Methods for treating or preventing ophthalmic symptoms

Abstract

To provide drugs useful for the treatment or prevention of ophthalmic diseases or disorders. [Solution] An anti-C5 agent is provided for use in reducing the growth of geographic atrophy (GA) lesions in subjects requiring reduction of the growth of GA lesions, wherein the anti-C5 agent is a C5-specific aptamer or a pharmaceutically acceptable salt thereof, comprising a specific nucleotide sequence conjugated to a polyethylene glycol portion via a linker, and the anti-C5-specific aptamer is administered to the subject at a dose of 2 mg / eye.

Description

[Technical Field]

[0001] Cross-reference of related applications This application is incorporated herein by reference in whole by U.S. Provisional Patent Applications No. 61 / 845,938 (filed July 12, 2013), 61 / 845,935 (filed July 12, 2013), 61 / 845,936 (filed July 12, 2013), 61 / 866,502 (filed August 15, 2013), 61 / 866,503 (filed August 15, 2013), 61 / 866,507 (filed August 15, 2013), and 61 / 911,854 (filed December 4, 2013), each of which is incorporated herein by reference in its entirety. We claim the interests of the following applications: 61 / 911,860 (filed on December 4, 2013), 61 / 911,894 (filed on December 4, 2013), 61 / 926,812 (filed on January 13, 2014), 61 / 926,825 (filed on January 13, 2014), 61 / 926,848 (filed on January 13, 2014), 61 / 931,116 (filed on January 24, 2014), 61 / 931,125 (filed on January 24, 2014), and 61 / 931,135 (filed on January 24, 2014).

[0002] Sequence List The sequence listing associated with this application is provided in text format instead of being a paper copy and is incorporated herein by reference. The name of the text file containing the sequence listing is OPHT_012_06WO_SeqList_ST25.txt. The text file is approximately 372KB in size, was created on July 10, 2014, and was submitted electronically via EFS-Web.

[0003] The present invention relates to methods and compositions useful for the treatment or prevention of ophthalmic diseases or disorders, comprising the administration of an effective amount of antagonist A or another pharmaceutically acceptable salt thereof. [Background technology]

[0004] Various eye disorders are characterized by, caused by, or result from choroidal neovascularization, retinal neovascularization, iris neovascularization, or retinal edema. One of these disorders is macular degeneration. Age-related macular degeneration (AMD) is a disease that affects approximately 1 in 10 Americans over the age of 65. One type of AMD is "wet AMD," which accounts for only about 10% of cases of age-related macular degeneration, but it accounts for approximately 90% of legal blindness due to macular degeneration in older adults. Another eye disorder is diabetic retinopathy. Diabetic retinopathy can affect up to 80% of all patients who have had diabetes for 10 years or more, and it is the third leading cause of blindness in adults, accounting for nearly 7% of blindness in the United States. Other disorders include hypertensive retinopathy, central serous chorioretinopathy, cystoid macular edema, Coats' disease, and tumors of the eyeball and adnexa, such as choroidal hemangioma, retinal pigment epithelial carcinoma, retinal vein occlusion, and intraocular lymphoma.

[0005] Therefore, although progress has been made in understanding molecular events involving neovascularization, there is a need to leverage this understanding to develop improved methods for treating or preventing neovascular disorders, including neovascular diseases and disorders of the eye such as neovascularization in AMD, diabetic retinopathy, and retinal vein occlusion. [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] The present invention relates to methods and compositions useful for the treatment or prevention of ophthalmic diseases or disorders.

[0007] The present invention relates to a method for treating or preventing wet age-related macular degeneration (wet AMD). The present invention provides a method comprising administering to a subject in need (a) an antagonist A or another pharmaceutically acceptable salt thereof, and (b) a VEGF antagonist, wherein (a) and (b) are administered in amounts effective to treat or prevent wet AMD, the administration occurring once every 1 month ± approximately 7 days over a first administration period of at least 3 consecutive months, and thereafter administering (a) and (b) at a frequency of at least every 1 month ± approximately 7 days over a second administration period, starting 2 months ± approximately 7 days after the last month of the first administration period in which (a) and (b) were administered.

[0008] The present invention also provides a method for treating or preventing subretinal fibrosis, comprising administering to a subject in need (a) an antagonist A or another pharmaceutically acceptable salt thereof in an amount effective for treating or preventing subretinal fibrosis.

[0009] Methods for treating or preventing von Hippel-Lindau (VHL) disease are also provided herein, comprising administering to a subject in need thereof an antagonist A or another pharmaceutically acceptable salt thereof in an amount effective for treating or preventing VHL disease. [Brief explanation of the drawing]

