Treatment methods for age-related macular degeneration and diabetic macular edema

Abstract

This specification discloses a method for treating neovascular age-related macular degeneration ("nAMD") and diabetic macular edema ("DME") in patients requiring treatment, using a fusion protein (e.g., ephdamlovsp alfa) that inhibits both VEGF and the complement pathway. This disclosure includes, in particular, a treatment regimen including a loading phase and a maintenance phase.

Description

[Technical Field]

[0001] 1. References to electronically submitted sequence listings This application incorporates, by reference, an XML file titled "621A005WO03_SL" created on August 12, 2024, with a size of 10,104 bytes, as an array listing.

[0002] 2. Related applications This application claims priority to China Patent Application No. 202311040983.7 filed on 17 August 2023, PCT Patent Application No. PCT / CN2023 / 129352 filed on 2 November 2023, and China Patent Application No. 202411119292.0 filed on 15 August 2024. Each of these applications is incorporated herein by reference in its entirety.

[0003] 3. field This invention relates to medicine. Specifically, it relates to a method for using a bispecific fusion protein that inhibits the activation of the complement pathway and the vascular endothelial growth factor ("VEGF") pathway in the treatment of age-related macular degeneration and diabetic macular edema. [Background technology]

[0004] 4. background Age-related macular degeneration ("AMD") is the most common cause of blindness in developed countries, particularly among the elderly aged 60 and over. AMD primarily affects the macula of the retina. With the global increase in average life expectancy, the prevalence of AMD is projected to surge. The number of AMD patients was projected to reach 196 million in 2020 and is expected to increase to 288 million by 2040. Similarly, diabetic macular edema (DME) is one of the leading causes of visual impairment in diabetic patients. Like AMD, DME also primarily affects the macula of the retina, causing edema and decreased vision. With the global increase in the number of diabetic patients, the prevalence of DME is also rising. Currently, existing treatments for AMD face numerous challenges, including limitations in therapeutic efficacy, significant financial burdens, and the need for repeated medical interventions. Therefore, there is an urgent need to develop more effective treatments for both AMD and DME. The compositions and methods described herein meet these needs and offer relative advantages. [Overview of the project]

[0005] 5. overview This specification provides a method for treating nAMD in subjects requiring treatment. The method comprises administering a fusion protein that specifically binds to human vascular endothelial growth factor (VEGF) and human complement receptor 1 ("CR1"), the fusion protein comprising, from N-terminus to C-terminus, a VEGF inhibitory domain ("VID"), an immunoglobulin Fc region, a peptide linker, and a complement inhibitory domain ("CID"); wherein the fusion protein has an amino acid sequence that is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to SEQ ID NO: 1, and the fusion protein is administered to the affected eye in a dose of about 1.0 to about 8.0 mg. In some embodiments, the fusion protein is efdamrofusp alfa (SEQ ID NO: 1).

[0006] In one embodiment of the method provided herein, the best corrected visual acuity ("BCVA") of the diseased eye is in the range of 19 to 78 characters (inclusive) as measured by the Early Diabetic Retinopathy Treatment Study ("ETDRS") chart. In some embodiments, the BCVA of the affected eye is in the range of 24 to 78 ETDRS characters (inclusive). In some embodiments, the BCVA of the affected eye is in the range of 24 to 73 ETDRS characters (inclusive). In some embodiments, the BCVA of the affected eye is at least 64 ETDRS characters. In some embodiments, the BCVA of the affected eye is 63 or less ETDRS characters. In some embodiments, the subject has active submacular or perimacular choroidal neovascularization ("CNV") secondary to nAMD, or active CNV affecting the macula. In some embodiments, the CNV area (including classical and latent types) in the affected eye accounts for at least 50% of the total lesion area (including hemorrhage, CNV, atrophy, and fibrosis). In some embodiments, the affected eye has (1) active submacular or perimacular CNV secondary to nAMD; (2) a CNV area (including classical and latent types) occupying 50% or more of the total lesion area (including hemorrhage, CNV, atrophy, and fibrosis); and (3) a BCVA in the range of 24 to 73 ETDRS letters (including endpoints). In some embodiments, the affected eye has (1) active submacular CNV secondary to nAMD, or active CNV perimacular or extramacular but affecting the macula; (2) a CNV area (including classical and latent types) occupying at least 50% of the total lesion area (including hemorrhage, CNV, atrophy, and fibrosis); and (3) a BCVA in the range of 24 to 78 ETDRS letters (including endpoints). In some embodiments, the affected eye has (1) active submacular cytosis secondary to nAMD, or active macula-affecting cytosis, and (2) a BCVA in the range of 19 to 78 ETDRS letters (including both extremes). In some embodiments, the affected eye has type II cytosis. In some embodiments, the affected eye does not have type II cytosis. In some embodiments, the affected eye has a subcentral retinal thickness (CST) greater than 280 μm, 300 μm, or 325 μm as measured by spectral domain optical coherence tomography (SD-OCT).In some embodiments, the subject has been newly diagnosed with nAMD. In some embodiments, up to 12 years have passed since the subject was diagnosed with nAMD. In some embodiments, the subject has previously received treatment for nAMD. In some embodiments, the subject has previously received treatment with anti-VEGF drugs. In some embodiments, the subject has not previously received treatment for nAMD. In some embodiments, the subject is a human being 50 years of age or older.

[0007] In some embodiments of the methods described herein, the fusion protein is administered by intravitreous injection. In some embodiments, the fusion protein is administered as a solution. In some embodiments, the solution contains the fusion protein at a concentration ranging from about 40 mg / ml to about 100 mg / ml. In some embodiments, the solution contains the fusion protein at a concentration of about 80 mg / ml. In some embodiments, the injection volume is between about 0.01 mL and about 0.2 mL. In some embodiments, the injection volume is about 0.1 mL. In some embodiments, the fusion protein is administered in doses of about 2.0 mg, about 3.2 mg, about 4.0 mg, about 6.4 mg, or about 8.0 mg. In some embodiments, the fusion protein is administered at least three times. In some embodiments, the at least three administrations are performed at intervals of about once a week to about once every four weeks.

[0008] In some embodiments of the method described herein, the method includes a loading phase and a maintenance phase, during which the fusion protein is administered 3 to 5 times, and during the maintenance phase, the fusion protein is administered 2 or more times. In some embodiments, the fusion protein is administered 3 times during the loading phase. In some embodiments, the fusion protein is administered at intervals ranging from about once a week to about once every 4 weeks during the loading phase. In some embodiments, the fusion protein is administered at intervals of about 4 weeks during the loading phase. In some embodiments, the fusion protein is administered at intervals ranging from about once every 8 weeks to about once every 16 weeks during the maintenance phase. In some embodiments, the administration interval during the maintenance phase is about once every 8 weeks. In some embodiments, the administration interval during the maintenance phase is about once every 12 weeks. In some embodiments, the administration interval during the maintenance phase is about once every 16 weeks. In one embodiment of the method described herein, (1) during the loading phase, the fusion protein is administered once every 4 weeks for a total of 3 times, and (2) during the maintenance phase, the fusion protein is administered at least twice, once every 8 weeks. Here, the fusion protein is efdamlovsp alfa, and each dose is 2.0 mg or 4.0 mg. In some embodiments of the method described herein, (1) during the loading phase, the fusion protein is administered at least three times, once every four weeks, and (2) during the maintenance phase, the fusion protein is administered at least twice, once every 12 weeks or once every 16 weeks. Here, the fusion protein is efdamlovsp alfa, and each dose is 6.4 mg or 8.0 mg.

[0009] In some embodiments of the methods described herein, during the maintenance phase, the fusion protein is administered at intervals determined by evaluating the treated eye after the final dose of the loading phase. In some embodiments, the evaluation includes measuring changes in BCVA based on an ETDRS chart. In some embodiments, the evaluation includes measuring changes in CST using SD-OCT. In some embodiments, the evaluation includes determining the presence or absence of disease activity ("DA"). In some embodiments, DA is determined to be present if at least one of the following conditions is met: (1) CST has increased by more than 50 μm compared to the mean CST over the past two months as measured by SD-OCT; (2) CST has increased by 75 μm or more compared to the lowest CST over the past two months as measured by SD-OCT; (3) BCVA has decreased by 5 letters or more compared to the mean BCVA over the past two months due to the progression of age-related macular degeneration (nAMD); (4) BCVA has decreased by 10 letters or more compared to the best BCVA over the past two months due to the progression of age-related macular degeneration (nAMD); and (5) a new foveal hemorrhage has occurred due to the progression of age-related macular degeneration (nAMD). In some embodiments, DA is determined to be present in a subject if at least one of the following conditions is met: (1) BCVA is decreased by 5 letters or more compared to the most recent value; (2) CST measured by SD-OCT is increased by 50 μm or more compared to the most recent value; (3) fluid persists under the retina / intraretina / subretinal pigment epithelium ("RPE"); (4) a new CNV has occurred; and (5) a new macular hemorrhage has occurred. In some embodiments, (1) during the loading phase, the fusion protein is administered four times, once every four weeks; and (2) during the maintenance phase, the fusion protein is administered at least twice. Specifically, (a) once every eight weeks if DA is present eight weeks after the last dose of the loading phase, or (b) once every 12 weeks if DA is not present approximately eight weeks after the last dose of the loading phase. Here, the fusion protein is efdamlovsp alfa, and each dose is 6.4 mg or 8.0 mg.In some embodiments, (1) during the loading phase, the fusion protein is administered once every four weeks for a total of three doses; and (2) during the maintenance phase, the fusion protein is administered at least twice: (a) once every eight weeks if DA is present approximately eight weeks after the last dose of the loading phase; (b) once every 12 weeks if DA is not present approximately eight weeks after the last dose of the loading phase but is present approximately 12 weeks later; or (c) once every 16 weeks if DA is not present both eight and twelve weeks after the last dose of the loading phase; where the fusion protein is efdamlovsp alfa, and each dose is 8.0 mg.

[0010] In some embodiments of the methods described herein, the interval between the final dose of the loading phase and the first dose of the maintenance phase is the same as the interval between doses in the maintenance phase. In some embodiments, the fusion protein is administered at least two, three, four, five, six, seven, or eight times during the maintenance phase.

[0011] In one embodiment of the method described herein, the method improves the BCVA of the affected eye by at least 0 ETDRS characters, at least 5 ETDRS characters, at least 10 ETDRS characters, or at least 15 ETDRS characters. In some embodiments, the method improves the BCVA by about 10 to about 15 ETDRS characters. In some embodiments, the method reduces the CST of the affected eye, as measured by SD-OCT, by at least 50 μm, at least 75 μm, at least 100 μm, at least 125 μm, or at least 150 μm. In some embodiments, the method reduces the CST, as measured by SD-OCT, by about 125 μm to about 150 μm. In some embodiments, the method reduces or prevents the occurrence of pigment epithelial detachment ("PED") in the affected eye. In some embodiments, the method reduces or prevents the occurrence of intraretinal fluid ("IRF") or subretinal fluid ("SRF") in the affected eye. In some embodiments, the method reduces or prevents (1) the development of new macular atrophy ("MA"), or (2) the area of ​​MA, or both, in the affected eye. In some embodiments, the method reduces or prevents the development of geographical atrophy ("GA") in the affected eye. In some embodiments, the method reduces or prevents retinal fibrosis in the affected eye. In some embodiments, the method reduces (1) CNV area, (2) CNV leakage area, or (3) total lesion area (including hemorrhage, CNV, atrophy, and fibrosis), or any combination thereof, in the affected eye. In some embodiments, the method reduces retinal neovascularization ("RNV") area, RNV leakage area, or both. In some embodiments, the method reduces macular retinal edema. In some embodiments, the method improves the subject's visual acuity-related quality of life.

[0012] Furthermore, this specification also provides a method for treating diabetic macular edema ("DME") in subjects requiring treatment. This method comprises administering a fusion protein that specifically binds to human VEGF and human CR1, the fusion protein comprising a VID, an immunoglobulin Fc region, a peptide linker, and a CID from the N-terminus to the C-terminus, wherein the fusion protein is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to SEQ ID NO: 1; and the fusion protein is administered to the affected eye in a dose of about 1.0 to about 8.0 mg. In some embodiments, the fusion protein is efdamlovsp alfa (SEQ ID NO: 1).

[0013] In some embodiments of the methods described herein, the subject has centrally affecting diabetic macular edema (CI-DME). In some embodiments, the subject has focal diabetic macular edema. In some embodiments, the subject has diffuse diabetic macular edema. In some embodiments, the BCVA of the affected eye is within the range of 24 to 73 ETDRS letters (including the endpoints). In some embodiments, the CST of the affected eye, as measured by SD-OCT, is at least 280 μm, at least 300 μm, or at least 325 μm. In some embodiments, the affected eye has (1) visual impairment due to foveal-affecting DME, (2) a CST of 280 μm or greater as measured by SD-OCT, and (3) a BCVA within the range of 24 to 73 ETDRS letters (including the endpoints). In some embodiments, the subject has been newly diagnosed with DME. In some embodiments, the subject has been diagnosed with DME up to 12 years ago. In some embodiments, the subject has not previously received treatment with anti-VEGF drugs. In some embodiments, the subject has previously received treatment with anti-VEGF drugs. In some embodiments, the subject has proliferative diabetic retinopathy ("PDR"). In some embodiments, the subject is human.

[0014] In some embodiments of the methods described herein, the fusion protein is administered by intravitreous injection. In some embodiments, the fusion protein is injected as a solution. In some embodiments, the solution contains the fusion protein at a concentration ranging from about 40 mg / ml to about 100 mg / ml. In some embodiments, the solution contains the fusion protein at a concentration of about 80 mg / ml. In some embodiments, the injection volume is between about 0.01 mL and about 0.2 mL. In some embodiments, the injection volume is about 0.1 mL. In some embodiments, the fusion protein is administered in doses of about 3.2 mg, about 6.4 mg, or about 8.0 mg. In some embodiments, the fusion protein is administered at least three times. In some embodiments, the at least three administrations are performed at intervals of about once a week to about once every four weeks.

[0015] In some embodiments, the method described herein includes a loading phase and a maintenance phase, during which the fusion protein is administered 3 to 5 times, and during the maintenance phase, the fusion protein is administered once or more as needed based on the evaluation of the treated eye after the final dose of the loading phase. In some embodiments, the fusion protein is administered 3 times during the loading phase. In some embodiments, during the loading phase, the fusion protein is administered at intervals of approximately once a week to approximately once every 4 weeks. In some embodiments, during the loading phase, the fusion protein is administered at intervals of approximately once every 4 weeks. In some embodiments, the evaluation includes measuring the change in BCVA based on an ETDRS chart. In some embodiments, the evaluation includes measuring the change in CST measured by SD-OCT. In some embodiments, the evaluation includes performing an evaluation of the Diabetic Retinopathy Severity Score ("DRSS"). In some embodiments, during the maintenance administration period, the fusion protein is administered if (1) BCVA has decreased by 5 letters or more compared to the most recent value, or (2) CST measured by SD-OCT has increased by more than 50 μm compared to the most recent value. In one embodiment of the method described herein, (1) during the loading phase, the fusion protein is administered once every four weeks for a total of three doses; (2) during the maintenance phase, the fusion protein is administered as a maintenance dose between four and eight weeks after the last dose of the loading phase if (1) BCVA decreases by more than 5 ETDRS letters compared to the most recent value, or (2) CST increases by more than 50 μm compared to the most recent value measured by SD-OCT. Here, the fusion protein is e-Efdamlovsp alfa, and the doses are 3.2 mg, 6.4 mg, or 8.0 mg.

[0016] In some embodiments, the methods described herein improve the BCVA of the affected eye by at least 1 character, at least 5 characters, at least 10 characters, or at least 15 characters. In some embodiments, the methods described herein improve the BCVA by about 10 to about 15 ETDRS characters. In some embodiments, the methods described herein reduce the CST of the affected eye, as measured by SD-OCT, by at least 50 μm, at least 75 μm, at least 100 μm, at least 125 μm, or at least 150 μm. In some embodiments, the methods described herein reduce the CST, as measured by SD-OCT, by about 125 μm to about 150 μm. In some embodiments, the methods described herein reduce macular retinal edema. In some embodiments, the methods described herein improve the quality of life related to visual acuity of the subject.

[0017] Also provided herein are single drug dose units containing a fusion protein that inhibits the VEGF pathway and the complement pathway, wherein the amount of the fusion protein is approximately 4 mg, 5 mg, 6.4 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 12.8 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg.

[0018] 6. Brief explanation of the drawing [Brief explanation of the drawing]

[0019] [Figure 1] Figure 1 shows the anti-retinal neovascularization effect of evdamlovsp alfa (IBI302) in a Dutch rabbit model of retinal neovascularization (RNV) induced by DL-α-AAA (DL-α-aminoadipic acid). [Figure 2] Figure 2 shows a schematic diagram of the Phase I clinical trial of Efdamlovsp alfa. [Figure 3]Figures 3A and 3B show the change in BCVA from baseline during the treatment period. Figure 3A shows the change in BCVA (ETDRS letters) in nAMD patients during the treatment period. Figure 3B shows the change in BCVA (ETDRS letters) in DME patients during the treatment period. [Figure 4] Figures 4A-4B show the change from baseline in CST during the treatment period, as measured by SD-OCT. Figure 4A shows the change from baseline in CST in nAMD patients during the treatment period, as measured by SD-OCT. Figure 4B shows the change from baseline in CST in DME patients during the treatment period, as measured by SD-OCT. [Figure 5] Figure 5 shows the mean change from baseline in BCVA scores during the treatment period in the efdamlovsp alfa 2 mg group, the efdamlovsp alfa 4 mg group, and the aflibercept 2 mg group. [Figure 6] Figure 6 shows the mean change in CST from baseline during the treatment period in the Efdamlovsp alfa-2mg group, the Efdamlovsp alfa-4mg group, and the Efdamlovsp alfa-2mg group. [Figure 7] Figure 7 shows the mean change from baseline in CNV area, as measured by FFA, in the efdamlovsp alfa 2 mg group, the efdamlovsp alfa 4 mg group, and the aflibercept 2 mg group during the treatment period. [Figure 8] Figure 8 shows the mean change in CNV leakage area from baseline, as measured by FFA during the treatment period, in the efdamlovsp alfa 2 mg group, the efdamlovsp alfa 4 mg group, and the aflibercept 2 mg group. [Figure 9] Figure 9 shows the mean change in BCVA score from baseline during the treatment period in the efdamlovsp alfa 6.4 mg group, the efdamlovsp alfa 8 mg group, and the aflibercept 2 mg group. [Figure 10A]Figure 10A shows the mean change from baseline during the treatment period in the efdamlovsph alfa 6.4 mg group (Q8W), efdamlovsph alfa 8 mg group (Q8W), efdamlovsph alfa 6.4 mg group (every 12 weeks), and efdamlovsph alfa 8 mg group (every 12 weeks). [Figure 10B] Figure 10B shows the mean change from baseline during the treatment period in the efdamlovsph alfa 6.4 mg group (Q8W), efdamlovsph alfa 8 mg group (Q8W), efdamlovsph alfa 6.4 mg group (every 12 weeks), and efdamlovsph alfa 8 mg group (every 12 weeks). [Figure 11] Figure 11 shows the mean change in CST from baseline during the treatment period in the efdamlovsp alfa 6.4 mg group, the efdamlovsp alfa 8 mg group, and the aflibercept 2 mg group. [Figure 12A-B] Figures 12A-12C show the percentage of subjects who exhibited serous PED (Figure 12A), IRF (Figure 12B), or SRF (Figure 12C) as measured by OCT during the treatment period in the efdamlovsph alfa 6.4 mg group, the efdamlovsph alfa 8 mg group, and the aflibercept 2 mg group. [Figure 12C] Figures 12A-12C show the percentage of subjects who exhibited serous PED (Figure 12A), IRF (Figure 12B), or SRF (Figure 12C) as measured by OCT during the treatment period in the efdamlovsph alfa 6.4 mg group, the efdamlovsph alfa 8 mg group, and the aflibercept 2 mg group. [Figure 13] Figure 13 shows the percentage of subjects in the efdamlovsph alfa 6.4 mg group, the efdamlovsph alfa 8 mg group, and the aflibercept 2 mg group who did not show retinal fluid in the subcentral region during the treatment period. [Figure 14] Figure 14 shows the mean change in CNV area from baseline in the efdamlovsp alfa 6.4 mg group, the efdamlovsp alfa 8 mg group, and the aflibercept 2 mg group at weeks 40 and 52. [Figure 15]Figure 15 shows the mean change in CNV leakage area from baseline in the efdamlovsp alfa 6 mg group, the efdamlovsp alfa 8 mg group, and the aflibercept 2 mg group at weeks 40 and 52. [Figure 16] Figure 16 shows the mean change from baseline in total lesion area in the efdamlovsup alfa 6.4 mg group, the efdamlovsup alfa 8 mg group, and the aflibercept 2 mg group at weeks 40 and 52. [Figure 17] Figure 17 shows the percentage of patients who developed new fibrosis as measured by CFP at 40 weeks in the efdamlovsph alfa 6.4 mg group, the efdamlovsph alfa 8 mg group, and the aflibercept 2 mg group. [Figure 18] Figures 18A and 18B show the proportion of subjects with MA (Figure 18A) and the proportion of subjects with newly formed MA (Figure 18B) in the efdamlovsp alfa 6.4 mg group, the efdamlovsp alfa 8 mg group, and the aflibercept 2 mg group, as measured by OCT during the treatment period. [Figure 19A-B] Figures 19A-19C show the mean change in MA area from baseline, measured by OCT during the treatment period in the efdamlovsph alfa 6.4 mg group, the efdamlovsph alfa 8 mg group, and the aflibercept 2 mg group (Figure 19A); and also show the mean change in MA area from baseline, measured by FAF at weeks 40 and 52, respectively, in the efdamlovsph alfa 6.4 mg group, the efdamlovsph alfa 8 mg group, and the aflibercept 2 mg group (Figures 19B-19C). [Figure 19C]Figures 19A-19C show the mean change in MA area from baseline, measured by OCT during the treatment period in the efdamlovsph alfa 6.4 mg group, the efdamlovsph alfa 8 mg group, and the aflibercept 2 mg group (Figure 19A); and also show the mean change in MA area from baseline, measured by FAF at weeks 40 and 52, respectively, in the efdamlovsph alfa 6.4 mg group, the efdamlovsph alfa 8 mg group, and the aflibercept 2 mg group (Figures 19B-19C). [Figure 20] Figure 20 shows the pre-administration intraocular pressure (IOP) values ​​of the test eye in the efdamlovsp alfa 6.4 mg group, the efdamlovsp alfa 8 mg group, and the aflibercept 2 mg group during the treatment period. [Modes for carrying out the invention]

[0020] 7. Detailed explanation This disclosure provides a method for treating AMD and DME, comprising administering a therapeutically effective dose of efdamlovsp alfa (IBI302) to subjects in need of treatment for AMD and DME. Specific treatment regimens used in this disclosure are also described.

[0021] Age-related macular degeneration (AMD) is a chronic and progressive disease of the central retina that primarily affects individuals aged 45 and older, with its prevalence increasing with age. As is well known to those skilled in the art, the central retina refers to the central region of the retina where cone cells, responsible for photopic vision (daylight) and color vision, are densely concentrated. Lesions in this region can lead to a significant decrease in central visual acuity and may manifest as color vision deficiencies, visual distortion, and central scotoma. This region is particularly vulnerable to various pathological changes, including hemorrhage, edema, retinal thickening, and atrophy. The macula, essential for clear and detailed vision, is located precisely in the center of the central retina.

[0022] The Age-Related Eye Disease Study group at the U.S. National Eye Institute classifies AMD into three stages: early, intermediate, and late. Early AMD is mainly characterized by the presence of drusen, and while its incidence is high, the rate of blindness is low. However, as AMD progresses to the late stage, vision is severely impaired, and it is classified into two types based on its pathological characteristics: atrophic AMD and exudative AMD.

[0023] Exudative AMD, also known as wet AMD or neovascular AMD (nAMD), is characterized by a pathological increase in the release of vascular endothelial growth factor (VEGF), which forms immature choroidal neovascularization (CNVs) between the retinal pigment epithelium (RPE) and photoreceptors. Although nAMD is less common than atrophic AMD, it carries a high risk of blindness due to subretinal rupture, hemorrhage, and damage to the retinal pigment epithelium and Bruch's membrane.

[0024] The precise pathological mechanisms of AMD are not fully understood. However, it is widely accepted that angiogenesis driven by increased VEGF expression is a major cause of nAMD. Furthermore, complement gene mutations and abnormal complement activation that induce inflammatory responses are also considered important factors in AMD. Complement system activation directly damages the retinal pigment epithelium (RPE), leading to RPE atrophy and degeneration of central retinal cells, resulting in geographical atrophy (GA) in atrophic AMD. A similar process disrupts the blood-retinal barrier, causing inflammation, further VEGF expression, and neovascularization, ultimately leading to nAMD.

[0025] Currently, the treatment of wet age-related macular degeneration (wet AMD) often involves intravitreal injection of anti-complement and anti-VEGF agents. While this combination therapy offers the potential for synergistic effects, it also carries risks associated with injection procedures. Furthermore, the need for repeated administration over a long period leads to decreased patient adherence and increased psychological and economic burdens. Efdamlovsp alfa, a fusion protein that inhibits both VEGF and complement activity, has the potential to reduce the risks associated with current treatments, and its development is underway to address these challenges.

[0026] Diabetic macular edema (DME) is a serious complication of diabetic retinopathy (DR), one of the most common retinal vascular diseases worldwide. While DME can develop at any stage of DR, its incidence increases as DR progresses from non-proliferative diabetic retinopathy (NPDR) to proliferative diabetic retinopathy (PDR). DME is a leading cause of vision loss in diabetic patients.

[0027] DME is primarily associated with increased permeability of retinal blood vessels and leakage from abnormal capillaries, which causes fluid accumulation within the inner and outer plexiform layers of the retina, leading to retinal thickening. With advances in imaging technology, DME is now typically diagnosed using optical coherence tomography (OCT), which provides detailed images of the retinal structure.

[0028] According to the Early Diabetic Retinopathy Treatment Study (ETDRS), macular edema is defined as retinal thickening or hard exudate within one optic nerve head diameter from the center of the macula. Clinically significant macular edema (CSME) is further characterized by meeting one of the following criteria: 1. Retinal thickening within 500 μm from the center of the macula. 2. Hard exudate within 500 μm from the center of the macula, accompanied by retinal thickening. 3. Retinal thickening located within one optic nerve head diameter (1,500 μm) from the center of the macula, covering at least one optic nerve head area. Clinicians often classify DME into two types: focal and diffuse. This classification is essential for determining the most appropriate treatment strategy.

[0029] The primary goal of DME treatment is to improve and maintain visual function. Common treatments include anti-VEGF intravitreal injections, laser photocoagulation, and intravitreal corticosteroid injections (such as triamcinolone, dexamethasone, and fluocinolone acetonide). The choice of treatment depends on various factors, including the presence or absence of macular involvement, baseline visual acuity, edema thickness, vitreomacular adhesion, chronicity of the disease, history and response to past treatments, specific type of DME lesion (localized, diffuse, chronic, persistent, recurrent), and imaging findings.

[0030] Currently, anti-VEGF drugs such as ranibizumab and aflibercept are considered first-line treatments for diabetic eye disease (DR / DME). Anti-VEGF therapy has significantly improved visual prognosis and safety compared to conventional standard treatments such as laser photocoagulation. However, despite these advances, the effects are limited in many patients, and frequent injections over long periods are often required to maintain therapeutic efficacy. Furthermore, anti-VEGF monotherapy cannot completely suppress other pathways that contribute to the progression of diabetic eye disease, such as inflammation.

[0031] Recent studies have highlighted the crucial role of inflammatory factors in the onset and progression of DME. As a result, corticosteroids, powerful anti-inflammatory agents, have become the second-line treatment, particularly for patients with recurrent and persistent DME. The EURETINA guidelines recommend their use in these cases where they demonstrate superior efficacy. However, corticosteroid use carries inherent risks, including increased intraocular pressure and complications such as cataracts. Therefore, there remains a need for improvements in the safety and efficacy of intraocular anti-inflammatory treatments.

[0032] Given the limitations of current treatments and the multifactorial nature of DME, there is an urgent need to develop more effective new therapies that can address both the vascular and inflammatory aspects of this disease. Efdamlovsp alfa, a fusion protein that inhibits both VEGF and complement activity, may be a promising treatment that can address these challenges.

[0033] Before further discussion of this disclosure, it should be understood that this disclosure is not limited to the specific embodiments described herein, and that the terms used herein are for the purpose of describing specific embodiments and are not intended to limit them.

[0034] 7.1 Definition Unless otherwise defined herein, scientific and technical terms used herein have the meanings generally understood by those skilled in the art. Furthermore, unless the context requires otherwise, singular terms shall include plural forms, and plural terms shall include singular forms. Generally, the nomenclature and techniques used herein in relation to cell and tissue culture, molecular biology, immunology, microbiology, genetics, and the chemistry and hybridization of proteins and nucleic acids are well known and commonly used in the art.

[0035] In this specification, the terms “one” or “a certain entity” refer to one or more entities. For example, “a certain antibody” is understood to represent one or more antibodies.

[0036] In this specification, the term “and / or” is construed to mean that each of the two specified features or components is specifically disclosed, whether or not accompanied by the other. Accordingly, the term “and / or” as used in expressions such as “A and / or B” is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Similarly, the term “and / or” as used in phrases such as “A, B, and / or C” is intended to include each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0037] In this specification, the term “approximately” is used to indicate that the value includes the error variability inherent in the apparatus, the method used to determine the value, or the variability present between objects. The term “approximately” includes the exact numerical value stated. In some embodiments, “approximately” means within ±10% of a given value or range. In some embodiments, “approximately” means that the variation is ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, ±0.2%, or ±0.1% of the value that “approximately” refers to. In some embodiments, “approximately” means that the variation is ±1%, ±0.5%, ±0.2%, or ±0.1% of the value that “approximately” refers to.

[0038] The terms “polypeptide,” “peptide,” “protein,” and their grammatical equivalents, as used interchangeably herein, refer to polymers of amino acids of any length, which may be linear or branched. These may include unnatural or modified amino acids, or may be interrupted by non-amino acids. Polypeptides, peptides, or proteins may also be modified, for example, by the formation of disulfide bonds, glycosylation, lipidation, acetylation, phosphorylation, or any other operation or modification.

[0039] As used herein, the term “fusion protein” refers to a polypeptide consisting of two or more domains covalently linked. Each domain may originate from a different protein. These domains are linked directly by a single peptide bond or via a peptide linker containing one or more amino acid residues. Typically, the two domains and the linker are in the same reading frame and are constructed using recombinant technology. Fusion proteins designed to inhibit VEGF and complement pathways may have a complement inhibitory domain (CID), a VEGF inhibitory domain (VID), and a half-life extension domain. A detailed description of “CID,” “VID,” and “half-life extension domain” is provided in WO2013082563A1, which is incorporated herein in its entirety.

[0040] In this specification, the term “variant” as used in relation to a protein or polypeptide having a particular sequence feature (“reference protein” or “reference polypeptide”) means a different protein or polypeptide having one or more (e.g., about 1 to about 30, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) amino acid substitutions, deletions, and / or additions. Changes to the amino acid sequence may be amino acid substitutions. Changes to the amino acid sequence may be conserved amino acid substitutions. Changes to the amino acid sequence may be amino acid deletions. A variant may be a fragment of the reference protein or polypeptide. Functional variants of a protein or polypeptide maintain the basic structural and functional properties of the reference protein or polypeptide.

[0041] In this specification, the term “pharmaceutically acceptable” means a substance (e.g., an active ingredient or carrier) that, when used in contact with the tissues and organs of interest, does not cause excessive irritation, allergic reactions, immunogenicity, or toxicity, satisfies a reasonable risk-benefit ratio, and is effective for its intended use. The term “pharmaceutically acceptable carrier” means a substance suitable for administering a drug to a subject together with an active ingredient without causing undesirable biological effects or adverse interactions with any other components of the pharmaceutical composition. pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, and preservatives.

[0042] In this specification, the term “formulation” or “pharmaceutical composition” refers to a composition comprising at least one active ingredient and at least one carrier, suitable for administration to animals, preferably mammals (including humans). Formulations and pharmaceutical compositions may take the form of a liquid, which is referred to as a “liquid formulation” or “liquid composition.” Liquid formulations may be, for example, injectable formulations. Lipid formulations or pharmaceutical compositions contain a solvent. In this specification, the term “solvent” refers to a liquid substance used to dissolve or suspend active and non-active ingredients to form a liquid formulation. Solvents include, but are not limited to, organic solvents for injection, such as water for injection and oil for injection, ethanol, propylene glycol, or combinations thereof.

[0043] As used herein, the term “to treat” and its grammatical synonyms refer to measures taken to control the disease or condition of interest. This includes suppression, elimination, reduction, or improvement of symptoms, as well as prevention, delay, mitigation, or reversal of the progression or severity of the condition. Desired therapeutic effects include symptom relief, reduction of disease severity, stabilization of the condition, delay or slowing of disease progression, and potential reduction or remission of the disease. A patient in need of treatment refers to a person experiencing symptoms or effects of the disease or condition of interest.

[0044] As used herein, the term “prevent” and its grammatical synonyms refer to the suppression or avoidance of the onset or progression of symptoms associated with a disease or condition. Individuals with a family history of the disease may be appropriate subjects for preventive intervention. Typically, “prevention” includes administering drugs or treatments to individuals identified as particularly at risk before any signs or symptoms appear.

