Methods for treating ophthalmic conditions

Abstract

The present invention relates to a method for treating a subject having risk factors for progression to iRORA, iRORA, nGA, cRORA, GA, AMD, intermediate AMD, dry AMD, and / or wet AMD in a subject in need thereof, comprising administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof. The present invention also relates to a method for treating an ophthalmic disease, disorder, and / or condition in a subject having high-risk drusen, comprising administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof.

Description

Technical Field

[0001] Cross - reference to related applications This application claims the benefit of U.S. Provisional Application No. 63 / 108,427, filed on November 1, 2020; U.S. Provisional Application No. 63 / 108,428, filed on November 1, 2020; U.S. Provisional Application No. 63 / 212,102, filed on June 17, 2021; and U.S. Provisional Application No. 63 / 212,098, filed on June 17, 2021, and U.S. Provisional Application No. 63 / 257,565, and incorporates all of them by reference in their entirety.

[0002] Sequence listing The sequence listing related to this application is provided in text format instead of a written copy and is incorporated herein by reference. The text file name containing the sequence listing is seq.txt. This text file is approximately 4 KB, was created on November 1, 2020, and was submitted via EFS - Web using a computer.

[0003] The present invention relates to a method for treating a subject having a risk factor for progression to iRORA, iRORA, nGA, cRORA, GA, AMD, intermediate AMD, dry AMD, and / or wet AMD, including a subject having a high - risk drusen, the method comprising administering an effective amount of an anti - C5 agent or a pharmaceutically acceptable salt thereof.

Background Art

[0004] Age - related macular degeneration ( "AMD") is a disease characterized by progressive degenerative abnormalities in the macula, the area at the center of the retina. Age - related macular degeneration is a complex and gradually progressive eye disorder that can lead to distortion and / or blind spots (scotomas), changes in dark adaptation (diagnosis of the health of rod cells), changes in color interpretation (diagnosis of the health of cone cells), decreased visual acuity, or irreversible blindness.

[0005] AMD is typically a disease of the elderly and is the leading cause of blindness in people over 50 in developed countries. In the United States, it is estimated that approximately 6% of people aged 65-74 and 20% of people aged 75 and over have AMD. With life expectancy increasing in both developed and developing countries, the elderly portion of the population is expected to increase at its largest rate over the next few decades. Without adequate preventive or therapeutic measures, the number of cases of AMD with vision loss is expected to increase with age.

[0006] Non-exudative AMD is a non-neovascular ("dry") form of the disease. Dry AMD accounts for approximately 90% of all AMD cases. Dry AMD can be characterized by macular degeneration, which, if left untreated for several years, can eventually lead to central retinal atrophy with central visual field loss, also known as geographic atrophy. Dry AMD is a major cause of moderate to severe central visual field loss and is bilateral in most patients. In dry AMD, thinning of retinal pigment epithelial cells (RPE) in the macula occurs along with other age-related changes in the adjacent retinal tissue layers.

[0007] Choroidal neovascularization can be an early sign of wet AMD. When neovascularization occurs in non-exudative AMD and leakage begins, the disease is called exudative AMD, or the ("wet") form of the disease ("wet AMD"), while non-exudative AMD remains present in the patient and continues to progress potentially. Wet AMD, especially if left untreated, can suddenly cause often substantial loss of central vision.

[0008] Recent advances in imaging technology, specifically optical coherence tomography ("OCT"), and more specifically spectral domain optical coherence tomography ("SD-OCT"), have enabled the reproducible and reliable measurement of morphological changes in the eyes of subjects exhibiting AMD disease and the monitoring of disease progression over time. Such disease conditions include incomplete retinal pigment epithelium ("RPE") and outer retinal atrophy ("iRORA"), risk factors for progression to iRORA, mid-stage AMD, complete RPE and outer retinal atrophy ("cRORA"), nascent geographic atrophy ("nGA"), and / or geographic atrophy ("GA"). See, for example, Guymer et al., Incomplete Retinal Pigment Epithelial and Outer Retinal Atrophy in Age-Related Macular Degeneration: Classification of Atrophy Meeting Report 4, Ophthalmology 2020; Vol. 127: pp. 394-409; also see Wu et al., Optical Coherence Tomography-Defined Changes Preceding the Development of Drusen-Associated Atrophy in Age-Related Macular Degeneration, Ophthalmology 2014; Vol. 121: pp. 2415-2422.

[0009] Drusens are localized accumulations of extracellular material (including lipids and proteins) typically located between the basement membrane of the RPE and the collagenous layer inside Bruch's membrane. Drusens are considered one of the earliest signs of AMD. Drusens are dynamic structures that can increase in size, fuse, or disappear, and whose number, shape, and distribution can change. Drusens can experience repeated cycles of growth and contraction. Some morphological features of drusens are associated with an increased risk of progression to late AMD, including GA, macular neovascularization, or both.

[0010] Studies measuring the natural progression of drusen morphology have identified three distinct drusen growth patterns. See Filho et al., Change in Drusen Volume as a Novel Clinical Trial Endpoint for the Study of Complement Inhibition in Age-related Macular Degeneration, Ophthalmic Surg Lasers Imaging Retina. 2014; Vol. 45: pp. 18-31 at 18. For example, most eyes showed an increase in drusen volume, while some eyes showed a stable drusen morphology. Some eyes showed a decrease in drusen volume without apparent sequelae, which was shown to be a "rare event." See the same literature. Furthermore, it is possible that the pathological processes responsible for disease progression at different stages of the disease may differ. See, for example, Schaal et al., Anatomic Clinical Trial Endpoints for Nonexudative Age-Related Macular Degeneration, Ophthalmology 2016, Vol. 123: pp. 1060-1079 at 1075. Therefore, for example, an effective therapy to delay the onset of GA in late-stage AMD may or may not be beneficial when applied to an earlier stage of the disease. (Ibid.)

[0011] Therefore, there is a need for therapies to treat patients with high-risk drusen, risk factors for progression to iRORA, iRORA, nGA, cRORA, GA, AMD, intermediate-stage AMD, dry AMD, and / or wet AMD. [Prior art documents] [Patent Documents]

[0012] [Patent Document 1] U.S. Patent No. 10,526,315 [Patent Document 2] U.S. Patent No. 10,730,832 [Patent Document 3] U.S. Patent Application Publication No. 16 / 312,247 [Non-patent literature]

[0013] [Non-Patent Document 1] Guymer et al., Incomplete Retinal Pigment Epithelial and Outer Retinal Atrophy in Age-Related Macular Degeneration: Classification of Atrophy Meeting Report 4, Ophthalmology 2020; 127: 394-409 [Non-Patent Document 2] Wu et al., Optical Coherence Tomography-Defined Changes Preceding the Development of Drusen-Associated Atrophy in Age-Related Macular Degeneration, Ophthalmology 2014;121:2415~2422 [Non-Patent Document 3] Filho et al., Change in Drusen Volume as a Novel Clinical Trial Endpoint for the Study of Complement Inhibition in Age-related Macular Degeneration, Ophthalmic Surg Lasers Imaging Retina. 2014;45:18-31 at 18 [Non-Patent Document 4] Schaal et al., Anatomic Clinical Trial Endpoints for Nonexudative Age-Related Macular Degeneration, Ophthalmology 2016, Vol. 123: pp. 1060-1079 at 1075 [Non-Patent Document 5] Garcia-Layana et al., Clinical Interventions in Aging 2017;12:1579-1587 [Non-Patent Document 6] National Technical Information Service, 5285 Port Royal Road, Springfield, VA 22161; Accession No. PB8S 223006 / AS; Ferris et al., Am J Ophthalmol 94:91-96, 1982 [Non-Patent Document 7] https: / / www.ophthalmologyweb.com / Neuro-Ophthalmology / 5650-ETDRS-Visual-Acuity-Charts / Compare / ?compare=55134,49475,55138,55135,55420&catid=5650 [Summary of the Invention] [Means for Solving the Problems]

[0014] Aspects of the present invention relate to methods of treating a subject having risk factors for progression to iRORA.

[0015] Aspects of the present invention relate to methods of treating a subject having iRORA.

[0016] Aspects of the present invention relate to methods of treating a subject having nGA.

[0017] Aspects of the present invention relate to methods of treating a subject having cRORA. ]>

[0018] Aspects of the present invention relate to methods of treating a subject having early AMD.

[0019] \[[ID=]38] Aspects of the present invention relate to methods of treating a subject having intermediate AMD.

[0020] Aspects of the present invention relate to methods useful for treating ophthalmic diseases or disorders in subjects having high-risk drusen.

[0021] Aspects of the present invention relate to methods of treating a subject having high-risk drusen.

[0022] Aspects of the present invention relate to methods of treating a subject having high-risk drusen and risk factors for progression to iRORA.

[0023] Aspects of the present invention relate to methods of treating a subject having high-risk drusen and risk factors for progression to cRORA.

[0024] Aspects of the present invention relate to methods of treating a subject having high-risk drusen and iRORA.

[0025] Aspects of the present invention relate to methods of treating a subject having high-risk drusen and nGA.

[0026] Aspects of the present invention relate to methods of treating a subject having high-risk drusen and cRORA.

[0027] [[ID=�]]Aspects of the present invention relate to methods of treating a subject having high-risk drusen and GA.

[0028] Aspects of the present invention relate to methods of treating a subject having high-risk drusen and AMD.

[0029] Aspects of the present invention relate to methods of treating a subject having high-risk drusen and intermediate AMD.

[0030] Aspects of the present invention relate to methods of treating a subject having high-risk drusen and dry AMD.

[0031] Aspects of the present invention relate to methods of treating a subject having high-risk drusen and wet AMD.

[0032] One aspect of the present invention relates to a method for treating subjects having drusen with a diameter of <63 μm.

[0033] One aspect of the present invention relates to a method for treating subjects having drusen with a diameter of ≥63 μm and <125 μm.

[0034] One aspect of the present invention relates to a method for treating subjects having drusen with a diameter of ≥125 μm.

[0035] One aspect of the present invention relates to a method for treating subjects having drusen with a diameter of less than 63 μm.

[0036] One aspect of the present invention relates to a method for treating subjects having drusen with a diameter between 63 μm and less than 125 μm.

[0037] One aspect of the present invention relates to a method for treating subjects having drusen with a diameter of 125 μm or more.

[0038] One aspect of the present invention relates to a method for treating subjects having drusen with a diameter of approximately <63 μm.

[0039] One aspect of the present invention relates to a method for treating subjects having drusen with a diameter of approximately ≥63 μm and <125 μm.

[0040] One aspect of the present invention relates to a method for treating subjects having drusen with a diameter of approximately ≥125 μm.

[0041] Aspects of the present invention relate to methods for treating subjects with high-risk drusen and early, mid-stage, or late-stage AMD.

[0042] Aspects of the present invention relate to a method for treating ophthalmic diseases, disorders, and / or conditions, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject in need having (i) high-risk drusen and (ii) an ophthalmic disease, disorder, and / or condition selected from the group consisting of iRORA, nGA, cRORA, GA, AMD, intermediate-stage AMD, dry AMD, and wet AMD.

[0043] Aspects of the present invention relate to a method for treating ophthalmic diseases, disorders, and / or conditions, comprising the steps of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject in need having (i) high-risk drusen and (ii) an ophthalmic disease, disorder, and / or condition selected from the group consisting of iRORA, nGA, cRORA, GA, AMD, intermediate-stage AMD, dry AMD, and wet AMD, wherein the progression of the ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0044] Aspects of the present invention relate to a method for treating ophthalmic diseases, disorders, and / or conditions, comprising the steps of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject in need having (i) high-risk drusen and (ii) an ophthalmic disease, disorder, and / or condition selected from the group consisting of iRORA, nGA, cRORA, GA, AMD, intermediate-stage AMD, dry AMD, and wet AMD, wherein at least one characteristic of the drusen (e.g., number, degree, area, volume, shape, density, and reflectance) is reduced, slowed, suppressed, prevented, improved, and / or restored.