[0010] Refer to the following detailed description, which will specify exemplary embodiments and accompanying drawings. [Figure 1A] Figures 1A-F show the chemical structure of antagonist A, whose aptamer (SEQ ID NO: 1) has a 5' end modified with Me(OCH2CH2)nOC(O)NH(CH2)4CH(NHC(O)O(CH2CH2O)nMe)C(O)NH(CH2)6-, where n is approximately 450. Symbols (B)-(F) indicate continuation from the previous panel. [Figure 1B]Figures 1A - F show the chemical structure of antagonist A, and the 5'-end of its aptamer (SEQ ID NO: 1) is modified with Me(OCH2CH2)nOC(O)NH(CH2)4CH(NHC(O)O(CH2CH2O)nMe)C(O)NH(CH2)6-, where n is about 450. Symbols (B)-(F) indicate continuation from the previous panel. [Figure 1C] Figures 1A - F show the chemical structure of antagonist A, and the 5'-end of its aptamer (SEQ ID NO: 1) is modified with Me(OCH2CH2)nOC(O)NH(CH2)4CH(NHC(O)O(CH2CH2O)nMe)C(O)NH(CH2)6-, where n is about 450. Symbols (B)-(F) indicate continuation from the previous panel. [Figure 1D] Figures 1A - F show the chemical structure of antagonist A, and the 5'-end of its aptamer (SEQ ID NO: 1) is modified with Me(OCH2CH2)nOC(O)NH(CH2)4CH(NHC(O)O(CH2CH2O)nMe)C(O)NH(CH2)6-, where n is about 450. Symbols (B)-(F) indicate continuation from the previous panel. [Figure 1E] Figures 1A - F show the chemical structure of antagonist A, and the 5'-end of its aptamer (SEQ ID NO: 1) is modified with Me(OCH2CH2)nOC(O)NH(CH2)4CH(NHC(O)O(CH2CH2O)nMe)C(O)NH(CH2)6-, where n is about 450. Symbols (B)-(F) indicate continuation from the previous panel. [Figure 1F] Figures 1A - F show the chemical structure of antagonist A, and the 5'-end of its aptamer (SEQ ID NO: 1) is modified with Me(OCH2CH2)nOC(O)NH(CH2)4CH(NHC(O)O(CH2CH2O)nMe)C(O)NH(CH2)6-, where n is about 450. Symbols (B)-(F) indicate continuation from the previous panel. [Figure 2]Graph showing the mean change in visual acuity of wet AMD patients in a Phase 2b clinical trial treated with 0.5 mg of Lucentis® alone or with either 0.5 mg of Lucentis® and 1.5 mg of antagonist A or 0.3 mg of antagonist A. [Figure 3] Bar graph showing the comparative visual benefit in wet AMD patients treated with either 0.5 mg of Lucentis® and 1.5 mg or 0.3 mg of antagonist A compared to treatment with Lucentis® monotherapy (0.5 mg). [Figure 4] Graph depicting the sequential early and sustained visual improvement in wet AMD patients treated with Lucentis® monotherapy (0.5 mg) or with either 0.5 mg of Lucentis® and 1.5 mg of antagonist or 0.3 mg of antagonist A. [Figure 5] Figures 5A and 5B provide bar graphs showing that the increased efficacy of treatment with either 0.5 mg of Lucentis® and 1.5 mg or 0.3 mg of antagonist A compared to treatment with Lucentis® monotherapy (0.5 mg) in patients with wet AMD is independent of baseline lesion size or baseline vision. Figure 5A shows the mean change in visual acuity for patients at each of the indicated four baseline lesion sites, and Figure 5B shows the mean change in visual acuity for patients with the indicated baseline vision. [Figure 6] Figures 6A and 6B provide bar graphs showing that a greater percentage of patients had significant visual improvement (Figure 6A) and fewer patients had visual loss (Figure 6B) in the cohort of patients treated with 0.5 mg of Lucentis® and 1.5 mg of antagonist A in combination compared to the cohort of patients treated with Lucentis® monotherapy (0.5 mg). [Figure 7]Figures 7A–C provide bar graphs showing that patients treated with 0.5 mg of Lucentis® and 1.5 mg of antagonist A exhibited greater mean improvement in final visual acuity compared to patients treated with Lucentis® monotherapy (0.5 mg). Figure 7A shows the percentage of patients who demonstrated 20 / 40 or better visual acuity; Figure 7B shows the percentage of patients who demonstrated 20 / 25 or better visual acuity; and Figure 7C shows the percentage of patients who demonstrated 20 / 200 or worse visual acuity. [Figure 8] Figures 8A and 8B provide bar graphs showing the increased reduction in choroidal neovascularization (CNV) lesion size in large and small baseline CNV lesions in patients with moist AMD treated with both 0.5 mg of Lucentis® and 1.5 mg of antagonist A, compared to patients treated with Lucentis® monotherapy (0.5 mg). Figure 8A shows the results for all patients, and Figure 8B shows the results for patients with visual results >3 lines. [Figure 9] This graph shows the mean change in geographic atrophy (GA) lesion area measured at 24 weeks in patients with dry AMD who were treated with either 0.3 mg or 1 mg of ARC1905 once a month from weeks 0 to 24 in a Phase 2a clinical trial. [Figure 10] This graph shows the mean change in GA lesion area measured at weeks 24 and 48 in patients with dry AMD who were treated with either 0.3 mg or 1 mg of ARC1905 once a month from weeks 0 to 48 in a Phase 2a clinical trial. [Figure 11] Figure 11 shows Chart 1 of the Early Treatment Study for Diabetic Retinopathy (ETDRS). [Figure 12] Figure 12 shows Chart 2 of the Early Treatment Study for Diabetic Retinopathy (ETDRS). [Figure 13] Figure 13 shows the Chart R of the Early Treatment Study for Diabetic Retinopathy (ETDRS). [Modes for carrying out the invention]

[0011] In certain embodiments, the present invention provides novel and improved methods and compositions for treating and preventing ophthalmic diseases and disorders, including, for example, novel uses, combination therapies, treatment and administration regimens, and co-formulations.

[0012] In one embodiment, the present invention relates to a method for treating or preventing ophthalmic diseases or disorders. The present invention provides a method comprising administering an effective amount of antagonist A or another pharmaceutically acceptable salt thereof to a subject requiring it. In certain embodiments, the subject is administered antagonist A or another pharmaceutically acceptable salt thereof and not an anti-C5 agent. In some embodiments, the subject is administered antagonist A or another pharmaceutically acceptable salt thereof and not a VEGF antagonist.

[0013] In certain embodiments, antagonist A or another pharmaceutically acceptable salt thereof is administered in combination with a VEGF antagonist. In one embodiment, antagonist A or another pharmaceutically acceptable salt thereof is administered in combination with ranibizumab, bevacizumab, aflibercept, pegaptanib sodium, or ESBA1008.

[0014] In certain embodiments, antagonist A or another pharmaceutically acceptable salt thereof is administered in combination with a VEGF antagonist and an anti-C5 agent. In one embodiment, antagonist A or another pharmaceutically acceptable salt thereof is administered in combination with a VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept, pegaptanib sodium, or ESBA1008) and ARC1905.

[0015] The present invention also provides a treatment plan, including treatment and administration plans, relating to the co-administration of antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist (optionally also used in combination with an anti-C5 agent).

[0016] In further embodiments, another agent useful for treating or preventing an ophthalmic disease or disorder (e.g., an agent other than antagonist A, a VEGF antagonist, or an anti-C5 agent) is administered. In some embodiments, the method includes administering one or more (e.g., two) VEGF antagonists and / or one or more (e.g., two) anti-C5 agents to a subject in need.

[0017] In another embodiment, the present invention provides a method for treating or preventing an ophthalmic disease or disorder, comprising administering an effective amount of an anti-C5 agent (e.g., ARC1905) to a subject in need thereof. In certain embodiments, the subject is not administered antagonist A or another pharmaceutically acceptable salt thereof. In some embodiments, the subject is not administered a VEGF antagonist.

[0018] In addition, the present invention provides a co-formulation comprising antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist. In certain embodiments, the co-formulation further comprises an anti-C5 agent. In certain embodiments, the co-formulation is a pharmaceutical composition comprising an effective amount of antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist, and a pharmaceutically acceptable carrier or vehicle. In certain embodiments, the co-formulation is a pharmaceutical composition comprising an effective amount of antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist, and an anti-C5 agent, and a pharmaceutically acceptable carrier or vehicle.

[0019] In one embodiment, the present invention provides a method for treating or preventing an ophthalmic disease or disorder, comprising administering an antagonist A or another pharmaceutically acceptable salt thereof and optionally a VEGF antagonist to a subject in need thereof, and further comprising performing surgery to treat the ophthalmic disease or disorder and / or administering an anti-C5 agent.

[0020] Definitions and Abbreviations

[0021] As used herein, the following terms and phrases shall have the meanings set forth below. Unless otherwise specified, all technical and scientific terms used herein shall have the same meanings as those commonly understood by those skilled in the art to which this invention pertains.

[0022] The term "approximately" when used in relation to a given number means up to 10% more or less than the given number. For example, "approximately 100" means between 90 and 110, and "approximately 6" means between 5.4 and 6.6.

