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WO2025036488A1 - Méthodes de traitement de la dégénérescence maculaire liée à l'âge et de l'oedème maculaire diabétique - Google Patents

Méthodes de traitement de la dégénérescence maculaire liée à l'âge et de l'oedème maculaire diabétique Download PDF

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WO2025036488A1
WO2025036488A1 PCT/CN2024/112767 CN2024112767W WO2025036488A1 WO 2025036488 A1 WO2025036488 A1 WO 2025036488A1 CN 2024112767 W CN2024112767 W CN 2024112767W WO 2025036488 A1 WO2025036488 A1 WO 2025036488A1
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weeks
fusion protein
bcva
administered
subject
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WO2025036488A9 (fr
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Shujie Lu
Yiming Li
Xiaoyu Chen
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Innovent Biologics Suzhou Co Ltd
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Innovent Biologics Suzhou Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/179—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators

Definitions

  • the present invention relates to medicine. Specifically, the present invention relates to methods of using a bispecific fusion protein inhibiting the activation of the complement pathway and the vascular endothelial growth factor ( “VEGF” ) pathway in the treatment of age-related macular degeneration and diabetes macular edema.
  • VEGF vascular endothelial growth factor
  • Age-related macular degeneration ( “AMD” ) is the most common cause of blindness in developed countries, particularly in people older than 60 years. AMD mainly affects the macular region of the retina. Given the escalating life expectancy worldwide, the prevalence of AMD is projected to surge. The projected number of people with AMD in 2020 is 196 million, increasing to 288 million in 2040. Similarly, Diabetic Macular Edema ( “DME” ) is a significant cause of vision impairment in individuals with diabetes. Like AMD, DME primarily affects the macular region of the retina, leading to swelling and vision loss. With the global rise in diabetes cases, the prevalence of DME is also on the rise.
  • compositions and methods provided herein meet these needs and provide relative advantages.
  • a fusion protein that specifically binds to human Vascular Endothelial Growth Factor VEGF and human Complement Receptor 1 ( “CR1” ) , 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 wherein the fusion protein is administered to a diseased eye at a dose between about 1.0 to about 8.0 mg.
  • the fusion protein is efdamrofusp alfa (SEQ ID NO:1) .
  • the Best-Corrected Visual Acuity ( “BCVA” ) of the diseased eye ranges between 19 and 78 letters (inclusive of end values) , as determined by Early Treatment Diabetic Retinopathy Study ( “ETDRS” ) chart.
  • the BCVA of the diseased eye ranges between 24 and 78 ETDRS letters (inclusive of end values) .
  • the BCVA of the diseased eye ranges between 24 and 73 ETDRS letters (inclusive of end values) .
  • the BCVA of the diseased eye is at least 64 ETDRS letters.
  • the BCVA of the diseased eye is no more than 63 ETDRS letters.
  • the subject has active subfoveal or parafoveal choroidal neovascularization ( “CNV” ) secondary to nAMD or active CNV involving the fovea.
  • CNV active subfoveal or parafoveal choroidal neovascularization
  • the CNV area (including classic and occult) in the diseased eye is at least 50%of the total lesion area (including hemorrhage, CNV, atrophy and fibrosis) .
  • the diseased eye has (1) active subfoveal or parafoveal CNV secondary to nAMD; (2) a CNV area (including classic and occult) that is no less than 50%of the total lesion area (including hemorrhage, CNV, atrophy and fibrosis) ; and (3) BCVA ranging between 24 and 73 ETDRS letters (inclusive of end values) .
  • the diseased eye has (1) active subfoveal CNV secondary to nAMD or active CNV that is parafoveal or outside fovea but involves the fovea; (2) a CNV area (including classic and occult) that is at least 50%of the total lesion area (including hemorrhage, CNV, atrophy and fibrosis) ; and (3) BCVA ranging between 24 and 78 ETDRS letters (inclusive of end values) .
  • the diseased eye has (1) active subfoveal CNV secondary to nAMD or active CNV involving the fovea; and (2) BCVA ranging between 19 and 78 ETDRS letters (inclusive of end values) .
  • the diseased eye has Type II CNV. In some embodiments, the diseased eye does not have Type II CNV. In some embodiments, the diseased eye has central subfield retinal thickness ( “CST” ) greater than 280 ⁇ m, 300 ⁇ m, or 325 ⁇ m as measured by spectral-domain optical coherence tomography ( “SD-OCT” ) .
  • the subject is newly diagnosed with nAMD. In some embodiments, the subject has been diagnosed of nAMD for up to 12 years. In some embodiments, the subject has been previously treated for nAMD. In some embodiments, the subject has been previously treated with an anti-VEGF therapeutic. In some embodiments, the subject has not been previously treated for nAMD. In some embodiments, the subject is a human of at least 50 years old.
  • the fusion protein is administered by intravitreal injection.
  • the fusion protein is injected as a liquid formulation.
  • the liquid formulation has the fusion protein at a concentration ranging from about 40 mg/ml to about 100 mg/ml.
  • the liquid formulation has the fusion protein at the concentration of about 80 mg/ml.
  • the injection volume is between about 0.01 mL to about 0.2 mL.
  • the injection volume is about 0.1 mL.
  • the fusion protein is administered at a dose of about 2.0 mg, about 3.2 mg, about 4.0 mg, about 6.4 mg, or about 8.0 mg.
  • at least three doses of the fusion protein are administered.
  • the at least three doses are administered at intervals ranging from about once every week to about once every four weeks.
  • fusion protein is administered at intervals ranging from about once every week to about once every four weeks. In some embodiments, during the loading phase, the fusion protein is administered at intervals of about once every four weeks. In some embodiments, during the maintenance phase, the fusion protein is administered at intervals ranging from about once every eight weeks to about once every 16 weeks.
  • the dosing interval during the maintenance phase is about once every eight weeks. In some embodiments, the dosing interval during the maintenance phase is about once every 12 weeks. In some embodiments, the dosing interval during the maintenance phase is about once every 16 weeks. In some embodiments of the methods provided herein, (1) during the loading phase, three doses of the fusion protein are administered once every 4 weeks; and (2) during the maintenance phase, at least two doses of the fusion protein are administered once every 8 weeks; wherein the fusion protein is efdamrofusp alfa, and each dose is 2.0 mg or 4.0 mg.
  • (1) during the loading phase at least three doses of the fusion protein are administered once every 4 weeks; and (2) during the maintenance phase, at least two doses of the fusion protein are administered once every twelve weeks or once every 16 weeks; wherein the fusion protein is efdamrofusp alfa, and each dose is 6.4 mg or 8.0 mg.
  • the fusion protein is administered at intervals determined by assessing the treated eye after the last dosing of the loading phase.
  • the assessment comprises measuring changes in BCVA according to the ETDRS chart.
  • the assessment comprises measuring changes in CST using SD-OCT.
  • the assessment comprises determining the presence or absence of disease activity ( “DA” ) .
  • DA is determined to be present ifat least one of the following conditions is met: (1) CST is increased by > 50 ⁇ m compared with the average CST of the previous two months as measured by SD-OCT; (2) CST is increased by ⁇ 75 ⁇ m compared with the lowest CST of the previous two months as measured by SD-OCT; (3) BCVA is lowered by ⁇ 5 ETDRS letters compare with the average BCVA of the previous two months due to the progression of nAMD; (4) BCVA is lowered by ⁇ 10 ETDRS letters compare with the best BCVA of the previous two months due to the progression ofnAMD; and (5) new occurrence of hemorrhage involving the fovea due to the progression of nAMD.
  • DA is determined to be present in the subject if at least one of the following conditions is present: (1) BCVA is lowered by ⁇ 5 ETDRS letters compared to most recent value; (2) the CST is increased by > 50 ⁇ m compared to the most recent value as measured by SD-OCT; (2) persistent subretinal/intraretinal/sub-retinal pigment epithelium ( “RPE” ) fluid; (3) new occurrence of CNV; and (4) new occurrence of macular hemorrhage.
  • RPE persistent subretinal/intraretinal/sub-retinal pigment epithelium
  • (1) during the loading phase four doses of the fusion protein are administered once every 4 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 at eight weeks after the last dosing of the loading phase, or (b) once every 12 weeks, if DA is absent about eight weeks after the last dosing of the loading phase; wherein the fusion protein is efdamrofusp alfa, and each dose is 6.4 mg or 8.0 mg.
  • (1) during the loading phase three doses of the fusion protein are administered once every 4 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 at about eight weeks after the last dosing of the loading phase, (b) once every 12 weeks if DA is absent at about eight weeks after the last dosing of the loading phase but present at about 12 weeks after the last dosing of the loading phase, or (c) once every 16 weeks ifDA is absent at both eight weeks and 12 weeks after the last dosing of the loading phase; wherein the fusion protein is efdamrofusp alfa and each dose is 8.0 mg.
  • the interval between the last dosing of the loading phase and the first dosing of the maintenance phase is the same as the dosing interval of the maintenance phase. In some embodiments, at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight doses of the fusion protein are administered during the maintenance phase.
  • the method increases BCVA of the diseased eye by at least 0 ETDRS letters, at least 5 ETDRS letters, at least 10 ETDRS letters, or at least 15 ETDRS letters. In some embodiments, the method increases BCVA by about 10 to about 15 ETDRS letters. In some embodiments, the method decreases CST of the diseased eye by at least 50 ⁇ m, at least 75 ⁇ m, at least 100 ⁇ m, at least 125 ⁇ m, or at least 150 ⁇ m as measured by SD-OCT. In some embodiments, the method decreases CST by about 125 ⁇ m to about 150 ⁇ m as measured by SD-OCT.
  • the method reduces or prevents occurrence of pigment epithelial detachment ( “PED” ) in the diseased eye. In some embodiments, the method reduces or prevents the occurrence ofintraretinal fluid ( “IRF” ) or subretinal fluid ( “SRF” ) in the diseased eye. In some embodiments, the method reduces or prevents (1) the occurrence of new macular atrophy ( “MA” ) or (2) the area of MA, or both (1) and (2) , in the diseased eye. In some embodiments, the method reduces or prevents the occurrence of geographic atrophy ( “GA” ) in the diseased eye. In some embodiments, the method reduces or prevents retinal fibrosis in the diseased eye.
  • IRF intraaretinal fluid
  • SRF subretinal fluid
  • the method decreases (1) CNV area, (2) CNV leakage area, or (3) total lesion area (including hemorrhage, CNV, atrophy and fibrosis) , or any combination thereof, in the diseased eye.
  • the method decreases retinal neovascularization ( “RNV” ) area, RNV leakage area, or both.
  • the method decreases macular retinal edema.
  • the method increases the vision-related quality of life of the subject.
  • DME diabetic macular edema
  • a fusion protein that specifically binds to human VEGF and human CR1, comprising, from N-terminus to C-terminus, a VID, an immunoglobulin Fc region, a peptide linker, and a 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 wherein the fusion protein is administered to a diseased eye at a dose between about 1.0 to about 8.0 mg.
  • the fusion protein is efdamrofusp alfa (SEQ ID NO: 1) .
  • the subject has center-involved DME (CI-DME) .
  • the subject has focal DME.
  • the subject has diffuse DME.
  • the BCVA of the diseased eye ranges between 24 and 73 ETDRS letters (inclusive of end values) .
  • the diseased eye has CST that is at least 280 ⁇ m, at least 300 ⁇ m, or at least 325 ⁇ m as measured by SD-OCT.
  • the diseased eye has (1) visual impairments due to DME involving the fovea; (2) CST ⁇ 280 ⁇ m as measured by SD-OCT; and (3) BCVA ranging between 24 and 73 ETDRS letters (inclusive of end values) .
  • the subject is newly diagnosed with DME.
  • the subject has been diagnosed of DME for up to 12 years.
  • the subject has not been previously treated with an anti-VEGF therapeutic.
  • the subject has been previously treated with an anti-VEGF therapeutic.
  • the subject has proliferative diabetic retinopathy ( “PDR” ) .
  • the subject is a human.
  • the fusion protein is administered by intravitreal injection.
  • the fusion protein is injected as a liquid formulation.
  • the liquid formulation has the fusion protein at a concentration ranging from about 40 mg/ml to about 100 mg/ml.
  • the liquid formulation has the fusion protein at the concentration of about 80 mg/ml.
  • the injection volume is between about 0.01 mL to about 0.2 mL.
  • the injection volume is about 0.1 mL.
  • the fusion protein is administered at a dose of about 3.2 mg, about 6.4 mg, or about 8.0 mg.
  • at least three doses of the fusion protein are administered.
  • the at least three doses are administered at intervals ranging from about once every week to about once every four weeks.
  • the methods provided herein comprise a loading phase and a maintenance phase, wherein during the loading phase, three to five doses of the fusion protein are administered; and during the maintenance phase, one or more doses of the fusion protein are administered as needed as determined by assessing the treated eye after the last dosing of the loading phase.
  • three doses of the fusion protein are administered.
  • the fusion protein is administered at intervals ranging from about once every week to about once every four weeks.
  • the fusion protein is administered at intervals of about once every four weeks.
  • the assessment comprises measuring changes in BCVA according to the ETDRS chart.
  • the assessment comprises measuring changes in CST as measured by SD-OCT. In some embodiments, the assessment comprises conducting Diabetic Retinopathy Severity Score ( “DRSS” ) evaluation. In some embodiments, during the maintenance phase, the fusion protein is administered if (1) BCVA is lowered by ⁇ 5 ETDRS letters compared to most recent value or (2) the CST is increased by > 50 ⁇ m compared to most recent value as measured by SD-OCT.
  • DRSS Diabetic Retinopathy Severity Score
  • (1) during the loading phase three doses of the fusion protein are administered once every four weeks; (2) during the maintenance dose, the fusion protein is administered if, between four and eight weeks after the last dosing of the loading phase, (1) BCVA is lowered by ⁇ 5 ETDRS letters compared to most recent value, or (2) the CST is increased by > 50 ⁇ m compared to most recent value as measured by SD-OCT; wherein the fusion protein is efdamrofusp alfa, and each dose is 3.2mg, 6.4 mg or 8.0 mg.
  • the methods provided herein increase BCVA of the diseased eye by at least 1 ETDRS letter, at least 5 ETDRS letters, at least 10 ETDRS letters, or at least 15 ETDRS letters. In some embodiments, the methods provided herein increase BCVA by about 10 to about 15 ETDRS letters. In some embodiments, the methods provided herein decrease CST of the diseased eye by at least 50 ⁇ m, at least 75 ⁇ m, at least 100 ⁇ m, at least 125 ⁇ m, or at least 150 ⁇ m as measured by SD-OCT. In some embodiments, the methods provided herein decrease CST by about 125 ⁇ m to about 150 ⁇ m as measured by SD-OCT. In some embodiments, the methods provided herein decrease macular retinal edema. In some embodiments, the methods provided herein increase the vision-related quality of life of the subject.
  • single pharmaceutical dosage units comprising a fusion protein disclosed herein that inhibits a VEGF pathway and a complement pathway, wherein the fusion protein is in the amount 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 12.8mg, 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.
  • FIG. 1 describes the anti-retinal neovascularization effect of efdamrofusp alfa (IBI302) in a DL- ⁇ -AAA (DL- ⁇ -aminoadipic acid) induced Dutch rabbit retinal neovascularization (RNV) model.
  • IBI302 efdamrofusp alfa
  • RSV retinal neovascularization
  • FIG. 2 provides a schematic diagram of the Phase I clinical study of efdamrofusp alfa.
  • FIGs. 3A-3B show the changes in BCVA from baseline during the treatment period.
  • FIG. 3A shows BCVA changes (ETDRS letters) of nAMD patients during the treatment period.
  • FIG. 3B shows BCVA changes (ETDRS letters) of DME patients during the treatment period.
  • FIGs. 4A-4B show the changes in CST from baseline during the treatment period, as measured by SD-OCT.
  • FIG. 4A shows CST changes in nAMD patients from baseline during the treatment period as measured by SD-OCT.
  • FIG. 4B shows CST changes in DME patients from baseline during the treatment period as measured by SD-OCT.
  • FIG. 5 shows the mean changes from baseline in BCVA scores in the efdamrofusp alfa-2 mg group, the efdamrofusp alfa-4 mg group, and the aflibercept-2 mg group during the treatment period.
  • FIG. 6 shows the mean changes in CST from baseline in the efdamrofusp alfa-2 mg group, the efdamrofusp alfa-4 mg group and the aflibercept-2 mg group during the treatment period.
  • FIG. 7 shows the mean changes in CNV areas from baseline as measured by FFA in efdamrofusp alfa-2 mg group, efdamrofusp alfa-4 mg group and aflibercept 2 mg group during the treatment period.
  • FIG. 8 shows the mean changes in CNV leakage areas from baseline as measured by FFA in efdamrofusp alfa-2 mg group, efdamrofusp alfa-4 mg group and aflibercept 2 mg group during the treatment period.
  • FIG. 9 shows the mean changes in BCVA scores from baseline in the efdamrofusp alfa-6.4 mg group, the efdamrofusp alfa-8 mg group, and the aflibercept-2 mg group during the treatment period.
  • FIGs. 10A-10B show the mean changes in BCVA scores (FIG. 10A) and in CST (FIG. 10B) from baseline in the efdamrofusp alfa-6.4 mg group Q8W, the efdamrofusp alfa-8 mg group Q8W, efdamrofusp alfa-6.4 mg group Q12W, and the efdamrofusp alfa-8 mg group Q12W during the treatment period.
  • FIG. 11 shows the mean changes in CST from baseline in the efdamrofusp alfa-6.4 mg group, the efdamrofusp alfa-8 mg group, and the aflibercept-2 mg group during the treatment period.
  • FIGs. 12A-12C show the proportions of subjects having serous PED (FIG. 12A) , IRF (FIG. 12B) , or SRF (FIG. 12C) as measured by OCT in the efdamrofusp alfa-6.4 mg group, the efdamrofusp alfa-8 mg group, and the aflibercept-2 mg group during the treatment period.
  • FIG. 13 shows the proportions of subjects without retinal fluid in the center subfield in the efdamrofusp alfa-6.4 mg group, the efdamrofusp alfa-8 mg group, and the aflibercept-2 mg group during the treatment period.
  • FIG. 14 shows the mean changes in CNV area from baseline in the efdamrofusp alfa-6.4 mg group, the efdamrofusp alfa-8 mg group, and the aflibercept-2 mg group at Week 40 and 52.
  • FIG. 15 shows the mean changes in CNV leakage area from baseline in the efdamrofusp alfa-6.4 mg group, the efdamrofusp alfa-8 mg group, and the aflibercept-2 mg group at Week 40 and 52.
  • FIG. 16 shows the mean changes in total lesion area from baseline in the efdamrofusp alfa-6.4 mg group, the efdamrofusp alfa-8 mg group, and the aflibercept-2 mg group at Week 40 and 52.
  • FIG. 17 shows the proportions of subjects having newly formed fibrosis as measured by CFP in the efdamrofusp alfa-6.4 mg group, the efdamrofusp alfa-8 mg group, and the aflibercept-2 mg group at Week 40.
  • FIGs. 18A-18B show the proportion of subjects having MA (FIG. 18A) and newly formed MA (FIG. 18B) , respectively, as measured by OCT in the efdamrofusp alfa-6.4 mg group, the efdamrofusp alfa-8 mg group, and the aflibercept-2 mg group during the treatment period.
  • FIGs. 19A-19C shows the mean change in MA area from baseline as measured by OCT in the efdamrofusp alfa-6.4 mg group, the efdamrofusp alfa-8 mg group, and the aflibercept-2 mg group during the treatment period (FIG. 19A) ; and the mean change in MA area from baseline as measured by FAF in the efdamrofusp alfa-6.4 mg group, the efdamrofusp alfa-8 mg group, and the aflibercept-2 mg group at Week 40 and 52, respectively (FIG. 19B-19C) .
  • FIG. 20 shows the pre-dose intraocular pressure (IOP) value of the study eye in the efdamrofusp alfa-6.4 mg group, the efdamrofusp alfa-8 mg group, and the aflibercept-2 mg group during the treatment period.
  • IOP intraocular pressure
  • the present disclosure provides methods of treating AMD and DME in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of efdamrofusp alfa (IBI302) .
  • a pharmaceutical composition comprising a therapeutically effective amount of efdamrofusp alfa (IBI302) .
  • IBI302 efdamrofusp alfa
  • AMD also known as senile macular degeneration
  • central retina refers to the area of the retina located in the central region, where cone cells-responsible for photopic (daylight) and color vision-are densely concentrated. Lesions in this area can lead to a significant decrease in central vision and may manifest as color vision abnormalities, visual distortions, and central scotomas.
  • This region is particularly vulnerable to various pathological changes, including bleeding, edema, increased retinal thickness, and atrophy.
  • the macula which is crucial for sharp, detailed vision, is situated at the very center of the central retina.
  • AMD The National Eye Institute's “Age-Related Eye Disease Study” group categorizes AMD into early, intermediate, and late stages.
  • Early AMD is mainly characterized by the presence of drusen, which has a high incidence but a low rate of blindness.
  • drusen the drusen
  • it significantly impairs visual acuity and can be classified into two types based on its pathological features: atrophic AMD and exudative AMD.
  • Exudative AMD also known as wet AMD or neovascular AMD (nAMD)
  • nAMD neovascular AMD
  • VEGF vascular endothelial growth factor
  • CNV immature choroidal neovascularization
  • RPE retinal pigment epithelium
  • nAMD has a lower incidence than atrophic AMD, it carries a higher risk of blindness due to subretinal rupture, hemorrhage, and damage to the retinal pigment epithelium and Bruch′s membrane.
  • DME diabetic retinopathy
  • DR diabetic retinopathy
  • NPDR non-proliferative diabetic retinopathy
  • PDR proliferative diabetic retinopathy
  • DME is primarily associated with increased retinal vascular permeability and abnormal capillary leakage, leading to fluid accumulation within the inner and outer plexiform layers of the retina, causing retinal thickening.
  • OCT optical coherence tomography
  • macular edema is defined by the presence of retinal thickening or hard exudates within one disc diameter of the center of the macula.
  • Clinically significant macular edema is further characterized by any of the following criteria: 1. Retinal thickening within 500 ⁇ m of the center of the macula. 2. Hard exudates within 500 ⁇ m of the center of the macula, accompanied by retinal thickening. 3. Retinal thickening of at least one disc area, located within one disc diameter (1,500 ⁇ m) of the center of the macula.
  • Clinicians often categorize DME into two types: focal and diffuse. The classification is essential for determining the most appropriate treatment approach.
  • DME treatment The primary goals of DME treatment are to improve and maintain visual function.
  • Common treatment methods include anti-VEGF vitreous injections, laser photocoagulation, and intravitreal corticosteroid injections (such as triamcinolone, dexamethasone, and fluocinolone acetonide) .
  • the choice of treatment depends on various factors, including whether the macula is involved, baseline vision, the thickness of the edema, vitreomacular adhesion, the chronicity of the disease, previous treatments and responses, and the specific type of DME lesion (focal, diffuse, chronic, persistent, recurrent) , as well as imaging results.
  • anti-VEGF drugs such as ranibizumab and aflibercept
  • Anti-VEGF therapy has significantly improved vision outcomes and safety compared to previous standard care methods like laser photocoagulation.
  • many patients experience limited benefits and often require frequent injections over extended periods to maintain treatment effects.
  • anti-VEGF monotherapy does not fully address other pathways contributing to the progression of diabetic eye disease, such as inflammation.
  • corticosteroids which are potent anti-inflammatory agents, have become a second-line treatment option, particularly for patients with recurrent and persistent DME.
  • the EURETINA guidelines recommend corticosteroids in these cases, where they have shown better efficacy.
  • the use of corticosteroids carries inherent risks of complications, including increased intraocular pressure and cataracts. Therefore, there is an ongoing need for improvements in the safety and efficacy of intraocular anti-inflammatory treatments.
  • Efdamrofusp alfa a fusion protein that inhibits both VEGF and complement activity, represents a promising potential therapy that can address these challenges.
  • an entity refers to one or more of that entity; for example, “an antibody, ” is understood to represent one or more antibodies.
  • the term “and/or” is to be taken as specific disclosure of each of the two specified features or components with or without the other.
  • the term “and/or” as used in a phrase such as “A and/or B” herein is intended to include “A and B, ” “A or B, ” “A” (alone) , and B” (alone) .
  • the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass 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) .
  • the term “about” is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects.
  • the term “about” encompasses the exact number recited.
  • “about” means within plus or minus 10%of a given value or range.
  • “about” means that the variation is ⁇ 5%, ⁇ 4%, ⁇ 3%, ⁇ 2%, ⁇ 1%, ⁇ 0.5%, ⁇ 0.2%, or ⁇ 0.1%of the value to which “about” refers.
  • “about” means that the variation is ⁇ 1%, ⁇ 0.5%, ⁇ 0.2%, or ⁇ 0.1%of the value to which “about” refers.
  • polypeptide, ” “peptide, ” “protein, ” and their grammatical equivalents refer to polymers of ammo acids of any length, which can be linear or branched. It can include unnatural or modified amino acids or be interrupted by non-amino acids.
  • a polypeptide, peptide, or protein can also be modified with, for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification.
  • fusion protein refers to a polypeptide with two or more domains that are covalently linked. Each domain can be derived from different proteins. These domains can be directly linked by a single peptide bond or through 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 produced using recombinant technology.
  • a fusion protein designed to inhibit VEGF and complement pathway can have a complement inhibitory domain (CID) , a VEGF inhibitory domain (VID) , and a half-life extension domain. Detailed descriptions of “CID, ” “VID, ” and “half-life extension domain, ” can be found in WO2013082563A 1, which is incorporated herein in its entirety.
  • variant refers to a different protein or polypeptide having one or more (such as, for example, 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 as compared to the reference protein or reference polypeptide.
  • the changes to an amino acid sequence can be amino acid substitutions.
  • the changes to an amino acid sequence can be conservative amino acid substitutions.
  • the changes to an amino acid sequence can be amino acid deletions.
  • a variant can be a fragment of the reference protein or polypeptide.
  • a functional variant of a protein or polypeptide maintains the basic structural and functional properties of the reference protein or polypeptide.
  • the term “pharmaceutically acceptable” refers to a substance (e.g., an active ingredient or a carrier) that is suitable for use in contact with the tissues and organs of a subject without excessive irritation, allergic response, immunogenicity and toxicity, is commensurate with a reasonable benefit/risk ratio, and is effective for its intended use.
  • pharmaceutically acceptable carrier refers to a material that is suitable for drug administration to a subject along with an active agent without causing undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition.
  • Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, and preservatives.
  • formulation or “pharmaceutical composition” refer to a composition suitable for administration to animals, preferably mammals (including humans) , comprising at least one active ingredient and at least one carrier.
  • the formulation and pharmaceutical composition can be in liquid form, which is referred to as “liquid formulation” or “liquid composition. ”
  • a liquid formulation can be, for example, an injectable.
  • a lipid formulation or pharmaceutical composition contain a solvent.
  • solvent refers to a liquid substance used to dissolve or suspend active and inactive ingredients to form a liquid formulation. Solvents include, but are not limited to, water for injection, organic solvents for injection such as oils for injection, ethanol, propylene glycol, or combinations thereof.
  • the term “treat” and its grammatical equivalents refer to actions taken to manage a disease or condition in a subject. This includes the suppression, elimination, reduction, or amelioration of symptoms, as well as the prevention, delay, alleviation, or reversal of the progression or severity of the condition. Desired therapeutic effects encompass symptom relief, reduction in disease severity, stabilization of the condition, delay or slowing of disease progression, and potential alleviation or remission of the disease. Patients in need of treatment are those experiencing the symptoms or effects of the disease or condition being addressed.
  • prevention refers to the inhibition or avoidance of the onset or progression of symptoms associated with a disease or condition. Individuals with a family history of the disease can be suitable candidates for preventive interventions. Typically, “prevention” involves administering a medication or therapy prior to the appearance of any signs or symptoms, particularly in individuals identified as being at risk.
  • administer and its grammatical equivalents refer to the act of delivering, or causing to be delivered, a therapeutic or a pharmaceutical composition to the body of a subject by a method described herein or otherwise known in the art.
  • Administering a therapeutic or a pharmaceutical composition includes prescribing a therapeutic or a pharmaceutical composition to be delivered into the body of a subject.