[0045] As used herein, the term “administer” and its grammatical synonyms refer to the act of delivering or causing a therapeutic composition or pharmaceutical composition into the body of a subject by the methods described herein or by methods well known to those skilled in the art. Administration of a therapeutic composition or pharmaceutical composition includes prescribing a therapeutic composition or pharmaceutical composition to be delivered into the body of a subject. Examples of dosage forms include oral dosage forms such as tablets, capsules, syrups, and suspensions; injectable dosage forms such as intravenous (IV), intramuscular (IM), and intraperitoneal (IP); transdermal dosage forms including creams, jellies, powders, and patches; buccal dosage forms; and inhalation powders, sprays, suspensions, and rectal suppositories. A therapeutic composition or pharmaceutical composition may also be administered in combination with one or more additional therapeutic agents or treatments to achieve a beneficial therapeutic effect. Combination therapy or combination treatment includes the simultaneous or sequential administration of different drugs or treatments.

[0046] As used herein, “effective dose,” “therapeutic effective dose,” and their grammatical synonyms refer to the administration of a drug to a subject. This is an amount administered alone or as part of a pharmaceutical composition, either as a single dose or as part of a series of doses, that, when administered to the subject, produces a detectable desirable effect against any symptom, aspect, or characteristic of a disease, disorder, or condition. The therapeutic effective dose can be determined by measuring the relevant physiological effect. The exact amount required varies from subject to subject, depending on the subject's age, weight, general condition, the severity of the condition being treated, and the clinician's judgment. The appropriate “effective dose” for individual cases can be determined by a person skilled in the art through standard testing. The “effective dose” of a therapeutic agent can be described using various units of measurement, such as milligrams (mg). In this specification, when referring to the administration of a therapeutic agent to a diseased eye, a specified dose, such as X mg, indicates the dose per eye.

[0047] In this specification, the term “subject” means any animal, including but not limited to livestock (e.g., cattle, goats, rabbits, corn dogs, horses), primates (e.g., humans and non-human primates such as monkeys), and rodents (e.g., mice, rats), that is the subject of a particular treatment. A subject may be a human being, such as an adolescent or an adult. A subject may have a particular disease or condition.

[0048] Scope: Throughout this specification, various aspects of the invention may be presented in range form. Range form descriptions are for convenience and brevity only and should not be interpreted as strict limitations on the scope of the invention. Therefore, range descriptions should be considered to specifically disclose not only the individual numerical values ​​within that range, but also all conceivable subranges. For example, a range description such as "1 to 6" is considered to include the individual numerical values ​​within that range (e.g., 1, 2, 2.7, 3, 4, 5, 5.3, and 6). This applies regardless of the breadth of the range.

[0049] In this specification, exemplary genes and polypeptides are described with reference to their GenBank numbers, GI numbers, and / or sequence numbers. Those skilled in the art will understand that homologous sequences can be readily identified by referring to sequence sources, including but not limited to GenBank (ncbi.nlm.nih.gov / genbank / ) and EMBL (embl.org / ).

[0050] 7.2 Composition This specification provides fusion protein molecules designed and synthesized to simultaneously inhibit both the VEGF pathway and the complement pathway. In some embodiments, the fusion protein comprises a VEGF inhibitory domain ("VID"), a half-life extension domain, a peptide linker, and a complement inhibitory domain ("CID") from the N-terminus to the C-terminus. In some embodiments, the half-life extension region is an immunoglobulin Fc region.

[0051] In some embodiments, the CID domain inhibits complement activation. In some embodiments, CID may have an amino acid sequence that is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to SEQ ID NO: 2. In some embodiments, CID may have an amino acid sequence that is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to SEQ ID NO: 3. In some embodiments, CID has an amino acid sequence that is at least 95% identical to SEQ ID NO: 2. In some embodiments, CID has the amino acid sequence of SEQ ID NO: 2. In some embodiments, CID has an amino acid sequence that is at least 95% identical to SEQ ID NO: 3. In some embodiments, CID has the amino acid sequence of SEQ ID NO: 3.

[0052] In some embodiments, the VID domain inhibits the VEGF pathway and includes the immunoglobulin-like (Ig) domain 2 of human VEGFR-1 and the Ig-like domain 3 of human VEGFR-2. In some embodiments, VID may have an amino acid sequence that is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to SEQ ID NO: 4. In some embodiments, VID may have an amino acid sequence that is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to SEQ ID NO: 5. In some embodiments, VID has an amino acid sequence that is at least 95% identical to SEQ ID NO: 4. In some embodiments, VID has the amino acid sequence of SEQ ID NO: 4. In some embodiments, VID has an amino acid sequence that is at least 95% identical to SEQ ID NO: 5. In some embodiments, VID has the amino acid sequence of SEQ ID NO: 5.

[0053] In some embodiments, the half-life extension domain includes the Fc region of an immunoglobulin such as human IgG1, IgG2, IgG3, or IgG4. In some embodiments, the half-life extension domain may have an amino acid sequence that is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to SEQ ID NO: 6. In some embodiments, the half-life extension domain has an amino acid sequence that is at least 95% identical to SEQ ID NO: 6. In some embodiments, the half-life extension domain has the amino acid sequence of SEQ ID NO: 6.

[0054] In some embodiments, the fusion protein has an amino acid sequence that is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to SEQ ID NO: 1. In some embodiments, the fusion protein is Efdamlovsp Alpha (SEQ ID NO: 1).

[0055] Efdamlovsp alfa is a fusion protein containing a complement inhibitory domain (CID), a VEGF inhibitory domain (VID), and a half-life extension domain. Therefore, Efdamlovsp alfa can inhibit both the VEGF pathway and the complement pathway. Efdamlovsp alfa has the amino acid sequence of SEQ ID NO: 1. (Sequence ID 1)

[0056] Additional information regarding efdamlovsp alfa (including its bifunctional properties in vitro and in vivo, as well as its pharmacodynamic, pharmacokinetic, and toxicological characteristics) is described in WO2013082563A1 and WO2021129658, which are incorporated herein by reference in their entirety. Methods for preparing recombinant fusion proteins are well known to those skilled in the art. The method for preparing efdamlovsp alfa is also described in WO2013082563A1.

[0057] Furthermore, compositions comprising efdamlovsp alpha are disclosed herein. In some embodiments, pharmaceutical compositions comprising efdamlovsp alpha and a pharmaceutically acceptable carrier are disclosed herein. The compositions disclosed herein are useful for the treatment of AMD, such as nAMD, in subjects requiring treatment. The compositions disclosed herein are useful for the treatment of DME in subjects requiring treatment.

[0058] In some embodiments, this specification provides pharmaceutical compositions comprising Efdamlovsp alfa and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier includes, but is not limited to, buffers, excipients, stabilizers, or preservatives. Pharmacologically acceptable carriers that may be included in compositions used in the methods described herein include any physiologically compatible solvent, dispersion medium, coating agent, antimicrobial and antifungal agent, isotonic agent, and absorption retarder. In some embodiments, the carrier is suitable for topical administration (e.g., by intravitreal injection).

[0059] In some embodiments, the pharmaceutical compositions provided herein are available in liquid form, such as injectable solutions, or as dry powder formulations. The liquid formulation may include: (i) a fusion protein disclosed herein (e.g., Efdamlovsp alfa); (ii) a buffer; and (iii) a solvent. Buffers that may be pH buffers may be selected from histidine, glutamic acid, phosphoric acid, acetic acid, citrate, or tris(hydroxymethyl)aminomethane. Solvents usable with these compositions include water, Ringer's solution, phosphate-buffered saline, isotonic sodium chloride solution, and water for injection. Organic solvents such as ethanol, propylene glycol, and oil for injection may also be used. Furthermore, sterile non-volatile oils containing synthetic monoglycerides or diglycerides can be used as solvents or suspension media, and fatty acids such as oleic acid are suitable for the preparation of injectable formulations. In the case of dry powder formulations, the composition is a lyophilized powder and can be reconstituted into pharmaceutically acceptable liquid carriers as described above to form injectable solutions.

[0060] In some embodiments, the liquid formulations provided herein contain various concentrations of efdamlovsp alpha. In some embodiments, the liquid formulations provided herein contain 20 to 100 mg / mL of efdamlovsp alpha. In some embodiments, the liquid formulations provided herein contain 40 to 100 mg / mL of efdamlovsp alpha. In some embodiments, the liquid formulations provided herein contain about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, or about 100 mg / mL of efdamlovsp alpha. In some embodiments, the liquid formulations provided herein contain about 40 mg / mL of efdamlovsp alpha. In some embodiments, the liquid formulations provided herein contain about 80 mg / mL of efdamlovsp alpha.

[0061] In some embodiments, the liquid pharmaceutical formulations provided herein are suitable for injection.

[0062] In some embodiments, the pharmaceutical compositions provided herein may be in the form of a dry powder formulation. For example, the composition may be a lyophilized powder and may be prepared into a pharmaceutically acceptable liquid carrier for injection. The pharmaceutically acceptable liquid carrier may be, for example, sterile water, Ringer's solution, phosphate-buffered saline, or isotonic sodium chloride solution.

[0063] In some embodiments, this specification provides pharmaceutical compositions comprising Efdamlovsp alfa. In some embodiments, the pharmaceutical composition comprises the following additives: sodium citrate (dihydrate), arginine, sucrose, and polysorbate 20. In some embodiments, the pH of the pharmaceutical composition is 6.2.

[0064] In some embodiments, the single dose of the pharmaceutical composition provided herein is a liquid formulation of 0.2 mL or less. Therefore, the injection volume is 0.2 mL or less. In some embodiments, the injection volume is between 0.01 mL and 0.2 mL. In some embodiments, the single dose of the pharmaceutical composition described herein is a liquid formulation of about 0.1 mL. Therefore, in some embodiments, the injection volume is about 0.1 mL.

[0065] In some embodiments, the pharmaceutically acceptable compositions provided herein are provided as single-dose units. “Single-dose unit” means a specific amount or quantity of the active pharmaceutical ingredient (e.g., efdamlovsp alfa) intended for single administration to an individual. It is a pre-measured unit designed for one-time use or administration. A single-dose unit may be in the form of a vial, ampoule, pre-filled needle, or pre-filled syringe for injection. A single-dose unit may be in the form of a liquid solution or a lyophilized powder. In some embodiments, a single-dose unit contains efdamlovsp alfa in amounts of about 4 mg, about 5 mg, about 6.4 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 12.8 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg. In some embodiments, a single-dose unit contains approximately 6.4 mg of efdamlovsp alfa. In some embodiments, a single-dose unit contains approximately 8 mg of efdamlovsp alfa. In some embodiments, a single-dose unit contains approximately 12.8 mg of efdamlovsp alfa. In some embodiments, a single-dose unit contains approximately 16 mg of efdamlovsp alfa. In some embodiments, a single-dose unit may contain more of the active pharmaceutical ingredient than is administered, and the remaining ingredient is discarded after administration. For example, a single-dose unit may contain 0.2 ml:16 mg of efdamlovsp alfa in one vial, and the single dose for injection may be 8 mg. It is common practice for the healthcare professional administering the injection to adjust the injection volume based on the actual dose, i.e., 0.1 ml:8 mg, and discard the remaining 0.1 ml after injection. In some embodiments, a single-dose unit contains 0.2 ml:8 mg of efdamlovsp alfa in a vial. In some embodiments, a single dose unit contains 0.2 ml:16 mg of efdamlovs alfa in a vial.

[0066] In some embodiments, the single dose of the pharmaceutical composition provided herein is a liquid formulation of 0.2 mL or less. Therefore, the injection volume is 0.2 mL or less. In some embodiments, the injection volume is between 0.01 mL and 0.2 mL. In some embodiments, the single dose of the pharmaceutical composition described herein is a liquid formulation of about 0.1 mL. Therefore, in some embodiments, the injection volume is about 0.1 mL.

[0067] In some embodiments, a single dose unit contains 2.94 mg / ml of sodium citrate (dihydrate), 13.94 mg / ml of arginine, 50.00 mg / ml of sucrose, and 0.3 mg / ml of polysorbate 20, in a liquid solution with a pH of 6.2 containing efdamlovsp alfa.

[0068] Furthermore, a drug kit containing a single-dose unit of Efdamlovsp alfa as described herein is also provided.

[0069] This specification provides safe and effective treatment regimens for ophthalmic vascular diseases, specifically formulated for the treatment of nAMD and DME, using efdamlovsp alfa.

[0070] 7.3 Treatment method: AMD The bispecific fusion proteins (e.g., efdamlovsp alfa) and pharmaceutical compositions disclosed herein, which have the ability to neutralize both VEGF activity and complement activity, can be used to treat AMD (e.g., nAMD). In some embodiments, the herein provides a method for treating AMD (e.g., nAMD) in a subject requiring treatment. This method comprises administering a therapeutically effective amount of efdamlovsp alfa to the subject.

[0071] In some embodiments, the subject may be human. In some embodiments, the subject may have AMD (e.g., nAMD). In some embodiments, the subject may be at risk of developing AMD (e.g., nAMD). In some embodiments, the subject may have one “affected eye,” i.e., an eye diagnosed with AMD (e.g., nAMD). In some embodiments, the subject may have two affected eyes. As is clear from the context, in this specification, treatment of the “subject” is synonymous with treatment of the “affected eye (or both eyes) of the subject.” Characterization of the “treated subject” (e.g., BCVA score, presence or absence of active CNV, GA, etc.) is performed on the “affected eye (eye) of the treated subject.” Similarly, evaluation of the treatment effect in the “treated subject” (e.g., improvement in BCVA, reduction in CNV, etc.) is also performed on the “affected eye (eye) of the treated subject.”

[0072] In some embodiments, the subjects receiving treatment are 18 years of age or older. In some embodiments, the subjects are 30 years of age or older. In some embodiments, the subjects are 40 years of age or older. In some embodiments, the subjects are 45 years of age or older. In some embodiments, the subjects are 50 years of age or older. In some embodiments, the subjects are 55 years of age or older. In some embodiments, the subjects are at least 60 years of age. In some embodiments, the subjects have been newly diagnosed with nAMD. In some embodiments, the subjects have been diagnosed with nAMD within the last month. In some embodiments, the subjects have been diagnosed with nAMD for up to 12 years. In some embodiments, the subjects have been diagnosed with nAMD for, for example, from 1 month to 12 years, specifically 6 months, 1 year, 3 years, 5 years, 8 years, 12 years, or longer.

[0073] In some embodiments, this specification provides uses of efdamlovsp alfa in the treatment of AMD (e.g., nAMD). In some embodiments, this specification provides uses of efdamlovsp alfa in the manufacture of pharmaceuticals for the treatment of AMD (e.g., nAMD). In some embodiments, the pharmaceutical compositions provided herein can be administered alone or in combination with additional therapeutic agents for AMD (e.g., nAMD). In some embodiments, efdamlovsp alfa is used alone in treatment. In some embodiments, efdamlovsp alfa is used in combination therapy with other treatments such as laser therapy.

[0074] 7.3.1 Subtypes / Patient Populations of AMD This specification provides a method for using efdamlovsp alfa in the treatment of AMD. In one embodiment, AMD is nAMD. Subjects having nAMD may have one or more of the following symptoms: decreased visual acuity, metamorphopsia, central scotoma, dyslexia, macular retinal edema, retinal hemorrhage, neovascularization, scar fibrosis, geographical atrophy, and similar conditions.

[0075] Macular atrophy ("MA") and geographical atrophy ("GA"): MA refers to the progressive degeneration and thinning of the macula. MA involves the loss of RPE cells, which leads to the death of photoreceptors in the macula and results in loss of central vision in nAMD. GA is characterized by widespread and well-defined loss of RPE and photoreceptor cells in the macula, forming a distinct "geographical" pattern, such as circular or oval areas, in patients with dry AMD. MA or GA can be detected by optical coherence tomography ("OCT"). The areas of MA or GA can also be measured by OCT. Furthermore, in the later stages of AMD, retinal fibrosis may occur due to the accumulation of cellular debris caused by the death of RPE cells or the progression of choroidal neovascularization (CNV), destroying normal retinal structures. This induces a wound healing process and the formation of fibrous tissue. Retinal fibrosis can be detected by color fundus photography (CFP). The fibrotic areas can also be measured by CFP.

[0076] In some embodiments, the subject treated by the method disclosed herein has newly developed MA. In some embodiments, the subject has retinal fibrosis. In some embodiments, the subject has GA.

[0077] Choroidal neovascularization (CNV): As those skilled in the art will understand, CNV refers to the abnormal proliferation of blood vessels in the choroid, which is located beneath the retina. CNV can occur through tears in Bruch's membrane, between Bruch's membrane and the retinal pigment epithelium (RPE), between the neurosensory retina and the RPE, or between the RPE and the choroid.

[0078] CNVs are classified as follows: Type I (or latent) CNV refers to blood vessels located beneath the RPE. Type I CNV shows latent leakage on fluorescein angiography. Polypoid choroidal neovascularization ("PCV") is a subtype of Type I CNV, characterized by polypoidal aneurysmal dilation in a branched vascular network. Type II (or classical) CNV refers to blood vessels that dilate into the subretinal space between the sensory retina and the RPE. Type III refers to retinal angiomatoid proliferation (RAP), which corresponds to neovascularization that originates within the sensory retina and progresses posteriorly into the subretinal space.

[0079] As used herein, a subject is considered to have "active CNV" if the presence of intraretinal fluid (IRF) or subretinal fluid (SRF) is detected by OCT, or if fluorescence leakage is detected by fundus fluorescein angiography (FFA).

[0080] Pigment epithelial detachment ("PED") is also one of the characteristics of CNV in nAMD that can be detected by OCT. The pigment epithelium is a cell layer located directly beneath the photoreceptor cells of the retina, and PED refers to detachment from this underlying layer and separation between layers.

[0081] A CNV area refers to the physical extent or size of the area occupied by choroidal neovascularization, i.e., newly formed blood vessels. A CNV leakage area refers to a specific area where abnormal blood vessels are actively leaking fluid, blood, or other substances into the surrounding tissue. Both CNV areas and CNV leakage areas can be detected by FFA. In some embodiments, the CNV area (including classical and latent types) in a diseased eye can account for more than 50% of the total lesion area (including hemorrhage, CNV, atrophy, and fibrosis).

[0082] In some embodiments, subjects treated by the methods disclosed herein have CNVs. In some embodiments, subjects have active CNVs. In some embodiments, subjects have active subfoveal CNVs secondary to nAMDs, or active CNVs affecting the fovea. In this specification, “fovea” refers to a 1 mm diameter circle at the center of the macula. In some embodiments, subjects have active submacular CNVs secondary to nAMDs. In some embodiments, subjects have active perimacular CNVs secondary to nAMDs. In some embodiments, subjects have active macular CNVs affecting the macula, where the active CNV may be perimacular or extramacular. In some embodiments, subjects have type II CNVs. In some embodiments, subjects do not have type II CNVs.

[0083] In some embodiments, the subject treated by the method disclosed herein has IRF or SRF. In some embodiments, the subject has PED.

[0084] Best Corrected Visual Acuity ("BCVA"): BCVA is an index that measures the best visual acuity a person can achieve with the use of corrective lenses (glasses or contact lenses) or other visual aids, and reflects the actual visual acuity of the subject (or the eye being tested). Typically, it is evaluated using a visual acuity chart (e.g., the ETDRS visual acuity chart, an abbreviation for the Early Diabetic Retinopathy Treatment Study (ETDRS)). The ETDRS visual acuity chart consists of 14 rows (70 characters) with 5 characters of uniform difficulty in each row, and standardized spacing between characters and lines. An ETDRS character score can be calculated if 20 or more characters can be correctly read at 4.0 meters. The visual acuity character score is the total number of characters correctly read at 4.0 meters plus 30. If fewer than 20 characters can be correctly read at 4.0 meters, the visual acuity character score is the total number of characters correctly read at 4.0 meters (number of characters recorded in row 1.0) plus the total number of characters in the first 6 rows correctly read at 1.0 meter. Therefore, the ETDRS character score can be up to 100 points. Generally, a decrease in reading ability of three or more lines (15 or more characters) on the ETDRS chart corresponds to twice the field of vision and is considered moderate visual impairment. On the other hand, a decrease in reading ability of six or more lines (30 or more characters) corresponds to four times the field of vision and is considered severe visual impairment.

[0085] In some embodiments, the BCVA of the affected eye to be treated by the method described herein is less than 82 characters. In some embodiments, the BCVA of the target is 81 characters or less in ETDRS characters. In some embodiments, the BCVA of the target is 80 characters or less in ETDRS characters. In some embodiments, the BCVA of the target is 79 characters or less in ETDRS characters. In some embodiments, the BCVA of the target is 78 characters or less in ETDRS characters. In some embodiments, the BCVA of the target is 77 characters or less in ETDRS characters. In some embodiments, the BCVA of the target is 76 characters or less in ETDRS characters. In some embodiments, the BCVA of the target is 75 characters or less in ETDRS characters. In some embodiments, the BCVA of the target is 74 characters or less in ETDRS characters. In some embodiments, the BCVA of the target is 73 characters or less in ETDRS characters. In some embodiments, the BCVA of the target is 72 characters or less in ETDRS characters. In some embodiments, the BCVA of the target is 71 characters or less in ETDRS characters. In some embodiments, the BCVA of the target is 70 characters or less in ETDRS characters. In some embodiments, the BCVA of the affected eye of the subject treated by the method described herein is at least 18 ETDRS characters. In some embodiments, the BCVA of the subject is at least 19 ETDRS characters. In some embodiments, the BCVA of the subject is at least 20 ETDRS characters. In some embodiments, the BCVA of the subject is at least 21 ETDRS characters. In some embodiments, the BCVA of the subject is at least 22 ETDRS characters. In some embodiments, the BCVA of the subject is at least 23 ETDRS characters. In some embodiments, the BCVA of the subject is at least 24 ETDRS characters. In some embodiments, the BCVA of the subject is at least 25 ETDRS characters.

[0086] In some embodiments, the BCVA of the affected eye treated by the method described herein (i.e., baseline BCVA) is in the range of 19 to 78 ETDRS characters (inclusive). In some embodiments, the BCVA of the affected eye treated by the method described herein is in the range of 24 to 73 ETDRS characters (inclusive). In some embodiments, the BCVA of the affected eye treated by the method described herein is in the range of 24 to 78 ETDRS characters (inclusive). In some embodiments, the BCVA of the subject is at least 64. In some embodiments, the BCVA of the subject is 63 or less. In some embodiments, the BCVA of the affected eye treated by the method described herein is in the range of 19 to 63 ETDRS characters (inclusive). In some embodiments, the BCVA of the affected eye treated by the method described herein is in the range of 24 to 63 ETDRS characters (inclusive). In some embodiments, the BCVA of the affected eye treated by the method described herein is in the range of 64 to 78 ETDRS characters (inclusive). In some embodiments, the BCVA of the affected eye treated by the method described herein is in the range of 64 to 73 ETDRS characters (inclusive). In some embodiments, the BCVA of the affected eye treated by the method described herein is in the range of 50 to 73 ETDRS characters (inclusive). In some embodiments, the BCVA of the affected eye treated by the method described herein is in the range of 30 to 65 ETDRS characters (inclusive). In some embodiments, the BCVA of the affected eye treated by the method described herein is in the range of 24 to 50 ETDRS characters (inclusive).

[0087] Subcenter thickness (CST): This is an index that quantitatively measures the thickness of the subcenter region of the macula. CST is often measured using SD-OCT to monitor the progression of AMD and the effectiveness of treatment. An increase in CST suggests the presence of macular edema and disease progression, while a decrease in CST suggests a good response and reduction of macular edema.

[0088] In some embodiments, the CST in the affected eye of a subject treated by the method disclosed herein is at least 250 μm, at least 280 μm, at least 300 μm, or at least 325 μm as measured by SD-PCT. In some embodiments, the CST in the affected eye of a subject treated by the method described herein is at least 250 μm as measured by SD-PCT. In some embodiments, the CST in the affected eye of a subject treated by the method described herein is at least 280 μm as measured by SD-PCT.

[0089] Total lesion area: In this specification, the term “total lesion area” as used according to the understanding of those skilled in the art encompasses the area of ​​all lesions, including CNV, hemorrhage, PED, fibrosis, and atrophy. The total lesion area, or total lesion diameter, can be measured by FFA and CFP.

[0090] Anti-VEGF therapy: Anti-VEGF therapy, which inhibits the action of VEGF, is a widely used and effective treatment for nAMD. Approved anti-VEGF agents for the treatment of nAMD include, for example, ranibizumab, bevacizumab, aflibercept, brolucizumab, and falisimab-svoa. In some embodiments, subjects treated by the methods disclosed herein have previously received anti-VEGF therapy. In some embodiments, subjects treated by the methods disclosed herein have not previously received anti-VEGF therapy. In some embodiments, subjects treated by the methods disclosed herein have previously received treatment with ranibizumab. In some embodiments, subjects treated by the methods disclosed herein have previously received treatment with bevacizumab. In some embodiments, subjects treated by the methods described herein have previously received treatment with aflibercept. In some embodiments, subjects treated by the methods described herein have previously received treatment with brolucizumab. In some embodiments, subjects treated by the methods described herein have previously received treatment with falisimab-svoa.

[0091] In some embodiments, subjects treated by the methods described herein have not received any prior treatment within 30, 90, or 120 days prior to the commencement of the treatment described herein, namely, treatment with anticomplement agents, retinal grid laser or panretinal photocoagulation, laser posterior capsulotomy, or intraocular or periorbital corticosteroid injections. In some embodiments, subjects treated by the methods disclosed herein have not undergone vitreoretinal surgery.

[0092] In some embodiments, subjects treated by the methods disclosed herein satisfy the following characteristics: (1) being 50 years of age or older; (2) having active submacular or perimacular vascular necrosis (CNV) secondary to age-related macular degeneration (nAMD); (3) the CNV area (including classical and latent types) occupies 50% or more of the total lesion area (including hemorrhage, CNV, atrophy, and fibrosis); and (4) the BCVA of the affected eye is within the range of 24 to 73 (including endpoints). In some embodiments, the affected eye of the subject has type II CNV. In some embodiments, the affected eye of the subject does not have type II CNV. In some embodiments, the affected eye of the subject has previously received treatment for AMD. In some embodiments, the affected eye of the subject has not previously received treatment for AMD. In some embodiments, the affected eye of the subject has type II CNV and has previously received treatment for AMD. In some embodiments, the affected eye does not have type II CNV and has previously received treatment for AMD. In some embodiments, the affected eye has type II CNV and has not previously received treatment for AMD. In some embodiments, the affected eye does not have type II CNV and has not previously received treatment for AMD. CNV can be detected using OCT.

[0093] In some embodiments, subjects treated by the methods disclosed herein meet the following characteristics: (1) are 50 years of age or older; (2) have active submacular CNV secondary to nAMD, or active CNV located perimacula or extramacula but affecting the macula; (3) the CNV area (including classical and latent types) accounts for at least 50% of the total lesion area (including hemorrhage, CNV, atrophy, and fibrosis); and (4) have a BCVA between 24 and 78 (including both extremes). In some embodiments, the BCVA of the affected eye is 64 characters or more. In some embodiments, the BCVA of the affected eye is 63 characters or less. In some embodiments, the affected eye has previously been treated for AMD. In some embodiments, the eye has not previously been treated for AMD. In some embodiments, the BCVA of the affected eye is 64 characters or more and has previously been treated for AMD. In some embodiments, the BCVA of the affected eye is 63 characters or less and has previously been treated for AMD. In some embodiments, the BCVA of the affected eye is 64 characters or more, and the patient has not previously received treatment for AMD. In some embodiments, the BCVA of the affected eye is 63 characters or less, and the patient has not previously received treatment for AMD. CNV can be detected using OCT.

[0094] In some embodiments, subjects treated by the methods disclosed herein meet the following characteristics: (1) are 50 years of age or older; (2) have active submacular CNV secondary to nAMD, or active CNV affecting the fovea; and (3) the BCVA of the affected eye is within the range of 19 to 78 ETDRS letters (inclusive). In some embodiments, the affected eye of the subject has type II CNV. In some embodiments, the affected eye of the subject does not have type II CNV. In some embodiments, the affected eye of the subject has previously received anti-VEGF treatment. In some embodiments, the affected eye of the subject has not previously received anti-VEGF treatment. In some embodiments, the eye of the subject has type II CNV and has previously received anti-VEGF treatment. In some embodiments, the eye of the subject does not have type II CNV and has previously received anti-VEGF treatment. In some embodiments, the eye of the subject has type II CNV and has not previously received anti-VEGF treatment. In some embodiments, the eye of the subject does not have type II CNV and has not previously received anti-VEGF treatment. CNV can be detected using OCT.

[0095] In some embodiments, subjects treated by the methods disclosed herein have one or more of the following symptoms and / or signs: decreased visual acuity, increased central retinal thickness, subretinal / intraretinal / sub-RPE fluid, neovascularization, macular hemorrhage, visual distortion, central scotoma, dyslexia, macular edema, fundus hemorrhage, scar fibrosis, geographical atrophy, or any combination thereof. In other embodiments, subjects treated by the methods described herein have one or more of the following symptoms and / or signs: decreased visual acuity, increased central retinal thickness, subretinal / intraretinal / sub-RPE fluid, neovascularization, macular hemorrhage, or any combination thereof.

[0096] 7.3.2 Treatment regimen A pharmaceutical composition disclosed herein, comprising a fusion protein (e.g., ephdamlovsp alfa) disclosed herein, can be administered to a subject in need to treat AMD (e.g., nAMD). In some embodiments, the pharmaceutical composition disclosed herein is administered topically. In some embodiments, the pharmaceutical composition disclosed herein is administered topically. In some embodiments, the pharmaceutical composition disclosed herein is administered intralesionally. In some embodiments, the pharmaceutical composition disclosed herein is administered intravenously.

[0097] In some embodiments, the pharmaceutical composition comprising the fusion protein disclosed herein (e.g., Efdamlovsp alfa) is administered directly to the eye or ocular tissue. This administration can be achieved by a variety of methods, including topical application to the eye or injection into the eye or related tissue. Injection methods include, but are not limited to, intravitreal injection, periorbital injection, subretinal injection, scleral transperfusion injection, subscleral injection, choroidal injection, anterior chamber injection, subconjunctival injection, sub-Tenon's capsule injection, posterior injection, periorbital injection, posterior injection, posterior parascleral administration, or periscleral administration. The pharmaceutical composition may also be administered to the vitreous humor, optic nerve, aqueous humor, sclera, conjunctiva, the area between the sclera and conjunctiva, retinal and choroidal tissue, macula, or other areas inside or around the eye.

[0098] In some embodiments, the pharmaceutical compositions disclosed herein are administered by intravitreous injection. In some embodiments, the fusion proteins disclosed herein (e.g., efdamlovsp alfa) are administered by intravitreous injection.

[0099] Furthermore, this specification also describes therapeutic regimens comprising administering multiple doses of the pharmaceutical compositions disclosed herein, each dose containing a therapeutically effective amount of efdamlovsp alfa. In some embodiments, the therapeutically effective dose for a single dose is 0.01–8 mg, 0.05–8 mg, 0.05–6 mg, 0.5–5 mg, 1–5 mg, 2–5 mg, 0.5–2 mg, 1–3 mg, 2–4 mg, 2–3 mg, or 3–5 mg. In some embodiments, the therapeutically effective dose is 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg, 2.0mg, 2.1mg, 2.2mg, 2.3mg, 2.4mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9 mg, 3.0mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8mg, 3.9mg, 4.0mg, 4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5.0mg, 5.1mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8 mg, 5.9mg, 6.0mg, 6.1mg, 6.2mg, 6.3mg, 6.4mg, 6.5mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7.0mg, 7.1mg, 7.2mg, The effective doses are 7.3 mg, 7.4 mg, 7.5 mg, 7.6 mg, 7.7 mg, 7.8 mg, 7.9 mg, 8.0 mg, 8.1 mg, 8.2 mg, 8.3 mg, 8.4 mg, 8.5 mg, 8.6 mg, 8.7 mg, 8.8 mg, 8.9 mg, 9.0 mg, 9.1 mg, 9.2 mg, 9.3 mg, 9.4 mg, 9.5 mg, 9.6 mg, 9.7 mg, 9.8 mg, 9.9 mg, or 10.0 mg. In some embodiments, the effective therapeutic dose of efdamlovsp alfa is in the range of about 1.0 mg to about 8.0 mg. In some embodiments, the effective therapeutic dose of a single dose of efdamlovsp alfa is in the range of about 2.0 mg to about 8.0 mg.In some embodiments, the therapeutically effective dose of efdamlovsp alfa in a single dose is approximately 2.0 mg. In some embodiments, the therapeutically effective dose of efdamlovsp alfa in a single dose is approximately 3.2 mg. In some embodiments, the therapeutically effective dose of efdamlovsp alfa in a single dose may be approximately 4.0 mg. In some embodiments, the therapeutically effective dose of efdamlovsp alfa in a single dose may be approximately 6.4 mg. In some embodiments, the therapeutically effective dose of efdamlovsp alfa in a single dose may be approximately 8.0 mg. In this specification, specified doses, such as 1.0 to 8.0 mg, indicate the amount administered per eye.

[0100] In some embodiments, Efdamlovsp alfa is administered by intravitreal injection. In some embodiments, the injection volume is in the range of 0.01 mL to 0.1 mL. In some embodiments, the injection volume is in the range of 0.04 mL to 0.08 mL. In some embodiments, the injection volume is about 0.04 mL, 0.08 mL, or 0.1 mL. In some embodiments, the injection volume is about 0.1 mL.

