one embodiment of the invention the pharmaceutical formulation comprises 10 mM - 50 mM sodium chloride or magnesium chloride.

[0166] Pharmaceutical formulations for use in a method as set forth herein can also have a pharmaceutically acceptable viscosity for ocular administration, for example, intravitreal injection. Viscosity generally refers to the measure of resistance of a fluid which is being deformed by either shear stress or tensile stress (typically measured by techniques known in the art, viscometer or rheometer, for example). Typical viscosities of formulations for use in a method set forth herein are from about 5.0 cP (centipoise) to about 15 cP, from about 11 cP to about 14 cP, from about 12 cP to about 15 cP or from about 11 cP to about 12 cP. As such, formulation viscosity herein can be about 5.0 cP, about 6.0, about 7.1 cP, about 7.2 cP, about 7.3 cP, about 7.4 cP, about 7.5 cP, about 7.6 cP, about 10 cP, about 10.5 cP, about 11.0 cP, about 11.5 cP, about 12.0 cP, about 12.5 cP, about 13.0 cP, about 13.5 cP, about 14.0 cP, about 14.5 cP, or about 15.0 cP (e.g., when measured at 20°C). In one embodiment of the invention the viscosity of the pharmaceutical formulation is 12 cP to about 15 cP at 20°C.

[0167] Various embodiments herein do not require inclusion of an inorganic salt, or other viscosity reducing agent, to maintain these highly useful viscosities. Typically, high concentration protein solutions require viscosity reducing agents to avoid protein aggregation and higher viscosity, making the formulations difficult for intravitreal injection and reducing the potency of the VEGF receptor fusion protein. As such, embodiments herein include methods of using formulations that have had substantially no, or no added, sodium chloride (NaCI), magnesium chloride (MgCk), D- or L-arginine (e.g., L-arginine hydrochloride), lysine or other viscosity reducing agent.

[0168] Osmolality is a critical attribute for injectable pharmaceutical formulations for use in a method of the present invention. It is desirable to have products match physiological osmotic conditions. Furthermore, osmolality provides confirmation of soluble content in solution. In an embodiment of the invention, the osmolality of a formulation for use in a method of the present invention is less than or equal to about 506 mmol / Kg or from about 250 to about 506 mmol / Kg, e.g., about 250, 260, 270, 280, 290, 299, 300, 310, 314, 315, 316, 324, 343, 346, 349, 369, 384, 403, 426, 430 or 506 mmol / Kg. In an embodiment of the invention, the osmolality is lower than about 250 mmol / Kg. In an embodiment of the invention, the formulation is isotonic.

[0169] In an embodiment of the invention, the VEGF antagonist (e.g., aflibercept) is in an aqueous pharmaceutical composition wherein the composition characterized by a color: (i) which is no more brown-yellow than European Color Standard BY2; (ii) which is no more brownyellow than European Color Standard BY3; (iii) which is no more brown-yellow than European Color Standard BY4; (iv) which is no more brown-yellow than European Color Standard BY5; (v) which is no more brown-yellow than European Color Standard BY6; (vi) which is no more brown-yellow than European Color Standard BY7; (vi) which is between European Color Standard BY2 and BY3; (vii) which is between European Color Standard BY2 and BY4. For example, in an embodiment of the invention, the VEGF antagonist was expressed in a chemically defined medium. In an embodiment of the invention, one or more histidines on the antagonist is a 2-oxo-his.

[0170] Brown-yellow color of a composition discussed herein may be described in relation to the European Color Standards. See European Pharmacopoeia. Chapter 2.2.2. Degree of coloration of liquids. 8thed. EP Color is used typically in the pharmaceutical industry to assign a color rating to liquid samples indicative, for example, of product quality. The European Pharmacopoeia Color is a visual liquid color scale used in the pharmaceutical industry. EP 2.2.2. Degree of Coloration of Liquids 2 outlines the preparation of 37 separate “Reference Solutions” that belong to the following five color families: greenish-yellow (GY), yellow (Y), brownish-yellow (BY), brown (B), and red (R). Of the 7 brown-yellow standards (BY standards), BY1 is the darkest standard and BY7 is the least dark. Matching a given sample to that of a BY color standard is routinely done in the art.

[0171] Illustrative pharmaceutical formulations for use in the methods of the present invention include the following:Formulation A: 80 mg / ml aflibercept, 10 mM histidine-based buffer, 5 % (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.Formulation B: 80 mg / ml aflibercept, 10 mM phosphate-based buffer, 5 % (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.Formulation C: 80 mg / ml aflibercept, 10 mM citrate-based buffer, 5 % (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.Formulation D: 80 mg / ml aflibercept, 10 mM histidine-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 80, and 40 mM sodium chloride, with a pH of 6.2.Formulation E: 80 mg / ml aflibercept, 10 mM phosphate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.Formulation F: 80 mg / ml aflibercept, 10 mM citrate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.Formulation G: 80 mg / ml aflibercept, 10 mM histidine-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.Formulation H: 80 mg / ml aflibercept, 10 mM phosphate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.Formulation I: 80 mg / ml aflibercept, 10 mM citrate-based buffer, 8 % (w / v) sucrose, and 0.03% (w / v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.Formulation J: 80 mg / ml aflibercept, 10 mM histidine-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.Formulation K: 80 mg / ml aflibercept, 10 mM phosphate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.Formulation L: 80 mg / ml aflibercept, 10 mM citrate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.Formulation M: 150 mg / ml aflibercept, 10 mM histidine-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.Formulation N: 150 mg / ml aflibercept, 10 mM phosphate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.Formulation O: 150 mg / ml aflibercept, 10 mM citrate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.Formulation P: 150 mg / ml aflibercept, 10 mM histidine-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 80, and 40 mM sodium chloride, with a pH of 6.2.Formulation Q: 150 mg / ml aflibercept, 10 mM phosphate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.Formulation R: 150 mg / ml aflibercept, 10 mM citrate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.Formulation S: 150 mg / ml aflibercept, 10 mM histidine-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.Formulation T: 150 mg / ml aflibercept, 10 mM phosphate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 20, with a pH of 5.8 to 6.2 (e.g., 6.2), and, optionally, specifically excluding a viscosity reducing agent.Formulation U: 150 mg / ml aflibercept, 10 mM citrate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.Formulation V: 150 mg / ml aflibercept, 10 mM histidine-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.Formulation W: 150 mg / ml aflibercept, 10 mM phosphate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.Formulation X: 150 mg / ml aflibercept, 10 mM citrate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.Formulation Y: 80 mg / ml conbercept, 10 mM histidine-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.Formulation Z: 80 mg / ml conbercept, 10 mM phosphate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.Formulation AA: 80 mg / ml conbercept, 10 mM citrate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.Formulation BB: 80 mg / ml conbercept, 10 mM histidine-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 80, and 40 mM sodium chloride, with a pH of 6.2.Formulation CC: 80 mg / ml conbercept, 10 mM phosphate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.Formulation DD: 80 mg / ml conbercept, 10 mM citrate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.Formulation EE: 80 mg / ml conbercept, 10 mM histidine-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.Formulation FF: 80 mg / ml conbercept, 10 mM phosphate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.Formulation GG: 80 mg / ml conbercept, 10 mM citrate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.Formulation HH: 80 mg / ml conbercept, 10 mM histidine-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.Formulation II: 80 mg / ml conbercept, 10 mM phosphate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.Formulation JJ: 80 mg / ml conbercept, 10 mM citrate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.Formulation KK: 150 mg / ml conbercept, 10 mM histidine-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.Formulation LL: 150 mg / ml conbercept, 10 mM phosphate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.Formulation MM: 150 mg / ml conbercept, 10 mM citrate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.Formulation NN: 150 mg / ml conbercept, 10 mM histidine-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 80, and 40 mM sodium chloride, with a pH of 6.2.Formulation OO: 150 mg / ml conbercept, 10 mM phosphate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.Formulation PP: 150 mg / ml conbercept, 10 mM citrate-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.Formulation QQ: 150 mg / ml conbercept, 10 mM histidine-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.Formulation RR: 150 mg / ml conbercept, 10 mM phosphate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.Formulation SS: 150 mg / ml conbercept, 10 mM citrate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.Formulation TT: 150 mg / ml conbercept, 10 mM histidine-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.Formulation UU: 150 mg / ml conbercept, 10 mM phosphate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.Formulation VV: 150 mg / ml conbercept, 10 mM citrate-based buffer, 8 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.Formulation WW: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 10 mM histidine-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 20, and 50 mM taurine, with a pH of 5.8.Formulation XX: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine-based buffer, 4 % (w / v) proline, 0.03 % (w / v) polysorbate 20, and 50 mM arginine (e.g., arginine hydrochloride), with a pH of 5.8.Formulation YY: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine-based buffer, 2.5 % (w / v) sucrose, 2.0 % (w / v) proline, 0.03 % (w / v) polysorbate 20, and 50 mM taurine, with a pH of 5.8.Formulation ZZ: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 10 mM histidine-based buffer, 2.5 % (w / v) sucrose, 2.0 % (w / v) proline, 0.03 % (w / v) polysorbate 20, and 50 mM arginine (e.g., arginine hydrochloride), with a pH of 5.8.Formulation AAA: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine-based buffer, 5 % (w / v) sucrose, 0.03% (w / v) polysorbate 20, and 50 mM PSA, with a pH of 5.8. Formulation BBB: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine-based buffer, 2.5 % (w / v) sucrose, 2.0 % (w / v) proline, 0.03 % (w / v) polysorbate 20, and 50 mM PSA, with a pH of 5.8.Formulation CCC: 80, 100, 120 or 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 20, and 50 mM arginine (e.g., arginine hydrochloride), with a pH of 5.8.Formulation DDD: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 10 mM histidine-based buffer, 4 % (w / v) proline, 0.03 % (w / v) polysorbate 20, and 50 mM PSA, with a pH of 5.8.Formulation EEE: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine-based buffer, 5 % (w / v) sucrose, and 0.03 % (w / v) polysorbate 20 and, optionally, no thermal stabilizer, with a pH of 5.8.Formulation FFF: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 10mM sodium phosphate, 5 % (w / v) sucrose and 0.03 % polysorbate 20 with a pH of 6.2.Formulation GGG: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5% sucrose; 0.03 % polysorbate 20; 50 mM sodium sulfateFormulation HHH: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5% sucrose; 0.03 % polysorbate 20; 50 mM sodium thiocyanateFormulation III: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose, 0.03 % polysorbate 20; 40 mM sodium citrateFormulation JJJ: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5% Sucrose, 0.03 % polysorbate 20; 50 mM glycineFormulation KKK: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose, 0.03 % polysorbate 20; 50 mM sodium chlorideFormulation LLL: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose; 0.03 % polysorbate 20; 50 mM lysineFormulation MMM: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose; 0.03% polysorbate 20; 50 mM sodium aspartateFormulation NNN: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose; 0.03 % polysorbate 20; 50 mM sodium glutamateFormulation OOO: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose; 0.03% polysorbate 20; 50 mM sodium citrate; 50 mM arginine (e.g., arginine hydrochloride)Formulation PPP: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose; 0.03% polysorbate 20; 50 mM glycine; 50 mM arginine (e.g., arginine hydrochloride)Formulation QQQ: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose; 0.03% polysorbate 20; 50 mM sodium aspartate; 50 mM arginine (e.g., arginine hydrochloride)Formulation RRR: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5 % sucrose; 0.03% polysorbate 20; 50 mM sodium glutamate; 50 mM arginine (e.g., arginine hydrochloride)Formulation SSS: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM His, pH 5.8; 5 % sucrose; 0.03 % polysorbate 20; 10 mM L-arginine (e.g., L-arginine hydrochloride) Formulation TTT: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM His, pH 5.8; 5 % sucrose; 0.03 % polysorbate 20; 100 mM L-arginine (e.g., L-arginine hydrochloride) Formulation UUU: 30 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 10 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, pH 6.2Formulation VVV: 30 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 20 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, pH 6.2Formulation WWW: 60 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 10 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, pH 6.2Formulation XXX: 60 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 20 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, pH 6.2Formulation YYY: 120 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 10 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, pH 6.2Formulation ZZZ: 120 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 20 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, pH 6.2Formulation AAAA: 120 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 10 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, 50 mM NaCI, pH 6.2Formulation BBBB: 120 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 20 % sucrose, 10 mM phosphate, 0.03 % polysorbate 20, 50 mM NaCI, pH 6.2Formulation CCCC: 140 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 10 mM sodium phosphate, 5 % sucrose, 40 mM sodium chloride, 0.03 % PS20, pH 6.2Formulation DDDD: 80 mg / ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine-based buffer, 5 % (w / v) sucrose, 0.03 % (w / v) polysorbate 20, and 50 mM L-arginine (e.g., L-arginine hydrochloride), with a pH of 5.8.Formulation EEEE: 120.0 mg / ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., ± 12 mg / ml), 20 mM histidine-based buffer (e.g., ± 2 mM), 5 % (w / v) sucrose (e.g., ± 0.5%), 0.03 % (w / v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine (e.g., L-arginine hydrochloride) (e.g., ± 5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1).Formulation FFFF: 113.3 mg / ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., 102-125 mg / ml), 20 mM histidine-based buffer (e.g., ± 2 mM), 5 % (w / v) sucrose (e.g., ± 0.5%), 0.03 % (w / v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine (e.g., L-arginine monohydrochloride) (e.g., ± 5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1).Formulation GGGG: 114.3 mg / ml VEGF receptor fusion protein (e.g., aflibercept) (or, 103-126 mg / ml), 10 mM histidine-based buffer, for example, including Histidine and Histidine-HCI (e.g., ± 1 mM), 5 % (w / v) sucrose (e.g., ± 0.5%), 0.03 % (w / v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine (e.g., L-arginine monohydrochloride) (e.g., ± 5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1).Formulation HHHH: 100.0 mg / ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., ± 10 mg / ml), 20 mM histidine-based buffer (e.g., ± 2 mM), 5 % (w / v) sucrose (e.g., ± 0.5%), 0.03 % (w / v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine (e.g., L-arginine monohydrochloride) (e.g., ± 5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1).Formulation IIII: 133.3 mg / ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., ± 13 mg / ml), 20 mM histidine-based buffer (e.g., ± 2 mM), 5 % (w / v) sucrose (e.g., ± 0.5%), 0.03 % (w / v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine (e.g., L-arginine monohydrochloride) (e.g., ± 5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1).Formulation JJJJ: 150 mg / ml aflibercept (e.g., aflibercept) (e.g., ± 15 mg / ml), 10 mM sodium phosphate, 8% (w / v) sucrose (e.g., ± 0.8%), 0.03% (w / v) polysorbate 20 (e.g., 0.02-0.04%) and 50 mM L-arginine (e.g., arginine hydrochloride), pH 6.2 (e.g., 6.0-6.4 or 5.9-6.5).Formulation KKKK: 114.3 mg / ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., ± 14 mg / ml), 20 mM histidine-based buffer (e.g., ± 2 mM), 5% (w / v) sucrose (e.g., ± 0.5%), 0.03% (w / v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine (e.g., arginine monohydrochloride) (e.g., ± 5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1);

[0172] See International Patent Application Publication No. WO2019 / 217927.

[0173] In any of the embodiments set out herein, unless otherwise stated, it may be that the VEGF receptor fusion protein is aflibercept and the pharmaceutical composition is present in is Formulation GGGG: 114.3 mg / ml VEGF receptor fusion protein (e.g., aflibercept) (or, 103-126 mg / ml), 10 mM histidine-based buffer, for example, including Histidine and Histidine-HCI (e.g., ± 1 mM), 5 % (w / v) sucrose (e.g., ± 0.5%), 0.03 % (w / v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine (e.g., L-arginine monohydrochloride) (e.g., ± 5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1).

[0174] In an embodiment of the invention, the 8 mg (±0.8 mg) VEGF receptor fusion protein, preferably aflibercept, when administered, is in an aqueous pharmaceutical formulation comprising: a VEGF receptor fusion protein comprising two polypeptides that each comprises an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of VEGFR2, and a multimerizing component (e.g., which comprises amino acids 27-457 of SEQ ID NO: 2) at a concentration of greater than about 100 mg / ml; about 5% sucrose; L-arginine (e.g., L-argininemonohydrochloride); a histidine-based buffer (e.g., containing histidine HCI); and about 0.03% surfactant; wherein the formulation has a pH of about 5.0 to about 6.8 (e.g., 5.8 to 6.5, for example 5.8). Preferably the formulation is suitable for intravitreal administration. Other components that may be included are sodium sulfate, sodium thiocyanate, glycine, NaCI, sodium aspartate and / or sodium glutamate. In an embodiment of the invention, the VEGF receptor fusion protein is at a concentration of: about 100 mg / ml; about 111.5 mg / ml; about 112.0 mg / ml; about 113.3 mg / ml; about 114.3 mg / ml; about 115.6 mg / ml; about 116.3 mg / ml; about 120 mg / ml; about 133 mg / ml; about 140 mg / ml; about 150 mg / ml; about 200 mg / ml; or about 250 mg / ml. The formulation may be characterized by (i) an osmolality of about 299 to about 506 mmol / Kg; and / or (ii) a viscosity of from about 6-15 cP at 20°C. The surfactant may be a non-ionic surfactant such as polysorbate 20, polysorbate 80, poloxamer 188, polyethylene glycol 3350 or mixtures thereof. The histidine-based buffer may be at a concentration of about 10 mM to 20 mM. In an embodiment of the invention, the VEGF receptor fusion protein has less than about 3.5% high molecular weight species immediately after manufacture and purification and / or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C.

[0175] In an embodiment of the invention, the 8 mg (±0.8 mg) VEGF receptor fusion protein is, when administered in an aqueous pharmaceutical formulation, comprising: greater than about 100 mg / ml of a VEGF receptor fusion protein comprising two polypeptides that each comprises an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of VEGFR2, and a multimerizing component (e.g., aflibercept); about 10-100 mM L-arginine; sucrose; a histidine-based buffer; and a surfactant; wherein the formulation has a pH of about 5.0 to about 6.8; wherein the VEGF receptor fusion protein has less than about 3.5% high molecular weight species immediately after manufacture and purification and / or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C.

[0176] In an embodiment of the invention, the aqueous pharmaceutical formulation includes:• > about 100 mg / ml VEGF receptor fusion protein (e.g., aflibercept), histidine-based buffer and L-arginine;• about 140 mg / ml aflibercept; 20 mM histidine-based buffer; 5% sucrose; 0.03 % polysorbate 20; 10 mM L-arginine; pH 5.8;• about 150 ± 15 mg / ml aflibercept, 10 mM phosphate-based buffer, 8 ± 0.8% (w / v) sucrose, 0.02-0.04% (w / v) polysorbate 20 and 50 mM L-arginine, pH 5.9-6.5;• about 103-126 mg / ml aflibercept, 10 ± 1 mM histidine-based buffer, 5 ± 0.5% (w / v) sucrose, 0.02-0.04% (w / v) polysorbate 20, and 50 ± 5 mM L-arginine, pH 5.5-6.1;• about 140 mg / ml aflibercept, 10 mM histidine-based buffer, 2.5 % (w / v) sucrose, 2.0 % (w / v) proline, 0.03 % (w / v) polysorbate 20 and 50 mM L-arginine, pH 5.8;• about 114.3 mg / ml aflibercept, 10 mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20 and 50 mM L-arginine, pH 5.8;• > about 100 mg / ml aflibercept, histidine-based buffer and L-arginine;• > about 100 mg / ml aflibercept at about pH 5.8, wherein the formulation forms <3% HMW aggregates after incubation at 5°C for 2 months;• about 114.3 mg / mL aflibercept; 10 mM - 50 mM histidine-based buffer, sugar, non-ionic surfactant, L-Arginine, pH 5.8;or• about 114.3 mg / mL aflibercept; 10 mM Histidine-based buffer, 5% sucrose, 0.03% polysorbate-20, 50 mM L-Arginine, pH 5.8.

[0177] In an embodiment of the invention, the 8 mg (±0.8 mg) VEGF receptor fusion protein is aflibercept, and is administered in an aqueous pharmaceutical formulation comprising: aflibercept at a concentration of at least about 100 mg / ml (e.g., about 111.5 mg / ml; 112.0 mg / ml; 113.3 mg / ml; about 114.3 mg / ml; about 115.6 mg / ml; or about 116.3 mg / ml);a thermal stabilizer which is a sugar, an amino acid, sucrose, mannitol, sorbitol, trehalose, L-proline, glycine, glycerol, taurine or propane sulfonic acid (e.g., at about 2% (w / v) to about 10% (w / v), for example, 5% (w / v)); a buffer which is a histidine-based buffer, a phosphate-based buffer, an acetate-based buffer (e.g., at a concentration of about 5-25 mM, e.g., 10 mM or 20 mM); or a citrate-based buffer; a non-ionic surfactant, such as for example, polyoxyethylenebased, polysorbate 20, polysorbate 80, poloxamer 188 or polyethylene glycol 3350 (e.g., at a concentration of about 0.02% to about 0.1 % (w / v), e.g., 0.03% (w / v)); and a viscosity reducing agent which is NaCI, MgCh, D-arginine, L-arginine or L-lysine (e.g., at a concentration of about 10-100 mM, e.g., 50 mM), wherein the formulation has a pH of about 5.0 to about 6.8 (e.g., 5.0-6.0 or 5.8).

[0178] In an embodiment of the invention, the VEGF receptor fusion protein, e.g., aflibercept, is at a concentration in the aqueous pharmaceutical formulation of about 100 mg / ml; 101 mg / ml; 102 mg / ml; 103 mg / ml; 104 mg / ml; 105 mg / ml; 106 mg / ml; 107 mg / ml; 108 mg / ml; 109 mg / ml; 110 mg / ml; 111 mg / ml; 112 mg / ml; 113 mg / ml; 113.3 mg / ml; 114 mg / ml; 114.1 mg / ml; 114.2 mg / ml; 114.3 mg / ml; 114.4 mg / ml; 114.5 mg / ml; 114.6 mg / ml; 114.7 mg / ml; 114.8 mg / ml; 114.9 mg / ml; 115 mg / ml; 116 mg / ml; 117 mg / ml; 118 mg / ml; 119 mg / ml; 120 mg / ml; 121 mg / ml; 122 mg / ml; 123 mg / ml; 124 mg / ml; 125 mg / ml; 126 mg / ml; 127 mg / ml; 128 mg / ml; 129 mg / ml; 130 mg / ml; 131 mg / ml; 132 mg / ml; 133 mg / ml; 133.3 mg / ml; 133.4 mg / ml; 134 mg / ml; 135 mg / ml;136 mg / ml; 137 mg / ml; 138 mg / ml; 139 mg / ml; 140 mg / ml; 141 mg / ml; 142 mg / ml; 143 mg / ml; 144 mg / ml; 145 mg / ml; 146 mg / ml; 147 mg / ml; 148 mg / ml; 149 mg / ml; 150 mg / ml; 151 mg / ml; 152 mg / ml; 153 mg / ml; 154mg / ml; 155 mg / ml; 156 mg / ml; 157mg / ml; 158 mg / ml; 159 mg / ml; 160 mg / ml; 161 mg / ml; 162 mg / ml; 163 mg / ml; 164 mg / ml; 165 mg / ml; 166 mg / ml; 167 mg / ml; 168 mg / ml; 169 mg / ml; 170 mg / ml; 171 mg / ml; 172 mg / ml; 173 mg / ml; 174 mg / ml; 175 mg / ml; 176 mg / ml; 177 mg / ml; 178 mg / ml; 179 mg / ml; 180 mg / ml; 181 mg / ml; 182 mg / ml; 183 mg / ml; 184 mg / ml; 185 mg / ml; 186 mg / ml; 187 mg / ml; 188 mg / ml; 189 mg / ml; 190 mg / ml; 191 mg / ml; 192 mg / ml; 193 mg / ml; 194 mg / ml; 195 mg / ml; 196 mg / ml; 197 mg / ml; 198 mg / ml; 199 mg / ml; 200 mg / ml; 201 mg / ml; 202 mg / ml; 203 mg / ml; 204 mg / ml; 205 mg / ml; 206 mg / ml; 207 mg / ml; 208 mg / ml; 209 mg / ml; 210 mg / ml; 211 mg / ml; 212 mg / ml; 213 mg / ml; 214 mg / ml; 215 mg / ml; 216 mg / ml; 217 mg / ml; 218 mg / ml; 219 mg / ml; 220 mg / ml; 221 mg / ml; 222 mg / ml; 223 mg / ml; 224 mg / ml; 225 mg / ml; 226 mg / ml; 227 mg / ml; 228 mg / ml; 229 mg / ml; 230 mg / ml; 231 mg / ml; 232 mg / ml; 233 mg / ml; 234 mg / ml; 235 mg / ml; 236 mg / ml; 237mg / ml; 238 mg / ml; 239 mg / ml; 240 mg / ml; 241 mg / ml; 242 mg / ml; 243 mg / ml; 244 mg / ml; 245 mg / ml; 246 mg / ml; 247 mg / ml; 248 mg / ml; 249 mg / ml; 250 mg / ml; 251 mg / ml; 252 mg / ml; 253 mg / ml; 254 mg / ml; 255 mg / ml; 256 mg / ml; 257 mg / ml; 258 mg / ml; 259 mg / ml; 260 mg / ml; 261 mg / ml; 262 mg / ml; 263 mg / ml; 264 mg / ml; 265 mg / ml; 266 mg / ml; 267 mg / ml; 268 mg / ml; 269 mg / ml; 270 mg / ml; 271 mg / ml; 272 mg / ml; 273 mg / ml; 274 mg / ml; or 275 mg / ml. In an embodiment of the invention, the VEGF receptor fusion protein, e.g., aflibercept, is at a concentration in the aqueous pharmaceutical formulation of about 80 mg / ml to about 140 mg / ml. In an embodiment of the invention, the VEGF receptor fusion protein, e.g., aflibercept, is at a concentration in the aqueous pharmaceutical formulation of about 100 mg / ml to about 120 mg / ml. In one embodiment aflibercept is at a concentration of 114.3 mg / mL.