  • Exemplary forms of administration include oral dosage forms, such as tablets, capsules, syrups, suspensions; injectable dosage forms, such as intravenous (IV) , intramuscular (IM) , or intraperitoneal (IP) ; transdermal dosage forms, including creams, jellies, powders, or patches; buccal dosage forms; inhalation powders, sprays, suspensions, and rectal suppositories.
  • IV intravenous
  • IM intramuscular
  • IP intraperitoneal
  • transdermal dosage forms including creams, jellies, powders, or patches
  • buccal dosage forms inhalation powders, sprays, suspensions, and rectal suppositories.
  • a therapeutic or a pharmaceutical composition can also be administered in combination with one or more additional therapeutic agents or therapies to achieve a beneficial therapeutic outcome.
  • the combined treatment or combination treatment can include simultaneous administration or sequential administration of different agents or therapies.
  • the terms “effective amount, ” “therapeutically effective amount, ” and their grammatical equivalents refer to the administration of an agent to a subject, either alone or as a part of a pharmaceutical composition and either in a single dose or as part of a series of doses, in an amount that is capable of having any detectable, positive effect on any symptom, aspect, or characteristics of a disease, disorder or condition when administered to the subject.
  • the therapeutically effective amount can be ascertained by measuring relevant physiological effects. The exact amount required varies from subject to subject, depending on the age, weight, and general condition of the subject, the severity of the condition being treated, the judgment of the clinician, and the like.
  • an appropriate “effective amount” in any individual case can be determined by one of ordinary skills in the art using routine experimentation.
  • An “effective amount” of a therapeutic agent can be described with various units of measurement, such as milligrams (mg) .
  • the specified dosage for example, X mg, indicates the amount administered per eye.
  • the term “subject” refers to any animal (e.g., a mammal) , including, but not limited to, domestic animals (e.g., cattle, goats, rabbits, cats, dogs, and horses) , primates (e.g., human and non-human primates such as monkeys) , and rodents (e.g., mice and rats) , which is to be the recipient of a particular treatment.
  • a subject can be a human, such as an adolescent or an adult.
  • a subject can have a particular disease or condition.
  • Ranges throughout this disclosure, various aspects of the invention can be presented in a range format.
  • the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range.
  • description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.
  • GenBank numbers GI numbers and/or SEQ ID NOS. It is understood that one skilled in the art can readily identify homologous sequences by reference to sequence sources, including but not limited to GenBank (ncbi. nlm. nih. gov/genbank/) and EMBL (embl. org/) .
  • the fusion protein comprises, from N-terminus to C-terminus, a VEGF inhibitory domain ( “VID” ) , a half-life extension domain, a peptide linker, and a complement inhibitory domain ( “CID” ) .
  • the half-life extension region is an immunoglobulin Fc region.
  • the CID domain inhibits complement activation.
  • the CID can 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.
  • the CID can 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.
  • the CID has an amino acid sequence that is at least 95%identical to SEQ ID NO: 2.
  • the CID has the amino acid sequence of SEQ ID NO: 2.
  • the CID has an amino acid sequence that is at least 95%identical to SEQ ID NO: 3.
  • the CID has the amino acid sequence of SEQ ID NO: 3.
  • the VID domain inhibits the VEGF pathway and contains immunoglobulin-like (Ig) domain 2 of human VEGFR-1 and Ig-like domain 3 of human VEGFR-2.
  • the VID can 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.
  • the VID can 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.
  • the VID has an amino acid sequence that is at least 95%identical to SEQ ID NO: 4. In some embodiments, the VID has the amino acid sequence of SEQ ID NO: 4. In some embodiments, the VID has an amino acid sequence that is at least 95%identical to SEQ ID NO: 5. In some embodiments, the VID has the amino acid sequence of SEQ ID NO: 5.
  • the half-life extension domain includes the Fc region of an immunoglobulin, such as human IgG1, IgG2, IgG3, or IgG4.
  • the half-life extension domain can 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.
  • the half-life extension domain has an amino acid sequence that is at least 95%identical to SEQ ID NO: 6.
  • the half-life extension domain has the amino acid sequence of SEQ ID NO: 6.
  • 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 efdamrofusp alfa (SEQ ID NO: 1) .
  • Efdamrofusp alfa is a fusion protein that comprises a complement inhibitory domain (CID) , a VEGF inhibitory domain (VID) and a half-life extending domain. As such, efdamrofusp alfa can inhibit both the VEGF pathway and the complement pathway. Efdamrofusp alfa has the amino acid sequence of SEQ ID NO: 1
  • efdamrofusp alfa including its bifunctional activity in vitro and in vivo, along with its pharmacodynamic, pharmacokinetic, and toxicological characteristics can be found in WO2013082563A1 and WO2021129658, which are hereby incorporated by reference in its entirety.
  • the method for preparation of recombinant fusion protein is well known in the art. Methods for preparing efdamrofusp alfa are also described in WO2013082563A1.
  • compositions comprising efdamrofusp alfa.
  • pharmaceutical compositions comprising efdamrofusp alfa and a pharmaceutically acceptable carrier.
  • Compositions provided herein can be useful in treating AMD, such as nAMD, in a subject in need thereof.
  • Compositions provided herein can be useful in treating DME, in a subject in need thereof.
  • compositions comprising efdamrofusp alfa and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carriers include, but are not limited to a buffer, an excipient, a stabilizer or a preservative.
  • Pharmaceutically acceptable carriers that can be included in compositions to be used in methods provided herein include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier is suitable for local administration (e.g., by intravitreal injection) .
  • the pharmaceutical compositions provided herein are available in liquid form, such as injectable solutions, or as dry powder formulations.
  • the liquid formulation can include: (i) the fusion protein disclosed herein (e.g., efdamrofusp alfa) ; (ii) a buffer; and (iii) a solvent.
  • the buffer which can be a pH buffer, may be selected from histidine, glutamate, phosphate, acetate, citrate, or tris (hydroxymethyl) aminomethane.
  • Solvents that can be used in 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 oils for injection can also be utilized.
  • sterile non-volatile oils including synthetic monoglycerides or diglycerides, can be used as solvents or suspending media, with fatty acids such as oleic acid being suitable for preparing injectables.
  • the composition can be a lyophilized powder that is reconstituted in a pharmaceutically acceptable liquid carrier, such as those mentioned, to form an injectable solution.
  • the liquid formulations provided herein comprise efdamrofusp alfa at various concentrations. In some embodiments, the liquid formulations provided herein comprise efdamrofusp alfa at 20-100 mg/mL. In some embodiments, the liquid formulations provided herein comprise efdamrofusp alfa at 40-100 mg/mL. In some embodiments, the liquid formulations provided herein comprise efdamrofusp alfa at 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.
  • the liquid formulations provided herein comprise efdamrofusp alfa at about 40 mg/ml. In some embodiments, the liquid formulations provided herein comprise efdamrofusp alfa at about 80 mg/ml.
  • liquid pharmaceutical formulation provided herein is suitable for injection.
  • the pharmaceutical composition provided herein can be a dry powder formulation.
  • the composition is a lyophilized powder, which can be formulated in a pharmaceutically acceptable liquid carrier for injection.
  • the pharmaceutically acceptable liquid carrier may be, for example, sterile water, Ringer′s solution, phosphate buffered saline, isotonic sodium chloride solution and the like.
  • compositions comprising efdamrofusp alfa.
  • the pharmaceutical compositions comprise the following excipients: sodium citrate (dihydrate) , arginine, sucrose, polysorbate 20.
  • the pH of the pharmaceutical composition is 6.2.
  • a single dose of the pharmaceutical composition provided herein has no more than 0.2 ml of the liquid formulation. As such, the injection volume is no more than 0.2 mL. In some embodiments, the injection volume is between 0.01 mL to 0.2 mL. In some embodiments, a single dose of the pharmaceutical composition provided herein about 0.1 ml of the liquid formulation. As such, in some embodiments, the injection volume is about 0.1 mL.
  • compositions provided herein are provided in single dose units.
  • a “single dose unit” refers to a specific amount or quantity of a drug substance (e.g., efdamrofusp alfa) that is intended to be administered as a single dose to an individual. It is a premeasured unit designed for one-time consumption or application.
  • a single dose unit can be a vial, an ampoule, a pre-filled needle or a pre-filled syringe for injection.
  • a single dose unit can be in the form of liquid solution or lyophilized powder.
  • the single dose unit comprises efdamrofusp alfa in the amount 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.
  • a single dose unit comprises efdamrofusp alfa in the amount of: about 6.4 mg.
  • a single dose unit comprises efdamrofusp alfa in the amount of: about 8 mg.
  • a single dose unit comprises efdamrofusp alfa in the amount of: about 12.8 mg. In some embodiments, a single dose unit comprises efdamrofusp alfa in the amount of: about 16 mg. In some embodiments, the single dose unit can contain more drug substance than the amount to be injected, and the remaining drug substance after the injection is to be discarded. For example, a single dose unit can contain 0.2 ml: 16 mg efdamrofusp alfa in one vial, and single dose for injection can be 8 mg.
  • a single dose unit comprises 0.2 ml: 8 mg efdamrofusp alfa in a vial. In some embodiments, a single dose unit comprises 0.2 ml: 16 mg efdamrofusp alfa in a vial.
  • a single dose of the pharmaceutical composition provided herein has no more than 0.2 ml of the liquid formulation. As such, the injection volume is no more than 0.2 mL. In some embodiments, the injection volume is between 0.01 mL to 0.2 mL. In some embodiments, a single dose of the pharmaceutical composition provided herein about 0.1 ml of the liquid formulation. As such, in some embodiments, the injection volume is about 0.1 mL.
  • single dose unit comprises efdamrofusp alfa in a liquid solution having 2.94 mg/ml sodium citrate (dihydrate) , 13.94 mg/ml arginine, 50.00 mg/ml sucrose, 0.3 mg/ml polysorbate 20, at pH 6.2.
  • kits comprising the single dose unit of efdamrofusp alfa as disclosed herein.
  • the bispecific fusion protein e.g., efdamrofusp alfa
  • pharmaceutical compositions disclosed herein can be used for treating AMD (e.g., nAMD) .
  • AMD e.g., nAMD
  • methods of treating AMD (e.g., nAMD) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of efdamrofusp alfa.
  • the subject can be a human.
  • the subject can have AMD (e.g., nAMD) .
  • the subject can be at risk of developing AMD (e.g., nAMD) .
  • the subject can have one “diseased eye, ” namely, the eye diagnosed with AMD (e.g., nAMD) .
  • the subject can have two diseased eyes.
  • treating “a subject” is equivalent to treating “the diseased eye (or eyes) of the subject” ; characterization of “the treated subject” (e.g., BCVA score, presence of active CNV, GA, etc.
  • the diseased eye (eyes) of the treated subject is assessed in “the diseased eye (eyes) of the treated subject” ; and characterization of the efficacy of treatment (e.g., improvement in BCVA, reduction in CNV, etc. ) in “the treated subject” is also in assessed in “the diseased eye (eyes) of the treated subject. ”
  • the subject to be treated is at least 18 years old. In some embodiments, the subject is at least 30 years old. In some embodiments, the subject is at least 40 years old. In some embodiments, the subject is at least 45 years old. In some embodiments, the subject is at least 50 years old. In some embodiments, the subject is at least 55 years old. In some embodiments, the subject is at least 60 years old. In some embodiments, the subject has been newly diagnosed with nAMD. In some embodiments, the subject has been diagnosed with nAMD for up to 1 month. In some embodiments, the subject has been diagnosed with nAMD for up to 12 years. In some embodiments, the subject has been diagnosed with nAMD for, for example, 1 month to 12 years, such as six months, 1 year, 3 years, 5 years, 8 years, 12 years, or longer.
  • efdamrofusp alfa in the treatment of AMD (e.g., nAMD) .
  • efdamrofusp alfa in the manufacture of a medicament for treating AMD (e.g., nAMD) .
  • the pharmaceutical compositions provided herein can be administered alone or in combination with an additional therapeutic agent for AMD (e.g., nAMD) .
  • efdamrofusp alfa is used alone in the treatment.
  • efdamrofusp alfa is used in a combination therapy with other treatments, such as laser therapy.
  • the AMD is nAMD.
  • the subject having nAMD can have one or more of the following symptoms: visual acuity decrease, metamorphopsia, central scotoma, dyslexia, macular retinal swelling, fundus hemorrhage, neovascularization, scar fibrosis, geographic atrophy, and the like.
  • MA Macular atrophy
  • GA geographic atrophy
  • MA refers to the gradual degeneration and thinning of the macula. A loss of RPE cells occurs in MA, which leads to death of photoreceptors in macular and resulting in loss of central vision in nAMD. GA is characterized by large, well-defined areas of RPE and photoreceptor cell loss in macula creating distinct “geographic” patterns, such as circular or oval-shaped regions in dry AMD patients.
  • MA or GA can be detected by Optical Coherence Tomography ( “OCT” ) . The MA or GA area can also be measured by OCT.
  • fibrosis can occur in the retina as the death of RPE cells or progress of the choroid neovascularization ( “CNV” ) results in accumulation of cellular debris and disruption of normal retinal structure, which triggers the wound-healing process and formation of fibrotic tissue.
  • Retina fibrosis can be detected with Color Fundus Photography ( “CFP” ) .
  • CFP Color Fundus Photography
  • the subjects to be treated with methods disclosed herein have newly developed MA.
  • the subjects have retinal fibrosis.
  • the subjects have GA.
  • CNV Choroid neovascularization
  • Type I or occult CNV refers to vessels beneath the RPE.
  • Type 1 CNV demonstrates occult leakage on fluorescein angiography.
  • Polypoidal choroidal vasculoplathy (“PCV” ) is a subtype of Type I CNV that is characterized by the presence of polyp-like aneurysmal dilations of the branching vascular network.
  • Type II or classic CNV refers to vessels expanding into the subretinal space between the neurosensory retina and the RPE.
  • Type III refers to retinal angiomatous proliferation ( “RAP” ) , which corresponds to neovascularization that develops within the neurosensory retina and progresses posteriorly into the subretinal space.
  • RAP retinal angiomatous proliferation
  • a subject is considered to have “active CNV” if the presence of intraretinal fluid ( “IRF” ) or subretinal fluid ( “SRF” ) can be detected by OCT or fluorescence leakage can be detected by Fundus Fluorescence Angiography ( “FFA” ) .
  • IRF intraretinal fluid
  • SRF subretinal fluid
  • FFA Fundus Fluorescence Angiography
  • Pigment epithelial detachment is also a feature of CNV in nAMD detectable by OCT.
  • the pigment epithelium is a layer of cells located just beneath the light-sensitive cells of the retina, and PED refers to its detachment from the underlying layer and the separation between the layers.
  • the CNV area refers to the physical extent or size of the choroidal neovascular membrane, that is, the region occupied by the newly formed blood vessels.
  • the CNV leakage area refers to the specific region where the abnormal blood vessels are actively leaking fluid, blood, or other substances into the surrounding tissues. Both the CNV area and the CNV leakage area can be detected with FFA.
  • the CNV area in the diseased eye can be ⁇ 50%of the total lesion area (including hemorrhage, CNV, atrophy and fibrosis) .
  • subjects to be treated with methods disclosed herein have CNV.
  • the subjects have active CNV.
  • the subjects have active subfoveal CNV secondary to nAMD or active CNV involving the fovea.
  • “fovea” refers to the circle with a diameter of 1 mm at the center of the macula.
  • the subjects have active subfoveal CNV secondary to nAMD.
  • the subjects have active parafoveal CNV secondary to nAMD.
  • the subjects have active CNV involving the fovea, wherein the active CNV can be parafoveal or outside fovea.
  • the subjects have Type II CNV. In some embodiments, the subjects do not have Type II CNV.
  • the subjects to be treated with methods disclosed herein have IRF or SRF. In some embodiments, the subjects have PED.
  • BCVA Best-Corrected Visual Acuity
  • ETDRS letter score can be calculated when 20 or more letters are read correctly at 4.0 meters; the visual acuity letter score is equal to the total number of letters read correctly at 4.0 meters plus 30. If fewer than 20 letters are read correctly at 4.0 meters, the visual acuity letter score is equal to the total number of letters read correctly at 4.0 meters (number of letters recorded on line 1.0) , plus the total number of letters in the first six lines read correctly at 1.0 meter. Therefore, the ETDRS letter score could result in a maximum score of 100.
  • a loss of three or more lines (greater than or equal to 15 letters) on an ETDRS chart corresponds to a doubling of the visual angle and is considered moderate visual loss
  • a loss of six or more lines (greater than or equal to 30 letters) corresponds to a quadrupling of the visual angle and is considered severe.
  • the BCVA of the diseased eye in the subject to be treated by methods described herein is less than 82 ETDRS letters. In some embodiments, the BCVA of the subject is no more than 81 ETDRS letters. In some embodiments, the BCVA of the subject is no more than 80 ETDRS letters. In some embodiments, the BCVA of the subject is no more than 79 ETDRS letters. In some embodiments, the BCVA of the subject is no more than 78 ETDRS letters. In some embodiments, the BCVA of the subject is no more than 77 ETDRS letters. In some embodiments, the BCVA of the subject is no more than 76 ETDRS letters. In some embodiments, the BCVA of the subject is no more than 75 ETDRS letters.
  • the BCVA of the subject is no more than 74 ETDRS letters. In some embodiments, the BCVA of the subject is no more than 73 ETDRS letters. In some embodiments, the BCVA of the subject is no more than 72 ETDRS letters. In some embodiments, the BCVA of the subject is no more than 71 ETDRS letters. In some embodiments, the BCVA of the subject is no more than 70 ETDRS letters. In some embodiments, the BCVA of the diseased eye in the subject to be treated by methods described herein is at least 18 ETDRS letters. In some embodiments, the BCVA of the subject is at least 19 ETDRS letters. In some embodiments, the BCVA of the subject is at least 20 ETDRS letters.
  • the BCVA of the subject is at least 21 ETDRS letters. In some embodiments, the BCVA of the subject is at least 22 ETDRS letters. In some embodiments, the BCVA of the subject is at least 23 ETDRS letters. In some embodiments, the BCVA of the subject is at least 24 ETDRS letters. In some embodiments, the BCVA of the subject is at least 25 ETDRS letters.
  • the BCVA of the diseased eye in the subject to be treated by methods described herein ranges between 19 to 78 ETDRS letters (inclusive of both end values) . In some embodiments, the BCVA of the diseased eye in the subject to be treated by methods described herein ranges between 24 to 73 ETDRS letters (inclusive of both end values) . In some embodiments, the BCVA of the diseased eye in the subject to be treated by methods described herein ranges between 24 to 78 ETDRS letters (inclusive of both end values) . In some embodiments, the subject has BCVA of at least 64. In some embodiments, the subject has BCVA of no more than 63.
  • the BCVA of the diseased eye in the subject to be treated by methods described herein ranges between 19 to 63 ETDRS letters (inclusive of both end values) . In some embodiments, the BCVA of the diseased eye in the subject to be treated by methods described herein ranges between 24 to 63 ETDRS letters (inclusive of both end values) . In some embodiments, the BCVA of the diseased eye in the subject to be treated by methods described herein ranges between 64 to 78 ETDRS letters (inclusive of both end values) . In some embodiments, the BCVA of the diseased eye in the subject to be treated by methods described herein ranges between 64 to 73 ETDRS letters (inclusive of both end values) .
  • the BCVA of the diseased eye in the subject to be treated by methods described herein ranges between 50 to 73 ETDRS letters (inclusive of both end values) . In some embodiments, the BCVA of the diseased eye in the subject to be treated by methods described herein ranges between 30 to 65 ETDRS letters (inclusive of both end values) . In some embodiments, the BCVA of the diseased eye in the subject to be treated by methods described herein ranges between 24 to 50 ETDRS letters (inclusive of both end values) .
  • Central subfield thickness A quantitative measure of the thickness of the central subfield of the macula, CST is often measured using SD-OCT to monitor the progression of AMD and the effectiveness of a treatment. An increase in CST can indicate the presence of macular edema and disease progression, and a reduction in CST can suggest a positive response and decreased macular edema.
  • the CST in the diseased eye in the subject to be treated by methods disclosed herein is at least 250 ⁇ m, at least 280 ⁇ m, at least 300 ⁇ m, of at least 325 ⁇ m as measured by SD-PCT. In some embodiments, the CST in the diseased eye in the subject to be treated by methods disclosed herein is at least 250 ⁇ m as measured by SD-PCT. In some embodiments, the CST in the diseased eye in the subject to be treated by methods disclosed herein is at least 280 ⁇ m as measured by SD-PCT.
  • total lesion area includes the area of all lesions including CNV, hemorrhage, PED, fibrosis, and atrophy.
  • the total lesion area, or diameter of the total lesion, can be measured by FFA and CFP.
  • Anti-VEGF therapies which inhibit the action of VEGF, are widely used and effective treatment for nAMD.
  • Approved anti-VEGF medications for the treatment for nAMD include, for example, ranibizumab, bevacizumab, aflibercept, brolucizumab, and faricimab-svoa.
  • the subjects to be treated with the methods disclosed herein have previously been treated with an anti-VEGF treatment.
  • the subjects to be treated with the methods disclosed herein have not previously been treated with an anti-VEGF treatment.
  • the subjects to be treated with the methods disclosed herein have previously been treated with ranibizumab.
  • the subjects to be treated with the methods disclosed herein have previously been treated with bevacizumab. In some embodiments, the subjects to be treated with the methods disclosed herein have previously been treated with aflibercept. In some embodiments, the subjects to be treated with the methods disclosed herein have previously been treated with brolucizumab. In some embodiments, the subjects to be treated with the methods disclosed herein have previously been treated with faricimab-svoa.
  • the subjects to be treated with methods disclosed herein have not ever received, or have not received within 30 days, 90 days, or 120 days before the start of the treatment disclosed herein, any of the following prior treatments: anti-complement drug treatment, retinal grid laser or panretinal photocoagulation, laser posterior capsulotomy, intraocular or periocular corticosteroid injections.
  • the subjects to be treated with methods disclosed herein have not undergone vitreoretinal surgery.
  • the subjects to be treated with methods disclosed herein meet the following characterizations: (1) at least 50 years old; (2) having active subfoveal or parafoveal CNV secondary to nAMD; (3) having a CNV area (including classic and occult) that is no less than 50%of the total lesion area (including hemorrhage, CNV, atrophy and fibrosis) ; and (4) BCVA of the diseased ranging between 24 and 73 (inclusive of end values) .
  • the diseased eye of the subjects has type II CNV.
  • the diseased eye of the subjects does not have type II CNV.
  • the diseased eye of the subjects has previously received treatment for AMD.
  • the diseased eye of the subjects has not previously received treatment for AMD. In some embodiments, the diseased eye of the subjects has type II CNV and has previously received treatment for AMD. In some embodiments, the diseased eye of the subjects does not have type II CNV and has previously received treatment for AMD. In some embodiments, the diseased eye of the subjects has type II CNV and has not previously received treatment for AMD. In some embodiments, the diseased eye of the subjects does not have type II CNV and has not previously received treatment for AMD.
  • the CNV can be detected using OCT.
  • the subjects to be treated with methods disclosed herein meet the following characterizations: (1) at least 50 years old; (2) having active subfoveal CNV secondary to nAMD or active CNV that is parafoveal or outside fovea but involves the fovea; (3) having a CNV area (including classic and occult) that is at least 50%of the total lesion area (including hemorrhage, CNV, atrophy and fibrosis) ; and (4) having BCVA ranging between 24 and 78 (inclusive of end values) .
  • the diseased eye of the subjects has BCVA of ⁇ 64 letters. In some embodiments, the diseased eye of the subjects has BCVA of ⁇ 63 letters.
  • the diseased eye of the subjects has previously received treatment for AMD. In some embodiments, the diseased eye of the subjects has not previously received treatment for AMD. In some embodiments, the diseased eye of the subjects has BCVA of ⁇ 64 letters and has previously received treatment for AMD. In some embodiments, the diseased eye of the subjects has BCVA of ⁇ 63 letters and has previously received treatment for AMD. In some embodiments, the diseased eye of the subjects has BCVA of ⁇ 64 letters and has not previously received treatment for AMD. In some embodiments, the diseased eye of the subjects has BCVA of ⁇ 63 letters and has not previously received treatment for AMD. The CNV can be detected using OCT.
  • the subjects to be treated with methods disclosed herein meet the following characterizations: (1) at least 50 years old; (2) having active subfoveal macular CNV secondary to nAMD or active CNV involving the fovea; and (3) BCVA of the diseased eye ranging between 19 and 78 ETDRS letters (inclusive of both end values) .
  • the diseased eye of the subjects has type II CNV. In some embodiments, the diseased eye of the subjects does not have type II CNV.
  • the diseased eye of the subjects has previously received anti-VEGF treatment. In some embodiments, the diseased eye of the subjects has not previously received anti-VEGF treatment.
  • the diseased eye of the subjects has type II CNV and has previously received anti-VEGF treatment. In some embodiments, the diseased eye of the subjects does not have type II CNV and has previously received anti-VEGF treatment. In some embodiments, the diseased eye of the subjects has type II CNV and has not previously received anti-VEGF treatment. In some embodiments, the diseased eye of the subjects does not have type II CNV and has not previously received anti-VEGF treatment.
  • the CNV can be detected using OCT.
  • the subjects to be treated with methods disclosed herein have one or more of the following symptoms and/or signs: decreased vision, increased central retinal thickness, subretinal/intraretinal/sub-RPE fluid, neovascularization, macular hemorrhage, visual distortion, central scotoma, reading difficulty, macular edema, fundus hemorrhage, scar fibrosis, geographic atrophy, or any combination thereof.
  • the subjects to be treated with methods disclosed herein have one or more of the following symptoms and/or signs: decreased vision, increased central retinal thickness, subretinal/intraretinal/sub-RPE fluid, neovascularization, macular hemorrhage, or any combination thereof.
  • compositions disclosed herein containing a fusion protein disclosed herein can be administered to a subject in need thereof to treat AMD (e.g., nAMD) .
  • the pharmaceutical compositions disclosed herein are administered locally.
  • the pharmaceutical compositions disclosed herein are administered topically.
  • the pharmaceutical compositions disclosed herein are administered intralesionally.
  • the pharmaceutical compositions disclosed herein are administered intravenously.
  • the pharmaceutical compositions containing a fusion protein disclosed herein are administered directly to an eye or ocular tissue.
  • This administration can be achieved through various methods, including topical application to the eye or injection into the eye or associated tissues.
  • Injection methods include, but are not limited to, intravitreal injection, periocular injection, subretinal injection, transscleral injection, subscleral injection, intrachoroidal injection, anterior chamber injection, subconjunctival injection, subtenon injection, retrobulbar injection, peribulbar injection, posterior injection, posterior juxtascleral delivery, or periscleral delivery of the composition.
  • the pharmaceutical composition can also be administered to areas such as the vitreous, optic nerve, aqueous humor, sclera, conjunctiva, the area between the sclera and conjunctiva, retinal-choroidal tissue, macula, or other regions in or near the eye.
  • the pharmaceutical compositions disclosed herein are administered by intravitreal injection.
  • the fusion protein disclosed herein e.g., efdamrofusp alfa
  • intravitreal injection is administered by intravitreal injection.
  • treatment regimens comprising administering multiple doses of a pharmaceutical composition disclosed herein that comprises a therapeutically effective amount of efdamrofusp alfa.
  • the therapeutically effective amount for a single dose 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.
  • the therapeutically effective amount can be 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, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5.0 mg, 5.1 mg, 5.2 mg
  • the therapeutically effective amount of efdamrofusp alfa can range between about 1.0 mg and about 8.0 mg. In some embodiments, the therapeutically effective amount for a single dose of efdamrofusp alfa can range between about 2.0 mg and about 8.0 mg. In some embodiments, the therapeutically effective amount for a single dose of efdamrofusp alfa can be about 2.0 mg. In some embodiments, the therapeutically effective amount for a single dose of efdamrofusp alfa can be about 3.2 mg. In some embodiments, the therapeutically effective amount for a single dose of efdamrofusp alfa can be about 4.0 mg.
  • the therapeutically effective amount for a single dose of efdamrofusp alfa can be about 6.4 mg. In some embodiments, the therapeutically effective amount for a single dose of efdamrofusp alfa can be about 8.0 mg. As used herein, the specified dosage, for example, 1.0-8.0 mg, indicates the amount administered per eye.
  • efdamrofusp alfa is administered by intravitreal injection.