[0101] In some embodiments, multiple doses of the pharmaceutical compositions disclosed herein may be administered at different dosing intervals. For example, they may be administered at intervals of approximately once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, once every eleven weeks, once every twelve weeks, once every thirteen weeks, once every fourteen weeks, once every fifteen weeks, or once every sixteen weeks. In some embodiments, the pharmaceutical compositions disclosed herein may be administered at dosing intervals ranging from once every four weeks to once every sixteen weeks. In some embodiments, the pharmaceutical compositions disclosed herein may be administered at a frequency of once every four weeks. In some embodiments, the pharmaceutical compositions disclosed herein may be administered once every eight weeks. In some embodiments, the pharmaceutical compositions disclosed herein may be administered once every twelve weeks. In some embodiments, the pharmaceutical compositions disclosed herein can be administered once every 16 weeks.

[0102] In some embodiments, a pharmaceutical composition comprising the fusion protein disclosed herein (e.g., efdamlovsp alfa) can be administered in two phases: a loading phase and a maintenance phase.

[0103] In this specification, the term “loading phase” refers to a therapeutic phase in which a fusion protein (e.g., efdamlovsp alfa) is administered to induce a desired therapeutic effect, such as clinical remission, clinical response, OCT remission, OCT disappearance, and / or symptom relief. In some embodiments, the desired therapeutic effect is improvement of visual acuity and / or improvement of macular structure. In some embodiments, the desired therapeutic effect is the subject achieving stable visual acuity and / or stabilization of the lesion. In some embodiments, the therapeutic effect is improvement of visual acuity and / or anatomical structure as observed on OCT. In some embodiments, the therapeutic effect is improvement of CST and / or BCVA.

[0104] The dose of the fusion protein administered during the loading phase is called the "loading dose." The length of the loading treatment period can be, for example, 4 weeks, 8 weeks, or 12 weeks. Patient evaluation can be performed 1 week, 4 weeks, or 8 weeks after the last loading dose. During the loading phase, one or more "loading doses" may be administered. In some embodiments, multiple doses are administered during the loading phase at predetermined intervals (called "loading intervals").

[0105] The terms “maintenance phase” and “on-demand phase,” used interchangeably in this specification, refer to the therapeutic phase following the loading phase, during which the fusion protein (e.g., efdamlovsp alfa) is administered at doses and intervals determined according to the patient’s condition to maintain the desired therapeutic effect. The dose of the fusion protein administered during the loading phase is called the “maintenance dose,” which may be the same as or different from the loading dose. During the maintenance phase, one or more “maintenance doses” may be administered. In some embodiments, multiple doses are administered at regular intervals during the maintenance phase (referred to as “maintenance intervals”).

[0106] During the loading phase, subjects receive more frequent doses than during the maintenance phase to obtain a rapid and powerful response to the treatment. The loading phase may be shorter than the maintenance phase. In some embodiments, the loading phase consists of the first two to eight weeks of the treatment regimen. In some embodiments, the loading phase consists of the first four to sixteen weeks of the treatment regimen. In some embodiments, the loading phase consists of the first eight to sixteen weeks of the treatment regimen. In some embodiments, the loading phase consists of the first twelve to sixteen weeks of the treatment regimen. In some embodiments, the loading phase consists of the first eight weeks. In some embodiments, the loading phase consists of the first twelve weeks. In some embodiments, the loading phase consists of the first sixteen weeks.

[0107] In some embodiments, a pharmaceutical composition comprising the fusion protein disclosed herein (e.g., efdamlovsp alfa) may be administered at intervals of approximately 3 to 5 weeks during the loading phase. In some embodiments, the pharmaceutical composition disclosed herein may be administered at intervals of approximately 4 weeks during the loading phase. In some embodiments, the loading phase may comprise 2 to 4 doses of the pharmaceutical composition disclosed herein, administered at intervals of approximately 3 to 5 weeks. In some embodiments, the loading phase may comprise at least 2 doses of the pharmaceutical composition disclosed herein, administered at intervals of approximately 3 to 5 weeks. In some embodiments, the loading phase may comprise 3 doses of the pharmaceutical composition disclosed herein, administered at intervals of approximately 3 to 5 weeks. In some embodiments, the loading phase may comprise 4 doses of the pharmaceutical composition disclosed herein, administered at intervals of approximately 3 to 5 weeks. In some embodiments, the loading phase may comprise 3 doses of the pharmaceutical composition disclosed herein, administered at intervals of approximately 4 weeks. In some embodiments, the loading period comprises four doses of the pharmaceutical composition disclosed herein, administered at intervals of approximately four weeks.

[0108] In some embodiments, the method provided herein includes a loading phase consisting of the first 8 to 16 weeks after the start of treatment, during which the pharmaceutical composition disclosed herein is administered two to four times, approximately every three to five weeks. In some embodiments, the method provided herein includes a loading phase consisting of the first 8 weeks of treatment, during which the pharmaceutical composition disclosed herein is administered three times at intervals of approximately four weeks. In some embodiments, the method provided herein includes a loading phase consisting of the first 12 weeks of treatment, during which the pharmaceutical composition disclosed herein is administered four times at intervals of approximately four weeks.

[0109] In some embodiments, the loading period can last longer than 12 weeks. In some embodiments, the loading period lasts for 4, 5, 6, or 7 months, and the fusion protein is administered once or twice a month. In some embodiments, the fusion protein is administered once a month.

[0110] During the loading phase, the single dose of the fusion protein (e.g., efdamlovsp alfa) is 0.01–8 mg, 0.05–8 mg, 0.05–6 mg, 0.5–5 mg, 1–5 mg, 2–5 mg, 0.5–2 mg, 1–3 mg, 2–4 mg, 2–3 mg, or 3–5 mg. In some embodiments, each single dose is 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg, 2.0mg, 2.1mg, 2.2mg, 2.3mg, 2.4mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9 mg, 3.0mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8mg, 3.9mg, 4.0mg, 4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5.0mg, 5.1mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8 mg, 5.9mg, 6.0mg, 6.1mg, 6.2mg, 6.3mg, 6.4mg, 6.5mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7.0mg, 7.1mg, 7.2mg, The dosages are 7.3 mg, 7.4 mg, 7.5 mg, 7.6 mg, 7.7 mg, 7.8 mg, 7.9 mg, 8.0 mg, 8.1 mg, 8.2 mg, 8.3 mg, 8.4 mg, 8.5 mg, 8.6 mg, 8.7 mg, 8.8 mg, 8.9 mg, 9.0 mg, 9.1 mg, 9.2 mg, 9.3 mg, 9.4 mg, 9.5 mg, 9.6 mg, 9.7 mg, 9.8 mg, 9.9 mg, or 10.0 mg. In some embodiments, each single-dose loading dose of Efdamlovsp alfa ranges from about 1.0 mg to about 8.0 mg. In some embodiments, each single-dose loading dose of Efdamlovsp alfa ranges from about 2.0 mg to about 8.0 mg. In some embodiments, each single-dose loading dose of Efdamlovsp alfa is about 2.0 mg.In some embodiments, each single dose of efdamlovsp alfa is approximately 3.2 mg. In some embodiments, each single dose of efdamlovsp alfa is approximately 4.0 mg. In some embodiments, each single dose of efdamlovsp alfa is approximately 6.4 mg. In some embodiments, each single dose of efdamlovsp alfa is approximately 8.0 mg. In this specification, specified doses, such as 1.0 to 8.0 mg, indicate the amount administered per eye.

[0111] The maintenance phase (i.e., the on-demand phase) follows the loading phase and aims to sustain the therapeutic effects achieved during the loading phase. The goal is to reduce the frequency of administration and use a more sustainable dose to provide continuous management and control of the disease or symptoms. In some embodiments, during the maintenance phase, the fusion protein disclosed herein (e.g., efdamlovsp alfa) may be administered as needed, determined by evaluating the treated eye after the final dose of the loading phase. In some embodiments, at least one dose of the fusion protein is administered during the maintenance phase. In some embodiments, multiple doses of the fusion protein are administered during the maintenance phase.

[0112] In some embodiments, during the maintenance phase, the pharmaceutical composition comprising the fusion protein disclosed herein (e.g., efdamlovsp alfa) can be administered at intervals of approximately 4 to 16 weeks. In some embodiments, the pharmaceutical composition disclosed herein can be administered at intervals of approximately 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, or 16 weeks during the maintenance period. In some embodiments, the pharmaceutical composition disclosed herein can be administered once every 8 weeks during the maintenance phase. In some embodiments, the pharmaceutical composition disclosed herein can be administered once every 12 weeks during the maintenance phase. In some embodiments, the pharmaceutical composition disclosed herein can be administered once every 16 weeks during the maintenance phase. The administration interval can also be adjusted as needed during the maintenance phase. In some embodiments, the administration interval is adjusted based on the evaluation of the treated eye at follow-up visits.

[0113] In some embodiments, the maintenance period is at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 52 weeks, at least 56 weeks, at least 60 weeks, at least 64 weeks, at least 68 weeks, at least 72 weeks, at least 76 weeks, at least 80 weeks, at least 84 weeks, at least 88 weeks, at least 92 weeks, at least 96 weeks, or at least 100 weeks.

[0114] In some embodiments, the methods provided herein include a maintenance phase comprising at least 24 weeks of treatment, during which the pharmaceutical composition disclosed herein is administered at intervals of approximately 8 weeks, approximately 12 weeks, or approximately 16 weeks. In some embodiments, the pharmaceutical composition disclosed herein is administered once every approximately 8 weeks during the maintenance therapy period. In some embodiments, the pharmaceutical composition disclosed herein is administered once every approximately 12 weeks during the maintenance therapy period. In some embodiments, the pharmaceutical composition disclosed herein is administered once every approximately 16 weeks during the maintenance therapy period.

[0115] During the maintenance phase, the single dose of the fusion protein (e.g., efdamlovsp alfa) can be 0.01–8 mg, 0.05–8 mg, 0.05–6 mg, 0.5–5 mg, 1–5 mg, 2–5 mg, 0.5–2 mg, 1–3 mg, 2–4 mg, 2–3 mg, or 3–5 mg. In some embodiments, each single maintenance dose is 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg g, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg, 2.0mg, 2.1mg, 2.2mg, 2.3mg, 2.4mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2 .9mg, 3.0mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8mg, 3.9mg, 4.0mg, 4.1mg, 4.2mg, 4.3mg , 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5.0mg, 5.1mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5. 8mg, 5.9mg, 6.0mg, 6.1mg, 6.2mg, 6.3mg, 6.4mg, 6.5mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7.0mg, 7.1mg, 7.2mg The doses are 7.3 mg, 7.4 mg, 7.5 mg, 7.6 mg, 7.7 mg, 7.8 mg, 7.9 mg, 8.0 mg, 8.1 mg, 8.2 mg, 8.3 mg, 8.4 mg, 8.5 mg, 8.6 mg, 8.7 mg, 8.8 mg, 8.9 mg, 9.0 mg, 9.1 mg, 9.2 mg, 9.3 mg, 9.4 mg, 9.5 mg, 9.6 mg, 9.7 mg, 9.8 mg, 9.9 mg, or 10.0 mg. In some embodiments, each single maintenance dose of Evdamlovsp alfa is in the range of about 1.0 mg to about 8.0 mg. In some embodiments, each single maintenance dose of Evdamlovsp alfa is in the range of about 2.0 mg to about 8.0 mg. In some embodiments, each single maintenance dose of Evdamlovsp alfa is about 2.0 mg.In some embodiments, each single maintenance dose of efdamlovsp alfa is approximately 3.2 mg. In some embodiments, each single maintenance dose of efdamlovsp alfa is approximately 4.0 mg. In some embodiments, each single maintenance dose of efdamlovsp alfa is approximately 6.4 mg. In some embodiments, each single maintenance dose of efdamlovsp alfa is approximately 8.0 mg. In this specification, specified doses, such as 1.0 to 8.0 mg, indicate the amount administered per eye.

[0116] In some embodiments, the single dose remains constant throughout the entire treatment, including both the loading and maintenance phases. In some embodiments, the single dose is modified during treatment. In some embodiments, the single dose remains constant between the loading and maintenance phases, but is adjusted between the loading and maintenance phases.

[0117] In some embodiments, the single dose remains constant throughout the treatment period and ranges from approximately 1.0 mg to approximately 8.0 mg. In some embodiments, each single dose throughout the treatment period is approximately 2.0 mg. In some embodiments, each single dose throughout the treatment period is approximately 3.2 mg. In some embodiments, each single dose throughout the treatment may be approximately 4.0 mg. In some embodiments, each single dose throughout the treatment may be approximately 6.4 mg. In some embodiments, each single dose throughout the treatment may be approximately 8.0 mg.

[0118] In some embodiments, the methods provided herein include evaluating disease progression and response to treatment in subjects who have completed the loading phase, and using the evaluation results to determine a specific regimen for the maintenance phase. This evaluation can be performed about 6 to 10 weeks after the last dose of the loading phase. In some embodiments, this evaluation can be performed about 8 weeks after the last dose of the loading phase. In some embodiments, the methods described herein include performing a single evaluation. In some embodiments, the methods described herein include performing two evaluations at intervals of about 2 to 6 weeks. In some embodiments, the two evaluations can be performed at intervals of 4 weeks.

[0119] In some embodiments, the interval between the last dose of the loading phase and the first dose of the maintenance phase is the same as the interval between doses of the maintenance phase.

[0120] In some embodiments, the methods described herein include follow-up assessments during both the loading phase and the on-demand treatment phase to monitor the patient's condition and / or response to treatment. Assessments may include one or more of the following: (1) Measuring the change in BCVA from baseline using an ETDRS chart, e.g., an increase in ETDRS characters from baseline (e.g., ≥0 characters, ≥5 characters, ≥10 characters, or ≥15 characters), or a decrease in ETDRS characters from baseline (e.g., ≥0 characters, ≥5 characters, ≥10 characters, or ≥15 characters); (2) Measuring the change in CST from baseline using SD-OCT, e.g., a decrease in CST (e.g., ≥50 μm or ≥75 μm, or ≥0%, 10%, or ≥20%); an increase in CST, e.g., ≥50 μm or ≥75 μm, or ≥0%, 10%, or ≥20%; (3) Assessment of subretinal / intraretinal / RPE fluid, new CNVs, and / or new macular hemorrhages.

[0121] In some embodiments, follow-up evaluations are performed approximately one week after each administration of the fusion protein (e.g., efdamlovsp alfa) during the loading therapy phase. In some embodiments, follow-up evaluations are performed approximately two weeks after each administration of the fusion protein (e.g., efdamlovsp alfa) during the loading therapy phase. In some embodiments, follow-up evaluations are performed every four weeks during the on-demand therapy phase.

[0122] In some embodiments, the methods provided herein include (a) a loading phase in which a fusion protein (e.g., efdamlovsp alfa) is intravitreal administered at loading doses, with multiple consecutive doses at loading intervals until the desired therapeutic effect is achieved; and (b) an evaluation after a first follow-up interval (e.g., one week after each loading dose), which includes, for example, changes in BCVA (increase in ETDRS characters from baseline, e.g., 0, 5, 10, or 15 or more characters; decrease in ETDRS characters from baseline, e.g., 0, 5, 10, or 15 or more characters) and changes in CST. (c) Assessment of changes in value or percentage (e.g., ≥ 50 μm or ≥ 75 μm, or ≥ 0%, 10%, or ≥ 20%; assessment of value or percentage (e.g., ≥ 50 μm or ≥ 75 μm, or ≥ 0%, 10%, or ≥ 20%), and optionally, assessment of subretinal / intraretinal / RPE fluid, new CNVs, and / or new macular hemorrhages; and (c) assessment of the post-loading stage after a second follow-up period (e.g., 4 weeks after the last loading dose), assessment of changes in the patient's condition (e.g., changes in BCVA and / or CST), and maintenance (i.e., on-demand) administration based on that assessment.

[0123] In some embodiments, during the maintenance phase, follow-up evaluations are conducted to determine whether the subject meets the criteria for retreatment. In this specification, “retreatment” or its grammatical equivalent means that, in one or more follow-up evaluations during the maintenance phase, the patient was evaluated and determined not to require further drug administration. However, subsequent evaluations reveal a decline in treatment effectiveness or progression of the disease, necessitating additional treatment.

[0124] In some embodiments, the criteria for retreatment include: (i) a decrease of 5 or more letters in BCVA or an increase of 50 μm or more in CST compared to the previous visit; (ii) persistent subretinal / intraretinal / RPE fluid; (iii) new CNV; or (iv) new macular hemorrhage.

[0125] Therefore, in some embodiments, step (c) (evaluation after loading period) is repeated, so that the maintenance dose may include multiple treatment cycles, each cycle independently including evaluating changes in the patient's condition (e.g., changes in BCVA and / or CST) after a second follow-up interval and administering a maintenance dose based on that evaluation. In some embodiments, the maintenance dose is continued until the lesions regress and / or the patient's vision returns to normal. The maintenance dose may be continued for at least one, two, three, four, five years, or longer, or until the disease progresses.

[0126] In some embodiments, the single loading dose is in the range of 1 mg to 8 mg, for example, about 3.2 mg, about 6.4 mg, or about 8.0 mg. The method may include administering multiple doses during the loading phase at fixed loading intervals, such as once every four weeks. It may also include administering multiple doses during the maintenance phase at maintenance intervals, which may be the same or different. The maintenance interval may be the same as or longer than the loading interval. For example, every four weeks, every eight weeks, every twelve weeks, every sixteen weeks, every twenty weeks, every twenty-four weeks, or longer.

[0127] The methods described herein explicitly assume the selection of therapeutic doses and / or treatment intervals of the fusion protein during the loading and / or maintenance phases, with the aim of improving or maintaining visual acuity and / or improving or maintaining macular anatomical structure, in order to avoid overtreatment and undertreatment. After the loading phase (e.g., monthly administration for 2, 3, 4, 5, or 6 months), maintenance administration is performed. During the maintenance phase, the treatment interval is adjusted based on an assessment of the disease state, e.g., changes in BCVA or CST, or the presence or absence of subretinal / intraretinal / RPE fluid, new CNVs, and / or new macular hemorrhages.

[0128] In some embodiments, the initial follow-up interval at the start of maintenance therapy may be 4 weeks or 8 weeks. If the patient's condition is confirmed to be stable (e.g., stable CST and BCVA) after two consecutive follow-ups, the treatment interval may be extended, for example, by 4 weeks, while maintaining the initial follow-up interval. If the patient's condition deteriorates (e.g., deterioration of CST and / or BCVA) after two consecutive follow-ups, the patient continues treatment at the initial follow-up interval (e.g., 4 weeks).

[0129] In some embodiments, CST is considered stable if it increases by 50 μm or less between visits. BCVA is considered stable if it decreases by 5 letters or less between visits. A decrease of 5 letters or more between visits in BCVA due to nAMD is considered worsening. An increase of 50 μm or more between visits in CST due to nAMD is also considered worsening. Worsening may be indicated by worsening of BCVA or CST, persistent subretinal / intraretinal / RPE fluid, new CNVs, or new macular hemorrhages. In some embodiments, after a loading period (e.g., three consecutive monthly doses), follow-up assessments of CST and BCVA are performed at maintenance intervals (e.g., 4 weeks). If BCVA decreases by 5 letters or more, or CST increases by 50 μm or more, due to nAMD since the last visit, the patient continues loading dose therapy at the same follow-up intervals.

[0130] In some embodiments, the methods described herein include assessing disease activity ("DA") in subjects who have completed the loading phase. In some embodiments, DA is considered "present" if any of the following five criteria are met: (1) CST is increased by 50 μm or more compared to the mean CST over the past two months; (2) CST is increased by 75 μm or more compared to the lowest CST over the past two months; (3) BCVA is decreased by 5 letters or more compared to the mean BCVA over the past two months due to the progression of nAMD; (4) BCVA is decreased by 10 letters or more compared to the highest BCVA over the past two months due to the progression of age-related macular degeneration (nAMD); (5) A new macular hemorrhage occurs due to the progression of age-related macular degeneration (nAMD). The maintenance phase dosing interval can then be adjusted based on the presence or absence of DA.

[0131] In some embodiments, the method provided herein includes performing an evaluation on a subject that has completed the DA loading period, and if DA is detected at the time of evaluation, the pharmaceutical composition disclosed herein may be administered at a first maintenance interval. On the other hand, if DA is not detected at the time of evaluation, the pharmaceutical composition disclosed herein may be administered at a second maintenance interval (e.g., once every 12 weeks), the second maintenance interval being relatively longer than the first maintenance interval. In some embodiments, the first maintenance interval is every 8 weeks and the second maintenance interval is every 12 weeks. In some embodiments, the first maintenance interval is every 12 weeks and the second maintenance interval is every 16 weeks.

[0132] In some embodiments, the methods provided herein include performing an evaluation on subjects who have completed a DA loading phase, and if DA is present at the time of evaluation, the pharmaceutical compositions disclosed herein can be administered approximately every 8 weeks during the maintenance phase. On the other hand, if DA is not present at the time of evaluation, the pharmaceutical compositions disclosed herein can be administered approximately every 12 weeks during the maintenance phase.

[0133] In some embodiments, the method described herein includes performing a first evaluation on a subject that has completed the DA loading period. If DA is present at the time of the first evaluation, the pharmaceutical composition described herein may be administered at a first maintenance interval. If DA is not present at the time of the first evaluation, a second evaluation is performed approximately four weeks after the first evaluation. If DA is present at the time of the second evaluation, the pharmaceutical composition disclosed herein may be administered at a second maintenance interval. If DA is not present at the time of the second evaluation, the pharmaceutical composition disclosed herein may be administered at a third maintenance interval, where the third maintenance interval is longer than the second maintenance interval, and the second maintenance interval is longer than the first maintenance interval. In some embodiments, the first maintenance interval is once every four weeks, the second maintenance interval is once every eight weeks, and the third maintenance interval is once every twelve weeks. In some embodiments, the first maintenance interval is once every eight weeks, the second maintenance interval is once every twelve weeks, and the third maintenance interval is once every sixteen weeks.

[0134] In some embodiments, the method provided herein includes performing a first evaluation on a subject that has completed a DA loading phase. If DA is present at the time of the first evaluation, the pharmaceutical composition disclosed herein may be administered once approximately every 8 weeks during the maintenance phase. If DA is not present at the time of the first evaluation, a second evaluation is performed approximately 4 weeks after the first evaluation. If DA is detected at the time of the second evaluation, the pharmaceutical composition disclosed herein may be administered approximately every 12 weeks during the maintenance period. If DA is not detected at the time of the second evaluation, the pharmaceutical composition disclosed herein may be administered approximately every 16 weeks during the maintenance period.

[0135] In some embodiments, the method described herein comprises (1) administering a pharmaceutical composition containing about 2.0 mg or about 4.0 mg of efdamlovsp alfa to the affected eye of the subject three times at intervals of about 4 weeks; and then (2) administering the pharmaceutical composition to the affected eye of the subject at least two times at intervals of about 8 weeks. In some embodiments, the pharmaceutical composition may contain about 2.0 mg of efdamlovsp alfa. In some embodiments, the pharmaceutical composition may contain about 4.0 mg of efdamlovsp alfa. In some embodiments, the maintenance phase comprises administering the pharmaceutical composition disclosed herein at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, or at least 12 times. In some embodiments, the maintenance phase comprises administering the pharmaceutical composition disclosed herein about 5 times.

[0136] In some embodiments, this specification provides a method for treating nAMD in subjects requiring treatment. The method comprises (1) a loading phase in which a pharmaceutical composition containing about 6.4 mg or about 8.0 mg of efdamlovsp alfa is administered to the affected eye of the subject three or four times at intervals of about four weeks; and then (2) a maintenance phase in which the subject's DA is evaluated about eight weeks after the last dose of the loading phase, and if DA is observed at the time of evaluation, the formulation is administered to the affected eye of the subject at intervals of (a) once every eight weeks, or if DA is not observed, at intervals of (b) once every twelve weeks. In some embodiments, the pharmaceutical composition may contain about 6.4 mg of efdamlovsp alfa. In some embodiments, the pharmaceutical composition may contain about 8.0 mg of efdamlovsp alfa. In some embodiments, the loading phase comprises administering the pharmaceutical composition described herein about three times. In some embodiments, the loading phase comprises administering the pharmaceutical composition disclosed herein about four times. In some embodiments, the maintenance period includes administering the pharmaceutical composition disclosed herein at least once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, eleven times, or twelve times. In some embodiments, the maintenance period includes administering the pharmaceutical composition disclosed herein about three times. In some embodiments, the maintenance period includes administering the pharmaceutical composition disclosed herein about four times.

[0137] In some embodiments, this specification provides a method for treating nAMD in subjects requiring treatment. This method comprises (1) a loading phase in which a pharmaceutical composition containing approximately 8.0 mg of efdamlovsp alfa is administered to the affected eye of the subject three times at intervals of approximately 4 weeks; followed by (2) a maintenance phase in which a first evaluation of the subject's DA is performed approximately 8 weeks after the last dose of the loading phase, and (a) if DA is observed in the first evaluation, the pharmaceutical composition is administered to the affected eye of the subject at intervals of approximately 8 weeks; or (b) if DA is not observed at the first evaluation, a second evaluation of the subject's DA is performed approximately 4 weeks after the first evaluation, and if DA is observed at the second evaluation, the pharmaceutical composition is administered to the affected eye of the subject at intervals of (i) approximately 12 weeks; otherwise, (ii) once approximately 16 weeks. In some embodiments, the maintenance period includes administering the pharmaceutical composition disclosed herein at least once, at least twice, at least three times, at least four times, at least five times, at least six times, at least seven times, at least eight times, at least nine times, at least ten times, at least eleven times, or at least twelve times. In some embodiments, the maintenance period includes administering the pharmaceutical composition disclosed herein about five times. In some embodiments, the maintenance period includes administering the pharmaceutical composition disclosed herein about seven times. In some embodiments, the maintenance period includes administering the pharmaceutical composition disclosed herein about eleven times.

[0138] As used herein in relation to a treatment regimen, “week n” means the “nth” week from the start of treatment. For example, week 0 refers to week 6 from D0 (the start date of treatment), and week 4 refers to week 28 from week 34. Generally, the dose administered in a particular week is administered on the first day of that week. As those skilled in the art will understand, in some embodiments, the dose may be administered a few days earlier (e.g., 0–3 days) or a few days later (e.g., 0–3 days) without affecting the overall efficacy of the treatment.

[0139] In some embodiments, the efdamlovsp alfa treatment regimen described herein includes a loading phase and a maintenance phase, the loading phase lasting 16 weeks (weeks 0 to 15) and the maintenance phase lasting at least 32 weeks (weeks 20 to 52 and beyond). During the loading phase, efdamlovsp alfa is administered four times every four weeks, i.e., at weeks 0, 4, 8, and 12. At week 20 (eight weeks after the last dose of the loading phase), the presence or absence of DA in the subject is assessed. If DA is not detected at week 20, efdamlovsp alfa is administered every eight weeks during the maintenance phase, starting at week 20 (eight weeks after the last dose of the loading phase), i.e., at weeks 20, 28, 36, 44, and so on. If DA is not detected at week 20, efdamlovsp alfa is administered every 12 weeks during the maintenance phase, starting at week 24 (twelve weeks after the last dose of the loading phase). In some embodiments, efdamlovsp alfa is administered at weeks 24, 36, 48, etc. In some embodiments, each dose contains 6.4 mg or 8.0 mg of efdamlovsp alfa.

[0140] In some embodiments, DA is considered to be present at week 20 if any of the following five criteria are met: (1) CST is increased by 50 μm or more compared to the mean CST at weeks 8 and 12; (2) CST is increased by 75 μm or more compared to the lowest CST at weeks 8 and 12; (3) BCVA is decreased by 5 letters or more compared to the mean BCVA at weeks 8 and 12 due to the progression of nAMD; (4) BCVA is decreased by 10 letters or more compared to the highest BCVA at weeks 8 and 12 due to the progression of nAMD; (5) A new macular hemorrhage occurs due to the progression of nAMD.

[0141] In some embodiments, the efdamlovsp alfa treatment regimen described herein includes a loading phase and a maintenance phase, the loading phase lasting 16 weeks (weeks 0 to 16) and the maintenance phase lasting at least 24 weeks (weeks 16 to 44 or more). During the loading phase, efdamlovsp alfa is administered three times every four weeks, i.e., at week 0, week 4, and week 8. At week 16 (eight weeks after the last dose of the loading phase), the presence or absence of DA in the subject is assessed. If DA is not detected at week 16, efdamlovsp alfa is administered every eight weeks during the maintenance phase, starting from week 16 (eight weeks after the last dose of loading therapy). Therefore, in some embodiments, efdamlovsp alfa is administered at weeks 16, 24, 32, 40, and 48, etc. (optionally, it may also be administered at one or more of weeks 56, 64, 72, 80, 88, and 96). If DA is not detected at week 16, the subject is evaluated for the presence or absence of DA at week 20. If DA is detected at week 20, efdamlovsp alfa is started at week 20 (12 weeks after the last dose of the loading phase) and administered every 12 weeks during the maintenance phase. In some embodiments, efdamlovsp alfa is administered at weeks 20, 32, and 44, etc. (optionally, it may also be administered at one or more of weeks 56, 68, 80, and 92). If no DA is observed at week 20, efdamlovsp alfa is initiated at week 24 (16 weeks after the last dose of the loading phase) and administered every 16 weeks during the maintenance phase. In some embodiments, efdamlovsp alfa is administered at weeks 24, 40, etc. (optionally, it may also be administered at one or more of weeks 56, 72, and 88). In some embodiments, each dose contains 8.0 mg of efdamlovsp alfa.

[0142] In some embodiments, the criteria for the presence of DA at week 16 are as follows: DA is considered to be present at week 16 if any of the following five criteria are met: (1) CST is increased by 50 μm or more compared to the mean CST at weeks 8 and 12; (2) CST is increased by 75 μm or more compared to the lowest CST at weeks 8 and 12; (3) BCVA is decreased by 5 letters or more compared to the mean BCVA at weeks 8 and 12 due to the progression of nAMD; (4) BCVA is decreased by 10 letters or more compared to the highest BCVA at weeks 8 and 12 due to the progression of nAMD; (5) A new macular hemorrhage occurs due to the progression of nAMD. Subsequently, the maintenance dosing interval can be adjusted based on the presence or absence of DA.

[0143] In some embodiments, the criteria for the presence or absence of DA at week 20 are as follows: DA is considered “present” if any of the following five criteria are met: (1) CST is increased by 50 μm or more compared to the mean CST at weeks 12 and 16; (2) CST is increased by 75 μm or more compared to the lowest CST at weeks 12 and 16; (3) BCVA is decreased by 5 letters or more compared to the mean BCVA at weeks 12 and 16 due to the progression of nAMD; (4) BCVA is decreased by 10 letters or more compared to the highest BCVA at weeks 12 and 16 due to the progression of non-atrophic age-related macular degeneration (nAMD); (5) A new foveal hemorrhage occurs due to the progression of non-atrophic age-related macular degeneration (nAMD). Subsequently, the maintenance dosing interval can be adjusted based on the presence or absence of DA.

[0144] 7.3.3 Effectiveness The methods described herein are useful for the treatment of AMD (e.g., age-related macular degeneration). In some embodiments, the methods described herein alleviate or improve the symptoms of AMD in the patient. In some embodiments, the methods described herein improve the visual acuity of the patient. In some embodiments, the methods described herein prevent visual impairment in the patient. In some embodiments, the methods described herein improve or restore the patient's visual acuity over a long period of time (e.g., at least 6 months, 1 year, 2 years, 3 years, or longer). In some embodiments, the methods described herein reduce the central retinal thickness of the patient. In some embodiments, the methods described herein prevent or reduce CNV and / or leakage areas in the patient. In some embodiments, the methods described herein prevent or reduce retinal neovascularization (RNV) and / or leakage areas in the patient. In some embodiments, the methods described herein prevent or reduce retinal fibrosis in the patient. In some embodiments, the methods described herein prevent or reduce GA in the patient.

[0145] Visual acuity / BCVA In some embodiments, the methods described herein improve the BCVA of a patient. In some embodiments, the methods described herein prevent a decrease in the BCVA of a patient. In some embodiments, the methods described herein increase the BCVA of a patient by at least 0 ETDRS characters, at least 5 ETDRS characters, at least 10 ETDRS characters, at least 15 ETDRS characters, at least 20 ETDRS characters, at least 25 ETDRS characters, or at least 30 ETDRS characters. In some embodiments, the methods described herein improve the BCVA of a target by at least 0 ETDRS characters. In some embodiments, the methods described herein improve the BCVA of a target by at least 5 ETDRS characters. In some embodiments, the methods described herein improve the BCVA of a target by at least 10 ETDRS characters. In some embodiments, the methods described herein improve the BCVA of a target by at least 15 ETDRS characters. In some embodiments, the methods described herein improve the BCVA by at least 20 ETDRS characters. In some embodiments, the methods described herein improve the BCVA by at least 25 ETDRS characters. In some embodiments, the methods described herein improve BCVA by at least 30 ETDRS characters. In some embodiments, the methods described herein improve BCVA by at least 35 ETDRS characters.