[0179] In an embodiment of the invention, the aqueous pharmaceutical formulation includes VEGF receptor fusion protein, e.g., aflibercept, at a concentration of greater than about 100 mg / ml; sucrose, mannitol, sorbitol, trehalose; a histidine-based buffer; polysorbate 20 or polysorbate 80; and L-arginine, at a pH of about 5.0 to about 6.8; wherein the VEGF receptor fusion protein, e.g., aflibercept, has less than about 3.5% high molecular weight species immediately after manufacture and purification and / or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C.

[0180] In an embodiment of the invention, the sucrose, mannitol, sorbitol or trehalose is at a concentration of about 2-10% (w / v); the L-arginine is at a concentration of about 10-100 mM; the polysorbate 20 or polysorbate 80 is at a concentration of about 0.02-0.1% (w / v); and the histidine-based buffer is at a concentration of about 5-25 mM; at a pH of about 5.0 to about 6.8.Treatment and Administration

[0181] The present disclosure provides methods for treating and preventing angiogenic eye disorders including angiogenic eye disorders secondary to retinal vein occlusion (e.g., macular edema secondary to RVO (MERVO)), and treating retinal vein occlusion by sequentially administering one or more initial loading doses (e.g., 2 mg or more, 4 mg or more or, preferably, about 8 mg (±0.8 mg) or more of VEGF antagonist, for example, a VEGF receptor fusion protein such as aflibercept), for example, about every 2-4 or 3-5 weeks, preferably 4 weeks, optionally, followed by additional doses every 4 or 8 or 12 or 16, or 20 or 24 or 28 or 32 or 36 or 4-8 or 8-12 and / or 4-12 weeks and / or by a Pro re nata or Treat & Extend treatment regimen. In one embodiment, the doses are 8 mg (±0.8 mg) of aflibercept administered intravitreally.

[0182] In one embodiment, the doses are 8 mg (±0.8 mg) of aflibercept administered intravitreally.

[0183] As used herein, terms “injection interval” or “dosing interval” or “treatment interval” are used interchangeably and refer to the time interval between two consecutive injections of an VEGF antagonist (e.g., 8 mg aflibercept) into the eye of a subject.

[0184] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise(i) administering to the eye of the subject one or more intravitreal injections of 8 mg (±0.8 mg) aflibercept every month or every 4 weeks ± 7 days, for example, for the first 3, 4 or 5 or 3-5 or 6 or 7 consecutive injections, preferably 3; and(ii) one or more further injections of 8 mg (±0.8 mg) aflibercept administered once every 8 weeks ± 7 days; optionally, followed by administering one or more 8 mg injections on a Treat & Extend or Pro re nata basis or wherein the interval between doses is based on the physician’s judgement of visual and / or anatomic outcomes, e.g., starting at week 36. For example, in an embodiment of the invention, the method includes the steps of administering to the eye of the subject one or more intravitreal injections of 8 mg (±0.8 mg) aflibercept every month or every 4 weeks ± 7 days for the first 3 consecutive injections; and one or more further injections of 8 mg (±0.8 mg) aflibercept administered once every 8 weeks ± 7 days.

[0185] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise(i) administering to the eye of the subject one or more intravitreal injections of 8 mg (±0.8 mg) aflibercept every month or every 4 weeks ± 7 days; optionally, followed by administering one or more 8 mg (±0.8 mg) injections on a Treat & Extend or Pro re nata basis or wherein the interval between doses is based on the physician’s judgement of visual and / or anatomic outcomes, e.g., starting at week 36. For example, in an embodiment of the invention, the method includes the steps of administering to the eye of the subject one or more intravitreal injections of 8 mg (±0.8 mg) aflibercept every month or every 4 weeks ± 7 days wherein no doses other than every month or every 4 weeks ± 7 days is administered.

[0186] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise(i) administering to the eye of the subject one or more intravitreal injections of 8 mg (±0.8 mg) aflibercept every month or every 4 weeks ± 7 days, for example, for the first 3, 4 or 5 or 3-5 or 6 or 7 consecutive injections, preferably 3; and(ii) one or more further injections of 8 mg (±0.8 mg) aflibercept administered once every 12 weeks ± 7 days; optionally, followed by administering one or more 8 mg injections on a Treat & Extend or Pro re nata basis or wherein the interval between doses is based on the physician’s judgement of visual and / or anatomic outcomes, e.g., starting at week 36. For example, in an embodiment of the invention, the method includes the steps of administering to the eye of the subject one or more intravitreal injections of 8 mg (±0.8 mg) aflibercept every month or every 4 weeks ± 7 days for the first 3 consecutive injections; and one or more further injections of 8 mg (±0.8 mg) aflibercept administered once every 12 weeks ± 7 days.

[0187] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise(i) administering to the eye of the subject one or more intravitreal injections of 8 mg (±0.8 mg) aflibercept every month or every 4 weeks ± 7 days and; optionally, e.g., after the first 3, 4 or 5 or 3-5 or 6 or 7 such doses(ii) one or more further injections of 8 mg administered on a Treat & Extend or Pro re nata basis or wherein the interval between doses is based on the physician’s judgement of visual and / or anatomic outcomes.

[0188] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise(i) administering to the eye of the subject one or more intravitreal injections of 8 mg (±0.8 mg) aflibercept every month or every 4 weeks ± 7 days for the 3, 4 or 5 or 3-5 or 6 or 7 consecutive injections; and(ii) one or more further injections of 8 mg (±0.8 mg) aflibercept after said first consecutive injections (e.g., 3) wherein the injection interval between two consecutive injections is adjusted based on the physician’s judgement of visual and / or anatomic outcomes, e.g., by Treat & Extend or Pro re nata.

[0189] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in an subject; wherein the methods comprise(i) administering, to the eye of the subject, one or more intravitreal injections of 8 mg aflibercept every month or every 4 weeks for the first 3 consecutive injections; and(ii) one or more further injections of 8 mg (±0.8 mg) aflibercept after said first 3 consecutive injections wherein the injection interval between two consecutive injections is adjusted based on the physician’s judgement of visual and / or anatomic outcomes.

[0190] In one embodiment of the invention, the method for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise(i) administering to the eye of the subject one or more intravitreal injections of 8 mg aflibercept every month or every 4 weeks for the first 3 consecutive injections and(ii) one or more further injections of 8 mg (±0.8 mg) aflibercept after said first 3 consecutive injections, wherein the injection interval between two consecutive injections is first extended to 8 weeks or 2 months for one or more injections and then adjusted based on the physicians judgement of visual and / or anatomic outcomes, wherein the treatment interval between two consecutive injections is between 4 weeks (1 month) and 20 weeks (5 months).

[0191] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visualimpairment due to macular edema secondary to retinal vein occlusion in an subject in a subject; wherein the method comprises administering to the eye of the subject,(i) a single initial dose of 8 mg (±0.8 mg) aflibercept, followed by(ii) two secondary doses of said 8 mg aflibercept, followed by one or more tertiary doses of 8 mg (±0.8 mg) aflibercept;wherein each secondary dose is administered 4 weeks or one month after the immediately preceding dose; andwherein the treatment interval between two consecutive tertiary doses is adjusted based on the physician’s judgement of visual and / or anatomic outcomes.

[0192] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,a single initial dose of 8 mg (±0.8 mg) aflibercept, followed by;one or more secondary and / or tertiary doses of 8 mg (±0.8 mg) aflibercept;wherein the treatment interval between two consecutive tertiary doses is adjusted based on the physician’s judgement of visual and / or anatomic outcomes; andwherein the subject has been treated with a different anti-angiogenic treatment prior to said single initial dose of 8 mg (±0.8 mg) aflibercept. Such anti-angiogenic treatment is for example an anti-VEGF treatment using for e.g., 2 mg aflibercept, faricimab, ranibizumab or bevacizumab. In one embodiment of the invention, the subject was treated with 2 mg aflibercept or faricimab prior to said single initial dose of 8 mg (±0.8 mg) aflibercept. In one embodiment of the invention, the subject was treated with ranibizumab or bevacizumab prior to said single initial dose of 8 mg (±0.8 mg) aflibercept (e.g., >3 anti-VEGF ocular injections over the prior 5 months (-150 days).

[0193] Adjustment of treatment interval means that the interval between two consecutive administrations of 8 mg (±0.8 mg) aflibercept is extended or shortened based on the physician’s judgement of visual and / or anatomic outcomes.

[0194] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise(i) administering to the eye of the subject, one or more intravitreal injections of 8 mg (±0.8 mg) aflibercept every month or every 4 weeks for the first 3 consecutive injections; and(ii) one or more further injections of 8 mg (±0.8 mg) aflibercept after said first 3 consecutive injections wherein the injection interval between two consecutive injections is extended based on the physician’s judgement of visual and / or anatomic outcomes.

[0195] In one embodiment of the invention, the method for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise(i) administering to the eye of the subject one or more intravitreal injections of 8 mg (±0.8 mg) aflibercept every month or every 4 weeks for the first 3 consecutive injections; and(ii) one or more further injections of 8 mg (±0.8 mg) aflibercept after said first 3 consecutive injections, wherein the injection interval between two consecutive injections is first extended to 8 weeks or 2 months for one or more injections and then further extended to up to 12 weeks (3 months) or 16 weeks (4 months) or 20 weeks (5 months) based on the physicians judgement of visual and / or anatomic outcomes.

[0196] The present disclosure provides methods comprising administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by 2, 3 or 4 or 2-4 secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein; followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2, 3, 4, or 2-4 weeks (±7 days) after the immediately preceding dose; and wherein:(a) each tertiary dose is administered about 8 weeks (±7 days) after the immediately preceding dose;(b) one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then subsequent tertiary doses are administered about 4 weeks (±7 days) after the immediately preceding dose;(c) 2-4 secondary doses are administered every 4 weeks and each tertiary dose is administered about 8 weeks (±7 days) after the immediately preceding dose;(d) 2 secondary doses are administered every 4 weeks and each tertiary dose is administered about 8 weeks (±7 days) after the immediately preceding dose;(e) 3 secondary doses are administered every 4 weeks and each tertiary dose is administered about 8 weeks (±7 days) after the immediately preceding dose;(f) 4 secondary doses are administered every 4 weeks and each tertiary dose is administered about 8 weeks (±7 days) after the immediately preceding dose;(g) one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then subsequent tertiary doses are administered about 4 weeks (±7 days) after the immediately preceding dose;(h) 2-4 secondary doses are administered about every 4 weeks (±7 days) and one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then subsequent tertiary doses are administered about 4 weeks (±7 days) after the immediately preceding dose;(i) 2 secondary doses are administered about every 4 weeks (±7 days) and one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then subsequent tertiary doses are administered about 4 weeks (±7 days) after the immediately preceding dose;(j) 3 secondary doses are administered about every 4 weeks (±7 days) and one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then subsequent tertiary doses are administered about 4 weeks (±7 days) after the immediately preceding dose;(k) 4 secondary doses are administered about every 4 weeks (±7 days) and one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then subsequent tertiary doses are administered about 4 weeks (±7 days) after the immediately preceding dose;(l) one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then the interval between subsequent tertiary doses are shortened to about 4 weeks (±7 days) after the immediately preceding dose;(m) 2-4 secondary doses are administered about every 4 weeks (±7 days) and one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then the interval between subsequent tertiary doses are shortened to about 4 weeks (±7 days) after the immediately preceding dose;(n) 2 secondary doses are administered about every 4 weeks (±7 days) and one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then the interval between subsequent tertiary doses are shortened to about 4 weeks (±7 days) after the immediately preceding dose;(o) 3 secondary doses are administered about every 4 weeks (±7 days) and one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then the interval between subsequent tertiary doses are shortened to about 4 weeks (±7 days) after the immediately preceding dose;(p) 4 secondary doses are administered about every 4 weeks (±7 days) and one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then the interval between subsequent tertiary doses are shortened to about 4 weeks (±7 days) after the immediately preceding dose;(q) one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then one or more subsequent tertiary doses are administered on a Treat & Extend or pro re nata basis, or are adjusted based on the physician’s judgement of visual and / or anatomic outcomes;(r) 2 or 3 tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose and then one or more subsequent tertiary doses are administered on a Treat & Extend or pro re nata basis, or are adjusted based on the physician’s judgement of visual and / or anatomic outcomes;(s) 4 of said secondary doses are administered, then 2 tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose and then one or more tertiary doses are administered on a Treat & Extend or pro re nata basis, or are adjusted based on the physician’s judgement of visual and / or anatomic outcomes;(t) 2 of said secondary doses are administered, then 3 tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose and then one or more tertiary doses are administered on a Treat & Extend or pro re nata basis, or are adjusted based on the physician’s judgement of visual and / or anatomic outcomes; and / or(u) one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose and then each subsequent tertiary dose is administered about 4 weeks (±7 days) after the immediately preceding dose; and then one or more tertiary doses are administered on a Treat & Extend or pro re nata basis, or are adjusted based on the physician’s judgement of visual and / or anatomic outcomes.

[0197] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,a single initial dose of 8 mg (±0.8 mg) aflibercept, followed bytwo secondary doses of said 8 mg (±0.8 mg) aflibercept, followed byone or more tertiary doses of 8 mg (±0.8 mg) aflibercept;wherein each secondary dose is administered 4 weeks or one month after the immediately preceding dose; andwherein the treatment interval between two consecutive tertiary doses is extended based on the physician’s judgement of visual and / or anatomic outcomes.

[0198] In one embodiment of the invention, the first tertiary dose or a dosing regimen set forth herein is administered 8 weeks (2 months) after the immediately preceding dose and one or more further tertiary doses are administered 8 weeks (2 months), or 12 weeks (3 months), or 16 weeks (4 months), or 20 weeks (5 months) after the immediately preceding dose. In one embodiment of the invention, the first tertiary dose is administered 8 weeks (2 months) after the immediately preceding dose and then the treatment interval between two consecutive injections is extended to up to 16 weeks (4 months) or 20 weeks (5 months) based on the physician’s judgement of visual and / or anatomic outcomes.

[0199] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,a single initial dose of 8 mg (±0.8 mg) aflibercept, followed by;one or more secondary or tertiary doses of 8 mg (±0.8 mg) aflibercept;wherein the treatment interval between two consecutive secondary or tertiary doses is extended based on the physician’s judgement of visual and / or anatomic outcomes and wherein the subject has been treated with a different anti-angiogenic treatment prior to said single initial dose of 8 mg (±0.8 mg) aflibercept. Such anti-angiogenic treatment is for example an anti-VEGF treatment using for e.g., 2 mg aflibercept, faricimab, ranibizumab or bevacizumab. In one embodiment of the invention, the subject was treated with 2 mg aflibercept or faricimab prior to said single initial dose of 8 mg (±0.8 mg) aflibercept (e.g., >3 anti-VEGF ocular injections over the prior 5 months (~ 150 days). In one embodiment of the invention, the subject was treated with ranibizumab or bevacizumab prior to said single initial dose of 8 mg (±0.8 mg) aflibercept (e.g., >3 anti-VEGF ocular injections over the prior 5 months (-150 days).

[0200] In one embodiment of the invention said treatment interval between two consecutive injections is extended if the subject (i) exhibits <5 letters loss of BOVA from reference visit and / or (ii) has a CRT (central retinal thickness) <320 pm measured by Heidelberg Spectralis or < 300 pm measured by Cirrus or Topcon spectral domain optical coherence tomography (SD-OCT).

[0201] In one embodiment, the reference visit is the visit at the previous injection.

[0202] In one embodiment such reference visit is the visit at the second monthly or 4-weekly secondary dosing or the visit at 12 weeks (3 months) after initiation of treatment.

[0203] In one embodiment of the invention, said treatment interval between two consecutive doses is extended by 2 or 4 or 2-4 weeks. In one embodiment of the invention, said treatment interval between two consecutive doses is extended by 2 or 4 weeks. In one embodiment of the invention said treatment interval between two consecutive doses is 4 weeks (1 month) or 8 weeks (2 month) or 12 weeks (3 months) or 16 weeks (4 months), or 20 weeks (5 months).

[0204] In one embodiment of the invention, said treatment interval between two consecutive doses is 8 weeks or 2 months. In one embodiment of the invention, said treatment interval between two consecutive doses is 12 weeks or 3 months. In one embodiment of the invention, said treatment interval between two consecutive doses is 16 weeks or 4 months. In one embodiment of the invention, said treatment interval between two consecutive doses is 20 weeks or 5 months. In one embodiment of the invention, said treatment interval between two consecutive doses is extended from 8 weeks or 2 months to 12 weeks or 3 months. In one embodiment of the invention, said treatment interval between two consecutive doses is extended from 12 weeks or 3 months to 16 weeks or 4 months. In one embodiment of the invention, said treatment interval between two consecutive doses is extended from 16 weeks or 4 months to 20 weeks or 5 months.

[0205] In one embodiment of the invention, the first tertiary dose is administered 8 weeks (2 months) after the immediately preceding dose and one or more further tertiary doses are administered 8 weeks (2 months) or 12 weeks (3 months) after the immediately preceding dose.

[0206] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise(i) administering to the eye of the subject one or more intravitreal injections of 8 mg (±0.8 mg) aflibercept every month or every 4 weeks for the first 3 consecutive injections; and(ii) one or more further injections of 8 mg (±0.8 mg) aflibercept after said first 3 consecutive injections wherein the injection interval between two consecutive injections is shortened based on the physician’s judgement of visual and / or anatomic outcomes.

[0207] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,a single initial dose of 8 mg aflibercept, followed bytwo secondary doses of said 8 mg aflibercept, followed byone or more tertiary doses of 8 mg aflibercept;wherein each secondary dose is administered 4 weeks or one month after the immediately preceding dose; andwherein the treatment interval between two consecutive tertiary doses is shortened based on the physician’s judgement of visual and / or anatomic outcomes.

[0208] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,a single initial dose of 8 mg aflibercept, followed by;one or more secondary and / or tertiary doses of 8 mg aflibercept;wherein the treatment interval between two consecutive tertiary doses is shortened based on the physician’s judgement of visual and / or anatomic outcomes; andwherein the subject has been treated with a different anti-angiogenic treatment prior to said single initial dose of 8 mg aflibercept. Such anti-angiogenic treatment is, for example, an anti-VEGF treatment using for e.g., 2 mg aflibercept, faricimab, ranibizumab or bevacizumab. In one embodiment of the invention the subject was treated with 2 mg aflibercept or faricimab prior to said single initial dose of 8 mg aflibercept. In one embodiment of the invention, the subject was treated with ranibizumab or bevacizumab prior to said single initial dose of 8 mg aflibercept (e.g., >3 anti-VEGF ocular injections over the prior 5 months (-150 days).

[0209] In one embodiment of the invention said treatment interval between two consecutive tertiary doses is shortened if the subject (i) exhibits >5 letters loss of BOVA from reference visit; and / or (ii) >50 pm increase in CRT (central retinal thickness) from reference visit.

[0210] In one embodiment the reference visit is the visit at the previous injection.

[0211] In one embodiment of the invention said treatment interval between two consecutive doses is shortened by 2 or 4 weeks. In one embodiment of the invention said treatment interval between two consecutive doses is shortened from 20 weeks or 5 months to 16 weeks or 4 months. In one embodiment of the invention, said treatment interval between two consecutive doses is shortened from 16 weeks or 4 months to 12 weeks or 3 months. In one embodiment of the invention, said treatment interval between two consecutive doses is shortened from 12 weeks or 3 months to 8 weeks or 2 months. In one embodiment of the invention, said treatment interval between two consecutive doses is shortened from 8 weeks or 2 months to 4 weeks or 1 month.

[0212] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject in a subject; wherein the method comprises administering to the eye of the subject,a single initial dose of 8 mg aflibercept, followed by;two secondary doses of said 8 mg (±0.8 mg) aflibercept, followed by;one or more tertiary doses of 8 mg (±0.8 mg) aflibercept;wherein each secondary dose is administered 4 weeks or one month after the immediately preceding dose; andwherein the treatment interval between two consecutive tertiary doses is adjusted based on the physician’s judgement of visual and / or anatomic outcomes.

[0213] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,a single initial dose of 8 mg (±0.8 mg) aflibercept, followed by;two secondary doses of 8 mg (±0.8 mg) aflibercept, followed by;one or more tertiary doses of 8 mg (±0.8 mg) aflibercept;wherein each secondary dose is administered 4 weeks or one month after the immediately preceding dose; andwherein the treatment interval between two consecutive tertiary doses is extended based on the physician’s judgement of visual and / or anatomic outcomes.

[0214] In one embodiment of the invention such treatment interval between two consecutive tertiary injections is extended if the subject(i) exhibits <5 letters loss of BCVA from reference visit and / or(ii) has a CRT (central retinal thickness) <320 pm measured by Heidelberg Spectralis or < 300 pm measured by Cirrus or Topcon spectral domain optical coherence tomography (SD-OCT). In one embodiment, such reference visit is the visit at the second monthly or 4-weekly secondary dosing or the visit at 12 weeks (3 month) after initiation of treatment.

[0215] In one embodiment the reference visit is the visit at the previous injection.

[0216] In one embodiment such reference visit is the visit at the second monthly or 4-weekly secondary dosing or the visit at 12 weeks (3 months) after initiation of treatment.

[0217] In one embodiment of the invention said treatment interval between two consecutive tertiary doses is extended by 2 or 4 or 2-4 weeks. In one embodiment of the invention thetreatment interval between two consecutive tertiary closes is 4 weeks (1 month) or 8 weeks (2 month) or 12 weeks (3 month).

[0218] In one embodiment of the invention, the first tertiary dose is administered 8 weeks (2 months) after the immediately preceding dose and one or more further tertiary doses are administered 8 weeks (2 months) or 12 weeks (3 months) after the immediately preceding dose.

[0219] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,a single initial dose of 8 mg (±0.8 mg) aflibercept, followed bytwo secondary doses of said 8 mg (±0.8 mg) aflibercept, followed byone or more tertiary doses of 8 mg (±0.8 mg) aflibercept;wherein each secondary dose is administered 4 weeks or one month after the immediately preceding dose; andwherein the treatment interval between two consecutive tertiary doses is shortened based on the physician’s judgement of visual and / or anatomic outcomes.

[0220] In one embodiment of the invention said treatment interval between two consecutive tertiary doses is shortened if the subject(i) exhibits >5 letters loss of BCVA from reference visit; and / or(ii) >50 pm increase in CRT (central retinal thickness) from reference visit.

[0221] In one embodiment the reference visit is the visit at the previous injection.

[0222] In one embodiment of the invention said treatment interval between two consecutive tertiary doses is shortened by 2 or 4 weeks. In one embodiment of the invention said treatment interval between two consecutive tertiary doses is 4 weeks (1 month) or 8 weeks (2 month) or 12 weeks (3 months).

[0223] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,a single initial dose of 8 mg (±0.8 mg) aflibercept, followed by;one or more tertiary doses of 8 mg (±0.8 mg) aflibercept;wherein the treatment interval between two consecutive tertiary doses is adjusted based on the physician’s judgement of visual and / or anatomic outcomes; andwherein the subject was treated with 2 mg aflibercept, faricimab, ranibizumab or bevacizumab prior to said single initial dose of 8 mg (±0.8 mg) aflibercept (e.g., >3 anti-VEGF ocular injections over the prior 5 months (-150 days).

[0224] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,a single initial dose of 8 mg (±0.8 mg) aflibercept, followed by;one or more tertiary doses of 8 mg (±0.8 mg) aflibercept;wherein the treatment interval between two consecutive tertiary doses is extended based on the physician’s judgement of visual and / or anatomic outcomes; andwherein the subject was treated with 2 mg aflibercept, faricimab, ranibizumab or bevacizumab prior to said single initial dose of 8 mg (±0.8 mg) aflibercept (e.g., >3 anti-VEGF ocular injections over the prior 5 months (-150 days).

[0225] In one embodiment of the invention said treatment interval between two consecutive tertiary doses is extended if the subject(i) exhibits <5 letters loss of BOVA from reference visit and / or(ii) has a CRT (central retinal thickness) <320 pm measured by Heidelberg Spectralis or < 300 pm measured by Cirrus or Topcon spectral domain optical coherence tomography (SD-OCT).

[0226] In one embodiment the reference visit is the visit at the previous injection.

[0227] In one embodiment of the invention, said treatment interval between two consecutive tertiary doses is extended by 2 or 4 or 2-4 weeks. In one embodiment of the invention, said treatment interval between two consecutive tertiary doses is 4 weeks (1 month) or 8 weeks (2 months) or 12 weeks (3 months).

[0228] The present disclosure provides methods for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,a single initial dose of 8 mg (±0.8 mg) aflibercept, followed by;one or more tertiary doses of 8 mg (±0.8 mg) aflibercept;wherein the treatment interval between two consecutive tertiary doses is shortened based on the physician’s judgement of visual and / or anatomic outcomes; andwherein the subject was treated with 2 mg aflibercept, faricimab, ranibizumab or bevacizumab prior to said single initial dose of 8 mg (±0.8 mg) aflibercept (e.g., >3 anti-VEGF ocular injections over the prior 5 months (-150 days).

[0229] In one embodiment of the invention said treatment interval between two consecutive tertiary doses is shortened if the subject(i) exhibits >5 letters loss of BOVA from reference visit; and / or(ii) >50 pm increase in CRT (central retinal thickness) from reference visit.

[0230] In one embodiment the reference visit is the visit at the previous injection.

[0231] In one embodiment of the invention, said treatment interval between two consecutive tertiary doses is shortened by 2 or 4 or 2-4 weeks. In one embodiment of the invention, said treatment interval between two consecutive tertiary doses is 4 weeks (1 month) or 8 weeks (2 month) or 12 weeks (3 month).

[0232] In one embodiment of the invention the subject was treated with 2 mg aflibercept or faricimab prior to said single initial dose of 8 mg (±0.8 mg) aflibercept. In one embodiment of the invention, the subject was treated with ranibizumab or bevacizumab prior to said single initial dose of 8 mg (±0.8 mg) aflibercept (e.g., >3 anti-VEGF ocular injections over the prior 5 months (-150 days).