  • the injection volume can range from 0.01 mL to 0.1 mL. In some embodiments, the injection volume can range from 0.04 mL to 0.08 mL. In some embodiments, the injection volume can be about 0.04 mL, 0.08 mL, or 0.1 mL. In some embodiments, the injection volume can be about 0.1 mL.
  • the multiple doses of the pharmaceutical compositions disclosed herein can be administered at different dosing intervals, for example, about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once every five weeks, about once every six weeks, about once every seven weeks, about once every eight weeks, about once every nine weeks, about once every ten weeks, about once every eleven weeks, about once every 12 weeks, about once every 13 weeks, about once every 14 weeks, about once every 15 weeks, or about once every 16 weeks.
  • pharmaceutical compositions disclosed herein can be administered at a dosing interval that ranges from about once every four weeks to about once every 16 weeks.
  • pharmaceutical compositions disclosed herein can be administered about once every four weeks.
  • pharmaceutical compositions disclosed herein can be administered about once every eight weeks.
  • pharmaceutical compositions disclosed herein can be administered about once every 12 weeks.
  • pharmaceutical compositions disclosed herein can be administered about once every 16 weeks.
  • compositions disclosed herein comprising the fusion protein can be administered in two phases, namely, a loading phase and a maintenance phase.
  • the term “loading phase” refers to the treatment phase where the fusion protein (e.g., efdamrofusp alfa) is administered to induce the desired therapeutic effect, such as clinical remission, clinical response, OCT remission, OCT resolution, and/or symptomatic relief.
  • the desired therapeutic effect can be vision improvement and/or macular structural improvement.
  • the desired therapeutic effect is for the subject to achieve stable vision and/or lesion stabilization.
  • the therapeutic effect is the improvement of vision and/or anatomical structure as seen on OCT.
  • the therapeutic effect is the improvement of CST and/or BCVA.
  • the dose at which the fusion protein is administered during loading phase is referred to as the “loading dose. ”
  • the length of the loading treatment period can be, for example, 4, 8, or 12 weeks.
  • Patient evaluations can be conducted 1 week, 4 weeks, or 8 weeks after the last loading dose.
  • a single or multiple “loading doses” can be administered.
  • multiple doses are administered at a fixed interval during the loading phase, referred to as the “loading interval. ”
  • the terms “maintenance phase” and “on-demand phase” refer to the treatment phase following the loading phase, during which the fusion protein (e.g., efdamrofusp alfa) is administered at the dose and interval as determined by the patient's condition to maintain the desired therapeutic effect.
  • the dose at which the fusion protein is administered during loading phase is referred to as the “maintenance dose, ” which can be the same or different from the loading dose.
  • a single or multiple “maintenance doses” can be administered. In some embodiments, multiple doses are administered at certain interval during the maintenance phase, referred to as the “maintenance interval. ”
  • the loading phase consists of the first two to eight weeks of a treatment regimen. In some embodiments, the loading phase consists of the first four to 16 weeks of a treatment regimen. In some embodiments, the loading phase consists of the first eight to 16 weeks of a treatment regimen. In some embodiments, the loading phase consists of the first 12 to 16 weeks of a treatment regimen. In some embodiments, the loading phase consists of the first eight weeks. In some embodiments, the loading phase consists of the first 12 weeks. In some embodiments, the loading phase consists of the first 16 weeks.
  • compositions disclosed herein comprising the fusion protein can be administered at a dosing interval of about once every three to five weeks during the loading phase.
  • pharmaceutical compositions disclosed herein can be administered about once every four weeks during the loading phase.
  • the loading phase can include two to four doses of pharmaceutical compositions disclosed herein, administered at a dosing interval of about once every three to five weeks.
  • the loading phase can include at least two doses of pharmaceutical compositions disclosed herein, administered at a dosing interval of about once every three to five weeks.
  • the loading phase can include three doses of pharmaceutical compositions disclosed herein, administered at a dosing interval of about once every three to five weeks. In some embodiments, the loading phase can include four doses of pharmaceutical compositions disclosed herein, administered at a dosing interval of about once every three to five weeks. In some embodiments, the loading phase can include three doses of pharmaceutical compositions disclosed herein, administered at a dosing interval of about once every four weeks. In some embodiments, the loading phase can include four doses of pharmaceutical compositions disclosed herein, administered at a dosing interval of about once every four weeks.
  • methods provided herein comprise a loading phase which consists of the first eight to 16 weeks of treatment, in which two to four doses pharmaceutical compositions disclosed herein are administered at a dosing interval of about once every three to five weeks. In some embodiments, methods provided herein comprise a loading phase which consists of the first eight weeks of treatment, in which three doses pharmaceutical compositions disclosed herein are administered at a dosing interval of about once every four weeks. In some embodiments, methods provided herein comprise a loading phase which consists of the first 12 weeks of treatment, in which four doses pharmaceutical compositions disclosed herein are administered at a dosing interval of about once every four weeks.
  • the loading phase can last longer than 12 weeks. In some embodiments, the loading phase can last 4 months, 5 months, 6 months, or 7 months, with the fusion protein administered once or twice a month. In some embodiments, the fusion protein is administered once a month.
  • each single dose of the fusion protein (e.g., efdamrofusp 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.
  • each single loading dose can be 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, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5.0 mg, 5.1 mg, 5.2 mg,
  • each single loading dose of efdamrofusp alfa can range between about 1.0 mg and about 8.0 mg. In some embodiments, each single loading dose of efdamrofusp alfa can range between about 2.0 mg and about 8.0 mg. In some embodiments, each single loading dose of efdamrofusp alfa can be about 2.0 mg. In some embodiments, each single loading dose of efdamrofusp alfa can be about 3.2 mg. In some embodiments, each single loading dose of efdamrofusp alfa can be about 4.0 mg. In some embodiments, each single loading dose of efdamrofusp alfa can be about 6.4 mg. In some embodiments, each single loading dose of efdamrofusp alfa can be about 8.0 mg. As used herein, the specified dosage, for example, 1.0-8.0 mg, indicates the amount administered per eye.
  • the maintenance phase (i.e., on-demand phase) follows the loading phase and aims to sustain the therapeutic effect achieved during the loading phase, with the goal being providing ongoing management and control of the condition or symptoms with a less frequent, more sustainable dosage.
  • the fusion protein disclosed herein e.g., efdamrofusp alfa
  • the fusion protein disclosed herein can be administered as needed as determined by assessing the treated eye after the last dosing of the loading phase.
  • at least one dose of the fusion protein is administered during the maintenance phase.
  • multiple doses of the fusion protein are administered during the maintenance phase.
  • the pharmaceutical compositions disclosed herein comprising the fusion protein can be administered at a dosing interval of about once every four to 16 weeks during the maintenance phase.
  • pharmaceutical compositions disclosed herein can be administered at a dosing interval of about once every six weeks, about once every seven weeks, about once every eight weeks, about once every nine weeks, about once every ten weeks, about once every eleven weeks, about once every 12 weeks, about once every 13 weeks, about once every 14 weeks, about once every 15 weeks, or about once every 16 weeks during the maintenance phase.
  • pharmaceutical compositions disclosed herein can be administered about once every eight weeks during the maintenance phase.
  • compositions disclosed herein can be administered about once every 12 weeks during the maintenance phase. In some embodiments, pharmaceutical compositions disclosed herein can be administered about once every 16 weeks during the maintenance phase.
  • the dosing interval can also be adjusted as needed during the maintenance phase. In some embodiments, the dosing interval is adjusted based on the assessment of the treated eye during follow-up visits.
  • the maintenance phase comprises 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.
  • methods provided herein comprise a maintenance phase comprising at least 24 weeks of treatment, in which pharmaceutical compositions disclosed herein are administered at a dosing interval of about once every eight weeks, about once every 12 weeks, or about once every 16 weeks. In some embodiments, pharmaceutical compositions disclosed herein are administered about once every eight weeks during the maintenance phase. In some embodiments, pharmaceutical compositions disclosed herein are administered about once every 12 weeks during the maintenance phase. In some embodiments, pharmaceutical compositions disclosed herein are administered about once every 16 weeks during the maintenance phase.
  • each single dose of the fusion protein (e.g., efdamrofusp 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.
  • each single maintenance dose can be 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, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5.0 mg, 5.1 mg, 5.2 mg,
  • each single maintenance dose of efdamrofusp alfa can range between about 1.0 mg and about 8.0 mg. In some embodiments, each single maintenance dose of efdamrofusp alfa can range between about 2.0 mg and about 8.0 mg. In some embodiments, each single maintenance dose of efdamrofusp alfa can be about 2.0 mg. In some embodiments, each single maintenance dose of efdamrofusp alfa can be about 3.2 mg. In some embodiments, each single maintenance dose of efdamrofusp alfa can be about 4.0 mg. In some embodiments, each single maintenance dose of efdamrofusp alfa can be about 6.4 mg. In some embodiments, each single maintenance dose of efdamrofusp alfa can be about 8.0 mg. As used herein, the specified dosage, for example, 1.0-8.0 mg, indicates the amount administered per eye.
  • the single dose amount remains unchanged across the entire treatment, including both the loading phase and the maintenance phase. In some embodiments, the single dose amount is changed during the treatment. In some embodiments, the single dose amount remains unchanged during the loading phase and during the maintenance phase, but is adjusted between the loading phase and the maintenance phase.
  • each single dose amount remains unchanged across the entire treatment, which range between about 1.0 mg and about 8.0 mg.
  • each single dose during the entire treatment can be about 2.0 mg.
  • each single dose during the entire treatment can be about 3.2 mg.
  • each single dose during the entire treatment can be about 4.0 mg.
  • each single dose during the entire treatment can be about 6.4 mg.
  • each single dose during the entire treatment can be about 8.0 mg.
  • methods provided herein comprise assessing the subject that has completed the loading phase for disease progression and responsiveness for treatment, and the results of the assessment are used to determine the specific regimen for the maintenance phase.
  • the assessment can be conducted about six to about ten weeks after the last dosing of the loading phase. In some embodiments, the assessment can be conducted about eight weeks after the last dosing of the loading phase.
  • methods provided herein comprise conducting one assessment. In some embodiments, methods provided herein comprise conducting two assessments that are about two to about six weeks apart. In some embodiments, the two assessments can be conducted four weeks apart.
  • the interval between the last dose of the loading phase and the first dose of the maintenance phase is the same as the dosing interval of the maintenance phase.
  • methods provided herein include follow-up assessments during both the loading and on-demand treatment phases to monitor the patient's condition and/or treatment responsiveness.
  • the assessments can include one or more of the following: (1) measuring changes in BCVA from baseline using the ETDRS chart; for example, number of ETDRS letters gained from baseline, e.g., ⁇ 0, 5, 10, or 15 letters; number of ETDRS letters lost from baseline, e.g., ⁇ 0, 5, 10, or 15 letter; (2) measuring changes in CST from baseline using SD-OCT; for example, CST reduction, e.g., ⁇ 50 ⁇ m or ⁇ 75 ⁇ m, or ⁇ 0%, 10%, or 20%; CST increase, e.g., ⁇ 50 ⁇ m or ⁇ 75 ⁇ m, or ⁇ 0%, 10%, or 20%; (3) evaluating subretinal/intraretinal/RPE fluid, new CNV, and/or new macular hemorrhage.
  • follow-up assessments are conducted about one week after each administration of the fusion protein (e.g., efdamrofusp alfa) during the loading treatment phase. In some embodiments, follow-up assessments are conducted about two weeks after each administration of the fusion protein (e.g., efdamrofusp alfa) during the loading treatment phase. In some embodiments, follow-up assessments are conducted every four weeks during the on-demand treatment phase.
  • the fusion protein e.g., efdamrofusp alfa
  • follow-up assessments are conducted every four weeks during the on-demand treatment phase.
  • methods provided herein include (a) a loading phase, during which the fusion protein (e.g., efdamrofusp alfa) is administered intravitreally at a loading dose with multiple consecutive doses at a loading interval until the desired therapeutic effect is achieved; (b) evaluation after a first follow-up interval (e.g., one week after each loading dose) , including determining if the desired therapeutic effect has been achieved by, for example, measuring BCVA changes (number of ETDRS letters gained from baseline e.g., ⁇ 0, 5, 10, or 15 letters; number of ETDRS letters lost from baseline, e.g., ⁇ 0, 5, 10, or 15 letters) and CST changes (reduction in values or percentages, e.g., ⁇ 50 ⁇ m or ⁇ 75 ⁇ m, or ⁇ 0%, 10%, or 20%; increase in values or percentages, e.g., ⁇ 50 ⁇ m or ⁇ 75 ⁇ m, or ⁇ 0%, 10%, or 20%) , and
  • follow-up assessments are conducted to determine whether the subjects meet the criteria for re-treatment.
  • the term “re-treat” or its grammatically equivalent terms means that a patient is assessed and determined not to require further drug administration at one or more follow-up assessment during the maintenance phase. However, at a subsequent assessment, it is determined that the therapeutic effect has diminished or that the disease has progressed, necessitating additional treatment.
  • the re-treatment criteria include: (i) decrease in BCVA by ⁇ 5 letters or increase in CST by >50 ⁇ m from the previous visit; (ii) persistent subretinal/intraretinal/RPE fluid; (iii) new CNV; or (iv) new macular hemorrhage.
  • step (c) post-loading phase evaluation
  • maintenance dosing can include multiple treatment cycles, each independently including: assessing changes in the patient's condition (e.g., BCVA and/or CST changes) after a second follow-up interval and administering maintenance doses based on assessment.
  • maintenance dosing continues until the lesion regresses and/or the patient's vision returns to normal. Maintenance dosing can continue for at least 1 year, 2 years, 3 years, 4 years, 5 years, or longer, or until the disease progresses.
  • 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 methods can include administering multiple doses during the loading phase at a fixed loading interval, such as once every 4 weeks.
  • Maintenance phase can also include administering multiple doses at maintenance intervals, which can be the same or different.
  • the maintenance interval can be the same as or longer than the loading interval, for example, once every 4 weeks, once every 8 weeks, once every 12 weeks, once every 16 weeks, once every 20 weeks, once every 24 weeks, or longer.
  • the methods provided herein include selecting the therapeutic dose and/or treatment interval of the fusion protein during the loading and/or maintenance phases to improve or maintain vision and/or improve or maintain macular anatomy, in order to avoid overtreatment and undertreatment.
  • the loading phase e.g., monthly dosing for 2, 3, 4, 5, or 6 months
  • maintenance dosing is administered.
  • the treatment interval is adjusted based on the assessment of the condition, for example, based on changes in BCVA or CST, or the presence of subretinal/intraretinal/RPE fluid, new CNV, and/or new macular hemorrhage.
  • the initial follow-up interval can be 4 weeks or 8 weeks. If two consecutive follow-ups show stable patient condition (e.g., stable CST and BCVA) , the treatment interval is extended, for example, by 4 weeks, while maintaining the original follow-up interval. If two consecutive follow-ups show worsening condition (e.g., worsening CST and/or BCVA) , the patient continues treatment with the original follow-up interval (e.g., 4 weeks) .
  • stable patient condition e.g., stable CST and BCVA
  • the treatment interval is extended, for example, by 4 weeks, while maintaining the original follow-up interval. If two consecutive follow-ups show worsening condition (e.g., worsening CST and/or BCVA) , the patient continues treatment with the original follow-up interval (e.g., 4 weeks) .
  • CST is considered stable if it increases by ⁇ 50 ⁇ m between visits.
  • BCVA is considered stable if it decreases by ⁇ 5 letters between visits. If BCVA decreases by ⁇ 5 letters between visits due to nAMD, it is considered worsening. If CST increases by >50 ⁇ m between visits due to nAMD, it is considered worsening. Worsening can be indicated by BCVA or CST worsening, persistent subretinal/intraretinal/RPE fluid, new CNV, or new macular hemorrhage.
  • follow-up assessments for CST and BCVA are conducted at maintenance intervals (e.g., 4 weeks) . If BCVA decreases by ⁇ 5 letters or CST increases by >50 ⁇ m due to nAMD since the last visit, the patient continues loading dose treatment with the same follow-up interval.
  • methods provided herein comprise conducting an assessment of the subjects who have completed the loading phase for disease activity ( “DA” ) .
  • DA is considered “present” if any of the following five criteria is met: (1) the CST is increased by >50 ⁇ m compared with the average CST of the previous two months; (2) the CST is increased by ⁇ 75 ⁇ m compared with the lowest CST of the previous two months; (3) the BCVA is lowered by ⁇ 5 letters compare to the average BCVA of the previous two months due to the progression of nAMD; (4) the BCVA is lowered by ⁇ 10 letters compare to the best BCVA of the previous two months due to the progression of nAMD; (5) occurrence of a new macular hemorrhage due to the progression of nAMD.
  • the dosing intervals for the maintenance phase can then be adjusted based on the presence or absence of DA.
  • methods provided herein comprise conducting an assessment of the subjects who have completed the loading phase for DA, and if DA is present at the assessment, the pharmaceutical compositions disclosed herein can be administered at a first maintenance interval; whereas if DA is not present at the assessment, the pharmaceutical compositions disclosed herein can be administered about a second maintenance interval (e.g., once every 12 weeks) , the second maintenance interval is relatively longer than the first maintenance interval.
  • the first maintenance interval is once every 8 weeks and second maintenance interval is once every 12 weeks.
  • the first maintenance interval is once every 12 weeks and second maintenance interval is once every 16 weeks.
  • methods provided herein comprise conducting an assessment of the subjects who have completed the loading phase for DA, and if DA is present at the assessment, the pharmaceutical compositions disclosed herein can be administered about once every eight weeks during the maintenance phase; whereas if DA is not present at the assessment, the pharmaceutical compositions disclosed herein can be administered about once every 12 weeks during the maintenance phase.
  • methods provided herein comprise conducting a first assessment of the subjects who have completed the loading phase for DA, if DA is present at the first assessment, the pharmaceutical compositions disclosed herein can be administered about a first maintenance interval; whereas if DA is not present at the first assessment, a second assessment is conducted about four weeks after the first assessment. If DA is present at the second assessment, the pharmaceutical compositions disclosed herein can be administered at a second maintenance interval; whereas if DA is not present at the second assessment, the pharmaceutical compositions disclosed herein can be administered a third maintenance interval; wherein the third maintenance interval is longer than the second, and the second longer than the first.
  • the first maintenance interval is once every four weeks
  • the second maintenance interval is once every eight weeks
  • the third maintenance interval is once every 12 weeks.
  • the first maintenance interval is once every eight weeks
  • the second maintenance interval is once every 12 weeks
  • the third maintenance interval is once every 16 weeks.
  • methods provided herein comprise conducting a first assessment of the subjects who have completed the loading phase for DA, if DA is present at the first assessment, the pharmaceutical compositions disclosed herein can be administered about once every eight weeks during the maintenance phase; whereas if DA is not present at the first assessment, a second assessment is conducted about four weeks after the first assessment. If DA is present at the second assessment, the pharmaceutical compositions disclosed herein can be administered about once every 12 weeks during the maintenance phase, whereas if DA is not present at the second assessment, the pharmaceutical compositions disclosed herein can be administered about once every 16 weeks during the maintenance phase.
  • methods provided herein comprise (1) as a loading phase, administering three doses of a pharmaceutical composition comprising about 2.0 mg or about 4.0 mg efdamrofusp alfa to a diseased eye of the subject, at a dosing interval of about once every 4 weeks; and consecutively (2) as a maintenance phase, administering at least two doses of the pharmaceutical composition to the diseased eye of the subject, at a dosing interval of about once every 8 weeks.
  • the pharmaceutical composition can have about 2.0 mg efdamrofusp alfa.
  • the pharmaceutical composition can have about 4.0 mg efdamrofusp alfa.
  • the maintenance phase comprises administering at least one dose, at least two doses, at least three doses, at least four doses, at least five doses, at least six doses, at least seven doses, at least eight doses, at least nine doses, at least ten doses, at least eleven doses, or at least twelve doses of the pharmaceutical composition disclosed herein. In some embodiments, the maintenance phase comprises administering about five doses of the pharmaceutical composition disclosed herein.
  • nAMD in a subject in need thereof, comprising (1) as a loading phase, administering three or four doses of a pharmaceutical composition comprising about 6.4 mg or about 8.0 mg efdamrofusp alfa to a diseased eye of the subject, at a dosing interval of about once every 4 weeks; and consecutively (2) as a maintenance phase, conducting an assessment of the subject for DA about eight weeks after the last dosing of the loading phase, and administering the pharmaceutical composition to the diseased eye of the subject at a dosing interval of (a) about once every 8 weeks, if DA is present at the assessment or (b) about once every 12 weeks, if DA is not present at the assessment.
  • the pharmaceutical composition can have about 6.4 mg efdamrofusp alfa. In some embodiments, the pharmaceutical composition can have about 8.0 mg efdamrofusp alfa. In some embodiments, the loading phase comprises administering about three doses of the pharmaceutical composition disclosed herein. In some embodiments, the loading phase comprises administering about four doses of the pharmaceutical composition disclosed herein. In some embodiments, the maintenance phase comprises administering at least one dose, at least two doses, at least three doses, at least four doses, at least five doses, at least six doses, at least seven doses, at least eight doses, at least nine doses, at least ten doses, at least eleven doses, or at least twelve doses of the pharmaceutical composition disclosed herein. In some embodiments, the maintenance phase comprises administering about three doses of the pharmaceutical composition disclosed herein. In some embodiments, the maintenance phase comprises administering about four doses of the pharmaceutical composition disclosed herein.
  • nAMD in a subject in need thereof, comprising (1) as a loading phase, administering three doses of a pharmaceutical composition comprising about 8.0 mg efdamrofusp alfa to a diseased eye of the subject, at a dosing interval of about once every 4 weeks; and consecutively (2) as a maintenance phase, conducting a first assessment of the subject for DA about eight weeks after the last dosing of the loading phase, and (a) if DA is present at the first assessment, administering the pharmaceutical composition to the diseased eye of the subject at a dosing interval of about once every 8 weeks; or (b) if DA is not present at the first assessment, conducting a second assessment of the subject for DA about four weeks after the first assessment, and administering the pharmaceutical composition to the diseased eye of the subject at a dosing interval of (i) about once every 12 weeks if DA is present at the second assessment or (ii) about once every 16 weeks if DA is not present at the
  • the maintenance phase comprises administering at least one dose, at least two doses, at least three doses, at least four doses, at least five doses, at least six doses, at least seven doses, at least eight doses, at least nine doses, at least ten doses, at least eleven doses, or at least twelve doses of the pharmaceutical composition disclosed herein. In some embodiments, the maintenance phase comprises administering about five doses of the pharmaceutical composition disclosed herein. In some embodiments, the maintenance phase comprises administering about seven doses of the pharmaceutical composition disclosed herein. In some embodiments, the maintenance phase comprises administering about eleven doses of the pharmaceutical composition disclosed herein.
  • Week n means the “nth” week (s) , since the initiation of treatment.
  • Week 0 refers to Day 0 to Day 6, with D0 being the day of treatment initiation; and Week 4 refers to Day 28 to Day 34.
  • a dose administered in a specified week is administered on the first day of that week.
  • the dose can be administered a few (e.g., 0-3) days early or a few (e.g., 0-3) days late, without affecting the overall efficacy of the treatment.
  • treatment regimens provided herein for efdamrofusp alfa include a loading phase and a maintenance phase, wherein the loading phase lasts 16 weeks (from Week 0 to Week 15) and the maintenance phase lasts at least 32 weeks (Week 20 to Week 52 or more) .
  • the loading phase lasts 16 weeks (from Week 0 to Week 15) and the maintenance phase lasts at least 32 weeks (Week 20 to Week 52 or more) .
  • four doses of efdamrofusp alfa are administered every four weeks, namely, at Week 0, Week 4, Week 8, and Week 12.
  • Week 20 8 weeks after last dosing of the loading phase
  • the subject is evaluated for the presence of DA.
  • efdamrofusp alfa is administered every eight weeks during the maintenance phase, starting from Week 20 (8 weeks after last dosing of the loading phase) , that is, administered at Week 20, Week 28, Week 36, and Week 44, and so on. If DA is not present at Week 20, then efdamrofusp alfa is administered every 12 weeks during the maintenance phase, starting from Week 24 (12 weeks after last dosing of the loading phase) . In some embodiments, efdamrofusp alfa is administered at Week 24, Week 36, and Week 48, and so on. In some embodiments, each dose has 6.4 mg or 8.0 mg efdamrofusp alfa.
  • DA is considered present at Week 20 if any of the following five criteria is met: (1) CST is increased by > 50 ⁇ m compared with the average CST of Week 8 and Week 12; (2) the CST is increased by ⁇ 75 ⁇ m compared with the lowest CST of Week 8 and Week 12; (3) the BCVA is lowered by ⁇ 5 letters compare to the average BCVA of Week 8 and Week 12 due to the progression of nAMD; (4) the BCVA is lowered by ⁇ 10 letters compare to the best BCVA of Week 8 and Week 12 due to the progression of nAMD; (5) occurrence of a new macular hemorrhage due to the progression of nAMD.
  • treatment regimens provided herein for efdamrofusp alfa include a loading phase and a maintenance phase, wherein the loading phase lasts 16 weeks (Week 0 to Week 16) and the maintenance phase lasts at least 24 weeks (Week 16 to Week 44 or more) .
  • the loading phase lasts 16 weeks (Week 0 to Week 16) and the maintenance phase lasts at least 24 weeks (Week 16 to Week 44 or more) .
  • three doses of efdamrofusp alfa are administered every four weeks, namely at Week 0, Week 4, and Week 8.
  • Week 16 (8 weeks from the last dose of the loading phase)
  • the subject is evaluated for the presence of DA. If DA is not present at Week 16, efdamrofusp alfa is administered every eight weeks during the maintenance phase, starting from Week 16 (8 weeks from the last dose of the loading phase) .
  • efdamrofusp alfa is administered at Week 16, Week 24, Week 32, Week 40, and Week 48, and so on (optionally also at one or more of Week 56, Week 64, Week 72, Week 80, Week 88, and Week 96) . If DA is not present at Week 16, then the subject is evaluated for the presence of DA at Week 20. If DA is present at Week 20, efdamrofusp alfa is administered every 12 weeks during the maintenance phase, starting from Week 20 (12 weeks from the last dose of the loading phase) .
  • efdamrofusp alfa is administered at Week 20, Week 32, and Week 44, and so on (optionally also at one or more of Week 56, Week 68, Week 80, and Week 92) . If DA is not present at Week 20, efdamrofusp alfa is administered every 16 weeks during the maintenance phase, starting from Week 24 (16 weeks from the last dose of the loading phase) . In some embodiments, efdamrofusp alfa is administered at Week 24, Week 40, and so on (optionally also at one or more of Week 56, Week 72, and Week 88) . In some embodiments, each dose has 8.0 mg efdamrofusp alfa.
  • DA is considered present at Week 16 if any of the following five criteria is met: (1) CST is increased by > 50 ⁇ m compared with the average CST of Week 8 and Week 12; (2) the CST is increased by ⁇ 75 ⁇ m compared with the lowest CST of Week 8 and Week 12; (3) the BCVA is lowered by ⁇ 5 letters compare to the average BCVA of Week 8 and Week 12 due to the progression of nAMD; (4) the BCVA is lowered by ⁇ 10 letters compare to the best BCVA of Week 8 and Week 12 due to the progression of nAMD; (5) occurrence of a new macular hemorrhage due to the progression of nAMD.
  • the dosing intervals for the maintenance phase can then be adjusted based on the presence or absence of DA.
  • DA is considered “present” if any of the following five criteria is met: (1) CST is increased by > 50 ⁇ m compared with the average CST of Week 12 and Week 16; (2) the CST is increased by ⁇ 75 ⁇ m compared with the lowest CST of Week 12 and Week 16; (3) the BCVA is lowered by ⁇ 5 letters compare to the average BCVA of Week 12 and Week 16 due to the progression of nAMD; (4) the BCVA is lowered by ⁇ 10 letters compare to the best BCVA of Week 12 and Week 16 due to the progression of nAMD; (5) occurrence of a new macular hemorrhage due to the progression of nAMD.
  • the dosing intervals for the maintenance phase can then be adjusted based on the presence or absence of DA.
  • Methods provided herein are useful in treating AMD (e.g., AMD) .
  • methods provided herein reduce or ameliorate a symptom of AMD in the treated subject.