[0045] Aspects of the present invention relate to a method for treating an ophthalmic disease, disorder, and / or condition, comprising the steps of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject in need having an ophthalmic disease, disorder, and / or condition selected from the group consisting of (i) high-risk drusen and (ii) risk factors for progression to iRORA, iRORA, nGA, cRORA, GA, AMD, intermediate-stage AMD, dry AMD, and wet AMD, wherein the progression of the ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or restored, and at least one characteristic of the drusen (e.g., number, degree, area, volume, shape, density, and reflectance) is reduced, slowed, inhibited, prevented, improved, and / or restored.

[0046] Aspects of the present invention relate to a method for treating an ophthalmic disease, disorder, and / or condition selected from the group consisting of risk factors for progression to iRORA, iRORA, nGA, intermediate-stage AMD, and cRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject in need.

[0047] Aspects of the present invention relate to a method for treating an ophthalmic disease, disorder, and / or condition selected from the group consisting of iRORA, nGA, cRORA, GA, AMD, intermediate-stage AMD, dry AMD, and wet AMD, in which the subject has high-risk drusen, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to the subject in need.

[0048] Aspects of the present invention relate to a method for treating an ophthalmic disease, disorder, and / or condition selected from the group consisting of risk factors for progression to iRORA, iRORA, nGA, mid-stage AMD, and cRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the progression of the ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0049] Aspects of the present invention relate to a method for treating an ophthalmic disease, disorder, and / or condition selected from the group consisting of risk factors for progression to iRORA, iRORA, nGA, cRORA, GA, AMD, intermediate-stage AMD, dry AMD, and wet AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the subject has high-risk drusen, and the progression of the ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0050] Aspects of the present invention relate to a method for treating an ophthalmic disease, disorder, and / or condition selected from the group consisting of risk factors for progression to iRORA, iRORA, nGA, mid-stage AMD, and cRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein at least one characteristic of the drusen (e.g., number, degree, area, volume, shape, density, and reflectance) is reduced, slowed, suppressed, prevented, improved, and / or restored.

[0051] Aspects of the present invention relate to a method for treating an ophthalmic disease, disorder, and / or condition selected from the group consisting of risk factors for progression to iRORA, iRORA, nGA, cRORA, GA, AMD, intermediate-stage AMD, dry AMD, and wet AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the subject has high-risk drusen, and at least one characteristic of the drusen (e.g., number, degree, area, volume, shape, density, and reflectance) is reduced, slowed, suppressed, prevented, improved, and / or restored.

[0052] Aspects of the present invention relate to a method for treating an ophthalmic disease, disorder, and / or condition selected from the group consisting of risk factors for progression to iRORA, iRORA, nGA, mid-stage AMD, and cRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the progression of the ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or restored, and at least one feature of a drusen (e.g., number, degree, area, volume, shape, density, and reflectance) is reduced, slowed, inhibited, prevented, improved, and / or restored.

[0053] Aspects of the present invention relate to a method for treating an ophthalmic disease, disorder, and / or condition selected from the group consisting of risk factors for progression to iRORA, iRORA, nGA, cRORA, GA, AMD, intermediate-stage AMD, dry AMD, and wet AMD, comprising the steps of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the subject has high-risk drusen, and the progression of the ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or restored, and at least one characteristic of the drusen (e.g., number, degree, area, volume, shape, density, and reflectance) is reduced, slowed, inhibited, prevented, improved, and / or restored.

[0054] Aspects of the present invention relate to a therapeutic method in which an anti-C5 agent comprises a C5-specific aptamer having the sequence fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T (SEQ ID NO: 1), where fC and fU = 2' fluoronucleotides, mG and mA = 2'-OMe nucleotides, all other nucleotides are 2'-OH, and 3T represents inverted deoxythymidine.

[0055] Aspects of the present invention relate to administering an anti-C5 agent together with another agent, such as an HTRA1 inhibitor compound or a VEGF antagonist. [Brief explanation of the drawing]

[0056] [Figure 1] This figure shows a bar graph comparing the progression from large drusen to iRORA or cRORA at 6, 12, and 18 months after administration of 2 mg of anti-C5 agent versus a sham. [Figure 2] This figure shows the data in Figure 1 as a line graph. [Figure 3] This figure shows a bar graph comparing the progression from iRORA to cRORA at 6 months, 12 months, and 18 months after administration of 2 mg of anti-C5 agent versus a simulated drug. [Figure 4] This figure shows the data in Figure 3 as a line graph. [Figure 5] This figure shows a table comparing the basic characteristics of GA lesion size, presence of large drusen, presence of iRORA, lesion site, and lesion localization in subjects who received 2 mg or a simulated anti-C5 agent. [Figure 6] This figure shows a graph comparing the least-squares mean change in baseline GA area at 6 and 12 months after administration of 2 mg of anti-C5 agent versus a simulated agent. [Figure 7] This figure shows a graph comparing the least-squares mean change from baseline in the square root GA area at 6 months, 12 months, and 18 months after administration of 2 mg of anti-C5 agent versus a simulated agent. [Modes for carrying out the invention]

[0057] One aspect of the present invention relates to a method for treating an ophthalmic disease, disorder, and / or condition selected from the group consisting of risk factors for progression to iRORA, iRORA, nGA, mid-stage AMD, and cRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject in need.

[0058] One aspect of the present invention relates to a method and composition useful for treating subjects having (i) high-risk drusen and (ii) ophthalmic diseases, disorders and / or conditions selected from the group consisting of iRORA, nGA, cRORA, GA, AMD, intermediate-stage AMD, dry AMD, and wet AMD, comprising the step of administering a pharmaceutically acceptable amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof.

[0059] Another aspect of the present invention relates to a method for treating an ophthalmic disease, disorder, and / or condition selected from the group consisting of risk factors for progression to iRORA, iRORA, nGA, cRORA, GA, AMD, intermediate-stage AMD, dry AMD, and wet AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the subject has high-risk drusen.

[0060] Anti-C5 agents The term "anti-C5 agent" refers to a drug that partially or completely reduces or inhibits the activity or production of C5 complement protein or its variants. Anti-C5 agents can directly or indirectly reduce or inhibit the activity or production of C5 complement protein or its variants. Anti-C5 agents can reduce or inhibit the conversion of C5 complement protein to its component polypeptides C5a and C5b. Anti-C5 agents can also reduce or inhibit the activity or production of C5a and / or C5b.

[0061] In embodiments of the present invention, the anti-C5 agent comprises a C5-specific aptamer, the aptamer comprising the nucleotide sequence fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUAfCfCfUmGfCmG-3T (SEQ ID NO: 1), where fC and fU are 2'-fluoronucleotides, mG and mA are 2'-OMe nucleotides, all other nucleotides are 2'-OH, and 3T represents reverse deoxythymidine.

[0062] In some embodiments, the aptamer can be bonded to a polyethylene glycol moiety (PEG) via a linker. The PEG moiety may have a molecular weight greater than about 10 kDa, for example, about 20 kDa, or about 30 kDa, or about 40 kDa, or about 50 kDa, or about 60 kDa. In some embodiments, the PEG moiety is bonded to the 5' end of the aptamer via a linker. In some embodiments, the PEG moiety bonded to the 5' end has a molecular weight of about 40 kDa. In detailed embodiments, the PEG moiety of about 40 kDa is a branched PEG moiety. The branched PEG moiety of about 40 kDa may be, for example, 1,3-bis(mPEG-[about 20 kDa])-propyl-2-(4'-butamide) or 2,3-bis(mPEG-[about 20 kDa])-propyl-1-carbamoyl.

[0063] The term "approximately," when used in relation to a referenced numerical representation, means a referenced numerical representation within plus or minus 20% of that representation. For example, "approximately 100" means 80 to 120, and "approximately 6" means 4.8 to 7.2. In one embodiment, the values ​​described herein may vary by less than 20% of the referenced numerical representation, for example, 10%, 5%, or less.

[0064] In some embodiments, the aptamer has the following structure

[0065] [ka]

[0066] The compound having ARC187, or a pharmaceutically acceptable salt thereof, the aptamer = fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUAfCfCfUmGfCmG-3T (SEQ ID NO: 1), where fC and fU = 2'-fluoronucleotides, mG and mA = 2'-OMe nucleotides, all other nucleotides are 2'-OH, and 3T represents reverse deoxythymidine. In some embodiments, each 20 kDa mPEG of the above structure has a molecular weight of approximately 20 kDa.

[0067] In some embodiments, the aptamer has the following structure:

[0068] [ka]

[0069] The compound having ARC1905, or a pharmaceutically acceptable salt thereof, the aptamer = fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUAfCfCfUmGfCmG-3T (SEQ ID NO: 1), where fC and fU = 2'-fluoronucleotides, mG and mA = 2'-OMe nucleotides, all other nucleotides are 2'-OH, and 3T represents reverse deoxythymidine. In some embodiments, each 20 kDa mPEG of the above structure has a molecular weight of approximately 20 kDa.

[0070] Examples of pharmaceutically acceptable salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannates, pantothenates, hydrogen tartrates, ascorbic acid, succinates, maleates, gentisinates, fumarates, glucons, glucaronates, saccharates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, camphorsulfonates, pamoates, phenylacetates, trifluoroacetates, acrylates, chlorobenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, and benzoic acid. This includes methyl, o-acetoxybenzoate, naphthalene-2-benzoate, isobutylate, phenylbutyrate, α-hydroxybutyrate, butyn-1,4-dicarboxylate, hexyn-1,4-dicarboxylate, caprirate, caprylate, cinnamate, glycolate, heptanoate, hippurate, malate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, phthalate, terephthalate, propiorate, propionate, phenylpropionate, sebacinate, suberinate, p-bromobenzenesulfonate, chlorobenzenesulfonate, ethylsulfonate, 2-hydroxyethylsulfonic acid, methylsulfonic acid, naphthalene-1-sulfonate, naphthalene-2-sulfonate, naphthalene-1,5-sulfonate, xylenesulfonate, and tartarate salt. The term "pharmaceutically acceptable salt" includes, but is not limited to, hydrates of the compounds of the present invention, and may also mean salts of the antagonists of the present invention having acidic functional groups, such as, but not limited to, carboxylic acid functional groups or hydrogen phosphate functional groups, and a base.Suitable bases include, but are not limited to, alkali metals such as sodium, potassium, and lithium hydroxides; alkaline earth metals such as calcium and magnesium hydroxides; other metals such as aluminum and zinc hydroxides; ammonia; and organic amines such as unsubstituted or hydroxy-substituted mono-, di-, or tri-alkylamines, dicyclohexylamines; tributylamine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-lower alkylamines) such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine; N,N-di-lower alkyl-N-(hydroxyl-lower alkyl)-amines such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine and lysine.

[0071] Early AMD and Druzen In some embodiments, the present invention relates to methods and compositions useful for subjects with incomplete retinal pigment epithelium (RPE) and outer retinal atrophy ("iRORA"). iRORA is an ophthalmic disease, disorder, and / or condition characterized by the following three features, which are vertically aligned and determined by OCT: (1) an area of ​​excessive signal transmission to the choroid, (2) a corresponding zone of RPE attenuation or damage, and (3) evidence or signs of overlying photoreceptor degeneration. Evidence or signs of overlying photoreceptor degeneration include sequestration of the inner granular layer ("INL") and outer plexiform layer ("OPL"), the presence of low-reflectivity wedge shapes in the layer of Henle's fibers ("HFL"), thinning of the outer granular layer ("ONL"), damage to the outer limiting membrane ("ELM"), and incompleteness of the ellipsoidal zone ("EZ"). iRORA should not be used to mean RPE tear. iRORA may progress to cRORA, nGA, GA, Mid-Term AMD, and / or Wet AMD.