[0023] The term “antagonist” refers to a drug that partially or completely inhibits the activity or production of a target molecule. Specifically, as selectively applied herein, the term “antagonist” means a drug that can reduce the level of gene expression, mRNA, protein, or protein activity of a target molecule. Exemplary forms of antagonists include, for example, proteins, polypeptides, peptides (such as cyclic peptides), antibodies or antibody fragments, peptide mimetic drugs, nucleic acid molecules, antisense molecules, ribozymes, aptamers, RNAi molecules, and small organic molecules. Exemplary, non-limiting mechanisms of antagonist inhibition include inhibiting ligand synthesis and / or stability (e.g., using antisense, ribozyme, or RNAi compositions targeting ligand genes / nucleic acids), blocking ligand binding to its cogenic receptor (e.g., using anti-ligand aptamers, antibodies, or soluble decoy cogenic receptors), inhibiting receptor synthesis and / or stability (e.g., using antisense, ribozyme, or RNAi compositions targeting ligand receptor genes / nucleic acids), blocking receptor binding to its cogenic receptor (e.g., using receptor antibodies), and blocking receptor activation by its cogenic ligand (e.g., using receptor tyrosine kinase inhibitors). In addition, antagonists may directly or indirectly inhibit target molecules.

[0024] The term "antibody fragment" includes an antibody that is an antigen-binding fragment or a single-chain portion thereof. An antibody fragment can be a synthetic or genetically engineered polypeptide. Examples of binding fragments included within the term "antigen-binding portion" of an antibody include (i) a monovalent fragment consisting of the Fab fragment, V L -, V H -, C L -, and C H1 domains; (ii) a bivalent fragment consisting of two Fab fragments linked by a disulfide bridge in the hinge region; (iii) an Fd fragment consisting of V H - and C H1 domains; (iv) an Fv fragment consisting of the V L - and V H domains of a single arm of an antibody; (v) a dAb fragment consisting of a V H domain (Ward et al., (1989) Nature 341:544-546); and (vi) an isolated complementarity-determining region (CDR). Further, the two domains of an Fv fragment, V L - and V H are encoded by separate genes, but they can be linked by a synthetic linker that allows them to be made as a single protein chain in which the V L - and V H regions pair to form a monovalent molecule (known as a single-chain antibody Fv (scFv); see, for example, Bird et al., (1988) Science 242:423-426; and Huston et al., (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single-chain antibodies are also intended to be included within the term "antigen-binding fragment" of an antibody. These antibody fragments are obtained using conventional techniques known to those of skill in the art, and the fragments can be screened for utility in the same manner as whole antibodies.

[0025] The term "aptamer" refers to a peptide or nucleic acid that has an inhibitory effect on a target. Inhibition of a target by an aptamer can occur by binding to the target, by catalytically altering the target, by reacting with the target in a way that modifies the target or its functional activity, by attaching to the target ionically or covalently in suicide inhibitors, or by facilitating a reaction between the target and another molecule. Aptamers are peptides, ribonucleotides, deoxyribonucleotides, other nucleic acids, or other molecules. The aptamer may be a mixture of nucleic acids of a certain type. The aptamer may contain one or more modified amino acids, bases, sugars, polyethylene glycol spacers, or phosphate backbone units, as will be described in more detail herein.

[0026] Nucleotide sequences are "complementary" to another nucleotide sequence if the bases of the two sequences match, that is, if they can form a Watson-Crick base pair. The complement of a nucleic acid chain can be the complement of the coding strand or the complement of the non-coding strand.

[0027] The phrase "conserved residues" refers to amino acids in a group of amino acids that share specific common properties. A functional method for defining the common properties between individual amino acids is to analyze the normal frequency of amino acid changes between corresponding homologous proteins. According to such analysis, a group of amino acids can be characterized if the amino acids within the group preferentially exchange with each other, and therefore are similar in many respects to each other in their influence on the overall structure of the protein (Schulz, G.E. and RHSchirmer, Principles of Protein). Structure (Springer-Verlag). Examples of groups of amino acids defined in this style include:

[0028] (i) A group of charged elements consisting of Glu, Asp, Lys, Arg, and His,

[0029] (ii) A group consisting of Lys, Arg, and His that have a positive charge,

[0030] (iii) A group consisting of Glu and Asp having a negative charge,

[0031] (iv) Aromatic group consisting of Phe, Tyr, and Trp,

[0032] (v) Nitrogen ring group consisting of His and Trp,

[0033] (vi) The macroaliphatic nonpolar group consisting of Val, Leu, and Ile,

[0034] (vii) Micropolarity group consisting of Met and Cys,

[0035] (viii) A group of small residues consisting of Ser, Thr, Asp, Asn, Gly, Ala, Glu, Gln, and Pro,

[0036] (ix) The aliphatic group consisting of Val, Leu, Ile, Met, and Cys,

[0037] (x) Examples include the minor hydroxyl group consisting of Ser and Thr.

[0038] Each of the members in the above groups is a conserved residue.

[0039] The term "label" includes, but is not limited to, radioisotopes, fluorophores, chemiluminescent moieties, enzymes, enzyme substrates, enzyme cofactors, enzyme inhibitors, dyes, metal ions, and ligands (e.g., biotin or haptens). Examples of fluorophore labeling include fluorescein, rhodamine, dansyl, umbelliferone, Texas Red, and luminol, NADPH, α-β-galactosidase, and horseradish peroxidase.

[0040] The term "nucleic acid" refers to polynucleotides such as deoxyribonucleic acid (DNA) or ribonucleic acid (RNA). The term also refers to RNA or DNA analogues created from nucleotide analogues, and, depending on the embodiment described, single-stranded (sense or antisense) and double-stranded polynucleotides, ESTs, chromosomes, cDNA, mRNA, and rRNA. include.

[0041] The terms “RNA interference,” “RNAi,” “miRNA,” and “siRNA” refer to any method by which the expression of a gene or gene product is reduced by introducing one or more double-stranded RNAs homologous to the gene of interest (in particular to the messenger RNA of the gene of interest, e.g., PDGF or VEGF) into a target cell.

[0042] The term "neovascularization" refers to the formation of new blood vessels in abnormal tissue or in abnormal locations.

[0043] The term "angiogenesis" refers to the formation of new blood vessels in normal or abnormal tissue or location.

[0044] The term "ophthalmic diseases" includes diseases of the eye and its adnexa.

[0045] The term "ocular neovascularization" refers to eye disorders characterized by neovascularization. In one embodiment, ocular neovascularization is a disorder other than cancer. Examples of ocular neovascularization include diabetic retinopathy and age-related macular degeneration.

[0046] The term "mammal" includes humans, monkeys, cattle, pigs, sheep, horses, dogs, cats, rabbits, rats, and mice. In certain embodiments, the subject is a mammal.