  • methods provided herein improve visual acuity in the treated subject.
  • methods provided herein prevent decrease in visual acuity in the treated subject.
  • methods provided herein improve or restore the patient's vision for a prolonged period (e.g., at least six months, one year, two years, three years, or longer) .
  • methods provided herein reduce central retinal thickness in the treated subject.
  • methods provided herein prevent or reduce CNV and/or the area of leakage in the treated subject.
  • methods provided herein prevent or reduce retinal neovascularization (RNV) and/or the area of leakage in the treated subject. In some embodiments, methods provided herein prevent or reduce retinal fibrosis in the treated subject. In some embodiments, methods provided herein prevent or reduce GA in the treated subject.
  • RMV retinal neovascularization
  • methods provided herein prevent or reduce GA in the treated subject.
  • methods provided herein improve BCVA in the treated subject. In some embodiments, methods provided herein prevent decrease in BCVA in the treated subject. In some embodiments, methods provided herein increase BCVA by at least 0 ETDRS letters, at least 5 ETDRS letters, at least 10 ETDRS letters, at least 15 ETDRS letters, at least 20 ETDRS letters, at least 25 ETDRS letters, or at least 30 ETDRS letters in the treated subject. In some embodiments, methods provided herein increase BCVA by at least 0 ETDRS letters. In some embodiments, methods provided herein increase BCVA by at least 5 ETDRS letters. In some embodiments, methods provided herein increase BCVA by at least 10 ETDRS letters.
  • methods provided herein increase BCVA by at least 15 ETDRS letters. In some embodiments, methods provided herein increase BCVA by at least 20 ETDRS letters. In some embodiments, methods provided herein increase BCVA by at least 25 ETDRS letters. In some embodiments, methods provided herein increase BCVA by at least 30 ETDRS letters. In some embodiments, methods provided herein increase BCVA by at least 35 ETDRS letters.
  • methods provided herein increase BCVA by a range of about 0 to about 30 ETDRS letters. In some embodiments, methods provided herein increase BCVA by a range of about 5 to about 35 ETDRS letters. In some embodiments, methods provided herein increase BCVA by a range of about 5 to about 30 ETDRS letters. In some embodiments, methods provided herein increase BCVA by a range of about 5 to about 25 ETDRS letters. In some embodiments, methods provided herein increase BCVA by a range of about 5 to about 20 ETDRS letters. In some embodiments, methods provided herein increase BCVA by a range of about 5 to about 15 ETDRS letters. In some embodiments, methods provided herein increase BCVA by a range of about 10 to about 30 ETDRS letters.
  • methods provided herein increase BCVA by a range of about 10 to about 25 ETDRS letters. In some embodiments, methods provided herein increase BCVA by a range of about 10 to about 20 ETDRS letters. In some embodiments, methods provided herein increase BCVA by a range of about 10 to about 15 ETDRS letters. In some embodiments, methods provided herein increase BCVA by a range of about 15 to about 30 ETDRS letters. In some embodiments, methods provided herein increase BCVA by a range of about 15 to about 25 ETDRS letters. In some embodiments, methods provided herein increase BCVA by a range of about 15 to about 20 ETDRS letters.
  • methods provided herein increase 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, about or 35 letters. In some embodiments, methods provided herein increase BCVA by about 5 letters. In some embodiments, methods provided herein increase BCVA by about 10 letters. In some embodiments, methods provided herein increase BCVA by about 15 letters. In some embodiments, methods provided herein increase BCVA by about 20 letters. In some embodiments, methods provided herein increase BCVA by about 25 letters. In some embodiments, methods provided herein increase BCVA by about 30 letters.
  • methods provided herein result in BCVA of at least about 50 ETDRS letters, at least about 55 ETDRS letters, at least about 60 ETDRS letters, at least about 65 ETDRS letters, at least about 70 ETDRS letters, at least about 75 ETDRS letters, or at least about 80 ETDRS letters in the treated subject.
  • methods provided herein result in BCVA of at least about 55 ETDRS letters.
  • methods provided herein result in BCVA of at least about 60 ETDRS letters.
  • methods provided herein result in BCVA of at least about 65 ETDRS letters.
  • methods provided herein result in BCVA of at least about 69 ETDRS letters.
  • methods provided herein result in BCVA of at least about 70 ETDRS letters.
  • methods provided herein result in BCVA of at least about 72 ETDRS letters.
  • methods provided herein increase BCVA by more than 5%compared to baseline. In some embodiments, methods provided herein increase BCVA by more than 10%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 100%, more than 110%, more than 120%, more than 130%, more than 140%, more than 150%compared to baseline. In some embodiments, methods provided herein increase BCVA by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%about 160%, about 170%, about 180%, about 190%, or about 200%compared to baseline.
  • methods provided herein increase BCVA by about 20%compared to baseline. In some embodiments, methods provided herein increase BCVA by about 50%compared to baseline. In some embodiments, methods provided herein increase BCVA by about 80%compared to baseline. In some embodiments, methods provided herein increase BCVA by about 100%compared to baseline. In some embodiments, methods provided herein increase BCVA by about 150% compared to baseline. In some embodiments, methods provided herein increase BCVA by about 200%compared to baseline. In some embodiments, methods provided herein increase BCVA by 10%-200%, 10%-150%, 10%-100%, 20%-100%, 50%-100%, 60%-100%, 20%-80%, 30%-70%, 50%-70%, or 60%-70%compared to baseline. In some embodiments, methods provided herein increase BCVA by 50%-70%compared to baseline.
  • methods provided herein provide therapeutic benefit that can be measured anatomically using OCT (e.g., SD-OCT) .
  • OCT e.g., SD-OCT
  • methods provided herein decrease CST in the treated subject.
  • methods provided herein reduce or prevent occurrence of SHM in the treated subject.
  • methods provided herein reduce or prevent occurrence of IRF or SRF in the treated subject.
  • methods provided herein reduce or prevent occurrence of PED in the treated subject.
  • methods provided herein reduce RA area in the treated subject.
  • methods provided herein reduce or prevent occurrence of new RA in the treated subject.
  • methods provided herein reduce MA area in the treated subject.
  • methods provided herein reduce or prevent occurrence of new MA in the treated subject. In some embodiments, methods provided herein reduce or prevent occurrence of GA in the treated subject.
  • SHM, IRF, SFR, RA, MA, and GA can be detected by OCT (e.g., SD-OCT) .
  • methods provided herein decrease CST in the treated subject, as measured by OCT (e.g., SD-OCT) .
  • OCT e.g., SD-OCT
  • methods provided herein decrease CST by at least 25 ⁇ m, at least 50 ⁇ m, at least 75 ⁇ m, at least 100 ⁇ m, at least 125 ⁇ m, at least 150 ⁇ m, at least 175 ⁇ m, at least 200 ⁇ m, at least 225 ⁇ m, at least 250 ⁇ m, at least 275 ⁇ m, or at least 300 ⁇ m in the treated subject, as measured by OCT (e.g., SD-OCT) .
  • methods provided herein decrease CST by about 25 ⁇ m, about 50 ⁇ m, about 75 ⁇ m, about 100 ⁇ m, about 125 ⁇ m, about 150 ⁇ m, about 175 ⁇ m, about 200 ⁇ m, about 225 ⁇ m, about 250 ⁇ m, about 275 ⁇ m, or about 300 ⁇ m in the treated subject, as measured by OCT (e.g., SD-OCT) .
  • OCT e.g., SD-OCT
  • methods provided herein decrease CST by at least 25 ⁇ m.
  • methods provided herein decrease CST by about 50 ⁇ m.
  • methods provided herein decrease CST by about 75 ⁇ m.
  • methods provided herein decrease CST by about 100 ⁇ m.
  • methods provided herein decrease CST by about 125 ⁇ m. In some embodiments, methods provided herein decrease CST by about 150 ⁇ m. In some embodiments, methods provided herein decrease CST by about 175 ⁇ m. In some embodiments, methods provided herein decrease CST by about 200 ⁇ m.
  • methods provided herein decrease CST by a range of about 25 to about 150 ⁇ m, about 50 to about 150 ⁇ m, about 75 to about 150 ⁇ m, about 100 to about 150 ⁇ m, about 125 to about 150 ⁇ m, about 25 to about 200 ⁇ m, about 50 to about 200 ⁇ m, about 75 to about 200 ⁇ m, about 100 to about 200 ⁇ m, about 125 to about 200 ⁇ m, about 150 to about 200 ⁇ m, about 175 to about 200 ⁇ m, about 50 to about 300 ⁇ m, about 75 to about 300 ⁇ m, about 100 to about 300 ⁇ m, about 125 to about 300 ⁇ m, about 150 to about 300 ⁇ m, about 175 to about 300 ⁇ m, about 200 to about 300 ⁇ m, about 250 to about 300 ⁇ m, or about 25 to about 350 ⁇ m in the treated subject, as measured by OCT (e.g., SD-OCT) .
  • OCT e.g., SD-OCT
  • methods provided herein decrease CST by a range of about 50 to about 200 ⁇ m. In some embodiments, methods provided herein decrease CST by a range of about 100 to about 200 ⁇ m. In some embodiments, methods provided herein decrease CST by a range of about 50 to about 150 ⁇ m. In some embodiments, methods provided herein decrease CST by a range of about 100 to about 150 ⁇ m. In some embodiments, methods provided herein decrease CST by a range of about 125 to about 150 ⁇ m.
  • methods provided herein decrease CST by more than 5%compared to baseline. In some embodiments, methods provided herein decrease CST by more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, or more than 70%compared to baseline. In some embodiments, methods provided herein decrease CST by 10%-70%compared to baseline. In some embodiments, methods provided herein decrease CST by 10%-60%compared to baseline. In some embodiments, methods provided herein decrease CST by 30%-50%compared to baseline. In some embodiments, methods provided herein decrease CST by 40%-50%compared to baseline. In some embodiments, methods provided herein decrease 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.
  • methods provided herein reduce or prevent occurrence of SHM in the treated subject, as detected by OCT (e.g., SD-OCT) .
  • methods provided herein reduce or prevent occurrence of IRF in the treated.
  • methods provided herein reduce or prevent occurrence of SRF in the treated subject.
  • methods provided herein reduce or prevent occurrence of both IRF and SRF in the treated subject.
  • methods provided herein result in the presence of neither IRF nor SRF detectable by OCT (e.g., SD-OCT) .
  • methods provided herein reduce or prevent occurrence of IRF in fovea.
  • methods provided herein reduce or prevent occurrence of SRF in fovea.
  • methods provided herein reduce or prevent occurrence of both IRF and SRF in fovea.
  • the IRF and SRF can be detected by OCT (e.g., SD-OCT) .
  • methods provided herein reduce or prevent occurrence of PED in the treated subject as detected by OCT (e.g., SD-OCT) . In some embodiments, methods provided herein result in absence of PED detectable by OCT (e.g., SD-OCT) .
  • methods provided herein reduce or prevent occurrence of new MA in the treated subject, as detected by OCT (e.g., SD-OCT) . In some embodiments, methods provided herein delay or prevent occurrence of GA in the treated subject. In some embodiments, methods provided herein reduce MA area in the treated subject, as detected by OCT (e.g., SD-OCT) .
  • methods provided herein provide therapeutic benefit that can be measured anatomically using FFA or CFP.
  • methods provided herein reduce the CNV area in the treated subject.
  • methods provided herein reduce the CNV leakage area in the treated subject.
  • methods provided herein reduce the RNV area in the treated subject.
  • methods provided herein reduce the RNV leakage area in the treated subject.
  • the CNV/RNV area and CNV/RNV leakage area can be measured on FFA.
  • methods provided herein reduce or prevent retinal fibrosis in the treated subject.
  • methods provided herein decrease retinal fibrosis area in the treated subject.
  • methods provided herein decrease the diameter of the largest lesion in the treated subject.
  • methods provided herein decrease total lesion area in the treated subject. Retinal fibrosis and total lesion can be detected by CFP.
  • methods provided herein reduce the CNV area in the treated subject. In some embodiments, methods provided herein reduce the 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,
  • methods provided herein reduce the CNV area by about 0.5 mm 2 . In some embodiments, methods provided herein reduce the CNV area by about 1.0 mm 2 . In some embodiments, methods provided herein reduce the CNV area by about 2.0 mm 2 . In some embodiments, methods provided herein reduce the CNV area by about 3.0 mm 2 . In some embodiments, methods provided herein reduce the CNV area by about 4.0 mm 2 . In some embodiments, methods provided herein reduce the CNV area by about 5.0 mm 2 . In some embodiments, methods provided herein reduce the CNV area by about 6.0 mm 2 . In some embodiments, methods provided herein reduce the CNV area by about 7.0 mm 2 .
  • methods provided herein reduce the CNV area by about 8.0 mm 2 . In some embodiments, methods provided herein reduce the CNV area by about 9.0 mm 2 . In some embodiments, methods provided herein reduce the CNV area by about 10.0 mm 2 . In some embodiments, methods provided herein reduce the CNV area by 0.1-20 mm 2 . In some embodiments, methods provided herein reduce the CNV area by 0.2-5 mm 2 . In some embodiments, methods provided herein reduce the CNV area by 0.3-2 mm 2 .
  • methods provided herein reduce the CNV area by more than 5%compared to baseline. In some embodiments, methods provided herein decrease CNV area by more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, or more than 70%compared to baseline. In some embodiments, methods provided herein decrease CNV area by 10%-70%compared to baseline. In some embodiments, methods provided herein decrease CNV area by 10%-60%compared to baseline. In some embodiments, methods provided herein decrease CNV area by 30%-50%compared to baseline. In some embodiments, methods provided herein decrease CNV area by 40%-50%compared to baseline. In some embodiments, methods provided herein decrease 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 baseline.
  • methods provided herein reduce the CNV leakage area in the treated subject. In some embodiments, methods provided herein reduce the CNV leakage 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
  • methods provided herein reduce the CNV leakage area by about 1.0 mm 2 . In some embodiments, methods provided herein reduce the CNV leakage area by about 2.0 mm 2 . In some embodiments, methods provided herein reduce the CNV leakage area by about 3.0 mm 2 . In some embodiments, methods provided herein reduce the CNV leakage area by about 4.0 mm 2 . In some embodiments, methods provided herein reduce the CNV leakage area by about 5.0 mm 2 . In some embodiments, methods provided herein reduce the CNV leakage area by about 6.0 mm 2 . In some embodiments, methods provided herein reduce the CNV leakage area by about 7.0 mm 2 .
  • methods provided herein reduce the CNV leakage area by about 8.0 mm 2 . In some embodiments, methods provided herein reduce the CNV leakage area by about 9.0 mm 2 . In some embodiments, methods provided herein reduce the CNV leakage area by about 10.0 mm 2 . In some embodiments, methods provided herein reduce the CNV leakage area by 0.1-20 mm 2 . In some embodiments, methods provided herein reduce the CNV leakage area by 0.2-5 mm 2 . In some embodiments, methods provided herein reduce the CNV leakage area by 0.3-2 mm 2 .
  • methods provided herein reduce the CNV leakage area by more than 5%compared to baseline. In some embodiments, methods provided herein decrease CNV leakage area by more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, or more than 70%compared to baseline. In some embodiments, methods provided herein decrease CNV leakage area by 10%-70%compared to baseline. In some embodiments, methods provided herein decrease CNV leakage area by 10%-60%compared to baseline. In some embodiments, methods provided herein decrease CNV leakage area by 30%-50%compared to baseline.
  • methods provided herein decrease CNV leakage area by 40%-50%compared to baseline. In some embodiments, methods provided herein decrease CNV 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.
  • methods provided herein reduce the RNV area in the treated subject. In some embodiments, methods provided herein reduce the RNV 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,
  • methods provided herein reduce the RNV area by about 0.5 mm 2 . In some embodiments, methods provided herein reduce the RNV area by about 1.0 mm 2 . In some embodiments, methods provided herein reduce the RNV area by about 2.0 mm 2 . In some embodiments, methods provided herein reduce the RNV area by about 3.0 mm 2 . In some embodiments, methods provided herein reduce the RNV area by about 4.0 mm 2 . In some embodiments, methods provided herein reduce the RNV area by about 5.0 mm 2 . In some embodiments, methods provided herein reduce the RNV area by about 6.0 mm 2 . In some embodiments, methods provided herein reduce the RNV area by about 7.0 mm 2 .
  • methods provided herein reduce the RNV area by about 8.0 mm 2 . In some embodiments, methods provided herein reduce the RNV area by about 9.0 mm 2 . In some embodiments, methods provided herein reduce the RNV area by about 10.0 mm 2 . In some embodiments, methods provided herein reduce the RNV area by 0.1-20 mm 2 . In some embodiments, methods provided herein reduce the RNV area by 0.2-5 mm 2 . In some embodiments, methods provided herein reduce the RNV area by 0.3-2 mm 2 .
  • methods provided herein reduce the RNV area by more than 5%compared to baseline. In some embodiments, methods provided herein decrease RNV area by more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, or more than 70%compared to baseline. In some embodiments, methods provided herein decrease RNV area by 10%-70%compared to baseline. In some embodiments, methods provided herein decrease RNV area by 10%-60%compared to baseline. In some embodiments, methods provided herein decrease RNV area by 30%-50%compared to baseline. In some embodiments, methods provided herein decrease RNV area by 40%-50%compared to baseline. In some embodiments, methods provided herein decrease 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 baseline.
  • methods provided herein reduce the RNV leakage area in the treated subject. In some embodiments, methods provided herein reduce the RNV leakage 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
  • methods provided herein reduce the RNV leakage area by about 1.0 mm 2 . In some embodiments, methods provided herein reduce the RNV leakage area by about 2.0 mm 2 . In some embodiments, methods provided herein reduce the RNV leakage area by about 3.0 mm 2 . In some embodiments, methods provided herein reduce the RNV leakage area by about 4.0 mm 2 . In some embodiments, methods provided herein reduce the RNV leakage area by about 5.0 mm 2 . In some embodiments, methods provided herein reduce the RNV leakage area by about 6.0 mm 2 . In some embodiments, methods provided herein reduce the RNV leakage area by about 7.0 mm 2 .
  • methods provided herein reduce the RNV leakage area by about 8.0 mm 2 . In some embodiments, methods provided herein reduce the RNV leakage area by about 9.0 mm 2 . In some embodiments, methods provided herein reduce the RNV leakage area by about 10.0 mm 2 . In some embodiments, methods provided herein reduce the RNV leakage area by 0.1-20 mm 2 . In some embodiments, methods provided herein reduce the RNV leakage area by 0.2-5 mm 2 . In some embodiments, methods provided herein reduce the RNV leakage area by 0.3-2 mm 2 .
  • methods provided herein reduce the RNV leakage area by more than 5%compared to baseline. In some embodiments, methods provided herein decrease RNV leakage area by more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, or more than 70%compared to baseline. In some embodiments, methods provided herein decrease RNV leakage area by 10%-70%compared to baseline. In some embodiments, methods provided herein decrease RNV leakage area by 10%-60%compared to baseline. In some embodiments, methods provided herein decrease RNV leakage area by 30%-50%compared to baseline.
  • methods provided herein decrease RNV leakage area by 40%-50%compared to baseline. In some embodiments, methods provided herein decrease RNV 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.
  • methods provided herein reduce the retinal leakage area by more than 5%compared to baseline. In some embodiments, methods provided herein decrease retinal leakage area by more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, or more than 70%compared to baseline. In some embodiments, methods provided herein decrease retinal leakage area by 10%-70%compared to baseline. In some embodiments, methods provided herein decrease retinal leakage area by 10%-60%compared to baseline. In some embodiments, methods provided herein decrease retinal leakage area by 30%-50%compared to baseline.
  • methods provided herein decrease retinal leakage area by 40%-50%compared to baseline. In some embodiments, methods provided herein decrease 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.
  • methods provided herein reduce the total lesion area in the treated subject. In some embodiments, methods provided herein reduce the total lesion area by about 0.1 mm 2 , about 0.2 mm 2 , about 0.5 mm 2 , about 0.8 mm 2 , about 1.0 mm 2 , about 1.2 mm 2 , about 1.5 mm 2 , about 1.8 mm 2 , about 2.0 mm 2 , about 2.2 mm 2 , about 2.5 mm 2 , about 2.8 mm 2 , about 3.0 mm 2 , about 3.2 mm 2 , about 3.5 mm 2 , about 3.8 mm 2 , about 4.0 mm 2 , about 4.2 mm 2 , about 4.5 mm 2 , about 4.8 mm 2 , or about 5.0 mm 2 in the treated subject.
  • methods provided herein reduce the total lesion area by about 0.5 mm 2 . In some embodiments, methods provided herein reduce the total lesion area by about 1.0 mm 2 . In some embodiments, methods provided herein reduce the total lesion area by about 2.0 mm 2 . In some embodiments, methods provided herein reduce the total lesion area by about 3.0 mm 2 . In some embodiments, methods provided herein reduce the total lesion area by about 4.0 mm 2 . In some embodiments, methods provided herein reduce the total lesion area by about 5.0 mm 2 .
  • methods provided herein reduce retinal fibrosis in the treated subject, as detected by CFP. In some embodiments, methods provided herein reduce retinal fibrosis area in the treated subject, as measured by CFP. In some embodiments, methods provided herein reduce the diameter of the largest lesion in the treated subject, as measured by CFP. In some embodiments, methods provided herein reduce total lesion area in the treated subject, as measured by CFP.
  • methods provided herein result in an improvement in vision-related quality of life in the treated subject. In some embodiments, methods provided herein result in an improvement in the NEI-VFQ-25 total score in the treated subject.
  • methods disclosed herein result in one or more of the following effects in the treated subject: (1) increase in BCVA score; (2) decrease in occurrence of IRF or SRF in macular fovea detectable on OCT; (3) decrease in CST as measured by OCT; (4) decrease in occurrence of PED detectable on OCT; (5) decrease in occurrence of new MA detectable on OCT; (6) decrease in MA area as detected on OCT; (7) decrease in occurrence of GA detectable on OCT; (8) decrease in retinal fibrosis detectable on CFP; (9) decrease in CNV area as measured by FFA; (10) decrease in CNV leakage area as measured by FFA; (11) decrease in total lesion area as measured by FFA; and (12) increase in NEI-VFQ-25 total score.
  • methods provided herein result in (1) increase in BCVA score and (2) decrease in occurrence of IRF or SRF in macular fovea detectable on OCT in the treated subject. In some embodiments, the methods provided herein further (3) decrease in CST as measured by OCT.
  • methods provided herein result in one or more of the following effects.
  • Reduction in CST by more than 25 ⁇ m compared to baseline such as a reduction of 25-350 ⁇ m, 50-300 ⁇ m, 50-200 ⁇ m, such as a reduction of 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, or 350 ⁇ m, or a reduction of more than 5%compared to baseline, such as 10%-70%, 10%-60%, 30%-50%, 40%-50%, such as 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70%.
  • Reduction in the CNV area by more than 0.1 mm 2 compared to baseline such as a reduction of 0.1-20 mm 2 , 0.2-5 mm 2 , 0.3-2 mm 2 , for example, 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 by more than 5%
  • Reduction in the area of retinal leakage by more than 5%compared to baseline such as a reduction of 10%-70%, 10%-60%, 30%-50%, 40%-50%, for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 80%, 90%, or 100%.
  • the methods disclosed herein achieve one or more of the above-described therapeutic benefits in 12 or less weeks, 16 or less weeks, 20 or less weeks, 24 or less weeks, 28 or less weeks, 32 or less weeks, 36 or less weeks, 40 or less weeks, 44 or less weeks, 48 or less weeks, 52 or less weeks, 56 or less weeks, 60 or less weeks, 64 or less weeks, 68 or less weeks, 72 or less weeks, 76 or less weeks, 80 or less weeks, 84 or less weeks, 88 or less weeks, 92 or less weeks, 96 or less weeks, or 100 or less weeks after initiating treatment.
  • the methods disclosed herein achieve one or more of the above-described therapeutic benefits 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, about or 100 weeks after initiating treatment. In some embodiments, the methods disclosed herein achieve one or more of the above-described therapeutic benefits in about 44 weeks after initiating treatment. In some embodiments, the methods disclosed herein achieve one or more of the above-described therapeutic benefits in about 48 weeks after initiating treatment.
  • the methods disclosed herein achieve one or more of the above-described therapeutic benefits in about 52 weeks after initiating treatment. In some embodiments, the methods disclosed herein achieve one or more of the above-described therapeutic benefits in about 96 weeks after initiating treatment. In some embodiments, the methods disclosed herein achieve one or more of the above-described therapeutic benefits in about 100 weeks after initiating treatment.
  • the therapeutic effects can last for an extended period of time after the last treatment. In some embodiments, the therapeutic effects can last 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, at least 48 weeks after the last treatment. In some embodiments, the therapeutic effects can last at least 8 weeks after treatment. In some embodiments, the therapeutic effects can last at least 12 weeks after treatment. In some embodiments, the therapeutic effects can last at least 24 weeks after treatment. In some embodiments, the therapeutic effects can last at least 36 weeks after treatment. In some embodiments, the therapeutic effects can last at least 48 weeks after treatment.
  • the bispecific fusion protein e.g., efdamrofusp alfa
  • pharmaceutical compositions disclosed herein can be used for treating DME.
  • methods of treating DME in a subject in need thereof comprising administering to the subject a therapeutically effective amount of efdamrofusp alfa.
  • the subject can be a human. In some embodiments, the subject can have DME. In some embodiments, the subject can be at risk of developing DME. In some embodiments, the subject can have one “diseased eye, ” namely, the eye diagnosed with DME. In some embodiments, the subject can have two diseased eyes.
  • treating “asubject” is equivalent to treating “the diseased eye (or eyes) of the subject” ; characterization of “the treated subject” (e.g., BCVA score, presence of active CNV, GA, etc.
  • the diseased eye (eyes) of the treated subject is assessed in “the diseased eye (eyes) of the treated subject” ; and characterization of the efficacy of treatment (e.g., improvement in B CVA, reduction in CNV, etc. ) in “the treated subject” is also in assessed in “the diseased eye (eyes) of the treated subject. ”
  • the subject to be treated is at least 18 years old. In some embodiments, the subject is at least 30 years old. In some embodiments, the subject is at least 40 years old. In some embodiments, the subject is at least 45 years old. In some embodiments, the subject is at least 50 years old. In some embodiments, the subject is at least 55 years old. In some embodiments, the subject is at least 60 years old. In some embodiments, the subject has been newly diagnosed with DME. In some embodiments, the subject has been diagnosed with DME for up to 1 month. In some embodiments, the subject has been diagnosed with DME for up to 12 years. In some embodiments, the subject has been diagnosed with DME for, for example, 1 month to 12 years, such as six months, 1 year, 3 years, 5 years, 8 years, 12 years, or longer.
  • provided herein are uses of efdamrofusp alfa in the treatment of DME. In some embodiments, provided here are uses of efdamrofusp alfa in the manufacture of a medicament for treating DME.
  • the pharmaceutical compositions provided herein can be administered alone or in combination with an additional therapeutic agent for DME.
  • efdamrofusp alfa is used alone in the treatment.
  • efdamrofusp alfa is used in a combination therapy with an additional therapy, such as laser therapy.
  • the additional therapy can be focal laser therapy. Laser photocoagulation can reduce vision loss and increase the recovery rate of DME.
  • fusion proteins disclosed herein e.g., efdamrofusp alfa
  • the subject having DME can have one or more of the following symptoms: blurred or distorted vision, floaters, double vision, central vision loss, dark areas in vision, difficult in night vision, and the like.
  • the subjects to be treated by methods disclosed herein have DME.
  • the subjects have center-involved DME (CI-DME) , which can be detected and quantified by OCT.
  • DME can be focal DME or diffuse DME.
  • Focal DME is characterized by specific areas of isolated and significant leakage in the macula with adequate blood flow. Diffuse DME is caused by leakage from the entire capillary bed around the macula due to disruption of the inner blood-retinal barrier.
  • the subjects can have focal DME.
  • the subjects can have diffuse DME.
  • the subjects to be treated by methods disclosed herein have CSME.
  • the subjects are non-CSME based on clinical examination.