[0072] In some embodiments, the present invention relates to methods and compositions useful for subjects with risk factors for progression to iRORA. Subjects exhibiting risk factors for progression to iRORA exhibit some, but not all, of the signs of iRORA, as described above. Furthermore, subjects with high-risk drusen and risk factors for progression to iRORA may also exhibit hyperreflective foci, heterogeneous internal reflectivity of drusen, and / or subretinal drusenoid deposition. Determining whether a subject has risk factors for progression to iRORA can also be achieved by multimodal imaging, which includes, but is not limited to, OCT. Subjects with risk factors for progression to iRORA may progress to iRORA, cRORA, nGA, GA, intermediate-stage AMD, and / or wet-type AMD.

[0073] In some embodiments, the present invention relates to methods and compositions useful for subjects with intermediate-stage AMD. Intermediate-stage AMD is a disease state that is between early-stage AMD, e.g., risk factors for progression to iRORA, and late-stage AMD, e.g., cRORA. In some embodiments, intermediate-stage AMD may include subjects exhibiting drusens, including high-risk drusen and drusen with a diameter greater than 125 μm. In some embodiments, intermediate-stage AMD may include subjects exhibiting drusens, including high-risk drusen and drusen with a diameter greater than 125 μm, and the subjects may also exhibit iRORA. In some embodiments, intermediate-stage AMD may include subjects exhibiting drusens, including high-risk drusen and drusen with a diameter greater than 125 μm, and the subjects may also exhibit iRORA, and the subjects may also exhibit highly reflective lesions.

[0074] In some embodiments, the present invention relates to methods and compositions useful for subjects with nGA. nGA is an ophthalmic disease, disorder, and / or condition characterized by (i) subsidence of the inner granular layer (INL) and outer plexiform later (OPL), and (ii) a low-reflectivity wedge-shaped band within the OPL, including within the layer of Henle fibers. nGA may also occur in association with interference of the RPE and increased excessive signal transmission to the choroid. Furthermore, features frequently present with subsidence of the OPL and INL may include disruption of the inner segment ellipsoid ("ISe"), disruption of the ELM, and traces of increased signal transmission beneath Bruch's membrane. Furthermore, features frequently present with a low-reflectivity wedge-shaped band include vortex-like subsidence of the OPL and INL, retraction of drusen, and traces of increased signal transmission beneath the RPE. The onset of nGA may also occur in conjunction with, or prior to, the regression of some or all drusen, followed by characteristic progressive atrophic changes in the covering retinal layer. nGA may also be associated with and / or occur concurrently with the iRORA disease state. Subjects exhibiting nGA may have previously shown risk factors for progression to iRORA, and subsequently may develop cRORA and / or GA.

[0075] In some embodiments, the present invention relates to methods and compositions useful for subjects with cRORA. cRORA is an ophthalmic disease, disorder, and / or condition that satisfies the requirements of iRORA and further requires evidence of altered RPE area, excessive transmission with a diameter of at least 250 μm in OCT B-scan, and a decrease in photoreceptors. cRORA may progress to nGA, GA, and / or wet-type AMD.

[0076] In some embodiments, the present invention includes a method of administration to subjects having high-risk drusen. High-risk drusen refers to drusen associated with high-risk AMD and / or high-risk disease progression from early AMD to late AMD. High-risk drusen may have any of the following characteristics: For example, high-risk drusen may have at least one drusen with a diameter of at least 250 μm as observed in a biomicroscope or color retinal photograph and / or a total volume of at least 0.03 mm² as measured by SD-OCT, with a circle diameter of 3 mm or less centered on the orbit. 3 It may be characterized by the following: In some embodiments, high-risk drusen may have a diameter of at least 300 μm and may be located within a circle diameter of 500 μm centered on the fossa. In other embodiments, high-risk drusen is characterized by the presence of at least one drusen having a diameter of at least about 150 μm.

[0077] Furthermore, high-risk drusen may be characterized by other morphological features. Additionally, high-risk drusen can be characterized with respect to the maximum height and diameter of the lesion, the internal reflectivity of the lesion, the presence and extent of a highly reflective lesion within the covering retina, and the thickness of the choroid subfovea and beneath the drusen. Furthermore, high-risk drusen may exhibit a highly reflective lesion covering the drusen, heterogeneous internal reflectivity of the drusen, or a choroidal thickness of less than 135 μm below the drusen baseline. Additionally, high-risk drusen may be soft, large, indistinct, and / or confluent.

[0078] Risk factors include, for example, hypertension, obesity, atherosclerosis, localized deposition of acellular organic deposits (detritus) between RPEs, a family history of AMD including genetic risk factors, smoking, high BMI, high-fat diet, low intake of antioxidants and zinc, history of cataract surgery, history of cardiovascular disease, higher-than-average plasma fibrinogen levels, and / or diabetes (see, for example, Garcia-Layana et al., Clinical Interventions in Aging 2017: Vol. 12, pp. 1579-1587, the contents of which are incorporated herein by reference in their entirety).

[0079] In some embodiments, the present invention relates to methods and compositions useful for subjects having high-risk drusen and incomplete RPE and iRORA. In some embodiments, the present invention relates to methods and compositions useful for subjects having risk factors for progression to high-risk drusen and iRORA. In some embodiments, the present invention relates to methods and compositions useful for subjects having high-risk drusen and cRORA. In some embodiments, the present invention relates to methods and compositions useful for subjects having high-risk drusen and nGA.

[0080] In some embodiments, the present invention relates to methods and compositions useful for subjects with high-risk drusen and GA. When the condition is severe, dry AMD results in significant thinning and / or atrophy of the macula, caused by a decrease in the rpectoral vascular area (RPE) and associated capillaries (choroidal capillaries). This form of late dry AMD is associated with thinning and loss of function of the neuroretina located above the affected RPE. This collective phenotype in late dry AMD is referred to as GA. GA may also mean a subset of cRORA, which may occur with or without the presence of current or past macular neovascularization.

[0081] In some embodiments, the present invention relates to methods and compositions useful for objects having drusen (i.e., "drupellets") with a diameter of <63 μm.

[0082] In some embodiments, the present invention relates to methods and compositions useful for objects having drusen with a diameter of ≥63 μm and <125 μm.

[0083] In some embodiments, the present invention relates to methods and compositions useful for subjects having drusen of ≥125 μm.

[0084] In some embodiments, the present invention relates to methods and compositions useful for subjects with high-risk drusen and exudative AMD, for example, when new blood vessels invade the covering retina (i.e., wet AMD).

[0085] In some embodiments, the present invention relates to methods and compositions useful for subjects with high-risk drusen and medium-term AMD.

[0086] In some embodiments, the subject exhibits hyperpigmentation or hypopigmentation. In some embodiments, increased hyperpigmentation is another way of indicating disease progression. In some embodiments, hypopigmentation is associated with a specific disease state.

[0087] SD-OCT provides a particularly reliable and reproducible method for measuring the morphology of drusen over time and other characteristics of AMD. Furthermore, SD-OCT algorithms are available for quantifying drusen features. Such algorithms can be fully automated and can reliably report drusen loading, drusen volume and area using cube root and square root transformations, respectively, as well as morphological changes over time. Advances in imaging using SD-OCT and color fundus imaging have made it possible to test and measure drusen morphology by providing a three-dimensional, geometric assessment. SD-OCT imaging also enables multimodal imaging, identifying drusen (identified as calcified drusen), intraretinal hyperreflectivity lesions, and other macular features that increase the risk of visual acuity loss, including decreased internal reflectivity of subretinal dorsenoid deposits. Instruments used for SD-OCT are known in the art, such as the Cirrus HD-OCT.

[0088] How to use In one embodiment, the present invention relates to a method for treating risk factors for progression to iRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having risk factors for progression to iRORA.

[0089] In one embodiment, the present invention relates to a method for treating iRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having iRORA.

[0090] In one embodiment, the present invention relates to a method for treating nGA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having nGA.

[0091] In one embodiment, the present invention relates to a method for treating intermediate-stage AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having intermediate-stage AMD.

[0092] In one embodiment, the present invention relates to a method for treating cRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having cRORA.

[0093] In one embodiment, the present invention relates to a method for treating risk factors for iRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having risk factors for iRORA, wherein the progression of ophthalmic diseases, disorders, and / or conditions is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0094] In one embodiment, the present invention relates to a method for treating iRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having iRORA, wherein the progression of an ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0095] In one embodiment, the present invention relates to a method for treating nGA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having nGA, wherein the progression of an ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0096] In one embodiment, the present invention relates to a method for treating intermediate-stage AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having intermediate-stage AMD, wherein the progression of the ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0097] In one embodiment, the present invention relates to a method for treating cRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having cRORA, wherein the progression of an ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0098] In one embodiment, the present invention relates to a method for treating a subject with high-risk drusen, comprising the step of administering to the subject with high-risk drusen an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof.

[0099] In one embodiment, the present invention relates to a method for treating ophthalmic diseases, disorders, and / or conditions, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject in need who has risk factors for progression to high-risk drusen and iRORA.

[0100] In one embodiment, the present invention relates to a method for treating ophthalmic diseases, disorders, and / or conditions, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having high-risk drusen and iRORA and requiring such treatment.

[0101] In one embodiment, the present invention relates to a method for treating ophthalmic diseases, disorders, and / or conditions, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having high-risk drusen and nGA and requiring such treatment.

[0102] In one embodiment, the present invention relates to a method for treating an ophthalmic disease, disorder, and / or condition, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having high-risk drusen and intermediate-stage AMD and requiring such treatment.

[0103] In one embodiment, the present invention relates to a method for treating ophthalmic diseases, disorders, and / or conditions, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having high-risk drusen and cRORA and requiring such treatment.

[0104] In one embodiment, the present invention relates to a method for treating ophthalmic diseases, disorders, and / or conditions, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having high-risk drusen and GA, and requiring such treatment.

[0105] In one embodiment, the present invention relates to a method for treating ophthalmic diseases, disorders, and / or conditions, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having high-risk drusen and AMD and requiring such treatment.

[0106] In one embodiment, the present invention relates to a method for treating an ophthalmic disease, disorder, and / or condition, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having high-risk drusen and dry AMD and requiring such treatment.

[0107] In one embodiment, the present invention relates to a method for treating an ophthalmic disease, disorder, and / or condition, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having high-risk drusen and wet-type AMD and requiring such treatment.

[0108] In one embodiment, the present invention relates to a method for treating an ophthalmic disease, disorder, and / or condition, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having a drusen having a diameter of <63 μm.

[0109] In one embodiment, the present invention relates to a method for treating an ophthalmic disease, disorder, and / or condition, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having drusen having a diameter of ≥63 μm and <125 μm.

[0110] In one embodiment, the present invention relates to a method for treating an ophthalmic disease, disorder, and / or condition, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having a drusen with a diameter of ≥125 μm.