[0146] In some embodiments, the methods provided herein improve the BCVA in the range of about 0 to about 30 ETDRS characters. In some embodiments, the methods provided herein improve the BCVA in the range of about 5 to about 35 ETDRS characters. In some embodiments, the methods provided herein improve the BCVA in the range of about 5 to about 30 ETDRS characters. In some embodiments, the methods described herein improve the BCVA in the range of about 5 to about 25 characters. In some embodiments, the methods described herein improve the BCVA in the range of about 5 to about 20 characters. In some embodiments, the methods described herein improve the BCVA in the range of about 5 to about 15 characters. In some embodiments, the methods described herein improve the BCVA in the range of about 10 to about 30 ETDRS characters. In some embodiments, the methods described herein improve the BCVA in the range of about 10 to about 25 ETDRS characters. In some embodiments, the methods described herein improve the BCVA in the range of about 10 to about 20 ETDRS characters. In some embodiments, the methods described herein improve the BCVA by about 10 to about 15 ETDRS characters. In some embodiments, the methods described herein improve the BCVA by about 15 to about 30 ETDRS characters. In some embodiments, the methods described herein improve the BCVA by about 15 to about 25 ETDRS characters. In some embodiments, the methods described herein improve the BCVA by about 15 to about 20 ETDRS characters.

[0147] In some embodiments, the methods described herein improve the BCVA by about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, or about 35 characters. In some embodiments, the methods described herein improve the BCVA by about 5 characters. In some embodiments, the methods described herein improve the BCVA by about 10 characters. In some embodiments, the methods described herein improve the BCVA by about 15 characters. In some embodiments, the methods described herein improve the BCVA by about 20 characters. In some embodiments, the methods described herein improve the BCVA by about 25 characters. In some embodiments, the methods described herein improve BCVA by approximately 30 characters.

[0148] In some embodiments, the method described herein yields a BCVA in a patient corresponding to at least about 50 characters, at least about 55 characters, at least about 60 characters, at least about 65 characters, at least about 70 characters, at least about 75 characters, or at least about 80 ETDRS characters. In some embodiments, the method described herein results in a BCVA of at least about 55 ETDRS characters. In some embodiments, the method described herein results in a BCVA of at least about 60 ETDRS characters. In some embodiments, the method described herein results in a BCVA of at least about 65 ETDRS characters. In some embodiments, the method described herein results in a BCVA of at least about 69 ETDRS characters. In some embodiments, the method described herein yields a BCVA of at least about 70 ETDRS characters. In some embodiments, the method described herein yields a BCVA of at least about 72 ETDRS characters.

[0149] In some embodiments, the methods described herein improve BCVA by 5% or more compared to baseline. In some embodiments, the methods described herein improve BCVA by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, or 150% compared to baseline. In some embodiments, the methods described herein increase BCVA by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 130%, 140%, or 150% compared to baseline. In some embodiments, the methods described herein increase BCVA by about 20% compared to the baseline. In some embodiments, the methods described herein increase BCVA by about 50% compared to the baseline. In some embodiments, the methods described herein increase BCVA by about 80% compared to the baseline. In some embodiments, the methods described herein increase BCVA by about 100% compared to the baseline. In some embodiments, the methods described herein increase BCVA by about 150% compared to the baseline. In some embodiments, the methods described herein increase BCVA by about 200% compared to the baseline. In some embodiments, the methods described herein increase BCVA by 10% to 200%, 10% to 150%, 10% to 100%, 20% to 100%, 50% to 100%, 60% to 100%, 20% to 80%, 30% to 70%, 50% to 70%, or 60% to 70% compared to the baseline. In some embodiments, the methods described herein increase BCVA by 50% to 70% compared to baseline.

[0150] Anatomical effectiveness detected by OCT In some embodiments, the methods described herein produce a therapeutic effect that can be anatomically measured using OCT (e.g., SD-OCT). For example, in some embodiments, the methods described herein reduce CST in the treated subject. In some embodiments, the methods described herein reduce or prevent the occurrence of SHM in the treated subject. In some embodiments, the methods described herein reduce or prevent the occurrence of IRF or SRF in the treated subject. In some embodiments, the methods described herein reduce or prevent the occurrence of PED in the treated subject. In some embodiments, the methods described herein reduce the RA area in the treated subject. In some embodiments, the methods described herein reduce or prevent the occurrence of new RA in the treated subject. In some embodiments, the methods described herein reduce the MA area in the treated subject. In some embodiments, the methods described herein reduce or prevent the occurrence of new MA in the treated subject. In some embodiments, the methods described herein reduce or prevent the occurrence of GA in the treated subject. SHM, IRF, SFR, RA, MA, and GA can be detected by OCT (e.g., SD-OCT).

[0151] In some embodiments, the methods described herein reduce the CST of a subject to be treated, as measured by OCT (e.g., SD-OCT). In some embodiments, the methods described herein reduce the CST by at least 25 μm, at least 50 μm, at least 75 μm, at least 100 μm, at least 125 μm, at least 150 μm, at least 175 μm, at least 200 μm, at least 225 μm, at least 250 μm, at least 275 μm, or at least 300 μm. In some embodiments, the methods described herein reduce the CST of a subject by about 25 μm, about 50 μm, about 75 μm, about 100 μm, about 125 μm, about 150 μm, about 175 μm, about 200 μm, about 225 μm, about 250 μm, about 275 μm, or about 300 μm as measured by OCT (e.g., SD-OCT). In some embodiments, the method described herein reduces the CST of an object measured by OCT (e.g., SD-OCT) by at least 25 μm. In some embodiments, the method described herein reduces the CST by about 50 μm. In some embodiments, the method described herein reduces the CST by about 75 μm. In some embodiments, the method described herein reduces the CST by about 100 μm. In some embodiments, the method described herein reduces the CST by about 125 μm. In some embodiments, the method described herein reduces the CST by about 150 μm. In some embodiments, the method described herein reduces the CST by about 175 μm. In some embodiments, the method described herein reduces the CST by about 200 μm.In some embodiments, the method described herein involves shaping the CST to approximately 25 μm to approximately 150 μm, approximately 50 μm to approximately 150 μm, approximately 75 μm to approximately 150 μm, approximately 100 μm to approximately 150 μm, approximately 125 μm to approximately 150 μm, approximately 25 μm to approximately 200 μm, approximately 50 μm to approximately 200 μm, approximately 75 μm to approximately 200 μm, approximately 100 μm to approximately 200 μm, approximately 125 μm to approximately 200 μm, The CST ranges are approximately 150 μm to 200 μm, approximately 175 μm to 200 μm, approximately 50 μm to 300 μm, approximately 75 to 300 μm, approximately 100 to 300 μm, approximately 125 to 300 μm, approximately 150 to 300 μm, approximately 175 to 300 μm, approximately 200 to 300 μm, approximately 250 μm to 300 μm, or approximately 25 μm to 350 μm, which are measured by OCT (e.g., SD-OCT). In some embodiments, the methods described herein reduce the CST in the range of approximately 50 μm to 200 μm. In some embodiments, the methods described herein reduce the CST in the range of approximately 100 μm to 200 μm. In some embodiments, the methods provided herein reduce the CST in the range of approximately 50 μm to 150 μm. In some embodiments, the methods provided herein reduce the CST in the range of about 100 μm to about 150 μm. In some embodiments, the methods provided herein reduce the CST in the range of about 125 μm to about 150 μm.

[0152] In some embodiments, the methods described herein reduce CST by 5% or more compared to the baseline. In some embodiments, the methods described herein reduce CST by 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, or 70% or more compared to the baseline. In some embodiments, the methods described herein reduce CST by 10% to 70% compared to the baseline. In some embodiments, the methods described herein reduce CST by 10% to 60% compared to the baseline. In some embodiments, the methods described herein reduce CST by 30% to 50% compared to the baseline. In some embodiments, the methods described herein reduce CST by 40% to 50% compared to the baseline. In some embodiments, the methods described herein reduce CST by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70% compared to baseline.

[0153] In some embodiments, the methods provided herein reduce or prevent the occurrence of SHM in a patient, as detected by OCT (e.g., SD-OCT). In some embodiments, the methods provided herein reduce or prevent the occurrence of IRF in a patient. In some embodiments, the methods provided herein reduce or prevent the occurrence of SRF in a patient. In some embodiments, the methods described herein reduce or prevent the occurrence of both IRF and SRF in a patient. In some embodiments, the methods described herein result in a state where neither IRF nor SRF is detectable by OCT (e.g., SD-OCT). In some embodiments, the methods described herein reduce or prevent the occurrence of IRF in the fovea. In some embodiments, the methods described herein reduce or prevent the occurrence of SRF in the fovea. In some embodiments, the methods described herein reduce or prevent the occurrence of both IRF and SRF in the fovea. IRF and SRF are detectable by OCT (e.g., SD-OCT).

[0154] In some embodiments, the methods provided herein reduce or prevent the occurrence of PEDs in objects detectable by OCT (e.g., SD-OCT). In some embodiments, the methods provided herein result in a state in which no PEDs detectable by OCT (e.g., SD-OCT) are present.

[0155] In some embodiments, the methods described herein reduce or prevent the development of new MAs in a treated patient as detected by OCT (e.g., SD-OCT). In some embodiments, the methods described herein delay or prevent the development of GAs in a treated patient. In some embodiments, the methods described herein reduce the area of ​​MAs in a treated patient as detected by OCT (e.g., SD-OCT).

[0156] Anatomical efficacy detected by FFA and CFP In some embodiments, the methods provided herein result in a therapeutic effect that can be anatomically measured using FFA or CFP. For example, in some embodiments, the methods provided herein reduce the CNV area of ​​the patient. In some embodiments, the methods provided herein reduce the CNV leakage area of ​​the patient. In some embodiments, the methods provided herein reduce the RNV area of ​​the patient. In some embodiments, the methods described herein reduce the RNV leakage area in the patient. The CNV / RNV area and CNV / RNV leakage area can be measured on FFA. In some embodiments, the methods described herein reduce or prevent retinal fibrosis in the patient. In some embodiments, the methods described herein reduce the retinal fibrosis area in the patient. In some embodiments, the methods described herein reduce the diameter of the largest lesion in the patient. In some embodiments, the methods described herein reduce the total lesion area in the patient. Retinal fibrosis and total lesions are detectable by CFP.

[0157] In some embodiments, the methods described herein reduce the CNV area in a treated subject. In some embodiments, the methods described herein reduce CNV area by about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, about 10, about 10.5, about 11, about 11.5, about 12, about 12.5, about 13, about 13.5, about 14, about 14.5, about 15, about 15.5, about 16, about 16.5, about 17, about 17.5, about 18, about 18.5, about 19, about 19.5, about 20 mm 2 . In some embodiments, the methods described herein 、 reduce CNV area by about 0.5 mm 2 . In some embodiments, the methods described herein reduce CNV area by about 1.0 mm 2 . In some embodiments, the methods described herein reduce CNV area by about 2.0 mm 2 . In some embodiments, the methods described herein reduce CNV area by about 3.0 mm 2 . In some embodiments, the methods described herein reduce CNV area by about 4.0 mm 2 . In some embodiments, the methods described herein reduce CNV area by about 5.0 mm 2 . In some embodiments, the methods described herein 、 reduce CNV area by about 6.0 mm 2 . In some embodiments, the methods described herein reduce CNV area by about 7.0 mm 2To reduce. In some embodiments, the methods described herein reduce the CNV area to about 8.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the CNV area to about 9.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the CNV area to about 10.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the CNV area to 0.1 to 20 mm². 2 To reduce. In some embodiments, the methods described herein reduce the CNV area to 0.2-5 mm². 2 To reduce. In some embodiments, the methods described herein reduce the CNV area to 0.3-2 mm². 2 To reduce.

[0158] In some embodiments, the methods described herein reduce the CNV area by 5% or more compared to the baseline. In some embodiments, the methods described herein reduce the CNV area by 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, or 70% or more compared to the baseline. In some embodiments, the methods described herein reduce the CNV area by 10% to 70% compared to the baseline. In some embodiments, the methods described herein reduce the CNV area by 10% to 60% compared to the baseline. In some embodiments, the methods described herein reduce the CNV area by 30% to 50% compared to the baseline. In some embodiments, the methods described herein reduce the CNV area by 40% to 50% compared to the baseline. In some embodiments, the methods described herein reduce the CNV area by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70% compared to a baseline.

[0159] In some embodiments, the methods described herein reduce the CNV leakage area in the treatment target. In some embodiments, the methods described herein reduce the CNV leakage area to about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6 Approximately 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20mm 2 In some embodiments, the methods provided herein reduce the CNV leakage area to about 1.0 mm². 2 To reduce. In some embodiments, the methods provided herein reduce the CNV leakage area to about 2.0 mm². 2 To reduce. In some embodiments, the methods provided herein reduce the CNV leakage area to about 3.0 mm². 2 To reduce. In some embodiments, the methods provided herein reduce the CNV leakage area to about 4.0 mm². 2 To reduce. In some embodiments, the methods provided herein reduce the CNV leakage area to about 5.0 mm². 2 To reduce. In some embodiments, the methods provided herein reduce the CNV leakage area to about 6.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the CNV leak area to about 7.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the CNV leak area to about 8.0 mm². 2To reduce. In some embodiments, the methods described herein reduce the CNV leak area to about 9.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the CNV leak area to about 10.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the CNV leak area to 0.1 to 20 mm². 2 To reduce. In some embodiments, the methods described herein reduce the CNV leak area to 0.2-5 mm². 2 To reduce. In some embodiments, the methods described herein reduce the CNV leak area to 0.3-2 mm². 2 To reduce.

[0160] In some embodiments, the methods described herein reduce the CNV leak area by 5% or more compared to a baseline. In some embodiments, the methods described herein reduce the CNV leak area by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% or more compared to a baseline. In some embodiments, the methods described herein reduce the CNV leak area by 10% to 70% compared to a baseline. In some embodiments, the methods described herein reduce the CNV leak area by 10% to 60% compared to a baseline. In some embodiments, the methods described herein reduce the CNV leak area by 30% to 50% compared to a baseline. In some embodiments, the methods described herein reduce the CNV leak area by 40% to 50% compared to a baseline. In some embodiments, the methods described herein reduce the CNV leak area by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70% compared to a baseline.

[0161] In some embodiments, the methods described herein reduce the RNV area of ​​the patient. In some embodiments, the methods described herein reduce the RNV area to about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, Approximately 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20mm 2 In some embodiments, the method described herein 、 The RNV area is approximately 0.5 mm². 2 To reduce. In some embodiments, the methods described herein reduce the RNV area to about 1.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the RNV area to about 2.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the RNV area to about 3.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the RNV area to about 4.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the RNV area to about 5.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the RNV area to about 6.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the RNV area to about 7.0 mm². 2To reduce. In some embodiments, the methods described herein reduce the RNV area to about 8.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the RNV area to about 9.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the RNV area to about 10.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the RNV area to 0.1 to 20 mm². 2 To reduce. In some embodiments, the methods described herein reduce the RNV area to 0.2-5 mm². 2 To reduce. In some embodiments, the methods described herein reduce the RNV area to 0.3-2 mm². 2 To reduce.

[0162] In some embodiments, the methods described herein reduce the RNV area by 5% or more compared to the baseline. In some embodiments, the methods described herein reduce the RNV area by 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, or 70% or more compared to the baseline. In some embodiments, the methods provided herein reduce the RNV area by 10% to 70% compared to the baseline. In some embodiments, the methods provided herein reduce the RNV area by 10% to 60% compared to the baseline. In some embodiments, the methods described herein reduce the RNV area by 30% to 50% compared to the baseline. In some embodiments, the methods described herein reduce the RNV area by 40% to 50% compared to the baseline. In some embodiments, the methods described herein reduce the RNV area by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70% compared to a baseline.

[0163] In some embodiments, the methods described herein reduce the RNV leakage area in the treatment subject. In some embodiments, the methods described herein reduce the RNV leakage area to about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, Approximately 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, or approximately 20 mm 2 In some embodiments, the methods described herein reduce the RNV leak area to approximately 1.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the RNV leak area to about 2.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the RNV leak area to about 3.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the RNV leak area to about 4.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the RNV leak area to about 5.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the RNV leak area to about 6.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the RNV leak area to about 7.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the RNV leak area to about 8.0 mm². 2To reduce. In some embodiments, the methods described herein reduce the RNV leak area to about 9.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the RNV leak area to about 10.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the RNV leak area to 0.1 to 20 mm². 2 To reduce. In some embodiments, the methods described herein reduce the RNV leak area to 0.2-5 mm². 2 To reduce. In some embodiments, the methods described herein reduce the RNV leak area to 0.3-2 mm². 2 To reduce.

[0164] In some embodiments, the methods described herein reduce the RNV leak area by 5% or more compared to a baseline. In some embodiments, the methods described herein reduce the RNV leak area by 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, or 70% or more compared to a baseline. In some embodiments, the methods described herein reduce the RNV leak area by 10% to 70% compared to a baseline. In some embodiments, the methods described herein reduce the RNV leak area by 10% to 60% compared to a baseline. In some embodiments, the methods provided herein reduce the RNV leak area by 30% to 50% compared to a baseline. In some embodiments, the methods provided herein reduce the RNV leak area by 40% to 50% compared to a baseline. In some embodiments, the methods provided herein reduce the RNV leak area by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70% compared to a baseline.

[0165] In some embodiments, the methods described herein reduce the retinal leakage area by 5% or more compared to baseline. In some embodiments, the methods described herein reduce the retinal leakage area by 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, or 70% or more compared to baseline. In some embodiments, the methods described herein reduce the retinal leakage area by 10% to 70% compared to baseline. In some embodiments, the methods described herein reduce the retinal leakage area by 10% to 60% compared to baseline. In some embodiments, the methods described herein reduce the retinal leakage area by 30% to 50% compared to baseline. In some embodiments, the methods described herein reduce the retinal leakage area by 40% to 50% compared to baseline. In some embodiments, the methods described herein reduce the retinal leakage area by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70% compared to baseline.

[0166] In some embodiments, the methods described herein reduce the total lesion area of ​​the patient. In some embodiments, the methods described herein reduce the total lesion area by about 0.1 mm 2 Approximately 0.2 mm 2 , about 0.5mm 2 Approximately 0.8 mm 2 Approximately 1.0 mm 2 Approximately 1.2 mm 2 , about 1.5mm 2 Approximately 1.8 mm 2 Approximately 2.0 mm 2 Approximately 2.2 mm 2 , about 2.5mm 2 Approximately 2.8 mm 2 Approximately 3.0 mm 2 Approximately 3.2 mm 2 , about 3.5mm 2 Approximately 3.8 mm 2 Approximately 4.0 mm 2Approximately 4.2 mm 2 , about 4.5mm 2 Approximately 4.8 mm 2 , or approximately 5.0 mm 2 In some embodiments, the methods described herein reduce the total lesion area to approximately 0.5 mm². 2 To reduce. In some embodiments, the methods described herein reduce the total lesion area to about 1.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the total lesion area to about 2.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the total lesion area to about 3.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the total lesion area to about 4.0 mm². 2 To reduce. In some embodiments, the methods described herein reduce the total lesion area to about 5.0 mm². 2 To reduce.

[0167] In some embodiments, the methods described herein reduce retinal fibrosis of a subject as detected by CFP. In some embodiments, the methods described herein reduce the area of ​​retinal fibrosis of a subject as measured by CFP. In some embodiments, the methods described herein reduce the diameter of the largest lesion of a subject as measured by CFP. In some embodiments, the methods described herein reduce the total lesion area of ​​a subject as measured by CFP.

[0168] Vision-related quality of life / NEI-VFQ-25: In some embodiments, the methods described herein result in an improvement in the subject's visual quality of life. In some embodiments, the methods described herein result in an improvement in the subject's NEI-VFQ-25 overall score.

[0169] In some embodiments, the methods disclosed herein result in one or more of the following effects in the patient: (1) an increase in the BCVA score; (2) a decrease in the incidence of IRF or SRF in the foveal center of the macular bone detectable by OCT; (3) a decrease in CST measured by OCT; (4) a decrease in the incidence of PED detected by OCT; (5) a decrease in the incidence of new MA detected by OCT; (6) a decrease in MA area detected by OCT; (7) a decrease in the incidence of GA detected by OCT; (8) a decrease in retinal fibrosis detectable by CFP; (9) a decrease in CNV area measured by FFA; (10) a decrease in CNV leakage area measured by FFA; (11) a decrease in the total lesion area measured by FFA; and (12) an improvement in the NEI-VFQ-25 overall score.

[0170] In some embodiments, the methods described herein result in (1) an increase in the BCVA score and (2) a decrease in the incidence of IRF or SRF in the foveal macula detectable by OCT. In some embodiments, the methods described herein further result in (3) a decrease in CST as measured by OCT.

[0171] In some embodiments, the methods described herein produce one or more of the following effects: (1) Improvement in BCVA by at least one ETDRS character, e.g., at least 5 characters, 5-35 characters, 5-25 characters, e.g., 5-10, 5-15, 5-20, 10-15, 10-20, 10-25, 15-20, or 15-25 characters, e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 characters, compared to the baseline. (2) an improvement in BCVA of 5% or more compared to baseline, for example 10% or more, specifically 10% to 200%, 10% to 150%, 10% to 100%, 20% to 100%, 50% to 100%, 60% to 100%, 20% to 80%, or 30% to 70%, 50% to 70%, 60% to 70%, etc., such as 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200%. (3) a reduction in CST of more than 25 μm compared to baseline, for example a reduction of 25 to 350 μm, 50 to 300 μm, 50 to 200 μm, specifically a reduction of 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, or 350 μm, or a reduction of more than 5% compared to baseline, for example in a range such as 10% to 70%, 10% to 60%, 30% to 50%, 40% to 50%, specifically 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70%. (4) the RNV area is 0.1 mm 2 or more reduced compared to baseline. For example, 0.1 to 20 mm 2 , preferably 0.2 to 5 mm 2 , more preferably 0.3 to 2 mm 2 reduction, specifically 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, or 20 mm 2or a reduction of 5% or more compared to baseline, for example, 10% to 70%, 10% to 60%, 30% to 50%, 40% to 50%, and for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70%. (5) the CNV area is 0.1 mm compared to baseline 2 or more reduction. For example, 0.1 to 20 mm 2 , 0.2 to 5 mm 2 , 0.3 to 2 mm 2 reduction, etc. Specifically, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, or 20 mm 2 or a reduction of 5% or more compared to baseline, for example, 10% to 70%, 10% to 60%, 30% to 50%, 40% to 50%, and for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70%. (6) the retinal leakage area is reduced by 5% or more compared to baseline. For example, a reduction of 10% to 70%, 10% to 60%, 30% to 50%, or 40% to 50%, for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 80%, 90%, or 100%.

[0172] In some embodiments, the methods disclosed herein achieve one or more of the above-mentioned therapeutic benefits within 12 weeks or less, 16 weeks or less, 20 weeks or less, 24 weeks or less, 28 weeks or less, 32 weeks or less, 36 weeks or less, 40 weeks or less, 44 weeks or less, 48 ​​weeks or less, 52 weeks or less, within 56 weeks, within 60 weeks, within 64 weeks, within 68 weeks, within 72 weeks, within 76 weeks, within 80 weeks, within 84 weeks, within 88 weeks, within 92 weeks, within 96 weeks, or within 100 weeks. In some embodiments, the methods disclosed herein achieve one or more of the above therapeutic benefits after 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, about 72 weeks, about 76 weeks, about 80 weeks, about 84 weeks, about 88 weeks, about 92 weeks, about 96 weeks, or about 100 weeks. In some embodiments, the methods disclosed herein achieve one or more of the above therapeutic benefits about 44 weeks after the start of treatment. In some embodiments, the methods disclosed herein achieve one or more of the above therapeutic benefits about 48 weeks after the start of treatment. In some embodiments, the methods disclosed herein achieve one or more of the above therapeutic benefits about 52 weeks after the start of treatment. In some embodiments, the methods disclosed herein achieve one or more of the above-mentioned therapeutic benefits approximately 96 weeks after the initiation of treatment. In some embodiments, the methods disclosed herein achieve one or more of the above-mentioned therapeutic benefits approximately 100 weeks after the initiation of treatment.

[0173] In some embodiments, the methods described herein achieve one or more of the therapeutic effects described above. In some embodiments, the therapeutic effect may persist for a long period after the last treatment. In some embodiments, the therapeutic effect may persist for at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, or at least 48 weeks after the last treatment. In some embodiments, the therapeutic effect may persist for at least 8 weeks after treatment. In some embodiments, the therapeutic effect may persist for at least 12 weeks after treatment. In some embodiments, the therapeutic effect may persist for at least 24 weeks after treatment. In some embodiments, the therapeutic effect may persist for at least 36 weeks after treatment. In some embodiments, the therapeutic effect may persist for at least 48 weeks after treatment.

[0174] 7.4 Treatment method: DME The bispecific fusion proteins (e.g., efdamlovsp alfa) and pharmaceutical compositions disclosed herein can be used to treat DME. In some embodiments, this specification provides a method for treating DME in a subject, comprising administering a therapeutically effective amount of efdamlovsp alfa to the subject in need of treatment.

[0175] In some embodiments, the subject may be human. In some embodiments, the subject may have DME. In some embodiments, the subject may be at risk of developing DME. In some embodiments, the subject may have one “affected eye,” i.e., an eye diagnosed with DME. In some embodiments, the subject may have two affected eyes. As is clear from the context, in this specification, treating a “subject” is synonymous with treating the “affected eye (or group of affected eyes) of the subject.” The characterization of the “treated subject” (e.g., BCVA score, presence or absence of active CNV, GA, etc.) is performed on the “affected eye (eye) of the treated subject.” The evaluation of the treatment effect in the “treated subject” (e.g., improvement in BCVA, reduction in CNV, etc.) is also performed on the “affected eye (eye) of the treated subject.”

[0176] In some embodiments, the subjects receiving treatment are 18 years of age or older. In some embodiments, the subjects are 30 years of age or older. In some embodiments, the subjects are 40 years of age or older. In some embodiments, the subjects are 45 years of age or older. In some embodiments, the subjects are 50 years of age or older. In some embodiments, the subjects are 55 years of age or older. In some embodiments, the subjects are at least 60 years of age. In some embodiments, the subjects have been newly diagnosed with DME. In some embodiments, the subjects have been diagnosed with DME for less than one month. In some embodiments, up to 12 years have passed since the subjects were diagnosed with DME. In some embodiments, the subjects have been diagnosed with DME for, for example, from one month to 12 years, specifically 6 months, 1 year, 3 years, 5 years, 8 years, 12 years, or longer.

[0177] In some embodiments, this specification provides uses of efdamlovsp alfa in the treatment of DME. In some embodiments, this specification provides uses of efdamlovsp alfa in the manufacture of pharmaceuticals for the treatment of DME. In some embodiments, the pharmaceutical compositions provided herein can be administered alone or in combination with additional therapeutic agents for DME. In some embodiments, efdamlovsp alfa is used alone in treatment. In some embodiments, efdamlovsp alfa is used as a combination therapy with additional therapies such as laser therapy. For subjects with CSME or refractory DME, topical laser therapy is used as an additional therapy. Laser photocoagulation can reduce vision loss and increase the recovery rate of DME.

[0178] 7.4.1 Subtypes / Patient Populations of DME This specification provides a method for using the fusion protein disclosed herein (e.g., Efdamlovsp alfa) in the treatment of DME. Subjects having DME may have one or more of the following symptoms: blurred or distorted vision, floaters, diplopia, loss of central vision, scotoma in the visual field, and decreased night vision.

[0179] In some embodiments, subjects treated by the methods disclosed herein have DME. In some embodiments, subjects have centrally affecting DME (CI-DME), which can be detected and quantified by OCT. DME may be localized or diffuse. Localized DME is characterized by isolated, significant leakage in a specific area within the macula with sufficient blood flow. Diffuse DME is caused by leakage from the entire capillary bed around the macula due to the breakdown of the retinal barrier. In some embodiments, subjects may have localized DME. In some embodiments, subjects may have diffuse DME.

[0180] In some embodiments, based on clinical testing, the subject treated by the method disclosed herein has CSME. In other embodiments, the subject is non-CSME based on clinical testing.

[0181] In some embodiments, the BCVA of the affected eye to be treated by the method described herein is less than 82 characters. In some embodiments, the BCVA of the target is 81 characters or less in ETDRS characters. In some embodiments, the BCVA of the target is 80 characters or less in ETDRS characters. In some embodiments, the BCVA of the target is 79 characters or less in ETDRS characters. In some embodiments, the BCVA of the target is 78 characters or less in ETDRS characters. In some embodiments, the BCVA of the target is 77 characters or less in ETDRS characters. In some embodiments, the BCVA of the target is 76 characters or less in ETDRS characters. In some embodiments, the BCVA of the target is 75 characters or less in ETDRS characters. In some embodiments, the BCVA of the target is 74 characters or less in ETDRS characters. In some embodiments, the BCVA of the target is 73 characters or less in ETDRS characters. In some embodiments, the BCVA of the target is 72 characters or less in ETDRS characters. In some embodiments, the BCVA of the target is 71 characters or less in ETDRS characters. In some embodiments, the BCVA of the target is 70 characters or less in ETDRS characters. In some embodiments, the BCVA of the affected eye of the subject treated by the method described herein is at least 18 ETDRS characters. In some embodiments, the BCVA of the subject is at least 19 ETDRS characters. In some embodiments, the BCVA of the subject is at least 20 ETDRS characters. In some embodiments, the BCVA of the subject is at least 21 ETDRS characters. In some embodiments, the BCVA of the subject is at least 22 ETDRS characters. In some embodiments, the BCVA of the subject is at least 23 ETDRS characters. In some embodiments, the BCVA of the subject is at least 24 ETDRS characters. In some embodiments, the BCVA of the subject is at least 25 ETDRS characters.

[0182] In some embodiments, the BCVA of the affected eye of the subject treated by the method described herein (i.e., baseline BCVA) is in the range of 19 to 78 ETDRS characters (inclusive). In some embodiments, the BCVA of the affected eye of the subject treated by the method described herein is in the range of 24 to 73 ETDRS characters (inclusive). In some embodiments, the BCVA of the affected eye of the subject treated by the method described herein is in the range of 24 to 78 ETDRS characters (inclusive). In some embodiments, the subject's BCVA is at least 64. In some embodiments, the subject's BCVA is 63 or less. In some embodiments, the BCVA of the affected eye of the subject treated by the method described herein is in the range of 19 to 63 ETDRS characters (inclusive). In some embodiments, the BCVA of the affected eye of the subject treated by the method described herein is in the range of 24 to 63 ETDRS characters (inclusive). In some embodiments, the BCVA of the affected eye of the subject treated by the method described herein is in the range of 64 to 78 ETDRS characters (inclusive). In some embodiments, the BCVA of the affected eye treated by the method described herein is in the range of 64 to 73 ETDRS characters (inclusive). In some embodiments, the BCVA of the affected eye treated by the method described herein is in the range of 50 to 73 ETDRS characters (inclusive). In some embodiments, the BCVA of the affected eye treated by the method described herein is in the range of 30 to 65 ETDRS characters (inclusive). In some embodiments, the BCVA of the affected eye treated by the method described herein is in the range of 24 to 50 ETDRS characters (inclusive).

[0183] In some embodiments, the CST in the affected eye of a subject treated by the method described herein is at least 250 μm, at least 280 μm, at least 300 μm, or at least 325 μm as measured by SD-PCT. In some embodiments, the CST in the affected eye of a subject treated by the method described herein is at least 280 μm as measured by SD-PCT.

[0184] In some embodiments, subjects treated by the methods disclosed herein have previously received anti-VEGF therapy. Anti-VEGF drugs approved for the treatment of DME include, for example, ranibizumab, bevacizumab, aflibercept, brolucizumab, and falisimab-svoa. In some embodiments, subjects treated by the methods disclosed herein have not previously received anti-VEGF therapy. In some embodiments, subjects treated by the methods disclosed herein have previously received treatment with ranibizumab. In some embodiments, subjects treated by the methods disclosed herein have previously received treatment with bevacizumab. In some embodiments, subjects treated by the methods disclosed herein have previously received treatment with aflibercept. In some embodiments, subjects treated by the methods disclosed herein have previously received treatment with brolucizumab. In some embodiments, subjects treated by the methods disclosed herein have previously received treatment with falisimab-svoa.

[0185] In some embodiments, subjects treated by the methods described herein have not received any prior treatment within 30, 90, or 120 days prior to the commencement of the treatment described herein, namely, treatment with anticomplement agents, retinal grid laser or panretinal photocoagulation, laser posterior capsulotomy, or intraocular or periorbital corticosteroid injections. In some embodiments, subjects treated by the methods disclosed herein have not undergone vitreoretinal surgery.

[0186] In some embodiments, subjects treated by the methods disclosed herein are in the stages of moderate NPDR, severe NPDR, or PDR. In some embodiments, subjects treated by the methods disclosed herein have mild to moderate NPDR without DME, and the treatment prevents the development of DME. In some embodiments, subjects treated by the methods described herein have severe NPDR with DME. In some embodiments, subjects treated by the methods described herein have non-high-risk PDR with DME, and the method treats DME. High-risk PDR is defined as having any three of the following four characteristics: (1) neovascularization (any site); (2) neovascularization on or near the optic disc; (3) at least moderate neovascularization, i.e., neovascularization covering 1 / 4 to 1 / 3 or more of the optic disc area within the optic disc diameter, or neovascularization covering at least half of the optic disc area in other sites; (4) vitreous hemorrhage or peripheral retinal hemorrhage.

[0187] In some embodiments, subjects receiving treatment by the methods disclosed herein have not received any antidiabetic drugs at least one month, at least two months, or at least three months prior to the commencement of the treatment disclosed herein. In some embodiments, subjects receiving treatment by the methods disclosed herein are not concomitantly using antidiabetic drugs. The antidiabetic drugs may be oral or injectable.