  • the BCVA of the diseased eye in the subject to be treated by methods described herein is less than 82 ETDRS letters. In some embodiments, the BCVA of the subject is no more than 81 ETDRS letters. In some embodiments, the BCVA of the subject is no more than 80 ETDRS letters. In some embodiments, the BCVA of the subject is no more than 79 ETDRS letters. In some embodiments, the BCVA of the subject is no more than 78 ETDRS letters. In some embodiments, the BCVA of the subject is no more than 77 ETDRS letters. In some embodiments, the BCVA of the subject is no more than 76 ETDRS letters. In some embodiments, the BCVA of the subject is no more than 75 ETDRS letters.
  • the BCVA of the subject is no more than 74 ETDRS letters. In some embodiments, the BCVA of the subject is no more than 73 ETDRS letters. In some embodiments, the BCVA of the subject is no more than 72 ETDRS letters. In some embodiments, the BCVA of the subject is no more than 71 ETDRS letters. In some embodiments, the BCVA of the subject is no more than 70 ETDRS letters. In some embodiments, the BCVA of the diseased eye in the subject to be treated by methods described herein is at least 18 ETDRS letters. In some embodiments, the BCVA of the subject is at least 19 ETDRS letters. In some embodiments, the BCVA of the subject is at least 20 ETDRS letters.
  • the BCVA of the subject is at least 21 ETDRS letters. In some embodiments, the BCVA of the subject is at least 22 ETDRS letters. In some embodiments, the BCVA of the subject is at least 23 ETDRS letters. In some embodiments, the BCVA of the subject is at least 24 ETDRS letters. In some embodiments, the BCVA of the subject is at least 25 ETDRS letters.
  • the BCVA of the diseased eye in the subject to be treated by methods described herein ranges between 19 to 78 ETDRS letters (inclusive of both end values) . In some embodiments, the BCVA of the diseased eye in the subject to be treated by methods described herein ranges between 24 to 73 ETDRS letters (inclusive of both end values) . In some embodiments, the BCVA of the diseased eye in the subject to be treated by methods described herein ranges between 24 to 78 ETDRS letters (inclusive of both end values) . In some embodiments, the subject has BCVA of at least 64. In some embodiments, the subject has BCVA of no more than 63.
  • the BCVA of the diseased eye in the subject to be treated by methods described herein ranges between 19 to 63 ETDRS letters (inclusive of both end values) . In some embodiments, the BCVA of the diseased eye in the subject to be treated by methods described herein ranges between 24 to 63 ETDRS letters (inclusive of both end values) . In some embodiments, the BCVA of the diseased eye in the subject to be treated by methods described herein ranges between 64 to 78 ETDRS letters (inclusive of both end values) . In some embodiments, the BCVA of the diseased eye in the subject to be treated by methods described herein ranges between 64 to 73 ETDRS letters (inclusive of both end values) .
  • the BCVA of the diseased eye in the subject to be treated by methods described herein ranges between 50 to 73 ETDRS letters (inclusive of both end values) . In some embodiments, the BCVA of the diseased eye in the subject to be treated by methods described herein ranges between 30 to 65 ETDRS letters (inclusive of both end values) . In some embodiments, the BCVA of the diseased eye in the subject to be treated by methods described herein ranges between 24 to 50 ETDRS letters (inclusive of both end values) .
  • the CST in the diseased eye in the subject to be treated by methods disclosed herein is at least 250 ⁇ m, at least 280 ⁇ m, at least 300 ⁇ m, of at least 325 ⁇ m as measured by SD-PCT. In some embodiments, the CST in the diseased eye in the subject to be treated by methods disclosed herein is at least 280 ⁇ m as measured by SD-PCT.
  • the subjects to be treated with the methods disclosed herein have previously been treated with an anti-VEGF treatment.
  • Approved anti-VEGF medications for the treatment for DME include, for example, ranibizumab, bevacizumab, aflibercept, brolucizumab, and faricimab-svoa.
  • the subjects to be treated with the methods disclosed herein have not previously been treated with an anti-VEGF treatment.
  • the subjects to be treated with the methods disclosed herein have previously been treated with ranibizumab.
  • the subjects to be treated with the methods disclosed herein have previously been treated with bevacizumab.
  • the subjects to be treated with the methods disclosed herein have previously been treated with aflibercept. In some embodiments, the subjects to be treated with the methods disclosed herein have previously been treated with brolucizumab. In some embodiments, the subjects to be treated with the methods disclosed herein have previously been treated with faricimab-svoa.
  • the subjects to be treated with methods disclosed herein have not ever received, or have not received within 30 days, 90 days, or 120 days before the start of the treatment disclosed herein, any of the following prior treatments: anti-complement drug treatment, retinal grid laser or panretinal photocoagulation, laser posterior capsulotomy, intraocular or periocular corticosteroid injections.
  • the subjects to be treated with methods disclosed herein have not undergone vitreoretinal surgery.
  • the subjects to be treated with methods disclosed herein are in the stage of moderate NPDR, severe NPDR, or PDR.
  • the subjects to be treated with methods disclosed herein have mild to moderate NPDR without DME, and the treatment prevents the occurrence of DME.
  • the subjects to be treated with methods disclosed herein have severe NPDR with DME.
  • the subjects to be treated with methods disclosed herein have non-high-risk PDR with DME, and the method treats DME.
  • High-risk PDR is defined as having any 3 of the following 4 characteristics: (1) neovascularization (any location) ; (2) neovascularization on or near the optic disc; (3) at least moderate neovascularization, i.e., within one disc diameter, neovascularization covering more than 1/4 to 1/3 of the disc area, or elsewhere, neovascularization covering at least half of the disc area; (4) vitreous or peripheral retinal hemorrhage.
  • the subjects to be treated with methods disclosed herein have not received with at least 1 month, at least 2 months, or at least 3 months before the start of the treatment disclosed herein, an anti-diabetic drug. In some embodiments, the subjects to be treated with methods disclosed herein do not concurrently receive anti-diabetic drug.
  • the anti-diabetic drug can be an oral or in. jectable medication.
  • the subjects to be treated with methods disclosed herein do not have any of the following symptoms: high-risk PDR, fibrosis or atrophy involving the macular center, or retinal hemorrhage involving more than two disc areas and affecting the central fovea.
  • the subjects to be treated by methods disclosed herein have the following characteristics: (a) visual impairment caused by DME involving the central fovea; (b) CST of at least 280 ⁇ m as measured by SD-OCT; and (c) BCVA between 24 and 73 ETDRS letters in the diseased eye.
  • compositions disclosed herein containing a fusion protein disclosed herein can be administered to a subject in need thereof to treat DME.
  • the pharmaceutical compositions disclosed herein are administered locally.
  • the pharmaceutical compositions disclosed herein are administered topically.
  • the pharmaceutical compositions disclosed herein are administered intralesionally.
  • the pharmaceutical compositions disclosed herein are administered intravenously.
  • the pharmaceutical compositions containing a fusion protein disclosed herein are administered directly to an eye or ocular tissue.
  • This administration can be achieved through various methods, including topical application to the eye or injection into the eye or associated tissues.
  • Injection methods include, but are not limited to, intravitreal injection, periocular injection, subretinal injection, transscleral injection, subscleral injection, intrachoroidal injection, anterior chamber injection, subconjunctival injection, subtenon injection, retrobulbar injection, peribulbar injection, posterior juxtascleral delivery, or periscleral delivery of the liquid composition.
  • the pharmaceutical composition can be administered to areas such as the vitreous, optic nerve, aqueous humor, sclera, conjunctiva, the area between the sclera and conjunctiva, retinal-choroidal tissue, macula, or other regions in or near the eye.
  • the pharmaceutical compositions disclosed herein are administered by intravitreal injection.
  • the fusion protein disclosed herein e.g., efdamrofusp alfa
  • intravitreal injection is administered by intravitreal injection.
  • treatment regimens comprising administering multiple doses of a pharmaceutical composition disclosed herein that comprises a therapeutically effective amount of efdamrofusp alfa.
  • the therapeutically effective amount for a single dose 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.
  • the therapeutically effective amount can be 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, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5.0 mg, 5.1 mg, 5.2 mg
  • the therapeutically effective amount of efdamrofusp alfa can range between about 1.0 mg and about 8.0 mg. In some embodiments, the therapeutically effective amount for a single dose of efdamrofusp alfa can range between about 2.0 mg and about 8.0 mg. In some embodiments, the therapeutically effective amount for a single dose of efdamrofusp alfa can be about 2.0 mg. In some embodiments, the therapeutically effective amount for a single dose of efdamrofusp alfa can be about 3.2 mg. In some embodiments, the therapeutically effective amount for a single dose of efdamrofusp alfa can be about 4.0 mg.
  • the therapeutically effective amount for a single dose of efdamrofusp alfa can be about 6.4 mg. In some embodiments, the therapeutically effective amount for a single dose of efdamrofusp alfa can be about 8.0 mg. As used herein, the specified dosage, for example, 1.0-8.0 mg, indicates the amount administered per eye.
  • efdamrofusp alfa is administered by intravitreal injection.
  • the injection volume can range from 0.01 mL to 0.1 mL. In some embodiments, the injection volume can range from 0.04 mL to 0.08 mL. In some embodiments, the injection volume can be about 0.04 mL, 0.08 mL, or 0.1 mL. In some embodiments, the injection volume can be about 0.1 mL.
  • the multiple doses of the pharmaceutical compositions disclosed herein can be administered at different dosing intervals, for example, about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once every five weeks, about once every six weeks, about once every seven weeks, about once every eight weeks, about once every nine weeks, about once every ten weeks, about once every eleven weeks, about once every 12 weeks, about once every 13 weeks, about once every 14 weeks, about once every 15 weeks, or about once every 16 weeks.
  • pharmaceutical compositions disclosed herein can be administered at a dosing interval that ranges from about once every four weeks to about once every 16 weeks.
  • pharmaceutical compositions disclosed herein can be administered about once every four weeks.
  • pharmaceutical compositions disclosed herein can be administered about once every eight weeks.
  • pharmaceutical compositions disclosed herein can be administered about once every 12 weeks.
  • pharmaceutical compositions disclosed herein can be administered about once every 16 weeks.
  • compositions disclosed herein comprising the fusion protein can be administered in two phases, namely, a loading phase and a maintenance phase.
  • the term “loading phase” refers to the treatment phase where the fusion protein (e.g., efdamrofusp alfa) is administered to induce the desired therapeutic effect, such as clinical remission, clinical response, OCT remission, OCT resolution, and/or symptomatic relief.
  • the desired therapeutic effect can be vision improvement and/or macular structural improvement.
  • the desired therapeutic effect is for the subject to achieve stable vision and/or lesion stabilization.
  • the therapeutic effect is the improvement of vision and/or anatomical structure as seen on OCT.
  • the therapeutic effect is the improvement of CST and/or BCVA.
  • the dose at which the fusion protein is administered during loading phase is referred to as the “loading dose. ”
  • the length of the loading treatment period can be, for example, 4, 8, or 12 weeks.
  • Patient evaluations can be conducted 1 week, 4 weeks, or 8 weeks after the last loading dose.
  • a single or multiple “loading doses” can be administered.
  • multiple doses are administered at a fixed interval during the loading phase, referred to as the “loading interval. ”
  • the term “maintenance phase” or “on-demand phase” refers to the treatment phase following the loading phase, during which the fusion protein (e.g., efdamrofusp alfa) is administered at the dose and interval as determined by the patient's condition to maintain the desired therapeutic effect.
  • the dose at which the fusion protein is administered during loading phase is referred to as the “maintenance dose, ” which can be the same or different from the loading dose.
  • a single or multiple “maintenance doses” can be administered. In some embodiments, multiple doses are administered at certain interval during the maintenance phase, referred to as the “maintenance interval. ”
  • the loading phase consists of the first two to eight weeks of a treatment regimen. In some embodiments, the loading phase consists of the first four to 16 weeks of a treatment regimen. In some embodiments, the loading phase consists of the first eight to 16 weeks of a treatment regimen. In some embodiments, the loading phase consists of the first 12 to 16 weeks of a treatment regimen. In some embodiments, the loading phase consists of the first eight weeks. In some embodiments, the loading phase consists of the first 12 weeks. In some embodiments, the loading phase consists of the first 16 weeks.
  • compositions disclosed herein comprising the fusion protein can be administered at a dosing interval of about once every three to five weeks during the loading phase.
  • pharmaceutical compositions disclosed herein can be administered about once every four weeks during the loading phase.
  • the loading phase can include two to four doses of pharmaceutical compositions disclosed herein, administered at a dosing interval of about once every three to five weeks.
  • the loading phase can include at least two doses of pharmaceutical compositions disclosed herein, administered at a dosing interval of about once every three to five weeks.
  • the loading phase can include three doses of pharmaceutical compositions disclosed herein, administered at a dosing interval of about once every three to five weeks. In some embodiments, the loading phase can include four doses of pharmaceutical compositions disclosed herein, administered at a dosing interval of about once every three to five weeks. In some embodiments, the loading phase can include three doses of pharmaceutical compositions disclosed herein, administered at a dosing interval of about once every four weeks. In some embodiments, the loading phase can include four doses of pharmaceutical compositions disclosed herein, administered at a dosing interval of about once every four weeks.
  • methods provided herein comprise a loading phase which consists of the first eight to 16 weeks of treatment, in which two to four doses pharmaceutical compositions disclosed herein are administered at a dosing interval of about once every three to five weeks. In some embodiments, methods provided herein comprise a loading phase which consists of the first eight weeks of treatment, in which three doses pharmaceutical compositions disclosed herein are administered at a dosing interval of about once every four weeks. In some embodiments, methods provided herein comprise a loading phase which consists of the first 12 weeks of treatment, in which four doses pharmaceutical compositions disclosed herein are administered at a dosing interval of about once every four weeks.
  • the loading phase can last longer than 12 weeks. In some embodiments, the loading phase can last 4 months, 5 months, 6 months, or 7 months, with the fusion protein administered once or twice a month. In some embodiments, the fusion protein is administered once a month.
  • each single dose of the fusion protein (e.g., efdamrofusp 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.
  • each single loading dose can be 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, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5.0 mg, 5.1 mg, 5.2 mg,
  • each single loading dose of efdamrofusp alfa can range between about 1.0 mg and about 8.0 mg. In some embodiments, each single loading dose of efdamrofusp alfa can range between about 2.0 mg and about 8.0 mg. In some embodiments, each single loading dose of efdamrofusp alfa can be about 2.0 mg. In some embodiments, each single loading dose of efdamrofusp alfa can be about 3.2 mg. In some embodiments, each single loading dose of efdamrofusp alfa can be about 4.0 mg. In some embodiments, each single loading dose of efdamrofusp alfa can be about 6.4 mg. In some embodiments, each single loading dose of efdamrofusp alfa can be about 8.0 mg. As used herein, the specified dosage, for example, 1.0-8.0 mg, indicates the amount administered per eye.
  • the maintenance phase (i.e., on-demand phase) follows the loading phase and aims to sustain the therapeutic effect achieved during the loading phase, with the goal being providing ongoing management and control of the condition or symptoms with a less frequent, more sustainable dosage.
  • the fusion protein disclosed herein e.g., efdamrofusp alfa
  • the fusion protein disclosed herein can be administered as needed as determined by assessing the treated eye after the last dosing of the loading phase.
  • at least one dose of the fusion protein is administered during the maintenance phase.
  • multiple doses of the fusion protein are administered during the maintenance phase.
  • the pharmaceutical compositions disclosed herein comprising the fusion protein can be administered at a dosing interval of about once every four to 16 weeks during the maintenance phase.
  • pharmaceutical compositions disclosed herein can be administered at a dosing interval of about once every six weeks, about once every seven weeks, about once every eight weeks, about once every nine weeks, about once every ten weeks, about once every eleven weeks, about once every 12 weeks, about once every 13 weeks, about once every 14 weeks, about once every 15 weeks, or about once every 16 weeks during the maintenance phase.
  • pharmaceutical compositions disclosed herein can be administered about once every eight weeks during the maintenance phase.
  • compositions disclosed herein can be administered about once every 12 weeks during the maintenance phase. In some embodiments, pharmaceutical compositions disclosed herein can be administered about once every 16 weeks during the maintenance phase.
  • the dosing interval can also be adjusted as needed during the maintenance phase. In some embodiments, the dosing interval is adjusted based on the assessment of the treated eye during follow-up visits.
  • the maintenance phase comprises 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.
  • methods provided herein comprise a maintenance phase comprising at least 24 weeks of treatment, in which pharmaceutical compositions disclosed herein are administered at a dosing interval of about once every eight weeks, about once every 12 weeks, or about once every 16 weeks. In some embodiments, pharmaceutical compositions disclosed herein are administered about once every eight weeks during the maintenance phase. In some embodiments, pharmaceutical compositions disclosed herein are administered about once every 12 weeks during the maintenance phase. In some embodiments, pharmaceutical compositions disclosed herein are administered about once every 16 weeks during the maintenance phase.
  • each single dose of the fusion protein (e.g., efdamrofusp 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.
  • each single maintenance dose can be 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, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5.0 mg, 5.1 mg, 5.2 mg,
  • each single maintenance dose of efdamrofusp alfa can range between about 1.0 mg and about 8.0 mg. In some embodiments, each single maintenance dose of efdamrofusp alfa can range between about 2.0 mg and about 8.0 mg. In some embodiments, each single maintenance dose of efdamrofusp alfa can be about 2.0 mg. In some embodiments, each single maintenance dose of efdamrofusp alfa can be about 3.2 mg. In some embodiments, each single maintenance dose of efdamrofusp alfa can be about 4.0 mg. In some embodiments, each single maintenance dose of efdamrofusp alfa can be about 6.4 mg. In some embodiments, each single maintenance dose of efdamrofusp alfa can be about 8.0 mg. As used herein, the specified dosage, for example, 1.0-8.0 mg, indicates the amount administered per eye.
  • the single dose amount remains unchanged across the entire treatment, including both the loading phase and the maintenance phase. In some embodiments, the single dose amount is changed during the treatment. In some embodiments, the single dose amount remains unchanged during the loading phase and during the maintenance phase, but is adjusted between the loading phase and the maintenance phase.
  • each single dose amount remains unchanged across the entire treatment, which range between about 1.0 mg and about 8.0 mg.
  • each single dose during the entire treatment can be about 2.0 mg.
  • each single dose during the entire treatment can be about 3.2 mg.
  • each single dose during the entire treatment can be about 4.0 mg.
  • each single dose during the entire treatment can be about 6.4 mg.
  • each single dose during the entire treatment can be about 8.0 mg.
  • methods provided herein comprise assessing the subject that has completed the loading phase for disease progression and responsiveness for treatment, and the results of the assessment are used to determine the specific regimen for the maintenance phase.
  • the assessment can be conducted about six to about ten weeks after the last dosing of the loading phase. In some embodiments, the assessment can be conducted about eight weeks after the last dosing of the loading phase.
  • methods provided herein comprise conducting one assessment. In some embodiments, methods provided herein comprise conducting two assessments that are about two to about six weeks apart. In some embodiments, the two assessments can be conducted four weeks apart.
  • the interval between the last dose of the loading phase and the first dose of the maintenance phase is the same as the dosing interval of the maintenance phase.
  • methods provided herein include follow-up assessments during both the loading and on-demand treatment phases to monitor the patient's condition and/or treatment responsiveness.
  • the assessments can include one or more of the following: (1) measuring changes in BCVA from baseline using the ETDRS chart; for example, number of ETDRS letters gained from baseline, e.g., ⁇ 0, 5, 10, or 15 letters; number of ETDRS letters lost from baseline, e.g., ⁇ 0, 5, 10, or 15 letter; (2) measuring changes in CST from baseline using SD-OCT; for example, CST reduction, e.g., ⁇ 50 ⁇ m or ⁇ 75 ⁇ m, or ⁇ 0%, 10%, or 20%; CST increase, e.g., ⁇ 50 ⁇ m or ⁇ 75 ⁇ m, or ⁇ 0%, 10%, or 20%; (3) assessing improvements in the Diabetic Retinopathy Severity Score (DRSS) from baseline, e.g., improvements by ⁇ 1, ⁇ 2, or ⁇ 3 levels.
  • DRSS Diabetic Re
  • follow-up assessments are conducted about one week after each administration of the fusion protein (e.g., efdamrofusp alfa) during the loading treatment phase. In some embodiments, follow-up assessments are conducted about two weeks after each administration of the fusion protein (e.g., efdamrofusp alfa) during the loading treatment phase. In some embodiments, follow-up assessments are conducted every four weeks during the on-demand treatment phase.
  • the fusion protein e.g., efdamrofusp alfa
  • follow-up assessments are conducted every four weeks during the on-demand treatment phase.
  • methods provided herein include (a) a loading phase, during which the fusion protein (e.g., efdamrofusp alfa) is administered intravitreally at a loading dose with multiple consecutive doses at a loading interval until the desired therapeutic effect is achieved; (b) evaluation after a first follow-up interval (e.g., one week after each loading dose) , including determining if the desired therapeutic effect has been achieved by, for example, measuring BCVA changes (number of ETDRS letters gained from baseline e.g., ⁇ 0, 5, 10, or 15 letters; number of ETDRS letters lost from baseline, e.g., ⁇ 0, 5, 10, or 15 letters) and CST changes (reduction in values or percentages, e.g., ⁇ 50 ⁇ m or ⁇ 75 ⁇ m, or ⁇ 0%, 10%, or 20%; increase in values or percentages, e.g., ⁇ 50 ⁇ m or ⁇ 75 ⁇ m, or ⁇ 0%, 10%, or 20%) , and
  • follow-up assessments are conducted to determine whether the subjects meet the criteria for re-treatment.
  • the term “re-treat” or its grammatically equivalent terms means that a patient is initially assessed and determined not to require further drug administration at one or more follow-up assessment during the maintenance phase. However, at a subsequent assessment, it is determined that the therapeutic effect has diminished or that the disease has progressed, necessitating additional treatment.
  • the re-treatment criteria include: decrease in BCVA by ⁇ 5 letters or increase in CST by >50 ⁇ m from the previous visit.
  • step (c) post-loading phase evaluation
  • maintenance dosing can include multiple treatment cycles, each independently including: assessing changes in the patient's condition (e.g., BCVA and/or CST changes) after a second follow-up interval and administering maintenance doses based on assessment.
  • maintenance dosing continues until the lesion regresses (e.g., DME regression) and/or the patient's vision returns to normal. Maintenance dosing can continue for at least 1 year, 2 years, 3 years, 4 years, 5 years, or longer, or until the disease progresses.
  • 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 methods can include administering multiple doses during the loading phase at a fixed loading interval, such as once every 4 weeks.
  • Maintenance phase can also include administering multiple doses at maintenance intervals, which can be the same or different.
  • the maintenance interval can be the same as or longer than the loading interval, for example, once every 4 weeks, once every 8 weeks, once every 12 weeks, once every 16 weeks, once every 20 weeks, once every 24 weeks, or longer.
  • the methods provided herein include selecting the therapeutic dose and/or treatment interval of the fusion protein during the loading and/or maintenance phases to improve or maintain vision and/or improve or maintain macular anatomy, in order to avoid overtreatment and undertreatment.
  • the loading phase e.g., monthly dosing for 2, 3, 4, 5, or 6 months
  • maintenance dosing is administered.
  • the treatment interval is adjusted based on the assessment of the condition, for example, based on changes in BCVA or CST.
  • the initial follow-up interval can be 4 weeks or 8 weeks. If two consecutive follow-ups show stable patient condition (e.g., stable CST and BCVA) , the treatment interval is extended, for example, by 4 weeks, while maintaining the original follow-up interval. Iftwo consecutive follow-ups show worsening condition (e.g., worsening CST and/or BCVA) , the patient continues treatment with the original follow-up interval (e.g., 4 weeks) .
  • stable patient condition e.g., stable CST and BCVA
  • worsening condition e.g., worsening CST and/or BCVA
  • CST is considered stable if it increases by ⁇ 50 ⁇ m between visits.
  • BCVA is considered stable if it decreases by ⁇ 5 letters between visits. If BCVA decreases by ⁇ 5 letters between visits due to DME, it is considered worsening. If CST increases by >50 ⁇ m between visits due to DME, it is considered worsening.
  • follow-up assessments for CST and BCVA are conducted at maintenance intervals (e.g., 4 weeks) . If BCVA decreases by ⁇ 5 letters or CST increases by >50 ⁇ m due to DME since the last visit, the patient continues loading dose treatment with the same follow-up interval.
  • Methods provided herein are useful in treating DME.
  • methods provided herein reduce or ameliorate a symptom of DME in the treated subject.
  • methods provided herein improve visual acuity in the treated subject.
  • methods provided herein prevent decrease in visual acuity in the treated subject.
  • methods provided herein improve or restore the patient's vision for a prolonged period (e.g., at least six months, one year, two years, three years, or longer) .
  • methods provided herein improvee retinal edema in DME.
  • methods provided herein improve BCVA in the treated subject. In some embodiments, methods provided herein prevent decrease in BCVA in the treated subject. In some embodiments, methods provided herein increase BCVA by at least 0 ETDRS letters, at least 5 ETDRS letters, at least 10 ETDRS letters, at least 15 ETDRS letters, at least 20 ETDRS letters, at least 25 ETDRS letters, or at least 30 ETDRS letters in the treated subject. In some embodiments, methods provided herein increase BCVA by at least 0 ETDRS letters. In some embodiments, methods provided herein increase BCVA by at least 5 ETDRS letters. In some embodiments, methods provided herein increase BCVA by at least 10 ETDRS letters.
  • methods provided herein increase BCVA by at least 15 ETDRS letters. In some embodiments, methods provided herein increase BCVA by at least 20 ETDRS letters. In some embodiments, methods provided herein increase BCVA by at least 25 ETDRS letters. In some embodiments, methods provided herein increase BCVA by at least 30 ETDRS letters. In some embodiments, methods provided herein increase BCVA by at least 35 ETDRS letters.
  • methods provided herein increase BCVA by a range of about 0 to about 30 ETDRS letters. In some embodiments, methods provided herein increase BCVA by a range of about 5 to about 35 ETDRS letters. In some embodiments, methods provided herein increase BCVA by a range of about 5 to about 30 ETDRS letters. In some embodiments, methods provided herein increase BCVA by a range of about 5 to about 25 ETDRS letters. In some embodiments, methods provided herein increase BCVA by a range of about 5 to about 20 ETDRS letters. In some embodiments, methods provided herein increase BCVA by a range of about 5 to about 15 ETDRS letters. In some embodiments, methods provided herein increase BCVA by a range of about 10 to about 30 ETDRS letters.
  • methods provided herein increase BCVA by a range of about 10 to about 25 ETDRS letters. In some embodiments, methods provided herein increase BCVA by a range of about 10 to about 20 ETDRS letters. In some embodiments, methods provided herein increase BCVA by a range of about 10 to about 15 ETDRS letters. In some embodiments, methods provided herein increase BCVA by a range of about 15 to about 30 ETDRS letters. In some embodiments, methods provided herein increase BCVA by a range of about 15 to about 25 ETDRS letters. In some embodiments, methods provided herein increase BCVA by a range of about 15 to about 20 ETDRS letters.
  • methods provided herein increase 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, about or 35 letters. In some embodiments, methods provided herein increase BCVA by about 5 letters. In some embodiments, methods provided herein increase BCVA by about 10 letters. In some embodiments, methods provided herein increase BCVA by about 15 letters. In some embodiments, methods provided herein increase BCVA by about 20 letters. In some embodiments, methods provided herein increase BCVA by about 25 letters. In some embodiments, methods provided herein increase BCVA by about 30 letters.
  • methods provided herein result in BCVA of at least about 50 ETDRS letters, at least about 55 ETDRS letters, at least about 60 ETDRS letters, at least about 65 ETDRS letters, at least about 70 ETDRS letters, at least about 75 ETDRS letters, or at least about 80 ETDRS letters in the treated subject.
  • methods provided herein result in BCVA of at least about 55 ETDRS letters.
  • methods provided herein result in BCVA of at least about 60 ETDRS letters.
  • methods provided herein result in BCVA of at least about 65 ETDRS letters.
  • methods provided herein result in BCVA of at least about 69 ETDRS letters.
  • methods provided herein result in BCVA of at least about 70 ETDRS letters.
  • methods provided herein result in BCVA of at least about 72 ETDRS letters.
  • methods provided herein increase BCVA by more than 5%compared to baseline. In some embodiments, methods provided herein increase BCVA by more than 10%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 100%, more than 110%, more than 120%, more than 130%, more than 140%, more than 150%compared to baseline. In some embodiments, methods provided herein increase BCVA by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%about 160%, about 170%, about 180%, about 190%, or about 200%compared to baseline.