[0111] In one embodiment, the present invention relates to a method for treating ophthalmic diseases, disorders, and / or conditions, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject in need who has risk factors for progression to high-risk drusen and iRORA, wherein the progression of the ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0112] In one embodiment, the present invention relates to a method for treating ophthalmic diseases, disorders, and / or conditions, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having high-risk drusen and iRORA, and in need thereof, wherein the progression of the ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0113] In one embodiment, the present invention relates to a method for treating ophthalmic diseases, disorders, and / or conditions, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having high-risk drusen and nGA, and in need thereof, wherein the progression of the ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0114] In one embodiment, the present invention relates to a method for treating an ophthalmic disease, disorder, and / or condition, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having high-risk drusen and intermediate-stage AMD, wherein the progression of the ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0115] In one embodiment, the present invention relates to a method for treating an ophthalmic disease, disorder, and / or condition, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having high-risk factors for progression to drusen and cRORA, wherein the progression of the ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0116] In one embodiment, the present invention relates to a method for treating ophthalmic diseases, disorders, and / or conditions, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having high-risk drusen and cRORA, and in need thereof, wherein the progression of the ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0117] In one embodiment, the present invention relates to a method for treating an ophthalmic disease, disorder, and / or condition, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having high-risk drusen and GA, and in need thereof, wherein the progression of the ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0118] In one embodiment, the present invention relates to a method for treating ophthalmic diseases, disorders, and / or conditions, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having high-risk drusen and AMD and in need thereof, wherein the progression of the ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0119] In one embodiment, the present invention relates to a method for treating an ophthalmic disease, disorder, and / or condition, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having high-risk drusen and dry AMD, wherein the progression of the ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0120] In one embodiment, the present invention relates to a method for treating an ophthalmic disease, disorder, and / or condition, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having high-risk drusen and wet-type AMD, wherein the progression of the ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0121] In one embodiment, the present invention relates to a method for treating an ophthalmic disease, disorder, and / or condition, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having a drusen having a diameter of <63 μm, wherein the progression of the ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0122] In one embodiment, the present invention relates to a method for treating an ophthalmic disease, disorder, and / or condition, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having a drusen having a diameter ≥63 μm and <125 μm, wherein the progression of the ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0123] In one embodiment, the present invention relates to a method for treating an ophthalmic disease, disorder, and / or condition, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having a drusen with a diameter of ≥125 μm, wherein the progression of the ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0124] In one embodiment, the present invention relates to a method for treating ophthalmic diseases, disorders, and / or conditions, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject in need who has high-risk drusen and risk factors for progression to iRORA, wherein progression to iRORA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0125] In one embodiment, the present invention relates to a method for treating ophthalmic diseases, disorders, and / or conditions, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject in need who has high-risk drusen and risk factors for progression to cRORA, wherein progression to cRORA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0126] In one embodiment, the present invention relates to a method for treating ophthalmic diseases, disorders, and / or conditions, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject in need who has high-risk factors for progression to drusen and iRORA, wherein progression to nGA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0127] In one embodiment, the present invention relates to a method for treating ophthalmic diseases, disorders, and / or conditions, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject in need who has high-risk drusen and risk factors for progression to nGA, wherein the progression to nGA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0128] In one embodiment, the present invention relates to a method for treating an ophthalmic disease, disorder, and / or condition, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having high-risk drusen and intermediate-stage AMD, wherein the progression of intermediate-stage AMD to cRORA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0129] In one embodiment, the present invention relates to a method for treating ophthalmic diseases, disorders, and / or conditions, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having high-risk drusen and iRORA, and in need thereof, wherein the progression of iRORA to cRORA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0130] In one embodiment, the present invention relates to a method for treating ophthalmic diseases, disorders, and / or conditions, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having high-risk drusen and iRORA, and in need thereof, wherein the progression of iRORA to GA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0131] In one embodiment, the present invention relates to a method for treating ophthalmic diseases, disorders, and / or conditions, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having high-risk drusen and nGA, in need thereof, wherein the progression of nGA to GA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0132] In one embodiment, the present invention relates to a method for treating ophthalmic diseases, disorders, and / or conditions, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having high-risk drusen and nGA, in need thereof, wherein the progression of nGA to cRORA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0133] In one embodiment, the present invention relates to a method for treating ophthalmic diseases, disorders, and / or conditions, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having high-risk drusen and cRORA, in which the progression of cRORA to wet AMD is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0134] In one embodiment, the present invention relates to a method for treating ophthalmic diseases, disorders, and / or conditions, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having high-risk drusen and GA, and in need thereof, wherein the progression of GA to wet AMD is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0135] In one embodiment, the present invention relates to a method for treating ophthalmic diseases, disorders, and / or conditions, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having high-risk drusen and dry AMD, wherein the progression of dry AMD to wet AMD is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0136] In one embodiment, the present invention relates to a method for treating an ophthalmic disease, disorder, and / or condition, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having a drusen having a diameter of <63 μm, wherein the progression of AMD is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0137] In one embodiment, the present invention relates to a method for treating ophthalmic diseases, disorders, and / or conditions, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having drusen having a diameter of ≥63 μm and <125 μm, wherein the progression of AMD is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0138] In one embodiment, the present invention relates to a method for treating ophthalmic diseases, disorders, and / or conditions, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having a drusen having a diameter of ≥125 μm, wherein the progression of AMD is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0139] In one embodiment, the present invention relates to a method for treating risk factors for progression to iRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having risk factors for progression to iRORA, wherein the subject has high-risk drusen.

[0140] In one embodiment, the present invention relates to a method for treating iRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having iRORA, wherein the subject has high-risk drusen.

[0141] In one embodiment, the present invention relates to a method for treating nGA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having nGA, wherein the subject has high-risk drusen.

[0142] In one embodiment, the present invention relates to a method for treating intermediate-stage AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having intermediate-stage AMD, wherein the subject has high-risk drusen.

[0143] In one embodiment, the present invention relates to a method for treating cRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having cRORA, wherein the subject has high-risk drusen.

[0144] In one embodiment, the present invention relates to a method for treating GA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having GA, wherein the subject has high-risk drusen.

[0145] In one embodiment, the present invention relates to a method for treating AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having AMD, wherein the subject has high-risk drusen.

[0146] In one embodiment, the present invention relates to a method for treating dry AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having dry AMD, wherein the subject has high-risk drusen.

[0147] In one embodiment, the present invention relates to a method for treating wet AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having wet AMD, wherein the subject has high-risk drusen.

[0148] In one embodiment, the present invention relates to a method for treating AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having drusen with a diameter of <63 μm.

[0149] In one embodiment, the present invention relates to a method for treating AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having drusen with a diameter of ≥63 μm and <125 μm.

[0150] In one embodiment, the present invention relates to a method for treating AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having drusen with a diameter of ≥125 μm.

[0151] In one embodiment, the present invention relates to a method for treating risk factors for progression to iRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having risk factors for progression to iRORA, wherein the subject has high-risk drusen, and the progression of ophthalmic disease, impairment, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0152] In one embodiment, the present invention relates to a method for treating iRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having iRORA, wherein the subject has high-risk drusen, and the progression of ophthalmic disease, impairment, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0153] In one embodiment, the present invention relates to a method for treating nGA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having nGA, wherein the subject has high-risk drusen, and the progression of ophthalmic disease, impairment, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0154] In one embodiment, the present invention relates to a method for treating intermediate-stage AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having intermediate-stage AMD, wherein the subject has high-risk drusen, and the progression of the ophthalmic disease, impairment, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0155] In one embodiment, the present invention relates to a method for treating cRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having cRORA, wherein the subject has high-risk drusen, and the progression of ophthalmic disease, impairment, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0156] In one embodiment, the present invention relates to a method for treating GA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having GA, wherein the subject has high-risk drusen, and the progression of the ophthalmic disease, impairment, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0157] In one embodiment, the present invention relates to a method for treating AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having AMD, wherein the subject has high-risk drusen, and the progression of the ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0158] In one embodiment, the present invention relates to a method for treating dry AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having dry AMD, wherein the subject has high-risk drusen, and the progression of ophthalmic disease, impairment, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0159] In one embodiment, the present invention relates to a method for treating wet AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having wet AMD, wherein the subject has high-risk drusen, and the progression of ophthalmic disease, impairment, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0160] In one embodiment, the present invention relates to a method for treating AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having drusen having a diameter of <63 μm, wherein the progression of an ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0161] In one embodiment, the present invention relates to a method for treating AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having drusen having a diameter of ≥63 μm and <125 μm, wherein the progression of ophthalmic disease, impairment, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0162] In one embodiment, the present invention relates to a method for treating AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having drusen with a diameter of ≥125 μm, wherein the progression of an ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0163] In one embodiment, the present invention relates to a method for treating risk factors for progression to iRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having risk factors for progression to iRORA, wherein progression to iRORA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0164] In one embodiment, the present invention relates to a method for treating risk factors for progression to iRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having risk factors for progression to iRORA, wherein the subject has high-risk drusen, and the progression to iRORA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0165] In one embodiment, the present invention relates to a method for treating risk factors for iRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having risk factors for iRORA, wherein the progression of the risk factors to iRORA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0166] In one embodiment, the present invention relates to a method for treating risk factors for iRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having risk factors for iRORA, wherein the subject has high-risk drusen, and the progression of the risk factors for iRORA to iRORA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0167] In one embodiment, the present invention relates to a method for treating risk factors for iRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having risk factors for iRORA, wherein the subject has high-risk drusen, and the progression of the iRORA risk factors to nGA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0168] In one embodiment, the present invention relates to a method for treating risk factors for iRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having iRORA, wherein the progression of the iRORA risk factors to nGA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0169] In one embodiment, the present invention relates to a method for treating risk factors for progression to iRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having risk factors for progression to iRORA, wherein the subject has high-risk drusen, and the progression of the iRORA risk factors to nGA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0170] In one embodiment, the present invention relates to a method for treating iRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having iRORA, wherein the progression of iRORA to cRORA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0171] In one embodiment, the present invention relates to a method for treating iRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having iRORA, wherein the subject has high-risk drusen, and the progression of iRORA to cRORA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0172] In one embodiment, the present invention relates to a method for treating iRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having iRORA, wherein the progression of iRORA to GA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0173] In one embodiment, the present invention relates to a method for treating iRORA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having iRORA, wherein the subject has high-risk drusen, and the progression of iRORA to GA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0174] In one embodiment, the present invention relates to a method for treating nGA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having nGA, wherein the progression of nGA to GA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0175] In one embodiment, the present invention relates to a method for treating nGA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having nGA, wherein the subject has high-risk drusen, and the progression of nGA to GA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0176] In one embodiment, the present invention relates to a method for treating nGA, comprising the step of administering to a subject having nGA an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof, wherein the progression of nGA to cRORA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0177] In one embodiment, the present invention relates to a method for treating nGA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having nGA, wherein the subject has high-risk drusen, and the progression of nGA to cRORA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0178] In one embodiment, the present invention relates to a method for treating intermediate-stage AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having intermediate-stage AMD, wherein the progression of intermediate-stage AMD to nGA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0179] In one embodiment, the present invention relates to a method for treating intermediate-stage AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having intermediate-stage AMD, wherein the subject has high-risk drusen, and the progression of intermediate-stage AMD to nGA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0180] In one embodiment, the present invention relates to a method for treating intermediate-stage AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having intermediate-stage AMD, wherein the progression of intermediate-stage AMD to GA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0181] In one embodiment, the present invention relates to a method for treating intermediate-stage AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having intermediate-stage AMD, wherein the subject has high-risk drusen, and the progression of intermediate-stage AMD to GA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0182] In one embodiment, the present invention relates to a method for treating intermediate-stage AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having intermediate-stage AMD, wherein the progression of intermediate-stage AMD to cRORA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0183] In one embodiment, the present invention relates to a method for treating intermediate-stage AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having intermediate-stage AMD, wherein the subject has high-risk drusen, and the progression of intermediate-stage AMD to cRORA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0184] In one embodiment, the present invention relates to a method for treating cRORA, comprising the step of administering to a subject having cRORA an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof, wherein the progression of cRORA to wet AMD is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0185] In one embodiment, the present invention relates to a method for treating cRORA, comprising the step of administering to a subject having cRORA an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof, wherein the subject has high-risk drusen, and the progression of cRORA to wet AMD is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0186] In one embodiment, the present invention relates to a method for treating intermediate-stage AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having drusen and / or iRORA and / or highly reflective lesions having a diameter greater than 125 μm, wherein the progression of intermediate-stage AMD to cRORA is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0187] In one embodiment, the present invention relates to a method for treating intermediate-stage AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having drusen and / or iRORA and / or highly reflective lesions having a diameter greater than 125 μm, wherein the subject has high-risk drusen and the progression of intermediate-stage AMD to cRORA is reduced, slowed, inhibited, prevented, improved and / or reversed.