[0188] In some embodiments, subjects treated by the methods disclosed herein do not have any of the following conditions: high-risk progressive diabetic retinopathy (PDR), fibrosis or atrophy with central macula, or retinal hemorrhage affecting two or more optic nerve head areas and the fovea.

[0189] In some embodiments, the subject treated by the method disclosed herein has the following characteristics: (a) visual impairment due to DME with fovea; (b) CST measured by SD-OCT is at least 280 μm; and (c) BCVA in the affected eye is 24 to 73 ETDRS letters.

[0190] 7.4.2 Treatment regimen A pharmaceutical composition disclosed herein, comprising a fusion protein (e.g., Efdamlovsp alfa) disclosed herein, can be administered to a subject in need to treat DME. In some embodiments, the pharmaceutical composition disclosed herein is administered topically. In some embodiments, the pharmaceutical composition disclosed herein is administered topically. In some embodiments, the pharmaceutical composition disclosed herein is administered intralesionally. In some embodiments, the pharmaceutical composition disclosed herein is administered intravenously.

[0191] In some embodiments, the pharmaceutical composition comprising the fusion protein disclosed herein (e.g., Efdamlovsp alfa) is administered directly to the eye or ocular tissue. This administration can be carried out by a variety of methods, including topical application to the eye or injection into the eye or related tissue. Injection methods include, but are not limited to, intravitreal injection, periorbital injection, subretinal injection, scleral transperfusion injection, subscleral injection, choroidal injection, anterior chamber injection, subconjunctival injection, sub-Tenon's capsule injection, posterior bulbar injection, periorbital injection, posterior scleral administration, or periscleral administration of the liquid composition. Furthermore, the pharmaceutical composition can be administered to the vitreous humor, optic nerve, aqueous humor, sclera, conjunctiva, the area between the sclera and conjunctiva, retinal and choroidal tissue, macula, or other areas inside or around the eye.

[0192] In some embodiments, the pharmaceutical compositions disclosed herein are administered by intravitreous injection. In some embodiments, the fusion proteins disclosed herein (e.g., efdamlovsp alfa) are administered by intravitreous injection.

[0193] Furthermore, this specification also describes therapeutic regimens comprising administering multiple doses of the pharmaceutical compositions disclosed herein, each dose containing a therapeutically effective amount of efdamlovsp alfa. In some embodiments, the therapeutically effective dose in a single dose is 0.01–8 mg, 0.05–8 mg, 0.05–6 mg, 0.5–5 mg, 1–5 mg, 2–5 mg, 0.5–2 mg, 1–3 mg, 2–4 mg, 2–3 mg, or 3–5 mg. In some embodiments, the therapeutically effective dose is 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg, 2.0mg, 2.1mg, 2.2mg, 2.3mg, 2.4mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9 mg, 3.0mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8mg, 3.9mg, 4.0mg, 4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5.0mg, 5.1mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8 mg, 5.9mg, 6.0mg, 6.1mg, 6.2mg, 6.3mg, 6.4mg, 6.5mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7.0mg, 7.1mg, 7.2mg, The effective doses are 7.3 mg, 7.4 mg, 7.5 mg, 7.6 mg, 7.7 mg, 7.8 mg, 7.9 mg, 8.0 mg, 8.1 mg, 8.2 mg, 8.3 mg, 8.4 mg, 8.5 mg, 8.6 mg, 8.7 mg, 8.8 mg, 8.9 mg, 9.0 mg, 9.1 mg, 9.2 mg, 9.3 mg, 9.4 mg, 9.5 mg, 9.6 mg, 9.7 mg, 9.8 mg, 9.9 mg, or 10.0 mg. In some embodiments, the effective therapeutic dose of efdamlovsp alfa is in the range of about 1.0 mg to about 8.0 mg. In some embodiments, the effective therapeutic dose of a single dose of efdamlovsp alfa is in the range of about 2.0 mg to about 8.0 mg.In some embodiments, the therapeutically effective dose of efdamlovsp alfa in a single dose is approximately 2.0 mg. In some embodiments, the therapeutically effective dose of efdamlovsp alfa in a single dose is approximately 3.2 mg. In some embodiments, the therapeutically effective dose of efdamlovsp alfa in a single dose may be approximately 4.0 mg. In some embodiments, the therapeutically effective dose of efdamlovsp alfa in a single dose may be approximately 6.4 mg. In some embodiments, the therapeutically effective dose of efdamlovsp alfa in a single dose may be approximately 8.0 mg. In this specification, specified doses, such as 1.0 to 8.0 mg, indicate the amount administered per eye.

[0194] In some embodiments, Efdamlovsp alfa is administered by intravitreal injection. In some embodiments, the injection volume is in the range of 0.01 mL to 0.1 mL. In some embodiments, the injection volume is in the range of 0.04 mL to 0.08 mL. In some embodiments, the injection volume is about 0.04 mL, 0.08 mL, or 0.1 mL. In some embodiments, the injection volume is about 0.1 mL.

[0195] In some embodiments, multiple doses of the pharmaceutical compositions disclosed herein may be administered at different dosing intervals. For example, they may be administered at intervals of approximately once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, once every eleven weeks, once every twelve weeks, once every thirteen weeks, once every fourteen weeks, once every fifteen weeks, or once every sixteen weeks. In some embodiments, the pharmaceutical compositions disclosed herein may be administered at dosing intervals ranging from once every four weeks to once every sixteen weeks. In some embodiments, the pharmaceutical compositions disclosed herein may be administered at a frequency of once every four weeks. In some embodiments, the pharmaceutical compositions disclosed herein may be administered once every eight weeks. In some embodiments, the pharmaceutical compositions disclosed herein may be administered once every twelve weeks. In some embodiments, the pharmaceutical compositions disclosed herein can be administered once every 16 weeks.

[0196] In some embodiments, a pharmaceutical composition comprising the fusion protein disclosed herein (e.g., Efdamlovsp alfa) can be administered in two stages, namely, a loading phase and a maintenance phase.

[0197] In this specification, the term “loading phase” refers to a therapeutic phase in which a fusion protein (e.g., efdamlovsp alfa) is administered to induce a desired therapeutic effect, such as clinical remission, clinical response, OCT remission, OCT disappearance, and / or symptom relief. In some embodiments, the desired therapeutic effect is improvement of visual acuity and / or improvement of macular structure. In some embodiments, the desired therapeutic effect is the subject achieving stable visual acuity and / or stabilization of the lesion. In some embodiments, the therapeutic effect is improvement of visual acuity and / or anatomical structure as observed on OCT. In some embodiments, the therapeutic effect is improvement of CST and / or BCVA.

[0198] The dose of the fusion protein administered during the loading phase is called the "loading dose." The length of the loading treatment period can be, for example, 4 weeks, 8 weeks, or 12 weeks. Patient evaluation can be performed 1 week, 4 weeks, or 8 weeks after the last loading dose. During the loading phase, one or more "loading doses" may be administered. In some embodiments, multiple doses are administered during the loading phase at predetermined intervals (called "loading intervals").

[0199] In this specification, the terms “maintenance phase” or “on-demand phase” refer to the therapeutic phase following the loading phase, during which the fusion protein (e.g., efdamlovsp alfa) is administered at doses and intervals determined according to the patient’s condition in order to maintain the desired therapeutic effect. The dose of the fusion protein administered during the loading phase is called the “maintenance dose,” which may be the same as or different from the loading dose. During the maintenance phase, one or more “maintenance doses” may be administered. In some embodiments, multiple doses are administered during a specific period of the maintenance phase, which is called the “maintenance interval.”

[0200] During the loading phase, subjects receive more frequent doses than during the maintenance phase to obtain a rapid and powerful response to the treatment. The loading phase may be shorter than the maintenance phase. In some embodiments, the loading phase consists of the first two to eight weeks of the treatment regimen. In some embodiments, the loading phase consists of the first four to sixteen weeks of the treatment regimen. In some embodiments, the loading phase consists of the first eight to sixteen weeks of the treatment regimen. In some embodiments, the loading phase consists of the first twelve to sixteen weeks of the treatment regimen. In some embodiments, the loading phase consists of the first eight weeks. In some embodiments, the loading phase consists of the first twelve weeks. In some embodiments, the loading phase consists of the first sixteen weeks.

[0201] In some embodiments, a pharmaceutical composition comprising the fusion protein disclosed herein (e.g., ephdamlovsp alfa) can be administered at dosing intervals of approximately 3 to 5 weeks during the loading phase. In some embodiments, the pharmaceutical composition disclosed herein can be administered at dosing intervals of approximately 4 weeks during the loading phase. In some embodiments, the loading phase may comprise 2 to 4 doses of the pharmaceutical composition disclosed herein, administered at dosing intervals of approximately 3 to 5 weeks. In some embodiments, the loading phase may comprise at least 2 doses of the pharmaceutical composition disclosed herein, administered at dosing intervals of approximately 3 to 5 weeks. In some embodiments, the loading phase may comprise 3 doses of the pharmaceutical composition disclosed herein, administered at dosing intervals of approximately 3 to 5 weeks. In some embodiments, the loading phase may comprise 4 doses of the pharmaceutical composition disclosed herein, administered at dosing intervals of approximately 3 to 5 weeks. In some embodiments, the loading phase may comprise 3 doses of the pharmaceutical composition disclosed herein, administered at dosing intervals of approximately 4 weeks. In some embodiments, the loading period may include four doses of the pharmaceutical composition disclosed herein, administered at intervals of approximately four weeks.

[0202] In some embodiments, the method provided herein includes a loading period of 8 to 16 weeks at the beginning of treatment, during which the pharmaceutical composition disclosed herein is administered two to four times at intervals of approximately 3 to 5 weeks. In some embodiments, the method provided herein includes a loading period of 8 weeks at the beginning of treatment, during which the pharmaceutical composition disclosed herein is administered three times at intervals of approximately 4 weeks. In some embodiments, the method provided herein includes a loading period of 12 weeks at the beginning of treatment, during which the pharmaceutical composition disclosed herein is administered four times at intervals of approximately 4 weeks.

[0203] In some embodiments, the loading period can last longer than 12 weeks. In some embodiments, the loading period lasts for 4, 5, 6, or 7 months, and the fusion protein is administered once or twice a month. In some embodiments, the fusion protein is administered once a month.

[0204] During the loading phase, the single dose of the fusion protein (e.g., efdamlovsp alfa) is 0.01–8 mg, 0.05–8 mg, 0.05–6 mg, 0.5–5 mg, 1–5 mg, 2–5 mg, 0.5–2 mg, 1–3 mg, 2–4 mg, 2–3 mg, or 3–5 mg. In some embodiments, each single dose is 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg, 2.0mg, 2.1mg, 2.2mg, 2.3mg, 2.4mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9 mg, 3.0mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8mg, 3.9mg, 4.0mg, 4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5.0mg, 5.1mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8 mg, 5.9mg, 6.0mg, 6.1mg, 6.2mg, 6.3mg, 6.4mg, 6.5mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7.0mg, 7.1mg, 7.2mg, The dosages are 7.3 mg, 7.4 mg, 7.5 mg, 7.6 mg, 7.7 mg, 7.8 mg, 7.9 mg, 8.0 mg, 8.1 mg, 8.2 mg, 8.3 mg, 8.4 mg, 8.5 mg, 8.6 mg, 8.7 mg, 8.8 mg, 8.9 mg, 9.0 mg, 9.1 mg, 9.2 mg, 9.3 mg, 9.4 mg, 9.5 mg, 9.6 mg, 9.7 mg, 9.8 mg, 9.9 mg, or 10.0 mg. In some embodiments, each single-dose loading dose of Efdamlovsp alfa ranges from about 1.0 mg to about 8.0 mg. In some embodiments, each single-dose loading dose of Efdamlovsp alfa ranges from about 2.0 mg to about 8.0 mg. In some embodiments, each single-dose loading dose of Efdamlovsp alfa is about 2.0 mg.In some embodiments, each single dose of efdamlovsp alfa is approximately 3.2 mg. In some embodiments, each single dose of efdamlovsp alfa is approximately 4.0 mg. In some embodiments, each single dose of efdamlovsp alfa is approximately 6.4 mg. In some embodiments, each single dose of efdamlovsp alfa is approximately 8.0 mg. In this specification, specified doses, such as 1.0 to 8.0 mg, indicate the amount administered per eye.

[0205] The maintenance phase (i.e., the on-demand phase) follows the loading phase and aims to sustain the therapeutic effects achieved during the loading phase, with the goal of continuous management and control of the disease or symptoms at a less frequent and more sustainable dose. In some embodiments, during the maintenance phase, the fusion protein disclosed herein (e.g., efdamlovsp alfa) may be administered as needed, determined by evaluating the treated eye after the final dose of the loading phase. In some embodiments, at least one dose of the fusion protein is administered during the maintenance phase. In some embodiments, multiple doses of the fusion protein are administered during the maintenance phase.

[0206] In some embodiments, during the maintenance therapy phase, a pharmaceutical composition comprising the fusion protein disclosed herein (e.g., ephdamlovsp alfa) may be administered at intervals of approximately 4 to 16 weeks. In some embodiments, the pharmaceutical composition disclosed herein may be administered during the maintenance phase at intervals of approximately 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, or 16 weeks. In some embodiments, the pharmaceutical composition disclosed herein may be administered once at intervals of approximately 8 weeks during the maintenance phase. In some embodiments, the pharmaceutical composition disclosed herein may be administered once at intervals of approximately 12 weeks during the maintenance phase. In some embodiments, the pharmaceutical composition disclosed herein may be administered once at intervals of approximately 16 weeks during the maintenance phase. The administration interval may also be adjusted as needed during the maintenance phase. In some embodiments, the administration interval is adjusted based on the evaluation of the treated eye at follow-up visits.

[0207] In some embodiments, the maintenance period is at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 52 weeks, at least 56 weeks, at least 60 weeks, at least 64 weeks, at least 68 weeks, at least 72 weeks, at least 76 weeks, at least 80 weeks, at least 84 weeks, at least 88 weeks, at least 92 weeks, at least 96 weeks, or at least 100 weeks.

[0208] In some embodiments, the methods provided herein include a maintenance phase comprising at least 24 weeks of treatment, during which the pharmaceutical composition disclosed herein is administered at intervals of approximately 8 weeks, approximately 12 weeks, or approximately 16 weeks. In some embodiments, the pharmaceutical composition disclosed herein is administered once every approximately 8 weeks during the maintenance therapy period. In some embodiments, the pharmaceutical composition disclosed herein is administered once every approximately 12 weeks during the maintenance therapy period. In some embodiments, the pharmaceutical composition disclosed herein is administered once every approximately 16 weeks during the maintenance therapy period.

[0209] During the maintenance phase, the single dose of the fusion protein (e.g., efdamlovsp alfa) can be 0.01–8 mg, 0.05–8 mg, 0.05–6 mg, 0.5–5 mg, 1–5 mg, 2–5 mg, 0.5–2 mg, 1–3 mg, 2–4 mg, 2–3 mg, or 3–5 mg. In some embodiments, each single maintenance dose is 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg g, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg, 2.0mg, 2.1mg, 2.2mg, 2.3mg, 2.4mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2 .9mg, 3.0mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8mg, 3.9mg, 4.0mg, 4.1mg, 4.2mg, 4.3mg , 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5.0mg, 5.1mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5. 8mg, 5.9mg, 6.0mg, 6.1mg, 6.2mg, 6.3mg, 6.4mg, 6.5mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7.0mg, 7.1mg, 7.2mg The doses are 7.3 mg, 7.4 mg, 7.5 mg, 7.6 mg, 7.7 mg, 7.8 mg, 7.9 mg, 8.0 mg, 8.1 mg, 8.2 mg, 8.3 mg, 8.4 mg, 8.5 mg, 8.6 mg, 8.7 mg, 8.8 mg, 8.9 mg, 9.0 mg, 9.1 mg, 9.2 mg, 9.3 mg, 9.4 mg, 9.5 mg, 9.6 mg, 9.7 mg, 9.8 mg, 9.9 mg, or 10.0 mg. In some embodiments, each single maintenance dose of Evdamlovsp alfa is in the range of about 1.0 mg to about 8.0 mg. In some embodiments, each single maintenance dose of Evdamlovsp alfa is in the range of about 2.0 mg to about 8.0 mg. In some embodiments, each single maintenance dose of Evdamlovsp alfa is about 2.0 mg.In some embodiments, each single maintenance dose of efdamlovsp alfa is approximately 3.2 mg. In some embodiments, each single maintenance dose of efdamlovsp alfa is approximately 4.0 mg. In some embodiments, each single maintenance dose of efdamlovsp alfa is approximately 6.4 mg. In some embodiments, each single maintenance dose of efdamlovsp alfa is approximately 8.0 mg. In this specification, specified doses, such as 1.0 to 8.0 mg, indicate the amount administered per eye.

[0210] In some embodiments, the single dose remains constant throughout the entire treatment, including both the loading and maintenance phases. In some embodiments, the single dose is modified during treatment. In some embodiments, the single dose remains constant between the loading and maintenance phases, but is adjusted between the loading and maintenance phases.

[0211] In some embodiments, the single dose remains constant throughout the treatment, ranging from approximately 1.0 mg to approximately 8.0 mg. In some embodiments, each single dose throughout the treatment is approximately 2.0 mg. In some embodiments, each single dose throughout the treatment is approximately 3.2 mg. In some embodiments, each single dose throughout the treatment is approximately 4.0 mg. In some embodiments, each single dose throughout the treatment is approximately 6.4 mg. In some embodiments, each single dose throughout the treatment is approximately 8.0 mg.

[0212] In some embodiments, the method provided herein includes evaluating the disease progression and response to treatment in subjects who have completed the loading phase, and using the evaluation results to determine a specific treatment regimen for the maintenance phase. This evaluation can be performed about 6 to 10 weeks after the last dose of the loading phase. In some embodiments, this evaluation can be performed about 8 weeks after the last dose of the loading phase. In some embodiments, the method described herein includes performing a single evaluation. In some embodiments, the method described herein includes performing two evaluations at intervals of about 2 to 6 weeks. In some embodiments, the two evaluations can be performed at intervals of 4 weeks.

[0213] In some embodiments, the interval between the last dose of the loading phase and the first dose of the maintenance phase is the same as the interval between doses of the maintenance phase.

[0214] In some embodiments, the methods provided herein include follow-up assessments in both the loading phase and the on-demand treatment phase to monitor the patient's condition and / or response to treatment. The assessments may include one or more of the following: (1) measuring the change in BCVA from baseline using an ETDRS chart, e.g., an increase in ETDRS characters from baseline (e.g., 0 or more characters, 5 or more characters, 10 or more characters, or 15 or more characters), or a decrease in ETDRS characters from baseline (e.g., 0 or more characters, 5 or more characters, 10 or more characters, or 15 or more characters); (2) measuring the change in CST from baseline using SD-OCT, e.g., a decrease in CST (e.g., 50 μm or 75 μm or 0%, 10%, or 20%); an increase in CST, e.g., 50 μm or 75 μm or 0%, 10%, or 20%; (3) assessing improvement in the Diabetic Retinopathy Severity Score (DRSS) from baseline, e.g., an improvement of one or more levels, two or more levels, or three or more levels.

[0215] In some embodiments, follow-up assessment is performed approximately one week after each administration of the fusion protein (e.g., efdamrofusp alfa) during the loading treatment phase. In some embodiments, follow-up assessment is performed approximately two weeks after each administration of the fusion protein (e.g., efdamrofusp alfa) during the loading treatment phase. In some embodiments, follow-up assessment is performed every four weeks during the on-demand treatment phase.

[0216] In some embodiments, the methods described herein comprise: (a) a loading phase, in which the fusion protein (e.g., efdamrofusp alfa) is intravitreally administered at a loading dose, and multiple consecutive administrations are performed at loading intervals until the desired therapeutic effect is achieved; (b) assessment after a first follow-up interval (e.g., one week after each loading administration), which comprises, for example, changes in BCVA (increase in the number of ETDRS letters from baseline, such as 0, 5, 10, or 15 or more letters; decrease in the number of ETDRS letters from baseline, such as 0, 5, 10, or 15 or more letters) and changes in CST (decrease in numerical value or percentage, for example, 50 µm or 75 µm or more, or 0%, 10%, or 20% or more; increase in numerical value or percentage, for example, 50 µm or 75 µm or more, or 0%, 10%, or 20% or more), and optionally, assessing improvement in DRSS from baseline, for example, improvement by 1 or more stages, 2 or more stages, or 3 or more stages; and (c) performing post-loading administration assessment after a second follow-up period (e.g., four weeks after the last loading administration), evaluating changes in the patient's condition (e.g., changes in BCVA and / or CST), and performing maintenance (i.e., on-demand) administration based on the assessment results.

[0217] In some embodiments, during the maintenance phase, follow-up assessments are performed to determine whether a subject meets the criteria for retreatment. As used herein, "retreatment" or grammatically equivalent terms means that a patient was initially assessed in one or more follow-up assessments during the maintenance phase and determined not to require further drug administration. However, subsequent assessments reveal that the therapeutic effect has decreased or the disease has progressed, necessitating additional treatment.

[0218] In some embodiments, criteria for retreatment include a decrease in BCVA of 5 or more letters or an increase in CST of 50 µm or more compared with the previous visit.

[0219] Accordingly, in some embodiments, step (c) (assessment after the loading phase) is repeated, whereby maintenance administration may comprise multiple treatment cycles, each cycle independently comprising assessing a change in the patient's condition after a second follow-up period (e.g., a change in BCVA and / or CST) and administering a maintenance dose based on the assessment. In some embodiments, maintenance administration is continued until the lesion regresses (e.g., regression of DME) and / or the patient's vision returns to normal. Maintenance administration can be continued for at least 1 year, 2 years, 3 years, 4 years, 5 years, or more, or until the disease progresses.

[0220] In some embodiments, a single loading dose ranges from 1 mg to 8 mg, for example about 3.2 mg, about 6.4 mg, or about 8.0 mg. The method can comprise multiple administrations at fixed loading intervals, such as once every 4 weeks, during the loading phase. The maintenance phase may also comprise multiple administrations at maintenance intervals, which intervals may be the same or different. The maintenance interval may be the same as or longer than the loading interval, for example every 4 weeks, every 8 weeks, every 12 weeks, every 16 weeks, every 20 weeks, every 24 weeks, or longer.

[0221] The methods described herein explicitly assume the selection of therapeutic doses and / or treatment intervals of the fusion protein during the loading and / or maintenance phases, with the aim of improving or maintaining visual acuity and / or improving or maintaining the anatomical structure of the macula, in order to avoid overtreatment and undertreatment. After the loading phase (e.g., once monthly for 2, 3, 4, 5, or 6 months), maintenance doses are administered. During the maintenance phase, the treatment interval is adjusted based on an assessment of the disease state, e.g., changes in BCVA or CST.

[0222] In some embodiments, the initial follow-up interval at the start of maintenance therapy may be 4 weeks or 8 weeks. If the patient's condition is confirmed to be stable (e.g., stable CST and BCVA) after two consecutive follow-ups, the treatment interval may be extended, for example, by 4 weeks, while maintaining the initial follow-up interval. If the patient's condition deteriorates (e.g., deterioration of CST and / or BCVA) after two consecutive follow-ups, the patient continues treatment at the initial follow-up interval (e.g., 4 weeks).

[0223] In some embodiments, CST is considered stable if it increases by 50 μm or less between visits. BCVA is considered stable if it decreases by 5 letters or less between visits. If BCVA decreases by 5 letters or more between visits due to DME, it is considered worsening. If CST increases by more than 50 μm between visits due to DME, it is considered worsening. After the loading phase (e.g., 3 consecutive monthly administrations), follow-up evaluations of CST and BCVA are performed at maintenance intervals (e.g., 4 weeks). If BCVA decreases by 5 letters or more, or CST increases by 50 μm or more, due to DME since the last visit, the patient continues loading dose therapy at the same follow-up interval.

[0224] 7.4.3 Effectiveness The methods described herein are useful for the treatment of DME. In some embodiments, the methods described herein alleviate or improve the symptoms of DME in a patient. In some embodiments, the methods described herein improve the visual acuity of a patient. In some embodiments, the methods described herein prevent further vision loss in a patient. In some embodiments, the methods described herein improve or restore a patient's visual acuity over a long period of time (e.g., at least 6 months, 1 year, 2 years, 3 years, or longer). In some embodiments, the methods described herein improve retinal edema in DME.

[0225] Visual acuity / BCVA In some embodiments, the methods described herein improve the BCVA of a patient. In some embodiments, the methods described herein prevent a decrease in the BCVA of a patient. In some embodiments, the methods described herein improve the BCVA of a target by at least 0 ETDRS characters, at least 5 ETDRS characters, at least 10 ETDRS characters, at least 15 ETDRS characters, at least 20 ETDRS characters, at least 25 ETDRS characters, or at least 30 ETDRS characters. In some embodiments, the methods described herein improve the BCVA of a target by at least 0 ETDRS characters. In some embodiments, the methods described herein improve the BCVA of a target by at least 5 ETDRS characters. In some embodiments, the methods described herein improve the BCVA of a target by at least 10 ETDRS characters. In some embodiments, the methods described herein improve the BCVA of a target by at least 15 ETDRS characters. In some embodiments, the methods described herein improve the BCVA by at least 20 ETDRS characters. In some embodiments, the methods described herein improve the BCVA by at least 25 ETDRS characters. In some embodiments, the methods described herein improve BCVA by at least 30 ETDRS characters. In some embodiments, the methods described herein improve BCVA by at least 35 ETDRS characters.

[0226] In some embodiments, the methods provided herein improve the BCVA in the range of about 0 to about 30 ETDRS characters. In some embodiments, the methods provided herein improve the BCVA in the range of about 5 to about 35 ETDRS characters. In some embodiments, the methods provided herein improve the BCVA in the range of about 5 to about 30 ETDRS characters. In some embodiments, the methods described herein improve the BCVA in the range of about 5 to about 25 characters. In some embodiments, the methods described herein improve the BCVA in the range of about 5 to about 20 characters. In some embodiments, the methods described herein improve the BCVA in the range of about 5 to about 15 characters. In some embodiments, the methods described herein improve the BCVA in the range of about 10 to about 30 ETDRS characters. In some embodiments, the methods described herein improve the BCVA in the range of about 10 to about 25 ETDRS characters. In some embodiments, the methods described herein improve the BCVA in the range of about 10 to about 20 ETDRS characters. In some embodiments, the methods described herein improve the BCVA by about 10 to about 15 ETDRS characters. In some embodiments, the methods described herein improve the BCVA by about 15 to about 30 ETDRS characters. In some embodiments, the methods described herein improve the BCVA by about 15 to about 25 ETDRS characters. In some embodiments, the methods described herein improve the BCVA by about 15 to about 20 ETDRS characters.

[0227] In some embodiments, the methods described herein improve the BCVA by about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, or about 35 characters. In some embodiments, the methods provided herein improve the BCVA by about 5 characters. In some embodiments, the methods described herein improve the BCVA by about 10 characters. In some embodiments, the methods described herein improve the BCVA by about 15 characters. In some embodiments, the methods described herein improve the BCVA by about 20 characters. In some embodiments, the methods described herein improve the BCVA by about 25 characters. In some embodiments, the methods described herein improve BCVA by approximately 30 characters.

[0228] In some embodiments, the method described herein yields a BCVA in a patient corresponding to at least about 50 characters, at least about 55 characters, at least about 60 characters, at least about 65 characters, at least about 70 characters, at least about 75 characters, or at least about 80 ETDRS characters. In some embodiments, the method described herein results in a BCVA of at least about 55 ETDRS characters. In some embodiments, the method described herein results in a BCVA of at least about 60 ETDRS characters. In some embodiments, the method described herein results in a BCVA of at least about 65 ETDRS characters. In some embodiments, the method described herein results in a BCVA of at least about 69 ETDRS characters. In some embodiments, the method described herein yields a BCVA of at least about 70 ETDRS characters. In some embodiments, the method described herein yields a BCVA of at least about 72 ETDRS characters.

[0229] In some embodiments, the methods described herein improve BCVA by 5% or more compared to baseline. In some embodiments, the methods described herein improve BCVA by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, or 150% compared to baseline. In some embodiments, the methods described herein increase BCVA by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 130%, 140%, or 150% compared to baseline. In some embodiments, the methods described herein increase BCVA by about 20% compared to the baseline. In some embodiments, the methods described herein increase BCVA by about 50% compared to the baseline. In some embodiments, the methods described herein increase BCVA by about 80% compared to the baseline. In some embodiments, the methods described herein increase BCVA by about 100% compared to the baseline. In some embodiments, the methods described herein increase BCVA by about 150% compared to the baseline. In some embodiments, the methods described herein increase BCVA by about 200% compared to the baseline. In some embodiments, the methods described herein increase BCVA by 10% to 200%, 10% to 150%, 10% to 100%, 20% to 100%, 50% to 100%, 60% to 100%, 20% to 80%, 30% to 70%, 50% to 70%, or 60% to 70% compared to the baseline. In some embodiments, the methods described herein increase BCVA by 50% to 70% compared to baseline.

[0230] Anatomical effectiveness detected by OCT In some embodiments, the methods provided herein produce anatomically measurable therapeutic effects using OCT (e.g., SD-OCT). For example, in some embodiments, the methods provided herein reduce CST in the treated subject. In some embodiments, the methods provided herein reduce or prevent the occurrence of SHM in the treated subject. In some embodiments, the methods provided herein reduce or prevent the occurrence of IRF or SRF in the treated subject. In some embodiments, the methods provided herein reduce or prevent the occurrence of PED in the treated subject. In some embodiments, the methods provided herein reduce the RA area in the treated subject. In some embodiments, the methods provided herein reduce or prevent the occurrence of new RA in the treated subject. In some embodiments, the methods described herein reduce the MA area in the treated subject. In some embodiments, the methods described herein reduce or prevent the occurrence of new MA in the treated subject. In some embodiments, the methods described herein reduce or prevent the occurrence of GA in the treated subject. SHM, IRF, SFR, RA, MA, and GA can be detected by OCT (e.g., SD-OCT).

[0231] In some embodiments, the methods described herein reduce the CST of a patient as measured by OCT (e.g., SD-OCT). In some embodiments, the methods described herein reduce the CST by at least 25 μm, at least 50 μm, at least 75 μm, at least 100 μm, at least 125 μm, at least 150 μm, at least 175 μm, at least 200 μm, at least 225 μm, at least 250 μm, at least 275 μm, or at least 300 μm. In some embodiments, the methods described herein reduce the CST of a subject by about 25 μm, about 50 μm, about 75 μm, about 100 μm, about 125 μm, about 150 μm, about 175 μm, about 200 μm, about 225 μm, about 250 μm, about 275 μm, or about 300 μm as measured by OCT (e.g., SD-OCT). In some embodiments, the method described herein reduces the CST of an object measured by OCT (e.g., SD-OCT) by at least 25 μm. In some embodiments, the method described herein reduces the CST by about 50 μm. In some embodiments, the method described herein reduces the CST by about 75 μm. In some embodiments, the method described herein reduces the CST by about 100 μm. In some embodiments, the method described herein reduces the CST by about 125 μm. In some embodiments, the method described herein reduces the CST by about 150 μm. In some embodiments, the method described herein reduces the CST by about 175 μm. In some embodiments, the method described herein reduces the CST by about 200 μm.In some embodiments, the method described herein involves shaping the CST in the following sizes: approximately 25 μm to approximately 150 μm, approximately 50 μm to approximately 150 μm, approximately 75 μm to approximately 150 μm, approximately 100 μm to approximately 150 μm, approximately 125 μm to approximately 150 μm, approximately 25 μm to approximately 200 μm, approximately 50 μm to approximately 200 μm, approximately 75 μm to approximately 200 μm, approximately 100 μm to approximately 200 μm, approximately 125 μm to approximately 200 μm, and approximately 15 The CST ranges are 0 μm to approximately 200 μm, approximately 175 μm to approximately 200 μm, approximately 50 μm to approximately 300 μm, approximately 75 μm to approximately 300 μm, approximately 100 μm to approximately 300 μm, approximately 125 μm to approximately 300 μm, approximately 150 μm to approximately 300 μm, approximately 175 μm to approximately 300 μm, approximately 200 μm to approximately 300 μm, approximately 250 μm to approximately 300 μm, or approximately 25 μm to approximately 350 μm, which are measured by OCT (e.g., SD-OCT). In some embodiments, the methods described herein reduce the CST in the range of approximately 50 μm to approximately 200 μm. In some embodiments, the methods described herein reduce the CST in the range of approximately 100 μm to approximately 200 μm. In some embodiments, the methods described herein reduce the CST in the range of approximately 50 μm to approximately 150 μm. In some embodiments, the methods described herein reduce the CST in the range of about 100 μm to about 150 μm. In some embodiments, the methods described herein reduce the CST in the range of about 125 μm to about 150 μm.

[0232] In some embodiments, the methods described herein reduce CST by 5% or more compared to the baseline. In some embodiments, the methods described herein reduce CST by 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, or 70% or more compared to the baseline. In some embodiments, the methods described herein reduce CST by 10% to 70% compared to the baseline. In some embodiments, the methods described herein reduce CST by 10% to 60% compared to the baseline. In some embodiments, the methods described herein reduce CST by 30% to 50% compared to the baseline. In some embodiments, the methods described herein reduce CST by 40% to 50% compared to the baseline. In some embodiments, the methods described herein reduce CST by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70% compared to baseline.