[0233] According to the invention the treatment interval between two consecutive doses is not shorter than 1 month (4 weeks).

[0234] According to the invention retinal vein occlusion includes branch RVO (BRVO), central RVO (CRVO), and hemiretinal RVO (HRVO).

[0235] In one embodiment each injection of 8 mg aflibercept is administered intravitreally in a volume of 70 pL.

[0236] In one embodiment of the invention said treatment with 8 mg aflibercept will be discontinued if visual and / or anatomic outcomes indicate that the patient is not benefiting from continued treatment. Such visual outcomes can be decreased visual acuity or > 5 letter loss of BCVA. Such anatomic outcomes can be retinal fluid, subretinal fluid, CNV lesion size, total lesion size or central retinal thickness (CRT).

[0237] In one embodiment, a method of the present invention may comprise a period of Treat and Extend (T& E), for instance after an initial period of dosing. In one embodiment, T& E is employed during administration of tertiary doses.

[0238] In an embodiment of the invention a subject will initiate treatment with injections of 8 mg (±0.8 mg) aflibercept q4w for a total of 3, 4, or 5 or 3-5 doses, followed by extension of the treatment interval to at least 8 weeks, then beginning, e.g., at week 36, T& E is employed

[0239] In an embodiment of the invention a subject will initiate treatment with injections of 8 mg (±0.8 mg) aflibercept q4w for a total of 3 or 5 doses, followed by extension of the treatment interval of 8 weeks, then beginning, e.g., at week 36, T& E is employed.

[0240] In an embodiment of the invention a subject will receive a total of 6 injections of 8 mg (±0.8 mg) aflibercept dosed every 4 weeks (e.g., from initiation through week 20) followed by an extension of the dosing interval to every 12 weeks.

[0241] The present invention encompasses methods for treating and preventing angiogenic eye disorders including angiogenic eye disorders secondary to retinal vein occlusion (e.g., macular edema secondary to RVO (MERVO)) by sequentially administering one or more (preferably 3 or 5) initial loading dose (preferably, about 8 mg (±0.8 mg) of VEGF antagonist, preferably, aflibercept) about every 4 weeks (±7 days), followed by one or more doses administered on a Treat & Extend basis. Treat & Extend may initiate at any point, for example, at week 36 from treatment initiation.

[0242] The present invention provides methods for treating or preventing angiogenic eye disorders including angiogenic eye disorders secondary to retinal vein occlusion (e.g., MERVO) by administering:• one or more (e.g., 2 or 3 or 4 or 5 or 6) doses of about 8 mg (±0.8 mg) or more of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) about every 2-4, 2, 3, 4, or 3-5 weeks, preferably, every 4 weeks (±7 days);• one or more (e.g., 2 or 3 or 4 or 5 or 6) doses of about 8 mg (±0.8 mg) or more of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) about every 4 weeks or every month (±7 days);• one or more (e.g., 2 or 3 or 4 or 5 or 6) doses of about 8 mg (±0.8 mg) or more of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) about every 4 weeks (±7 days) [may be referred to herein as 8q4 or 8q4w];• one or more (e.g., 2 or 3 or 4 or 5 or 6 or 7 or 3-5) doses of about 8 mg (±0.8 mg) or more of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) about every 2-4, 4 or 3-5 weeks, preferably, every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) or more VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) every 4 or 8 or 12 or 4-8 or 8-12 or 4-12 weeks (±7 days);• 2 or 3 or 4 or 5 or 6 or 7 or 3-5 doses of about 8 mg (±0.8 mg) or more of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) about every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) or more VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) every 8 weeks (±7 days);optionally, after one or more doses every 8 weeks, a Treat & Extend (T& E) treatment or PRN regimen may initiate, e.g., starting about 36 weeks after treatment initiation, which may later revert to dosing every 8 weeks (±7 days);• three doses of about 8 mg (±0.8 mg) or more of aflibercept about every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) or more aflibercept every 8 weeks (±7 days) [may be referred to herein as 3x8q4w->8q8w or 8q8 / 3];• four doses of about 8 mg (±0.8 mg) or more of aflibercept about every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) or more aflibercept every 8 weeks (±7 days) [may be referred to herein as 4x8q4w->8q8w or 8q8 / 4];• five doses of about 8 mg (±0.8 mg) or more of aflibercept about every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) or more aflibercept every 8 weeks (±7 days) [may be referred to herein as 5x8q4w->8q8w or 8q8 / 5]• three to five doses of about 8 mg (±0.8 mg) or more of aflibercept about every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) or more aflibercept every 8 weeks (±7 days) [may be referred to herein as 3-5x8q4w->8q8w or 8q8 / 3-5]• 2 or 3 or 4 or 5 or 6 or 7 doses of about 8 mg (±0.8 mg) or more of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) about every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) or more VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) every 12 weeks (±7 days);• 2 or 3 or 4 or 5 or 6 or 7 doses of about 8 mg (±0.8 mg) or more of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) about every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) or more VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) every 12 weeks (±7 days), then one or more doses every 8 weeks (±7 days) (e.g., starting about 28 or 32 weeks after treatment initiation);• 6 doses of about 8 mg (±0.8 mg) or more of aflibercept about every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) or more aflibercept every 12 weeks (±7 days) [may be referred to herein as 6x8q4w->8q12w],In such embodiments each administered dose comprises 8 mg aflibercept.

[0243] In one embodiment, a method of the present invention comprises administering three doses of about 8 mg (±0.8 mg) or more of aflibercept about every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) or more aflibercept every 8 weeks (±7 days) [may be referred to herein as 3x8q4w->8q8w or 8q8 / 3]. In one such embodiment,administration is via intravitreal injection. In one such embodiment, each administered dose comprises 8 mg aflibercept.

[0244] In one embodiment, a method of the present invention comprises administering five doses of about 8 mg (±0.8 mg) or more of aflibercept about every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) or more aflibercept every 8 weeks (±7 days) [may be referred to herein as 3x8q4w->8q8w or 8q8 / 3]. In one such embodiment, administration is via intravitreal injection. In one such embodiment, each administered dose comprises 8 mg aflibercept.

[0245] The present invention provides a method for treating or preventing macular edema following retinal vein occlusion (RVO) comprising administering 8 mg (±0.8 mg) aflibercept by intravitreal injection every 4 weeks (+ / - 7 days) for the first three or four to five or 3-5 doses (e.g., every 3, 4 or 5 weeks), followed by 8 mg (±0.8 mg) aflibercept via intravitreal injection once every 4 to 8 weeks (+ / - 1 week). The present invention provides, for example, a method for treating or preventing macular edema following retinal vein occlusion (RVO) comprising administering 8 mg (±0.8 mg) of aflibercept in a pharmaceutical formulation comprising 114.3 mg / ml aflibercept in a volume of 0.07 mL by intravitreal injection every 4 weeks or approximately every 28 days (+ / - 7 days) for the first three to five doses, followed by 8 mg (±0.8 mg) of aflibercept in a pharmaceutical formulation comprising 114.3 mg / ml aflibercept in a volume of 0.07 mL via intravitreal injection once every 4 to 8 weeks (+ / - 1 week).

[0246] The dosing regimen including the about 4 or 8 or 4-8 or 8-12 or 4-12 week tertiary dosing interval may be referred to herein as a 4 or 8 or 12 or 4-8 or 8-12 or 4-12 week dosing regimen or 8q4 or 8q8 or 8q12 or 8q4-8 or 8q8-12 or 8q4-12.

[0247] In an embodiment of the disclosure, a subject begins receiving the >8 mg (±0.8 mg) maintenance doses, e.g., of about every 8 or 12 weeks, after the >8 mg (±0.8 mg) monthly loading doses with no intervening doses. The subject enters the maintenance dose phase rapidly / immediately after the loading dose phase. In an embodiment of the disclosure, the subject continues receiving the maintenance doses without any intervening doses. In one such embodiment each administered dose comprises 8 mg (±0.8 mg) aflibercept.

[0248] For example, the present disclosure also provides methods for treating angiogenic eye disorders including angiogenic eye disorders secondary to RVO (e.g., MERVO) as discussed herein including administering doses of about >8 mg (±0.8 mg) VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) in a volume of about 100 pl or less, about 75 pl or less or about 70 p.1 or less, e.g., about 50 pl; 51 pl; 52 pl; 53 pl; 54 pl; 55 pl; 56 pl; 57 pl; 58 pl; 59 pl; 60 pl; 61 pl; 62 pl; 63 pl; 64 pl; 65 pl; 66 pl; 67 pl; 68 pl; 69 pl; 70 pl; 71 pl; 72 pl; 73 pl; 74pl; 75 >il; 76 pl; 77 pl; 78 pl; 79 JLLI; 80 pl; 81 pl; 82 pl; 83 pl; 84 j l; 85 pl; 86 pl; 87 pl; 88 pl; 89 pl; 90 pl; 91 pl; 92 pl; 93 pl; 94 pl; 95 pl; 96 pl; 97 pl; 98 pl; 99 pl; or 100 pl. In one such embodiment, the volume is about 100 pl or less. In one such embodiment, the volume is about 50 pl to about 100 pl. In one embodiment, the volume is about 60 pl to about 80 pl. In one embodiment, the volume is about 70 pl. In one such embodiment each administered dose comprises 8 mg aflibercept.

[0249] In an embodiment of the disclosure, the subject does not receive a dosing regimen modification (DRM) or does not terminate treatment for at least 1, 2, 3, 4 or 5 years.

[0250] The present disclosure also provides methods for improving visual acuity in subjects with an angiogenic eye disorder including angiogenic eye disorders secondary to RVO (e.g., MERVO) by administering, sequentially, one or more (e.g., 3 or 4 or 5 or 6) doses about every month (or about every 28 days, 28 ± 5 days or about every 4 weeks), followed by one or more doses every 4 or 8 or 12 or 4-8 or 8-12 or 4-12 weeks.

[0251] The terms "initial dose," "secondary doses," and "tertiary doses," refer to the temporal sequence of administration of the VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept). Thus, the "initial dose" is the dose which is administered at the beginning of the treatment regimen (also referred to as the "baseline dose"); the "secondary doses" are the doses which are administered after the initial dose; and the "tertiary doses" are the doses which are administered after the secondary doses. The initial, secondary, and tertiary doses may all contain the same amount of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), but will generally differ from one another in terms of frequency of administration. In certain embodiments, however, the amount of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) contained in the initial, secondary and / or tertiary doses will vary from one another (e.g., adjusted up or down as appropriate) during the course of treatment.

[0252] Thus, a dosing regimen of the present disclosure may be expressed as follows: a method for treating an angiogenic eye disorder e.g., an angiogenic eye disorder secondary to RVO (e.g., MERVO) in a subject in need thereof including administering (e.g., intravitreally) to the subject in need thereof, a single initial dose of about >8 mg (±0.8 mg) VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), for example, in a volume of about 100 pl or less, about 75 pl or less or about 70 pl or less, e.g., about 50 pl; 51 pl; 52 pl; 53 pl; 54 pl; 55 pl; 56 pl; 57 pl; 58 pl; 59 pl; 60 pl; 61 pl; 62 pl; 63 pl; 64 pl; 65 pl; 66 pl; 67 pl; 68 pl; 69 pl; 70 pl; 71 pl; 72 pl; 73 pl; 74 pl; 75 pl; 76 pl; 77 pl; 78 pl; 79 pl; 80 pl; 81 pl; 82 pl; 83 pl; 84 pl; 85 pl; 86 pl; 87 pl; 88 pl; 89 pl; 90 pl; 91 pl; 92 pl; 93 pl; 94 pl; 95 pl; 96 pl; 97 pl; 98 pl; 99 pl; or 100 pl), followed by one or more (e.g., 2, or 3 or 2-4 or 4 or 5) secondary doses of the VEGFantagonist (e.g., a VEGF receptor fusion protein such as aflibercept), followed by one or more tertiary doses of the VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept); wherein each secondary dose is administered about 2 to 4 weeks (preferably, about every 4 weeks) after the immediately preceding dose; and wherein each tertiary dose is administered about 4 or 8 or 12 or 4-8 or 8-12 or 4-12 weeks after the immediately preceding dose. In one embodiment, the doses are administered in a 100 pel or less via intravitreal injection with the tertiary doses administered at about 8 to 12 week intervals. In one such embodiment, the secondary doses are administered at about 4 week intervals.

[0253] The present disclosure also provides methods for treating an angiogenic eye disorder including angiogenic eye disorders secondary to RVO (e.g., MERVO) including administering to a subject in need thereof about >8 mg (±0.8 mg) (for example, in about 100 |il or less, about 75 |il or less or about 70 pl or less, e.g., about 50 p.1; 51 pl; 52 pl; 53 pl; 54 pl; 55 pl; 56 pl; 57 pl; 58 pl; 59 pl; 60 pl; 61 pl; 62 pl; 63 pl; 64 pl; 65 pl; 66 pl; 67 pl; 68 pl; 69 pl; 70 pl; 71 pl; 72 pl; 73 pl; 74 pl; 75 pl; 76 pl; 77 pl; 78 pl; 79 pl; 80 pl; 81 pl; 82 pl; 83 pl; 84 pl; 85 pl; 86 pl; 87 pl; 88 pl; 89 pl; 90 pl; 91 pl; 92 pl; 93 pl; 94 pl; 95 pl; 96 pl; 97 pl; 98 pl; 99 pl; or 100 pl) of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) on a pro re nata (PRN) or Treat & Extend basis or based on the physician’s judgement of visual and / or anatomic outcomes. In an embodiment of the invention, one or more PRN doses are administered following any tertiary doses that were administered once every 4 or 8 or 12 or 4-8 or 8-12 or 4-12 weeks. Such PRN doses can be inserted into any dosing regimen discussed herein at any point, e.g., after or before an initial, secondary and / or tertiary dose.

[0254] A pro re nata (PRN) treatment protocol calls for intervals between doctor visits to remain fixed (e.g., once every 2, 3, 4, 8, 12, 16, 20 or 24 weeks) and decisions to carry out an injection of VEGF receptor fusion protein (e.g., aflibercept) to be based on the anatomic findings at each respective visit (e.g., as per OCT findings). A capped PRN dosing regimen is PRN wherein subjects must be treated at a certain minimal frequency, e.g., at least once every 2 or 3 or 4 or 6 months. Any treatment regimen set forth herein may further include one or more PRN and / or capped PRN dosing intervals.

[0255] Treat & Extend (T& E) treatment regimen is a gradual approach in which the treatment intervals between two consecutive injections are gradually extended as long as the patient's condition remains stable or improves or shortened when the patient's condition becomes worse or deteriorates. This method aims to reduce the treatment burden while maintaining the effectiveness of the therapy. Treat & Extend (T& E) regimens call for the time interval between doctor visits to be adjusted based on the patient’s clinical course — e.g., if a subject shows nosign of an active disease (e.g., the macula remains dry, without any leakage), the next one or more intervals can be extended; if there is fluid accumulation, the next interval will be shortened. At each visit following T& E, an injection of VEGF receptor fusion protein will be performed; the current clinical status only has an impact on the duration of the next injection interval. Any treatment regimen set forth herein may further include one or more T& E dosing intervals. In an embodiment of the invention, one or more T& E doses are administered following tertiary doses that were administered once every 4 or 8 or 12 or 4-8 or 8-12 or 4-12 weeks. In an embodiment of the invention, T& E is initiated after the loading dose phase of treatment.

[0256] See e.g., Lanzetta et al., Vision Academy Steering Committee. Fundamental principles of an anti-VEGF treatment regimen: optimal application of intravitreal anti-vascular endothelial growth factor therapy of macular diseases. Graefes Arch Clin Exp Ophthalmol2017;255(7):1259-1273.

[0257] The present disclosure also provides methods for treating an angiogenic eye disorder including angiogenic eye disorders secondary to RVO by administering to a subject in need thereof a single initial dose of about 8 mg (±0.8 mg) aflibercept and, then 2 secondary doses of about 8 mg (±0.8 mg) aflibercept every month (4 weeks); and after said 3 doses (initial dose and 2 secondary doses) injection intervals between two doses of about 8 mg (±0.8 mg) aflibercept are extended based on the physician’s judgement of visual and / or anatomic outcomes.

[0258] The present disclosure also provides methods for treating an angiogenic eye disorder including angiogenic eye disorders secondary to RVO by administering to a subject in need thereof 70 pL of an pharmaceutical formulation comprising 8 mg (±0.8 mg) aflibercept, wherein after the administration of a single initial dose of about 8 mg (±0.8 mg) aflibercept 2 secondary doses of about 8 mg (±0.8 mg) aflibercept are administered every month (4 weeks). After said 3 doses (initial dose and 2 secondary doses) injection intervals between two doses of about 8 mg (±0.8 mg) aflibercept may then be extended based on the physician’s judgement of visual and / or anatomic outcomes.

[0259] In one embodiment the dosing interval after said 3 initial doses ((initial dose and 2 secondary doses) is extended if the subject exhibits (i) <5 letters loss of BOVA from reference visit; and / or (ii) CRT (central retinal thickness) is <320 pm measured by Heidelberg Spectralis or < 300 pm measured by Cirrus or Topcon spectral domain optical coherence tomography (SD-OCT).

[0260] In one embodiment, such reference visit is the visit at the second monthly or 4-weekly secondary dosing or the visit at 12 weeks (3 months) after initiation of treatment.

[0261] In one embodiment, the reference visit is the visit at the previous injection.

[0262] In one embodiment, the tertiary dosing interval is extended by 2 or 4 weeks.

[0263] The present disclosure also provides methods for treating an angiogenic eye disorder including angiogenic eye disorders secondary to RVO by administering to a subject in need thereof 70 pL of an pharmaceutical formulation comprising 8 mg (±0.8 mg) aflibercept, wherein after the administration of a single initial dose of about 8 mg (±0.8 mg) aflibercept 4 secondary doses of about 8 mg (±0.8 mg) aflibercept are administered every month (4 weeks). After said 5 doses (initial dose and 4 secondary doses) injection intervals between two doses of about 8 mg (±0.8 mg) aflibercept may then be extended based on the physician’s judgement of visual and / or anatomic outcomes.

[0264] The present disclosure includes embodiments wherein, at any point during a 8q4 or 8q8 or 8q12 or 8q4-8 or 8q8-12 or 8q4-12 treatment regimen, the patient can be switched to a PRN, capped PRN or T& E regimen. The PRN, capped PRN and / or T& E may be continued indefinitely or can be stopped at any point and then the 8q4 or 8q8 or 8q12 or 8q4-8 or 8q8-12 or 8q4-12 regimen is re-initiated at any phase thereof. Any 8q4 or 8q8 or 8q12 or 8q4-8 or 8q8-12 or 8q4-12 regimen can be preceded or followed by a period of PRN, capped PRN and / or T& E.

[0265] The present disclosure includes methods wherein one or more additional, nonscheduled doses, in addition to any of the scheduled initial, secondary and / or tertiary doses of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) are administered to a subject. Such doses are typically administered at the discretion of the treating physician depending on the particular needs of the subject.

[0266] Thus, the present disclosure includes methods comprising administering the required doses as set forth herein, wherein each of the tertiary doses is administered, e.g., about 4, 8, or 12 weeks after the immediately preceding dose, wherein the treatment interval between two tertiary doses is extended (e.g., by one or more increments of 4 weeks), for example, until signs of disease activity recur or vision deteriorates and then either continuing dosing at the last tertiary interval used or the penultimate tertiary interval used.

[0267] The present disclosure includes methods comprising administering the required doses of a treatment regimen as discussed herein, wherein the treatment interval between any two tertiary doses is reduced (e.g., by one or more increments of 4 weeks), for example, until signs of disease activity decrease or vision improves (e.g., BOVA stabilizes or improves) whereupon, optionally, the interval between doses can be extended, e.g., back to a greater interval length.

[0268] For example, in an embodiment of the disclosure, the interval between doses, can be extended, for example by one or more 4 week increments as appropriate in the judgment of the treating physician, for example if there is:• <5 letter loss in BCVA, e.g., relative to BCVA at time of the previous dose or measurement (e.g., at week 12 or 16); and / or• Central subfield thickness (CST) <315 pm on SD-OCT (or <325 pm on Spectralis SD- OCT).

[0269] For example, in an embodiment of the disclosure, the interval between doses, can be shortened (e.g., beginning at week 16 or 20 relative to treatment initiation), for example by one or more 4 week increments as appropriate in the judgment of the treating physician, for example if there is:• BCVA loss of >5 letters, e.g., relative to BCVA at time of the previous dose or measurement (e.g., at week 12 or 16 or 24 or 32), for example, that is accompanied by persistent or worsening disease activity; and / or• >50 micrometer increase in CST, e.g., relative to CST at time of the previous dose or measurement (e.g., at week 12 or 16).

[0270] In an embodiment of the disclosure, the interval between doses, can be shortened, for example by one or more 4 week increments as appropriate, for example if there is >5 letters loss of BCVA from e.g., relative to BCVA at time of the previous dose or measurement with persistent or worsening disease activity.

[0271] In an embodiment of the invention, the shortest interval between doses is about 4 weeks.

[0272] In an embodiment of the invention, the interval between intervals is shortened if criterial for such (e.g., BCVA loss of >5 letters, e.g., relative to BCVA at time of the previous dose or measurement (e.g., at week 12 or 16), for example, that is accompanied by persistent or worsening disease activity) are met at week 28 after treatment initiation.

[0273] In an embodiment of the disclosure, a method of treating an angiogenic eye disorder, e.g., an angiogenic eye disorder secondary to RVO (e.g., MERVO), as set forth herein includes the step of evaluating BCVA and / or CST and, optionally, lengthening or shortening the interval between doses.

[0274] In an embodiment of the invention, a tertiary dosing interval is increased or decreased at increments of 4 weeks, e.g., from 4 to 8, 8 to 12, 12 to 8 or 8 to 4. Decisions to increase or decrease a tertiary dosing interval can be made at one or more office visits to the treatingphysician. In an embodiment of the invention, the dosing interval is lengthened to about 16, 20, 24, 28 or 32 weeks (± 7 days).

[0275] Administration about every 4 weeks as discussed herein may be referred to as dosing about every month, about 12 times per year, about every 28 days, 30 days or 31 days.

[0276] Dosing every “month” or after a “month” refers to dosing after about 28 days, about 4 weeks, or about 28 ± 7 days and may encompass up to 5 weeks ± 7 days. Dosing every “4 weeks” or after “4 weeks” refers to dosing after about 28 days (± 7 days), about a month or about 28 (± 7 days), and may encompass up to every 5 weeks (± 7 days).

[0277] Administration about every 8 weeks as discussed herein may be referred to as dosing about every 2 months, about every other month, about 6 times per year, about every 56, 57, 58, 59, 60 or 61 or 62 days.

[0278] Dosing every “12 weeks” or after “12 weeks” refers to dosing after about 3 months, about 84 days (± 7 days), 85 days (± 7 days), 86 days (± 7 days), 87 days (± 7 days), 88 days (± 7 days), 89 days (± 7 days), or about 90 days (± 7 days). Dosing every “16 weeks” or after “16 weeks” refers to dosing after about 4 months or about 112 days (± 7 days).

[0279] Dosing every “2-4 weeks” or after “2-4 weeks” refers to dosing after about 2 weeks (± 7 days), 3 weeks (± 7 days) or, preferably, 4 weeks (± 7 days). Dosing every “8 weeks” or after “8 weeks” refers to dosing after about 2 months (± 7 days) or about 56 (± 7 days).

[0280] A dose of > 8 mg encompasses a dose of about 8 mg (± 0.8 mg) or doses exceeding 8 mg, for example, about 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg.

[0281] Any dosing frequency specified herein encompasses the specific frequency “± 5 days” (e.g., where “4 weeks” is stated, the present invention also includes embodiments such as 4 weeks ± 7 days). The term ± 7 days includes ±1, ±2, ±3, ±4 days, ±5 days, ±6 days and / or ±7 days.

[0282] " Sequentially administering" means that each dose of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) is administered to the eye of a subject at a different point in time, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks or months). The present disclosure includes methods which comprise sequentially administering to the eye of a subject a single initial dose of a VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), followed by one or more secondary doses of the VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept), followed by one or more tertiary doses of the VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept).

[0283] Baseline values refer to values prior to or at the time of initiation of a treatment.

[0284] In an embodiment of the invention, an angiogenic eye disorder is neovascular age-related macular degeneration (wet), macular edema, an angiogenic eye disorder secondary to RVO, macular edema following retinal vein occlusion, retinal vein occlusion (RVO), central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), hemiretinal vein occlusion (HRVO), diabetic macular edema (DME), choroidal neovascularization (CNV), iris neovascularization, neovascular glaucoma, post-surgical fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), optic disc neovascularization, corneal neovascularization, retinal neovascularization, vitreal neovascularization, pannus, pterygium, vascular retinopathy, diabetic retinopathy, non-proliferative diabetic retinopathy and / or proliferative diabetic retinopathy.

[0285] An "angiogenic eye disorder secondary to RVO" means any disease of the eye which is caused by or associated with the growth or proliferation of blood vessels or by blood vessel leakage following retinal vein occlusion, such as macular edema following retinal vein occlusion (ME-RVO or MERVO). Retinal vein occlusion includes central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), and hemiretinal vein occlusion (HRVO). In one embodiment, the retinal vein occlusion is selected from central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), and hemiretinal vein occlusion (HRVO). In one embodiment, it is selected from central retinal vein occlusion (CRVO), and branch retinal vein occlusion (BRVO).