  • methods provided herein increase BCVA by about 20%compared to baseline. In some embodiments, methods provided herein increase BCVA by about 50%compared to baseline. In some embodiments, methods provided herein increase BCVA by about 80%compared to baseline. In some embodiments, methods provided herein increase BCVA by about 100%compared to baseline. In some embodiments, methods provided herein increase BCVA by about 150%compared to baseline. In some embodiments, methods provided herein increase BCVA by about 200%compared to baseline. In some embodiments, methods provided herein increase BCVA by 10%-200%, 10%-150%, 10%-100%, 20%-100%, 50%-100%, 60%-100%, 20%-80%, 30%-70%, 50%-70%, or 60%-70%compared to baseline. In some embodiments, methods provided herein increase BCVA by 50%-70%compared to baseline.
  • methods provided herein provide therapeutic benefit that can be measured anatomically using OCT (e.g., SD-OCT) .
  • OCT e.g., SD-OCT
  • methods provided herein decrease CST in the treated subject.
  • methods provided herein reduce or prevent occurrence of SHM in the treated subject.
  • methods provided herein reduce or prevent occurrence of IRF or SRF in the treated subject.
  • methods provided herein reduce or prevent occurrence of PED in the treated subject.
  • methods provided herein reduce RA area in the treated subject.
  • methods provided herein reduce or prevent occurrence of new RA in the treated subject.
  • methods provided herein reduce MA area in the treated subject.
  • methods provided herein reduce or prevent occurrence of new MA in the treated subject. In some embodiments, methods provided herein reduce or prevent occurrence of GA in the treated subject.
  • SHM, IRF, SFR, RA, MA, and GA can be detected by OCT (e.g., SD-OCT) .
  • methods provided herein decrease CST in the treated subject, as measured by OCT (e.g., SD-OCT) .
  • OCT e.g., SD-OCT
  • methods provided herein decrease CST by at least 25 ⁇ m, at least 50 ⁇ m, at least 75 ⁇ m, at least 100 ⁇ m, at least 125 ⁇ m, at least 150 ⁇ m, at least 175 ⁇ m, at least 200 ⁇ m, at least 225 ⁇ m, at least 250 ⁇ m, at least 275 ⁇ m, or at least 300 ⁇ m in the treated subject, as measured by OCT (e.g., SD-OCT) .
  • methods provided herein decrease CST by about 25 ⁇ m, about 50 ⁇ m, about 75 ⁇ m, about 100 ⁇ m, about 125 ⁇ m, about 150 ⁇ m, about 175 ⁇ m, about 200 ⁇ m, about 225 ⁇ m, about 250 ⁇ m, about 275 ⁇ m, or about 300 ⁇ m in the treated subject, as measured by OCT (e.g., SD-OCT) .
  • OCT e.g., SD-OCT
  • methods provided herein decrease CST by at least 25 ⁇ m.
  • methods provided herein decrease CST by about 50 ⁇ m.
  • methods provided herein decrease CST by about 75 ⁇ m.
  • methods provided herein decrease CST by about 100 ⁇ m.
  • methods provided herein decrease CST by about 125 ⁇ m. In some embodiments, methods provided herein decrease CST by about 150 ⁇ m. In some embodiments, methods provided herein decrease CST by about 175 ⁇ m. In some embodiments, methods provided herein decrease CST by about 200 ⁇ m.
  • methods provided herein decrease CST by a range of about 25 to about 150 ⁇ m, about 50 to about 150 ⁇ m, about 75 to about 150 ⁇ m, about 100 to about 150 ⁇ m, about 125 to about 150 ⁇ m, about 25 to about 200 ⁇ m, about 50 to about 200 ⁇ m, about 75 to about 200 ⁇ m, about 100 to about 200 ⁇ m, about 125 to about 200 ⁇ m, about 150 to about 200 ⁇ m, about 175 to about 200 ⁇ m, about 50 to about 300 ⁇ m, about 75 to about 300 ⁇ m, about 100 to about 300 ⁇ m, about 125 to about 300 ⁇ m, about 150 to about 300 ⁇ m, about 175 to about 300 ⁇ m, about 200 to about 300 ⁇ m, about 250 to about 300 ⁇ m, or about 25 to about 350 ⁇ m in the treated subject, as measured by OCT (e.g., SD-OCT) .
  • OCT e.g., SD-OCT
  • methods provided herein decrease CST by a range of about 50 to about 200 ⁇ m. In some embodiments, methods provided herein decrease CST by a range of about 100 to about 200 ⁇ m. In some embodiments, methods provided herein decrease CST by a range of about 50 to about 150 ⁇ m. In some embodiments, methods provided herein decrease CST by a range of about 100 to about 150 ⁇ m. In some embodiments, methods provided herein decrease CST by a range of about 125 to about 150 ⁇ m.
  • methods provided herein decrease CST by more than 5%compared to baseline. In some embodiments, methods provided herein decrease CST by more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, or more than 70%compared to baseline. In some embodiments, methods provided herein decrease CST by 10%-70%compared to baseline. In some embodiments, methods provided herein decrease CST by 10%-60%compared to baseline. In some embodiments, methods provided herein decrease CST by 30%-50%compared to baseline. In some embodiments, methods provided herein decrease CST by 40%-50%compared to baseline. In some embodiments, methods provided herein decrease 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.
  • methods provided herein reduce or prevent occurrence of SHM in the treated subject, as detected by OCT (e.g., SD-OCT) .
  • methods provided herein reduce or prevent occurrence of IRF in the treated.
  • methods provided herein reduce or prevent occurrence of SRF in the treated subject.
  • methods provided herein reduce or prevent occurrence of both IRF and SRF in the treated subject.
  • methods provided herein result in the presence of neither IRF nor SRF detectable by OCT (e.g., SD-OCT) .
  • methods provided herein reduce or prevent occurrence of IRF in fovea.
  • methods provided herein reduce or prevent occurrence of SRF in fovea.
  • methods provided herein reduce or prevent occurrence of both IRF and SRF in fovea.
  • the IRF and SRF can be detected by OCT (e.g., SD-OCT) .
  • methods provided herein reduce or prevent occurrence of PED in the treated subject as detected by OCT (e.g., SD-OCT) . In some embodiments, methods provided herein result in absence of PED detectable by OCT (e.g., SD-OCT) .
  • methods provided herein reduce or prevent occurrence of new MA in the treated subject, as detected by OCT (e.g., SD-OCT) . In some embodiments, methods provided herein delay or prevent occurrence of GA in the treated subject. In some embodiments, methods provided herein reduce MA area in the treated subject, as detected by OCT (e.g., SD-OCT) .
  • methods provided herein reduce macular edema. In some embodiments, methods provided herein eliminate macular edema.
  • methods provided herein result in an improvement in vision-related quality of life in the treated subject. In some embodiments, methods provided herein result in an improvement in the NEI-VFQ-25 total score in the treated subject.
  • methods disclosed herein result in one or more of the following effects in the treated subject: (1) increase in BCVA score; (2) decrease in occurrence of IRF or SRF in macular fovea detectable on OCT; (3) decrease in CST as measured by OCT; (4) decrease in occurrence of PED detectable on OCT; (12) increase in NEI-VFQ-25 total score.
  • methods provided herein result in (1) increase in BCVA score and (2) decrease in occurrence of IRF or SRF in macular fovea detectable on OCT in the treated subject. In some embodiments, the methods provided herein further (3) decrease in CST as measured by OCT.
  • methods provided herein result in one or more of the following effects.
  • Reduction in CST by more than 25 ⁇ m compared to baseline such as a reduction of 25-350 ⁇ m, 50-300 ⁇ m, 50-200 ⁇ m, such as a reduction of 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, or 350 ⁇ m, or a reduction of more than 5%compared to baseline, such as 10%-70%, 10%-60%, 30%-50%, 40%-50%, such as 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70%.
  • the methods disclosed herein achieve one or more of the above-described therapeutic benefits in 12 or less weeks, 16 or less weeks, 20 or less weeks, 24 or less weeks, 28 or less weeks, 32 or less weeks, 36 or less weeks, 40 or less weeks, 44 or less weeks, 48 or less weeks, 52 or less weeks, 56 or less weeks, 60 or less weeks, 64 or less weeks, 68 or less weeks, 72 or less weeks, 76 or less weeks, 80 or less weeks, 84 or less weeks, 88 or less weeks, 92 or less weeks, 96 or less weeks, or 100 or less weeks after initiating treatment.
  • the methods disclosed herein achieve one or more of the above-described therapeutic benefits 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, about or 100 weeks after initiating treatment. In some embodiments, the methods disclosed herein achieve one or more of the above-described therapeutic benefits in about 44 weeks after initiating treatment. In some embodiments, the methods disclosed herein achieve one or more of the above-described therapeutic benefits in about 48 weeks after initiating treatment.
  • the methods disclosed herein achieve one or more of the above-described therapeutic benefits in about 52 weeks after initiating treatment. In some embodiments, the methods disclosed herein achieve one or more of the above-described therapeutic benefits in about 96 weeks after initiating treatment. In some embodiments, the methods disclosed herein achieve one or more of the above-described therapeutic benefits in about 100 weeks after initiating treatment.
  • the therapeutic effects can last for an extended period of time after the last treatment. In some embodiments, the therapeutic effects can last 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, at least 48 weeks after the last treatment. In some embodiments, the therapeutic effects can last at least 8 weeks after treatment. In some embodiments, the therapeutic effects can last at least 12 weeks after treatment. In some embodiments, the therapeutic effects can last at least 24 weeks after treatment. In some embodiments, the therapeutic effects can last at least 36 weeks after treatment. In some embodiments, the therapeutic effects can last at least 48 weeks after treatment.
  • Methods provided herein including multiple intravitreal injections of 1-8 mg/eye of the fusion protein (e.g., efdamrofusp alfa) , result in low systemic exposure to free/total fusion protein low, and therefore pose zero or minimal systemic safety risk. In some embodiments, methods provided herein do not or minimally pose a systemic immunogenicity risk.
  • methods provided herein further comprise monitoring for ocular and systemic adverse events (AE) during the administration of efdamrofusp alfa or a pharmaceutical composition having efdamrofusp alfa and optionally, interrupting or terminating the administration.
  • AEs include, but are not limited to, the following: exacerbation of a pre-existing medical condition/disease (including exacerbation of symptoms, signs, or abnormal laboratory tests) ; occurrence of any new adverse medical condition (including symptoms, signs, or newly diagnosed disease) ; any abnormal laboratory test value or result that has significant clinical significance.
  • an AE can be an AE of special interest (AESI) , which refers to an AE that requires close monitoring to enhance the understanding of the safety of the subject drug.
  • AESI can be non-serious AE.
  • AESI includes vision-threatening AEs that meet any of the following criteria will be defined as AESI: (1) noninfectious intraocular inflammation; (2) BCVA decrease by ⁇ 30 ETDRS letters from the most recent visit and lasts for >1 hour; (3) intraocular pressure ⁇ 30 mmHg after administration, with >10 mmHg increase compared with before administration, and lasted for more than 24 hours.
  • methods provided herein further comprise monitoring for AESIs during the administration of efdamrofusp alfa or a pharmaceutical composition having efdamrofusp alfa and optionally, interrupting or terminating the administration. In some embodiments, methods disclosed herein do not cause any AESI.
  • methods provided herein further comprise monitoring for serious adverse events (SAE) during the administration of efdamrofusp alfa or a pharmaceutical composition having efdamrofusp alfa and optionally, interrupting or terminating the administration.
  • SAE serious adverse events
  • SAEs include, for example, AEs that (1) cause death; (2) are life-threatening (i.e., posing a risk of death to the subject when they occur) ; (3) require hospitalization or prolong hospitalization; (4) result in permanent or severe disability/incapacitation (significant interference with ability to carry out normal life) ; (5) causes congenital anomalies/birth defects; and (6) may threaten the subject with severe visual impairment and may require medical or surgical intervention such as: infectious endophthalmitis; BCVA decrease by ⁇ 30 ETDRS letters; events that require surgery or other medical intervention (e.g., vitrectomy, vitreous filling, intravitreal injection of anti-infective drugs, etc. ) to prevent permanent visual impairment.
  • methods disclosed herein do not cause any SAE.
  • methods disclosed herein do not result in dose-limiting toxicity (DLT) events.
  • Methods of treatment provided herein reference certain methods of diagnosis, methods of evaluation (e.g., of severity of condition, progress of condition, or of improvement of condition) . Standard procedures of such methods are well known by and available to persons of ordinary skill in the art. For exemplary purposes, some representative methods and procedures are described here.
  • OCT optical coherence tomography
  • SD-OCT Spectral-domain OCT
  • TD-OCT time-domain OCT
  • CFP Color Fundus Photography
  • Fluorescein Fundus Angiography FFA is an invasive technique that involves injecting fluorescein dye into the veins. The dye travels up to the eye, and an eye care professional captures images inspired by selected wavelength laser with a fundus camera. The images enable an eye care professional to assess for leaking blood vessels while they analyze the anatomy, physiology, and pathology of circulation in the retinal and choroidal parts of the eye. FFA is particularly useful if there is a need to clear loose subretinal fluid from nAMD.
  • FAF Fundus autofluorescence
  • OCTA Optical Coherence Tomography Angiography
  • OCTA is used to visualize the blood vessels in the eye without the need for invasive contrast agents. OCTA measures the interference of light waves as they interact with moving red blood cells, and provides high-resolution, three-dimensional images of the retinal and choroidal vasculature, allowing for the detailed assessment of blood flow patterns, capillary density, and the presence of abnormal vessels.
  • NEI-VFQ-25 National Eye Institute Visual Functioning Questionnaire-25 (NEI-VFQ-25) : the NEI-VFQ measures vision-targeted quality of life.
  • the questionnaire comprises 11 subscales related to general vision, ocular pain, near vision, distance vision, social functioning, mental health, role functioning, dependency, driving, peripheral vision, and color vision, and a single-item general-health component. Responses for each item are converted to a 0 to 100 scale, with 0 representing the worst, and 100 the best visual functioning. Items within each construct, or subscale, are averaged to create 12 subscale scores, and averaging of the subscale scores produces the overall composite score. Different scoring approaches for the VFQ-25 have been proposed.
  • kits for conveniently and/or effectively carrying out methods of the present disclosure.
  • kits comprising the fusion proteins (e.g., efdamrofusp alfa) disclosed herein.
  • kits will comprise sufficient amounts and/or numbers of components to allow a user to perform multiple treatments of a subject (s) and/or to perform multiple experiments.
  • kits can further include reagents and/or instructions for creating and/or synthesizing compounds and/or pharmaceutical compositions of the present disclosure. In some embodiments, kits can also include one or more buffers.
  • kit components can be packaged either in aqueous media or in lyophilized form.
  • the container means of the kits will generally include at least one vial, test tube, flask, bottle, syringe or other container means, into which a component can be placed, and suitably aliquoted.
  • kits can also generally contain second, third or other additional containers into which additional components may be separately placed.
  • kits can also comprise a second container means for containing sterile, pharmaceutically acceptable buffers and/or other diluents.
  • various combinations of components can be comprised in one or more vials.
  • Kits of the present disclosure can also typically include means for containing compounds and/or pharmaceutical compositions of the present disclosure, e.g., proteins, nucleic acids, and any other reagent containers in close confinement for commercial sale.
  • Such containers can include injection or blow-molded plastic containers into which desired vials are retained.
  • kit components are provided in one and/or more liquid solutions.
  • liquid solutions are aqueous solutions, with sterile aqueous solutions being particularly used.
  • kit components can be provided as dried powder (s) . When reagents and/or components are provided as dry powders, such powders can be reconstituted by the addition of suitable volumes of solvent. In some embodiments, it is envisioned that solvents can also be provided in another container means.
  • kits provided herein comprise the delivery device for the fusion proteins (e.g., efdamrofusp alfa) disclosed herein.
  • fusion proteins e.g., efdamrofusp alfa
  • the delivery device is an intravitreal injection device.
  • Intravitreal injection devices are specialized syringes equipped with fine-gauge needles, typically 30-gauge or smaller, designed for insertion into the vitreous humor of the eye. These devices are engineered to minimize trauma and reduce the risk of complications, such as infection or retinal detachment.
  • the devices often include ergonomic features to enhance control and precision during the injection process, such as a comfortable grip and a stopper to prevent over-insertion.
  • the delivery device is an intraocular injection device.
  • These devices are used to administer the pharmaceutical composition to specific areas within the eye, such as the anterior chamber, posterior chamber, or other ocular tissues.
  • the design of these devices can include additional features like adjustable needle lengths or pre-filled syringes to simplify the administration process and ensure the correct placement of the drug.
  • the inclusion of such devices in the kit ensures that healthcare providers have the necessary tools to administer the fusion proteins effectively and safely, tailored to the specific needs of the treatment area within the eye.
  • kits can include instructions for employing kit components as well the use of any other reagent not included in the kit. Instructions can include variations that may be implemented.
  • Embodiment 1 A method for treating neovascular age-related macular degeneration ( “nAMD” ) in a subject in need thereof comprising administering a fusion protein that specifically binds to human Vascular Endothelial Growth Factor ( “VEGF” ) and human Complement Receptor 1 ( “CR1” ) , 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 wherein the fusion protein is administered to a diseased eye at a dose between about 1.0 to about 8.0 mg.
  • VEGF Vascular Endothelial Growth Factor
  • Embodiment 2 The method of Embodiment 1, wherein the fusion protein is efdamrofusp alfa (SEQ ID NO: 1) .
  • Embodiment 3 The method of Embodiment 1 or 2, wherein the Best-Corrected Visual Acuity ( “BCVA” ) of the diseased eye ranges between 19 and 78 letters (inclusive of end values) , as determined by Early Treatment Diabetic Retinopathy Study ( “ETDRS” ) chart.
  • BCVA Best-Corrected Visual Acuity
  • Embodiment 4 The method of Embodiment 0, wherein the BCVA of the diseased eye ranges between 24 and 78 ETDRS letters (inclusive of end values) .
  • Embodiment 5 The method of Embodiment 0, wherein the BCVA of the diseased eye ranges between 24 and 73 ETDRS letters (inclusive of end values) .
  • Embodiment 6 The method of any one of Embodiments 0 to 0, wherein the BCVA of the diseased eye is at least 64 ETDRS letters.
  • Embodiment 7 The method of any one of Embodiments 0 to 0, wherein the BCVA of the diseased eye is no more than 63 ETDRS letters.
  • Embodiment 8 The method of any one of Embodiments 1 to 0, wherein the subject has active subfoveal or parafoveal choroidal neovascularization ( “CNV” ) secondary to nAMD or active CNV involving the fovea.
  • CNV active subfoveal or parafoveal choroidal neovascularization
  • Embodiment 9 The method of Embodiment 0, wherein the CNV area (including classic and occult) in the diseased eye is at least 50%of the total lesion area (including hemorrhage, CNV, atrophy and fibrosis) .
  • Embodiment 10 The method of Embodiment 1 or 2, wherein the diseased eye has (1) active subfoveal or parafoveal CNV secondary to nAMD; (2) a CNV area (including classic and occult) that is no less than 50%of the total lesion area (including hemorrhage, CNV, atrophy and fibrosis) ; and (3) BCVA ranging between 24 and 73 ETDRS letters (inclusive of end values) .
  • Embodiment 11 The method of Embodiment 1 or 2, wherein the diseased eye has (1) active subfoveal CNV secondary to nAMD or active CNV that is parafoveal or outside fovea but involves the fovea; (2) a CNV area (including classic and occult) that is at least 50%of the total lesion area (including hemorrhage, CNV, atrophy and fibrosis) ; and (3) BCVA ranging between 24 and 78 ETDRS letters (inclusive of end values) .
  • Embodiment 12 The method of Embodiment 1 or 2, wherein the diseased eye has (1) active subfoveal CNV secondary to nAMD or active CNV involving the fovea; and (2) BCVA ranging between 19 and 78 ETDRS letters (inclusive of end values) .
  • Embodiment 13 The method of any one of Embodiments 1 to 0, wherein the diseased eye has Type II CNV.
  • Embodiment 14 The method of any one of Embodiments 1 to 0, wherein the diseased eye does not have Type II CNV.
  • Embodiment 15 The method of any one of Embodiments 1 to 0, wherein the diseased eye has central subfield retinal thickness ( “CST” ) greater than 280 ⁇ m, 300 ⁇ m, or 325 ⁇ m as measured by spectral-domain optical coherence tomography ( “SD-OCT” ) .
  • CST central subfield retinal thickness
  • SD-OCT spectral-domain optical coherence tomography
  • Embodiment 16 The method of any one of Embodiments 1 to 0, wherein the subject is newly diagnosed with nAMD.
  • Embodiment 17 The method of any one of Embodiments 1 to 0, wherein the subject has been diagnosed ofnAMD for up to 12 years.
  • Embodiment 18 The method of any one of Embodiments 1 to 0, wherein the subject has been previously treated for nAMD.
  • Embodiment 19 The method of Embodiment 0, wherein the subject has been previously treated with an anti-VEGF therapeutic.
  • Embodiment 20 The method of any one of Embodiments 1 to 0, wherein the subject has not been previously treated for nAMD.
  • Embodiment 21 The method of any one of Embodiments 1 to 0, wherein the subject is a human of at least 50 years old.
  • Embodiment 22 The method of any one of Embodiments 1 to 0, wherein the fusion protein is administered by intravitreal injection.
  • Embodiment 23 The method of Embodiment 0, wherein the fusion protein is injected as a liquid formulation.
  • Embodiment 24 The method of Embodiment 0, wherein the liquid formulation has the fusion protein at a concentration ranging from about 40 mg/ml to about 100 mg/ml.
  • Embodiment 25 The method of Embodiment 0, wherein the liquid formulation has the fusion protein at the concentration of about 80 mg/ml.
  • Embodiment 26 The method of any one of Embodiments 0 to 0, wherein the injection volume is between about 0.01 mL to about 0.2 mL
  • Embodiment 27 The method of Embodiment 0, wherein the injection volume is about 0.1 mL.
  • Embodiment 28 The method of any one of Embodiments 1 to 0, wherein the fusion protein is administered at a dose of about 2.0 mg, about 3.2 mg, about 4.0 mg, about 6.4 mg, or about 8.0 mg.
  • Embodiment 29 The method of any one of Embodiments 1 to 0, wherein at least three doses of the fusion protein are administered.
  • Embodiment 30 The method of Embodiment 0, wherein the at least three doses are administered at intervals ranging from about once every week to about once every four weeks.
  • Embodiment 32 The method of Embodiment 0, wherein during the loading phase, three doses of the fusion protein are administered.
  • Embodiment 33 The method of Embodiment 0 or 0, wherein during the loading phase, the fusion protein is administered at intervals ranging from about once every week to about once every four weeks.
  • Embodiment 34 The method of Embodiment 0, wherein during the loading phase, the fusion protein is administered at intervals of about once every four weeks.
  • Embodiment 35 The method of any one of Embodiments 0 to 0, wherein during the maintenance phase, the fusion protein is administered at intervals ranging from about once every eight weeks to about once every 16 weeks.
  • Embodiment 36 The method of Embodiment 0, wherein the dosing interval during the maintenance phase is about once every eight weeks.
  • Embodiment 37 The method of Embodiment 0, wherein the dosing interval during the maintenance phase is about once every 12 weeks.
  • Embodiment 39 The method of Embodiment 0, wherein (1) during the loading phase, three doses of the fusion protein are administered once every 4 weeks; and (2) during the maintenance phase, at least two doses of the fusion protein are administered once every 8 weeks; wherein the fusion protein is efdamrofusp alfa, and each dose is 2.0 mg or 4.0 mg.
  • Embodiment 40 The method of Embodiment 0, wherein (1) during the loading phase, at least three doses of the fusion protein are administered once every 4 weeks; and (2) during the maintenance phase, at least two doses of the fusion protein are administered once every twelve weeks or once every 16 weeks; wherein the fusion protein is efdamrofusp alfa, and each dose is 6.4 mg or 8.0 mg.
  • Embodiment 41 The method of any one of Embodiments 0 to 0, wherein during the maintenance phase, the fusion protein is administered at intervals determined by assessing the treated eye after the last dosing of the loading phase.
  • Embodiment 42 The method of Embodiment 0, wherein the assessment comprises measuring changes in BCVA according to the ETDRS chart.
  • Embodiment 43 The method of Embodiment 0 or 0, wherein the assessment comprises measuring changes in CST using SD-OCT.
  • Embodiment 44 The method of any one of Embodiments 0 to 0, wherein the assessment comprises determining the presence or absence of disease activity ( “DA” ) .
  • Embodiment 45 The method of Embodiment 0, wherein DA is determined to be present if at least one of the following conditions is met: (1) CST is increased by > 50 ⁇ m compared with the average CST of the previous two months as measured by SD-OCT; (2) CST is increased by ⁇ 75 ⁇ m compared with the lowest CST of the previous two months as measured by SD-OCT; (3) BCVA is lowered by ⁇ 5 ETDRS letters compare with the average BCVA of the previous two months due to the progression ofnAMD; (4) BCVA is lowered by ⁇ 10 ETDRS letters compare with the best BCVA of the previous two months due to the progression of nAMD; and (5) new occurrence of hemorrhage involving the fovea due to the progression of nAMD.
  • Embodiment 46 The method of Embodiment 0, wherein DA is determined to be present in the subject if at least one of the following conditions is present: (1) BCVA is lowered by ⁇ 5 ETDRS letters compared to most recent value; (2) the CST is increased by > 50 ⁇ m compared to the most recent value as measured by SD-OCT; (2) persistent subretinal/intraretinal/sub-retinal pigment epithelium ( “RPE” ) fluid; (3) new occurrence of CNV; and (4) new occurrence of macular hemorrhage.
  • RPE persistent subretinal/intraretinal/sub-retinal pigment epithelium
  • Embodiment 47 The method of any one of Embodiments 0 to 0, wherein (1) during the loading phase, four doses of the fusion protein are administered once every 4 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 at eight weeks after the last dosing of the loading phase, or (b) once every 12 weeks, if DA is absent about eight weeks after the last dosing of the loading phase; wherein the fusion protein is efdamrofusp alfa, and each dose is 6.4 mg or 8.0 mg.
  • Embodiment 48 The method of any one of Embodiments 0 to 0, wherein (1) during the loading phase, three doses of the fusion protein are administered once every 4 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 at about eight weeks after the last dosing of the loading phase, (b) once every 12 weeks if DA is absent at about eight weeks after the last dosing of the loading phase but present at about 12 weeks after the last dosing of the loading phase, or (c) once every 16 weeks if DA is absent at both eight weeks and 12 weeks after the last dosing of the loading phase; wherein the fusion protein is efdamrofusp alfa and each dose is 8.0 mg.
  • Embodiment 49 The method of any one of Embodiments 0 to 0, wherein the interval between the last dosing of the loading phase and the first dosing of the maintenance phase is the same as the dosing interval of the maintenance phase.
  • Embodiment 50 The method of any one of Embodiments 0 to 0, wherein at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight doses of the fusion protein are administered during the maintenance phase.
  • Embodiment 51 The method of any one of Embodiments 1 to 0, wherein the method increases BCVA of the diseased eye by at least 0 ETDRS letters, at least 5 ETDRS letters, at least 10 ETDRS letters, or at least 15 ETDRS letters.
  • Embodiment 52 The method of Embodiment 0, wherein the method increases BCVA by about 10 to about 15 ETDRS letters.
  • Embodiment 53 The method of any one of Embodiments 1 to 0, wherein the method decreases CST of the diseased eye by at least 50 ⁇ m, at least 75 ⁇ m, at least 100 ⁇ m, at least 125 ⁇ m, or at least 150 ⁇ m as measured by SD-OCT.
  • Embodiment 54 The method of Embodiment 0, wherein the method decreases CST by about 125 ⁇ m to about 150 ⁇ m as measured by SD-OCT.
  • Embodiment 55 The method of any one of Embodiments 1 to 0, wherein the method reduces or prevents occurrence of pigment epithelial detachment ( “PED” ) in the diseased eye.
  • PED pigment epithelial detachment
  • Embodiment 56 The method of any one of Embodiments 1 to 0, wherein the method reduces or prevents the occurrence of intraretinal fluid ( “IRF” ) or subretinal fluid ( “SRF” ) in the diseased eye.