[0233] In some embodiments, the methods described herein reduce or prevent the occurrence of SHM in a patient, as detected by OCT (e.g., SD-OCT). In some embodiments, the methods described herein reduce or prevent the occurrence of IRF in a patient. In some embodiments, the methods described herein reduce or prevent the occurrence of SRF in a patient. In some embodiments, the methods described herein reduce or prevent the occurrence of both IRF and SRF in a patient. In some embodiments, the methods described herein result in a state where neither IRF nor SRF is detectable by OCT (e.g., SD-OCT). In some embodiments, the methods described herein reduce or prevent the occurrence of IRF in the fovea. In some embodiments, the methods described herein reduce or prevent the occurrence of SRF in the fovea. In some embodiments, the methods described herein reduce or prevent the occurrence of both IRF and SRF in the fovea. IRF and SRF are detectable by OCT (e.g., SD-OCT).

[0234] In some embodiments, the methods provided herein reduce or prevent the occurrence of PEDs in objects detectable by OCT (e.g., SD-OCT). In some embodiments, the methods provided herein result in a state in which no PEDs detectable by OCT (e.g., SD-OCT) are present.

[0235] In some embodiments, the methods described herein reduce or prevent the development of new MAs in a treated patient as detected by OCT (e.g., SD-OCT). In some embodiments, the methods described herein delay or prevent the development of GAs in a treated patient. In some embodiments, the methods described herein reduce the area of ​​MAs in a treated patient as detected by OCT (e.g., SD-OCT).

[0236] In some embodiments, the methods provided herein reduce macular edema. In some embodiments, the methods provided herein eliminate macular edema.

[0237] Vision-related quality of life / NEI-VFQ-25: In some embodiments, the methods described herein result in an improvement in vision-related quality of life in a treated subject. In some embodiments, the methods described herein result in an improvement in the NEI-VFQ-25 composite score of a treated subject.

[0238] In some embodiments, the methods disclosed herein produce one or more of the following effects in a subject: (1) an increase in BCVA score; (2) a decrease in the occurrence of IRF or SRF in the fovea centralis maculae detectable by OCT; (3) a decrease in CST measured by OCT; (4) a decrease in the incidence of PED detectable by OCT; (12) an improvement in the NEI-VFQ-25 composite score.

[0239] In some embodiments, the methods described herein produce (1) an improvement in BCVA score and (2) a decrease in the incidence of IRF or SRF in the fovea centralis maculae detectable by OCT in a subject. In some embodiments, the methods described herein further produce (3) a decrease in CST measured by OCT.

[0240] In some embodiments, the methods described herein produce one or more of the following effects. (1) Improvement in BCVA compared to baseline of at least one ETDRS letter, for example at least 5 letters, 5 to 35 letters, 5 to 25 letters, such as 5 to 10, 5 to 15, 5 to 20, 10 to 15, 10 to 20, 10 to 25, 15 to 20, or 15 to 25 letters, such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 letters. (2) Improvement in BCVA of 5% or more compared to the baseline, for example, 10% or more, specifically 10%-200%, 10%-150%, 10%-100%, 20%-100%, 50%-100%, 60%-100%, 20%-80%, or 30%-70%, 50%-70%, 60%-70%, etc., such as 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200%. (3) A decrease of 25 μm or more compared to baseline, for example, 25-350 μm, 50-300 μm, 50-200 μm, or a decrease of 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, or 350 μm, or a decrease of 5% or more compared to baseline, for example, in the range of 10%-70%, 10%-60%, 30%-50%, 40%-50%, for example, a decrease of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% of CST.

[0241] In some embodiments, the methods disclosed herein achieve one or more of the above-mentioned therapeutic benefits within 12 weeks or less, 16 weeks or less, 20 weeks or less, 24 weeks or less, 28 weeks or less, 32 weeks or less, 36 weeks or less, 40 weeks or less, 44 weeks or less, 48 ​​weeks or less, 52 weeks or less, within 56 weeks, within 60 weeks, within 64 weeks, within 68 weeks, within 72 weeks, within 76 weeks, within 80 weeks, within 84 weeks, within 88 weeks, within 92 weeks, within 96 weeks, or within 100 weeks. In some embodiments, the methods disclosed herein achieve one or more of the therapeutic benefits described above in 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, about 72 weeks, about 76 weeks, about 80 weeks, about 84 weeks, about 88 weeks, about 92 weeks, about 96 weeks, or about 100 weeks. In some embodiments, the methods disclosed herein achieve one or more of the therapeutic benefits described above in about 44 weeks after the start of treatment. In some embodiments, the methods disclosed herein achieve one or more of the therapeutic benefits described above in about 48 weeks after the start of treatment. In some embodiments, the methods disclosed herein achieve one or more of the therapeutic benefits described above in about 52 weeks after the start of treatment. In some embodiments, the methods disclosed herein achieve one or more of the above-mentioned therapeutic benefits approximately 96 weeks after the initiation of treatment. In some embodiments, the methods disclosed herein achieve one or more of the above-mentioned therapeutic benefits approximately 100 weeks after the initiation of treatment.

[0242] In some embodiments, the methods described herein achieve one or more of the above-described therapeutic effects. In some embodiments, the therapeutic effect may persist for a long period after the last treatment. In some embodiments, the therapeutic effect may persist for at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, or at least 48 weeks after the last treatment. In some embodiments, the therapeutic effect may persist for at least 8 weeks after treatment. In some embodiments, the therapeutic effect may persist for at least 12 weeks after treatment. In some embodiments, the therapeutic effect may persist for at least 24 weeks after treatment. In some embodiments, the therapeutic effect may persist for at least 36 weeks after treatment. In some embodiments, the therapeutic effect may persist for at least 48 weeks after treatment.

[0243] 7.5 Safety The methods described herein (including, for example, the method of intravitreal injection of fusion proteins (e.g., efdamlovsp alfa) at doses of 1 to 8 mg per eye) have zero or minimal systemic safety risks due to low systemic exposure to free / total fusion proteins. In some embodiments, the methods described herein have no or minimal systemic immunogenicity risk.

[0244] In some embodiments, the methods described herein further include monitoring for ocular and systemic adverse events (AEs) during administration of efdamlovsp alfa or a pharmaceutical composition comprising efdamlovsp alfa, and interrupting or discontinuing administration as necessary. Adverse events (AEs) include, but are not limited to,: exacerbation of a pre-existing condition / disease (including worsening of symptoms, signs, or abnormal laboratory values); onset of a new adverse condition (including symptoms, signs, or a newly diagnosed disease); or abnormal laboratory values ​​or results of clinical importance.

[0245] In some embodiments, an adverse event (AE) may be an event of special concern (AESI). This refers to an adverse event that requires close monitoring to deepen the understanding of the safety of the drug in question. AESIs may be non-serious adverse events. In this specification, AESIs are defined as any visually threatening adverse event that meets any of the following criteria: (1) non-infectious endophthalmoinflammatory disease; (2) a decrease of 30 letters or more in BCVA compared to the most recent visit, lasting for 1 hour or more; (3) an intraocular pressure of 30 mmHg or more after administration, and an increase of 10 mmHg or more compared to pre-administration, lasting for 24 hours or more. In some embodiments, the methods described herein further include monitoring for AESIs during administration of efdamlovsp alfa or a pharmaceutical composition containing efdamlovsp alfa, and interrupting or discontinuing administration as necessary. In some embodiments, the methods described herein do not cause any AESIs.

[0246] In some embodiments, the methods described herein further include monitoring for serious adverse events (SAEs) during administration of efdamlovsp alfa or a pharmaceutical composition containing efdamlovsp alfa, and interrupting or discontinuing administration as necessary. SAEs include, for example, the following adverse events: (1) death; (2) life-threatening (i.e., those that pose a risk of death to the subject when they occur); (3) hospitalization or prolongation of hospitalization; (4) permanent or severe disability / loss of function (significant impairment of the ability to perform normal daily activities); (5) birth defects / absences; and (6) events that may result in severe visual impairment to the subject and may require medical or surgical intervention, such as: infectious endophthalmitis; a decrease of 30 or more letters in BCVA; or events requiring surgery or other medical intervention (e.g., vitrectomy, vitreous filling, intravitreal injection of an anti-infective agent) to prevent permanent visual impairment. In some embodiments, the methods disclosed herein do not cause any serious adverse events (SAEs).

[0247] In some embodiments, the methods disclosed herein do not cause dose-limiting toxicity (DLT) events.

[0248] 7.6 Evaluation Method The treatments described herein refer to specific diagnostic and evaluation methods (e.g., assessment of disease severity, disease progression, or improvement). Standard procedures for these methods are well known and available to those skilled in the art. For illustrative purposes, some representative methods and procedures are described below.

[0249] Optical Coherence Tomography (OCT): OCT is a technique that creates cross-sectional maps of retinal structures and quantifies retinal thickness. During an OCT scan, a series of intersecting radial sections of the retina are measured. Spectral-domain OCT (SD-OCT) can acquire data at a higher speed, has higher image resolution, and less motion artifacts compared to time-domain OCT (TD-OCT). OCT plays a crucial role in the diagnosis of AMD, the determination of treatment strategies, and the monitoring of responses to therapeutic interventions, particularly in nAMD, providing information on fluid accumulation, CNV activity, and structural changes in the macula. OCT can be used to visualize and quantify key features such as drusen size and number, retinal thickness, IRF, SRF, PED, CNV, MA, GA, changes in the outer retinal layer, subretinal hyperreflectivity, RPE integrity, and vitreoretinal traction (VMT). The term "subretinal hyperreflectivity (SHM)" is a comprehensive term representing the intensity of highly reflective signals on OCT. This may correspond to choroidal neovascularization membranes, and / or hemorrhage, and / or lipids, and / or thickened fibrin.

[0250] Color Fundus Photography (CFP): CFP is an imaging technique that measures various clinically relevant features of the fundus, including the visualization or quantification of drusen, fibrosis, atrophy, neovascularization, hemorrhage, and other morphological changes affecting the retina. CFP can detect a wide range of fundus abnormalities, including different subtypes of macular drusen and pigment abnormalities, and closely correlates with in vivo microscopy.

[0251] Fluorescein angiography (FFA): FFA is an invasive examination that involves injecting fluorescein dye into a vein. The dye travels into the eyeball, and the ophthalmologist uses a laser of a specific wavelength to take images with a fundus camera. These images allow the ophthalmologist to evaluate leakage from blood vessels while analyzing anatomical, physiological, and pathological findings related to retinal and choroidal circulation. FFA is particularly useful when it is necessary to remove subretinal fluid associated with age-related macular degeneration (nAMD).

[0252] Fundus autofluorescence (FAF): FAF is a non-invasive imaging technique for assessing the health of the retina and retinal pigment epithelium (RPE). It detects the spontaneous fluorescence emitted from the eye's intrinsic fluorescent substances when illuminated with light of a specific wavelength (usually blue or near-infrared). FAF images provide information about metabolic and structural changes in the RPE and surrounding retinal tissue.

[0253] Optical coherence tomography angiography (OCTA): OCTA is used to visualize blood vessels within the eye without the use of invasive contrast agents. By measuring the interference of light waves interacting with moving red blood cells, OCTA provides high-resolution three-dimensional images of the retinal and choroidal vascular systems, enabling detailed evaluation of blood flow patterns, capillary density, and the presence or absence of abnormal vessels.

[0254] The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25): The NEI-VFQ measures quality of life related to visual acuity. This questionnaire consists of 11 subscales related to overall visual acuity, eye pain, near visual acuity, distance visual acuity, social functioning, mental health, role functioning, dependency, driving, peripheral vision, and color vision, as well as a single-item component for overall health. Responses to each item are converted to a scale from 0 to 100, where 0 represents the worst state of visual function and 100 represents the best state. The items within each construct (subscale) are averaged to calculate 12 subscale scores, and the overall score is calculated by averaging the subscale scores. Different scoring methods have been proposed for the VFQ-25.

[0255] 7.7 Kit In some embodiments, the Disclosure provides a variety of kits for easily and / or effectively carrying out the methods of the Disclosure. In some embodiments, the Disclosure provides a kit comprising the fusion protein disclosed herein (e.g., efdamlovsp alfa).

[0256] Typically, a kit contains a sufficient quantity and / or number of components to allow the user to administer multiple treatments or conduct multiple experiments on a subject.

[0257] Any of the pharmaceutical compositions or vectors of this disclosure may be included in a kit. In some embodiments, the kit may further include reagents and / or instructions for preparing and / or synthesizing the compounds and / or pharmaceutical compositions of this disclosure. In some embodiments, the kit may also include one or more buffers.

[0258] In some embodiments, the components of the kit may be packaged either in an aqueous medium or in a lyophilized form. The kit's container means generally include at least one vial, test tube, flask, bottle, syringe, or other container means in which the components can be contained and appropriately dispensed. If the kit has multiple components (for example, if the labeled reagent and label are packaged together), the kit may generally include a second, third, or other additional container in which the additional components can be contained separately. In some embodiments, the kit may include a second container means for containing sterile, pharmaceutically acceptable buffers and / or other diluents. In some embodiments, various combinations of components can be contained in one or more vials. The kits of the present disclosure may typically include means for sealing and containing the compounds and / or pharmaceutical compositions of the present disclosure, e.g., proteins, nucleic acids, and other reagent containers for commercial purposes. Such containers include injection-molded or blow-molded plastic containers that hold the desired vials.

[0259] In some embodiments, the components of the kit are provided as one and / or more liquid solutions. In some embodiments, the liquid solutions are aqueous solutions, and in particular, sterile aqueous solutions are used. In some embodiments, the components of the kit may be provided as dry powders. If the reagents and / or components are provided as dry powders, such powders may be reconstituted by adding an appropriate amount of solvent. In some embodiments, it is assumed that the solvent may also be provided in a separate container.

[0260] In some embodiments, the kits provided herein include a delivery device for the fusion protein disclosed herein (e.g., Efdamlovsp alfa). These delivery devices are designed to facilitate the precise administration of the pharmaceutical composition into the eye, ensure accurate dosage, and minimize patient discomfort. In some embodiments, the delivery device is an intravitreal injection device. An intravitreal injection device is a specialized syringe, typically equipped with an ultrafine needle of 30 gauge or less, designed for insertion into the vitreous humor of the eye. These devices are designed to minimize trauma and reduce the risk of complications such as infection or retinal detachment. They also often feature ergonomic features that enhance operability and precision during the injection process, such as a comfortable grip and a stopper to prevent over-insertion.

[0261] In some embodiments, the administration device is an intraocular injection device. These devices are used to administer a pharmaceutical composition to a specific area within the eye, such as the anterior chamber, posterior chamber, or other ocular tissue. The design of these devices may include additional features such as adjustable needle length and pre-filled syringes to simplify the administration process and ensure accurate drug placement. Including such devices in a kit ensures that healthcare professionals have the tools necessary to effectively and safely administer fusion proteins to the specific needs of the treatment site within the eye.

[0262] In some embodiments, the kit may include instructions on how to use the kit components, as well as instructions on how to use other reagents not included in the kit. These instructions may include possible variations.

[0263] 7.8 Examples of Cases Embodiment 1. A method for treating neovascular age-related macular degeneration ("nAMD") in a subject requiring treatment, comprising administering a fusion protein that specifically binds to human vascular endothelial growth factor ("VEGF") and human complement receptor 1 ("CR1"), the fusion protein comprising a VEGF inhibitory domain ("VID"), an immunoglobulin Fc region, a peptide linker, and a complement inhibitory domain ("CID") from the N-terminus to the C-terminus; Here, the fusion protein has an amino acid sequence that is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to SEQ ID NO: 1; The fusion protein is administered to the affected eye in a dose of approximately 1.0 to 8.0 mg using the method described above.

[0264] Embodiment 2. The method according to Embodiment 1, wherein the fusion protein is efdamlovsp alfa (SEQ ID NO: 1).

[0265] Embodiment 3. The method according to Embodiment 1 or 2, wherein the best corrected visual acuity ("BCVA") of the affected eye is in the range of 19 to 78 characters (including the end value) when measured by the Early Diabetic Retinopathy Treatment Study ("ETDRS") chart.

[0266] Embodiment 4. The method according to Embodiment 3, wherein the BCVA of the affected eye is in the range of 24 to 78 ETDRS characters (including the endpoints).

[0267] Embodiment 5. The method according to Embodiment 3, wherein the BCVA of the affected eye is in the range of 24 to 73 ETDRS characters (including the endpoints).

[0268] Embodiment 6. The method according to any one of Embodiments 3 to 5, wherein the BCVA of the affected eye is at least 64 ETDRS characters.

[0269] Embodiment 7. The method according to any one of Embodiments 3 to 5, wherein the BCVA of the affected eye is 63 or less in the ETDRS letters.

[0270] Embodiment 8. The method according to any one of Embodiments 1 to 7, wherein the subject has active submacular or perimacular choroidal neovascularization ("CNV") secondary to nAMD, or active CNV extending to the fovea of ​​the macula.

[0271] Embodiment 9. The method according to Embodiment 8, wherein the CNV area (including classical and latent types) in the affected eye accounts for at least 50% of the total lesion area (including hemorrhage, CNV, atrophy, and fibrosis).

[0272] Embodiment 10. The method according to Embodiment 1 or 2, wherein the affected eye has (1) active submacular or perimacular CNV secondary to nAMD; (2) a CNV area (including classical and latent types) occupying 50% or more of the total lesion area (including hemorrhage, CNV, atrophy, and fibrosis); and (3) a BCVA in the range of 24 to 73 ETDRS letters (including endpoints).

[0273] Embodiment 11. The method according to Embodiment 1 or 2, wherein the affected eye has (1) active submacular CNV secondary to nAMD, or active CNV located perimacula or extramacula but affecting the macula; (2) CNV area (including classical and latent types) accounting for at least 50% of the total lesion area (including hemorrhage, CNV, atrophy, and fibrosis); and (3) BCVA in the range of 24 to 78 ETDRS letters (including endpoints).

[0274] Embodiment 12. The method according to Embodiment 1 or 2, wherein the affected eye has (1) active submacular cytosis secondary to nAMD, or active macula-affecting cytosis; and (2) BCVA in the range of 19 to 78 ETDRS letters (including the endpoints).

[0275] Embodiment 13. The method according to any one of Embodiments 1 to 12, wherein the affected eye has type II CNV.

[0276] Embodiment 14. The method according to any one of Embodiments 1 to 12, wherein the affected eye does not have type II CNV.

[0277] Embodiment 15. The method according to any one of Embodiments 1 to 14, wherein the affected eye has a subcentral retinal thickness ("CST") greater than 280 μm, 300 μm, or 325 μm when measured by spectral domain optical coherence tomography ("SD-OCT").

[0278] Embodiment 16. The method according to any one of Embodiments 1 to 15, wherein the subject is newly diagnosed with nAMD.

[0279] Embodiment 17. The method according to any one of Embodiments 1 to 15, wherein the subject has been diagnosed with nAMD for less than 12 years.

[0280] Embodiment 18. The method according to any one of Embodiments 1 to 15, wherein the subject has previously received treatment for nAMD.

[0281] Embodiment 19. The method according to Embodiment 18, wherein the subject has previously received treatment with an anti-VEGF drug.

[0282] Embodiment 20. The method according to any one of Embodiments 1 to 15, wherein the subject has not been previously treated for nAMD.

[0283] Embodiment 21. The method according to any one of Embodiments 1 to 20, wherein the subject is a human being 50 years of age or older.

[0284] Embodiment 22. The method according to any one of Embodiments 1 to 21, wherein the fusion protein is administered by intravitreous injection.

[0285] Embodiment 23. The method according to Embodiment 22, wherein the fusion protein is injected as a liquid.

[0286] Embodiment 24. The method according to Embodiment 23, wherein the liquid formulation has a fusion protein in a concentration ranging from about 40 mg / ml to about 100 mg / ml.

[0287] Embodiment 25. The method according to Embodiment 24, wherein the liquid formulation has a fusion protein at a concentration of approximately 80 mg / ml.

[0288] Embodiment 26. The method according to any one of Embodiments 23 to 25, wherein the injection volume is approximately 0.01 ml to approximately 0.2 ml.

[0289] Embodiment 27. The method according to Embodiment 26, wherein the injection volume is approximately 0.1 ml.

[0290] Embodiment 28. The method according to any one of Embodiments 1 to 27, wherein the fusion protein is administered in a dose of approximately 2.0 mg, approximately 3.2 mg, approximately 4.0 mg, approximately 6.4 mg, or approximately 8.0 mg.

[0291] Embodiment 29. The method according to any one of Embodiments 1 to 28, wherein the fusion protein is administered at least three times.

[0292] Embodiment 30. The method according to Embodiment 29, wherein at least three doses are administered at intervals ranging from about once a week to about once every four weeks.

[0293] Embodiment 31. The method according to any one of Embodiments 1 to 30, comprising a loading phase and a maintenance phase, wherein the fusion protein is administered 3 to 5 times during the loading phase and 2 or more times during the maintenance phase.

[0294] Embodiment 32. The method according to Embodiment 31, wherein the fusion protein is administered three times during the loading phase.

[0295] Embodiment 33. The method according to Embodiment 31 or 32, wherein the fusion protein is administered at intervals of approximately once a week to approximately once every four weeks during the loading phase.

[0296] Embodiment 34. The method according to Embodiment 33, wherein the fusion protein is administered at intervals of approximately once every four weeks during the loading phase.

[0297] Embodiment 35. The method according to any one of Embodiments 31 to 34, wherein the fusion protein is administered at intervals of approximately once every 8 weeks to approximately once every 16 weeks during the maintenance phase.

[0298] Embodiment 36. The method according to Embodiment 35, wherein the administration interval during the maintenance phase is approximately every 8 weeks.

[0299] Embodiment 37. The method according to Embodiment 35, wherein the administration interval during the maintenance phase is approximately once every 12 weeks.

[0300] Embodiment 38. The method according to Embodiment 35, wherein the administration interval during the actual maintenance phase is approximately once every 16 weeks.

[0301] Embodiment 39. The method according to Embodiment 35, wherein (1) during the loading phase, the fusion protein is administered once every 4 weeks for 3 times; and (2) during the maintenance phase, the fusion protein is administered once every 8 weeks for at least 2 times, where the fusion protein is efdamlovsp alfa, and each dose is 2.0 mg or 4.0 mg.

[0302] Embodiment 40. The method according to Embodiment 35, wherein (1) during the loading phase, the fusion protein is administered at least three times, once every four weeks; and (2) during the maintenance phase, the fusion protein is administered at least twice, once every 12 weeks or once every 16 weeks, wherein the fusion protein is efdamlovsp alfa, and each dose is 6.4 mg or 8.0 mg.

[0303] Embodiment 41. The method according to any one of Embodiments 31 to 34, wherein during the maintenance phase, the fusion protein is administered at intervals determined by evaluating the treated eye after the final dose of the loading phase.

[0304] Embodiment 42. The method according to Embodiment 41, wherein the evaluation includes measuring the change in BCVA according to an ETDRS chart.

[0305] Embodiment 43. The method according to Embodiment 41 or 42, wherein the evaluation includes measuring the change in CST using SD-OCT.

[0306] Embodiment 44. The method according to any one of Embodiments 41 to 43, wherein the evaluation includes determining the presence or absence of disease activity ("DA").

[0307] Embodiment 45. The method according to Embodiment 44, wherein DA is determined to be present if at least one of the following conditions is met: (1) CST has increased by more than 50 μm compared to the average CST over the past two months as measured by SD-OCT; (2) CST has increased by 75 μm or more compared to the lowest CST over the past two months as measured by SD-OCT; (3) BCVA has decreased by 5 or more ETDRS characters compared to the average BCVA over the past two months due to the progression of nAMD; (4) BCVA has decreased by 10 or more ETDRS characters compared to the highest BCVA over the past two months due to the progression of nAMD; and (5) new foveal hemorrhage has occurred due to the progression of nAMD.

[0308] Embodiment 46. The method according to Embodiment 44, wherein DA is determined to be present in the subject if at least one of the following conditions is present: (1) BCVA is decreased by 5 or more ETDRS letters compared to the most recent value; (2) CST is increased by more than 50 μm compared to the most recent value as measured by SD-OCT; (3) Persistent subretinal / intraretinal / subretinal pigment epithelial ("RPE") fluid; (4) Newly occurring CNV; and (5) Newly occurring macular hemorrhage.

[0309] Embodiment 47. The method according to any one of Embodiments 44 to 46, wherein (1) during the loading phase, the fusion protein is administered four times, once every four weeks; and (2) during the maintenance phase, at least two doses of the fusion protein are administered (a) once every eight weeks if DA is present eight weeks after the last dose of the loading phase, or (b) once every twelve weeks if DA is not present approximately eight weeks after the last dose of the loading phase, wherein the fusion protein is efdamlovsp alfa, and each dose is 6.4 mg or 8.0 mg.

[0310] Embodiment 48. The method according to any one of Embodiments 44 to 46, wherein (1) during the loading phase, the fusion protein is administered once every 4 weeks for a total of 3 doses, and (2) during the maintenance phase, the fusion protein is administered at least twice, the doses being (a) once every 8 weeks if DA is present approximately 8 weeks after the last dose of the loading phase, (b) once every 12 weeks if DA is not present approximately 8 weeks after the last dose of the loading phase but is present approximately 12 weeks later, or (c) once every 16 weeks if DA is not present both 8 weeks and 12 weeks after the last dose of the loading phase, the fusion protein is efdamlovsp alfa, and each dose is 8.0 mg.

[0311] Embodiment 49. The method according to any one of Embodiments 31 to 48, wherein the interval from the last dose during the loading phase to the first dose during the maintenance phase is the same as the dosing interval during the maintenance phase.

[0312] The method according to any one of Embodiments 31 to 49, wherein during the maintenance phase, the fusion protein is administered at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight times.

[0313] Embodiment 51. The method according to any one of Embodiments 1 to 50, wherein the method increases the BCVA of the affected eye by at least 0 ETDRS characters, at least 5 ETDRS characters, at least 10 ETDRS characters, or at least 15 ETDRS characters.

[0314] Embodiment 52. The method according to Embodiment 51, wherein the method divides the BCVA into approximately 10 to approximately 15 ETDRS characters.

[0315] Embodiment 53. The method according to any one of Embodiments 1 to 52, wherein the method reduces the CST of the affected eye by at least 50 μm, at least 75 μm, at least 100 μm, at least 125 μm, or at least 150 μm when measured by SD-OCT.

[0316] Embodiment 54. The method according to Embodiment 53, wherein the method reduces the CST by approximately 125 μm to approximately 150 μm when measured by SD-OCT.

[0317] Embodiment 55. The method according to any one of Embodiments 1 to 54, wherein the method reduces or prevents the occurrence of pigment epithelial detachment ("PED") in an affected eye.

[0318] Embodiment 56. The method according to any one of Embodiments 1 to 55, wherein the method reduces or prevents the generation of intraretinal fluid ("IRF") or subretinal fluid ("SRF") in the affected eye.

[0319] Embodiment 57. The method according to any one of Embodiments 1 to 56, wherein the method reduces or prevents (1) the occurrence of new macular atrophy ("MA") in the affected eye, or (2) the area of ​​MA, or both (1) and (2).

[0320] Embodiment 58. The method according to any one of Embodiments 1 to 57, wherein the method reduces or prevents the occurrence of geographic atrophy ("GA") in the affected eye.

[0321] Embodiment 59. The method according to any one of Embodiments 1 to 58, wherein the method reduces or prevents retinal fibrosis in an affected eye.

[0322] Embodiment 60. The method according to any one of Embodiments 1 to 59, wherein the method reduces (1) the area of ​​CNV, (2) the area of ​​CNV leakage, or (3) the total area of ​​lesions (including hemorrhage, CNV, atrophy, and fibrosis), or any combination thereof, in the affected eye.

[0323] Embodiment 61. The method according to any one of Embodiments 1 to 60, wherein the method reduces the area of ​​retinal neovascularization ("RNV"), the area of ​​RNV leakage, or both.

[0324] Embodiment 62. The method according to any one of Embodiments 1 to 61, wherein the method reduces macular retinal edema.

[0325] Embodiment 63. A method according to any one of Embodiments 1 to 62, wherein the method improves the visual-related quality of life of the subject.

[0326] Embodiment 64. A method for treating diabetic macular edema ("DME") in a subject requiring treatment, comprising administering a fusion protein that specifically binds to human VEGF and human CR1, the fusion protein comprising, from the N-terminus to the C-terminus, a VID, an immunoglobulin Fc region, a peptide linker, and a CID; Here, the fusion protein has an amino acid sequence that is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to SEQ ID NO: 1; The fusion protein is administered to the affected eye in a dose of approximately 1.0 to 8.0 mg using the method described above.

[0327] Embodiment 65. The method according to Embodiment 64, wherein the fusion protein is efdamlovsp alfa (SEQ ID NO: 1).

[0328] Embodiment 66. The method according to Embodiment 64 or 65, wherein the subject has diabetic macular edema (CI-DME) affecting the central area.

[0329] Embodiment 67. The method according to any one of Embodiments 64 to 66, wherein the subject has a localized DME.

[0330] Embodiment 68. The method according to any one of Embodiments 64 to 66, wherein the subject has diffuse DME.

[0331] Embodiment 69. The method according to any one of Embodiments 64 to 68, wherein the BCVA of the affected eye is in the range of 24 to 73 ETDRS letters (including the endpoints).

[0332] Embodiment 70. The method according to any one of Embodiments 64 to 69, wherein the CST of the affected eye is at least 280 μm, at least 300 μm, or at least 325 μm when measured by SD-OCT.

[0333] Embodiment 71. The method according to Embodiment 64 or 65, wherein the affected eye has (1) visual impairment due to diabetic macular edema (DME) extending to the fovea, (2) a central retinal thickness (CST) of 280 μm or more as measured by SD-OCT, and (3) a BCVA within the range of 24 to 73 ETDRS characters (including the endpoints).

[0334] Embodiment 72. The method according to any one of Embodiments 64 to 71, wherein the subject has been newly diagnosed with DME.

[0335] Embodiment 73. The method according to any one of Embodiments 64 to 71, wherein the subject has been diagnosed with DME for up to 12 years.

[0336] Embodiment 74. The method according to any one of Embodiments 64 to 73, wherein the subject has not previously received treatment with an anti-VEGF drug.

[0337] Embodiment 75. The method according to any one of Embodiments 64 to 73, wherein the subject has previously received treatment with an anti-VEGF drug.

[0338] Embodiment 76. The method according to any one of Embodiments 64 to 75, wherein the subject has proliferative diabetic retinopathy ("PDR").

[0339] Embodiment 77. The method according to any one of Embodiments 64 to 76, wherein the subject is a human.

[0340] Embodiment 78. The method according to any one of Embodiments 64 to 77, wherein the fusion protein is administered by intravitreous injection.

[0341] Embodiment 79. The method according to Embodiment 78, wherein the fusion protein is injected as a liquid.

[0342] Embodiment 80. The method according to Embodiment 79, wherein the liquid formulation has a fusion protein at a concentration in the range of about 40 mg / ml to about 100 mg / ml.

[0343] Embodiment 81. The method according to Embodiment 79, wherein the liquid formulation has a fusion protein at a concentration of approximately 80 mg / ml.

[0344] Embodiment 82. The method according to any one of Embodiments 79 to 81, wherein the injection volume is approximately 0.01 ml to approximately 0.2 ml.

[0345] Embodiment 83. The method according to Embodiment 82, wherein the injection volume is approximately 0.1 ml.

[0346] Embodiment 84. The method according to any one of Embodiments 64 to 83, wherein the fusion protein is administered in a dose of approximately 3.2 mg, approximately 6.4 mg, or approximately 8.0 mg.

[0347] Embodiment 85. The method according to any one of Embodiments 64 to 84, wherein the fusion protein is administered at least three times.

[0348] Embodiment 86. The method according to Embodiment 85, wherein at least three doses are administered at intervals ranging from about once a week to about once every four weeks.

[0349] Embodiment 87. The method according to any one of Embodiments 64 to 86, comprising a loading phase and a maintenance phase, wherein the fusion protein is administered 3 to 5 times during the loading phase, and the fusion protein is administered once or more as needed during the maintenance phase based on the evaluation of the treated eye after the last dose of the loading phase.

[0350] Embodiment 88. The method according to Embodiment 87, wherein the fusion protein is administered three times during the loading phase.

[0351] Embodiment 89. The method according to Embodiment 87 or 88, wherein the fusion protein is administered at intervals of approximately once a week to approximately once every four weeks during the loading phase.

[0352] Embodiment 90. The method according to Embodiment 89, wherein the fusion protein is administered at intervals of approximately once every four weeks during the loading phase.

[0353] Embodiment 91. The method according to any one of Embodiments 87-90, wherein the evaluation includes measuring the change in BCVA according to an ETDRS chart.

[0354] Embodiment 92. The method according to Embodiment 91, wherein the evaluation includes measuring the change in CST when measured by SD-OCT.

[0355] Embodiment 93. The method according to Embodiment 91 or 92, wherein the evaluation includes performing an evaluation of the Diabetic Retinopathy Severity Score ("DRSS").

[0356] Embodiment 94. The method according to any one of Embodiments 91 to 93, wherein during the maintenance phase, the fusion protein is administered if (1) BCVA has decreased by 5 or more ETDRS characters compared to the most recent value, or (2) CST has increased by more than 50 μm compared to the most recent value as measured by SD-OCT.

[0357] Embodiment 95. (1) During the loading phase, the fusion protein is administered once every four weeks for a total of three times; (2) During the maintenance phase, between four and eight weeks after the last dose of the loading phase, if (1) BCVA decreases by 5 or more ETDRS letters compared to the most recent value, or (2) CST increases by more than 50 μm compared to the most recent value as measured by SD-OCT, the maintenance dose is given, where the fusion protein is efdamlovsp alfa, and the doses are 3.2 mg, 6.4 mg, or 8.0 mg, as described in Embodiment 87.