[0286] The present disclosure provides methods for treating angiogenic eye disorders including angiogenic eye disorders secondary to RVO (e.g., MERVO), in a subject in need thereof, by sequentially administering an loading doses (e.g., about 8 mg (±0.8 mg) of VEGF antagonist, for example, a VEGF receptor fusion protein such as aflibercept) (e.g., about every 2-4 or 3-5 weeks, preferably every 4 weeks; preferably, three initial loading doses or five initial loading doses) followed by additional maintenance doses about every 4 or 8 or 12 or 4-8 or 8-12 or 4-12 weeks, wherein the subject achieves and / or maintains, e.g., by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92 or 96 weeks after treatment initiation:• achieves an improvement in BCVA by week 36 of about 17 or 16 or as high as 50 letters (or more); for example, wherein the subject has received an 8q8 / 3 dosing regimen;• achieves an improvement in BCVA by week 36 of about 18 or 19 or as high as 52 letters (or more); for example, wherein the subject has received an 8q8 / 5 dosing regimen;• achieves an improvement in BCVA by week 36 of about 17 or 18 or 16 or as high as 50 letters (or more); for example, wherein the subject has received an 8q8 / 3 dosing regimen; for example, wherein the subject has BRVO;• achieves an improvement in BCVA by week 36 of about 19 or 18 or as high as 52 letters (or more); for example, wherein the subject has received an 8q8 / 5 dosing regimen; for example, wherein the subject has BRVO;• achieves an improvement in BCVA by week 36 of about 16 or 17 or as high as 47 letters (or more); for example, wherein the subject has received an 8q8 / 3 dosing regimen; for example, wherein the subject has CRVO or HRVO;• achieves an improvement in BCVA by week 36 of about 17 or 18 or as high as 50 letters (or more); for example, wherein the subject has received an 8q8 / 5 dosing regimen; for example, wherein the subject has CRVO or HRVO;• achieves a reduction in CST by week 36 of about 363 or 233 or 318 or as high as 1259 or 233-1259 micrometers (or more); for example, wherein the subject has received an 8q8 / 3 dosing regimen;• achieves a reduction in CST by week 36 of about 355 or 307 or 8 or as high as 1146 or 8-1146 micrometers (or more); for example, wherein the subject has received an 8q8 / 5 dosing regimen;• achieves a reduction in CST by week 36 of about 275 or 236 or as high as 781 micrometers (or more); for example, wherein the subject has received an 8q8 / 3 dosing regimen; for example, wherein the subject has BRVO;• achieves a reduction in CST by week 36 of about 284 or 255 or 8 or as high as 927 or 8-927 micrometers (or more); for example, wherein the subject has received an 8q8 / 5 dosing regimen; for example, wherein the subject has BRVO;• achieves a reduction in CST by week 36 of about 458 or 439 or 38 or as high as 1259 or 38-1259 micrometers (or more); for example, wherein the subject has received an 8q8 / 3 dosing regimen; for example, wherein the subject has CRVO or HRVO;• achieves a reduction in CST by week 36 of about 431 or 376 or 38 or as high as 1146 or 38-1146 micrometers (or more); for example, wherein the subject has received an 8q8 / 5 dosing regimen; for example, wherein the subject has CRVO or HRVO;• A BCVA improvement of about 6, 7, 8 or 9 letters;• Does not lose 5 or more, 10 or more or 15 or more letters BCVA;• A BCVA of about 69, 70, 71, 72 or 73 letters;• No intraretinal fluid (IRF);• No subretinal fluid (SRF);• No IRF and no SRF;• No increase in CST;• No leakage observed on fluorescein angiography;• A NEI-VFQ-25 total score of about 80;• A NEI-VFQ-25 total score change from baseline of about 2 or 3;• No significant change in intraocular pressure;• No significant change in systolic blood pressure;• No significant change in diastolic blood pressure;• Non-inferior BVCA compared to that of aflibercept which is intravitreally dosed at 2 mg approximately every 4 weeks for the first 3, 4 or 5 injections followed by 2 mg approximately once every 8 weeks or once every 2 months;• Increase in BCVA (according to ETDRS letter score) of about 7, 8 or 9 letters by week 64 from start of treatment, wherein the baseline BCVA is about 61, 62 or 63;• BCVA (according to ETDRS letter score) of at least about 69 letters by week 36, 48, 60 or 64 from start of treatment;• Does not lose 5, 10, 15 or 69 letters or more BCVA after week 12, 24, 36, 49, 60, 64, 72, 84 or 90 from start of treatment;• Improvement in BCVA (according to ETDRS letter score) by week 12, 24, 36, 49, 60, 64, 72, 84 or 90 from start of treatment;• Improvement in BVCA by week 4, week 8, week 12, week 16, week 20, week 24, week 28, week 32, week 36, week 40, week 44, or week 48 from start of treatment;• Between weeks 48 and 64, a BCVA score (according to ETDRS letter score) of about 69, 70, 71, 72 or 73;• Between weeks 36 and 48, a change in BCVA score (according to ETDRS letter score) from initiation of treatment of about 7, 8 or 9 wherein the BCVA at any point between week 36 to 48 is about 60 or 70;• Between weeks 48 and 64, a change in BCVA score (according to ETDRS letter score) from initiation of treatment of about 7, 8 or 9, wherein the BCVA at any point between week 48 to 64 is about 69, 70, 71, 72 or 73;• Increase in BCVA as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart or Snellen equivalent by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 or 48 weeks from start of treatment by >4 letters, >5 letters, >6 letters, >7 letters, >8 letters, >9 letters or >10 letters;• Does not lose 5, 10 or 15 letters by week 48 or 64 from start of treatment (according to ETDRS letter score);• Gains at least 5, 10 or 15 letter by week 48 or 64 from start of treatment (according to ETDRS letter score);• Improvement in BCVA, by 4 weeks after initiation of treatment, of about 4 or 5 letters (ETDRS or Snellen equivalent);• Improvement in BCVA, by 8 weeks after initiation of treatment, of about 6 letters (ETDRS or Snellen equivalent);• Improvement in BCVA, by 12 weeks after initiation of treatment, of about 6 or 7 letters (ETDRS or Snellen equivalent);• Improvement in BCVA, by 16 weeks after initiation of treatment, of about 6 or 7 letters (ETDRS or Snellen equivalent);• Improvement in BCVA, by 20 weeks after initiation of treatment, of about 6 letters (ETDRS or Snellen equivalent);• Improvement in BCVA, by 24 weeks after initiation of treatment, of about 7 letters (ETDRS or Snellen equivalent);• Improvement in BCVA, by 28 weeks after initiation of treatment, of about 7 or 8 letters (ETDRS or Snellen equivalent);• Improvement in BCVA, by 32 weeks after initiation of treatment, of about 7 letters (ETDRS or Snellen equivalent);• Improvement in BCVA, by 36 weeks after initiation of treatment, of 8 letters (ETDRS or Snellen equivalent);• Improvement in BCVA, by 40 weeks after initiation of treatment, of about 8 letters (ETDRS or Snellen equivalent);• Improvement in BCVA, by 44 weeks after initiation of treatment, of about 8 letters (ETDRS or Snellen equivalent);• Improvement in BCVA, by 48 weeks after initiation of treatment, of about 8 or 9 letters (ETDRS or Snellen equivalent);• An improvement in BCVA by about week 8 after initiation of treatment which is maintained thereafter during the treatment regimen to at least week 48;• A BCVA by 4 weeks after initiation of treatment of about 68 letters (ETDRS or Snellen equivalent);• A BCVA by 8 weeks after initiation of treatment of about 70 letters (ETDRS or Snellen equivalent);• A BCVA by 12 weeks after initiation of treatment of about 70 letters (ETDRS or Snellen equivalent);• A BCVA by 16 weeks after initiation of treatment of about 71 letters (ETDRS or Snellen equivalent);• A BCVA by 20 weeks after initiation of treatment of about 70 letters (ETDRS or Snellen equivalent) when on an 8q4 or 8q8 or 8q12 or 8q4-8 or 8q8-12 or 8q4-12 regimen;• A BCVA by 24 weeks after initiation of treatment of about 71 letters (ETDRS or Snellen equivalent);• A BCVA by 28 weeks after initiation of treatment of about 72 letters (ETDRS or Snellen equivalent);• A BCVA by 32 weeks after initiation of treatment of about 71 letters (ETDRS or Snellen equivalent);• A BCVA by 36 weeks after initiation of treatment of about 71 letters (ETDRS or Snellen equivalent);• A BCVA by 40 weeks after initiation of treatment of about 72 letters (ETDRS or Snellen equivalent);• A BCVA by 44 weeks after initiation of treatment of about 72 letters (ETDRS or Snellen equivalent);• A BCVA by 48 weeks after initiation of treatment of about 73 letters (ETDRS or Snellen equivalent);• A BCVA improvement, by week 48 following treatment initiation, of about 9 or 10 letters (ETDRS or Snellen equivalent) when baseline BCVA is about <73 ETDRS letters;• A BCVA improvement, by week 48 following treatment initiation, of about 5 or 6 letters (ETDRS or Snellen equivalent) when baseline BCVA is about >73 ETDRS letters;• A BCVA improvement, by week 48 following treatment initiation, of about 8 or 9 letters (ETDRS or Snellen equivalent) when baseline BCVA is about <73 ETDRS letters;• A BCVA improvement, by week 48 following treatment initiation, of about 4 or 5 letters (ETDRS or Snellen equivalent) when baseline BCVA is about >73 ETDRS letters;• Gain of >5, >10 or >15 letters BCVA (according to ETDRS letter score) by week 12, 24, 36, 49, 60, 64, 72, 84 or 90 from start of treatment;• Retina without fluid (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF]) at the foveal center and in center subfield by week 12, 24, 36, 49, 60, 64, 72, 84 or 90 from start of treatment as measured by optical coherence tomography (OCT);• No vascular leakage as measured by fluorescein angiography (FA) by week 12, 24, 36, 49, 60, 64, 72, 84 or 90 from start of treatment;• Maintenance of a fluid-free retina (total fluid, IRF and / or SRF at foveal center and in the center subfield) by week 12, 24, 36, 49, 60, 64, 72, 84 or 90 from start of treatment;• Reduction in total area of fluorescein leakage within ETDRS grid (mm2) at week 48 or 64 by about 12, 13 or 14 mm2or more as measured by fluorescein angiography;• Retina free of fluid on spectral domain optical coherence tomography (SD-OCT) by week 12, 24, 36, 49, 60, 64, 72, 84 or 90 from start of treatment;• Retina without fluid (total fluid, intraretinal fluid [IRF] and / or subretinal fluid [SRF]) at the foveal center by week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 or 48 weeks from start of treatment;• Dry retina by week 12, 24, 36, 49, 60, 64, 72, 84 or 90 from start of treatment; • Foveal center without fluid by week 12, 24, 36, 49, 60, 64, 72, 84 or 90 from start of treatment as measured by optical coherence tomography (OCT);• Does not have anti-drug antibodies against aflibercept after 36, 48, 60 or 64 weeks of treatment;• Improvement from pre-treatment baseline in National Eye Institute Visual Function Questionnaire (NEI-VFQ) total score; and / or• Lack of macular edema.

[0287] In an embodiment of the invention, in a subject with an angiogenic eye disorder the subject achieves:• By Week 12 from treatment initiation achieving an improvement in BCVA of about 1 or 2 letters e.g., in a subject with nAMD; e.g., who has been receiving 8 mg (±0.8 mg) aflibercept once every 4 weeks;• By Week 16 from treatment initiation achieving an improvement in BCVA of about 1 or 2 letters e.g., in a subject with nAMD; e.g., who has been receiving 8 mg (±0.8 mg) aflibercept once every 4 weeks;• By Week 20 from treatment initiation achieving an improvement in BCVA of about 7 letters e.g., in a subject with nAMD; e.g., who has been receiving 8 mg (±0.8 mg) aflibercept once every 4 weeks;• By Week 4 from treatment initiation achieving an improvement in BCVA of about 1 or 2 letters e.g., in a subject with DME; e.g., who has been receiving 8 mg (±0.8 mg) aflibercept once every 4 weeks;• By Week 8 from treatment initiation achieving an improvement in BCVA of about 2 or 2 letters e.g., in a subject with DME; e.g., who has been receiving 8 mg (±0.8 mg) aflibercept once every 4 weeks;• By Week 12 from treatment initiation achieving an improvement in BCVA of about 3 or 2 letters e.g., in a subject with DME; e.g., who has been receiving 8 mg (±0.8 mg) aflibercept once every 4 weeks; and / or;• By Week 16 from treatment initiation achieving an improvement in BCVA of about 3 letters e.g., in a subject with DME; e.g., who has been receiving 8 mg (±0.8 mg) aflibercept once every 4 weeks.

[0288] In an embodiment of the disclosure, CST and / or retinal fluid is as measured on spectral domain optical coherence tomography (SD-OCT). In an embodiment of the disclosure, any of such achievements are maintained as long as the subject is receiving the treatment regimen.

[0289] In an embodiment of the disclosure, a subject receiving a treatment for an angiogenic eye disorder, e.g., an angiogenic eye disorder secondary to RVO (e.g., MERVO), or for treatment of RVO, does not experience or is no more likely to experience than a subject receiving Eylea according to the prescribed dosage regimen:• Ocular serious TEAE (e.g., through week 96 after treatment initiation), for example, cataract subcapsular, retinal detachment, ulcerative keratitis, vitreous haemorrhage or increased intraocular pressure, angle closure glaucoma, cataract, choroidal detachment, retinal detachment, retinal haemorrhage, skin laceration and / or vitreous haemorrhage;• TEAE intraocular inflammation (e.g., through week 96 after treatment initiation), for example, chorioretinitis, iridocyclitis, iritis, uveitis, vitreal cells and / or vitritis;• Non-ocular serious TEAEs (e.g., through week 96 after treatment initiation), for example, acute left ventricular failure, acute myocardial infarction, cardiac arrest, coronary artery disease, myocardial infarction, covid-19 pneumonia, gangrene, pneumonia, hyponatraemia, cerebrovascular accident, acute kidney injury, acute respiratory failure, angina pectoris, chest pain, cellulitis, pneumonia, pyelonephritis acute, urinary tract infection, upper limb fracture, hyponatraemia, osteoarthritis, bladder neoplasm and / or cerebrovascular accident;• Treatment emergent APTC event (e.g., through week 96 after treatment initiation), for example, non-fatal myocardial infarction, non-fatal stroke and / or vascular death;• Treatment emergent hypertension events (e.g., through week 96 after treatment initiation), for example, blood pressure increased (diastolic and / or systolic), hypertension, diastolic hypertension, systolic hypertension, hypertensive crisis, hypertensive emergency, hypertensive urgency, labile hypertension and / or white coat hypertension;• Potentially clinically significant values (e.g., through week 96 after treatment initiation), for example, systolic blood pressure>160 mmHg and an increase from baseline of >20 mmHg; and / or diastolic blood pressure >110 mmHg and an increase from baseline of >10 mmHg; and / or• Death (e.g., through week 96 after treatment initiation), for example, due to cardiac arrest, cardio-respiratory arrest, left ventricular failure, myocardial infarction, death, sudden death, covid-19, pneumonia, diabetic metabolic decompensation, endometrial cancer, acute kidney injury, abdominal strangulated hernia, pneumonia aspiration, skull fracture, metastatic neoplasm and / or non-small cell lung cancer

[0290] In one such embodiment, the subject has an angiogenic eye disorder secondary to RVO. In one such embodiment they have MERVO.

[0291] Some subjects may be excluded from administration according to the present invention, based, for example, on the existence of certain exclusion criteria. For example, in an embodiment of the disclosure, the exclusion criteria are any one or more of the following:1. Evidence of macular edema due to any cause other than RVO in an eye to be treated and / or the other eye not to be treated;2. DME or DR, defined in a diabetic subject as diabetic retinopathy lesions in the assessable area of the retina in an eye to be treated and / or the other eye not to be treated;3. Advanced age-related macular degeneration (nAMD or geographic atrophy) in an eye to be treated and / or the other eye not to be treated;4. Prior ocular or systemic treatment (with an investigational or approved agent) or surgery for RVO in an eye to be treated and / or the other eye not to be treated;5. Use of topical steroids within 4 weeks (28 days) of treatment in an eye to be treated and / or the other eye not to be treated;6. Use of intraocular or periocular steroids, e.g., within 16 weeks (112 days) of treatment, in an eye to be treated and / or the other eye not to be treated;7. Use of any intravitreal implantable agents (e.g., containing fluocinolone acetonide, dexamethasone or ranibizumab) in an eye to be treated and / or the other eye not to be treated;8. Prior treatment with ocriplasmin at any time in an eye to be treated and / or the other eye not to be treated;9. Prior treatment with pegcetacoplan injection or avacincaptad pegol injection in an eye to be treated and / or the other eye not to be treated;10. Prior treatment with retinal laser photocoagulation in an eye to be treated and / or the other eye not to be treated;11. Prior treatment with gene therapy and / or cell therapy in an eye to be treated and / or the other eye not to be treated;12. History of vitreoretinal surgery (including scleral buckle) in an eye to be treated and / or the other eye not to be treated;13. Any intraocular surgery, including cataract surgery, e.g., within 12 weeks (84 days) of treatment, in an eye to be treated and / or the other eye not to be treated;14. YAG capsulotomy in the study eye, e.g., within 4 weeks (28 days) of treatment; 15. IOP > 25 mm Hg in an eye to be treated and / or the other eye not to be treated;16. Uncontrolled glaucoma in an eye to be treated and / or the other eye not to be treated; (participant who has had filtration surgery in the past, or is likely to need filtration surgery in the future) based on physician assessment;17. Evidence of infectious blepharitis, keratitis, scleritis, or conjunctivitis in an eye to be treated and / or the other eye not to be treated;18. Any intraocular inflammation / infection (including trace, or above, cells in the anterior; chamber and / or vitreous), e.g., within 12 weeks (84 days) of treatment, in an eye to be treated and / or the other eye not to be treated;19. History of idiopathic or autoimmune uveitis in an eye to be treated and / or the other eye not to be treated;20. Vitreomacular traction or epiretinal membrane in an eye to be treated and / or the other eye not to be treated evident on biomicroscopy or OCT that is thought to affect central vision;21. Myopia of a spherical equivalent of 8 diopters or greater in an eye to be treated and / or the other eye not to be treated (prior to any refractive or cataract surgery, if applicable);22. History of corneal transplant in an eye to be treated and / or the other eye not to be treated;23. Any corneal dystrophy affecting the visual axis in an eye to be treated and / or the other eye not to be treated based on physician assessment;24. Aphakia, or pseudophakia with absence of posterior capsule (unless it occurred as a result of a YAG posterior capsulotomy, e.g., that was performed more than 28 days before treatment, in an eye to be treated and / or the other eye not to be treated;25. Any history of macular hole of stage 2 and above in an eye to be treated and / or the other eye not to be treated;26. Current anterior segment neovascularization, vitreous hemorrhage, or tractional retinal detachment visible in an eye to be treated and / or the other eye not to be treated; 27. Structural damage in an eye to be treated and / or the other eye not to be treated that is likely to preclude improvement in BCVA following the resolution of macular edema (e.g., atrophy of the retinal pigment epithelium, preretinal fibrosis, subretinal fibrosis or scar, significant macular ischemia, or organized hard exudates);28. Uncontrolled blood pressure (e.g., systolic > 160 mm Hg or diastolic > 95 mm Hg);29. History of cerebrovascular accident / transient ischemic attack or myocardial infarction / acute coronary syndrome, e.g., within 6 months (180 days) of treatment; 30. Renal failure, dialysis, or history of renal transplant;31. Known sensitivity to aflibercept;32. Presence of systemic infection or treatment for suspected or active systemic infection33. Presence of any contraindications to Eylea;34. Subject is a pregnant or breastfeeding woman; and / or35. Subject is of child bearing potential and is unwilling to practice highly effective contraception

[0292] In an embodiment of the disclosure, a subject receiving VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) is monitored for adverse events (AEs) such as conjunctival hemorrhage, cataract, vitreous detachment, vitreous floaters, corneal epithelium defect and / or increased intraocular pressure. If an AE is found, the AE can be treated in the subject and treatment can either be discontinued or continued.

[0293] The methods of present disclosure can include preparatory steps that include use of • one single-dose glass vial having a protective plastic cap and a stopper containing an aqueous formulation comprising 8 mg (±0.8 mg) aflibercept in about 70 microliters;• one 18-gauge x 11 / 2-inch, 5-micron, filter needle that includes a tip and a bevel;• one 30-gauge x1 / 2-inch injection needle; and• one 1-mL Luer lock syringe having a graduation line marking for 70 microliters of volume;packaged together (kits including such items form part of the present invention). The steps can include, for example: (1) visually inspecting the aqueous formulation in the vial and, if particulates, cloudiness, or discoloration are visible, then using another vial of aqueous formulation containing the aflibercept; (2) removing the protective plastic cap from the vial; and (3) cleaning the top of the vial with an alcohol wipe; then, using aseptic technique the following steps: (4) removing the 18-gauge x 1 Va-inch, 5-micron, filter needle and the 1 mL syringe from their packaging; (5) attaching the filter needle to the syringe by twisting it onto the Luer lock syringe tip; (6) pushing the filter needle into the center of the vial stopper until the needle is completely inserted into the vial and the tip touches the bottom or a bottom edge of the vial; (7) withdrawing all of the aflibercept vial contents into the syringe, keeping the vial in an upright position, slightly inclined, while ensuring the bevel of the filter needle is submerged into theliquid; (8) continuing to tilt the vial during withdrawal keeping the bevel of the filter needle submerged in the formulation; (9) drawing the plunger rod sufficiently back when emptying the vial in order to completely empty the filter needle; (10) removing the filter needle from the syringe and disposing of the filter needle; (11) removing the 30-gauge x Vz-inch injection needle from its packaging and attaching the injection needle to the syringe by firmly twisting the injection needle onto the Luer lock syringe tip; (12) holding the syringe with the needle pointing up, and checking the syringe for bubbles, wherein if there are bubbles, gently tapping the syringe with a finger until the bubbles rise to the top; and (13) slowly depressing the plunger so that the plunger tip aligns with the graduation line that marks 70 microliters on the syringe. Preferably injection of VEGF antagonist (e.g., a VEGF receptor fusion protein such as aflibercept) as performed in methods of the present invention is performed under controlled aseptic conditions, which comprise surgical hand disinfection and the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent) and anesthesia and a topical broadspectrum microbicide are administered prior to the injection.Treatment and Administration for neovascular (wet) age-related macular degeneration (nAMD) or visual impairment due to diabetic macular oedema (DME)

[0294] The present disclosure provides methods for treating or preventing neovascular (wet) age-related macular degeneration (nAMD) or visual impairment due to diabetic macular oedema (DME) in a subject; wherein the methods comprise(i) administering to the eye of the subject an intravitreal injection of 8 mg aflibercept every month or every 4 weeks + / - 1 week for the first 3 consecutive injections; and (ii) one or more further injections of 8 mg aflibercept after said first 3 consecutive injections wherein the injection interval between two consecutive injections is adjusted based on the physician’s judgement of visual and / or anatomic outcomes;wherein the injection interval between two consecutive injections is at least 4 weeks or one month.

[0295] The present disclosure provides methods for treating or preventing retinal neovascular (wet) age-related macular degeneration (nAMD) or visual impairment due to diabetic macular oedema (DME) in a subject; wherein the methods comprise(i) administering to the eye of the subject an intravitreal injection of 8 mg aflibercept every month or every 4 weeks + / - 1 week for the first 3 consecutive injections; and(ii) one or more further injections of 8 mg aflibercept after said first 3 consecutive injections wherein the injection interval between two consecutive injections is shortened based on the physician’s judgement of visual and / or anatomic outcomesand wherein the injection interval between two consecutive injections is at least 4 weeks or one month.

[0296] The present disclosure provides methods for treating or preventing neovascular (wet) age-related macular degeneration (nAMD) or visual impairment due to diabetic macular oedema (DME) in a subject; wherein the method comprises administering to the eye of the subject, a single initial dose of 8 mg aflibercept, followed bytwo secondary doses of said 8 mg aflibercept, followed by one or more tertiary doses of 8 mg aflibercept;wherein each secondary dose is administered 4 weeks or one month after the immediately preceding dose; andwherein the treatment interval between two consecutive tertiary doses is adjusted based on the physician’s judgement of visual and / or anatomic outcomes; andwherein the injection interval between two consecutive injections is at least 4 weeks or one month.

[0297] The present disclosure provides methods for treating or preventing neovascular (wet) age-related macular degeneration (nAMD) or visual impairment due to diabetic macular oedema (DME) in a subject; wherein the method comprises administering to the eye of the subject, a single initial dose of 8 mg aflibercept, followed bytwo secondary doses of said 8 mg aflibercept, followed byone or more tertiary doses of 8 mg aflibercept;wherein each secondary dose is administered 4 weeks or one month after the immediately preceding dose; andwherein the treatment interval between two consecutive tertiary doses is shortened based on the physician’s judgement of visual and / or anatomic outcomes andwherein the injection interval between two consecutive injections is at least 4 weeks or one month.

[0298] The present disclosure provides methods for treating or preventing neovascular (wet) age-related macular degeneration (nAMD) or visual impairment due to diabetic macular oedema (DME) in a subject; wherein the method comprises administering to the eye of the subject, a single initial dose of 8 mg aflibercept, followed by;one or more tertiary doses of 8 mg aflibercept;wherein the treatment interval between two consecutive tertiary closes is adjusted based on the physician’s judgement of visual and / or anatomic outcomes; andwherein the subject has been treated with a different anti-angiogenic treatment prior to said single initial dose of 8 mg aflibercept; andwherein the injection interval between two consecutive injections is at least 4 weeks or one month.

[0299] The present disclosure provides methods for treating or preventing neovascular (wet) age-related macular degeneration (nAMD) or visual impairment due to diabetic macular oedema (DME) in a subject; wherein the method comprises administering to the eye of the subject, a single initial dose of 8 mg aflibercept, followed by;one or more tertiary doses of 8 mg aflibercept;wherein the treatment interval between two consecutive tertiary doses is shortened based on the physician’s judgement of visual and / or anatomic outcomes; andwherein the subject has been treated with a different anti-angiogenic treatment prior to said single initial dose of 8 mg aflibercept; andwherein the injection interval between two consecutive injections is at least 4 weeks or one month. Such anti-angiogenic treatment is, for example, an anti-VEGF treatment using for e.g., 2 mg aflibercept, faricimab, ranibizumab or bevacizumab (e.g., >3 anti-VEGF ocular injections over the prior 5 months (~ 150 days). In one embodiment of the invention, the subject was treated with 2 mg aflibercept or faricimab prior to said single initial dose of 8 mg aflibercept (e.g., >3 anti-VEGF ocular injections over the prior 5 months (—150 days). In one embodiment of the invention, the subject was treated with ranibizumab or bevacizumab prior to said single initial dose of 8 mg aflibercept (e.g., >3 anti-VEGF ocular injections over the prior 5 months (-150 days).