[0047] The term "PDGF" refers to platelet-derived growth factor, which regulates cell growth or division. As used herein, the term "PDGF" includes various subtypes of PDGF, including PDGF-B (see SEQ ID NOs. 2(nucleic acid) and 3(polypeptide)), PDGF-A (see SEQ ID NOs. 4(nucleic acid) and 5(polypeptide)), PDGF-C (see SEQ ID NOs. 6(nucleic acid) and 7(polypeptide)), PDGF-D, variant 1 (see SEQ ID NOs. 8(nucleic acid) and 9(polypeptide)), and variant 2 (see SEQ ID NOs. 10(nucleic acid) and 11(polypeptide)), and their dimerized forms, including PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC, and PDGF-DD. Platelet-derived growth factors include homodimers or heterodimers of the A chain (PDGF-A) and B chain (PDGF-B), PDGFR-α (see SEQ ID NO: 12 (nucleic acid) and 13 (polypeptide)) and PDGFR-β (see SEQ ID NO: 14 (nucleic acid) and 15 (polypeptide)), which exert their effects through binding to and dimerization of two related receptor tyrosine kinases, platelet-derived growth factor cell surface receptors (i.e., PDGFR). In addition, two further protease-activating ligands for the PDGFR complex, PDGF-C and PDGF-D, have been identified (Li et al., (2000) Nat. Cell. Biol. 2:302-9; Bergsten et al., (2001) Nat. Cell. Biol. 3:512-6; and Uutele et al., (2001) Circulation 103:2242-47). Due to the two distinct ligand-binding specificities of PDGFR, PDGFR-α / α is known to bind PDGF-AA, PDGF-BB, PDGF-AB, and PDGF-CC; PDGFR-β / β binds PDGF-BB and PDGF-DD; while PDGFR-α / β binds PDGF-AB, PDGF-BB, PDGF-CC, and PDGF-DD (Betsholtz et al., (2001) BioEssays 23:494-507). As used herein, the term “PDGF” also refers to a member of the class of growth factors that induce DNA synthesis and phylogenetic division through the binding and activation of PDGFR on responsive cell types.PDGF contributes, for example, to directed cell migration (chemotaxis) and cell activation; phospholipase activation; increased phosphatidylinositol turnover and prostaglandin metabolism; stimulation of both collagen and collagenase synthesis by responsive cells; alteration of cellular metabolic activity, including matrix synthesis, cytokine production, and lipoprotein uptake; indirect induction of proliferation responses in cells lacking the PDGF receptor; and potent vasoconstrictive activity. The term "PDGF" may be used to refer to the "PDGF" polypeptide, the "PDGF" encoding gene or nucleic acid, or a dimerized form thereof.

[0048] The term "PDGF-A" refers to the A-chain polypeptide of PDGF or its corresponding encoding gene or nucleic acid.

[0049] The term "PDGF-B" refers to the B-chain polypeptide of PDGF or its corresponding encoding gene or nucleic acid.

[0050] The term "PDGF-C" refers to the C-chain polypeptide of PDGF or its corresponding encoding gene or nucleic acid.

[0051] The term "PDGF-D" refers to the D-chain polypeptide of PDGF or its corresponding encoding gene or nucleic acid, and includes variants 1 and 2 of the D-chain polypeptide of PDGF.

[0052] The term "PDGF-AA" refers to a dimer containing two PDGF-A chain polypeptides.

[0053] The term "PDGF-AB" refers to a dimer containing one PDGF-A chain polypeptide and one PDGF-B chain polypeptide.

[0054] The term "PDGF-BB" refers to a dimer containing two PDGF-B chain polypeptides.

[0055] The term "PDGF-CC" refers to a dimer containing two PDGF-C chain polypeptides.

[0056] The term "PDGF-DD" refers to a dimer containing two PDGF-D chain polypeptides.

[0057] The term "VEGF" refers to vascular endothelial growth factor that induces angiogenesis or the process of angiogenesis. As used herein, the term "VEGF" means, for example, VEGF 121 VEGF 165 , and VEGF 189 This includes various subtypes of VEGF resulting from alternative splicing of the VEGF-A / VPF gene (also known as vascular permeability factor (VPF) and VEGF-A) (see SEQ ID NOs. 16 (nucleic acid) and 17 (polypeptide)). Furthermore, as used herein, the term "VEGF" includes VEGF-related angiogenic factors such as PIGF (placental growth factor), VEGF-B, VEGF-C, VEGF-D, and VEGF-E, which act through the cognate VEFG receptor (i.e., VEGFR) to induce angiogenesis or the angiogenic process. The term "VEGF" includes any member of the class of growth factors that bind to the VEGF receptor, such as VEGFR-1 (Flt-1) (see SEQ ID NOs. 18 (nucleic acid) and 19 (polypeptide)), VEGFR-2 (KDR / Flk-1) (see SEQ ID NOs. 20 (nucleic acid) and 21 (polypeptide)), or VEGFR-3 (FLT-4). The term "VEGF" may be used to refer to a "VEGF" polypeptide or a "VEGF" encoding gene or nucleic acid.

[0058] The term "PDGF antagonist" refers to a drug that partially or completely reduces or inhibits the activity or production of PDGF. In certain embodiments, a PDGF antagonist inhibits one or more of PDGF-A, PDGF-B, PDGF-C, and PDGF-D. In certain embodiments, a PDGF antagonist inhibits PDGF - Inhibits one or more of PDGF-A, PDGF-B, and PDGF-C. In some embodiments, a PDGF antagonist inhibits dimerized forms of PDGF, such as PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC, and PDGF-DD. In certain embodiments, a PDGF antagonist inhibits PDGF-BB. In other embodiments, a PDGF antagonist inhibits PDGF-AB. A PDGF antagonist can directly or indirectly reduce or inhibit the activity or production of specific PDGFs, such as PDGF-B. Furthermore, a “PDGF antagonist” consistent with the above definition of “antagonist” includes agents that act on PDGF ligands or their cognate receptors to reduce or inhibit receptor signaling associated with PDGF. Examples of "PDGF antagonists" include antisense molecules, lipozymes, or RNAi that target PDGF nucleic acid; anti-PDGF aptamers, anti-PDGF antibodies against PDGF itself or its receptor, or soluble PDGF receptor decoys that prevent PDGF from binding to its cognate receptor; antisense molecules, lipozymes, or RNAi that target cognate PDGF receptor (PDGFR) nucleic acid; anti-PDGFR aptamers or anti-PDGFR antibodies that bind to the cognate PDGFR receptor; and PDGFR tyrosine kinase inhibitors.

[0059] The term "VEGF antagonist" refers to a drug that partially or completely reduces or inhibits the activity or production of VEGF. In certain embodiments, a VEGF antagonist inhibits one or more of VEGF-A, VEGF-B, VEGF-C, and VEGF-D. 165The activity or production of certain VEGFs, such as [specific VEGFs], can be directly or indirectly reduced or inhibited. Furthermore, a “VEGF antagonist” that matches the above definition of “antagonist” includes agents that act on either a VEGF ligand or its cognate receptor to reduce or inhibit receptor signaling associated with VEGF. Examples of “VEGF antagonists” include antisense molecules, lipozymes, or RNAi that target VEGF nucleic acids; anti-VEGF aptamers, anti-VEGF antibodies against VEGF itself or its receptor, or soluble VEGF receptor decoys that prevent VEGF from binding to its cognate receptor; antisense molecules, lipozymes, or RNAi that target cognate VEGF receptor (VEGFR) nucleic acids; anti-VEGFR aptamers or anti-VEGFR antibodies that bind to cognate VEGFR receptors; and VEGFR tyrosine kinase inhibitors. In certain embodiments, the VEGF antagonist is a peptide, for example, a peptide containing three or more amino acid residues. In certain embodiments, the VEGF antagonist is a bicyclic peptide.