[0188] In one embodiment, the present invention relates to a method for treating intermediate-stage AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having intermediate-stage AMD, wherein the progression of intermediate-stage AMD to wet-type AMD is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0189] In one embodiment, the present invention relates to a method for treating intermediate-stage AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having intermediate-stage AMD, wherein the subject has high-risk drusen, and the progression of intermediate-stage AMD to wet-type AMD is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0190] In one embodiment, the present invention relates to a method for treating GA, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having GA, wherein the subject has high-risk drusen, and the progression of GA to wet AMD is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0191] In one embodiment, the present invention relates to a method for treating dry AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having dry AMD, wherein the subject has high-risk drusen, and the progression of dry AMD to wet AMD is reduced, slowed, inhibited, prevented, improved, and / or reversed.

[0192] In one embodiment, the present invention relates to a method for treating early AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having drusen with a diameter of <63 μm, wherein the subject has high-risk drusen, and the progression of drusen with a diameter of <63 μm to drusen with a diameter of ≥63 μm and <125 μm is reduced, slowed, inhibited, prevented, improved and / or reversed.

[0193] In one embodiment, the present invention relates to a method for treating early AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject having drusen having a diameter of ≥63 μm and <125 μm, wherein the subject has high-risk drusen, and the progression of drusen having a diameter of ≥63 μm and <125 μm to drusen having a diameter of ≥125 μm is reduced, slowed, inhibited, prevented, improved and / or reversed.

[0194] In another embodiment, administration of an anti-C5 agent or a pharmaceutically acceptable salt thereof by the method of the present invention reduces, slows, inhibits, prevents, improves, and / or restores at least one feature of drusen (e.g., number, degree, area, volume, shape, density, and reflectance) in subjects having ophthalmic diseases, disorders, and / or conditions selected from the group consisting of risk factors for progression to iRORA, iRORA, nGA, cRORA, GA, AMD, intermediate-stage AMD, dry AMD, and / or wet AMD. In some embodiments, the reduction, slowing, inhibition, prevention, improvement, and / or restoration of at least one feature of drusen (e.g., number, degree, area, volume, shape, density, and reflectance) occurs in conjunction with the absence of apparent sequelae, progression of AMD disease, and / or transition to a more progressive disease state.

[0195] In some embodiments, administration of an anti-C5 agent or a pharmaceutically acceptable salt thereof can reduce, suppress, prevent, slow, and / or restore one or more symptoms of AMD-associated nGA, including, but not limited to, a reduction or loss of central visual field, loss of visual acuity, and a reduction or inability to decipher. In some embodiments, administration of an anti-C5 agent or a pharmaceutically acceptable salt thereof can suppress, prevent, slow, and / or restore one or more tissue- or cellular-level changes associated with AMD-associated nGA, including the growth of GA lesions, the rate of growth or change of nGA lesions, and the formation of drusen under RPE.

[0196] In some embodiments, administration of an anti-C5 agent or a pharmaceutically acceptable salt thereof can reduce, suppress, prevent, slow, and / or restore one or more symptoms of GA secondary to AMD, including, but not limited to, a reduction or loss of central visual field, loss of vision, and a reduction or inability to decipher. In some embodiments, administration of an anti-C5 agent or a pharmaceutically acceptable salt thereof can suppress, prevent, slow, and / or restore one or more tissue- or cellular-level changes associated with GA secondary to AMD, including the growth of GA lesions, the rate of growth or change of GA lesions, and the formation of drusen under RPE.

[0197] In some embodiments, the administration of an anti-C5 agent or a pharmaceutically acceptable salt thereof is carried out intravitreously.

[0198] In some embodiments, a method for treating an ophthalmic disease, disorder, and / or condition comprises administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject in need having an ophthalmic disease, disorder, and / or condition selected from the group consisting of (i) high-risk drusen and (ii) risk factors for progression to iRORA, iRORA, nGA, cRORA, GA, AMD, intermediate-stage AMD, dry-type AMD, and wet-type AMD, such that the progression of the ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or restored, and / or at least one characteristic of the drusen (e.g., number, degree, area, volume, shape, density, and reflectance) is reduced, slowed, inhibited, prevented, improved, and / or restored. In some embodiments, reduction, slowing, inhibition, prevention, improvement, and / or restoration include a reduction in the rate of progression from one disease state to a more progressive disease state. In some embodiments, reduction, gradual mitigation, suppression, prevention, improvement, and / or recovery include a decrease in the rate of AMD transition from early to late stages. In some embodiments, reduction, gradual mitigation, suppression, prevention, improvement, and / or recovery can be determined by comparing morphological features of the eye over a period of time with those of a subject not administered the anti-C5 agent or a pharmaceutically acceptable salt thereof, or with the subject's own baseline or previous state. In such embodiments, such comparisons may be made at baseline, with the first or early administration of the anti-C5 agent or a pharmaceutically acceptable salt thereof, and at least or about 1 month, at least or about 2 months, at least or about 3 months, at least or about 4 months, at least or about 5 months, at least or about 6 months, at least or about 7 months, at least or about 8 months, at least or about 9 months, at least or about 10 months, at least or about 11 months, at least or about 12 months, at least or about 15 months, at least or about 18 months, or at least or about 24 months.

[0199] In some embodiments, a method for treating an ophthalmic disease, disorder, and / or condition selected from the group consisting of risk factors for progression to iRORA, iRORA, nGA, cRORA, GA, AMD, intermediate-stage AMD, dry AMD, and / or wet AMD comprises the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the progression of the ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or restored, and / or at least one characteristic of the drusen (e.g., number, degree, area, volume, shape, density, and reflectance) is reduced, slowed, inhibited, prevented, improved, and / or restored. In some embodiments, reduction, slowing, inhibition, prevention, improvement, and / or restoration include a reduction in the rate of transition from one disease state to a more progressive disease state. In some embodiments, reduction, gradual mitigation, suppression, prevention, improvement, and / or recovery include a decrease in the rate of AMD transition from early to late stages. In some embodiments, reduction, gradual mitigation, suppression, prevention, improvement, and / or recovery can be determined by comparing morphological features of the eye over a period of time with those of a subject not administered the anti-C5 agent or a pharmaceutically acceptable salt thereof, or with the subject's own baseline or previous state. In such embodiments, such comparisons may be made at baseline, with the first or early administration of the anti-C5 agent or a pharmaceutically acceptable salt thereof, and at least or about 1 month, at least or about 2 months, at least or about 3 months, at least or about 4 months, at least or about 5 months, at least or about 6 months, at least or about 7 months, at least or about 8 months, at least or about 9 months, at least or about 10 months, at least or about 11 months, at least or about 12 months, at least or about 15 months, at least or about 18 months, or at least or about 24 months.

[0200] In some embodiments, the anti-C5 agent or a pharmaceutically acceptable salt thereof is administered in an amount effective in reducing the rate of drusen growth in subjects with high-risk drusen, compared to the rate of drusen growth before administration of the anti-C5 agent or the pharmaceutically acceptable salt thereof, or compared to the subject's own baseline or previous condition. In some embodiments, the rate of drusen growth is reduced to at least or about 5%, at least or about 10%, at least or about 15%, at least or about 20%, at least or about 25%, at least or about 30%, at least or about 35%, at least or about 40%, at least or about 45%, or at least or about 50%. Such a reduction in the rate of drusen growth can be determined by measuring how many drusen are formed subretin over a period of time, for example, between baseline and at least or about 1 month, at least or about 2 months, at least or about 3 months, at least or about 4 months, at least or about 5 months, at least or about 6 months, at least or about 7 months, at least or about 8 months, at least or about 9 months, at least or about 10 months, at least or about 11 months, at least or about 12 months, at least or about 15 months, at least or about 18 months, or at least or about 24 months. In another embodiment, an anti-C5 agent or a pharmaceutically acceptable salt thereof is administered in an amount effective in reducing the rate of drusen growth in subjects having drusen with a diameter of <63 μm, between ≥63 μm and <125 μm, or with a diameter of ≥125 μm.

[0201] In some embodiments, the anti-C5 agent or a pharmaceutically acceptable salt thereof is administered in an amount effective in maintaining approximately the same level of retinal drusen in a subject with high-risk drusen, or in reducing the level of retinal drusen (e.g., quantity, size, number, area, volume, shape, density, and / or reflectivity) compared to the level of retinal drusen before administration of the anti-C5 agent or the pharmaceutically acceptable salt thereof, or compared to the subject's own baseline or previous condition. In some embodiments, the level of drusen is reduced to at least or about 5%, at least or about 10%, at least or about 15%, at least or about 20%, at least or about 25%, at least or about 30%, at least or about 35%, at least or about 40%, at least or about 45%, or at least or about 50%. Such a decrease in the level of drusen can be determined by measuring how many drusen are formed subretinally over a period of time, for example, between baseline and at least or about 1 month, at least or about 2 months, at least or about 3 months, at least or about 4 months, at least or about 5 months, at least or about 6 months, at least or about 7 months, at least or about 8 months, at least or about 9 months, at least or about 10 months, at least or about 11 months, at least or about 12 months, at least or about 15 months, at least or about 18 months, or at least or about 24 months. In another embodiment, an anti-C5 agent or a pharmaceutically acceptable salt thereof is administered in an amount effective in maintaining approximately the same level of retinal drusen or reducing the level of retinal drusen (e.g., quantity, size, number, area, volume, shape, density, and / or reflectivity) in subjects having drusen with a diameter of <63 μm, a diameter between ≥63 μm and <125 μm, or a diameter of ≥125 μm.

[0202] In one embodiment, an anti-C5 agent or a pharmaceutically acceptable salt thereof is administered in an amount effective to slow and / or suppress the progression of drusen (e.g., quantity, size, number, area, volume, shape, density, reflectivity, and / or form) in a subject with high-risk drusen, compared to the level of retinal drusen before administration of the anti-C5 agent or the pharmaceutically acceptable salt thereof, or compared to the subject's own baseline or previous condition. In a detailed embodiment, the progression of drusen is reduced to at least or about 5%, at least or about 10%, at least or about 15%, at least or about 20%, at least or about 25%, at least or about 30%, at least or about 35%, at least or about 40%, at least or about 45%, or at least or about 50%. Slowing and / or inhibiting the progression can be determined by measuring how many drusen are formed subretinally over a period of time, for example, between baseline and at least or about 1 month, at least or about 2 months, at least or about 3 months, at least or about 4 months, at least or about 5 months, at least or about 6 months, at least or about 7 months, at least or about 8 months, at least or about 9 months, at least or about 10 months, at least or about 11 months, at least or about 12 months, at least or about 15 months, at least or about 18 months, or at least or about 24 months. In another embodiment, an anti-C5 agent or a pharmaceutically acceptable salt thereof is administered in an amount effective to slow and / or inhibit the progression of drusen (e.g., quantity, size, number, area, volume, shape, density, reflectivity, and / or morphology) in subjects having drusen with a diameter of <63 μm, a diameter between ≥63 μm and <125 μm, or a diameter of ≥125 μm.