[0300] In one embodiment of the invention said treatment interval between two consecutive tertiary doses is shortened if the subject(i) exhibits >5 letters loss of BCVA from reference visit; and / or(ii) (ii) >50 pm increase in CRT (central retinal thickness) from reference visit.In one embodiment the reference visit is the visit at the previous injection.In one embodiment of the invention said treatment interval between two consecutive doses is shortened by 2 or 4 weeks. In one embodiment of the invention, said treatment interval between two consecutive doses is shortened from 24 weeks or 6 months to 20 weeks or 5 months. In one embodiment of the invention said treatment interval between two consecutive doses is shortened from 20 weeks or 5 months to 16 weeks or 4 months. In one embodiment ofthe invention, said treatment interval between two consecutive doses is shortened from 16 weeks or 4 months to 12 weeks or 3 months. In one embodiment of the invention, said treatment interval between two consecutive doses is shortened from 12 weeks or 3 months to 8 weeks or 2 months. In one embodiment of the invention, said treatment interval between two consecutive doses is shortened from 8 weeks or 2 months to 4 weeks or 1 month. In one embodiment the tertiary dose interval is shortened by 1 week, provided that the new interval is at least about 4 weeks or one month. In one embodiment, the adjustment of the tertiary dose interval is shortened by about 4 weeks, provided that the new interval is at least about 4 weeks or 1 month. In one embodiment the tertiary dose interval is shortened by 2 weeks, provided that the new interval is at least about 4 weeks or 1 month. In one embodiment the treatment interval between two consecutive doses is at least 4 weeks or one month.Precision Dose Drug Delivery

[0301] The present invention provides methods as set forth herein wherein a VEGF antagonist (e.g., aflibercept) is delivered with a high amount of precision, e.g., with a drug delivery device (DDD) (e.g., with a 0.5 mL volume), whether pre-filled or capable of being filled from a vial, and delivering a volume of between 70 and 100 microliter with an average volume of about 81 or 82 or 81-82 microliters, e.g., with a standard deviation of about 4 or 5 or 4-5 microliters (e.g., about 4.5 or 4.46 microliters) or less. In an embodiment of the invention, the DDD is a syringe, e.g., with a 30 gauge,1Z> inch needle.

[0302] In one embodiment, doses of the VEGF antagonist are administered via intravitreal injection via syringe. One means for ensuring precision of a dose to be delivered with a device, such as a syringe, is by employing a syringe wherein the dose volume is device-determined. If the dose volume is device-determined, the device is designed only to deliver a single volume (e.g., 87 microliters) or a single volume with a limited amount of acceptable error (± 4-5 microliters). Thus, if used properly, the user cannot deliver the wrong dose (e.g., cannot deliver more than the intended volume from the device).

[0303] The present invention includes embodiments wherein, a precise dosage of about 8 mg (±0.8 mg) is a dose of about 9, 9.3, 9.33, 9.7, 9.8, 9.9, 9.7-9.9 mg or more ± about 0.5, or ± about 0.51 mg is delivered to a subject’s eye. The volume in which a dose is delivered can be, for example, about 70, 81, 82, 81.7, 85, 86, 87, 85-87 microliters ± about 4, 4.45, 4.5, or 5 microliters. Doses may be delivered with a dose delivery device (DDD) which is a syringe.

[0304] Highly precise doses of VEGF antagonist (e.g., aflibercept) may be delivered, for example, in a volume that is device-determined (wherein the device is a syringe), by a method that includes the steps: (a) priming the syringe (e.g., a pre-filled syringe), thereby removing airfrom the syringe and, thus avoiding injection of air into the eye, by advancing the plunger rod by a predetermined distance into the syringe body until advancement of the plunger rod is resisted by a stop; (b) rotating the plunger rod about a longitudinal axis; and (c) actuating the plunger rod to dispense a predetermined (device-determined) volume (e.g., about 70, 81, 82, 81.7, 85, 86, 87, 85-87 microliters, ± about 4, 4.45, 4.5, or 5 microliters) of the formulation.

[0305] In an embodiment of the invention, the drug delivery device (DDD), comprises:• a barrel including a longitudinal axis, a proximal end region, and a distal end region, the proximal end region including an opening, wherein the barrel is configured to receive a drug therein;• a plunger rod disposed at least partially inside the barrel and protruding from the opening, wherein the plunger rod includes a rack having a plurality of teeth; and• a pinion having a plurality of teeth configured to engage with the plurality of teeth of the rack,wherein rotation of the pinion against the rack moves at least a part of the plunger rod along the longitudinal axis of the barrel; for example, which further comprises a shaft affixed to the pinion, wherein rotation of the shaft rotates the pinion against the rack which may include a knob affixed to the shaft. In an embodiment of the invention, the DDD further includes a magnifier disposed on the distal end region of the barrel. In an embodiment of the invention, the DDD further includes a stopper inside the barrel, wherein the stopper is affixed to a distal end of the plunger rod. In an embodiment of the invention, the DDD further includes a circular ratchet disposed coaxially with the pinion, wherein the circular ratchet has a diameter smaller than a diameter of the pinion; a spring-loaded pawl disposed on an internal circumference of the pinion, wherein the pawl is configured to engage the ratchet; and a shaft affixed to the ratchet, wherein rotation of the shaft in one direction causes rotation of the pinion, and rotation of the shaft in a second direction does not cause rotation of the pinion for example wherein the ratchet is disposed inside the pinion. In an embodiment of the invention, the pinion includes a plurality of teeth having a first height, and a stopper tooth having a second height greater than the first height, for example, wherein the second height of the stopper tooth prevents the pinion from engaging the plurality of teeth of the rack, and / or wherein the second height of the stopper tooth is configured to contact one of the plunger rod and the rack to stop rotation of the pinion. In an embodiment of the invention, the plunger rod includes an inner column and an outer lumen, and wherein the rack is disposed on the inner column, e.g., wherein rotation of the pinion against the rack moves the inner column of the plunger rod independently of the outer lumen, and / or further including a shaft removably affixed to the pinion, wherein the shaft prevents movement of theouter lumen of the plunger rod relative to the barrel, and wherein removal of the shaft allows for movement of the outer lumen of the plunger rod relative to the barrel. In an embodiment of the invention, the plunger rod further includes a body and a flange, the flange extending partially along a longitudinal length of the body and having a width greater than a width of the body; wherein the barrel further comprises a plunger lock, the plunger lock including a through hole configured to allow the flange to pass through the second plunger lock in a specific orientation. In an embodiment of the invention, the drug delivery device (DDD), comprises:• a barrel including a longitudinal axis, a proximal end region, a distal end region, and an interior, the proximal end region including an opening and the interior including a threaded region; and• a plunger rod disposed at least partially inside the barrel and protruding from the opening, the plunger rod including a threaded region configured to engage the threaded region of the barrel interior,wherein rotation of the plunger rod about the longitudinal axis of the drug delivery device moves the plunger rod along the longitudinal axis. In an embodiment of the invention, the plunger rod further includes a tab protruding from the plunger rod in a first direction and located proximally from the threaded region of the plunger rod, and wherein the threaded region in the interior of the barrel further includes a slot sized and configured to allow for the tab to pass through the threaded region in the interior of the barrel, e.g., wherein the slot includes a first segment parallel to the longitudinal axis of the drug delivery device and a second segment perpendicular to the longitudinal axis of the drug delivery device — the slot may include a third segment parallel to the longitudinal axis of the drug delivery device, wherein the second segment is in between the first segment and the third segment. In an embodiment of the invention, the tab is a first tab, and wherein the plunger rod further includes a second tab protruding from the plunger rod in a second direction opposite to the first direction, and wherein the threaded region in the interior of the barrel further includes a second slot sized and configured to allow for the second tab to pass through the threaded region in the interior of the barrel.

[0306] In an embodiment of the invention, the drug delivery device, includes:• a barrel having a proximal end region, a distal end region, an opening in the proximal end region, an interior, and a threaded region in the interior;• a sleeve disposed partly inside the barrel and protruding from the opening in the proximal end region of the barrel, the sleeve including a threaded region engaged with the threaded region of the barrel interior;• a plunger rod disposed at least partially inside the sleeve; and• a stopper inside the barrel and located distally from the sleeve, the stopper connected to a distal end of the plunger rod,wherein rotation of the sleeve in a first direction around a longitudinal axis of the drug delivery device moves the sleeve towards the distal end region of the barrel. In an embodiment of the invention, rotation of the sleeve in the first direction moves the stopper towards the distal end region of the barrel. In an embodiment of the invention; the sleeve includes an inner passage, and the stopper has a diameter larger than a diameter of the inner passage; and / or the sleeve includes a tab disposed on an exterior of the sleeve, the tab located proximally from the threaded region of the barrel interior, and wherein the tab stops movement of the sleeve towards the distal end region of the barrel, e.g., wherein the tab is configured to stop movement of the sleeve towards the distal end region of the barrel after the drug delivery device has been primed or wherein the tab is a first tab, and wherein the sleeve further includes a second tab disposed on an exterior of the sleeve, the second tab located distally from the threaded region of the barrel interior, wherein the second tab stops movement of the sleeve towards the proximal end region of the barrel.

[0307] In an embodiment of the invention, the drug delivery device, comprises:• a barrel including a proximal end region and a distal end region, the proximal end region including an opening;• a plunger rod including a body and a flange, the flange extending partially along a longitudinal length of the body and having a width greater than a width of the body, the plunger rod disposed at least partially inside the barrel and protruding from the opening;• a first plunger lock disposed on the barrel, the first plunger lock configured to block the flange from entering the barrel; and• a second plunger lock disposed in the barrel, the second plunger lock including a through hole configured to allow the flange to pass through the second plunger lock in a specific orientation.

[0308] For example, in an embodiment of the invention, the first plunger lock is removable and / or frangible. In an embodiment of the invention, a distance between the first plunger lock and the second plunger lock is equivalent to the distance that the stopper must travel to prime the drug delivery device; and / or the plunger rod is rotatable around a longitudinal axis of the drug delivery device.Substances from such a DDD (e.g., a formulation including aflibercept as described herein), having a plunger rod and a barrel, may be dispensed as follows:• advancing the plunger rod by a predetermined distance into the barrel until advancement of the plunger rod is resisted by a stop;• deactivating the stop; and• actuating the plunger rod (e.g., which includes a flange, wherein the stop includes a lock that prevents the flange from entering the barrel; or which includes a flange, wherein the stop comprises a lock that prevents the flange from entering the barrel) to deliver the substance. Advancing the plunger rod may include the step of rotating a pinion against a rack disposed on the plunger rod, e.g., wherein the stop comprises a shaft removably affixed to the pinion, and wherein deactivating the stop comprises removing the shaft from the pinion. Deactivating the stop may include the step of rotating the plunger rod. In an embodiment of the invention, deactivating the stop includes the step of removing the lock and / or breaking the lock.In an embodiment of the invention, the drug delivery device, includes:• a barrel including a longitudinal axis, a proximal end region, and a distal end region, the proximal end region including an opening and a rack disposed on the interior of the barrel, the rack having a plurality of teeth, wherein the barrel is configured to receive a drug therein;• a plunger rod disposed at least partially inside the barrel and protruding from the opening, wherein the plunger rod includes a rack having a plurality of teeth; a pinion having a plurality of teeth configured to engage with the plurality of teeth of the plunger rod rack; and • an inner plunger coupled to the pinion by a rod, wherein rotation of the pinion against the plunger rod rack results in movement of the inner plunger along the longitudinal axis of the barrel;for example, wherein the teeth of the pinion are further configured to engage with the plurality of teeth of the rack disposed on the barrel. In an embodiment of the invention, the pinion is a first pinion, and further includes: a second pinion disposed coaxially with the first pinion, the second pinion having a diameter smaller than a diameter of the first pinion and a plurality of teeth configured to engage with the plurality of the teeth of the rack disposed on the barrel, wherein rotation of the first pinion results in rotation of the second pinion against the rack disposed on the barrel and in movement of the inner plunger along the longitudinal axis of the barrel.

[0309] See International patent application publication no. WO2019 / 118588.

[0310] In an embodiment of the invention, the drug delivery device (DDD), includes:• a body;• a plunger rod disposed partially inside the body;• a protrusion extending from the plunger rod; and• a blocking component coupled to a proximal end portion of the body, wherein the blocking component is a flange piece,wherein, when the protrusion is in a first position relative to the blocking component, the blocking component restricts distal movement of the plunger rod to a first stopping point, and when the protrusion is in a second position relative to the blocking component, the blocking component restricts distal movement of the plunger rod to a second stopping point. In an embodiment of the invention, the DDD further includes: a stopper disposed in the body, wherein distal movement of the plunger rod distally moves the stopper; and a drug substance disposed in the body in between the stopper and a distal end of the body, wherein distal movement of the plunger rod to the first stopping point primes the drug delivery device, and distal movement of the plunger rod to the second stopping point dispenses a predetermined volume of the drug substance from a distal end of the device.

[0311] In an embodiment of the invention, moving the protrusion from the first position to the second position includes twisting the plunger rod relative to the blocking component. In an embodiment of the invention, the DDD further includes: a cavity in a proximal side of the blocking component, the cavity sized and configured to receive a portion of the protrusion, wherein when the protrusion is in the second position relative to the blocking component, the protrusion is positioned proximally from the cavity, such that distal movement of the plunger rod moves the protrusion into the cavity; e.g., wherein the cavity is a first cavity, and further includes: a second cavity in a proximal side of the blocking component, the second cavity sized and configured to receive a portion of the protrusion, wherein the first and second cavity are located on opposite sides of a central longitudinal axis of the drug delivery device. In an embodiment of the invention, the plunger rod passes through an opening in the blocking component. In an embodiment of the invention the DDD further includes an actuation portion at a proximal end portion of the plunger rod, wherein the protrusion extends from the actuation portion, e.g., wherein the actuation portion includes a generally cylindrical shape having a diameter greater than a width of the remainder of the plunger rod, wherein the protrusion extends from a side of the generally cylindrical shape, and wherein the actuation portion further comprises: a thumb pad on a proximal end of the actuation portion; and a ring on an exterior surface on the side of the generally cylindrical shape; e.g., further including a proximal collar on the blocking component, wherein the actuation portion partially fits inside the proximal collar; e.g., wherein the plunger rod further includes a pair of extensions protruding distally from the actuation portion and the blocking component (e.g., which includes one or more indents formed along a bottom wall of the blocking component; and wherein a portion of each extension isconfigured to be received by the one or more indents upon distal movement of the plunger rod relative to the blocking component to allow distal movement of the plunger rod to the second stopping point; or, which includes one or more indents formed along a bottom wall of the blocking component; and wherein a portion of each extension is configured to be received by the one or more indents upon distal movement of the plunger rod relative to the blocking component to allow distal movement of the plunger rod to the second stopping point; or, which includes a pair of internal grooves formed along a sidewall of the blocking component; and wherein a portion of each extension is configured to be received by at least one of the pair of internal grooves upon rotation of the plunger rod relative to the blocking component to expand the extensions radially-outward from a compressed state to a relaxed state) includes a pair of openings; and wherein a portion of each extension is configured to be received by one of the pair of openings in the first stopping point. In an embodiment of the invention, the protrusion is a first protrusion, and further includes a second protrusion extending from the plunger rod in a direction opposite to the first protrusion. In an embodiment of the invention, the blocking component is slidably coupled to the body and includes a third cavity and a pair of ribs that extend into the third cavity, wherein the body includes a top flange and the pair of ribs are configured to engage the top flange received in the third cavity; wherein the pair of internal ribs are configured to apply a distally-directed force onto the top flange. In an embodiment of the invention, the blocking component is slidably coupled to the body and includes a pair of movable tabs that are configured to engage the body; and the pair of movable tabs are laterally deflectable upon receiving the body in the blocking component and are configured to apply a radially-inward directed force onto the body. In an embodiment of the invention, the blocking component further includes a pair of finger flanges, and each of the finger flanges includes a textured surface having a predefined pattern that increases a grip of the blocking component.

[0312] In an embodiment of the invention, the drug delivery device (DDD), includes:• a body;• a plunger rod having a distal end contacting a stopper inside the body, and a proximal end including an actuation portion with a thumb pad;• a plurality of protrusions extending from the actuation portion; and• a blocking component disposed on the body, the blocking component including a proximal collar having a plurality of slots,wherein, when the protrusions and the slots are in a first configuration relative to one another, the blocking component restricts distal movement of the plunger rod to a first stopping point, and when the protrusions and the slots are in a second configuration, the blocking componentrestricts distal movement of the plunger rod to a second stopping point, wherein, in the second configuration, the slots are configured to receive the protrusions upon distal movement of the plunger rod. In an embodiment of the invention, the protrusions and the slots are movable from the first configuration to the second configuration by rotation of the actuation portion about a longitudinal axis in relation to the blocking component, and wherein when the protrusions and the slots are in the second configuration, the protrusions and the slots are not movable to the first configuration; and / ora difference between the first stopping point and the second stopping point is equivalent to a distance that the stopper must travel to expel a predetermined volume of a drug product from a distal end of the body, and wherein the plunger rod is prevented from moving from the second stopping point to the first stopping point; and / or the plurality of protrusions includes two protrusions disposed symmetrically about the actuation portion; and / or the blocking component further comprises a pair of finger flanges; and / or the drug delivery device is a pre-filled syringe; and / or the drug delivery device is changeable: (a) from a pre-use state to a primed state, by longitudinally moving the plunger rod (e.g., wherein the plunger rod includes a neck disposed distally from the actuation portion, wherein the neck interfaces with an opening in the blocking component to prevent proximal movement of the plunger rod, for example, wherein the neck further interfaces with the opening in the blocking component to prevent movement of the drug delivery device from the delivery state to the primed state) until the plunger rod reaches the first stopping point; (b) from the primed state to a delivery state by rotating the plunger rod in relation to the blocking component until the protrusions and the blocking component are in the second configuration; and (c) from a delivery state to a used state by longitudinally moving the plunger rod until the plunger reaches the second stopping point, wherein the drug delivery device is not changeable from the used state to the delivery state, from the delivery state to the primed state, or from the primed state to the pre-use state. In an embodiment of the invention, when the plunger rod is at the second stopping point, the stopper does not contact a distal end of the body.

[0313] In an embodiment of the invention, a drug delivery device, includes:• a body;• a plunger rod, including:• a distal portion contacting a stopper inside the body;• a proximal end including a generally cylindrical actuation portion disposed outside of the body; and• two protrusions extending from opposite sides of the actuation portion in a symmetrical configuration; and• a blocking component coupled to the body, the blocking component including: a collar configured to accept a distal part of the actuation portion; and two cavities in the collar having proximally-facing openings, wherein each cavity is configured to accept a distal portion of one of the two protrusions;wherein the plunger rod is longitudinally movable and rotatable about a longitudinal axis relative to the blocking component, andwherein, when the drug delivery device is in a pre-use state, the protrusions and the cavity openings are not longitudinally aligned, and when the drug delivery device is in a delivery state, the protrusions and the cavity openings are longitudinally aligned. In an embodiment of the invention, the blocking component further includes a finger flange, and further includes a ribbed surface on a side of the actuation portion. In an embodiment of the invention, the plunger rod further includes: two extensions protruding distally from the actuation portion; and a plurality of openings in the collar of the blocking component, wherein a portion of each extension is configured to be received by one of the plurality of openings upon distal movement of the plunger rod relative to the blocking component.

[0314] In an embodiment of the invention, a drug delivery device includes:• a body;• a stopper disposed inside the body;• a sleeve having a proximal end and a distal end, the distal end being disposed inside the body, proximally from the stopper; and• a plunger rod disposed at least partially inside the sleeve;wherein, when the stopper is in a ready position, distal advancement of one of (a) only the sleeve, (b) only the plunger rod, or (c) both the sleeve and the plunger rod together, relative to the body advances the stopper to a primed position, and wherein, when the stopper is in the primed position, distal advancement of another of (a) only the sleeve, (b) only the plunger rod, or (c) both the sleeve and the plunger rod together, relative to the body advances the stopper to a dose completion position. For example, in an embodiment of the invention, a DDD further includes a removable blocking component (e.g., wherein the blocking component is a clip removably secured around at least a portion of the sleeve) disposed between a proximal portion of the sleeve and a proximal end of the body, the blocking component obstructing distal advancement of the sleeve relative to the body, wherein distal advancement of the sleeve relative to the body after removal of the blocking component advances the stopper to the primedposition. In an embodiment of the invention, the DDD further includes a removable locking component (e.g., a pin, a tab, or a bar) that couples the plunger rod to the sleeve, wherein distal advancement of both the sleeve and the plunger rod together relative to the body advances the stopper to the primed position, wherein distal advancement of only the plunger rod relative to the body after removal of the locking component advances the stopper to the dose completion position. In an embodiment of the invention, in the dose completion position, a proximal end of the plunger rod abuts against a distal end of the sleeve, such that the plunger rod is prevented from advancing distally any further relative to the body. In an embodiment of the invention, the DDD further includes a protrusion disposed on the plunger rod; and an inner protrusion disposed on an interior wall of the sleeve distally to the protrusion of the plunger rod, wherein distal advancement of only the plunger rod relative to the body advances the stopper to the primed position and causes the protrusion of the plunger rod to contact the inner protrusion of the sleeve, and wherein distal advancement of both the plunger rod and the sleeve relative to the body, after the protrusion of the plunger rod has contacted the inner protrusion of the sleeve, advances the stopper to the dose completion position. In an embodiment of the invention, the sleeve includes a finger flange. In an embodiment of the invention, the DDD further includes a stop disposed at a proximal end of the body, the stop sized to block distal advancement of the sleeve or the plunger rod once the stopper is in the completion position.

[0315] In an embodiment of the invention, a drug delivery device, includes:• a body;• a plunger rod having a distal portion disposed inside the body and a proximal portion disposed outside a proximal end of the body, the proximal portion having a width greater than a width of the distal portion; and• an obstruction that, in an obstructing position relative to the plunger rod, prevents distal advancement of the plunger rod from a primed position to a dose completion position, wherein displacement of the obstruction from the obstructing position permits distal advancement of the plunger rod to the dose completion position, for example, further including a collar affixed to a proximal end portion of the body, the collar surrounding the proximal portion of the plunger rod; and a collar projection extending radially inward from the collar, wherein the proximal portion of the plunger rod includes a channel into which the collar projection protrudes, the channel including a circumferential path and an axial dose completion path, wherein the obstruction comprises the collar projection, which, when disposed in the circumferential path of the channel, prevents distal advancement of the plunger rod to the dose completion position, and wherein displacement of the obstruction from the obstructing position comprises twisting theplunger rod about a longitudinal axis to align the collar projection with the axial dose completion path. For example, in an embodiment of the invention, the channel further includes an axial priming path offset from the axial dose completion path, and connected to the axial dose completion path by the circumferential path, and distal movement of the plunger rod such that the collar projection travels on the axial priming path advances the plunger rod to the primed position. In an embodiment of the invention, the DDD further includes a finger flange. In an embodiment of the invention, the proximal portion of the plunger rod includes a projection extending radially outward, and the drug delivery device further includes: a rotatable alignment component disposed in between the proximal portion of the plunger rod and the body, the alignment component including a channel, the channel sized and configured to accommodate the plunger rod projection, wherein the obstruction comprises a wall of the channel that blocks a distal axial path of the plunger rod projection when the plunger rod is in the primed position, and wherein displacement of the obstruction from the obstructing position comprises rotating the alignment component to remove the wall of the channel from the distal axial path of the plunger rod projection, e.g., further including a finger flange coupled to a proximal end portion of the body, wherein the rotatable alignment component is disposed between the finger flange and the proximal portion of the plunger rod. In an embodiment of the invention, the DDD further includes a flange piece disposed at the proximal end of the body, wherein the obstruction includes a removable cap that, when in the obstructing position relative to the plunger rod, is disposed partially in between the proximal portion of the plunger rod and the flange piece. In an embodiment of the invention, removal of the cap allows the proximal portion of the plunger rod to advance to a dose completion position, wherein, in the dose completion position, the proximal portion of the plunger rod contacts the flange piece. In an embodiment of the invention, the removable cap covers the proximal portion of the plunger rod when in the obstructing position. In an embodiment of the invention, the DDD further includes a collar disposed between the proximal end of the body and the proximal portion of the plunger rod, the collar defining an opening sized to accommodate the proximal portion of the plunger rod upon distal advancement of the plunger rod beyond a primed position; wherein the obstruction comprises a tab protruding radially outward from the proximal portion of the plunger rod, the tab preventing the proximal portion of the plunger rod from fitting into the opening of the collar, and wherein a depth of the collar opening coincides with a distance the plunger rod must travel to advance distally to the dose completion position, e.g., wherein displacement of the obstruction from the obstructing position comprises either removing the tab or compressing the tab into a side of the proximal portion of the plunger rod; and / or wherein the tab is a first tab, and wherein the obstructionfurther comprises a second tab protruding radially outward from the proximal portion of the plunger rod in a direction opposite the protruding direction of the first tab; and / or wherein the obstruction comprises a tab that, when in the obstructing position, is disposed between the body and the proximal portion of the plunger rod, and wherein the plunger rod includes a geometry disposed proximally from the tab, wherein the geometry cannot advance distally past the tab when the tab is in the obstructing position. For example, displacement of the obstruction may include removing the tab from the drug delivery device by pulling the tab. In an embodiment of the invention, the DDD further includes a flange piece, wherein a portion of the tab is disposed inside a cavity of the flange piece. In an embodiment of the invention, displacement of the obstruction comprises removing the tab from the drug delivery device by breaking the tab. In an embodiment of the invention, the obstruction includes a flange piece that, in the obstructing position, is disposed proximally from the proximal end of the body, between the proximal portion of the plunger rod and the body, and is spaced from the proximal end of the body by a removable blocking component, and wherein displacement of the obstruction from the obstructing position comprises: removing the blocking component; and shifting the flange piece distally towards the proximal end of the body. In an embodiment of the invention, the plunger rod includes a projection extending radially outward, wherein the obstruction includes a lever having an end that, in the obstructing position, is located distally from the projection and blocks distal movement of the projection and thereby distal movement of the plunger rod, and wherein displacement of the obstruction from the obstructing position comprises actuating the lever to remove the end of the lever from its location distal from the projection. In an embodiment of the invention, distal advancement of the plunger rod beyond the dose completion position is prevented by contact between the proximal portion of the plunger rod and a portion of a flange piece coupled to the body.