  • IRF intraretinal fluid
  • SRF subretinal fluid
  • Embodiment 57 The method of any one of Embodiments 1 to 0, wherein the method reduces or prevents (1) the occurrence of new macular atrophy ( “MA” ) or (2) the area of MA, or both (1) and (2) , in the diseased eye.
  • MA new macular atrophy
  • Embodiment 58 The method of any one of Embodiments 1 to 0, wherein the method reduces or prevents the occurrence of geographic atrophy ( “GA” ) in the diseased eye.
  • GA geographic atrophy
  • Embodiment 59 The method of any one of Embodiments 1 to 0, wherein the method reduces or prevents retinal fibrosis in the diseased eye.
  • Embodiment 60 The method of any one of Embodiments 1 to 0, wherein the method decreases (1) CNV area, (2) CNV leakage area, or (3) total lesion area (including hemorrhage, CNV, atrophy and fibrosis) , or any combination thereof, in the diseased eye.
  • Embodiment 61 The method of any one of Embodiments 1 to 0, wherein the method decreases retinal neovascularization ( “RNV” ) area, RNV leakage area, or both.
  • RNV retinal neovascularization
  • Embodiment 62 The method of any one of Embodiments 1 to 0, wherein the method decreases macular retinal edema.
  • Embodiment 63 The method of any one of Embodiments 1 to 0, wherein the method increases the vision-related quality of life of the subject.
  • Embodiment 64 A method for treating diabetic macular edema ( “DME” ) in a subject in need thereof comprising administering a fusion protein that specifically binds to human VEGF and human CR1, comprising, from N-terminus to C-terminus, a VID, an immunoglobulin Fc region, a peptide linker, and a CID;
  • DME diabetic macular edema
  • 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;
  • fusion protein is administered to a diseased eye at a dose between about 1.0 to about 8.0 mg.
  • Embodiment 65 The method of Embodiment 0, wherein the fusion protein is efdamrofusp alfa (SEQ ID NO: 1) .
  • Embodiment 66 The method of Embodiment 0 or 0, wherein the subject has center-involved DME (CI-DME) .
  • CI-DME center-involved DME
  • Embodiment 67 The method of any one of Embodiments 0 to 0, wherein the subject has focal DME.
  • Embodiment 68 The method of any one of Embodiments 0 to 0, wherein the subject has diffuse DME.
  • Embodiment 69 The method of any one of Embodiments 0 to 0, wherein the BCVA of the diseased eye ranges between 24 and 73 ETDRS letters (inclusive of end values) .
  • Embodiment 70 The method of any one of Embodiments 0 to 0, wherein the diseased eye has CST that is at least 280 ⁇ m, at least 300 ⁇ m, or at least 325 ⁇ m as measured by SD-OCT.
  • Embodiment 71 The method of Embodiment 0 or 0, wherein the diseased eye has (1) visual impairments due to DME involving the fovea; (2) CST ⁇ 280 ⁇ m as measured by SD-OCT; and (3) BCVA ranging between 24 and 73 ETDRS letters (inclusive of end values) .
  • Embodiment 72 The method of any one of Embodiments 0 to 0, wherein the subject is newly diagnosed with DME.
  • Embodiment 73 The method of any one of Embodiments 0 to 0, wherein the subject has been diagnosed of DME for up to 12 years.
  • Embodiment 74 The method of any one of Embodiments 0 to 0, wherein the subject has not been previously treated with an anti-VEGF therapeutic.
  • Embodiment 75 The method of any one of Embodiments 0 to 0, wherein the subject has been previously treated with an anti-VEGF therapeutic.
  • Embodiment 76 The method of any one of Embodiments 0 to 0, wherein the subject has proliferative diabetic retinopathy ( “PDR” ) .
  • Embodiment 77 The method of any one of Embodiments 0 to 0, wherein the subject is a human.
  • Embodiment 78 The method of any one of Embodiments 0 to 0, wherein the fusion protein is administered by intravitreal injection.
  • Embodiment 79 The method of Embodiment 0, wherein the fusion protein is injected as a liquid formulation.
  • Embodiment 80 The method of Embodiment 0, wherein the liquid formulation has the fusion protein at a concentration ranging from about 40 mg/ml to about 100 mg/ml.
  • Embodiment 81 The method of Embodiment 0, wherein the liquid formulation has the fusion protein at the concentration of about 80 mg/ml.
  • Embodiment 82 The method of any one of Embodiments 0 to 0, wherein the injection volume is between about 0.01 mL to about 0.2 mL.
  • Embodiment 83 The method of Embodiment 0, wherein the injection volume is about 0.1 mL.
  • Embodiment 84 The method of any one of Embodiments 0 to 0, wherein the fusion protein is administered at a dose of about 3.2 mg, about 6.4 mg, or about 8.0 mg.
  • Embodiment 85 The method of any one of Embodiments 0 to 0, wherein at least three doses of the fusion protein are administered.
  • Embodiment 86 The method of Embodiment 0, wherein the at least three doses are administered at intervals ranging from about once every week to about once every four weeks.
  • Embodiment 87 The method of any one of Embodiments 0 to 0, comprising a loading phase and a maintenance phase, wherein during the loading phase, three to five doses of the fusion protein are administered; and during the maintenance phase, one or more doses of the fusion protein are administered as needed as determined by assessing the treated eye after the last dosing of the loading phase.
  • Embodiment 88 The method of Embodiment 0, wherein during the loading phase, three doses of the fusion protein are administered.
  • Embodiment 89 The method of Embodiment 0 or 0, wherein during the loading phase, the fusion protein is administered at intervals ranging from about once every week to about once every four weeks.
  • Embodiment 90 The method of Embodiment 0, wherein during the loading phase, the fusion protein is administered at intervals of about once every four weeks.
  • Embodiment 91 The method of any one of Embodiments 0 to 0, wherein the assessment comprises measuring changes in BCVA according to the ETDRS chart.
  • Embodiment 92 The method of Embodiment 0, wherein the assessment comprises measuring changes in CST as measured by SD-OCT.
  • Embodiment 93 The method of Embodiment 0 or 0, wherein the assessment comprises conducting Diabetic Retinopathy Severity Score ( “DRSS” ) evaluation.
  • DRSS Diabetic Retinopathy Severity Score
  • Embodiment 94 The method of any one of Embodiments 0 to 0, wherein during the maintenance phase, the fusion protein is administered if (1) BCVA is lowered by ⁇ 5 ETDRS letters compared to most recent value or (2) the CST is increased by > 50 ⁇ m compared to most recent value as measured by SD-OCT.
  • Embodiment 95 The method of Embodiment 0, wherein (1) during the loading phase, three doses of the fusion protein are administered once every four weeks; (2) during the maintenance dose, the fusion protein is administered if, between four and eight weeks after the last dosing of the loading phase, (1) BCVA is lowered by ⁇ 5 ETDRS letters compared to most recent value, or (2) the CST is increased by > 50 ⁇ m compared to most recent value as measured by SD-OCT; wherein the fusion protein is efdamrofusp alfa, and each dose is 3.2mg, 6.4 mg or 8.0 mg.
  • Embodiment 96 The method of any one of Embodiments 0 to 0, wherein the method increases BCVA of the diseased eye by at least 1 ETDRS letter, at least 5 ETDRS letters, at least 10 ETDRS letters, or at least 15 ETDRS letters.
  • Embodiment 97 The method of Embodiment 0, wherein the method increases BCVA by about 10 to about 15 ETDRS letters.
  • Embodiment 98 The method of any one of Embodiments 0 to 0, wherein the method decreases CST of the diseased eye by at least 50 ⁇ m, at least 75 ⁇ m, at least 100 ⁇ m, at least 125 ⁇ m, or at least 150 ⁇ m as measured by SD-OCT.
  • Embodiment 99 The method of Embodiment 0, wherein the method decreases CST by about 125 ⁇ m to about 150 ⁇ m as measured by SD-OCT.
  • Embodiment 100 The method of any one of Embodiments 0 to 0, wherein the method decreases macular retinal edema.
  • Embodiment 101 The method of any one of Embodiments 0 to 0, wherein the method increases the vision-related quality of life of the subject.
  • Embodiment 102 A single pharmaceutical dosage unit, comprising a fusion protein inhibiting a VEGF pathway and a complement pathway, wherein the fusion protein is a fusion protein according to Embodiments 1-2 or Embodiments 64-65, and the the fusion protein is in the amount 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 12.8mg, 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.
  • efdamrofusp alfa The active pharmaceutical ingredient under investigation of the studies described below is efdamrofusp alfa. Briefly, results from the studies described below demonstrate that at the specified regimens, efdamrofusp alfa is safe and effective in treating AMD.
  • 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-maximal effective concentration
  • SAE serious adverse event
  • TEAE treatment-emergent adverse event
  • CR1 complement receptor 1
  • hRPE human retinal pigment epithelium.
  • a series of concentration gradients of efdamrofusp alfa were tested against a fixed concentration of VEGF-A165 to examine the varying proliferation capacities of HUVEC cells as the amount of free VEGF-A165 changed.
  • the numbers of viable HUVEC cells were determined using the CCK-8 assay kit to measure the proliferation inhibition efficiency of efdamrofusp alfa.
  • Aflibercept and bevacizumab were used as controls.
  • a human serum complement-stimulated sensitized sheep red blood cell model was used. Efdamrofusp alfa at concentrations ranging from 0.02 to 1080.26 nM was able to inhibit hemolysis of sensitized sheep red blood cells induced by human serum complement 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 efdamrofusp alfa could significantly inhibit the classical complement pathway, with an effect similar to CR1.
  • a human serum complement-stimulated rabbit red blood cell model was used. Efdamrofusp alfa at concentrations ranging from 1.50 to 383.39 nM was able to inhibit hemolysis of rabbit red blood cells induced by human serum complement in a concentration-dependent manner, with an EC50 value of 14.59 nM.
  • the EC50 value for CR1 was 15.30 nM, indicating that efdamrofusp alfa could significantly inhibit the alternative complement pathway, with an effect similar to CR1.
  • hRPE cells were divided into a normal group (nor) , a model group (ctr) , an aflibercept group (VEGF-Trap) , a CR1 group, and an efdamrofusp alfa group. Except for the normal group, all groups were treated with t-BHP and 10%normal human serum, while the normal group received an equivalent volume of PBS. The drug treatment groups were additionally treated with the respective drugs to achieve a final concentration of 1 ⁇ g/ml, while the normal and model groups received an equivalent volume of PBS. After 4 hours of incubation, the barrier function of the hRPE monolayer cells was assessed. ELISA was used to measure the levels of VEGF, chemokine (C-C motif) ligand 2 (CCL2) , C3a, C5a, and MAC secreted by hRPE cells after 4 hours.
  • CCL2 chemokine (C-C motif) ligand 2
  • mice C57BL/6J mice with four laser photocoagulation points.
  • the mice were randomly divided into six groups, each with two mice (four eyes) : laser-induced model group, PBS treatment group, and efdamrofusp alfa groups at doses of 1 ⁇ g/ ⁇ l, 3 ⁇ g/ ⁇ l, 5 ⁇ g/ ⁇ l, and 10 ⁇ g/ ⁇ l.
  • laser-induced model group PBS treatment group
  • efdamrofusp alfa groups at doses of 1 ⁇ g/ ⁇ l, 3 ⁇ g/ ⁇ l, 5 ⁇ g/ ⁇ l, and 10 ⁇ g/ ⁇ l.
  • 1 ⁇ l of each dose of efdamrofusp alfa or PBS was injected into the vitreous cavity of both eyes of the CNV mice.
  • fluorescein isothiocyanate-dextran perfusion through the orbital sinus and choroidal flat mount were performed to observe the effect of different doses of efdamrofusp alfa on the CNV area in mice.
  • Efdamrofusp alfa was injected into the vitreous cavity of both eyes of the CNV mice.
  • fundus fluorescein angiography was performed to measure the CNV. The mice were anesthetized with chloral hydrate and dilated with compound tropicamide.
  • Infrared fundus photographs were taken first, followed by FITC-Dextran, indocyanine green angiography (ICGA) , and fundus fluorescein angiography (FFA) . Finally, the concentrations of VEGF, CCL2, TNF- ⁇ , C3a, and C5a proteins in the RPE-choroid were measured by ELISA.
  • mice efdamrofusp alfa could inhibit the formation and leakage of laser-induced CNV in mice, likely through the simultaneous inhibition of VEGF and complement activation components C3a, C5a, MAC, CCL2, and TNF- ⁇ expression, which inhibited macrophage and neutrophil infiltration, reduced VEGF secretion, and suppressed neovascularization.
  • a laser was used to photocoagulate the macula of rhesus monkeys to induce CNV, creating an animal model similar to human CNV.
  • 25 monkeys both male and female
  • bevacizumab injection (1.25 mg/eye)
  • efdamrofusp alfa groups at doses of 0.25 mg/eye, 0.5 mg/eye, and 1.25 mg/eye, with 5 monkeys per group.
  • 21 days after photocoagulation each group received a single intravitreal injection of 50 ⁇ l/eye of the corresponding drug.
  • efdamrofusp alfa significantly reduced fluorescein leakage, fiuorescein spot area, and the number of fluorescein spots. It also reduced retinal thickness at lesion sites of fluorescein spot, restored the integrity and continuity of the retinal pigment epithelium, lowered VEGF levels in the aqueous humor, alleviated fibrous tissue proliferation, and inhibited the expression of CD31 and C5b-9 in the choroid. Efdamrofusp alfa was more effective than clinical doses of bevacizumab.
  • Dual targets efdamrofusp alfa specifically binds to VEGF family members (VEGF-A165, VEGF-A121, and PIGF) via its VID domain and to complement factors (C3b and C4b) via its CID domain, making it a dual-target drug.
  • Samples of aqueous humor, vitreous humor, lens, cornea, iris, retina, choroid, sclera, optic nerve, and serum were collected at 4h, 24h, 72h, 168h, 336h, and 504h after administration in the intravitreal injection group.
  • T 1/2 half-life of efdamrofusp alfa after intravitreal injection was significantly longer than after intravenous injection.
  • Ocular drug concentrations were significantly higher than serum drug concentrations, indicating a lower risk of systemic toxicity.
  • the drug was primarily distributed in ocular tissues such as the vitreous, retina, and choroid. The drug remained in the retina and choroid for a relatively long period, as indicated by both the terminal elimination half-life (T1/2) and mean residence time (MRT) , allowing for sustained efficacy.
  • Blood samples were collected before the first and last doses and 5 min, lh, 4h, 8h, 24h, 48h, 72h, 120h, 168h, and 336h after the first and last doses in efdamrofusp alfa 8 mg group to prepare sera.
  • Blood samples were collected before the first and last doses and lh, 4h, 8h, 24h, 48h, 72h, 120h, and 168h after the first and last doses in efdamrofusp alfa intravitreal injection groups to prepare sera.
  • the concentration of efdamrofusp alfa in serum was measured by ELISA.
  • the accumulation index was 0.7 after continuous intravenous injection of efdamrofusp alfa in rhesus monkeys.
  • the dose-proportional relationships for Cmax and AUC(0-t) were 1: 4.4: 5.5 and 1: 6.3: 13.4, respectively, indicating dose-dependency.
  • the dose-proportional relationships for 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 (could not be calculated because drug was not detected in certain individual animals after the last dose) , 0.3, and 0.4.
  • Tissue distribution After intravitreal injection, most of the drug was confined to the eye, with significantly higher local ocular drug concentrations than serum drug concentrations, suggesting that efdamrofusp alfa mainly exerted its pharmacological effects in the eye with minimal systemic toxicity risk. The highest drug distribution was in the vitreous, retina, and choroid, aligning with the intended targets.
  • Intraocular inflammation Intraocular inflammation observed with intravitreal injection of efdamrofusp alfa was associated with the formation of antidrug antibodies and immune complexes. Considering that efdamrofusp alfa was a fully human monoclonal antibody, the likelihood of clinical occurrence of antidrug antibodies and immune complexes was low, thus the risk of intraocular inflammation was minimal but should still be closely monitored in clinical studies.
  • Tissue specificity efdamrofusp alfa showed no significant cross-reactivity with normal human tissues and crab-eating monkey tissues, indicating no significant interactions with normal human tissues and very low target-related toxicity.
  • the anti-RNV effect of efdamrofusp alfa fusion protein was measured using a DL- ⁇ -AAA (DL- ⁇ -aminoadipic acid) -induced RNV model in Dutch rabbits.
  • DL- ⁇ -AAA DL- ⁇ -aminoadipic acid
  • Body Weight at Start of Dosing (D 1) : 1.84-2.74 kg.
  • Fluorescent leakage area reduction Pre-treatment leakage area -Post-treatment leakage area.
  • efdamrofusp alfa exhibited significant anti-neovascularization effects 7 days post-administration, which was comparable to aflibercept This demonstrated that efdamrofusp alfa could effectively inhibit retinal neovascularization.
  • This phase involved a multi-center, open-label, multiple intravitreal injection (IVT) dose-escalation study conducted in nAMD and DME subjects.
  • This phase planned to include 18-36 subjects in total, with 9-18 subjects each for nAMD and DME.
  • the study aimed to evaluate the safety, tolerability, preliminary efficacy, PK characteristics, and immunogenicity of efdamrofusp alfa in nAMD and DME patients.
  • Three dosage groups were studied: 3.2 mg/eye, 6.4 mg/eye, and 8.0 mg/eye (injection volumes of 0.04 mL, 0.08 mL, and 0.1 mL, respectively) .
  • a “3+3” dose-escalation design was used.
  • Dose escalation was conducted in nAMD and DME subjects under the same termination criteria, and the results were evaluated independently. Dose escalation was based on dose-limiting toxicity (DLT) observed within 7 days after the first dose (i.e., from D0 to W1) . Each group enrolled 3-6 subjects, three dose groups in total and 18-36 subjects in total. For safety, the first subject in each dose group must complete DLT observation before enrolling the remaining two subjects.
  • DLT dose-limiting toxicity
  • DLT was defined as any of the following efdamrofusp alfa-related adverse events occurring during the DLT observation period: 1) intraocular inflammation: change of three or more grades in anterior chamber flare, anterior chamber cells, or vitreous haze; 2) vitreous hemorrhage: Grade 2 or higher; 3) acute vision loss: decrease of ⁇ 15 letters not associated with intraocular inflammation, and lasting >24 hours; 4) increased intraocular pressure post-administration: >30 mmHg and lasting >240 minutes; 5) hemorrhage: intracranial or other clinically significant non-ocular hemorrhage; 6) serious adverse event (SAE) considered related to the study drug by the investigator.
  • intraocular inflammation change of three or more grades in anterior chamber flare, anterior chamber cells, or vitreous haze
  • 2) vitreous hemorrhage Grade 2 or higher
  • acute vision loss decrease of ⁇ 15 letters not associated with intraocular inflammation, and lasting >24 hours
  • DME subjects for example: Each dose group started with 1 subject, who was monitored for DLT within 7 days. If the first subject showed no DLT, 2 more subjects were enrolled. If DLT occurred in the first subject, a third subject should be enrolled after the second subject completed DLT observation.
  • the Safety Evaluation Committee could decide to introduce an intermediate dose group between the intolerable dose and the previous dose to better determine the MTD.
  • nAMD subjects between Weeks 12-16, if any of the following criteria due to nAMD progression were met, as judged by the investigator, subjects received an intravitreal injection of efdamrofusp alfa at their assigned dose and continue the visits: (i) BCVA decrease of ⁇ 5 letters or CST increase of >50 ⁇ m compared to the previous visit; (ii) persistent subretinal/intraretinal/RPE fluid; (iii) new CNV; or (iv) new macular hemorrhage.
  • Inclusion criteria (subjects were included in the study only if they meet all the following criteria at screening and baseline) : 1. Must obtain a signed informed consent prior to participation. 2. Male or female aged ⁇ 18 years. 3. Visual impairment in the study eye caused by DME affecting the central fovea, or active subfoveal or juxtafoveal CNV secondary to nAMD. 4. For DME subjects, confirmed CST ⁇ 280 ⁇ m in the study eye by SD-OCT at screening; no CST requirement for nAMD subjects. 5. BCVA in the study eye within the range of 24 to 73 ETDRS letters (inclusive) . 6. Female subjects of childbearing potential or male subjects with partners of childbearing potential must agree to use effective contraception from screening until 6 months post-treatment.
  • Ocular diseases 1. At screening or baseline, the study eye had systemic/ocular diseases that may cause the subject not to respond to the study treatment or confound the interpretation of the study results, as determined by the investigator. For example, high-risk PDR, fibrotic or atrophic lesions involving the fovea, retinal hemorrhages involving more than 2 disc areas in the fovea, retinal vein occlusion, retinal detachment, macular hole, posterior or pan-uveitis, vitreomacular traction affecting central vision, epiretinal membrane involving or disrupting the macular structure, and equivalent spherical refraction ⁇ -8.00D. 2. Intraocular pressure >2 lmmHg in the study eye. 3.
  • Active intraocular, periocular infection, or inflammation e.g., bacterial conjunctivitis, endophthalmitis
  • Severe media opacity or insufficient pupil dilation affecting BCVA or preventing adequate imaging (e.g., SD-OCT, FFA, CFP) for safety and efficacy evaluation.
  • BCVA ⁇ 19 ETDRS letters in the non-study eye.
  • Ocular treatments 6. Anti-VEGF treatment in the study eye within 90 days before baseline. 7. Anti-complement treatment in the study eye within 90 days before baseline. 8. Any vitrectomy surgery in the study eye at any time before baseline. 9. Grid or pan-retinal photocoagulation in the study eye within 90 days before baseline. 10. Any intraocular surgery (e.g., cataract extraction) in the study eye within 90 days before baseline. 11. YAG laser capsulotomy in the study eye within 30 days before baseline. 12. Intraocular or periocular steroid injection in either eye within 120 days before baseline. 13. Aphakic eye with posterior capsule defect in the study eye. 14. Anti-VEGF treatment in the non-study eye within 30 days before baseline.
  • Steroid treatment within 30 days before administration of study drugs except for external, intranasal, and intra-articular use
  • Active liver disease or liver insufficiency (defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the upper limit of normal (ULN) at screening) .
  • Serum creatinine (Cr) or urea (UREA) > 1.5 ⁇ ULN.
  • Presence of acute or chronic active hepatitis B at screening (defined as positive for hepatitis B surface antigen and/or hepatitis B core antibody, and HBV-DNA viral load ⁇ 2000 IU/mL) .
  • FIG. 3A The results of the changes in BCVA (EDTRS letters) at each visit for the study eyes of nAMD patients are shown in FIG. 3A.
  • FIG. 3B The results of the changes in BCVA (EDTRS letters) at each visit for the study eyes of DME patients are shown in FIG. 3B.
  • “Num” represents the number of patients with statistical data at the corresponding time point.
  • FIG. 4A The results of the changes in CST from baseline in the SD-OCT examination at each visit for the study eyes of nAMD patients are shown in FIG. 4A.
  • FIG. 4B The results of the changes in CST from baseline in the SD-OCT examination at each visit for the study eyes of DME patients are shown in FIG. 4B.
  • “Num” represents the number of patients with statistical data at the corresponding time point.
  • TEAEs were mild to moderate in both nAMD and DME patients. There was no TEAE or study drug related TEAE led to discontinuation of the study drug.
  • Exploratory goals (1) to explore effects of efdamrofusp alfa on fundus fibrosis; (2) to explore effects of efdamrofusp alfa on RA; (3) to explore the effect of efdamrofusp alfa on serious retinal PED; and (4) to evaluate effect of efdamrofusp alfa on neovascularization measured by OCT.
  • Subjects included in this study met the following criteria at the time of screening: (1) having signed informed consent; (2) aged ⁇ 50; (3) having active subfoveal or parafoveal CNV secondary to nAMD as confirmed by FFA or SD-OCT in study eye; (4) the CNV area in the study eye (including classic and occult) detected by FFA was ⁇ 50%of the total lesion area (including hemorrhage, CNV, atrophy and fibrosis) ; 5) the BCVA of the study eye within the range of 24 to 73 ETDRS letters (inclusive of both end values) .
  • Efdamrofusp alfa 0.2 mi: 8 mg per vial.
  • Control drug aflibercept : 0.1 mi: 4 mg per vial.
  • Loading Period D0 -end of W8, all subjects received three doses of with aflibercept or efdamrofusp alfa in respective group once every 4 weeks (Q4W) .
  • the primary endpoint was assessed at Week 36, and the last visit was at Week 52.
  • Intravitreal injections were used for all treatment.
  • the assessment of efficacy included vision assessment and anatomical assessment.
  • Anatomical assessment included using SD-OCT, CFP, FFA, FAF, OCTA for retinal imaging and angiograph. The following parameters were measured during the study period: BCVA (using ETDRS table) , CST, and the NEI-VFQ-25 score.
  • PK values and immunogenicity of efdamrofusp alfa; TEAEs, treatment-emergent SAEs, were also measured and summarized across treatment groups during the study period.
  • Primary endpoint Change from baseline in the BCVA score as measured with the ETDRS visual acuity chart at Week 36.
  • -Vision-related (1) changes from baseline in BCVA at each visit; (2) proportion of subjects having BCVA increased by ⁇ 0, 5, 10, and 15 ETDRS letters from baseline at Weeks 12, 28, 36, and 52; (3) proportion of subjects having BCVA decreased by ⁇ 0, 5, 10, and 15 ETDRS letters from baseline at Weeks 12, 28, 36, and 52; (4) proportion of sub jects having BCVA ⁇ 74 letters at Weeks 12, 28, 36, and 52; and (5) proportion of subjects having BCVA ⁇ 33 letters at Weeks 12, 28, 36, and 52.
  • -Anatomy-related on SD-OCT (1) changes from baseline in CST of the macula at Weeks 12, 28, 36, and 52; and (2) proportion of subjects with IRF or SRF at Weeks 12, 28, 36, and 52.
  • -Anatomy-related on FFA (1) changes from baseline in CNV area at Weeks 36 and 52; (2) changes from baseline in CNV leakage area at Weeks 36 and 52; and (3) changes from baseline in total lesion area at Weeks 36 and 52.
  • -Retinal fibrosis (1) proportion of subjects having fibrosis detectable on CFP at Weeks 36 and 52; (2) change from baseline in the maximum diameter of fibrosis detected on CFP at Weeks 36 and 52; (3) changes from baseline in maximum height of fibrosis on SD-OCT at Weeks 36 and 52.
  • -Retinal atrophy (1) change from baseline in total area of RA 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) proportion of subjects having new RA on SD-OCT and FAF at Weeks 36 and 52.
  • -PED (1) proportion 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 basal diameter of sPED on SD-OCT at Weeks 12, 36 and 52.
  • GVC maximum vessel diameter
  • GLD maximum lesion diameter
  • CNV area Change from baseline in maximum vessel diameter (GVC) , maximum lesion diameter (GLD) , and CNV area at Weeks 4, 12, 36 and 52.
  • the demographic distribution (age, sex) in all groups was balanced.
  • the mean baseline BCVA were 53.9 ⁇ 12.85, 56.1 ⁇ 13.29 and 53.6 ⁇ 13.91 ETDRS letters, respectively, and the mean baseline CST were 345.7 ⁇ 124.89 ⁇ m, 354.3 ⁇ 147.34 ⁇ m and 355.3 ⁇ 126.08 ⁇ m, respectively.
  • the baseline average CNV area on FFA were 7.200 ⁇ 6.6705 mm 2 , 7.679 ⁇ 6.7646 mm 2 and 7.867 ⁇ 6.4979 mm 2 , respectively
  • the baseline average CNV leakage area on FFA were 8.913 ⁇ 7.0456 mm 2 , 9.027 ⁇ 6.8027 mm 2 and 10.046 ⁇ 8.7537 mm 2 , respectively
  • the baseline average total lesion area on FFA were 8.131 ⁇ 7.6190 mm 2 , 8.750 ⁇ 7.3369 mm 2 and 9.298 ⁇ 7.9333 mm 2 , respectively.
  • the proportion of subjects with cystoid edema involving the central subfield of the retina on SD-OCT were 40.3%, 24.7%and 32.5%, respectively; the proportion of the subjects with subretinal fluid with definite involvement of the central subregion on SD-OCT were 68.8%, 67.5%and 57.1%, respectively; the proportion of the subjects with subretinal hyperreflective substance with definite involvement of the central subregion on SD-OCT were 75.3%, 68.8%and 75.3%, respectively.