[0203] In one embodiment, the anti-C5 agent described herein is administered in an amount effective to reduce drusen formation and / or reduce the rate of drusen formation and / or restore drusen formation in a subject with high-risk drusen, compared to the level of retinal drusen before administration of the anti-C5 agent or a pharmaceutically acceptable salt thereof, or compared to the subject's own baseline or previous condition. In a detailed embodiment, drusen formation and / or the rate of drusen formation is reduced to at least or about 5%, at least or about 10%, at least or about 15%, at least or about 20%, at least or about 25%, at least or about 30%, at least or about 35%, at least or about 40%, at least or about 45%, or at least or about 50%. The reduction in drusen formation and / or the rate of drusen formation can be determined by measuring how much drusen is formed subretin over a period of time, for example, between baseline and at least or about 1 month, at least or about 2 months, at least or about 3 months, at least or about 4 months, at least or about 5 months, at least or about 6 months, at least or about 7 months, at least or about 8 months, at least or about 9 months, at least or about 10 months, at least or about 11 months, at least or about 12 months, at least or about 15 months, at least or about 18 months, or at least or about 24 months. In detailed embodiments, the recovery of drusen formation is at least or about 5%, at least or about 10%, at least or about 15%, at least or about 20%, at least or about 25%, at least or about 30%, at least or about 35%, at least or about 40%, at least or about 45%, or at least or about 50%, compared to subjects not administered the anti-C5 agent or a pharmaceutically acceptable salt thereof.Recovery in drusen formation can be determined by measuring how many drusen are present subretin after a certain period, for example, after a period of at least or about 1 month, at least or about 2 months, at least or about 3 months, at least or about 4 months, at least or about 5 months, at least or about 6 months, at least or about 7 months, at least or about 8 months, at least or about 9 months, at least or about 10 months, at least or about 11 months, at least or about 12 months, at least or about 15 months, at least or about 18 months, or at least or about 24 months from baseline. In another embodiment, the anti-C5 agent described herein is administered in an amount effective to reduce drusen formation and / or reduce the rate of drusen formation and / or restore drusen formation in subjects having drusen with a diameter of <63 μm, a diameter between ≥63 μm and <125 μm, or a diameter of ≥125 μm.

[0204] In one embodiment, the present invention relates to a method for slowing and / or suppressing vision loss in subjects with high-risk drusen, comprising the step of administering an anti-C5 agent described herein to the subject. In some embodiments, administration of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject can slow and / or suppress the decline in best-corrected visual acuity (measured using Early Treatment of Diabetic Retinopathy Study (ETDRS) short reports) compared to subjects not administered the anti-C5 agent or a pharmaceutically acceptable salt thereof, or compared to the subject's own baseline or previous state. Such decline can be measured between baseline and at least or about 1 month, at least or about 2 months, at least or about 3 months, at least or about 4 months, at least or about 5 months, at least or about 6 months, at least or about 7 months, at least or about 8 months, at least or about 9 months, at least or about 10 months, at least or about 11 months, at least or about 12 months, at least or about 15 months, at least or about 18 months, or at least or about 24 months. In another embodiment, the present invention relates to a method for slowing and / or suppressing visual acuity loss in subjects having drusen with a diameter of <63 μm, a diameter between ≥63 μm and <125 μm, or a diameter of ≥125 μm.

[0205] In one embodiment, the present invention relates to a method for restoring vision loss in a subject with high-risk drusen, comprising the step of administering an anti-C5 agent described herein to the subject. In some embodiments, administration of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject can increase best corrected visual acuity (measured using ETDRS) compared to a subject not administered with the anti-C5 agent or a pharmaceutically acceptable salt thereof, or compared to the subject's own baseline or previous state. Such an increase can be measured between baseline and at least or about 1 month, at least or about 2 months, at least or about 3 months, at least or about 4 months, at least or about 5 months, at least or about 6 months, at least or about 7 months, at least or about 8 months, at least or about 9 months, at least or about 10 months, at least or about 11 months, at least or about 12 months, at least or about 15 months, at least or about 18 months, or at least or about 24 months. In another aspect, the present invention relates to a method for restoring vision loss in an object having a drusen with a diameter of <63 μm, a diameter between ≥63 μm and <125 μm, or a diameter of ≥125 μm.

[0206] In one embodiment, the present invention relates to a method for slowing and / or suppressing the loss of low-light visual acuity in subjects with high-risk drusen, comprising the step of administering an anti-C5 agent described herein to the subject. In some embodiments, administration of an anti-C5 agent to a subject can slow or suppress the decline in low-light best-corrected visual acuity (measured using ETDRS short reports) compared to subjects not administered the anti-C5 agent, or compared to the subject's own baseline or previous state. Such a decline can be measured between baseline and at least or about 1 month, at least or about 2 months, at least or about 3 months, at least or about 4 months, at least or about 5 months, at least or about 6 months, at least or about 7 months, at least or about 8 months, at least or about 9 months, at least or about 10 months, at least or about 11 months, at least or about 12 months, at least or about 15 months, at least or about 18 months, or at least or about 24 months. In another aspect, the present invention relates to a method for slowing and / or suppressing the loss of low-luminosity visual acuity in objects having drusen with a diameter of <63 μm, a diameter between ≥63 μm and <125 μm, or a diameter of ≥125 μm.

[0207] In one embodiment, the present invention relates to a method for restoring low-light vision loss in subjects with high-risk drusen, comprising the step of administering an anti-C5 agent to the subject. In some embodiments, administration of an anti-C5 agent to a subject can increase the best corrected low-light (measured using ETDRS) visual acuity compared to subjects not administered the anti-C5 agent, or compared to the subject's own baseline or previous state. Such an increase can be measured between baseline and at least or about 1 month, at least or about 2 months, at least or about 3 months, at least or about 4 months, at least or about 5 months, at least or about 6 months, at least or about 7 months, at least or about 8 months, at least or about 9 months, at least or about 10 months, at least or about 11 months, at least or about 12 months, at least or about 15 months, at least or about 18 months, or at least or about 24 months. In another aspect, the present invention relates to a method for restoring low-luminosity vision loss in an object having a drusen with a diameter of <63 μm, a diameter between ≥63 μm and <125 μm, or a diameter of ≥125 μm.

[0208] In some embodiments, measurements using ETDRS short reports may be as described in the Manual of Operations, Baltimore: ETDRS Coordinating Center, University of Maryland, by the Early Treatment Study Group for Diabetic Retinopathy (ETDRS). (National Technical Information Service, 5285 Port Royal Road, Springfield, VA 22161; Accession No. PB8S 223006 / AS; Ferris et al., Am J Ophthalmol, Vol. 94: pp. 91-96, available since 1982.) In some embodiments, the visual acuity test uses one or more charts available from, for example, ETDRS Visual Acuity Charts 1, 2 and / or R, as shown at https: / / www.ophthalmologyweb.com / Neuro-Ophthalmology / 5650-ETDRS-Visual-Acuity-Charts / Compare / ?compare=55134,49475,55138,55135,55420&catid=5650.

[0209] In some embodiments, the methods described herein may further include the step of identifying a subject to be treated by determining, for example, whether the subject has high-risk drusen, or risk factors for progression to iRORA, or whether the subject has iRORA, or whether the subject has nGA, or whether the subject has cRORA, or whether the subject has AMD, or whether the subject has intermediate-stage AMD, or whether the subject has dry AMD, or wet AMD, or whether the subject has GA secondary to AMD.

[0210] In some embodiments, the subject may be a mammal, and this includes, but is not limited to, humans, monkeys, cows, boars, sheep, horses, dogs, cats, rabbits, rats, and mice. In some embodiments, the subject is a human.

[0211] In some embodiments, the subjects may be treatment-naive, for example, those with high-risk drusen, or risk factors for progression to iRORA, or iRORA, or nGA, or cRORA, or AMD, or mid-stage AMD, or dry AMD, or wet AMD, or GA secondary to AMD, who have not been treated before.

[0212] In some embodiments, therapeutic efficacy may take into account a combination of one or more clinical endpoints, such as disease progression, drusen characteristics, and / or changes in pigmentation. In some embodiments, therapeutic efficacy is determined using scales, scores, and / or statistical analyses.

[0213] Compositions for therapeutic or prophylactic administration The anti-C5 agent can be administered as a component of a composition further comprising a pharmaceutically acceptable carrier or vehicle, for example, a pharmaceutical composition. The anti-C5 agent can be mixed with a suitable carrier material and is generally present in an amount of 1 to 95% by mass of the total mass of the composition. The composition can be provided in a dosage form suitable for injection, particularly for direct injection into the eye (e.g., intravitreal injection). The composition may be in the form of a suspension, emulsion, or solution, for example.

[0214] Formulations for injection include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Various aqueous carriers can be used, such as water, buffer water, or physiological saline. Such formulations may also contain additives, such as preservatives, wetting agents, buffering agents, emulsifiers, dispersants, and suspending agents.

[0215] In some embodiments, additives for compositions containing an anti-C5 agent include, but are not limited to, buffering agents, nonionic surfactants, preservatives, tonicity agents, sugars, amino acids, and pH adjusters. Suitable buffering agents include, but are not limited to, sodium dihydrogen phosphate, disodium phosphate, and sodium acetate. Suitable nonionic surfactants include, but are not limited to, polyoxyethylene sorbitan fatty acid esters, such as polysorbate 20 and polysorbate 80. Suitable preservatives include, but are not limited to, benzyl alcohol. Suitable tonicity agents include, but are not limited to, sodium chloride, mannitol, and sorbitol. Suitable sugars include, but are not limited to, α,α-trehalose. Suitable amino acids include, but are not limited to, glycine and histidine. Suitable pH adjusters include, but are not limited to, hydrochloric acid, acetic acid, and sodium hydroxide. In some embodiments, one or more pH adjusters are present in amounts effective to provide a pH of about 3 to about 8, about 6 to about 8, about 6.5 to about 8, about 4 to about 7, about 5 to about 6, about 6 to about 7, or about 7 to about 7.5. In some embodiments, one or more pH adjusters are present in amounts effective to provide a pH of about 6.8 to about 7.8. In some embodiments, the composition does not contain preservatives. In some embodiments, the composition does not contain antibacterial agents. In some embodiments, the composition does not contain bacteriostatic agents.

[0216] In some embodiments, the composition comprises sodium chloride, sodium dihydrogen phosphate (monohydrate), and disodium phosphate (heptahydrate), and the pH of the composition is about 6.8 to about 7.8.

[0217] In some embodiments, the concentration of the anti-C5 agent in the composition is about 0.5 mg / mL to about 100 mg / mL. In some embodiments, the concentration of the anti-C5 agent in the composition is less than 100 mg / mL or about 100 mg / mL, less than about 50 mg / mL, less than about 40 mg / mL, less than about 30 mg / mL, less than about 25 mg / mL, less than about 20 mg / mL, less than about 15 mg / mL, less than about 10 mg / mL, or less than about 5 mg / mL. In some embodiments, the concentration of the anti-C5 agent in the composition is about 0.3 mg / mL to about 100 mg / mL, about 0.3 mg / mL to about 50 mg / mL, about 1 mg / mL to about 50 mg / mL, about 5 mg / mL to about 40 mg / mL, about 10 to about 30 mg / mL, about 15 mg / mL to about 25 mg / mL, about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, or about 50 mg / mL. In detailed embodiments, the concentration of the anti-C5 agent in the composition is about 20 mg / mL.

[0218] Dosage and Administration The dosage of anti-C5 agents for ocular administration may be approximately 0.5 mg (0.5 mg / eye) to approximately 5 mg per eye, or approximately 1 mg to approximately 4 mg per eye, or approximately 2 mg to approximately 4 mg per eye, or approximately 1 mg per eye, or approximately 2 mg per eye, or approximately 3 mg per eye, or approximately 4 mg per eye. Anti-C5 agents can be administered to the eye, for example, by intravitreal injection. Anti-C5 agents can be administered once a week, every other week, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, once every 11 weeks, or once every 12 weeks. The dosage can be administered once a month, once every two months (for example, once every month), once every three months, once every four months, once every five months, once every six months, once every seven months, once every eight months, once every nine months, once every ten months, once every eleven months, or once every twelve months. In some embodiments, the dosage is administered once a month. In some embodiments, the dosage is administered once a year.