[0316] In an embodiment of the invention, the drug delivery device, includes:• a body;• a sleeve affixed to the body, the sleeve including a proximal end, a distal end, and an opening disposed in a circumferential wall of the sleeve;• a plunger rod passing through the sleeve, the plunger rod including a distal end portion disposed inside the body, and a radially-extending protrusion;wherein the plunger rod may be distally advanced into the body from a ready position to a primed position, wherein, in the primed position, the protrusion of the plunger rod is disposed inside the opening, and further distal advancement of the plunger rod is resisted by contact between the protrusion and a wall of the opening, and wherein pressure may be exerted on theprotrusion to overcome the resistance to further distal advancement of the plunger rod. In an embodiment of the invention, the opening in the sleeve is a second opening, and the sleeve further includes a first opening disposed in the circumferential wall of the sleeve proximally from the second opening, and a third opening disposed in the circumferential wall of the sleeve distally from the second opening, wherein, in the ready position, the protrusion of the plunger rod is disposed in the first opening, and further distal advancement of the plunger rod is resisted by contact between the protrusion and a wall of the first opening, and wherein, after further distal advancement of the plunger rod past the primed position, the protrusion of the plunger rod is disposed in the third opening, and further distal advancement of the plunger rod is prevented. In an embodiment of the invention, the radially-extending protrusion is a first protrusion, and wherein the plunger rod further includes a second radially-extending protrusion opposite the first protrusion, and wherein squeezing the first and second protrusions towards one another while applying axial pressure in the distal direction on the plunger rod overcomes the resistance to further distal advancement of the plunger rod. In an embodiment of the invention, the protrusion includes a distally-tapering profile to aid in distal advancement of the plunger rod.

[0317] In an embodiment of the invention, a drug delivery device, includes:• a body;• a plunger rod including a distal end portion disposed inside the body and a rotatable element; and• a sleeve affixed to the body, the sleeve including a proximal opening into which the plunger rod may be advanced,wherein rotating the rotatable element causes distal advancement of the plunger rod to a primed position, and wherein once the plunger rod is in the primed position, further rotation of the rotatable element is resisted. In an embodiment of the invention, the DDD further includes a collar disposed at a proximal end of the body, an interior of the collar including a proximal threaded portion forming a proximal helical path, wherein the rotatable element comprises a proximal portion of the plunger rod including a protrusion, wherein the proximal portion of the plunger rod may be rotated about a longitudinal axis to cause the protrusion to travel distally along the proximal helical path, and wherein once the protrusion reaches the end of the proximal threaded portion of the collar, the plunger rod is in the primed position, e.g., wherein once the plunger rod is in the primed position, the plunger rod may be depressed axially into the body to distally advance the plunger rod to a dose completion position; and / or wherein the interior of the collar further includes a distal threaded portion, wherein threads of the distal threaded portion form a distal helical path offset from, and opposite to, the proximal helical path,wherein alignment of the protrusion with the distal helical path places the plunger rod in the primed position, and wherein rotation of the proximal portion of the plunger rod to cause the protrusion to travel distally along the distal helical path causes distal advancement of the plunger rod to a dose completion position.

[0318] A substance may be dispensed using such a DDD having a plunger rod and a body, may be done by a method including:(a) advancing the plunger rod by a predetermined distance into the body until advancement of the plunger rod is resisted by a stop;(b) rotating the plunger rod about a longitudinal axis; and(c) actuating the plunger rod to dispense a predetermined volume of the substance, wherein none of steps (a), (b), and (c) are reversible. In an embodiment of the invention, the DDD further includes a flange piece having a collar, and advancing the plunger rod and actuating the plunger rod comprise pressing an actuation portion of the plunger rod into the collar of the flange piece; for example, wherein the plunger rod comprises a protrusion, and wherein the collar of the flange piece abuts against the protrusion to resist advancement of the plunger rod. For example, in an embodiment of the invention, wherein rotating the plunger rod comprises twisting an actuation portion of the plunger rod relative to the flange piece, until a protrusion on the plunger rod becomes longitudinally aligned with a cavity in the collar of the flange piece, which may further include advancing the protrusion into the cavity until the protrusion abuts a distal side of the cavity, wherein the predetermined volume of the substance is dispensed when the protrusion abuts the distal side of the cavity.

[0319] See International patent application publication no. WO2020 / 247686.Products for use and manufacture of medicaments

[0320] Wherever a method of treatment is referred to herein, also provided is a VEGF receptor fusion protein for use in such a method. For instance, aflibercept for use in such a method is provided.

[0321] Wherever a method of treatment is referred to herein, also provided is use of a VEGF receptor fusion protein in the manufacture of a medicament for use in such a method. For instance, use of aflibercept in the manufacture of such a medicament is provided.

[0322] Wherever a method of treatment is referred to herein, also provided is a pharmaceutical composition for use in such a method, where the pharmaceutical composition comprises a VEGF receptor fusion protein as set out herein.Further illustrative embodiments

[0323] The following represent further illustrative embodiments of the present invention:

[0001] A method for treating or preventing macular edema secondary to retinal vein occlusion (MERVO) comprising administering to an eye of the subject a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein;wherein each secondary dose is administered about 2 to 4 weeks (±7 days) after the immediately preceding dose; andwherein each tertiary dose is administered at least about four weeks (±7 days) after the immediately preceding dose.[2] The method of [1], wherein at least two secondary doses are administered.[3] The method of [1] or [2], wherein two to six secondary doses are administered.[4] The method of any one of [1] to [3], wherein two secondary doses are administered.[5] The method of any one of [1] to [3], wherein four secondary doses are administered.[6] The method of any one of [1] to [3], wherein five secondary doses are administered.[7] The method of any one of [1] to [6], wherein the secondary doses are administered at about monthly intervals.[8] The method of any one of [1] to [7], wherein the tertiary doses are administered at least 8 weeks after the immediately preceding dose.[9] The method of any one of [1] to [8], wherein the tertiary doses are administered at least 12 weeks after the immediately preceding dose.

[0010] The method of any one of [1] to [9], wherein the interval of at least eight weeks between tertiary doses is maintained throughout the tertiary dosing period.

[0011] The method of any one of [1] to

[0010] , wherein the subject is assessed during administration of the tertiary doses to determine whether to length, maintain, or shorten the interval between tertiary doses.

[0012] The method of any one of

[0001] to

[0011] , wherein the VEGF receptor fusion protein is aflibercept.

[0013] The method of any one of [1] to

[0012] , wherein the subject is treatment naive.

[0014] The method of any one of [1] to

[0013] , wherein administration is via intravitreal injection.

[0015] The method of

[0014] , wherein the intravitreal injection volume is less than about 100 pl.

[0016] The method of any one of [1] to

[0015] , wherein the retinal vein occlusion is central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO) and / or hemiretinal vein occlusion (HRVO).

[0017] The method of any one of

[0001] to

[0016] , wherein the subject is 18 years or older who have been diagnosed with macular edema secondary to RVO, involving the center of the macula, with a BCVA letter score of 73 to 24 (20 / 40 to 20 / 320) in the study eye.EXAMPLES

[0324] The present invention includes methods for achieving any of the individual results, for example, by the period of time after treatment initiation that is indicated (e.g., improvement in BCVA by X ETDRS letters by Y days after treatment initiation) as is set forth in the Examples section in a subject having an angiogenic eye disorder, e.g., an angiogenic eye disorder secondary to retinal vein occlusion by administering a VEGF receptor fusion protein treatment regimen to the subject.Example 1: A Randomized, Double-Masked, Active-Controlled Phase 3 Study of the Efficacy and Safety of High-Dose Aflibercept in Patients with Macular Edema Secondary to Retinal Vein Occlusion (MERVO) (QUASAR)

[0325] This is a Phase 3, multi-center, randomized, double-masked, active-controlled clinical study to assess the efficacy and safety of high dose (8 mg) aflibercept administered intravitreally (IVT) compared to 2 mg aflibercept treatment in participants with treatment-naive macular edema secondary to retinal vein occlusion (RVO). The trial is a global randomized, doublemasked, active-controlled phase III study evaluating the efficacy and safety of Eylea (aflibercept) 8 mg used with extended dosing intervals in treatment-naive patients with macular edema secondary to retinal vein occlusion including central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO) or hemiretinal vein occlusion (HRVO). The primary endpoint of this study is to document change in best corrected visual acuity (BCVA), as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score, from the date of randomization through 36 weeks of treatment. The study compares BCVA changes between patients who received Eylea 8 mg every 8 weeks following either 3 or 5 initial monthly doses compared to Eylea 2 mg every 4 weeks. Treatment intervals could be further adjusted based on treatment response continuously evaluated under clinically relevant dose regimen modification (DRM) criteria. Treatment intervals could be shortened by 4 weeks at any dosing visit if patients met DRM criteria. Treatment intervals could be extended based on DRM criteriafrom week 32 (for the study arms with aflibercept 2 mg and aflibercept 8 mg following 3 initial monthly doses) or week 40 (for the study arm with aflibercept 8 mg following 5 initial monthly doses). Patients will be treated up to week 60 followed by a monitoring period until week 64. The trial has enrolled more than 800 patients from 27 countries

[0326] The study population consists of men and women 18 years and older who have been diagnosed with macular edema secondary to RVO (BRVO, CRVO, or HRVO), involving the center of the macula, with a BCVA letter score of 73 to 24 (20 / 40 to 20 / 320) in the study eye.

[0327] A total of approximately 822 eligible participants with macular edema secondary to RVO are planned to be randomized in a 1:1:1 ratio to aflibercept 8 mg Q8W after 3 initial Q4W initiation doses group or aflibercept 8 mg Q8W after 5 initial Q4W initiation doses group or aflibercept 2 mg Q4W group. 804 were randomized to intervention and 802 were treated. The study consists of a screening / baseline period, and an end of study (EoS) visit at Week 64. No study intervention will be administered at the EoS visit at Week 64.

[0328] Figure 1 shows the dosing schedule.

[0329] Study visits will be scheduled Q4W throughout the study duration. At every visit until Week 60, the participants will receive an active or sham injection for masking purposes. During the first 32 weeks, the 2 mg group (2q4) will receive an active injection at every visit while the 8 mg groups will initiate treatment with injections Q4W for a total of 3 doses (8q8 / 3) or will initiate treatment with injections Q4W for a total of 5 doses (8q8 / 5), followed by extension of the treatment interval of 8 weeks. Beginning at Week 36 through Week 60, treat and extend (T& E) will be employed for the 2 mg Q4W group and 8 mg Q8W after 3 initial Q4W doses group and beginning at Week 44 through Week 60 for the 8 mg Q8W after 5 initial Q4W doses group. Extension or shortening of the dosing interval will depend on meeting dose regimen modification (DRM) criteria. The DRM criteria may also indicate active injections at Weeks 20 and 28 for participants in the 8 mg groups in the need of treatment.

[0330] The current study will investigate the efficacy and safety of aflibercept 8 mg with the intent of achieving non-inferior BCVA, while extending the dosing interval to reduce the number of injections and potentially improving visual and / or anatomic outcomes for aflibercept 8 mg vs. the currently approved aflibercept 2 mg dose regimen as well as maintaining the same safety profile as aflibercept 2 mg.

[0331] The primary, secondary, and exploratory objectives and endpoints for the study are shown in Table 1A, below.Table 1A. Objectives and EndpointsObjectives EndpointsPrimary• To determine if treatment with aflibercept Primary Endpoint:8 mg Q8W provides non-inferior BCVA • Change from baseline in BCVA measured by change compared to aflibercept 2 mg Q4W the ETDRS letter score at Week 36 Secondary - Efficacy• To determine if treatment with aflibercept Key Secondary Endpoint8 mg Q8W requires less injections • Number of active injections from baseline to compared to aflibercept 2 mg Q4W Week 641Secondary Endpoint• Number of active injections from baseline to Week 36• To determine the effect of aflibercept 8 mg Secondary Endpoints:Q8W compared to aflibercept 2 mg Q4W on • Change from baseline in BCVA measured by other visual and anatomic measures of the ETDRS letter score at Week 64 response • Participant gaining at least 15 letters in BCVA from baseline at Weeks 36 and 64• Participant achieving an ETDRS letter score of at least 69 (approximate 20 / 40 Snellen equivalent) at Weeks 36 and 64• Participant having no IRF and no SRF in the center subfield at Weeks 36 and 64• Change from baseline in GST at Weeks 36 and 64• To assess the efficacy of aflibercept 8 mg • Change from baseline in NEI-VFQ-25 total Q8W compared to aflibercept 2 mg score at Weeks 36 and 64aflibercept Q4W on vision-related QoLSecondary - Safety• To evaluate the safety of aflibercept 8 mg • Occurrence of TEAEs and SAEs through Q8W compared to aflibercept 2 mg Weeks 36 and 64aflibercept Q4WSecondary - Other• To evaluate duration of effect of aflibercept • Participant dosed only Q8W through Week 36 8 mg Q8W compared to aflibercept 2 mg in the 8 mg Q8W groupaflibercept Q4W • Participant having last treatment interval >12 or of 16 weeks at Week 64• Participant having next intended interval >12, >16 or of 20 weeks at Week 64• To evaluate the PK of aflibercept 8 mg Q8W • Systemic exposure to aflibercept as assessed compared to aflibercept 2 mg aflibercept by plasma concentrations of free, adjusted Q4W bound and total aflibercept from baselinethrough Weeks 36 and 64Objectives EndpointsExploratory• To determine the effect of aflibercept 8 mg • Participant with vision changes of at least 5, Q8W compared to aflibercept 2 mg Q4W on 10, or 15 letters in BCVA from baseline at further visual and anatomic measures of each visitresponse • Participant with no IRF and no SRF in the center subfield at each visit• Time to fluid-free retina over 36 and 64 weeks (total fluid, IRF, and / or SRF in the center subfield)• Participant having sustained fluid-free retina over 36 and 64 weeks (total fluid, IRF, and / or SRF in the center subfield)• Change in area of retinal ischemia at Weeks 36 and 64• Change in the area of fluorescein leakage at Weeks 36 and 64• To study molecular drivers of RVO or related • Evaluation of clinical efficacy parameters by diseases, clinical efficacy of aflibercept, and repertoire or frequency of genetic alterations affected molecular pathways (genomics substudy)• Treatment related changes in circulatingbiomarkers (FBR)AE=adverse event, BCVA=best-corrected visual acuity, CST=central subfield thickness, ETDRS=Early Treatment Diabetic Retinopathy Study, FBR=future biomedical research, IRF=intraretinal fluid, NEI-VFQ-25=National Eye Institute Visual Functioning Questionnaire-25, PK=pharmacokinetics, QoL=quality of life, Q4W=every 4 weeks, Q8W=every 8 weeks, RVO=retinal vein occlusion, SAE=serious adverse event, SRF=sub-retinal fluid, TEAE=treatment-emergent adverse event1Where premature treatment discontinue due to treatment related AE is considered as treatment-failure and the number of active injections from baseline to Week 64 is set to an unfavorable outcome (equal to 16, the maximum value).

[0332] The primary estimand for the primary objective is described by the following attributes:• Population: Adult participants with treatment-naive macular edema secondary to RVO• Endpoint: Change from baseline in BCVA measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score at Week 36• Treatment condition:o Aflibercept 8 mg administered with 3 initial Q4W initiation doses followed by extension of treatment interval to 8-weeks until Week 36 unless the treatment response indicates to continue with Q4Wo Aflibercept 8 mg administered with 5 initial Q4W initiation doses followed by extension of treatment interval to 8-weeks until Week 36 unless the treatment response indicates to continue with Q4Wo Aflibercept 2 mg administered Q4W

[0333] A delayed active injection resulting in an injection interval up to 4 weeks longer than planned is considered to be in line with the treatment regimen of interest.• Intercurrent events and strategies:o Premature treatment discontinuation - addressed by the hypothetical strategy (had participants continued treatment until Week 36)o Use of prohibited medication - addressed by the hypothetical strategy (had prohibited medications not been taken)o Missed study intervention:Missed active injection resulting in an injection interval up to 4 weeks longer than planned: treatment policy strategy (the effect of a missed active injection will be included in the estimate of the treatment effect)> Missed active injection resulting in an injection interval more than 4 weeks longer than planned: hypothetical strategy (had injection not been missed or delayed by less than 4 weeks)• Population-level summary: Difference in mean change from baseline to Week 36 in BCVA between each Aflibercept 8 mg group and the Aflibercept 2 mg group

[0334] The secondary estimand for the secondary objective is described by the following attributes:• Population: Adult participants with treatment-naive macular edema secondary to RVO • Endpoint: Number of active injections from baseline to Week 64 where premature treatment discontinuations due to treatment related adverse event (AE) is considered as treatmentfailure and the number of injections is set to an unfavorable outcome (equal to 16, the maximum value)• Treatment condition:o Aflibercept 8 mg administered with 3 initial Q4W initiation doses followed by extension of treatment interval to 8-weeks and further adjustment of intervals according to treatment responseo Aflibercept 8 mg administered with 5 initial Q4W initiation doses followed by extension of treatment interval to 8-weeks and further adjustment of intervals according to treatment responseo Aflibercept 2 mg administered Q4W until Week 32, followed by adjustment of treatment intervals according to treatment response

[0335] The minimum treatment interval is 4 weeks while the study duration allows the maximum treatment interval to be 16 weeks. Imperfect adherence other than premature treatment discontinuation is considered as part of the treatment.• Intercurrent events and strategies:o Premature treatment discontinuationDue to lack-of-efficacy: Hypothetical strategy (had participants continued treatment until Week 64)Due to treatment related AEs: Composite strategy (addressed in the endpoint definition)> Due to treatment unrelated AEs and other reasons: Hypothetical strategy (had participants continued treatment until Week 64)o Missed study intervention - addressed by treatment policy strategy (the effect of a missed active injection will be included in the estimate of the treatment effect)• Population-level summary: Difference in mean number of active injections up to Week 64 between each Aflibercept 8 mg group and the Aflibercept 2 mg group

[0336] Dosage Regimen Modification - study visits will be scheduled Q4W throughout the study duration. At every visit until Week 60, the participants will receive an active or sham injection for masking purposes. During the first 32 weeks, the 2 mg group will receive an active injection at every visit while the 8 mg groups will initiate treatment with injections Q4W for a total of 3 doses or will initiate treatment with injections Q4W for a total of 5 doses, followed by extension of the treatment interval of 8 weeks. Beginning at Week 36 through Week 60, T& E will be employed for 8 mg groups. Extension or shortening of the dosing interval will depend on meeting DRM criteria. The DRM criteria may also indicate active injections at Weeks 20 and 28 for participants in the 8 mg groups in the need of a treatment, as shown in Table 1 B.

[0337] DRM Shortening Criteria for 8 mg Groups Before Week 32: Beginning at Weeks 16 (for aflibercept 8 mg / 3 group) and 20 (for aflibercept 8 mg / 5 group), participants in the 8 mg groups will be eligible to have their dosing interval shortened by 4 weeks if both the following DRM shortening criteria are met at a dosing visit:1. Best-corrected visual acuity loss >5 letters from reference visit*, AND2. >50 pm increase in central subfield thickness (CST) from reference visit**Reference visit is Week 12 for the 8 mg Q8W after 3 initial Q4W doses group and Week 16 for the 8 mg Q8W after 5 initial Q4W doses group.

[0338] For example, in case the DRM shortening criteria are met at Weeks 16 and 24, participants will have their following dosing intervals shortened to 4 weeks, thus, will receiveadditional active doses at Weeks 20 and 28. In case the DRM shortening criteria are met at Week 24, participants will receive an additional active dose at Week 28. The minimum interval between dosing visits is 4 weeks. The actual interval between injections may be shorter than 28 days due to the allowed visit windows. Once a participant has their treatment interval shortened to Q4W, they will continue to be treated Q4W through Week 32.

[0339] DRM Extension Criteria Starting at Weeks 32 and 40: Starting at Week 32, all participants in all three treatment groups will be eligible for interval extension (by 4-week increments) if both the following DRM extension criteria are met at a dosing visit:1. Best-corrected visual acuity loss <5 letters from reference visit*, AND2. CST thickness <325 pm Heidelberg Spectralis <315 pm Cirrus or Topcon spectral domain optical coherence tomography (SD-OCT)*Reference visit is Week 12 for the 8 mg Q8W after 3 initial Q4W doses group and Week 16 for the 8 mg Q8W after 5 initial Q4W doses group.

[0340] When these criteria are met at a dosing visit, the participant receives the planned dose at that visit and has the next treatment interval extended by 4 weeks (e.g., if the last interval was 4 weeks, the next will be 8 weeks). If at a later dosing visit, the DRM extension criteria are met again, the participant receives the planned dose at that visit and the next interval will be extended by another 4 weeks (e.g., if the last interval was 8 weeks, the next will be 12 weeks). DRM Shortening Criteria Starting at Weeks 32 and 40: Additionally, starting at Week 32, participants in all three groups will have the dosing interval shortened by 4 weeks if both the following DRM shortening criteria are met at a dosing visit:1. Best-corrected visual acuity loss >5 letters from reference visit*, AND2. >50 pm increase in CST from reference visit**Reference visit is Week 12 for 8 mg Q8W after 3 initial Q4W doses group and Week 16 for 8 mg Q8W after 5 initial Q4W doses group.

[0341] For the assessment of DRM shortening and extension criteria, in case measurement is not available at the reference visit, the most recent measurement from previous visit should be used instead. For example, if Week 16 measurement is not available, the Week 12 measurement should be used instead. If both Weeks 12 and 16 measurements are not available, the Week 8 measurement should be used instead. If all Weeks 8, 12, and 16 measurements are not available, the Week 4 measurement should be used instead. In case there are no measurements at Weeks 4, 8, 12, and 16, the participant will be considered non-compliant and discontinued from the study.

[0342] For participants who do not meet the criteria for shortening or extension of the interval, the current dosing interval will be maintained.

[0343] The study design is illustrated in Figure 2.Table 1 B. Study Assessment and ProceduresStudy Phase Screening Baseline TreatmentVisit 1 2 3 4 5 6 7 8 9 10 Week -3 0 4 8 12 16 20 24 28 32 Day -21 to -1 1 29 57 85 113 141 169 197 225 Window±5 ±5 ±5 ±5 ±5 ±5 ±5 ±5 (day)aAdministrative:ICF XGenomicXSubstudy ICFbFBR ICFcXInclusion / ExcluX Xdsion EligibilityMedical History XDemographics XPrior and / orConcomitantX X X X X X X X X XMedications / TreatmentRandomization XStudy Intervention®:StudyInterventionX X X X X X X X X(Active orSham)DRM X X X X XAssessment*Ocular Efficacy and Safety (bilateral unless indicated):NEI-VFQ-259 XBCVA(ETDRS) and X X X X X X X X X X RefractionIOPhX X X X X X X X X X Slit Lamp X X X X X X X X X XStudy Phase Screening Baseline TreatmentVisit 1 2 3 4 5 6 7 8 9 10 Week -3 0 4 8 12 16 20 24 28 32 Day -21 to -1 1 29 57 85 113 141 169 197 225 Window±5 ±5 ±5 ±5 ±5 ±5 ±5 ±5 (day)aExamination'IndirectOphthalmosco X X X X X X X X X X pyiFA, FPkX XSD-OCTkX X X X X X X X X X OCT-A1X X X Nonocular Safety:PhysicalXExaminationVital SignsmX X X X X X X X X X ECG X AEs X X X X X X X X X X Laboratory Testingn:Hematology XBloodXChemistryPregnancyX X X X X X X X X XTestSerum Urine Urine Urine Urine Urine Urine Urine Urine Urine (WOCBP)0Urinalysis,X UPGRPharmacokinetics and Other Sampling:PK SampleX X X XP(Sparse)pGenomic DNASample X(optional)13Table 1-B, ContinuedStudy Phase Treatment EoS or ED Visit 11 12 13 14 15 16 17 18 Week 36 40 44 48 52 56 60 64 Day 253 281 309 337 365 393 421 449 Window±5 ±5 ±5 ±5 ±5 ±5 ±5 ±5 (day)aAdministrative:IGFGenomicSubstudy ICFbFBR ICFCInclusion / Exclusion EligibilityMedicalHistoryDemographicsPrior and / orConcomitantX X X X X X X XMedications / TreatmentRandomizationStudy Intervention®:StudyInterventionX X X X X X X(Active orSham)DRM X X X X X X XAssessment’Ocular Efficacy and Safety (bilateral unless indicated):NEI-VFQ-259 X X BCVA(ETDRS) and X X X X X X X X RefractionIOPhX X X X X X X X Slit LampX X X X X X X XExamination'IndirectOphthalmosco X X X X X X X X pyiFA, FPkX X SD-OCTkX X X X X X X XStudy Phase Treatment EoS or EDVisit 11 12 13 14 15 16 17 18Week 36 40 44 48 52 56 60 64Day 253 281 309 337 365 393 421 449Window±5 ±5 ±5 ±5 ±5 ±5 ±5 ±5(day)aOCT-A1X XNonocular Safety:PhysicalX XExaminationVital SignsmX X X X X X X XECG X X AEs X X X X X X X XLaboratory Testingn:Hematology X XBloodX XChemistryPregnancyX X X X X X X XTestUrine Urine Urine Urine Urine Urine Urine Urine(WOCBP)0Urinalysis,X X UPGRPharmacokinetics and Other Sampling:PK SampleX X(Sparse)PGenomic DNASample(optional)15AE=adverse event, BCVA=best corrected visual acuity, DNA=deoxyribonucleic acid, DRM=dose regimen modification, ECG=electrocardiogram, ED=early discontinuation, EoS=end of study, ETDRS=Early Treatment Diabetic Retinopathy Study, FA=fluorescein angiography, FBR=future biomedical research, FP=fundus photography, ICF=informed consent form, IOP=intraocular pressure, I VT=intravitreally, NEI-VFQ-25=National Eye Institute Visual Functioning Questionnaire-25, OCT-A=optical coherence tomography angiography, PK=pharmacokinetics, SD-OCT=spectral domain optical coherence tomography, UPCR=urine protein:creatinine ratio, WOCBP=women of childbearing potential Footnotes for the Schedule of Activities (SoA) Tablesa. Visit schedules may deviate by up to ±5 days. Set schedule visits use baseline for the calculation.The procedures required at each visit have to be complete within 3 days, i.e., split visits are allowed. Additionally, all procedures have to be complete within the 5-day window. Slit lamp (anteriorsegment), IOP measurement, and indirect ophthalmoscopy are recommended to take place on the same day as the IVT injection.b. The optional genomic substudy ICF should be presented to participants at the screening visit and may be signed at any subsequent visit at which the participant chooses to participate after screening. The genomic DNA blood sample should be collected on Day 1 / baseline (pre-injection) or at any time during the study, only from participants who consent to participate in the genomic subs...