[0358] Embodiment 96. The method according to any one of Embodiments 64 to 95, wherein the method increases the BCVA of the affected eye by at least 1 ETDRS character, at least 5 ETDRS characters, at least 10 ETDRS characters, or at least 15 ETDRS characters.

[0359] Embodiment 97. The method according to Embodiment 96, wherein the method increases the BCVA from about 10 to about 15 ETDRS characters.

[0360] Embodiment 98. The method according to any one of Embodiments 64 to 97, wherein the method reduces the CST of the affected eye by at least 50 μm, at least 75 μm, at least 100 μm, at least 125 μm, or at least 150 μm when measured by SD-OCT.

[0361] Embodiment 99. The method according to Embodiment 98, wherein the method reduces the CST by approximately 125 μm to approximately 150 μm when measured by SD-OCT.

[0362] Embodiment 100. The method according to any one of Embodiments 64 to 99, wherein the method reduces macular retinal edema.

[0363] Embodiment 101. A method according to any one of Embodiments 64 to 100, wherein the method improves the quality of life related to the visual acuity of the subject.

[0364] Embodiment 102. A single pharmaceutical dosage unit comprising a fusion protein that inhibits the VEGF pathway and the complement pathway, wherein the fusion protein is the fusion protein described in Embodiments 1-2 or Embodiments 64-65, and the amount of the fusion protein is approximately 4 mg, approximately 5 mg, approximately 6.4 mg, approximately 7 mg, approximately 8 mg, approximately 9 mg, approximately 10 mg, approximately 11 mg, approximately 12 mg, approximately 12.8 mg, approximately 13 mg, approximately 14 mg, approximately 15 mg, approximately 16 mg, approximately 17 mg, approximately 18 mg, approximately 19 mg, or approximately 20 mg.

[0365] 7.9 Experiment The embodiments described below are for illustrative purposes only and are not intended to limit the invention unless otherwise specified. Therefore, the present invention should not be construed as being limited to the embodiments described below, but rather as encompassing all variations that become apparent as a result of the teachings described herein.

[0366] The active ingredient examined in the study described below is efdamlovsph alfa. In short, the results of the study described below demonstrate that efdamlovsph alfa is safe and effective in treating AMD when administered according to a prescribed regimen.

[0367] Abbreviations: AMD: Age-related macular degeneration; DME: Diabetic macular edema; RNV: Retinal neovascularization; BCVA: Best corrected visual acuity; OCT: Optical coherence tomography; CNV: Choroidal neovascularization; AE: Adverse event; DLT: Dose-limiting toxicity; EC50: Half effective concentration; SAE: Serious adverse event; TEAE: Post-treatment adverse event; CR1: Complement receptor 1; hRPE: Human retinal pigment epithelium.

[0368] 7.9.1 Example 1: In vitro pharmacodynamics test In vitro pharmacodynamic studies were conducted on efdamlovsp alfa (see WO2021 / 129658 for details, which is incorporated here in its entirety by reference).

[0369] Affinity of efdamlovsp alfa for VEGF family members and complement family cytokines: The affinity of efdamlovsp alfa to related ligands, including VEGF family cytokines and complement factors C3b and C4b, was investigated using Biacore T200.

[0370] As a result, the affinity of efdamlovsup alfa for VEGF family cytokines was comparable to that of aflibercept and significantly stronger than that of bevacizumab. The affinity of efdamlovsup alfa for C4b was comparable to that of CR1, while its affinity for C3b was slightly weaker than that of CR1, but still at the nM level.

[0371] Inhibition of VEGF-A-induced HUVEC proliferation by Efdamlovsp alfa: To investigate how the proliferative capacity of HUVEC cells changes with varying concentrations of free VEGF-A165, we conducted tests by gradually setting a concentration gradient of efdamlovsp alfa relative to a constant concentration of VEGF-A165. To measure the proliferation inhibitory efficiency of efdamlovsp alfa, we measured the number of viable HUVEC cells using the CCK-8 assay kit. Aflavelcept and bevacizumab were used as controls.

[0372] As a result, efdamlovsp alfa significantly suppressed VEGF-induced HUVEC proliferation, and its activity was comparable to that of aflibercept and slightly stronger than bevacizumab.

[0373] Inhibition of the classical complement pathway by Evdamlovsp alfa: A model of sensitized sheep erythrocytes stimulated by human serum complement was used. Efdamlovsp alfa in the range of 0.02 to 1080.26 nM inhibited hemolysis of human serum complement-induced sensitized sheep erythrocytes in a concentration-dependent manner, with an EC50 value of 2.514 nM. The EC50 value for human complement receptor type I (CR1) was 2.254 nM, indicating that efdamlovsp alfa exhibits a similar effect to CR1 and can significantly inhibit the classical complement pathway.

[0374] Inhibition of the complement alternative pathway by efdamlovsp alfa: A human serum complement-stimulated rabbit erythrocyte model was used. Efdamlovs alfa in the range of 1.50 to 383.39 nM inhibited human serum complement-induced hemolysis of rabbit erythrocytes in a concentration-dependent manner, with an EC50 value of 14.59 nM. The EC50 value for CR1 was 15.30 nM, indicating that efdamlovs alfa can significantly inhibit the alternative complement pathway with a similar effect to CR1.

[0375] The effects and mechanisms of efdamlovsp alfa on the barrier function of human retinal pigment epithelium (hRPE) cells damaged by complement activation: In cell and animal models, complement has been shown to play a crucial role in the inflammatory process following oxidative stress (DOI:10.1016 / s0161-5890(99)00116-9). We investigated the effects of complement and VEGF inhibition on the barrier function of hRPE cells after oxidative damage.

[0376] hRPE cells were divided into four groups: a normal group (nor), a model group (ctr), an aflibercept group (VEGF-Trap), a CR1 group, and an efdamlovsph alfa group. All groups except the normal group were supplemented with t-BHP and 10% normal human serum, while the normal group received the same amount of PBS. The drug-treated groups received additional doses of each drug to reach a final concentration of 1 μg / ml, while the control and model groups received the same amount of PBS. After 4 hours of culture, the barrier function of hRPE monolayer cells was evaluated. Using ELISA, the concentrations of VEGF, chemokine (CC motif) ligand 2 (CCL2), C3a, C5a, and MAC secreted from hRPE cells after 4 hours were measured.

[0377] The results showed that efdamlovsp alfa exhibits a protective effect against the barrier function of hRPE cells damaged by complement activation-induced oxidation. This mechanism is thought to involve the simultaneous inhibition of VEGF and complement activation products C3a, C5a, and MAC, which reduces the secretion of CCL2 and VEGF by hRPE cells.

[0378] 7.9.2 Example 2: In vivo pharmacodynamics test In vivo pharmacodynamic studies were conducted on efdamlovsp alfa (see WO2021 / 129658 for details, which is incorporated here in its entirety by reference).

[0379] Studies on the effects and mechanism of action of efdamlovsp alfa on laser-induced CNV in mice: In this experiment, C57BL / 6J mice that underwent laser photocoagulation at four locations were used. The mice were randomly divided into six groups (two mice per group, totaling four eyes): a laser-induced model group, a PBS administration group, and a group administered efdamlovsph alfa at doses of 1 μg / μl, 3 μg / μl, 5 μg / μl, and 10 μg / μl. Seven days after laser photocoagulation, 1 μl each of efdamlovsph alfa or PBS at each concentration was injected into the vitreous cavity of both eyes of the CNV mice. Perfusion of fluorescein isothiocyanate-dextran (FITC-dextran) into the orbital venous sinus and choroidal flat mounting were performed to observe the effect of each dose of efdamlovsph alfa on the CNV region in the mice.

[0380] Furthermore, the mice were divided into four groups: efdamlovsph alfa, aflibercept (VEGF-Trap), CR1, and PBS. Both efdamlovsph alfa and the control drug were administered at a concentration of 10 μg / μl. Immediately after laser photocoagulation, 1 μl of each sample was injected into the vitreous cavity of both eyes of CNV mice. Seven days after laser photocoagulation, fundus fluorescein angiography was performed to measure CNV. The mice were anesthetized with chloral hydrate and their pupils were dilated with complex tropicamide. First, infrared fundus photographs were taken, followed by FITC-dextran, indocyanine green angiography (ICGA) and fundus fluorescein angiography (FFA). Finally, the concentrations of VEGF, CCL2, TNF-α, C3a, and C5a proteins in the RPE-choroid were measured by ELISA.

[0381] As a result, it was shown that Efdamlovsp alfa can suppress the formation and leakage of laser-induced CNVs in mice by simultaneously suppressing the expression of VEGF and complement activators C3a, C5a, MAC, CCL2, and TNF-α, thereby suppressing macrophage and neutrophil infiltration, reducing VEGF secretion, and inhibiting neovascularization.

[0382] Inhibition of laser-induced CNV in rhesus monkeys by ephdamlovsp alpha: A model similar to human CNV was created by laser photocoagulation of the macula of rhesus monkeys. Twenty-five monkeys (mixed males and females) that successfully modeled both eyes were divided into five groups: a model control group, a bevacizumab injection group (1.25 mg / eye), and efdamlovsp alfa groups (each dosed at 0.25 mg / eye, 0.5 mg / eye, and 1.25 mg / eye), with five monkeys in each group. Twenty-one days after photocoagulation, each group received a single intravitreal injection of the corresponding drug at a dose of 50 μl / eye.

[0383] Color photographs of the fundus and fluorescein angiography were performed on days 14 and 28 after administration. On days 11 and 25 after administration, OCT was performed to measure the inhibitory effect of efdamlovsp alfa on CNV. On day 29, aqueous humor was collected from both eyes to detect VEGF; histopathological examination was performed on the left eye, and immunohistochemical staining for CD31 and C5b-9 was performed on the right eye.

[0384] As a result, efdamlovsph alfa significantly reduced fluorescein leakage, fluorescein plaque area, and the number of fluorescein plaques. It also reduced retinal thickness at the lesion sites of fluorescein plaques, restored the integrity and continuity of the retinal pigment epithelium, decreased VEGF levels in aqueous humor, reduced fibrous tissue proliferation, and suppressed CD31 and C5b-9 expression in the choroid. Efdamlovsph alfa was more effective than the clinical dose of bevacizumab.

[0385] The above results indicate that efdamlovsp alfa has the following pharmacodynamic properties:

[0386] (1) Dual target: Efdamlovsph alfa is a dual-target drug because it specifically binds to the VEGF family (VEGF-A165, VEGF-A121, and PIGF) via its VID domain and specifically binds to complement factors (C3b and C4b) via its CID domain.

[0387] (2) Clear mechanism of action: The CID of efdamlovsph alfa specifically binds to C3b and C4b, inhibiting the activation of classical and alternative complement pathways, thereby reducing the inflammatory response mediated by complement activation. The VID domain blocks VEGF-mediated signaling pathways, inhibiting endothelial cell survival and proliferation, thereby suppressing angiogenesis, reducing vascular permeability, and decreasing vascular leakage.

[0388] (3) Efficacy in animal models: Efdamlovsph alfa showed a significant protective effect on hRPE cells in a t-BHP-induced hRPE oxidative stress model. It also showed remarkable anti-angiogenic and anti-leakage effects in laser-induced CNV models in mice and rhesus monkeys.

[0389] (4) Superior to commercially available anti-VEGF drugs: In t-BHP-induced hRPE oxidative stress models and laser-induced CNV models in mice and rhesus monkeys, efdamlovsp alfa was more effective than aflibercept or bevacizumab.

[0390] 7.9.3 Example 3: Pharmacokinetic Study Pharmacokinetic studies were conducted on the absorption and distribution of efdamlovsp alfa (see WO2021 / 129658 for details, which is incorporated here in its entirety by reference).

[0391] Pharmacokinetic studies of ephdamlovsp alfa in rhesus monkeys: In a pharmacokinetic study of efdamlovsp alfa administered as a single intravenous or intravitreous dose in rhesus monkeys, 27 monkeys were randomly divided into an intravenous and an intravitreous administration group. The intravitreous group consisted of 21 monkeys (11 females and 10 males), and the intravenous administration group consisted of 6 monkeys (3 females and 3 males). In the intravenous administration group, blood was collected from the animals before administration and at 0.5, 1, 2, 4, 10, 24, 48, 72, 96, 144, 192, 240, 336, and 504 hours after administration, and serum was separated. In the intravitreal injection group, samples of aqueous humor, vitreous humor, lens, cornea, iris, retina, choroid, sclera, optic nerve, and serum were collected at 4, 24, 72, 168, 336, and 504 hours after administration.

[0392] As a result, the half-life (T1 / 2) of efdamlovsp alfa after intravitreal injection was significantly longer than after intravenous injection. Intraocular drug concentrations were significantly higher than serum drug concentrations, suggesting a lower risk of systemic toxicity. The drug was mainly distributed to ocular tissues such as the vitreous humor, retina, and choroid. Both the terminal elimination half-life (T1 / 2) and mean residence time (MRT) indicated that the drug remained in the retina and choroid for a relatively long period, suggesting the possibility of sustained efficacy.

[0393] Repeated-dose pharmacokinetic study of efdamlovsp alfa: In a 4-week repeated-dose pharmacokinetic study of efdamlovsp alfa administered intravitreously to rhesus monkeys, 50 monkeys were randomly divided into five groups: a control group, an intravenous efdamlovsp alfa group (8 mg / monkey), and three intravitreous injection groups (0.5 mg / eye, 2 mg / eye, and 4 mg / eye). Efdamlovsp alfa was administered every two weeks for a total of three consecutive doses. Each group consisted of 10 animals, with an equal number of males and females. In the control group, blood samples were collected before the first and last doses, and 24 hours after the first and last doses, and serum was prepared. In the efdamlovsp alfa 8 mg groups, blood samples were collected before the first and last doses, and 5 minutes, 1 hour, 4 hours, 8 hours, 24 hours, 48 ​​hours, 72 hours, 120 hours, 168 hours, and 336 hours after the first and last doses, and serum was prepared. In the group receiving intravitreal injection of efdamlovsp alfa, blood samples were collected before the first and last doses, and at 1, 4, 8, 24, 48, 72, 120, and 168 hours after the first and last doses, and serum was prepared. The concentration of efdamlovsp alfa in the serum was measured by ELISA.

[0394] The results showed that the accumulation index after continuous intravenous infusion of efdamlovsp alfa in rhesus monkeys was 0.7. In the intravitreous injection group, the dose-proportional relationships of Cmax and AUC(0-t) after the initial administration of 0.5 mg / eye, 2 mg / eye, and 4 mg / eye were 1:4.4:5.5 and 1:6.3:13.4, respectively, indicating dose dependence. After the final administration, the dose-proportional relationships of Cmax and AUC(0-t) were 1:2.3:7.9 and 1:15.7:54.6, respectively. The accumulation coefficients for the doses of 0.5 mg / eye, 2 mg / eye, and 4 mg / eye were NA (cannot be calculated because the drug was not detected in some individuals after the final administration), 0.3, and 0.4.

[0395] These results indicate that multiple intravitreal injections of efdamlovsp alfa into rhesus monkeys resulted in a dose-dependent increase in drug exposure and peak concentration. Since serum drug exposure after the final dose was lower than after the initial dose, it was suggested that anti-antibodies existed and that accumulation due to repeated administration was not observed.

[0396] The above studies revealed the following pharmacokinetic properties of efdamlovsp alfa.

[0397] (1) Tissue distribution: After intravitreal injection, the majority of the drug remained in the eye, and local intraocular drug concentrations were significantly higher than serum drug concentrations. This suggests that efdamlovsp alfa exerts its pharmacological effects primarily in the eye, with minimal risk of systemic toxicity. The highest drug distribution was observed in the vitreous humor, retina, and choroid, which coincided with the target tissues.

[0398] (2) Duration of action: As indicated by the terminal elimination half-life (T1 / 2) and mean residence time (MRT), efdamlovsph alfa remained in the retina and choroid for a long period, enabling a sustained therapeutic effect.

[0399] (3) Accumulation: In repeated intravenous or intravitreal administration of efdamlovsp alfa to rhesus monkeys, no accumulation was observed because the drug exposure level after the final dose was lower than that at the time of the first dose.

[0400] (4) Immunogenicity: The decrease in serum drug exposure levels after the final dose compared to the initial dose suggests that antibodies against efdamlovsp alfa were produced in some animals.

[0401] 7.9.4 Example 4: Toxicity Test Toxicity testing of Evdamlovsp alfa was conducted using rhesus monkeys (see WO2021 / 129658 for details, which is incorporated here in its entirety by reference). Evdamlovsp alfa exhibited the following toxicological properties:

[0402] (1) Single dose: Efdamlovsp alfa was administered as a single intravitreal injection to rhesus monkeys at doses of 2 mg / eye or 4 mg / eye. No significant toxic reactions were observed, and there were no notable effects on the central nervous system, respiratory system, or circulatory system, demonstrating high safety with single intravitreal injection.

[0403] (2) Repeated administration: Rhesus monkeys were administered efdamlovsup alfa intravitreally at doses of 0.5 mg / eye, 2 mg / eye, or 4 mg / eye, or intravenously at a dose of 8 mg / animal every two weeks for three consecutive doses, followed by a 74-day recovery period. No significant systemic toxicity was observed. The main symptoms were intraocular inflammation of varying degrees and associated inflammatory pathological changes in the eye and optic nerve, which significantly improved by the end of the recovery period. This suggests that the toxic reaction to efdamlovsup alfa is localized to the eye and reversible, confirming its good safety.

[0404] (3) Immunotoxicity and immunogenicity: No immunotoxicity was observed with multiple intravitreal injections of efdamlovsup alfa in rhesus monkeys. Antidrug antibodies were produced at all doses, and the incidence was high, suggesting that efdamlovsup alfa has some degree of immunogenicity in rhesus monkeys, and close monitoring is necessary in clinical trials.

[0405] (4) Intraocular inflammation: Intraocular inflammation observed with intravitreal injection of efdamlovsp alfa was associated with the formation of anti-drug antibodies and immune complexes. Considering that efdamlovsp alfa is a fully human monoclonal antibody, the clinical likelihood of anti-drug antibodies and immune complexes occurring was low, and therefore the risk of intraocular inflammation was minimal; however, close monitoring is still necessary in clinical trials.

[0406] (5) Local irritation test: Japanese white rabbits were continuously administered 0.5 mg / eye or 2 mg / eye of efdamlovsph alfa as eye drops once a week for 4 weeks. No irritation was observed in the rabbits' eyes, indicating that efdamlovsph alfa is not irritating to the eyes.

[0407] (6) Tissue specificity: Efdamlovsp alfa did not show significant cross-reactivity with normal human tissue or crab-eating monkey tissue. This indicates that there was no significant interaction with normal human tissue and that the target-related toxicity was extremely low.

[0408] 7.9.5 Example 5: Efdamlovsp alfa for the treatment of RNV The anti-RNV effect of the Efdamlovsp alpha fusion protein was measured using a DL-α-AAA (DL-α-aminoadipic acid) induced RNV model in Dutch rabbits.

[0409] Laboratory animals: Species and lineage: Dutch rabbit Animal grade: General grade Supplier: Pijou Oriental Breeding Co., Ltd. (Animal Production Permit Number SCX(Su)2017-0002, Quality Certificate Number 202120537 Age at the start of administration (D1): 6-7 months. Body weight at the start of administration (D1): 1.84-2.74 kg

[0410] Experimental method: RNV was successfully induced in 27 Dutch male rabbits (41 eyes) by intravitreal injection of DL-α-AAA (DL-α-aminoadipic acid). Based on the fluorescence leakage area of ​​RNV in the modeled eyes, the animals were divided into 7 groups (group 4 had 5 eyes, and the others had 6 eyes). On day 1 (D1), groups 1-3 were intravitreal-injected with 50 μL of PBS, aflibercept (EYLEA®) (0.5 mg / eye), or efdamlovsp alfa (0.5 mg / eye), respectively.

[0411] Daily clinical observations were performed during the experimental period. Red light cutoff imaging was performed before administration and on days 15 and 29 after administration to identify the temporal, central, and nasal nerve fiber layers. Efficacy was evaluated based on the fluorescence leakage area of ​​the RNV and the morphology of the RNV.

[0412] Before administration and on days D1, D8, D15, D22, and D29, animal weight measurement and fluorescence angiography (FFA) were performed. Prior to FFA, fluorescein sodium (10 mg / kg, 100 mg / mL) was administered intravenously to the animals. Images were taken in the early phase (0-1.5 min) and late phase (1.5-3 min). Fluorescence leakage and the presence or absence of RNV were evaluated, and the fluorescence leakage area was measured to calculate the reduction and improvement rates. Reduction in fluorescence leakage area = Leakage area before treatment - Leakage area after treatment

[0413] Research design table:

[0414] [Table 1]

[0415] As shown in Figure 1, efdamlovsp alfa showed a significant anti-neovascular effect 7 days after administration, which was comparable to that of aflibercept (EYLEA®). This demonstrated that efdamlovsp alfa can effectively suppress retinal neovascularization.

[0416] 7.9.6 Example 6: Phase I trial in the treatment of nAMD and DME Overview of the study design This phase involved a multicenter, open-label, multiple intravitreal (IVT) dose-escalation study in patients with nAMD and DME. The study planned to include 9–18 patients in each group (nAMD and DME), for a total of 18–36 patients. The study aimed to evaluate the safety, tolerability, preliminary efficacy, pharmacokinetic (PK) properties, and immunogenicity of efdamlovspraf alfa in patients with nAMD and DME. Three dose groups (3.2 mg / eye, 6.4 mg / eye, and 8.0 mg / eye: infusion volumes of 0.04 mL, 0.08 mL, and 0.1 mL, respectively) were investigated. A "3+3" dose-escalation design (see Figure 2) was employed. Dose escalation was performed under the same discontinuation criteria in both nAMD and DME patients, and results were evaluated individually. Dose escalation was based on dose-limiting toxicity (DLT) observed within 7 days after the initial dose (i.e., from D0 to W1). Each dose group consisted of 3 to 6 subjects, resulting in a total of 3 dose groups and 18 to 36 subjects. For safety reasons, the first subject in each dose group had to complete DLT observation before enrolling the remaining two subjects.

[0417] DLT was defined as any of the following adverse events related to efdamlovsp alfa that occurred during the DLT observation period: 1) Intraocular inflammation: three or more grades of change observed in anterior chamber flare, anterior chamber cells, or vitreous opacity; 2) Vitreous hemorrhage: Grade 2 or higher; 3) Acute visual impairment: a visual impairment of 15 letters or more not attributable to intraocular inflammation and lasting for 24 hours or longer; 4) Post-administration intraocular pressure elevation: exceeding 30 mmHg and lasting for 240 minutes or longer; 5) Hemorrhage: intracranial hemorrhage or other clinically significant non-ocular hemorrhage; 6) Serious adverse events (SAEs) judged by the principal investigator to be related to the investigational drug.

[0418] Taking DME subjects as an example: Each dose group starts with one subject, and the presence or absence of DLTs is observed within 7 days. If no DLTs are observed in the first subject, two more subjects are enrolled. If DLTs occur in the first subject, a third subject should be enrolled after the second subject completes DLT observation.

[0419] 1. If none of the 3 subjects experienced DLT, the group proceeded to the next dose group. 2. If two or more of the 3 subjects experienced DLT, dose escalation was discontinued, and the dose was considered unacceptable. 3. If one of the 3 subjects developed DLT, three additional DME subjects were enrolled. If one or fewer of the 6 subjects developed DLT, the group proceeded to the next dose group. If two or more of the 6 subjects developed DLT, dose escalation was discontinued, and the dose was considered unacceptable. 4. After an unacceptable dose was determined, the dose immediately preceding it became the maximum tolerated dose (MTD). 5. If the MTD was not reached at the planned maximum dose of 8.0 mg / eye, dose escalation was discontinued, and 8.0 mg / eye was considered the maximum dose for this study. 6. If more than 2 / 3 of the subjects or more than 2 out of 6 subjects developed DLT at 3.2 mg / eye, the Safety Evaluation Committee assessed the need for dose reduction for future clinical studies.

[0420] The Safety Evaluation Committee was able to decide to establish an intermediate dose group between the untolerable dose and the previous dose in order to more appropriately determine the MTD.

[0421] The subjects received intravitreal injections of efdamlovsp alfa on day 0, week 4, and week 8, and underwent follow-up visits on day 1 and one week after each injection (weeks 1, 5, and 9). Furthermore, the subjects also had follow-up visits at weeks 12, 16, and 20.

[0422] For patients with DME, if, between weeks 12 and 16, the BCVA decreased by 5 letters or more compared to the previous visit, or the CST increased by 50 μm or more, and the principal investigator determined that this was due to DME, the patient received an intravitreal injection of the assigned dose of efdamlovsp alfa and continued treatment. For patients with nAMD, if, between weeks 12 and 16, the principal investigator determined that any of the following criteria were met due to the progression of nAMD, the patient received an intravitreal injection of the assigned dose of efdamlovsp alfa and continued treatment: (i) the BCVA decreased by 5 letters or more compared to the previous visit, or the CST increased by 50 μm or more; (ii) persistent subretinal / intraretinal / RPE fluid; (iii) new CNV; or (iv) new macular hemorrhage.

[0423] The last visit was at 20 weeks.

[0424] Research objectives and evaluation criteria:

[0425] [Table 2]

[0426] Target group: 1) Inclusion Criteria (Participants were included in this study only if they met all of the following criteria at screening and baseline): 1. Signed informed consent was obtained prior to participation. 2. The participant was a male or female aged 18 years or older. 3. The participant had visual impairment in the study eye due to DME affecting the central retinal macula, or active submacular or paramacular vascular variation (CNV) secondary to nAMD. 4. For participants with DME, the CST of the study eye was confirmed to be 280 μm or larger by SD-OCT at screening. There is no CST requirement for participants with nAMD. 5. The BCVA of the study eye was within the range of 24 to 73 letters (including both ends). 6. Participants who were of childbearing potential, or men with childbearing partners, had to agree to use effective contraception from screening until 6 months after treatment.

[0427] 2) Exclusion Criteria (If any of the following criteria were met at the time of screening or baseline, the subject was not included in this study): Ocular Diseases: 1. If, at the time of screening or at baseline, the principal investigator determines that a systemic / ocular disease is present in the investigational eye that could cause the subject to fail to respond to the investigational treatment or that could complicate the interpretation of the trial results. For example, high-risk progressive diabetic retinopathy (PDR), fibrous or atrophic lesions extending to the fovea, retinal hemorrhage extending to two or more disk areas in the fovea, retinal vein occlusion, retinal detachment, macular hole, posterior or panubetus, vitreomacular traction affecting central visual acuity, epiretinal membranes affecting or destroying the macular structure, and spherical refractive error ≤ -8.00D. 2. If the intraocular pressure of the test eye exceeds 21 mmHg. 3. Active intraocular or periocular infection or inflammation (e.g., bacterial conjunctivitis, endophthalmitis). 4. Severe intraocular opacity or pupillary dilation failure that interferes with imaging diagnostics necessary for evaluating safety and efficacy (e.g., SD-OCT, FFA, CFP) or affects BCVA. 5. BCVA of the non-test eye is less than 19 characters (ETDRS).

[0428] Ophthalmic treatments: 6. Anti-VEGF treatment received in the study eye within 90 days prior to baseline. 7. Anti-complement treatment received in the study eye within 90 days prior to baseline. 8. History of vitrectomy in the test eye at any time prior to baseline. 9. Grid or panretinal photocoagulation in the test eye within 90 days prior to baseline. 10. Any intraocular surgery (e.g., cataract extraction) in the test eye within 90 days prior to baseline. 11. YAG laser capsulotomy in the test eye within 30 days prior to baseline. 12. Intraocular or periorbital steroid injection in any eye within 120 days prior to baseline. 13. Aphakic eye with posterior capsule defect in the study eye. 14. Anti-VEGF treatment in a non-study eye within 30 days prior to baseline.

[0429] General conditions or treatments: 15. Patients with confirmed diabetic retinopathy (DME) who have received treatment with antidiabetic drugs (oral and / or injectable) within 90 days prior to administration of the study drug. 16. Patients with glycated hemoglobin (HbA1c) exceeding 10% within 28 days prior to administration of the study drug. 17. Poorly controlled hypertension (defined as resting systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg. If the initial measurement exceeds the above criteria, remeasurement is permitted on the same day or at another day during the screening period. If the subject is taking oral antihypertensive drugs, they must have been taking the same medication stably for at least 30 days prior to screening). 18. Steroid treatment (excluding topical, intranasal, and intra-articular administration) within 30 days prior to administration of the study drug. 19. Systemic anti-VEGF drug treatment within 90 days prior to administration of the study drug. 20. Systemic anti-complement drug treatment within 90 days prior to administration of the study drug. 21. Other diseases, metabolic disorders, physical examination findings, or laboratory findings that suggest a contraindication to the study drug, affect the interpretation of study results, or indicate a high risk of treatment complications in the subject (including, but not limited to, hemorrhagic disorders, cerebrovascular events within 180 days prior to screening, transient ischemic attack, myocardial infarction, or a history of treated or untreated malignant tumors within the past 5 years). 22. Active liver disease or liver dysfunction (defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels exceeding 3 times the upper limit of normal (ULN) at the time of screening). 23. Serum creatinine (Cr) or urea (UREA) levels exceeding 1.5 times the ULN. 24. Subjects who have undergone major or moderate surgery or suffered severe trauma within 90 days prior to administration of the study drug. 25. Subjects who tested positive for human immunodeficiency virus (HIV) antibodies at the time of screening. 26. Individuals with acute or chronic active hepatitis B at the time of screening (defined as positive for hepatitis B surface antigen and / or hepatitis B core antibody, and with an HBV-DNA viral load of 2000 IU / mL or higher). 27. Individuals who are positive for syphilis-specific antibodies and, based on the results of nonspecific antibody tests, are determined by the researcher to be in the active phase or require treatment.28. If you have a history of severe allergic reactions to the active ingredients or additives of the investigational drug or positive control drug, or to sodium fluorescein or povidone-iodine. 29. If you participated in another clinical trial 90 days prior to baseline (or within 5 times the half-life of the drug, whichever is longer), or if you are scheduled to participate in another clinical trial during the trial period. Other circumstances that the researcher deems unsuitable for participation in this trial (e.g., drug abuse, inability to comply with the trial protocol, or unwillingness to comply with it).

[0430] result: As of April 13, 2023, the data cutoff date, this study had enrolled 9 participants in the nAMD category and 9 participants in the DME category.

[0431] 1. Baseline characteristics and past treatments of the target ocular disease: The results are shown in the table below:

[0432] [Table 3]

[0433] 2. Change in BCVA from baseline: Figure 3A shows the changes in BCVA (EDTRS letters) at each visit in the test eye of nAMD patients. Figure 3B shows the changes in BCVA (EDTRS letters) at each visit in the test eye of DME patients. In Figures 3A and 3B, "Num" represents the number of patients for whom statistical data is available at the corresponding time point.

[0434] 3. Changes in CST from baseline in SD-OCT examination: Figure 4A shows the change in CST from baseline in SD-OCT examinations at each visit for the test eye of nAMD patients. Figure 4B shows the change in CST from baseline in SD-OCT examinations at each visit for the test eye of DME patients. In Figures 4A and 4B, "Num" represents the number of patients for whom statistical data is available at the corresponding time point.

[0435] 4.Safety overview: In 9 nAMD patients: -Efdamlovsph alfa 3.2mg group: 1 patient (33.3%) experienced TEAE (subconjunctival hemorrhage of the test eye). -Efdamlovsph alfa 6.4 mg group: Two patients (66.7%) experienced TEAE. One patient (33.3%) experienced TEAE in the test eye, including eye pain and eye itchiness (one patient each), and one patient (33.3%) experienced elevated blood glucose levels. -Efdamlovsp alfa 8.0 mg group: One patient (33.3%) experienced TEAE (conjunctival hyperemia of the test eye).

[0436] In 9 DME patients: -Efdamlovsph alfa 3.2mg group: TEAEs were observed in 2 cases (66.7%). Two cases (66.7%) showed TEAEs in the test eye, including dry eye and vitreous hemorrhage (1 case each), and one case (33.3%) showed a TEAE in the non-test eye, which was dry eye. - In the Efdamlovsp alfa 6.4 mg group, TEAE was observed in 1 case (33.3%). This included anterior chamber flash and conjunctival hyperemia in the test eye (1 case each). -Efdamlovsp alfa 8.0mg group: No TEAEs were observed.

[0437] In both nAMD and DME patients, TEAEs were mild to moderate. There were no cases of discontinuation of the investigational drug due to TEAE or TEAE related to the investigational drug.

[0438] 5. Conclusion: Results from a dose-escalation Phase I trial showed that multiple intravitreal injections of efdamlovsp alfa 3.2 mg, 6.4 mg, and 8.0 mg were safe and well-tolerated in patients with nAMD and DME, with no DLT events observed. The maximum dose in this phase was 8.0 mg (100 μL injection). Multiple intravitreal injections of different doses of efdamlovsp alfa improved BCVA and macular retinal edema in patients with nAMD or DME, and the effect lasted for 8–12 weeks. After multiple intravitreal injections of different doses of efdamlovsp alfa, systemic exposure to free / total efdamlovsp alfa was extremely low, and the risk to systemic safety was minimal. The risk of systemic immunogenic reactions with multiple intravitreal injections of efdamlovsp alfa was also extremely low.