  • the primary endpoint was the change from baseline in BCVA of the study eye at Week 36.
  • MMRM Mixed Model for Repeated Measures
  • mITT modified intent to treat
  • the mean changes of BCVA from baseline in the efdamrofusp alfa-2 mg group, the efdamrofusp alfa-4 mg group, and the afiibercept-2 mg group at Week 36 were 10.56 ⁇ 1.17 ETDRS letters, 11.42 ⁇ 1.18 ETDRS letters, and 11.97 ⁇ 1.17 ETDRS letters, respectively (FIG. 5) .
  • the least square means (LSM) of BCVA changes from baseline in the efdamrofusp alfa-2 mg group and the efdamrofusp alfa-4 mg group were -1.42 letters of ETDRS (95%CI: -4.62, 1.79) and -0.56 letters of ETDRS (95%CI: -3.79, 2.68) , respectively, as compared with the afiibercept-2 mg group.
  • the mean changes from baseline in BCVA of efdamrofusp alfa-2 mg group and efdamrofusp alfa-4 mg group were noninferior to that of afiibercept 2 mg group at Week 36.
  • the secondary endpoints included vision-related efficacy, SD-OCT anatomy-related efficacy and FFA anatomy-related efficacy.
  • the proportion of subjects with BCVA ⁇ 74 letters The proportion of subjects with BCVA ⁇ 74 ETDRS letters in efdamrofusp alfa-2 mg group, efdamrofusp alfa-4 mg group and aflibercept 2 mg group were similar. The difference was not statistically significant.
  • the proportion of subjects with BCVA ⁇ 33 letters The proportion of subjects with BCVA ⁇ 33 ETDRS letters in efdamrofusp alfa-2 mg group, efdamrofusp alfa-4 mg group and aflibercept 2 mg group were similar. The difference was not statistically significant.
  • the mean changes in CST from baseline in the efdamrofusp alfa-2 mg group, the efdamrofusp alfa-4 mg group and the aflibercept-2 mg group were -143.87 ⁇ 6.92 ⁇ m, -139.32 ⁇ 6.98 ⁇ m and -142.50 ⁇ 6.91 ⁇ m respectively; compared to the aflibercept-2 mg group, the efdamrofusp alfa-2 mg group and the efdamrofusp alfa-4 mg group had mean changes in CST from baseline with LSM of-1.38 (95%CI: -20.28, 17.53) and 3.18 (95%CI: -15.85, 22.21) , respectively.
  • the mean changes in CST from baseline in efdamrofusp alfa-2 mg group, efdamrofusp alfa-4 mg group and aflibercept 2 mg group were -151.83 ⁇ 5.68 ⁇ m, -147.67 ⁇ 5.71 ⁇ m and -152.42 ⁇ 5.68 ⁇ m, respectively; compared to the aflibercept 2 mg group, the efdamrofusp alfa-2 mg group and efdamrofusp alfa-4 mg group had mean changes in CST from baseline with LSM of 0.59 (95%CI: -14.82, 16.00) and 4.74 (95%CI: -10.75, 20.24) , respectively.
  • the proportion of subjects having IRF, SRF, or subretinal hyperreflective substance The proportions of subjects having IRF, SRF, or subretinal hyperreflective substance were similar in efdamrofusp alfa-2 mg group, efdamrofusp alfa-4 mg group and aflibercept 2 mg group, and the difference among the groups was not statistically significant.
  • the mean changes from baseline in efdamrofusp alfa-2 mg group, efdamrofusp alfa-4 mg group and aflibercept 2 mg group were -0.80 ⁇ 0.424 mm 2 , -0.51 ⁇ 0.445 mm 2 and 0.39 ⁇ 0.426 mm 2 , respectively.
  • the mean changes from baseline in efdamrofusp alfa-2 mg group, efdamrofusp alfa-4 mg group and aflibercept 2 mg group were -1.04 ⁇ 0.432 mm 2 , -0.64 ⁇ 0.452 mm 2 and -0.08 ⁇ 0.435 mm 2 , respectively.
  • the mean changes from baseline in efdamrofusp alfa-2 mg group, efdamrofusp alfa-4 mg group and aflibercept 2 mg group were -5.36 ⁇ 0.531 mm 2 , -5.10 ⁇ 0.558 mm 2 and -5.37 ⁇ 0.536 mm 2 , respectively.
  • the mean changes from baseline in efdamrofusp alfa-2 mg group, efdamrofusp alfa-4 mg group and aflibercept 2 mg group were -6.82 ⁇ 0.490 mm 2 , -6.86 ⁇ 0.520 mm 2 and -6.74 ⁇ 0.495 mm 2 , respectively.
  • the mean changes from baseline in efdamrofusp alfa-2 mg group, efdamrofusp alfa-4 mg group and aflibercept 2 mg group were -0.96 ⁇ 0.471 mm 2 , -0.90 ⁇ 0.495 mm 2 and -0.83 ⁇ 0.475 mm 2 , respectively.
  • the mean change from baseline in efdamrofusp alfa-2 mg group, efdamrofusp alfa-4 mg group and aflibercept 2 mg group were -1.57 ⁇ 0.436 mm 2 , -1.10 ⁇ 0.456 mm 2 and -0.90 ⁇ 0.439 mm 2 , respectively.
  • the efdamrofusp alfa-2mg group had 1 (1.3%) subject who had TRAE unrelated to eye, and neither the efdamrofusp alfa-4mg group nor the aflibercept-2 mg group had occurrence of TRAE unrelated to eye.
  • -Most of the TEAE/TRAE in the efdamrofusp alfa-2 mg group, efdamrofusp alfa-4 mg group and aflibercept-2 mg group were mild to moderate.
  • a small number of TEAE/TRAE were severe.
  • -TEAE led to halt of treatment in 4 (5.2%) , 4 (5.2%) and 4 (3.9%) patients in the efdamrofusp alfa-2 mg group, the efdamrofusp alfa-4 mg group and the aflibercept-2 mg group, respectively.
  • TEAE led to halt of treatment in 2 (2.6%) subjects in efdamrofusp alfa-2 mg group and 1 (1.3%) subject in the efdamrofusp alfa-4 mg group, but not in the aflibercept-2 mg group.
  • ADA positive rate was 2.0% (3/153) at baseline and 14.4% (22/153) during treatment. ADA might be associated with the occurrence of uveitis, but had no effect on efficacy.
  • Efdamrofusp alfa was safe and well tolerated. Like aflibercept-2, no new safety concern was identified. The systemic exposure of efdamrofusp alfa after intravitreal injection was low, the risk of systemic immunogenic reaction was low, the systemic risk was low, and there was no significant accumulation after multiple administration. The systemic risk with multiple administration was low.
  • Eligible subjects were randomly assigned 1: 1: 1 to the treatment groups, 44 subjects in each group. Subjects were stratified based on: (1) baseline BCVA of the study eye: ⁇ 64 vs. ⁇ 63 ETDRS letters, and (2) whether the study eye had previously been treated. At least 50%of the subjects had not been previously treated.
  • Exploratory objectives (1) to explore effects of efdamrofusp alfa on retinal fibrosis; (2) to explore effects of efdamrofusp alfa on macular atrophy; and (3) to explore the effect of efdamrofusp alfa on controlling disease activity.
  • Subjects must meet the following criteria to be included in this study: (1) having signed informed consent; (2) aged ⁇ 50; (3) having active subfoveal CNV secondary to nAMD or active CNV that was parafoveal or outside fovea but involved the fovea (active CNV was defined as the presence of IRF, SRF, or fluorescence leakage detectable by FFA or SD-OCT; (4) the CNV area in the study eye (including classic and occult) detected by FFA was ⁇ 50%of the total lesion area (including hemorrhage, CNV, atrophy and fibrosis) at the baseline; and (5) the BCVA of the study eye within the range of 24 to 78 ETDRS letters (inclusive of both end values) .
  • Efdamrofusp alfa 0.2 ml: 16 mg per vial.
  • Excipients 2.94 mg/ml sodium citrate (dihydrate) , 13.94 mg/ml arginine, 50.00 mg/ml sucrose, 0.3 mg/ml polysorbate 20, pH 6.2.
  • Control drug aflibercept 0.1 ml: 4 mg per vial.
  • Excipients 10 mmol/L sodium phosphate, 40 mmol/L sodium chloride, 5%sucrose, 0.03%polysorbate 20, pH 6.2.
  • Q4W once every 4 weeks
  • Q8W once every 8 weeks
  • Q12W once every 12 weeks.
  • the treatment period of the study started on Day 0 (D0) and lasted until Week 48. Last visit is at Week 52.
  • Intravitreal injections were used for all treatment.
  • the activity control (aflibercept) group From D0 to Week 8, all subjects received a loading dose of 2 mg aflibercept once every 4 weeks (3 times total at D0, Week 4 and Week 8) ; from Week 12 to Week 48, subjects visited study center once every 4 weeks, and received 2 mg of aflibercept once every 8 weeks (i.e., total of 5 treatments at Weeks 16, 24, 32, 40, and 48) .
  • the efdamrofusp alfa group (6.4 mg and 8.0 mg) : All subjects received a loading dose of efdamrofusp alfa every 4 weeks from D0 to Week 12 (i.e., 4 times total at D0, Week 4, Week 8 and Week 12) ; from Week 16 to Week 48, subjects visited study center once every 4 weeks, and received disease activity ( “DA” ) evaluation at Week 20. Dosing interval was to be adjusted according to DA assessment.
  • DA was considered “present” if any of the following six criteria was met: (1) the central subfield thickness ( “CST” ) on this visit was increased by > 50 ⁇ m compared with the average CST of the previous two scheduled visits; (2) the CST on this visit was increased by ⁇ 75 ⁇ m compared with the lowest CST of the previous two scheduled visits; (3) the BCVA on this visit was lowered by ⁇ 5 letters compare to the average of the previous two scheduled visits due to the progression of nAMD; (4) the BCVA on this visit was lowered by ⁇ 10 letters compare to the best result of the previous two scheduled visits due to the progression of nAMD; (5) occurrence of new macular hemorrhage on this visit due to the progression of nAMD; and (6) evaluated by the investigator as requiring immediate administration due to other apparent nAMD disease activity.
  • CST central subfield thickness
  • the subsequent dosing interval was kept at Q8W (i.e., 4 doses administered at Weeks 20, 28, 36 and 44) ; if no DA at Week 20, the subsequent dosing interval was adjusted to Q12W (i.e., 3 doses administered at Weeks 24, 36, and 48) .
  • the assessment of efficacy included vision assessment and anatomical assessment.
  • Anatomical assessment included using SD-OCT, CFP, and FFA for retinal imaging and angiograph. The following parameters were measured during the study period: BCVA (using ETDRS table) , CST, and the NEI-VFQ-25 score.
  • PK values and immunogenicity of efdamrofusp alfa; treatment-emergent adverse events (TEAEs) , treatment-emergent SAEs, were also measured and summarized across treatment groups during the study period.
  • Primary endpoint Change from baseline in the mean BCVA score in the study eye at Week 40.
  • -Vision-related (1) changes from baseline in BCVA at each visit; (2) proportion of subjects having BCVA increased by ⁇ 0, 5, 10, and 15 ETDRS letters from baseline at Weeks 40 and 52; (3) proportion of subjects having BCVA decreased by ⁇ 0, 5, 10, and 15 ETDRS letters from baseline at Weeks 40 and 52; (4) proportion of subjects having BCVA ⁇ 34 letters at Weeks 40 and 52; (5) proportion of subjects having BCVA ⁇ 69 letters at Weeks 40 and 52; and (6) proportion of subjects having BCVA ⁇ 79 letters at Weeks 40 and 52.
  • -Anatomy-related (1) changes from baseline in CST of the macula as measured by SD-OCT at each visit; (2) proportion of subjects with IRF, SRF, and PED detectable by SD-OCT at each visit; (3) changes from baseline in CNV area as measured by FFA at Weeks 40 and 52; (4) changes from baseline in CNV leakage area as measured by FFA at Weeks 40 and 52; and changes from baseline in total leasion area as measured by FFA at Weeks 40 and 52.
  • -Dosing intervals proportion of subjects receiving treatment of efdamrofusp alfa at Q8W and Q12W intervals at Weeks 20, 40, and 52.
  • AE ocular and systemic Adverse Events
  • TEAE Treatment Emergent Adverse Event
  • SAE Severe Adverse Event
  • -Retinal fibrosis (1) proportion of subjects having fibrosis detectable on CFP at Weeks 40 and 52; (2) change from baseline in the maximum diameter, perimeter, and area of fibrosis detected on CFP at Weeks 40 and 52; and (3) changes from baseline in maximum height of fibrosis on SD-OCT at Weeks 40 and 52.
  • -Retinal atrophy (1) change from baseline in total area of MA on SD-OCT at Weeks 40 and 52; (2) change from baseline in MA area on FAF at Weeks 36 and 52; and (3) control of disease activity by efdamrofusp alfa.
  • the demographic distribution (age, sex) in all groups was balanced.
  • the mean baseline B CVA were 57.8 ⁇ 14.17, 54.6 ⁇ 14.13 and 57.2 ⁇ 13.59 ETDRS letters, respectively, and the mean baseline CST were 415.4 ⁇ 146.80 ⁇ m, 449.6 ⁇ 183.65 ⁇ m and 385.2 ⁇ 110.95 ⁇ m, respectively.
  • the baseline average CNV area on FFA were 9.955 ⁇ 9.2758 mm 2 , 8.992 ⁇ 7.4318 mm 2 and 10.029 ⁇ 9.9917 mm 2 , respectively, the baseline average CNV leakage area on FFA were 10.580 ⁇ 10.1027 mm 2 , 10.184 ⁇ 7.0185 mm 2 and 10.580 ⁇ 9.4759 mm 2 , respectively, the baseline average total lesion area on FFA were 10.837 ⁇ 10.3539 mm 2 , 9.750 ⁇ 7.5368 mm 2 and 11.111 ⁇ 11.1325 mm 2 , respectively, and the baseline average IOP were 14.66 ⁇ 2.497 mmHg, 14.58 ⁇ 3.070 mmHg and 14.02 ⁇ 2.324 mmHg, respectively.
  • the proportion of subjects were 52.3%, 51.1%, and 62.8%respectively;
  • the baseline average time since nAMD diagnosis were 1.8 ⁇ 2.28 year (wherein 0.2 ⁇ 0.44 year for the subject and 3.4 ⁇ 2.33 year for the treated subject) , 1.7 ⁇ 2.57 year (wherein 0.7 ⁇ 2.57 year for the subject and 2.8 ⁇ 2.13 year for the treated subject) and 2.0 ⁇ 3.11 year (wherein 0.5 ⁇ 1.41 year for the subject and 4.4 ⁇ 3.67 year for the treated subject) , respectively;
  • the baseline average frequency of IVT anti-VEGF on the treated subject since the diagnosis of nAMD were 8.63 ⁇ 5.795, 9.53 ⁇ 6.577 and 8.38 ⁇ 5.328, respectively.
  • the primary endpoint was the change from baseline in BCVA of the study eye.
  • the observed BCVA changes from baseline in the efdamrofusp alfa-6.4 mg group, the efdamrofusp alfa-8 mg group, and the aflibercept-2 mg group were 10.48 ETDRS letters, 11.00 ETDRS letters, and 9.78 ETDRS letters, respectively
  • the least square means (LSM) of BCVA changes from baseline in the efdamrofusp alfa-6.4 mg group, the efdamrofusp alfa-8 mg group, and the aflibercept-2 mg group at Week 40 were 10.53 ⁇ 1.50 ETDRS letters, 9.17 ⁇ 1.49 ETDRS letters, and 9.69 ⁇ 1.52 ETDRS letters, respectively.
  • the difference in LSM of BCVA changes from baseline in the efdamrofusp alfa-6.4 mg group and the efdamrofusp alfa-8 mg group were 0.84 ⁇ 2.10 letters of ETDRS (2-sided 80%CI: -1.87, 3.55) and -0.52 ⁇ 2.12 letters o f ETDRS (2-sided 80%CI: -3.25, 2.21) , respectively, as compared with the aflibercept-2 mg group.
  • the mean changes from baseline in BCVA of efdamrofusp alfa-6.4 mg group and efdamrofusp alfa-8 mg group were nonin
  • the observed BCVA changes from baseline in the efdamrofusp alfa-6.4 mg group, the efdamrofusp alfa-8 mg group, and the aflibercept-2 mg group were 10.79 ETDRS letters, 11.26 ETDRS letters, and 10.03 ETDRS letters, respectively.
  • the secondary endpoints included vision-related efficacy, SD-OCT anatomy-related efficacy and FFA anatomy-related efficacy.
  • the Q12W subgroup showed a more stable BCVA gain than the Q8W subgroup.
  • the observed value of mean change in CST from baseline in efdamrofusp alfa-6.4 mg group, efdamrofusp alfa-8 mg group and aflibercept 2 mg group were -163.19 ⁇ m, -184.46 ⁇ m and -108.23 ⁇ m, respectively;
  • the LSM changes in CST from baseline in the efdamrofusp alfa-6.4 mg group, the efdamrofusp alfa-8 mg group and the aflibercept-2 mg group were -157.45 ⁇ 9.87 ⁇ m, -161.93 ⁇ 10.00 ⁇ m and -126.65 ⁇ 10.21 ⁇ m, respectively;
  • the efdamrofusp alfa-6.4 mg group and the efdamrofusp alfa-8 mg group had difference in LSM changes in CST from baseline of-30.80 ⁇ 14.05 ⁇ m (2-sided 80%CI: -48.92, -12
  • the observed value of mean change in CST from baseline in efdamrofusp alfa-6.4 mg group, efdamrofusp alfa-8 mg group and aflibercept 2 mg group were -154.58 ⁇ m, -174.69 ⁇ m and -131.18 ⁇ m, respectively.
  • the LSM value and/or the observed value showed that both the efdamrofusp alfa-6.4 mg group and the efdamrofusp alfa-8 mg group have a greater change of CST from baseline than the aflibercept 2 mg group at Week 40 and Week 52.
  • the efdamrofusp alfa-8 mg group showed significantly greater reduction of CST from baseline than the efdamrofusp alfa-6.4 mg group at Week 40 and Week 52.
  • the Q12W subgroup showed a more stable CST reduction than the Q8W subgroup.
  • the proportion of subjects having serous PED, IRF, SRF, or retinal fluid in the center subfield As shown in FIGs. 12A-12C, the proportions of subjects having serous PED, IRF, SRF on OCT were similar in efdamrofusp alfa-6.4 mg group, efdamrofusp alfa-8 mg group and aflibercept 2 mg group at Week 40 and Week 52. As shown in FIG. 12A-12C, the proportions of subjects having serous PED, IRF, SRF on OCT were similar in efdamrofusp alfa-6.4 mg group, efdamrofusp alfa-8 mg group and aflibercept 2 mg group at Week 40 and Week 52. As shown in FIG.
  • the LSM changes in CNV areas from baseline in efdamrofusp alfa-6.4 mg group, efdamrofusp alfa-8 mg group and aflibercept 2 mg group were -2.18 ⁇ 0.405 mm 2 , -1.83 ⁇ 0.421 mm 2 and -1.63 ⁇ 0.422 mm 2 , respectively.
  • the LSM changes in CNV leakage area from baseline in efdamrofusp alfa-6.4 mg group, efdamrofusp alfa-8 mg group and aflibercept 2 mg group were -6.43 ⁇ 1.045 mm 2 , -5.44 ⁇ 1.117 mm 2 and -7.13 ⁇ 1.009 mm 2 , respectively.
  • the LSM changes in total lesion areas from baseline in efdamrofusp alfa-6.4 mg group, efdamrofusp alfa-8 mg group and aflibercept 2 mg group were -1.89 ⁇ 0.398 mm 2 , -2.09 ⁇ 0.413 mm 2 and -2.17 ⁇ 0.416 mm 2 , respectively.
  • Table 5 Total lesion area changes from baseline at Week 40 and Week 52
  • the exploratory endpoints included evaluation of retinal fibrosis and retinal atrophy.
  • the proportions of subjects with newly formed MA in the efdamrofusp alfa-6.4 mg group, the efdamrofusp alfa-8 mg group and the aflibercept-2 mg group were 4.7%, 5.1%and 7.7%respectively.
  • PE primary endpoint
  • IOI intraocular inflammation
  • data are mean (SD) or n (%)
  • Eligible subjects are randomly assigned 1: 1 to efdamrofusp alfa group and aflibercept group, 300 subjects each.
  • Subjects are stratified based on: (1) whether the study eye has type II CNV detectable by OCT, and (2) whether the study eye has previously received anti-VEGF treatment. At least 50%of the subjects have type II CNV detectable by OCT in the study eye, and at least 50%of the subjects have not previously received anti-VEGF treatment in the study eye.
  • Secondary objectives (1) to evaluate other therapeutic effects of efdamrofusp alfa on vision in the treatment of nAMD; (2) to evaluate the anatomy-related efficacy of efdamrofusp alfa in the treatment of nAMD; (3) to evaluate the dosing intervals of efdamrofusp alfa; (4) to evaluate the effects of efdamrofusp alfa on visual acuity related quality of life; (5) to evaluate the safety of efdamrofusp alfa; (6) to evaluate the systemic pharmacokinetics (PK) profile of intravitreal injection of efdamrofusp alfa; and (7) to evaluate the immunogenicity profile of efdamrofusp alfa.
  • PK systemic pharmacokinetics
  • Exploratory objectives (1) to explore other effects of efdamrofusp alfa on retinal fibrosis; and (2) to explore other effects of efdamrofusp alfa on macular atrophy (MA) .
  • MA macular atrophy
  • Subjects must meet the following criteria to be included in this study: (1) having signed informed consent; (2) aged ⁇ 50; (3) having active subfoveal CNV secondary to nAMD or active CNV involving the fovea (active CNV is defined as the presence of intra-or subretinal fluid detectable by OCT or the presence of fluorescence leakage detected by FFA; the fovea is defined as the circle with a diameter of 1 mm centered on the foveal pit) ; and (4) at the baseline, BCVA of the study eye falls within the range of 19 to 78 ETDRS letters (inclusive of both end values) .
  • Efdamrofusp alfa 0.2 ml: 16 mg per vial.
  • Excipients 2.94 mg/ml sodium citrate (dihydrate) , 13.94 mg/ml arginine, 50.00 mg/ml sucrose, 0.3 mg/ml polysorbate 20, pH 6.2.
  • Control drug aflibercept 0.1 ml: 4 mg per vial.
  • Excipients 10 mmol/L sodium phosphate, 40 mmol/L sodium chloride, 5%sucrose, 0.03%polysorbate 20, pH 6.2.
  • Q4W once every 4 weeks
  • Q8W once every 8 weeks
  • Q12W once every 12 weeks
  • Q16W once every 16 weeks.
  • the treatment period of the study starts on Day 0 (D0) and lasts until Week 96.
  • the activity control (aflibercept) group From D0 to Week 8, all subjects receive a loading dose of 2 mg once every 4 weeks (3 times total at D0, Week 4 and Week 8) ; from Week 12 to Week 96, subjects visit study center once every 4 weeks, and receive 2 mg of aflibercept once every 8 weeks (i.e., total of 11 treatments at Weeks 16, 24, 32, 40, 48, 56, 64, 72, 80, 88 and 96) .
  • the efdamrofusp alfa group All subjects receive a loading dose of 8 mg efdamrofusp alfa every 4 weeks from D0 to Week 8 (i.e., 3 times total at D0, Week 4 and Week 8) ; from Week 12 to Week 96, subjects visit study center once every 4 weeks, and receive disease activity ( “DA” ) evaluation at Weeks 16 and 20. Dosing interval is to be adjusted according to DA evaluation.
  • DA is considered “present” if any of the following five criteria is met: (1) the CST on this visit is increased by > 50 ⁇ m compared with the average CST of the previous two scheduled visits; (2) the CST on this visit is increased by ⁇ 75 ⁇ m compared with the lowest CST of the previous two scheduled visits; (3) the BCVA on this visit is lowered by ⁇ 5 letters compare to the average of the previous two scheduled visits due to the progression of nAMD; (4) the BCVA on this visit is lowered by ⁇ 10 letters compare to the best result of the previous two scheduled visits due to the progression of nAMD; (5) occurrence of a macular hemorrhage on this visit due to the progression of nAMD.
  • the subsequent dosing interval is adjusted to Q8W (i.e., 11 doses administered at Weeks 16, 24, 32, 40, 48, 56, 64, 72, 80, 88, and 96) ; if no DA at Week 16, the DA is assessed again at Week 20. If DA is present at Week 20, the subsequent dosing interval is adjusted to Q12W (i.e., 7 doses administered at Weeks 20, 32, 44, 56, 68, 80, and 92) , if still no DA at Week 20, the subsequent dosing interval is adjusted to Q16W (i.e., 5 doses administered at Weeks 24, 40, 56, 72, and 88) .
  • Q8W i.e., 11 doses administered at Weeks 16, 24, 32, 40, 48, 56, 64, 72, 80, 88, and 96
  • Remedial treatment There is no remedial treatment. Subjects who meet the following criteria will be evaluated by investigator and can exit the study and receive other treatment: due to nAMD disease activity, the BCVA is decreased by ⁇ 15 letters compared to baseline on a visit at Week 24 or later.
  • the primary endpoint is the change from baseline in mean BCVA at Weeks 44, 48, and 52. To maintain blinding status, subjects will receive sham injections at all scheduled non-dosing visits (except for Week 12) .
  • the last visit is scheduled at Week 100.
  • Intravitreal injections are used for all treatments.
  • the assessment of efficacy includes vision assessment and anatomical assessment.
  • Anatomical assessment includes using Spectral-Domain Optical Coherence Tomography (SD-OCT) , Color Fundus Photography (CFP) , and Fluorescein Fundus Angiography (FFA) for retinal imaging and angiograph.
  • SD-OCT Spectral-Domain Optical Coherence Tomography
  • CFP Color Fundus Photography
  • FFA Fluorescein Fundus Angiography
  • PK values and immunogenicity of efdamrofusp alfa; treatment-emergent adverse events (TEAEs) , treatment-emergent SAEs are also measured and summarized across treatment groups during the study period.
  • Primary endpoint Change from baseline in the mean BCVA score in the study eye, as measured by the ETDRS visual acuity chart, at Weeks 44, 48, and 52.
  • Secondary endpoint-main Proportion of subjects with neither intraretinal fluid (IRF) nor subretinal fluid (SRF) in the study eye as detectable by OCT at week 16.
  • IRF intraretinal fluid
  • SRF subretinal fluid
  • Anatomy-related efficacy (a) Change from baseline in the CST of macula detectable by OCT at Weeks 52 and 100; (b) proportion of subjects with IRF/SRF/Pigment epithelial detachment (PED) detectable by OCT at Weeks 52 and 1 00; (c) proportion of subjects of with new MA detectable by OCT at Weeks 52 and 100; (d) proportion of retinal fibrosis on color fundus photography (CFP) at Weeks 52 and 100; (e) changes from baseline in CNV area measured by fundus fluorescence angiography (FFA) at Weeks 52 and 100; (f) changes from baseline in CNV leakage area measured by FFA at Weeks 52 and 100; (g) changes from baseline in total lesion area measured by FFA at Weeks 52 and 1 00.
  • CFP retinal fibrosis on color fundus photography
  • Dosing intervals (a) Proportion of subjects in efdamrofusp alfa group receiving treatment in Q8W, Q12W and Q16W intervals at Weeks 52 and 100; (b) proportion of subjects in each group receiving retreatment at Weeks 52 and 100.
  • PK Descriptive statistics of serum drug concentrations.
  • retinal fibrosis in the study eye changes from baseline in the fibrosis area and the diameter of the largest lesion measured by CFP at Weeks 52 and 100.

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Abstract

L'invention concerne des méthodes de traitement de la dégénérescence maculaire liée à l'âge néovasculaire ("nAMD") et de l'oedème maculaire diabétique ("DME") chez un sujet en ayant besoin à l'aide d'une protéine de fusion qui inhibe à la fois les voies VEGF et complément (par exemple, efdamrofusp alfa). L'invention concerne, entre autres, des régimes de traitement comprenant une phase de chargement et une phase de maintenance.
PCT/CN2024/112767 2023-08-17 2024-08-16 Méthodes de traitement de la dégénérescence maculaire liée à l'âge et de l'oedème maculaire diabétique Pending WO2025036488A1 (fr)

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