Claims

We claim:

1. A method(i) for treating or preventing an angiogenic eye disorder, neovascular age related macular degeneration or diabetic macular edema;(ii) for treating or preventing an angiogenic eye disorder secondary to retinal vein occlusion in a subject in need thereof,(iii) for improving best corrected visual acuity with an angiogenic eye disorder secondary to retinal vein occlusion in a subject in need thereof,(iv) for treating or preventing retinal vein occlusion in a subject in need thereof, and / or(v) for treating or preventing macular edema secondary to retinal vein occlusion; comprising or consisting of administering to an eye of the subject, one or more doses of about 8 mg (±0.8 mg) of a VEGF receptor fusion protein about once every4-8 weeks (±7 days),4 weeks (±7 days),8 weeks (±7 days),4 weeks (±7 days) and then 8 weeks (±7 days),4 weeks (±7 days) and then 8 weeks (±7 days) and then 4 weeks (±7 days),12 weeks (±7 days),16 weeks (±7 days),20 weeks (±7 days),24 weeks (±7 days), and / or32 weeks (±7 days).

2. The method of claim 1,(i) comprising administering to an eye of the subject, one or more doses of about 8 mg (±0.8 mg) of a VEGF receptor fusion protein about once every 4 weeks (±7 days);(ii) comprising administering to an eye of the subject, one or more doses of about 8 mg (±0.8 mg) of a VEGF receptor fusion protein about once every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein on a Treat & Extend or Pro re nata basis or are adjusted based on the physician’s judgement of visual and / or anatomic outcomes;(iii) comprising administering to an eye of the subject, 7 doses of about 8 mg (±0.8 mg) of a VEGF receptor fusion protein about once every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein on a Treat & Extend or Pro re nata basis or are adjusted based on the physician’s judgement of visual and / or anatomic outcomes;(iv) consisting of administering to an eye of the subject, one or more doses of about 8 mg (±0.8 mg) of a VEGF receptor fusion protein about once every 4 weeks (±7 days);or(v) consisting of administering to an eye of the subject, one or more doses of about 8 mg (±0.8 mg) of a VEGF receptor fusion protein about once every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein on a Treat & Extend or Pro re nata basis or are adjusted based on the physician’s judgement of visual and / or anatomic outcomes;and / or(vi) consisting of administering to an eye of the subject, 7 doses of about 8 mg (±0.8 mg) of a VEGF receptor fusion protein about once every 4 weeks (±7 days), followed by one or more doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein on a Treat & Extend or Pro re nata basis or are adjusted based on the physician’s judgement of visual and / or anatomic outcomes;optionally, with respect to any of (i)-(vi), wherein, no doses are administered at an interval of greater than about 4 weeks.

3. The method of any one of the preceding claims, comprising administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein;wherein each secondary dose is administered about 2, 3, 4 or 2 to 4 weeks (±7 days) after the immediately preceding dose; andwherein each tertiary dose is administered about4-8 weeks (±7 days),4 weeks (±7 days),8 weeks (±7 days),12 weeks (±7 days),16 weeks (±7 days),20 weeks (±7 days),24 weeks (±7 days), and / or32 weeks (±7 days),after the immediately preceding dose;and / or on a Treat & Extend or Pro re nata basis or are adjusted based on the physician’s judgement of visual and / or anatomic outcomes.

4. The method of any one of the preceding claims, comprising administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by 2, 3, 4, 5, or 6 or 2-6 secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein;wherein each secondary dose is administered about 2, 3, 4, or 2-4 weeks (±7 days) after the immediately preceding dose; andwherein each tertiary dose is administered about 8 weeks (±7 days) after the immediately preceding dose;optionally, wherein no doses are administered greater than about 8 weeks (±7 days) after the immediately preceding dose; and / oroptionally, wherein the tertiary doses are followed by one or more doses administered:• about every 4 weeks (±7 days),• on a Treat & Extend basis;• on a Pro re nata basis; or• which are adjusted based on the physician’s judgement of visual and / or anatomic outcomes.

5. The method of claim 4, wherein the tertiary doses are followed by one or more doses administered:• about every 4 weeks (±7 days),• on a Treat & Extend basis;• on a Pro re nata basis; or• which are adjusted based on the physician’s judgement of visual and / or anatomicoutcomes.

6. The method of any one of the preceding claims, comprising administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by 2 or 3 or 4 or 2-4 secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein;wherein each secondary dose is administered about 2, 3, 4, or 2-4 weeks (±7 days) after the immediately preceding dose; andwherein each tertiary dose is administered about 8 weeks (±7 days) after the immediately preceding dose;optionally, wherein no doses are administered greater than about 8 weeks (±7 days) after the immediately preceding dose; and / oroptionally, wherein the tertiary doses are followed by one or more doses administered about every 4 weeks (±7 days); and / oroptionally, wherein tertiary doses are followed by one or more doses administered on a Treat & Extend or on a Pro re nata basis or are adjusted based on the physician’s judgement of visual and / or anatomic outcomes.

7. The method of any one of the preceding claims, comprising administering to the eye of the subject, 3-5 doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein in a formulation that comprises about 114.3 mg / ml VEGF receptor fusion protein at an interval of once every 4 weeks (±7 days); wherein after said 3 doses, administering one or more doses of the VEGF receptor fusion protein at an interval which is lengthened up to 8 or more weeks (±7 days); optionally, further comprising administering to the eye one or more doses about every 4 weeks (±7 days).

8. The method of any one of the preceding claims, comprising administering to the eye of the subject, 3 doses or 4 doses or 5 doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein in a formulation that comprises about 114.3 mg / ml VEGF receptor fusion protein at an interval of once every 4 weeks (±7 days); wherein after said 5 doses, administering one or more doses of the VEGF receptor fusion protein at an interval which is lengthened up to 8 or more weeks (±7 days); optionally, further comprising administering to the eye one or more doses about every 4 weeks (±7 days).

9. The method of any one of claims 1 or 3, comprising administering, to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein;wherein each secondary dose is administered about 2, 3, 4, or 2-4 weeks (±7 days) after the immediately preceding dose; andwherein each tertiary dose is administered about 12 weeks (±7 days) after the immediately preceding dose;optionally, wherein no doses are administered greater than about 12 weeks (±7 days) after the immediately preceding dose; and / oroptionally, wherein tertiary doses are followed by one or more doses administered on a Treat & Extend or Pro re nata basis or are adjusted based on the physician’s judgement of visual and / or anatomic outcomes.

10. The method of any one of claims 1, 3 or 9, comprising administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by 5 secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein;wherein each secondary dose is administered about 2, 3, 4, or 2-4 weeks (±7 days) after the immediately preceding dose; andwherein each tertiary dose is administered about 12 weeks (±7 days) after the immediately preceding dose;optionally, wherein no doses are administered greater than about 12 weeks (±7 days) after the immediately preceding dose; and / oroptionally, wherein tertiary doses are followed by one or more doses administered on a Treat & Extend or Pro re nata basis or are adjusted based on the physician’s judgement of visual and / or anatomic outcomes.

11. The method of any one of the preceding claims comprising administering to the eye of the subject, a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by 5 secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein;wherein each secondary dose is administered about 2, 3, 4, or 2-4 weeks (±7 days) after the immediately preceding dose; andwherein:(a) each tertiary dose is administered about 12 weeks (±7 days) after the immediately preceding dose;(b) each tertiary dose is administered about 8 weeks (±7 days) after the immediately preceding dose;(c) one tertiary dose is administered about 12 weeks (±7 days) after the immediately preceding dose and then each subsequent tertiary dose is administered about 8 weeks (±7 days) after the immediately preceding tertiary dose; or(d) one tertiary dose is administered about 8 weeks (±7 days) after the immediately preceding dose, and then each subsequent tertiary dose is administered about 12 weeks (±7 days) after the immediately preceding tertiary dose; and / or(e) one tertiary dose is administered about 12 weeks (±7 days) after the immediately preceding dose, then each subsequent tertiary dose administered about 8 weeks (±7 days) after the immediately preceding tertiary dose; and then each subsequent tertiary dose is administered about 4 weeks (±7 days) after the immediately preceding tertiary dose.

12. The method of claim 11 wherein one tertiary dose is administered about 12 weeks (±7 days) after the immediately preceding dose by week 36 from treatment initiation.

13. The method of claim 1, comprising administering to the eye of the subject,a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by 2, 3 or 4 or 2-4 secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein; followed byone or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2, 3, 4, or 2-4 weeks (±7 days) after the immediately preceding dose; andwherein:(a) each tertiary dose is administered about 8 weeks (±7 days) after the immediately preceding dose;(b) one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then subsequent tertiary doses are administered about 4 weeks (±7 days) after the immediately preceding dose;(c) 2-4 secondary doses are administered every 4 weeks and each tertiary dose is administered about 8 weeks (±7 days) after the immediately preceding dose;(d) 2 secondary doses are administered every 4 weeks and each tertiary dose is administered about 8 weeks (±7 days) after the immediately preceding dose;(e) 3 secondary doses are administered every 4 weeks and each tertiary dose is administered about 8 weeks (±7 days) after the immediately preceding dose;(f) 4 secondary doses are administered every 4 weeks and each tertiary dose is administered about 8 weeks (±7 days) after the immediately preceding dose;(g) one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then subsequent tertiary doses are administered about 4 weeks (±7 days) after the immediately preceding dose;(h) 2-4 secondary doses are administered about every 4 weeks (±7 days) and one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then subsequent tertiary doses are administered about 4 weeks (±7 days) after the immediately preceding dose;(i) 2 secondary doses are administered about every 4 weeks (±7 days) and one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then subsequent tertiary doses are administered about 4 weeks (±7 days) after the immediately preceding dose;(j) 3 secondary doses are administered about every 4 weeks (±7 days) and one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then subsequent tertiary doses are administered about 4 weeks (±7 days) after the immediately preceding dose;(k) 4 secondary doses are administered about every 4 weeks (±7 days) and one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then subsequent tertiary doses are administered about 4 weeks (±7 days) after the immediately preceding dose;(l) one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then the interval between subsequent tertiary doses are shortened to about 4 weeks (±7 days) after the immediately preceding dose;(m) 2-4 secondary doses are administered about every 4 weeks (±7 days) and one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then the interval between subsequent tertiary doses are shortened to about 4 weeks (±7 days) after the immediately preceding dose;(n) 2 secondary doses are administered about every 4 weeks (±7 days) and one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then the interval between subsequent tertiary doses are shortened to about 4 weeks (±7 days) after the immediately preceding dose;(o) 3 secondary doses are administered about every 4 weeks (±7 days) and one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then the interval between subsequent tertiary doses are shortened to about 4 weeks (±7 days) after the immediately preceding dose;(p) 4 secondary doses are administered about every 4 weeks (±7 days) and one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then the interval between subsequent tertiary doses are shortened to about 4 weeks (±7 days) after the immediately preceding dose;(q) one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose, and then one or more subsequent tertiary doses are administered on a Treat & Extend or pro re nata basis, or are adjusted based on the physician’s judgement of visual and / or anatomic outcomes;(r) 2 or 3 tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose and then one or more subsequent tertiary doses are administered on a Treat & Extend or pro re nata basis, or are adjusted based on the physician’s judgement of visual and / or anatomic outcomes;(s) 4 of said secondary doses are administered, then 2 tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose and then one or more tertiary doses are administered on a Treat & Extend or pro re nata basis, or are adjusted based on the physician’s judgement of visual and / or anatomic outcomes;(t) 2 of said secondary doses are administered, then 3 tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose and then one or more tertiary doses are administered on a Treat & Extend or pro re nata basis, or are adjusted based on the physician’s judgement of visual and / or anatomic outcomes; and / or(u) one or more tertiary doses are administered about 8 weeks (±7 days) after the immediately preceding dose and then each subsequent tertiary dose is administered about 4 weeks (±7days) after the immediately preceding dose; and then one or more tertiary doses are administered on a Treat & Extend or pro re nata basis, or are adjusted based on the physician’s judgement of visual and / or anatomic outcomes.

14. A method for treating or preventing an angiogenic eye disorder in a subject in need thereof comprising administering to an eye of the subject one or more doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein about once every 4 weeks (±7 days).

15. The method of any one of the preceding claims wherein the angiogenic eye disorder is neovascular age-related macular degeneration (wet), macular edema, macular edema following retinal vein occlusion, retinal vein occlusion (RVO), hemiretinal vein occlusion, central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), diabetic macular edema (DME), choroidal neovascularization (CNV), iris neovascularization, neovascular glaucoma, post-surgical fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), optic disc neovascularization, corneal neovascularization, retinal neovascularization, vitreal neovascularization, pannus, pterygium, vascular retinopathy, diabetic retinopathy, non-proliferative diabetic retinopathy and / or proliferative diabetic retinopathy.

16. The method of any one of the preceding claims, wherein one or more secondary doses is 2 doses, 3 doses or 4 doses or 5 doses or 6 doses or 7 doses.

17. The method of any one of the preceding claims, wherein secondary doses are administered with about 4 weeks (±7 days) after the immediately preceding dose.

18. The method of any one of the preceding claims, wherein, after one or more tertiary doses are administered, the tertiary dosing interval is• shortened from about 12 weeks to about 8 weeks or about 4 weeks or about 4-8 weeks;or wherein the tertiary dosing interval is shortened from about 8 weeks to about 4 weeks; or• lengthened from about 4 weeks to about 8, 12, 16, 20, 24, 28, or 32 weeks or from about 8 weeks to about 12, 16, 20, 24, 28, or 32 weeks.

19. The method of any one of the preceding claims, wherein, after one or more tertiary doses are administered, the tertiary dosing interval is shortened if the subject exhibits any one or more of:• >5 letters loss of BCVA from best previous BCVA;• >5 letters loss of BCVA from best previous BCVA with persistent or worsening macular edema; and / or• >50 pm increase in CST relative to CST measured at any previous time.

20. The method of any one of the preceding claims, wherein said tertiary dosing interval is lengthened if the subject exhibits any one or more of:• Best-corrected visual acuity loss <5 letters relative to BCVA measured at any previous time; and / or• CST thickness of <300 pm, <320 pm, <325 pm or <315 pm.

21. The method of claim 20 wherein CST thickness is as measured by Heidelberg Spectralis or Cirrus or Topcon SD-OCT.

22. The method of any one of the preceding claims, comprising administering to the eye of the subject,a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed byone or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein; wherein each secondary dose is administered about 2, 3, 4 or 2-4 weeks (±7 days) after the immediately preceding dose; andwherein each tertiary dose is administered about 12 weeks (±7 days) after the immediately preceding dose;wherein said tertiary dosing interval is shortened if the subject exhibits any one or more of:• >5 letters loss of BCVA from best previous BCVA; and / or• >5 letters loss of BCVA from best previous BCVA with persistent or worsening macular edema.

23. The method of any one of the preceding claims, comprising administering to the eye of the subject,a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by one or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein;wherein each secondary dose is administered about 4 weeks (±7 days) after the immediately preceding dose; andwherein each tertiary dose is administered about 8 weeks (±7 days) after the immediately preceding dose;wherein said tertiary dosing interval is shortened if the subject exhibits any one or more of:• >5 letters loss of BOVA from best previous BOVA;• >5 letters loss of BCVA from best previous BCVA with persistent or worsening macular edema; and / or• >50 pm increase in GST relative to GST measured at any previous time.

24. The method of any one of the preceding claims, comprising administering to the eye of the subject,a single initial dose of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed by 2, 3 or 4 or 2-4 secondary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein, followed byone or more tertiary doses of about 8 mg (±0.8 mg) of the VEGF receptor fusion protein; wherein each secondary dose is administered about 4 weeks (±7 days) after the immediately preceding dose; andwherein each tertiary dose is administered about 8 weeks (±7 days) after the immediately preceding dose;wherein said tertiary dosing interval is lengthened if the subject exhibits any one or more of:• Best-corrected visual acuity loss <5 letters relative to BCVA measured at any previous time; and / or• GST thickness of <325 pm or <315 pm.

25. The method of any one of the preceding claims, wherein the subject suffers from macular edema secondary to retinal vein occlusion.

26. The method of any one of the preceding claims, wherein the retinal vein occlusion is central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), and / or hemiretinal vein occlusion (HRVO).

27. The method of any one of the preceding claims, wherein lengthening or shortening the interval between tertiary doses is lengthened or shortened about one or more or 2, 3, 4, 5, 6 or 7 times by about one or more 4-week increments.

28. The method of any one or the preceding claims, wherein the interval between tertiary doses was lengthened or shortened one or more or 2, 3, 4 or 5 times prior.

29. The method of any one or the preceding claims, wherein the interval between tertiary doses was lengthened one or more or 2, 3, 4, 5 or 6 times prior from:about 8 weeks to about 12, 16, 20, 24, 28, 32 or 36 weeks;about 12 weeks to about 16, 20, 24, 28, 32 or 36 weeks; and / orabout 16 weeks to about 20, 24, 28, 32 or 36 weeks.

30. The method of any one of the preceding claims, wherein about 8 weeks (±7 days) is 8 weeks.

31. The method of any one of the preceding claims, wherein about 12 weeks (±7 days) is 12 weeks.

32. The method of any one of the preceding claims, wherein the <325 pm or <315 pm is measured by spectral domain optical coherence tomography (SD-OCT).

33. The method of any one of the preceding claims, wherein the subject exhibits one or more of:• Having had at least 3 injections of a VEGF antagonist or VEGF receptor fusion protein within the past 5 months;• Having had at least 3 injections of about 2 mg VEGF receptor fusion protein within the past 5 months;• Having had at least 3 injections of about 8 mg VEGF receptor fusion protein within the past 5 months;• Treatment-naive macular edema;• Treatment-naive macular edema involving the foveal center secondary to RVO;• Treatment-naive macular edema involving the foveal center secondary to BRVO, HRVO and / or CRVO;• A Mean CST >300 pm on OCT or >320 pm on Heidelberg Spectralis;• Macular edema following RVO involving the foveal center;• Macular edema following BRVO, CRVO and / or HRVO involving the foveal center;• A BCVA or about 46, 55, 57, 66 or 46-66 letters;• A CST of about 459, 583, 631, 759 or 459-759, >581 or <581 micrometers;• Perifoveal and / or parafoveal ischemia;• Macular ischemia;• Macular ischemia with an area of about 0, 3, 4, 28 or 0-28 mm2;• Retinal areas of non-perfusion outside the macula;• A history of CNV lesions secondary to nAMD; and / or• A history of DME with central involvement.

34. The method of any one of the preceding claims, wherein the subject does not exhibit one or more of:• Evidence of macular edema due to any cause other than RVO;• Diabetic retinopathy;• Diabetic macular edema;• Advanced age-related macular degeneration (nAMD or geographic atrophy);• Use of any intravitreal implantable agent in an eye;• Prior treatment with ocriplasmin at any time in an eye;• Prior treatment with pegcetacoplan injection or avacincaptad pegol injection at any time in an eye;• Prior treatment with retinal laser photocoagulation at any time in an eye;• Prior treatment with gene therapy and / or cell therapy at any time in an eye;• History of vitreoretinal surgery at any time in an eye;• Any intraocular surgery, including cataract surgery, within 12 weeks of treatment in an eye;• YAG (Yttrium-aluminum-garnet) capsulotomy in an eye within 4 weeks of treatment; • IOP > 25 mm Hg in an eye;• Uncontrolled glaucoma in an eye;• Infectious blepharitis, keratitis, scleritis, or conjunctivitis in an eye;• Any intraocular inflammation / infection within 12 weeks of treatment in an eye;• History of idiopathic or autoimmune uveitis in an eye;• Vitreomacular traction or epiretinal membrane in an eye evident on biomicroscopy or OCT that affects central vision;• Myopia of a spherical equivalent of 8 diopters or greater in an eye;• History of corneal transplant in an eye;• Any corneal dystrophy affecting the visual axis in an eye;• Aphakia, or pseudophakia with absence of posterior capsule, unless it occurred as a result of a YAG posterior capsulotomy performed more than 28 days before treatment in an eye;• Any history of macular hole of stage 2 and above in an eye;• Current anterior segment neovascularization, vitreous hemorrhage, or tractional retinal detachment visible in an eye;• Structural damage in an eye that is likely to preclude improvement in BCVA following resolution of macular edema;• Uncontrolled blood pressure;• Uncontrolled diabetes mellitus (DM), defined by hemoglobin A1c (HbA1c) >12% at treatment;• History of cerebrovascular accident / transient ischemic attack or myocardial infarction / acute coronary syndrome within 6 months (180 days) of treatment;• Renal failure, dialysis, or history of renal transplant;• Known sensitivity to the VEGF receptor fusion protein, histidine, arginine, polysorbate or sucrose;• Presence of systemic infection or treatment for suspected or active systemic infection;• Subject is pregnant or is a breastfeeding woman;• Subject is a man or woman of child bearing potential who is not practicing a highly effective contraception prior to treatment or at least 4 months after cessation of treatment; wherein said highly effective contraception comprises stable use of combined estrogen and progestogen containing hormonal contraception by oral, intravaginal or transdermal route or progestogen-only hormonal, contraception, by oral, injectable, implantable route associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to treatment; intrauterine device; or intrauterine hormone-releasing system;bilateral tubal occlusion / ligation; vasectomy; condom plus contraceptive sponge, foam, or jelly, or diaphragm plus contraceptive sponge, foam, or jelly; and / or sexual abstinence.• Subretinal hemorrhage in the study eye >~50% of the total lesion area• DME or DR, defined in the diabetic participants with nAMD as DR lesions in the assessable area of the retina• Evidence of macular edema due to any other cause other than diabetes mellitus in the eye• Advanced age-related macular degeneration (nAMD or geographic atrophy) in the eye • Active proliferative DR in the eye; and / or• Panretinal photocoagulation (PRP) or macular laser photocoagulation in the eye within 12 weeks (84 days);optionally, wherein treatment is paused and / or terminated if the subject develops any one or more thereof after treatment initiation.

35. The method of claim 34 wherein an eye is the eye to which said VEGF receptor fusion protein is administered and / or the fellow eye.

36. The method of any one of the preceding claims, wherein the VEGF receptor fusion protein is in an aqueous pharmaceutical formulation comprising a histidine-based buffer, phosphate-based buffer, citrate-based buffer, phosphate / citrate-based buffer and / or acetate-based buffer.

37. The method of any one of the preceding claims, wherein the VEGF receptor fusion protein is in an aqueous pharmaceutical formulation comprising arginine.

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

39. The method of any one of the preceding claims, wherein a subject having any one or more of:ocular or periocular infection;active intraocular inflammation; and / orhypersensitivity;is excluded from administration of the VEGF receptor fusion protein to the eye.

40. The method of claim 39, further comprising a step of evaluating the subject for:ocular or periocular infection;active intraocular inflammation; and / orhypersensitivity;and excluding the subject from said administration if any one or more is found in the subject.

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

42. The method of any one of the preceding claims, comprising, prior to each administration, providing:• one single-dose glass vial having a protective plastic cap and a stopper containing an aqueous formulation comprising 8 mg (±0.8 mg) VEGF receptor fusion protein in about 70 microliters;• one 18-gauge x 11 / 2-inch, 5-micron, filter needle that includes a tip and a bevel;• one 30-gauge x1 / 2-inch injection needle; and• one 1-mL Luer lock syringe having a graduation line marking for 70 microliters of volume;packaged together; then(1) visually inspecting the aqueous formulation in the vial and, if particulates, cloudiness, or discoloration are visible, then using another vial of aqueous formulation containing the VEGF receptor fusion protein;(2) removing the protective plastic cap from the vial; and(3) cleaning the top of the vial with an alcohol wipe; thenusing aseptic technique:(4) removing the 18-gauge x 11 / 2-inch, 5-micron, filter needle and the 1 mL syringe from their packaging;(5) attaching the filter needle to the syringe by twisting it onto the Luer lock syringe tip;(6) pushing the filter needle into the center of the vial stopper until the needle is completely inserted into the vial and the tip touches the bottom or a bottom edge of the vial;(7) withdrawing all of the VEGF receptor fusion protein vial contents into the syringe, keeping the vial in an upright position, slightly inclined, while ensuring the bevel of the filter needle is submerged into the liquid;(8) continuing to tilt the vial during withdrawal keeping the bevel of the filter needle submerged in the formulation;(9) drawing the plunger rod sufficiently back when emptying the vial in order to completely empty the filter needle;(10) removing the filter needle from the syringe and disposing of the filter needle; (11) removing the 30-gauge x1 / 2-inch injection needle from its packaging and attaching the injection needle to the syringe by firmly twisting the injection needle onto the Luer lock syringe tip;(12) holding the syringe with the needle pointing up, and checking the syringe for bubbles, wherein if there are bubbles, gently tapping the syringe with a finger until the bubbles rise to the top; and(13) slowly depressing the plunger so that the plunger tip aligns with the graduation line that marks 70 microliters on the syringe.