[0060] The term “effective dose,” when used in reference to an activator, refers to the amount of an activator, such as a PDGF antagonist, VEGF antagonist, or anti-C5 agent, alone or in combination with another activator, that is useful in treating or preventing an ophthalmic disease or disorder. The “effective dose” may vary depending on the mode of administration, the specific location of the ophthalmic disease or disorder, age, weight, and the subject's overall health. The effective dose of two or more activators is the combined amount of activators that is useful in treating or preventing an ophthalmic disease or disorder, even if the amount of one activator alone would not be effective in treating or preventing the ophthalmic disease or disorder in the absence of one or more other agents.

[0061] A “variant” of polypeptide X refers to a polypeptide having an amino acid sequence of polypeptide X altered in one or more amino acid residues. A variant may have a “conservative” change in which the substituted amino acid has similar structural or chemical properties (e.g., substitution of leucine with isoleucine). More rarely, a variant may have a “non-conservative” change (e.g., substitution of glycine with tryptophan). Similar minor mutations may also include amino acid deletions, insertions, or both. Guidance on determining which amino acid residues may be substituted, inserted, or deleted without compromising biological or immunological activity can be found in computer programs known in the art, e.g., This can be determined using LASERGENE software (DNASTAR).

[0062] When used in the context of polynucleotide sequences, the term “mutant” can encompass polynucleotide sequences associated with a gene or its coding sequence. This definition also includes, for example, “allelic,” “splice,” “species,” or “polymorphic” mutants. Splice mutants may have significant identity with respect to a reference molecule, but generally will have more or fewer polynucleotides due to alternative splicing of exons during mRNA processing. The corresponding polypeptide may have additional functional domains or domain absences. Species mutants are polynucleotide sequences that differ by species. The resulting polypeptides will generally have significant amino acid identity with respect to one another. Polymorphic mutants are variations in the polynucleotide sequence of a particular gene between individuals of a given species.

[0063] The term “anti-C5 agent” refers to a drug that partially or completely reduces or inhibits the activity or production of the C5 complement protein or its variants. Anti-C5 agents can directly or indirectly reduce or inhibit the activity or production of the C5 complement protein or its variants. Anti-C5 agents can reduce or inhibit the conversion of the C5 complement protein to its constituent polypeptides C5a and C5b. Anti-C5 agents can also reduce or inhibit the activity or production of C5a and / or C5b. Examples of “anti-C5 agents” include antisense molecules, ribozymes, or RNAi that target the C5 nucleic acid; anti-C5 aptamers, including anti-C5a and anti-C5b aptamers; anti-C5 antibodies against C5, C5a, C5b, or C5b-9; or soluble C5 receptor decoys that prevent the binding of the C5 complement protein or its variants or fragments (e.g., C5a or C5b) to their binding partners or receptors.

[0064] Drugs useful for the treatment or prevention of ophthalmic diseases or disorders.

[0065] Antagonist A

[0066] Antagonist A has 2'-fluoro-2'-deoxyuridine at positions 6, 19, and 28; 2'-fluoro-2'-deoxycytidine at positions 8, 20, 26, and 27; 2'-O-methyl-2'-deoxyguanosine at positions 9, 14, 16, and 29; 2'-O-methyl-2'-deoxyadenosine at position 21; reverse T (i.e., 3'-3'- is attached) at position 30; and phosphodiester between the linker and each nucleotide. This is a PEGylated anti-PDGF aptamer having the sequence CAGGCUACGCGTAGAGCAUCATGATCCUGT (SEQ ID NO: 1) (see Example 3 of U.S. Patent Application Publication No. 20050096257, incorporated herein by reference in its entirety) which has two hexaethylene glycol phosphoramidite bonds linking the 9th and 10th nucleotides and the 21st and 22nd nucleotides together via a rib linkage.

[0067] The chemical name of antagonist A is [(monomethoxy20K polyethylene glycol carbamoyl-N2-)(monomethoxy20K polyethylene glycol carbamoyl-N6-)]-lysine-amide-6-hexandylyl-(1-5')-2'-deoxycytidylyl-(3'-5')-2'-deoxyadenylyl-(3'-5')-2'-deoxyguanylyl-(3'-5')-2'-deoxyguanylyl-(3'-5')-2'-deoxycytidylyl-(3'-5')-2'-deoxy-2'-fluorouridilyl-(3'-5')-2'-deoxyadenylyl-(3'-5')-2'-deoxy-2'-fluorocytidylyl-(3'-5')-2'-deoxy-2'-methoxyguanylyl Nylyl-(3'-1)-PO3-Hexa(ethyloxy)-(18-5')-2'-Deoxycytidylyl-(3'-5')-2'-Deoxyguanylyl-(3'-5')-Thimidylyl-(3'-5')-2'-Deoxyadenylyl-(3'-5')-2'-Deoxy-2'-Methoxyguanylyl-(3'-5')-2'-Deoxyadenylyl-(3'-5')-2'-Deoxy-2'-Methoxyguanylyl-(3'-5')-2'-Deoxycytidylyl-(3'-5')-2'-Deoxyadenylyl-(3'-5')-2'-Deoxy-2'-Fluorourydilyl-(3'-5')-2'-Deoxy The compound is C-2'-fluorocytidylyl-(3'-5')-2'-deoxy-2'-methoxyadenylyl-(3'-1)-PO3-hexa(ethyloxy)-(18-5')-thymidyl-(3'-5')-2'-deoxyguanylyl-(3'-5')-2'-deoxyadenylyl-(3'-5')-thymidyl-(3'-5')-2'-deoxy-2'-fluorocytidylyl-(3'-5')-2'-deoxy-2'-fluorocytidylyl-(3'-5')-2'-deoxy-2'-fluorouridilyl-(3'-5')-2'-deoxy-2'-methoxyguanylyl-(3'-3')-thymidine.

[0068] The structure of antagonist A is shown in Figure 1.

[0069] The sequence of antagonist A is:

[0070] 5'-[mPEG2 40kD]-[HN-(CH2)6O]CAGGCU f AC f G m [PO3(CH2CH2O)6]CGTAG m AG m CAU f C f A m [PO3(CH2CH2O)6]TGATC f C f U f G m It is -[3T]-3', and its aptamer sequence is specified in (SEQ ID NO: 1).

[0071] Here, [3T] refers to a reverse thymidine nucleotide attached to the 3' end of the oligonucleotide at the 3' position on the ribose sugar, and [mPEG2 40kD] represents two 20kD polyethylene glycol (PEG) polymer chains, which in one embodiment represent two approximately 20kD PEG polymer chains covalently attached to two amino groups of a lysine residue via a carbamate bond. This portion is then bonded to the oligonucleotide via an aminolinker, which is described below.

[0072] [HN-(CH2)6O] represents a bifunctional α-hydroxy-ω-aminolinker covalently attached to the PEG polymer via an amide bond. The linker is attached to the oligonucleotide at the -5' end of antagonist A via a phosphodiester bond.

[0073] [PO3(CH2CH2O)6] represents the hexaethylene glycol (HEX) moiety that links oligonucleotide segments via phosphodiester bonds. Antagonist A has two HEX bonds that link the 9th and 10th nucleotides, and the 21st and 22nd nucleotides together via phosphodiester bonds between the linker and each nucleotide.