[0219] In embodiments of the present invention, the anti-C5 agent may be administered in a dosing regimen comprising a loading phase and a maintenance phase. In some embodiments, the loading phase may include administering the anti-C5 agent at different doses, at different frequencies, or in combination thereof, compared to the maintenance phase. For example, the loading phase may include administering the anti-C5 agent at a dose of approximately 0.5 mg per eye, or approximately 1 mg per eye, or approximately 2 mg per eye, or approximately 3 mg per eye, or approximately 4 mg per eye; the maintenance phase may include administering the anti-C5 agent at a dose that is a percentage of or greater than the dose of the anti-C5 agent in the loading phase, for example, approximately 10%, approximately 20%, approximately 25%, or approximately 30% of the dose of the anti-C5 agent in the loading phase. Alternatively, the procedure may include administering an anti-C5 agent at a concentration of approximately 33%, 40%, 50%, 60%, 67%, 70%, 75%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, or 400%. Alternatively, the loading phase may include administering an anti-C5 agent at a frequency where the interval between doses is 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 2 months, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 3 months, 4 months, 5 months, or 6 months; the maintenance phase may include administering an anti-C5 agent at a frequency where the interval between doses is a percentage of the interval between doses in the loading phase, or more, for example, about 10% of the interval between doses in the loading phase, or about The procedure may include administering an anti-C5 agent at a concentration of 20%, or approximately 25%, or approximately 30%, or approximately 33%, or approximately 40%, or approximately 50%, or approximately 60%, or approximately 67%, or approximately 70%, or approximately 75%, or approximately 80%, or approximately 90%, or approximately 100%, or approximately 125%, or approximately 150%, or approximately 175%, or approximately 200%, or approximately 225%, or approximately 250%, or approximately 275%, or approximately 300%, or approximately 325%, or approximately 350%, or approximately 375%, or approximately 400%.In some embodiments, the load phase can last for a period of about 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 2 months, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 3 months, 4 months, 6 months, 8 months, 9 months, 12 months, 15 months, 18 months, 21 months, or 24 months; the maintenance phase can be initiated at the end of the load phase.

[0220] In some embodiments, the anti-C5 agent can be administered in a dosing regimen comprising a loading phase with a dose of approximately 2 mg per eye administered once a month for one year, followed by a maintenance phase with a dose of approximately 2 mg per eye administered once every two months. In some embodiments, the anti-C5 agent can be administered in a dosing regimen comprising a loading phase with a dose of approximately 4 mg per eye administered once a month for one year, followed by a maintenance phase with a dose of approximately 2 mg per eye administered once a month. In some embodiments, the anti-C5 agent can be administered in a dosing regimen comprising a loading phase with a dose of approximately 2 mg per eye administered once a month for about six months, followed by a maintenance phase with a dose of approximately 2 mg per eye administered once every two months.

[0221] The amount of the composition containing the anti-C5 agent administered to the subject may be in the range of approximately 0.01 mL to approximately 0.2 mL per eye, approximately 0.03 mL to approximately 0.15 mL per eye, or approximately 0.05 mL to approximately 0.10 mL per eye.

[0222] In some embodiments, subjects may receive two or more injections of lower doses per eye. For example, a subject may receive two injections of 2 mg each instead of a single 4 mg dose.

[0223] Other aspects of the present invention In some embodiments, the present invention treats subjects with risk factors for progression to iRORA; subjects with iRORA; subjects with nGA; subjects with intermediate-stage AMD; subjects with cRORA; subjects with high-risk drusen; in subjects in need, slows, suppresses, prevents, and / or reverses the progression of high-risk drusen to dry AMD; slows, suppresses, prevents, and / or reverses the progression of nGA to GA secondary to AMD; slows, suppresses, prevents, and / or reverses the progression of intermediate-stage AMD to cRORA, and / or recover; slow, suppress, prevent, and / or recover from the progression of dry AMD to wet AMD; slow, suppress, prevent, and / or recover from the progression of iRORA to wet AMD; slow, suppress, prevent, and / or recover from the progression of cRORA to wet AMD; and slow, suppress, prevent, and / or recover from the progression of nGA to GA secondary to AMD; slow, suppress, prevent, and / or recover from the progression of high-risk drusen; medium-term AM in areas where it is needed. To slow, inhibit, prevent, and / or reverse the progression of D; to slow, inhibit, prevent, and / or reverse the progression of dry AMD in subjects who need it; to slow, inhibit, prevent, and / or reverse the progression of GA in subjects who need it; to slow, inhibit, prevent, and / or reverse vision loss in subjects with high-risk drusen; to slow, inhibit, prevent, and / or reverse vision loss in subjects who need it; to slow, inhibit, prevent, and / or reverse low-intensity vision in subjects with high-risk drusen To slow, suppress, prevent, and / or restore the loss of vision; to slow, suppress, prevent, and / or restore the loss of low-light vision in subjects where it is needed; to treat high-risk drusen in subjects; to reduce the rate of drusen growth in subjects; to reduce the amount of drusen in subjects; to reduce the area of ​​drusen in subjects; to slow, suppress, prevent, and / or restore the progression of drusen in subjects; to reduce the formation of drusen in subjects; to reduce the rate of drusen formation in subjects;This invention relates to anti-C5 agents described herein for use in restoring drusen formation in a subject. Such use is carried out according to the methods of the present invention described herein.

[0224] In some embodiments, the present invention treats subjects with risk factors for progression to iRORA; subjects with iRORA; subjects with nGA; subjects with intermediate-stage AMD; subjects with cRORA; subjects with high-risk drusen; subjects who slow, suppress, prevent, and / or reverse the progression of high-risk drusen to dry AMD; subjects who slow, suppress, prevent, and / or reverse the progression of nGA to GA secondary to AMD; subjects who slow, suppress, prevent, and / or reverse the progression of intermediate-stage AMD to cRORA; and dry AMD To slow, suppress, prevent, and / or reverse the progression of wet AMD to iRORA; to slow, suppress, prevent, and / or reverse the progression of cRORA to wet AMD; and to slow, suppress, prevent, and / or reverse the progression of nGA to GA secondary to AMD; to slow, suppress, prevent, and / or reverse the progression of high-risk drusen in areas where it is needed; and to slow, suppress, prevent, and / or reverse the progression of mid-term AMD in areas where it is needed. To slow, inhibit, prevent, and / or reverse the progression of; to slow, inhibit, prevent, and / or reverse the progression of dry AMD in subjects who need it; to slow, inhibit, prevent, and / or reverse the progression of GA in subjects who need it; to slow, inhibit, prevent, and / or reverse vision loss in subjects with high-risk drusen; to slow, inhibit, prevent, and / or reverse vision loss in subjects who need it; to slow, inhibit, prevent, and / or reverse low-light vision in subjects with high-risk drusen To slow, suppress, prevent, and / or restore the loss of vision; to slow, suppress, prevent, and / or restore the loss of low-light vision in subjects in need; to treat high-risk drusen in subjects; to reduce the rate of drusen growth in subjects; to reduce the amount of drusen in subjects; to reduce the area of ​​drusen in subjects; to slow, suppress, prevent, and / or restore the progression of drusen in subjects; to reduce the formation of drusen in subjects; to reduce the rate of drusen formation in subjects;This invention relates to the use of anti-C5 agents described herein to restore drusen formation in a subject. Such use is carried out according to the methods of the present invention described herein.

[0225] In some embodiments, the present invention treats subjects with risk factors for progression to iRORA; subjects with iRORA; subjects with nGA; subjects with intermediate-stage AMD; subjects with cRORA; subjects with high-risk drusen; subjects who slow, suppress, prevent, and / or reverse the progression of high-risk drusen to dry AMD; subjects who slow, suppress, prevent, and / or reverse the progression of nGA to GA secondary to AMD; subjects who slow, suppress, prevent, and / or reverse the progression of intermediate-stage AMD to cRORA; and dry AMD To slow, suppress, prevent, and / or reverse the progression of wet AMD to iRORA; to slow, suppress, prevent, and / or reverse the progression of cRORA to wet AMD; and to slow, suppress, prevent, and / or reverse the progression of nGA to GA secondary to AMD; to slow, suppress, prevent, and / or reverse the progression of high-risk drusen in areas where it is needed; and to slow, suppress, prevent, and / or reverse the progression of mid-term AMD in areas where it is needed. To slow, suppress, prevent, and / or reverse the progression of; to slow, suppress, prevent, and / or reverse the progression of dry AMD in subjects who need it; to slow, suppress, prevent, and / or reverse the progression of GA in subjects who need it; to slow, suppress, prevent, and / or reverse vision loss in subjects with high-risk drusen; to slow, suppress, prevent, and / or reverse vision loss in subjects who need it; to slow, suppress, prevent, and / or reverse low-intensity vision in subjects with high-risk drusen To slow, suppress, prevent, and / or restore the loss of vision; to slow, suppress, prevent, and / or restore the loss of low-light vision in subjects where it is needed; to treat high-risk drusen in subjects; to reduce the rate of drusen growth in subjects; to reduce the amount of drusen in subjects; to reduce the area of ​​drusen in subjects; to slow, suppress, prevent, and / or restore the progression of drusen in subjects; to reduce the formation of drusen in subjects; to reduce the rate of drusen formation in subjects;This invention relates to the use of anti-C5 agents in the manufacture of pharmaceuticals for restoring drusen formation in subjects. These uses of pharmaceuticals are carried out according to the methods of the present invention described herein.

[0226] In some embodiments, the present invention relates to the use of anti-C5 agents in the manufacture of pharmaceuticals for the treatment of subjects in need having (i) high-risk drusen and (ii) risk factors for progression to iRORA, iRORA, nGA, cRORA, GA, AMD, intermediate-stage AMD, dry AMD, and / or wet AMD, wherein the progression of the ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or restored. In some embodiments described above, at least one characteristic of the drusen (e.g., number, degree, area, volume, shape, density, and reflectivity) is reduced, slowed, inhibited, prevented, improved, and / or restored.

[0227] In some embodiments, the present invention relates to the use of anti-C5 agents in the manufacture of pharmaceuticals for the treatment of iRORA, iRORA, nGA, cRORA, GA, AMD, intermediate-stage AMD, dry-type AMD, and / or wet-type AMD, comprising the step of administering an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof to a subject in need, wherein the subject has high-risk drusen, and the progression of the ophthalmic disease, disorder, and / or condition is reduced, slowed, inhibited, prevented, improved, and / or restored. In some embodiments described above, at least one characteristic of the drusen (e.g., number, degree, area, volume, shape, density, and reflectivity) is reduced, slowed, inhibited, prevented, improved, and / or restored.

[0228] In one embodiment, a subject with risk factors for progression to iRORA is administered ARC1905 intravitreally at a dose of 2 mg per eye monthly.

[0229] In one embodiment, the subject has iRORA and is administered ARC1905 intravitreally at a dose of 2 mg per eye every month.

[0230] In one embodiment, the subject has nGA and is administered ARC1905 intravitreally at a dose of 2 mg per eye monthly.

[0231] In one embodiment, the subject has intermediate-stage AMD and is administered ARC1905 intravitreally at a dose of 2 mg per eye monthly.

[0232] In one embodiment, the subject has cRORA and is administered ARC1905 intravitreally at a dose of 2 mg per eye every month.

[0233] In one embodiment, a subject with high-risk factors for drusen and iRORA is administered ARC1905 intravitreally at a dose of 2 mg per eye monthly.