43. The method of any one of the preceding claims, wherein administration of the VEGF receptor fusion protein is performed by intravitreal injection under controlled aseptic conditions, which comprise surgical hand disinfection and the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent) and anesthesia and a topical broad-spectrum microbicide are administered prior to the injection.11876WO0144. The method of any one of the preceding claims, wherein the VEGF receptor fusion protein comprises amino acids 27-457 of the amino acid sequence set forth in SEQ ID NO: 2.

45. The method of any one of the preceding claims, wherein the VEGF receptor fusion protein is selected from the group consisting of: aflibercept and conbercept.

46. The method of any one of the preceding claims, wherein the VEGF receptor fusion protein:(i) comprises two polypeptides that comprise (1) a VEGFR1 component comprising amino acids 27 to 129 of SEQ ID NO: 2; (2) a VEGFR2 component comprising amino acids 130-231 of SEQ ID NO: 2; and (3) a multimerization component comprising amino acids 232-457 of SEQ ID NO: 2;(ii) comprises two polypeptides that comprise an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of a VEGFR2, and a multimerizing component;(iii) comprises two polypeptides that comprise an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of VEGFR2, an Ig domain 4 of VEGFR2 and a multimerizing component; or(iv) comprises two VEGFR1 R2-FcAC1 (a) polypeptides encoded by the nucleic acid sequence of SEQ ID NO: 1.

47. The method of any one of the preceding claims, wherein the VEGF receptor fusion protein comprises two polypeptides that comprise an immunoglobin-like (Ig) domain 2 of VEGFR1, an Ig domain 3 of a VEGFR2, and a multimerizing component.

48. The method of any one of the preceding claims, wherein the VEGF receptor fusion protein is in an aqueous pharmaceutical formulation selected from the group consisting of formulations A to KKKK.

49. The method of any one of the preceding claims, wherein the VEGF receptor fusion protein is in an aqueous pharmaceutical formulation comprising about 114.3 mg / ml VEGF receptor fusion protein.

50. The method of any one of the preceding claims, comprising administering the VEGF receptor fusion protein to both eyes of the subject.

51. The method of any one of the preceding claims, wherein the VEGF receptor fusion protein is administered from a pre-filled syringe.

52. The method of claim 51, wherein the pre-filled syringe is glass or plastic, and / or sterile.

53. The method of any one of the preceding claims, wherein the VEGF receptor fusion protein is intravitreally injected with a 30 gauge x1 / 2-inch sterile injection needle.

54. The method of any one of the preceding claims, wherein the subject has previously received one or more doses of 2 mg VEGF receptor fusion protein.

55. The method of claim 54, wherein the 2 mg VEGF receptor fusion protein is in an aqueous pharmaceutical formulation comprising 40 mg / ml VEGF receptor fusion protein.

56. The method of any one of claims 54-55, wherein the 2 mg of VEGF receptor fusion protein is in an aqueous pharmaceutical formulation comprising: 40 mg / ml VEGF receptor fusion protein, 10 mM sodium phosphate, 40 mM NaCI, 0.03% polysorbate 20 and 5% sucrose, with a pH of 6.2.

57. The method of any one of the preceding claims, wherein one or more further doses of VEGF receptor fusion protein are administered.

58. The method of any one of the preceding claims, wherein 8 mg (±0.8 mg) of VEGF receptor fusion protein is in an aqueous pharmaceutical formulation that comprises a sugar or polyol.

59. The method of any one of the preceding claims, wherein 8 mg (±0.8 mg) of VEGF receptor fusion protein in an aqueous pharmaceutical formulation that comprises sucrose, trehalose or both sugar and trehalose.

60. The method of any one of the preceding claims, wherein 8 mg (±0.8 mg) of VEGF receptor fusion protein is in an aqueous pharmaceutical formulation that has a pH of about 5.8.

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

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

63. The method of any one of the preceding claims, wherein the VEGF receptor fusion protein is aflibercept in an aqueous pharmaceutical formulation, wherein the aflibercept has less than about 3.5% high molecular weight species immediately after manufacture and purification and / or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8°C.

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

65. The method any one of the preceding claims, wherein the VEGF receptor fusion protein is in an aqueous pharmaceutical formulation comprising:• >100 mg / ml VEGF receptor fusion protein, histidine-based buffer and L-arginine;• 140 mg / ml aflibercept; 20 mM histidine-based buffer; 5 % (w / v) sucrose; 0.03 % (w / v) polysorbate 20; 10 mM L-arginine; pH 5.8;• 150 ± 15 mg / ml aflibercept, 10 mM phosphate-based buffer, 8 ± 0.8% (w / v) sucrose, 0.02-0.04% (w / v) polysorbate 20 and 50 mM L-arginine, pH 5.9-6.5;• 103-126 mg / ml aflibercept, 10 ± 1 mM histidine-based buffer, 5 ± 0.5% (w / v) sucrose, 0.02-0.04% (w / v) polysorbate 20, and 50 ± 5 mM L-arginine, pH 5.5-6.1;• 140 mg / ml aflibercept, 10 mM histidine-based buffer, 2.5 % (w / v) sucrose, 2.0 % (w / v) proline, 0.03 % (w / v) polysorbate 20 and 50 mM L-arginine, pH 5.8;• 114.3 mg / ml aflibercept, 10 mM histidine-based buffer, 5% (w / v) sucrose, 0.03% (w / v) polysorbate 20 and 50 mM L-arginine, pH 5.8;• >100 mg / ml aflibercept, histidine-based buffer and L-arginine;• >100 mg / ml aflibercept at about pH 5.8, wherein the formulation forms <3% HMW aggregates after incubation at 5°C for 2 months;• about 114.3 mg / mL aflibercept; 10 mM - 50 mM histidine-based buffer, sugar, non-ionic surfactant, L-Arginine, pH 5.8; or• about 114.3 mg / mL aflibercept; 10 mM His / His-HCl-based buffer, 5% sucrose, 0.03% polysorbate-20, 50 mM L-Arginine, pH 5.8.

66. The method of any one of the preceding claims, wherein the VEGF receptor fusion protein is administered in a volume of about 100 pl or less, about 75 pl or less; about 70 pl or less; or about 50 pl; 51 pl; 52 pl; 53 pl; 54 pl; 55 pl; 56 pl; 57 pl; 58 pl; 59 pl; 60 pl; 61 pl; 62 pl; 63 pl; 64 pl; 65 pl; 66 pl; 67 pl; 68 pl; 69 pl; 70 pl; 71 pl; 72 pl; 73 pl; 74 pl; 75 pl; 76 pl; 77 pl; 78 pl; 79 pl; 80 pl; 81 pl; 82 pl; 83 pl; 84 pl; 85 pl; 86 pl; 87 pl; 88 pl; 89 pl; 90 pl; 91 pl; 92 pl; 93 pl; 94 pl; 95 pl; 96 pl; 97 pl; 98 pl; 99 pl; or 100 pl.

67. The method of claim 66, wherein the VEGF receptor fusion protein is administered in a volume of about 70 ± 4 or 5 microliters.

68. The method of any one of the preceding claims, wherein the interval between doses are adjusted (shortened or lengthened) or maintained based on visual and / or anatomic outcomes.

69. The method of any one of the preceding claims, further including one or more periods of treat and extend (T& E) and / or Pro re nata dosing.

70. The method of any one of the preceding claims, wherein the VEGF receptor fusion protein is aflibercept.

71. The method of any one of the preceding claims wherein the VEGF receptor fusion protein is administered by intravitreal injection.

72. The method of any one of the preceding claims wherein the subject receives about 6 or 7 injections of VEGF receptor fusion protein over the first 36 weeks of treatment.

73. The method of any one of the preceding claims wherein the subject:• achieves an improvement in BCVA by week 36 of about 17 or 16 or as high as 50 letters (or more) wherein the subject has received an 8q8 / 3 dosing regimen;• achieves an improvement in BCVA by week 36 of about 18 or 19 or as high as 52 letters (or more) wherein the subject has received an 8q8 / 5 dosing regimen;• achieves an improvement in BCVA by week 36 of about 17 or 18 or 16 or as high as 50 letters (or more) wherein the subject has received an 8q8 / 3 dosing regimen wherein the subject has BRVO;• achieves an improvement in BCVA by week 36 of about 19 or 18 or as high as 52 letters (or more) wherein the subject has received an 8q8 / 5 dosing regimen wherein the subject has BRVO;• achieves an improvement in BCVA by week 36 of about 16 or 17 or as high as 47 letters (or more) wherein the subject has received an 8q8 / 3 dosing regimen wherein the subject has CRVO or HRVO;• achieves an improvement in BCVA by week 36 of about 17 or 18 or as high as 50 letters (or more) wherein the subject has received an 8q8 / 5 dosing regimen wherein the subject has CRVO or HRVO;• achieves a reduction in CST by week 36 of about 363 or 233 or 318 or as high as 1259 or 233-1259 micrometers (or more) wherein the subject has received an 8q8 / 3 dosing regimen;• achieves a reduction in CST by week 36 of about 355 or 307 or 8 or as high as 1146 or 8-1146 micrometers (or more) wherein the subject has received an 8q8 / 5 dosing regimen;• achieves a reduction in CST by week 36 of about 275 or 236 or as high as 781 micrometers (or more) wherein the subject has received an 8q8 / 3 dosing regimen wherein the subject has BRVO;• achieves a reduction in CST by week 36 of about 284 or 255 or 8 or as high as 927 or 8-927 micrometers (or more) wherein the subject has received an 8q8 / 5 dosing regimen wherein the subject has BRVO;• achieves a reduction in CST by week 36 of about 458 or 439 or 38 or as high as 1259 or 38-1259 micrometers (or more) wherein the subject has received an 8q8 / 3 dosing regimen wherein the subject has CRVO or HRVO; and / or• achieves a reduction in CST by week 36 of about 431 or 376 or 38 or as high as 1146 or 38-1146 micrometers (or more) wherein the subject has received an 8q8 / 5 dosing regimen wherein the subject has CRVO or HRVO.

74. A method for treating or preventing macular edema following retinal vein occlusion (RVO) comprising administering 8 mg (±0.8 mg) aflibercept by intravitreal injection every 4 weeks (± 7 days) for the first three to five doses, followed by 8 mg (±0.8 mg) aflibercept via intravitreal injection once every 8 weeks (± 1 week), optionally, followed by 8 mg (±0.8 mg) aflibercept via intravitreal injection once every 4 weeks (± 1 week).

75. The method of claim 74 wherein three to five weeks is 3 weeks, 4 weeks or 5 weeks.

76. A method for treating or preventing macular edema following retinal vein occlusion (RVO) comprising administering 8 mg (±0.8 mg) of aflibercept in a pharmaceutical formulation comprising 114.3 mg / ml aflibercept in a volume of 0.07 mL by intravitreal injection every 4 weeks or approximately every 28 days (± 7 days) for the first three to five doses, followed by 8 mg (±0.8 mg) of aflibercept in a pharmaceutical formulation comprising 114.3 mg / ml aflibercept in a volume of 0.07 mL via intravitreal injection once every 8 weeks (± 1 week), optionally, followed by 8 mg (±0.8 mg) aflibercept via intravitreal injection once every 4 weeks (± 1 week).

77. The method of any one of the preceding claims for treating Macular Edema Following Retinal Vein Occlusion (RVO) comprising administering 8 mg aflibercept in a 0.07 ml volume of aqueous pharmaceutical formulation that comprises 114.3 mg / mL aflibercept by intravitreal injection every 4 weeks (approximately every 28 days ± 7 days) for the first three to five doses, followed by 8 mg aflibercept in a 0.07 mL volume of said formulation via intravitreal injection once every 8 weeks, ± 1 week, optionally, followed by 8 mg (±0.8 mg) aflibercept via intravitreal injection once every 4 weeks (± 1 week).

78. The method of claim 77 further comprising, after one or more of said doses once every 8 weeks + / - 1 week resuming administering said doses of 8 mg aflibercept in a 0.07 ml volume of aqueous pharmaceutical formulation that comprises 114.3 mg / mL aflibercept by intravitreal injection, every 4 weeks (approximately every 28 days ± 7 days).

79. The method of any one of the preceding claims wherein said aflibercept is provided in a kit that comprises(a)one single-dose vial comprising 0.07 mL of aqueous pharmaceutical formulation comprising 8 mg aflibercept which is at a concentration of 114.3 mg / mL;one 18-gauge x 11 / 2-inch, 5-micron, filter needleone 30-gauge x1 / 2-inch injection needle; andone 1 mL syringe;or(b)one single-dose vial comprising 0.07 mL of aqueous pharmaceutical formulation comprising 8 mg aflibercept which is at a concentration of 114.3 mg / mL.

80. The method of claim 80 wherein the kit further comprises prescribing information.

81. A method of any one of the preceding claims for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in an subject; wherein the methods comprise(i) administering to the eye of the subject an intravitreal injection of 8 mg aflibercept every month or every 4 weeks for the first 3 consecutive injections; and(ii) one or more further injections of 8 mg aflibercept after said first 3 consecutive injections; wherein the injection interval between two consecutive injections is adjusted based on the physician’s judgement of visual and / or anatomic outcomes.

82. A method of any one of the preceding claims for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairmentdue to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise(i) administering to the eye of the subject an intravitreal injection of 8 mg aflibercept every month or every 4 weeks for the first 3 consecutive injections; and(ii) one or more further injections of 8 mg aflibercept after said first 3 consecutive injections; wherein the injection interval between two consecutive injections is first extended to 8 weeks or 2 months for one or more injections and then adjusted based on the physician’s judgement of visual and / or anatomic outcomes;wherein the treatment interval between two consecutive injections is between 4 weeks (1 month) and 20 weeks (5 months).

83. A method of any one of the preceding claims for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,a single initial dose of 8 mg aflibercept; followed bytwo secondary doses of said 8 mg aflibercept; followed byone or more tertiary doses of 8 mg aflibercept;wherein each secondary dose is administered 4 weeks or one month after the immediately preceding dose; andwherein the treatment interval between two consecutive tertiary doses is adjusted based on the physician’s judgement of visual and / or anatomic outcomes.

84. A method of any one of the preceding claims for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,a single initial dose of 8 mg aflibercept, followed by;one or more tertiary doses of 8 mg aflibercept;wherein the treatment interval between two consecutive tertiary doses is adjusted based on the physician’s judgement of visual and / or anatomic outcomes; andwherein the subject has been treated with a different anti-angiogenic treatment prior to said single initial dose of 8 mg aflibercept.

85. The method of claim 84 wherein the anti-angiogenic treatment is 2 mg aflibercept, faricimab, ranibizumab or bevacizumab.

86. The method of claim 84 wherein the subject was treated with 2 mg aflibercept or faricimab prior to said single initial dose of 8 mg aflibercept.

87. The method of claim 84 wherein the subject was treated with ranibizumab or bevacizumab prior to said single initial dose of 8 mg aflibercept.

88. The method of any one of claims 84-87 wherein adjustment of treatment interval is extending or shortening the interval between doses based on the physician’s judgement of visual and / or anatomic outcomes.

89. A method of any one of the preceding claims for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise administering to the eye of the subject an intravitreal injection of(i) 8 mg aflibercept every month or every 4 weeks for the first 3 consecutive injections; and (ii) one or more further injections of 8 mg aflibercept after said first 3 consecutive injections; wherein the injection interval between two consecutive injections is extended based on the physician’s judgement of visual and / or anatomic outcomes.

90. A method of any one of the preceding claims for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the methods comprise administering to the eye of the subject an intravitreal injection of(i) 8 mg aflibercept every month or every 4 weeks for the first 3 consecutive injections; and (ii) one or more further injections of 8 mg aflibercept after said first 3 consecutive injections; wherein the injection interval between two consecutive injections is first extended to 8 weeks or 2 months for one or more injections and then further extended to up to 16 weeks (or 4 months) or 20 weeks (or 5 months) based on the physician’s judgement of visual and / or anatomic outcomes.

91. A method of any one of the preceding claims, for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in an subject in an subject; wherein the method comprises administering to the eye of the subject,a single initial dose of 8 mg aflibercept, followed bytwo secondary doses of said 8 mg aflibercept, followed by one or more tertiary doses of 8 mg aflibercept;wherein each secondary dose is administered 4 weeks or one month after the immediately preceding dose; andwherein the treatment interval between two consecutive tertiary doses is extended based on the physician’s judgement of visual and / or anatomic outcomes.

92. The method of any one of claims 91, wherein the first tertiary dose is administered 8 weeks (2 months) after the immediately preceding dose and one or more further tertiary doses are administered 8 weeks (2 months), or 12 weeks (3 months), or 16 weeks (4 months), or 20 weeks (5 month) after the immediately preceding dose.

93. The method of any one of claims 91-92, wherein the first tertiary dose is administered 8 weeks (2 months) after the immediately preceding dose and then the treatment interval between two consecutive injections is extended to up to 16 weeks (4 months) or 20 weeks (5 months) based on the physician’s judgement of visual and / or anatomic outcomes.

93. A method of any one of the preceding claims for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,a single initial dose of 8 mg aflibercept, followed by;one or more tertiary doses of 8 mg aflibercept;wherein the treatment interval between two consecutive tertiary doses is extended based on the physician’s judgement of visual and / or anatomic outcomes; andwherein the subject has been treated with a different anti-angiogenic treatment prior to said single initial dose of 8 mg aflibercept.

94. The method of any one of claims 93, wherein the anti-angiogenic treatment is 2 mg aflibercept, faricimab, ranibizumab or bevacizumab.

95. The method of any one of claims 93, wherein the subject was treated with 2 mg aflibercept or faricimab prior to said single initial dose of 8 mg aflibercept.

96. The method of any one of claims 93, wherein the subject was treated with ranibizumab or bevacizumab prior to said single initial dose of 8 mg aflibercept.

97. The method of any one of claims 93-96 wherein said treatment interval between two consecutive doses is 8 weeks or 2 months.

98. The method of any one of claims 93-96 wherein said treatment interval between two consecutive doses is 12 weeks or 3 months.

99. The method of any one of claims 93-96 wherein said treatment interval between two consecutive doses is 16 weeks or 4 months.

100. The method of any one of claims 93-96 wherein said treatment interval between two consecutive doses is 20 weeks or 5 months.

101. The method of any one of claims 93-96 wherein said treatment interval between two consecutive doses is extended from 8 weeks or 2 months to 12 weeks or 3 months.

102. The method of any one of claims 93-96 wherein said treatment interval between two consecutive doses is extended from 12 weeks or 3 months to 16 weeks or 4 months.

103. The method of any one of claims 93-96 wherein said treatment interval between two consecutive doses is extended from 16 weeks or 4 months to 20 weeks or 5 months.

104. A method of any one of the preceding claims, for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,a single initial dose of 8 mg aflibercept, followed bytwo secondary doses of said 8 mg aflibercept, followed byone or more tertiary doses of 8 mg aflibercept;wherein each secondary dose is administered 4 weeks or one month after the immediately preceding dose; andwherein the treatment interval between two consecutive tertiary doses is shortened based on the physician’s judgement of visual and / or anatomic outcomes.

105. A method of any one of the preceding claims for treating or preventing retinal vein occlusion (RVO), macular edema secondary to retinal vein occlusion (MERVO) and / or visual impairment due to macular edema secondary to retinal vein occlusion in a subject; wherein the method comprises administering to the eye of the subject,a single initial dose of 8 mg aflibercept, followed by;one or more tertiary doses of 8 mg aflibercept;wherein the treatment interval between two consecutive tertiary doses is shortened based on the physician’s judgement of visual and / or anatomic outcomes and wherein the subject has been treated with a different anti-angiogenic treatment prior to said single initial dose of 8 mg aflibercept.

106. The method of claim 105 wherein the anti-angiogenic treatment is 2 mg aflibercept, faricimab, ranibizumab or bevacizumab.

107. The method of claim 105 wherein the anti-angiogenic treatment is 2 mg aflibercept or faricimab prior to said single initial dose of 8 mg aflibercept.

108. The method of claim 105 wherein the anti-angiogenic treatment is ranibizumab or bevacizumab prior to said single initial dose of 8 mg aflibercept109. The method of any one of the preceding claims, for treating or preventing neovascular (wet) age-related macular degeneration (nAMD) or visual impairment due to diabetic macular oedema (DME) in a subject; wherein the methods comprise administering to the eye of the subjectan intravitreal injection of 8 mg aflibercept every month or every 4 weeks + / - 1 week for the first 3 consecutive injections; andone or more further injections of 8 mg aflibercept after said first 3 consecutive injections wherein the injection interval between two consecutive injections is adjusted based on the physician’s judgement of visual and / or anatomic outcomes;wherein the injection interval between two consecutive injections is at least 4 weeks or one month.

110. The method of any one of the preceding claims, for treating or preventing neovascular (wet) age-related macular degeneration (nAMD) or visual impairment due to diabetic macular oedema (DME) in a subject; wherein the methods comprise administering to the eye of the subject an intravitreal injection of8 mg aflibercept every month or every 4 weeks + / - 1 week for the first 3 consecutive injections; andone or more further injections of 8 mg aflibercept after said first 3 consecutive injections; wherein the injection interval between two consecutive injections is shortened based on the physician’s judgement of visual and / or anatomic outcomes; andwherein the injection interval between two consecutive injections is at least 4 weeks or one month.

111. The method of any one of the preceding claims for treating or preventing neovascular (wet) age-related macular degeneration (nAMD) or visual impairment due to diabetic macular oedema (DME) in a subject; wherein the method comprises administering to the eye of the subject, a single initial dose of 8 mg aflibercept, followed bytwo secondary doses of said 8 mg aflibercept, followed byone or more tertiary doses of 8 mg aflibercept;wherein each secondary dose is administered 4 weeks or one month after the immediately preceding dose; andwherein the treatment interval between two consecutive tertiary doses is adjusted based on the physician’s judgement of visual and / or anatomic outcomes; andwherein the injection interval between two consecutive injections is at least 4 weeks or one month.

112. The method of any one of the preceding claims for treating or preventing neovascular (wet) age-related macular degeneration (nAMD) or visual impairment due to diabetic macular oedema (DME) in a subject; wherein the method comprises administering to the eye of the subject,a single initial dose of 8 mg aflibercept, followed bytwo secondary doses of said 8 mg aflibercept, followed byone or more tertiary doses of 8 mg aflibercept;wherein each secondary dose is administered 4 weeks or one month after the immediately preceding dose; andwherein the treatment interval between two consecutive tertiary doses is shortened based on the physician’s judgement of visual and / or anatomic outcomes; andwherein the injection interval between two consecutive injections is at least 4 weeks or one month.

113. The method of any one of the preceding claims for treating or preventing neovascular (wet) age-related macular degeneration (nAMD) or visual impairment due to diabetic macular oedema (DME) in a subject; wherein the method comprises administering to the eye of the subject, a single initial dose of 8 mg aflibercept, followed by;one or more tertiary doses of 8 mg aflibercept;wherein the treatment interval between two consecutive tertiary doses is adjusted based on the physician’s judgement of visual and / or anatomic outcomes; andwherein the subject has been treated with a different anti-angiogenic treatment prior to said single initial dose of 8 mg aflibercept; andwherein the injection interval between two consecutive injections is at least 4 weeks or one month.

114. The method of any one of the preceding claims for treating or preventing neovascular (wet) age-related macular degeneration (nAMD) or visual impairment due to diabetic macular oedema (DME) in a subject; wherein the method comprises administering to the eye of the subject, a single initial dose of 8 mg aflibercept, followed by;one or more tertiary doses of 8 mg aflibercept;wherein the treatment interval between two consecutive tertiary doses is shortened based on the physician’s judgement of visual and / or anatomic outcomes; andwherein the subject has been treated with a different anti-angiogenic treatment prior to said single initial dose of 8 mg aflibercept; andwherein the injection interval between two consecutive injections is at least 4 weeks or one month.

115. The method of any one of claims 113-114 wherein the anti-angiogenic treatment is 2 mg aflibercept, faricimab, ranibizumab or bevacizumab.

116. The method of any one of claims 113-114, wherein the subject was treated with 2 mg aflibercept or faricimab prior to said single initial dose of 8 mg aflibercept.

117. The method of any one of claims 113-114wherein the subject was treated with ranibizumab or bevacizumab prior to said single initial dose of 8 mg aflibercept.

118. The method of any one of claims 109-117, wherein the interval between two consecutive tertiary doses is shortened if the subject(i) exhibits >5 letters loss of BCVA from reference visit; and / or(ii) >50 pm increase in CRT (central retinal thickness) from reference visit,wherein the reference visit is the visit at the previous injection.

119. The method of any one of claims 109-118, wherein the interval between two consecutive doses is shortened by 2 or 4 weeks.

120. The method of any one of claims 109-118, wherein the interval between two consecutive doses is shortened from 24 weeks or 6 months to 20 weeks or 5 months.

121. The method of any one of claims 109-118, wherein the interval between two consecutive doses is shortened from 20 weeks or 5 months to 16 weeks or 4 months.

122. The method of any one of claims 109-118, wherein the interval between two consecutive doses is shortened from 16 weeks or 4 months to 12 weeks or 3 months.

123. The method of any one of claims 109-118, wherein the interval between two consecutive doses is shortened from 12 weeks or 3 months to 8 weeks or 2 months.

124. The method of any one of claims 109-118, wherein the interval between two consecutive doses is shortened from 8 weeks or 2 months to 4 weeks or 1 month.

125. The method of any one of claims 109-118, wherein the interval between doses is shortened by 1 week, provided that the new interval is at least about 4 weeks or one month.

126. The method of any one of claims 109-118, wherein the tertiary dose interval is shortened by 4 weeks, provided that the new interval is at least about 4 weeks or 1 month.

127. The method of any one of claims 109-118, wherein the tertiary dose interval is shortened by 2 weeks, provided that the new interval is at least about 4 weeks or 1 month.

128. The method of any one of claims 109-118, wherein the interval between two consecutive doses is at least 4 weeks or one month.

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