[0074] C, A, G, and T represent single-letter symbols for the 2'-deoxy derivatives of cytosine, adenosine, guanosine, and thymidine nucleic acids, respectively. Antagonist A contains four 2'-deoxyribocytosine molecules, six 2'-deoxyriboadenosine molecules, four 2'-deoxyriboguanosine molecules, and four 2'-deoxyribothymidine molecules.

[0075] G m and A m These represent the 2'-methoxy-substituted forms of guanosine and adenosine, respectively. Antagonist A has four 2'-methoxyguanosine molecules and one 2'-methoxyadenosine molecule. C f and U f These represent the 2'-fluorosubstituted forms of cytosine and uridine, respectively. Antagonist A consists of four 2'-fluorocytosines and three 2'- It contains fluorouridine.

[0076] The phosphodiester bonds within the oligonucleotide, except for the 3'-terminus, connect the 5'- and 3'-oxygen atoms of the ribose ring with standard nucleoside phosphodiester bonds. The 3'-terminus thymidine and the second-to-last G m The phosphodiester bond between the two atoms binds their respective 3'-oxygen atoms and is called the 3',3'-cap.

[0077] Antagonist A has a molecular weight of 40,000 to 60,000 daltons, and in one embodiment, a molecular weight of about 40,000 to about 60,000 daltons, and may be colorless to slightly yellow in solution. Antagonist A can be present in solutions of monobasic sodium phosphate monohydrate and dibasic sodium phosphate heptahydrate as buffering agents, and in solutions of sodium chloride as a tonicity modifier. Antagonist A is a hydrophilic polymer. Antagonist A is soluble in water and phosphate-buffered saline (PBS) up to a solution of at least 50 mg (based on oligonucleotide weight) / mL, as evaluated by visual inspection.

[0078] Antagonist A can be synthesized using a repetitive chemical synthesis procedure to produce an oligonucleotide moiety, which is then covalently bonded to a PEGylation reagent as described in Example 4 of U.S. Patent Publication No. 2012 / 0100136.

[0079] Antagonist A is a persodium salt. However, other pharmaceutically acceptable salts of the antagonist are useful in the compositions and methods disclosed herein.

[0080] VEGF Antagonist

[0081] In some embodiments, the VEGF antagonist is ranibizumab (marketed under the trade name Lucentis® (Genentech, San Francisco, California); see Figure 1 of U.S. Patent No. 7,060,269 for heavy and light chain variable region sequences), bevacizumab (marketed under the trade name Avastin® (Genentech, San Francisco, California); see Figure 1 of U.S. Patent No. 6,054,297 for heavy and light chain variable region sequences), aflibercept (marketed under the trade name Eylea® (Regeneron, Tarrytown, New York)), KH902 VEGF receptor-Fc fusion protein (see Zhang et al., (2008) Mol Vis. 14:37-49), 2C3 antibody (see U.S. Patent No. 6,342,221, column 8, rows 48-67, column 9, rows 1-21), ORA102 (Ora (Available from Bio, Ltd.), pegaptanib (e.g., pegaptanib sodium; marketed as Macugen® (Valeant Pharmaceuticals, Bridgewater, New Jersey; see Figure 1 of U.S. Patent No. 6,051,698)), bevacilanib (see Dejneka et al., (2008) Mol Vis. 14:997-1005), SIRNA-027 (see Shen et al., (2006) Gene Ther. 13:225-34), declusin (see U.S. Patent No. 6,525,089 (column 3, lines 5-16)), declusinol (see Ahn et al., (1997) Planta Med. 63:360-1), picropodophyllin (Economou (2008) Investigative Ophthalmology & Visual See Science.49:2620-6), guggulsterone (see Kim et al., (2008) Oncol.Rep.20:1321-7), PLG101 (see Ahmadi and Lim (2008) Expert Opin Pharmacother.9:3045-52), PLG201 (see Ahmadi and Lim (2008)), eicosanoid LXA4 (see Baker et al., (2009) J Immun.182:3819-26), PTK787 (marketed under the trade name Vitalanib(trademark); see Barakat and Kaiser (2009) Expert Opin Investig Drugs 18:637-46), pazopanib (Takahashi et al., (2009) Arch See Ophthalmol. 127:494-9), axitinib (see Hu-Lowe et al., (2008) Clin Cancer Res. 14:7272-83), CDDO-Me (see Sogno et al., (2009) Recent Results Cancer Res. 181:209-12), CDDO-Imm (see Sogno et al., (2009)), shikonin (see Hisa et al., (1998) Anticancer See Res.18:783-90), β-hydroxyisovalerylsikonin (see Hisa et al., (1998)), ganglioside GM3 (see Chung et al., (2009) Glycobio.19:229-39), DC101 antibody (see U.S. Patent No. 6,448,077, column 2, lines 61-65), Mab25 antibody (see U.S. Patent No. 6,448,077, column 2, lines 61-65), Mab73 antibody (see U.S. Patent No. 6,448,077, column 2, lines 61-65), 4A5 antibody (see U.S. Patent No. 6,383,484 See Patent No. 6, column 12, lines 50-54), 4E10 antibody (see Patent No. 6,383,484, column 10, lines 66-67, column 11, lines 1-2), 5F12 antibody (see Patent No. 6,383,484, column 10, lines 62-65), VA01 antibody (see Patent No. 5,730,977, column 6, lines 26-30), BL2 antibody (see Patent No. 5,730,977, column 6, lines 30-32), VEGF-related protein (see Patent No. 6,451,764, Figure 1), sFLT01 (Pechan et al., (2009) Gene See Ther. 16:10-6), sFLT02 (see Pechan et al., (2009)), peptide B3 (see Lacal et al., (2008) Eur J Cancer 44:1914-21), TG100801 (see Palanki et al., (2008) J Med Chem. 51:1546-59), sorafenib (available under the trade name Nexavar®; see Kernt et al., (2008) Acta Ophthalmol.See 86:456-8), G6-31 antibody (see Crawford et al., (2009) Cancer Cell 15:21-34), ESBA1008 (see U.S. Patent No. 8,349,322), tivozanib (incorporated by reference in its entirety, U.S. Patent No. 6,821,987; see Campas et al., (2009) Drugs Fut 2009, 34(10):793), or a pharmaceutically acceptable salt thereof.

[0082] In another embodiment, the VEGF antagonist is an antibody or antibody fragment that binds to the epitope VEGF-A (SEQ ID NO: 22) or VEGF-B (SEQ ID NO: 23), or any portion of the epitope. In one embodiment, the VEGF antagonist is an antibody or antibody fragment that binds to one or more epitopes of VEGF (e.g., SEQ ID NOs: 22 and 23). In another embodiment, the VEGF antagonist is an antibody or antibody fragment that binds to an epitope of VEGF, such as the epitopes of VEGF-A, VEGF-B, VEGF-C, VEGF-D, or VEGF-E. In some embodiments, the VEGF antagonist binds to an epitope of VEGF in such a way that the binding of VEGF and VEGFR is inhibited. In one embodiment, the epitope comprises a component of the three-dimensional structure of VEGF, which is displayed so as to be exposed on the surface of a folded VEGF molecule. In one embodiment, the epitope is a linear amino acid sequence from VEGF.