[0439] 7.9.7 Example 7: Phase II Trial in the Treatment of nAMD - 1 This was a multicenter, randomized, double-blind, active-controlled phase II trial to evaluate the efficacy and safety of efdamlovsp alfa in patients with nAMD. Eligible participants were randomly assigned in a 1:1:1 ratio to one of three treatment groups, with 77 participants in each group. Participants were stratified based on (1) the type of CNV, i.e., whether the test eye was type II CNV, and (2) whether the participant had previously received treatment for nAMD. Participants without type II CNV accounted for less than 30% of the total randomized population, while untreated and previously treated participants each accounted for approximately 50%.

[0440] Research objectives: Primary objective: To evaluate the visual acuity benefits of efdamlovsp alfa in patients with nAMD. Secondary objectives: (1) to evaluate other therapeutic effects of efdamlovsp alfa on visual acuity; (2) to evaluate the anatomical efficacy of efdamlovsp alfa as detected by SD-OCT; (3) to evaluate the anatomical efficacy of efdamlovsp alfa as detected by FFA; (4) to evaluate the safety of efdamlovsp alfa; (5) to evaluate the systemic pharmacokinetic profile of efdamlovsp alfa after multiple intravitreal injections; and (6) to evaluate the immunogenicity profile of efdamlovsp alfa. The objectives of the study are: (1) to explore the effects of efdamlovsp alpha on fundus fibrosis; (2) to explore the effects of efdamlovsp alpha on retinal atrophy (RA); (3) to explore the effects of efdamlovsp alpha on severe retinal PED; and (4) to evaluate the effects of efdamlovsp alpha on neovascularization as measured by OCT.

[0441] Target group : Participants in this study met the following criteria at the time of screening: (1) had signed informed consent; (2) were 50 years of age or older; (3) had active submacular or perimacular vascular necrosis (CNV) secondary to nAMD, as confirmed by FFA or SD-OCT in the study eye; (4) the CNV area (including classical and latent types) detected by FFA in the test eye was 50% or more of the total lesion area (including hemorrhage, CNV, atrophy, and fibrosis); (5) the BCVA of the test eye was within the range of 24 to 73 ETDRS letters (including both extreme values).

[0442] Investigational drug: Efdamlovsp Alpha: 0.2 ml: 8 mg per vial. Control drug: Aflibercept (EYLEA®): 0.1 ml: 4 mg per vial.

[0443] [Table 4]

[0444] Treatment regimen:

[0445] Q4W: Once every 4 weeks; Q8W: Once every 8 weeks.

[0446] Administration period: From D0 to the end of W8. All subjects in each group received either Aflavelcept or Efdamlovsp alfa once every four weeks (Q4W) for a total of three doses.

[0447] Maintenance period: Weeks 12 to 48. All subjects received the drug every 8 weeks (Q8W), i.e., at weeks 16, 24, 32, 40, and 48. If the criteria for additional treatment were met, additional treatment with aflavelcept 2 mg was initiated.

[0448] The primary evaluation criteria were assessed in week 36, and the final visit was in week 52.

[0449] Intravitreal injection was used in all treatments.

[0450] evaluation: The evaluation of efficacy included visual acuity assessment and anatomical assessment. For anatomical assessment, SD-OCT, CFP, FFA, FAF, and OCTA were used for retinal imaging and angiography. The following parameters were measured during the study period: BCVA (using the ETDRS table), CST, and NEI-VFQ-25 score.

[0451] Furthermore, the pharmacokinetic (PK) values ​​and immunogenicity of efdamlovsp alfa, as well as treatment-related adverse events (TEAEs) and serious adverse events (SAEs) that occurred during treatment, were measured and aggregated among the treatment groups during the study period.

[0452] Evaluation criteria: Primary outcome measure: Change from baseline in BCVA score as measured using the ETDRS visual acuity chart at week 36.

[0453] Secondary evaluation items: - Visual acuity-related: (1) Change from baseline in BCVA at each visit; (2) Percentage of subjects whose BCVA improved by 0, 5, 10, and 15 letters or more from baseline at weeks 12, 28, 36, and 52; (3) Percentage of subjects whose BCVA decreased by 0, 5, 10, and 15 letters or more from baseline at weeks 12, 28, 36, and 52; (4) Percentage of subjects whose BCVA was 74 letters or more at weeks 12, 28, 36, and 52; and (5) Percentage of subjects whose BCVA was 33 letters or less at weeks 12, 28, 36, and 52.

[0454] - Anatomical findings by SD-OCT: (1) Change from baseline in central macula thickness (CST) at 12, 28, 36, and 52 weeks, and (2) Percentage of subjects exhibiting IRF or SRF at 12, 28, 36, and 52 weeks.

[0455] - Anatomical findings in FFA: (1) Change from baseline in CNV area at 36 and 52 weeks; (2) Change from baseline in CNV leakage area at 36 and 52 weeks; and (3) Change from baseline in total lesion area at 36 and 52 weeks.

[0456] - Safety: (1) Occurrence of ocular and systemic adverse events (AEs), treatment-related adverse events (TEAEs), and serious adverse events (SAEs), the association between SAEs and the study drug, and the severity of SAEs; (2) Changes from baseline in vital signs, physical findings, and laboratory results.

[0457] - Pharmacokinetic profile of Efdamlovsp alfa.

[0458] - Autoimmunity of Efdamlovsp alfa: Positive rates of ADA and neutralizing antibodies in the serum of the subjects.

[0459] Exploratory evaluation criteria: - Retinal fibrosis: (1) Percentage of subjects in whom fibrosis was detected by CFP at weeks 36 and 52; (2) Change from baseline in the maximum diameter of fibrosis detected by CFP at weeks 36 and 52; (3) Change from baseline in the maximum height of fibrosis on SD-OCT at weeks 36 and 52.

[0460] - Retinal atrophy: (1) Change from baseline in total RA area on SD-OCT and FAF at weeks 36 and 52; (2) Change from baseline in MA area on SD-OCT at weeks 36 and 52; (3) Percentage of subjects in whom new RA was observed on SD-OCT and FAF at weeks 36 and 52.

[0461] -PED: (1) Percentage of sPED on SD-OCT at weeks 12, 36, and 52; (2) Change from baseline in maximum height of sPED on SD-OCT at weeks 12, 36, and 52; and (3) Change from baseline in maximum horizontal base diameter of sPED on SD-OCT at weeks 12, 36, and 52.

[0462] -CNV: Changes from baseline in maximum vascular diameter (GVC), maximum lesion diameter (GLD), and CNV area at 4, 12, 36, and 52 weeks.

[0463] result: A total of 409 subjects underwent screening, of which 178 were deemed ineligible, and 231 were enrolled. 77 subjects were assigned to the efdamlovsph alfa 2mg group, the efdamlovsph alfa 4mg group, and the aflibercept 2mg group, respectively.

[0464] Baseline results: The demographic distribution (age, sex) across the entire group was balanced.

[0465] Characteristics of the disease: - In the efdamlovsp alfa 2mg group, efdamlovsp alfa 4mg group, and aflibercept 2mg group, the mean BCVA at baseline was 53.9±12.85, 56.1±13.29, and 53.6±13.91 ETDRS letters, respectively, and the mean CST at baseline was 345.7±124.89 μm, 354.3±147.34 μm, and 355.3±126.08 μm, respectively.

[0466] - In the efdamlovsph alfa 2mg group, the efdamlovsph alfa 4mg group, and the aflibercept 2mg group, the mean baseline CNV area on the FFA was 7.200 ± 6.6705 mm², respectively. 2 7.679±6.7646mm 2 , and 7.867±6.4979mm 2 The mean CNV leakage area at baseline in FFA was 8.913 ± 7.0456 mm², respectively. 2 , 9.027±6.8027mm 2 , 10.046±8.7537mm 2 The mean total lesion area at baseline in FFA was 8.131 ± 7.6190 mm². 2 , 8.750±7.3369mm 2 , 9.298±7.9333mm 2 That was the case.

[0467] - In the efdamlovsph alfa 2mg group, the efdamlovsph alfa 4mg group, and the aflibercept 2mg group, the proportion of subjects showing cystic edema extending to the subcentral retinal region on SD-OCT was 40.3%, 24.7%, and 32.5%, respectively; the proportion of subjects showing subretinal fluid with clear extension to a small central retinal region on SD-OCT was 68.8%, 67.5%, and 57.1%, respectively; and the proportion of subjects showing subretinal hyperreflectivity with clear extension to a small central retinal region on SD-OCT was 75.3%, 68.8%, and 75.3%, respectively.

[0468] - In the efdamlovsph alfa 2mg group, the efdamlovsph alfa 4mg group, and the aflibercept 2mg group, most subjects did not show macular atrophy on SD-OCT or subretinal fibrosis on CFP at baseline.

[0469] Efficacy results: The primary endpoint was the change from baseline in the test eye's BCVA at week 36. Based on the repeated measures mixed model (MMRM), the mean change from baseline in BCVA at week 36 in the modified intention to treat (mITT) population was 10.56 ± 1.17 ETDRS letters, 11.42 ± 1.18 ETDRS letters, and 11.97 ± 1.17 ETDRS letters, respectively, in the efdamlovssp alfa 2 mg, efdamlovssp alfa 4 mg, and aflibercept 2 mg groups (Figure 5). The least squares mean (LSM) of the change in BCVA from baseline at week 36 was -1.42 ETDRS letters (95% CI: -4.62, 1.79) and -0.56 ETDRS letters (95% CI: -3.79, 2.68), respectively, in the efdamlovssp alfa 2 mg and efdamlovssp alfa 4 mg groups. At week 36, the mean change from baseline in BCVA in the efdamlovsp alfa 2 mg group and the efdamlovsp alfa 4 mg group was non-inferior to that of the aflibercept 2 mg group.

[0470] Secondary endpoints included visual acuity-related efficacy, SD-OCT anatomical efficacy, and FFA anatomical efficacy.

[0471] Vision-related effectiveness: - Changes from baseline in BCVA of the test eye at each visit: During the study period, BCVA of the test eye in the efdamlovsph alfa 2mg group, efdamlovsph alfa 4mg group, and aflibercept 2mg group gradually increased over time during the initial treatment period (weeks 0-8, every 4 weeks x 3 times) and remained stable during the maintenance treatment period (every 8 weeks).

[0472] - Proportion of subjects with BCVA improvement of 0, 5, 10, and 15 or more ETDRS letters: At 52 weeks, the proportion of subjects with BCVA improvement of 10 or more ETDRS letters was lower in the efdamlovsph alfa 4 mg group than in the aflibercept 2 mg group. At other time points, there were no significant differences in the proportion of subjects with BCVA improvement of 0, 5, 10, and 15 or more ETDRS letters across all treatment groups.

[0473] - Proportion of subjects with a BCVA decrease of 0, 5, 10, or 15 ETDRS letters or more: At week 12, the proportion of subjects with a BCVA decrease of 0 or more ETDRS letters was higher in the efdamlovsph alfa 4 mg group than in the aflibercept 2 mg group. At week 28, the proportion of subjects with a BCVA decrease of 0 or more ETDRS letters was higher in the efdamlovsph alfa 2 mg group than in the aflibercept 2 mg group. At other time points, there were no significant differences among all treatment groups in the proportion of subjects with a BCVA decrease of 0, 5, 10, or 15 ETDRS letters or more.

[0474] - Proportion of subjects with BCVA of 74 characters or more: The proportion of subjects with BCVA of 74 characters or more was similar in the efdamlovsph alfa 2mg group, the efdamlovsph alfa 4mg group, and the aflibercept 2mg group. The difference was not statistically significant.

[0475] The proportion of subjects with BCVA of 33 characters or less was similar in the efdamlovsph alfa 2mg group, the efdamlovsph alfa 4mg group, and the aflibercept 2mg group. The difference was not statistically significant.

[0476] Anatomical effectiveness of SD-OCT: - Change in CST from baseline (Figure 6): During the study period, CST in all treatment groups gradually decreased during the loading period (days 0 to 8 weeks) and remained stable during the maintenance period (weeks 12 to 52). At week 36, the mean change in CST from baseline for the efdamlovsph alfa 2 mg group, efdamlovsph alfa 4 mg group, and aflibercept 2 mg group was -143.87±6.92 μm, -139.32±6.98 μm, and -142.50±6.91 μm, respectively; compared to the aflibercept 2 mg group, the mean change in CST from baseline for the efdamlovsph alfa 2 mg group and efdamlovsph alfa 4 mg group was -1.38 (95% CI: -20.28, 17.53) and 3.18 (95% CI: -15.85, 22.21), respectively. At 52 weeks, the mean change in CST from baseline in the efdamlovsp alfa 2 mg group, the efdamlovsp alfa 4 mg group, and the aflibercept 2 mg group was -151.83 ± 5.68 μm, -147.67 ± 5.71 μm, and -152.42 ± 5.68 μm, respectively; compared to the aflibercept 2 mg group, the mean change in CST from baseline in the efdamlovsp alfa 2 mg group and the efdamlovsp alfa 4 mg group was 0.59 (95% CI: -14.82, 16.00) and 4.74 (95% CI: -10.75, 20.24), respectively.

[0477] - Proportion of subjects showing IRF, SRF, or subretinal hyperreflectivity: The proportion of subjects showing IRF, SRF, or subretinal hyperreflectivity was similar in the efdamlovsph alfa 2mg group, the efdamlovsph alfa 4mg group, and the aflibercept 2mg group, and the differences between the groups were not statistically significant.

[0478] FFA anatomical effectiveness: - Change in CNV area from baseline (Figure 7): Based on the ANCOVA model, the mean change in CNV area from baseline, as measured by FFA, in the mITT population was 7.20 ± 6.670 mm for the efdamlovsph alfa 2 mg group, the efdamlovsph alfa 4 mg group, and the aflibercept 2 mg group, respectively. 2 7.68±6.765mm 2 and 7.87±6.498mm 2 At 36 weeks, the mean change from baseline in the efdamlovsp alfa 2mg group, the efdamlovsp alfa 4mg group, and the aflibercept 2mg group was -0.80 ± 0.424 mm, respectively. 2 -0.51±0.445mm 2 , and 0.39±0.426mm 2 At 52 weeks, the mean change from baseline in the efdamlovsp alfa 2mg group, the efdamlovsp alfa 4mg group, and the aflibercept 2mg group was -1.04 ± 0.432 mm, respectively. 2 -0.64±0.452mm 2 and -0.08±0.435mm 2 That was the case.

[0479] - Change from baseline in CNV leakage area (Figure 8): Based on the ANCOVA model, the mean change from baseline in CNV leakage area measured by FFA in the mITT population was 8.91 ± 7.046 mm² in the efdamlovsph alfa 2 mg group, the efdamlovsph alfa 4 mg group, and the aflibercept 2 mg group, respectively. 2 9.03±6.803mm 2 , and 10.05±8.754mm 2 At week 36, the mean change from baseline in the efdamlovsph alfa 2mg group, the efdamlovsph alfa 4mg group, and the aflibercept 2mg group was -5.36 ± 0.531 mm, respectively. 2 -5.10±0.558mm 2 and -5.37±0.536mm 2At 52 weeks, the mean change from baseline in the efdamlovsp alfa 2mg group, the efdamlovsp alfa 4mg group, and the aflibercept 2mg group was -6.82 ± 0.490 mm, respectively. 2 -6.86±0.520mm 2 , and -6.74±0.495mm 2 That was the case.

[0480] - Change in total lesion area from baseline: Based on the ANCOVA model, the mean change in total lesion area from baseline in the mITT population was 8.13 ± 7.619 mm for the efdamlovsph alfa 2 mg group, the efdamlovsph alfa 4 mg group, and the aflibercept 2 mg group, respectively. 2 8.75±7.337mm 2 , and 9.30±7.933mm 2 At 36 weeks, the mean change from baseline in the efdamlovsph alfa 2mg group, the efdamlovsph alfa 4mg group, and the aflibercept 2mg group was 、 Each value is -0.96 ± 0.471 mm. 2 -0.90±0.495mm 2 and -0.83±0.475mm 2 At 52 weeks, the mean change from baseline in the efdamlovsp alfa 2mg group, the efdamlovsp alfa 4mg group, and the aflibercept 2mg group was -1.57 ± 0.436 mm, respectively. 2 -1.10±0.45mm 2 , and -0.90±0.43mm 2 That was the case.

[0481] Pharmacokinetic results: In this study, descriptive statistics and analyses were performed on the systemic pharmacoki...

Claims

1. A method for treating neovascular age-related macular degeneration ("nAMD") in a patient requiring treatment, comprising administering a fusion protein that specifically binds to human vascular endothelial growth factor ("VEGF") and human complement receptor 1 ("CR1"), the fusion protein comprising a VEGF inhibitory domain ("VID"), an immunoglobulin Fc region, a peptide linker, and a complement inhibitory domain ("CID") from the N-terminus to the C-terminus; Here, the fusion protein has an amino acid sequence that is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to SEQ ID NO: 1; The fusion protein is administered to the affected eye in a dose of approximately 1.0 to 8.0 mg, as described above.

2. The method according to claim 1, wherein the fusion protein is efdamlovsp alfa (SEQ ID NO: 1).

3. The method according to claim 1 or 2, wherein the best corrected visual acuity ("BCVA") of the affected eye is in the range of 19 to 78 characters (including the end values) as measured by the Early Diabetic Retinopathy Treatment Study ("ETDRS") chart.

4. The method according to claim 3, wherein the BCVA of the affected eye is in the range of 24 to 78 ETDRS characters (including the endpoints).

5. The method according to claim 3, wherein the BCVA of the affected eye is in the range of 24 to 73 ETDRS characters (including the endpoints).

6. The method according to any one of claims 3 to 5, wherein the BCVA of the affected eye is at least 64 ETDRS characters.

7. The method according to any one of claims 3 to 5, wherein the BCVA of the affected eye is 63 or less, and the ETDRS character is such that.

8. The method according to any one of claims 1 to 7, wherein the subject has active submacular or perimacular choroidal neovascularization ("CNV") secondary to nAMD, or active CNV extending to the fovea of ​​the macula.

9. The method according to claim 8, wherein the CNV area (including classical and latent types) in the affected eye accounts for at least 50% of the total lesion area (including hemorrhage, CNV, atrophy, and fibrosis).

10. The method according to claim 1 or 2, wherein the affected eye has (1) active submacular or perimacular CNV secondary to nAMD; (2) a CNV area (including classical and latent types) occupying 50% or more of the total lesion area (including hemorrhage, CNV, atrophy, and fibrosis); and (3) BCVA in the range of 24 to 73 ETDRS letters (including endpoints).

11. The method according to claim 1 or 2, wherein the affected eye has (1) active submacular CNV secondary to nAMD, or active CNV located around or outside the macula but affecting the macula; (2) CNV area (including classical and latent types) accounting for at least 50% of the total lesion area (including hemorrhage, CNV, atrophy, and fibrosis); and (3) BCVA in the range of 24 to 78 ETDRS letters (including endpoints).

12. The method according to claim 1 or 2, wherein the affected eye has (1) active submacular CNV secondary to nAMD, or active CNV affecting the macula; and (2) BCVA in the range of 19 to 78 ETDRS letters (including the endpoints).

13. The method according to any one of claims 1 to 12, wherein the affected eye has type II CNV.

14. The method according to any one of claims 1 to 12, wherein the affected eye does not have type II CNV.

15. The method according to any one of claims 1 to 14, wherein the affected eye has a subcentral retinal thickness ("CST") greater than 280 μm, 300 μm, or 325 μm when measured by spectral domain optical coherence tomography ("SD-OCT").

16. The method according to any one of claims 1 to 15, wherein the subject is newly diagnosed with nAMD.

17. The method according to any one of claims 1 to 15, wherein the subject has been diagnosed with nAMD within the past 12 years.

18. The method according to any one of claims 1 to 15, wherein the subject has previously received treatment for nAMD.

19. The method according to claim 18, wherein the subject has previously received treatment with an anti-VEGF drug.

20. The method according to any one of claims 1 to 15, wherein the subject has not previously received treatment for nAMD.

21. The method according to any one of claims 1 to 20, wherein the subject is a human being 50 years of age or older.

22. The method according to any one of claims 1 to 21, wherein the fusion protein is administered by intravitreous injection.

23. The method according to claim 22, wherein the fusion protein is injected as a liquid.

24. The method according to claim 23, wherein the liquid preparation has a fusion protein in a concentration in the range of about 40 mg / ml to about 100 mg / ml.

25. The method according to claim 24, wherein the liquid preparation has a fusion protein at a concentration of about 80 mg / ml.

26. The method according to any one of claims 23 to 25, wherein the injection volume is approximately 0.01 ml to approximately 0.2 ml.

27. The method according to claim 26, wherein the injection volume is approximately 0.1 ml.

28. The method according to any one of claims 1 to 27, wherein the fusion protein is administered in a dose of approximately 2.0 mg, approximately 3.2 mg, approximately 4.0 mg, approximately 6.4 mg, or approximately 8.0 mg.

29. The method according to any one of claims 1 to 28, wherein the fusion protein is administered at least three times.

30. The method according to claim 29, wherein at least three doses are administered at intervals ranging from about once a week to about once every four weeks.

31. The method according to any one of claims 1 to 30, comprising a loading phase and a maintenance phase, wherein the fusion protein is administered three to five times during the loading phase and the fusion protein is administered two or more times during the maintenance phase.

32. The method according to claim 31, wherein the fusion protein is administered three times during the loading phase.

33. The method according to claim 31 or 32, wherein during the loading phase, the fusion protein is administered at intervals of approximately once a week to approximately once every four weeks.

34. The method according to claim 33, wherein the fusion protein is administered at intervals of approximately once every four weeks during the loading phase.

35. The method according to any one of claims 31 to 34, wherein the fusion protein is administered at intervals of approximately once every 8 weeks to approximately once every 16 weeks during the maintenance phase.

36. The method according to claim 35, wherein the administration interval during the maintenance phase is approximately every 8 weeks.

37. The method according to claim 35, wherein the administration interval during the maintenance phase is approximately once every 12 weeks.

38. The method according to claim 35, wherein the administration interval during the maintenance phase is approximately once every 16 weeks.

39. The method according to claim 35, wherein (1) during the loading phase, the fusion protein is administered once every four weeks for three times; and (2) during the maintenance phase, the fusion protein is administered once every eight weeks for at least two times, wherein the fusion protein is efdamlovsp alfa, and each dose is 2.0 mg or 4.0 mg.

40. The method according to claim 35, wherein (1) during the loading phase, the fusion protein is administered at least three times, once every four weeks; and (2) during the maintenance phase, the fusion protein is administered at least twice, once every 12 weeks or once every 16 weeks, wherein the fusion protein is efdamlovsp alfa, and each dose is 6.4 mg or 8.0 mg.

41. The method according to any one of claims 31 to 34, wherein during the maintenance phase, the fusion protein is administered at intervals determined by evaluating the treated eye after the final dose of the loading phase.

42. The method according to claim 41, wherein the evaluation includes measuring the change in BCVA according to an ETDRS chart.

43. The method according to claim 41 or 42, wherein the evaluation includes measuring the change in CST using SD-OCT.

44. The method according to any one of claims 41 to 43, wherein the evaluation includes determining whether or not there is disease activity ("DA").

45. The method according to claim 44, wherein DA is determined to be present if at least one of the following conditions is met: (1) CST has increased by more than 50 μm compared to the average CST over the past two months as measured by SD-OCT; (2) CST has increased by 75 μm or more compared to the lowest CST over the past two months as measured by SD-OCT; (3) BCVA has decreased by 5 or more ETDRS letters compared to the average BCVA over the past two months due to the progression of nAMD; (4) BCVA has decreased by 10 or more ETDRS letters compared to the highest BCVA over the past two months due to the progression of nAMD; and (5) new foveal hemorrhage has occurred due to the progression of nAMD.

46. The method of claim 44, wherein DA is determined to be present in a subject if at least one of the following conditions is present: (1) BCVA is 5 or more ETDRS letters lower than the most recent value; (2) CST is more than 50 μm higher than the most recent value as measured by SD-OCT; (3) persistent subretinal / intraretinal / subretinal pigment epithelial ("RPE") fluid; (4) newly occurring CNV; and (5) newly occurring macular hemorrhage.

47. The method according to any one of claims 44 to 46, wherein (1) during the loading phase, the fusion protein is administered four times, once every four weeks; and (2) during the maintenance phase, at least two doses of the fusion protein are administered (a) once every eight weeks if DA is present eight weeks after the last dose of the loading phase, or (b) once every twelve weeks if DA is not present approximately eight weeks after the last dose of the loading phase, wherein the fusion protein is efdamlovsp alfa, and each dose is 6.4 mg or 8.0 mg.

48. The method according to any one of claims 44 to 46, wherein (1) during the loading phase, the fusion protein is administered once every four weeks for a total of three times, and (2) during the maintenance phase, the fusion protein is administered at least twice, the administration of which is (a) once every eight weeks if DA is present approximately eight weeks after the last dose of the loading phase, (b) once every 12 weeks if DA is not present approximately eight weeks after the last dose of the loading phase but is present approximately twelve weeks later, or (c) once every sixteen weeks if DA is not present both eight weeks and twelve weeks after the last dose of the loading phase, the fusion protein is efdamlovsp alfa, and each dose is 8.0 mg.

49. The method according to any one of claims 31 to 48, wherein the interval from the last dose during the loading phase to the first dose during the maintenance phase is the same as the administration interval during the maintenance phase.

50. The method according to any one of claims 31 to 49, wherein during the maintenance phase, the fusion protein is administered at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight times.

51. The method according to any one of claims 1 to 50, wherein the method increases the BCVA of the affected eye by at least 0 ETDRS characters, at least 5 ETDRS characters, at least 10 ETDRS characters, or at least 15 ETDRS characters.

52. The method according to claim 51, wherein the method involves dividing the BCVA into approximately 10 to approximately 15 ETDRS characters.

53. The method according to any one of claims 1 to 52, wherein the method reduces the CST of the affected eye by at least 50 μm, at least 75 μm, at least 100 μm, at least 125 μm, or at least 150 μm when measured by SD-OCT.

54. The method according to claim 53, wherein the method reduces the CST by approximately 125 μm to approximately 150 μm when measured by SD-OCT.

55. The method according to any one of claims 1 to 54, wherein the method reduces or prevents the occurrence of pigment epithelial detachment ("PED") in an affected eye.

56. The method according to any one of claims 1 to 55, wherein the method reduces or prevents the generation of intraretinal fluid ("IRF") or subretinal fluid ("SRF") in the affected eye.

57. The method according to any one of claims 1 to 56, wherein the method reduces or prevents (1) the occurrence of new macular atrophy ("MA") in the affected eye, or (2) the area of ​​MA, or both (1) and (2).

58. The method according to any one of claims 1 to 57, wherein the method reduces or prevents the occurrence of geographical atrophy ("GA") in the affected eye.

59. The method according to any one of claims 1 to 58, wherein the method reduces or prevents retinal fibrosis in an affected eye.

60. The method according to any one of claims 1 to 59, wherein the method reduces (1) the area of ​​CNV, (2) the area of ​​CNV leakage, or (3) the total area of ​​lesions (including hemorrhage, CNV, atrophy, and fibrosis), or any combination thereof, in the affected eye.

61. The method according to any one of claims 1 to 60, wherein the method reduces the area of ​​retinal neovascularization ("RNV"), the area of ​​RNV leakage, or both.

62. The method according to any one of claims 1 to 61, wherein the method reduces macular retinal edema.

63. The method according to any one of claims 1 to 62, wherein the method improves the visual quality of life of the subject.

64. A method for treating diabetic macular edema ("DME") in a patient requiring treatment, comprising administering a fusion protein that specifically binds to human VEGF and human CR1, the fusion protein comprising a VID, an immunoglobulin Fc region, a peptide linker, and a CID from the N-terminus to the C-terminus; Here, the fusion protein has an amino acid sequence that is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to SEQ ID NO: 1; The fusion protein is administered to the affected eye in a dose of approximately 1.0 to 8.0 mg, as described above.

65. The method according to claim 64, wherein the fusion protein is efdamlovsp alfa (SEQ ID NO: 1).

66. The method according to claim 64 or 65, wherein the subject has diabetic macular edema (CI-DME) affecting the central area.

67. The method according to any one of claims 64 to 66, wherein the subject has a localized DME.

68. The method according to any one of claims 64 to 66, wherein the subject has diffuse DME.

69. The method according to any one of claims 64 to 68, wherein the BCVA of the affected eye is in the range of 24 to 73 ETDRS characters (including the endpoints).

70. The method according to any one of claims 64 to 69, wherein the CST of the affected eye is at least 280 μm, at least 300 μm, or at least 325 μm when measured by SD-OCT.

71. The method according to claim 64 or 65, wherein the affected eye has (1) visual impairment due to diabetic macular edema (DME) extending to the fovea, (2) a central retinal thickness (CST) of 280 μm or more as measured by SD-OCT, and (3) a BCVA within the range of 24 to 73 ETDRS letters (including the endpoints).

72. The method according to any one of claims 64 to 71, wherein the subject has been newly diagnosed with DME.

73. The method according to any one of claims 64 to 71, wherein the subject has been diagnosed with DME for up to 12 years.

74. The method according to any one of claims 64 to 73, wherein the subject has not previously received treatment with an anti-VEGF drug.

75. The method according to any one of claims 64 to 73, wherein the subject has previously received treatment with an anti-VEGF drug.

76. The method according to any one of claims 64 to 75, wherein the subject has proliferative diabetic retinopathy ("PDR").

77. The method according to any one of claims 64 to 76, wherein the subject is a human.

78. The method according to any one of claims 64 to 77, wherein the fusion protein is administered by intravitreous injection.

79. The method according to claim 78, wherein the fusion protein is injected as a liquid.

80. The method according to claim 79, wherein the liquid preparation has a fusion protein in a concentration in the range of about 40 mg / ml to about 100 mg / ml.

81. The method according to claim 79, wherein the liquid preparation has a fusion protein at a concentration of about 80 mg / ml.

82. The method according to any one of claims 79 to 81, wherein the injection volume is approximately 0.01 ml to approximately 0.2 ml.

83. The method according to claim 82, wherein the injection volume is approximately 0.1 ml.

84. The method according to any one of claims 64 to 83, wherein the fusion protein is administered in a dose of approximately 3.2 mg, approximately 6.4 mg, or approximately 8.0 mg.

85. The method according to any one of claims 64 to 84, wherein the fusion protein is administered at least three times.

86. The method according to claim 85, wherein at least three doses are administered at intervals ranging from about once a week to about once every four weeks.

87. The method according to any one of claims 64 to 86, comprising a loading phase and a maintenance phase, wherein the fusion protein is administered three to five times during the loading phase, and the fusion protein is administered once or more as needed during the maintenance phase based on the evaluation of the treated eye after the last administration during the loading phase.

88. The method according to claim 87, wherein the fusion protein is administered three times during the loading phase.

89. The method according to claim 87 or 88, wherein during the loading phase, the fusion protein is administered at intervals of approximately once a week to approximately once every four weeks.

90. The method according to claim 89, wherein the fusion protein is administered at intervals of approximately once every four weeks during the loading phase.

91. The method according to any one of claims 87 to 90, wherein the evaluation comprises measuring the change in BCVA according to an ETDRS chart.

92. The method according to claim 91, wherein the evaluation includes measuring the change in CST when measured by SD-OCT.

93. The method according to claim 91 or 92, wherein the evaluation includes performing an evaluation of the Diabetic Retinopathy Severity Score ("DRSS").

94. The method according to any one of claims 91 to 93, wherein, during the maintenance phase, the fusion protein is administered if (1) BCVA has decreased by 5 or more ETDRS letters compared to the most recent value, or (2) CST has increased by more than 50 μm compared to the most recent value as measured by SD-OCT.

95. The method according to claim 87, wherein (1) during the loading phase, the fusion protein is administered once every four weeks for a total of three times; (2) during the maintenance phase, between four and eight weeks after the last dose of the loading phase, a maintenance dose is administered if (1) BCVA decreases by 5 or more ETDRS letters compared to the most recent value, or (2) CST increases by more than 50 μm compared to the most recent value as measured by SD-OCT, where the fusion protein is efdamlovsp alfa, and the respective doses are 3.2 mg, 6.4 mg, or 8.0 mg.

96. The method according to any one of claims 64 to 95, wherein the method increases the BCVA of the affected eye by at least 1 ETDRS character, at least 5 ETDRS characters, at least 10 ETDRS characters, or at least 15 ETDRS characters.

97. The method according to claim 96, wherein the method increases the BCVA from about 10 to about 15 ETDRS characters.

98. The method according to any one of claims 64 to 97, wherein the method reduces the CST of the affected eye by at least 50 μm, at least 75 μm, at least 100 μm, at least 125 μm, or at least 150 μm when measured by SD-OCT.

99. The method according to claim 98, wherein the method reduces the CST by approximately 125 μm to approximately 150 μm when measured by SD-OCT.

100. The method according to any one of claims 64 to 99, wherein the method reduces macular retinal edema.

101. The method according to any one of claims 64 to 100, wherein the method improves the quality of life related to the subject's visual acuity.

102. A single pharmaceutical dosage unit comprising a fusion protein that inhibits the VEGF pathway and the complement pathway, wherein the fusion protein is the fusion protein described in claims 1-2 or claims 64-65, and the amount of the fusion protein is approximately 4 mg, approximately 5 mg, approximately 6.4 mg, approximately 7 mg, approximately 8 mg, approximately 9 mg, approximately 10 mg, approximately 11 mg, approximately 12 mg, approximately 12.8 mg, approximately 13 mg, approximately 14 mg, approximately 15 mg, approximately 16 mg, approximately 17 mg, approximately 18 mg, approximately 19 mg, or approximately 20 mg.

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