[0234] In one embodiment, subjects with high-risk drusen and iRORA are administered ARC1905 intravitreally at a dose of 2 mg per eye monthly.

[0235] In one embodiment, the subjects have high-risk drusen and nGA and are administered ARC1905 intravitreally at a dose of 2 mg per eye monthly.

[0236] In one embodiment, the subject has high-risk drusen and intermediate-stage AMD and is administered ARC1905 intravitreally at a dose of 2 mg per eye monthly.

[0237] In one embodiment, the subjects have high-risk drusen and cRORA and are administered ARC1905 intravitreally at a dose of 2 mg per eye monthly.

[0238] In one embodiment, the subjects have high-risk drusen and GA and are administered ARC1905 intravitreally at a dose of 2 mg per eye monthly.

[0239] In one embodiment, the subjects have high-risk drusen and AMD and are administered ARC1905 intravitreally at a dose of 2 mg per eye monthly.

[0240] In one embodiment, the subject has high-risk drusen and dry AMD and is administered ARC1905 intravitreally at a dose of 2 mg per eye monthly.

[0241] In one embodiment, the subjects have high-risk drusen and wet-type AMD and are administered ARC1905 intravitreally at a dose of 2 mg per eye monthly.

[0242] Other compounds In some embodiments, the methods described herein may further include the step of administering an anti-C5 agent or a pharmaceutically acceptable salt thereof, together with an HTRA1 inhibitor compound, for example, an HTRA1 inhibitor compound disclosed in U.S. Patent No. 10,526,315, U.S. Patent No. 10,730,832, and U.S. Patent Application Publication No. 16 / 312,247, the contents of which are incorporated herein in their entirety by reference.

[0243] The term "VEGF" refers to vascular endothelial growth factor that induces angiogenesis or the angiogenic process. As used herein, the term "VEGF" may include various subtypes of VEGF. Furthermore, as used herein, the term "VEGF" may include VEGF-related angiogenic factors, such as PIGF (placental growth factor), VEGF-B, VEGF-C, VEGF-D, and VEGF-E, which act on congeneral VEFG receptors (e.g., VEGFR) to induce angiogenesis or the angiogenic process. The term "VEGF" may also refer to the "VEGF" polypeptide or the gene or nucleic acid that encodes "VEGF".

[0244] The term "VEGF antagonist" refers to a drug that partially or completely reduces or inhibits the activity or production of VEGF. In some embodiments, a VEGF antagonist inhibits one or more of VEGF-A, VEGF-B, VEGF-C, and VEGF-D. A VEGF antagonist can directly or indirectly reduce or inhibit the activity or production of a specific VEGF, such as VEGFi65. Furthermore, a "VEGF antagonist" may include a drug that acts on a VEGF ligand or its homologous receptor to reduce or inhibit VEGF-related receptor signaling. Examples of "VEGF antagonists" may include antisense molecules, ribozymes, or RNAi targeting VEGF nucleic acids; anti-VEGF aptamers, anti-VEGF antibodies against VEGF itself or its receptors, or soluble VEGF receptor decoys that prevent VEGF from binding to its related receptors; antisense molecules, ribozymes, or RNAi targeting related VEGF receptor (VEGFR) nucleic acids; anti-VEGFR aptamers or anti-VEGFR antibodies that bind to related VEGFR receptors; and VEGFR tyrosine kinase inhibitors. In some embodiments, the VEGF antagonist is a peptide, for example, a peptide containing three or more amino acid residues. In some embodiments, the VEGF antagonist is a bicyclic peptide. In some embodiments, the VEGF antagonist is a gene therapy, vector, or delivery vehicle for delivering plasmids, genes, or other gene sequences capable of generating a portion that antagonizes VEGF. [Examples]

[0245] The subjects were administered 2 mg of an anti-C5 agent, ARC1905, or a sham, and the progression from large drusen to iRORA or cRORA was observed at 6, 12, and 18 months after administration. As shown in Figures 1 and 2, at 6 months, 3.8% of patients administered 2 mg of the anti-C5 agent progressed from large drusen to iRORA or cRORA, while 15.9% of the control group (i.e., "sham") progressed from large drusen to iRORA or cRORA. Furthermore, at 12 months, 7.6% of patients administered 2 mg of the anti-C5 agent progressed from large drusen to iRORA or cRORA, while 18.1% of the control group progressed from large drusen to iRORA or cRORA. Finally, at 18 months, 7.6% of patients treated with 2 mg of anti-C5 agent progressed from large drusen to iRORA or cRORA, compared to 27.2% of the control group. As a result, a 19.6% reduction in drusen progression to iRORA or cRORA was observed, representing a 76% relative reduction in risk with 2 mg of anti-C5 agent compared to the control group at 18 months. This effect was early and sustained, with no further patients progressing between M12 and M18. Furthermore, these observations highlight the potential for preserving non-atrophic cells in the presence of iRORA.

[0246] Progression from iRORA to cRORA was also observed at 6, 12, and 18 months after administration in subjects who received 2 mg of anti-C5 agent, ARC1905, or a simulated agent. As shown in Figures 3 and 4, at 6 months, 5.0% of patients who received 2 mg of anti-C5 agent progressed from iRORA to cRORA, compared to 11.8% of the control group. Furthermore, at 12 months, 15.0% of patients who received 2 mg of anti-C5 agent progressed from iRORA to cRORA, compared to 30.2% of the control group. Finally, at 18 months, 20.0% of patients who received 2 mg of anti-C5 agent progressed from iRORA to cRORA, compared to 41.8% of the control group. As a result, regarding the progression of incomplete RPE and outer retinal atrophy to complete RPE and outer retinal atrophy, an approximately 50% reduction in the rate of progression was observed with anti-C5 2 mg compared to the simulated group. This effect was early and persistent, observed at 6, 12, and 18 months.

[0247] Figure 5 compares the basic characteristics of GA lesion size, presence of large drusen, presence of iRORA, lesion site, and lesion localization in subjects administered 2 mg of anti-C5 agent or a simulated agent. 50% of patients administered 2 mg of anti-C5 agent had large drusen, while only 47.3% of subjects administered the simulated agent had large drusen. However, 38.5% of patients administered 2 mg of anti-C5 agent had iRORA, while 46.2% of the control group had iRORA.

[0248] Figure 6 compares the least-squares mean change from baseline GA area at 6 and 12 months after administration of 2 mg of anti-C5 agent versus a simulated group. In this regard, at 12 months, the least-squares mean change from baseline GA in patients administered 2 mg of anti-C5 agent was 1.592, while the least-squares mean change from baseline GA in the simulated group was 2.290.

[0249] Figure 7 compares the least-squares mean change from baseline in the square root GA area of ​​2 mg of anti-C5 agent versus simulated patients at 6, 12, and 18 months after administration. In this regard, at 18 months, the least-squares mean change from baseline GA in patients treated with 2 mg of anti-C5 agent was 0.430, while the least-squares mean change from baseline GA in the simulated patients was 0.599.

[0250] This example demonstrates that the administration of anti-C5 agents is an effective therapy for delaying the onset of GA in late-stage AMD and is beneficial when applied to an earlier stage of the disease.

[0251] The foregoing explanation is for the purpose of clarifying understanding, and no unnecessary limitations should be inferred therefrom, as modifications within the scope of the present invention will be obvious to those skilled in the art.

[0252] Throughout this specification and the following claims, unless otherwise required by context, the word “comprise,” and variations such as “comprises” and “comprising,” are understood to mean that they include a set of integers or steps, or a group of integers or steps, but not to exclude any other integers or steps, or a group of integers or steps.

[0253] Throughout this specification, where a composition is described as comprising components or materials, the composition may, unless otherwise stated, consist essentially of any combination of the listed components or materials, or may also consist of any combination of the listed components or materials. Similarly, where a method is described as comprising specific steps, the method may, unless otherwise stated, consist essentially of any combination of the listed steps, or may also consist of any combination of the listed steps. The inventions disclosed exemplary herein may, as appropriate, be carried out in the absence of any elements or steps not specifically disclosed herein.

[0254] The methods disclosed herein, and the execution of their individual steps, can be carried out manually and / or by utilizing electronic devices or by automation provided by electronic devices. Although the processes are described in relation to specific embodiments, those skilled in the art will readily understand that other ways of performing the actions related to the Method can be used. For example, the order of the various steps can be changed without departing from the scope or spirit of the Method unless otherwise stated. Furthermore, some of the individual steps may be used in combination, omitted, or subdivided into additional steps.

[0255] All patents, published documents, and references cited herein are fully incorporated by reference into this application. In the event of any conflict between this disclosure and the incorporated patents, published documents, and references, this disclosure should be regulated.

Claims

1. 1. A pharmaceutical composition comprising a pegylated anti-C5 agent for use in the treatment of an ophthalmic disease, disorder, and / or condition, the treatment comprising administering the pegylated anti-C5 agent intravitreally at a dose of about 2 mg per eye to a subject in need thereof having an ophthalmic disease, disorder, and / or condition selected from the group consisting of: (i) high risk drusen and (ii) risk factors for progression to iRORA, iRORA, and cRORA; A pharmaceutical composition wherein the pegylated anti-C5 agent is an aptamer, wherein the aptamer = fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T (sequence number 1), where fC and fU = 2' fluoro nucleotides, mG and mA = 2'-OMe nucleotides, all other nucleotides are 2'-OH, and 3T represents an inverted deoxythymidine.

2. The pegylated anti-C5 agent has the following structure: 【Chemistry 1】 The pharmaceutical composition of claim 1, comprising a C5-specific aptamer comprising:

3. The pharmaceutical composition of claim 1, wherein the subject has iRORA.

4. The pharmaceutical composition of claim 1, wherein the subject has cRORA.

5. 1. A pharmaceutical composition for use in treating an ophthalmic disease, disorder, and / or condition selected from the group consisting of risk factors for progression to iRORA, iRORA, and cRORA, comprising a pegylated anti-C5 agent, said treatment comprising administering intravitreally to a subject in need thereof the pegylated anti-C5 agent at a dose of about 2 mg per eye, wherein the subject has high risk drusen, A pharmaceutical composition wherein the pegylated anti-C5 agent is an aptamer, wherein the aptamer = fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T (sequence number 1), where fC and fU = 2' fluoro nucleotides, mG and mA = 2'-OMe nucleotides, all other nucleotides are 2'-OH, and 3T represents an inverted deoxythymidine.

6. The pegylated anti-C5 agent has the following structure: 【Chemistry 2】 The pharmaceutical composition according to claim 5, comprising a C5-specific aptamer comprising:

7. The pharmaceutical composition of claim 5, wherein the subject has iRORA or cRORA.

8. 1. A pharmaceutical composition for use in treating an ophthalmic disease, disorder, and / or condition selected from the group consisting of risk factors for progression to iRORA, iRORA, and cRORA, comprising a pegylated anti-C5 agent, said treatment comprising administering intravitreally to a subject in need thereof the pegylated anti-C5 agent at a dose of about 2 mg per eye; A pharmaceutical composition wherein the pegylated anti-C5 agent is an aptamer, wherein the aptamer = fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T (sequence number 1), where fC and fU = 2' fluoro nucleotides, mG and mA = 2'-OMe nucleotides, all other nucleotides are 2'-OH, and 3T represents an inverted deoxythymidine.

9. The pegylated anti-C5 agent has the following structure: 【Chemistry 3】 The pharmaceutical composition according to claim 8, comprising a C5-specific aptamer comprising:

10. The pharmaceutical composition of claim 8, wherein the subject has iRORA.

11. The pharmaceutical composition of claim 8, wherein the subject has a risk factor for progression to iRORA.

12. The pharmaceutical composition of claim 8, wherein the subject has cRORA.

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