[0083] In some embodiments, inhibitory antibodies against VEGF are known in the art, including, for example, those described in U.S. Patents 6,524,583, 6,451,764 (VRP antibody), 6,448,077, 6,416,758, 6,403,088 (vs. VEGF-C), 6,383,484 (vs. VEGF-D), 6,342,221 (anti-VEGF antibody), 6,342,219, 6,331,301 (VEGF-B antibody), and 5,730,977, and PCT Publications W096 / 30046, WO97 / 44453, and WO98 / 45331, whose contents are incorporated by reference throughout. .

[0084] Other non-antibody VEGF antagonists include antibody mimetic drugs with VEGF antagonist activity (e.g., Affibody® molecules, affilin, afitin, antikalin, avimer, Kunitz domain peptides, and monobodies). These include recombinant binding proteins containing an ankyrin repeat domain that binds to VEGF-A and prevents it from binding to VEGFR-2. One example is MP0112, also known as AGN150998 (DARPin®). The ankyrin binding domain may have the amino acid sequence of SEQ ID NO: 97.

[0085] Recombination-binding proteins containing an ankyrin repeat domain that bind to VEGF-A and prevent it from binding to VEGFR-2 are described in detail in WO2010 / 060748 and WO2011 / 135067.

[0086] More specific antibody mimetic drugs with VEGF antagonist activity include 40kD PEGylated antikalin PRS-050 and the monobody angiocept (CT-322).

[0087] The non-antibody VEGF antagonists described above can be modified to further improve their pharmacokinetic properties or bioavailability. For example, non-antibody VEGF antagonists can be chemically modified (e.g., PEGylated) to extend their in vivo half-life. Alternatively, or in addition, they can be modified by glycosylation or the addition of further glycosylation sites that are not present in the protein sequence of the native protein from which the VEGF antagonist is derived.

[0088] Another non-antibody VEGF antagonist immunoadhesin currently in preclinical development is a recombinant human soluble VEGF receptor fusion protein similar to the VEGF trap, containing extracellular ligand-binding domains 3 and 4 derived from VEGFR2 / KDR and domain 2 derived from VEGFR1 / Flt-1, where these domains are fused to a human IgG Fc protein fragment (Li et al., 2011 Molecular Vision 17:797-803). This antagonist binds to isotypes VEGF-A, VEGF-B, and VEGF-C. The molecule is prepared using two different manufacturing processes, resulting in different glycosylation patterns on the final protein. The two glycotypes are designated KH902 (convercept) and KH906. The fusion protein can have the amino acid sequence of SEQ ID NO: 98 and, like the VEGF trap, can exist as a dimer. This fusion protein and related molecules are further characterized in European Patent No. 1767546.

[0089] Anti-C5 agents

[0090] In certain embodiments, anti-C5 agents modulate the function of the C5 complement protein or its variants. In some embodiments, anti-C5 agents inhibit the function of the C5 complement protein or its variants. In one embodiment, the function inhibited by the anti-C5 agent is C5 complement protein cleavage.

[0091] C5 complement protein variants, as used herein, include variants that perform substantially the same function as the C5 complement protein. In some embodiments, C5 complement protein variants have substantially the same structure as the amino acid sequence of the C5 complement protein, including the amino acid sequence of SEQ ID NO: 24; in some embodiments, they have at least 80% sequence identity; in some embodiments, they have at least 90% sequence identity; and in some embodiments... It contains at least 95% sequence identity.

[0092] In some embodiments, the anti-C5 agent is selected from nucleic acid molecules, aptamers, antisense molecules, RNAi molecules, proteins, peptides, cyclic peptides, antibodies or antibody fragments, sugars, polymers, or small molecules. In a particular embodiment, the anti-C5 agent is the anti-C5 agent described in PCT patent application WO2007 / 103549.

[0093] In certain embodiments, the anti-C5 agent is an anti-C5 aptamer. An aptamer is a nucleic acid molecule that has a specific binding affinity to a molecule via an interaction different from classical Watson-Crick base pairing. Like peptides or monoclonal antibodies ("mAbs") produced by phage display, aptamers can specifically bind to a selected target and modulate the target's activity, for example, by blocking the target's ability to function via the bound aptamer. Aptamers may be non-PEGylated or PEGylated. In certain embodiments, the aptamer may contain one or more 2'-saccharide modifications, such as 2'-O-alkyl (e.g., 2'-O-methyl or 2'-O-methoxyethyl) or 2'-fluoro modifications.

[0094] Exemplary C5-specific aptamers include the aptamers disclosed in PCT Publication No. WO2007 / 103549, which are incorporated therein by reference. Exemplary C5-specific aptamers include aptamers ARC185 (SEQ ID NO: 25), ARC186 (SEQ ID NO: 26), ARC188 (SEQ ID NO: 27), ARC189 (SEQ ID NO: 28), ARC243 (SEQ ID NO: 29), ARC244 (SEQ ID NO: 30), ARC250 (SEQ ID NO: 31), ARC296 (SEQ ID NO: 32), ARC297 (SEQ ID NO: 33), ARC330 (SEQ ID NO: 34), ARC331 (SEQ ID NO: 35), ARC332 (SEQ ID NO: 36), ARC333 (SEQ ID NO: 37), ARC334 (SEQ ID NO: 38) ), ARC411 (sequence number 39), ARC412 (sequence number 40), ARC413 (sequence number 41), ARC414 (sequence number 42), ARC415 (sequence number 43), ARC416 (sequence number 44), ARC417 (sequence number 45), ARC418 (sequence number 46), ARC419 (sequence number 47), ARC420 (sequence number 48), ARC421 (sequence number 49), ARC422 (sequence number 50), ARC423 (sequence number 51), ARC424 (sequence number 52), ARC425 (sequence number 53), ARC4 26 (SEQ ID NO: 54), ARC427 (SEQ ID NO: 55), ARC428 (SEQ ID NO: 56), ARC429 (SEQ ID NO: 57), ARC430 (SEQ ID NO: 58), ARC431 (SEQ ID NO: 59), ARC432 (SEQ ID NO: 60), ARC433 (SEQ ID NO: 61), ARC434 (SEQ ID NO: 62), ARC435 (SEQ ID NO: 63), ARC436 (SEQ ID NO: 64), ARC437 (SEQ ID NO: 65), ARC438 (SEQ ID NO: 66), ARC439 (SEQ ID NO: 67), ARC440 (SEQ ID NO: 68), ARC45757 (SEQ ID NO: 54), ARC427 (SEQ ID NO: 55), ARC428 (SEQ ID NO: 56), ARC4 Number 69), ARC458 (Sequence ID 70), ARC459 (Sequence ID 71), ARC473 (Sequence ID 72), ARC522 (Sequence ID 73), ARC523 (Sequence ID 74), ARC524 (Sequence ID 75), ARC525 (Sequence ID 76), ARC532 (Sequence ID 77), ARC543 (Sequence ID 78), ARC544 (Sequence ID 79), ARC550 (Sequence ID 80), ARC551 (Sequence ID 81), ARC552 (Sequence ID 82), ARC553 (Sequence ID 83), ARC554 (Sequence ID 84),Examples include ARC657 (sequence number 85), ARC658 (sequence number 86), ARC672 (sequence number 87), ARC706 (sequence number 88), ARC913 (sequence number 89), ARC874 (sequence number 90), ARC954 (sequence number 91), ARC1537 (sequence number 92), ARC1730 (sequence number 93), or pharmaceutically acceptable salts thereof.

[0095] In some embodiments, the anti-C5 agent is an aptamer having SEQ ID NOs: 94, 95, or 96.

[0096] In certain embodiments, the anti-C5 agent is a C5-specific aptamer containing the nucleotide sequence of SEQ ID NO: 26 conjugated to a polyethylene glycol moiety via a linker. In some embodiments, the polyethylene glycol moiety has a molecular weight greater than about 10 kDa, specifically about 20 kDa, more specifically about 30 kDa, and more specifically about 40 kDa. In some embodiments, the polyethylene glycol moiety is conjugated to the 5-terminus of the aptamer via a linker. In some embodiments, the PEG conjugated to the 5-terminus is a PEG with a molecular weight of about 40 kDa. In certain embodiments, the PEG with about 40 kDa is a branched-chain PEG. In some embodiments, the branched-chain PEG with about 40 kDa is 1,3-bis(mPEG-[about 20 kDa])-propyl-2-(4'-butamide). In other embodiments, the branched-chain PEG with about 40 kDa is 2,3-bis(mPEG-[about 20 kDa])-propyl-1-carbamoyl.

[0097] In a particular embodiment, the C5-specific aptamer is a compound having the following structure, ARC187.

[0098] [ka]

[0099] or a pharmaceutically acceptable salt thereof, where aptamer =

[0100] fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T (Sequence ID 26),

[0101] In the formula, fC and fU = 2'-fluoronucleotide, mG and mA = 2'-OMe nucleotide, all other nucleotides are 2'-OH, and 3T represents inverted deoxythymidine. In some embodiments, each 20 kDa mPEG of the above structure has a molecular weight of approximately 20 kDa.

[0102] In another specific embodiment, the C5-specific aptamer is a compound having the structure described below, ARC1905.

[0103] [ka]

[0104] or a pharmaceutically acceptable salt thereof, where aptamer = fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCfCfUmGfCmG-3T (Sequence ID 26),

[0105] In the formula, fC and fU = 2'-fluoronucleotide, mG and mA = 2'-OMe nucleotide, all other nucleotides are 2'-OH, and 3T is an inverted deoxygenate. This shows cytymidine. In some embodiments, each 20 kDa mPEG of the above structure has a molecular weight of approximately 20 kDa.

[0106] In other embodiments, the anti-C5 agent is an antisense oligonucleotide and ribozyme that are targeted against C5 and exert a C5 inhibitory effect by inhibiting protein translation from messenger RNA or by targeting the degradation of the corresponding C5 mRNA.

[0107] In other embodiments, the anti-C5 agent is an anti-C5 RNA interference (RNAi) construct. Certain double-stranded oligonucleotides useful for exerting RNAi effects against C5 complement proteins are less than 30 base pairs long and may contain ribonucleic acids of approximately 25, 24, 23, 22, 21, 20, 19, 18, or 17 base pairs, and may contain sequences with substantial sequence identity to the mRNA sequence of complement C5 protein, particularly human complement C5 protein. Optionally, dsRNA oligonucleotides may contain a 3' overhang. Non-limiting exemplary 2-nucleotide 3' overhangs may consist of any type of ribonucleotide residue, and may even consist of a 2'-deoxythymidine residue, which can reduce the cost of RNA synthesis and enhance the nuclease resistance of siRNA in cell culture medium and in transfected cells (see Elbashi et al., (2001) Nature, 411:494-8).

[0108] Other medications for the treatment or prevention of ophthalmic diseases or disorders

[0109] In another embodiment, another agent useful for treating or preventing ophthalmic diseases or disorders is boroxiximab or a pharmaceutically acceptable salt thereof (which is incorporated herein by reference in its entirety, Ramakrishnan et al., (2008) J Exp Ther Oncol. 5:273-86).

[0110] In some embodiments, multiple aptamers can associate with a single non-immunogenic, high molecular weight compound such as polyalkylene glycol or PEG, or with a lipophilic compound such as a glycerolipid. The aptamers can all be for a single target or for different targets. In embodiments where the compound includes one or more PDGF aptamers, the affinity can be increased through multiple binding interactions with targets such as PDGF or VEGF. In further embodiments, multiple polyalkylene glycol, PEG, and glycerol lipid molecules can be attached to one another. In these embodiments, one or more aptamers can associate with each polyalkylene glycol, PEG, or glycerol lipid. This can result in an increased affinity of each aptamer to its target. In addition, in embodiments where there are aptamers for PDGF, or aptamers for different targets that associate with PDGF and polyalkylene glycol, PEG, or glycerol lipids, the drug can also be associated with polyalkylene glycol, PEG, or glycerol lipids, for example, by covalent bonding. Therefore, the compound will provide targeted delivery of a drug, accompanied by a polyalkylene glycol, PEG, or glycerol lipid acting as a linker, and optionally accompanied by one or more further linkers.

[0111] Aptamers can be 5'-capped and / or 3'-capped with a 5'-5' reverse nucleotide cap structure at the 5' end and / or a 3'-3' reverse nucleotide cap structure at the 3' end. In some embodiments, antagonist A, antagonist B, antagonist C, antagonist D, pegatanib, bevacilanib, and Sirna-027 are 5' or 3' end capped.

[0112] Methods for treating or preventing ophthalmic diseases or disorders

[0113] The present invention provides methods and compositions useful for treating or preventing any ophthalmic diseases and disorders described herein, including but not limited to those described herein.

[0114] In some embodiments, the methods for treating or preventing ophthalmic diseases or disorders described herein improve the success rate of retinal attachment, improve visual acuity, or stabilize vision. In some embodiments, the methods disclosed herein prevent or slow the rate of further vision deterioration in the subject.

[0115] In some embodiments, concomitant administration of antagonist A or another pharmaceutically acceptable salt thereof with a VEGF antagonist or a pharmaceutically acceptable salt thereof and / or an anti-C5 agent improves retinal reattachment success rates, improves visual acuity, or stabilizes vision to a greater extent than administration of antagonist A or another pharmaceutically acceptable salt thereof alone, administration of a VEGF antagonist or a pharmaceutically acceptable salt thereof alone, or administration of an anti-C5 agent alone. In some embodiments, administration of antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist or a pharmaceutically acceptable salt thereof, and optionally an anti-C5 agent, has a synergistic effect in the treatment or prevention of ophthalmic diseases or disorders. For example, administration of both antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist or a pharmaceutically acceptable salt thereof improves retinal reattachment success rates, improves visual acuity, or stabilizes vision to a greater extent than the additive effect of administration of both antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, administration of antagonist A alone or in combination with a VEGF antagonist and / or anti-C5 agent, according to the methods described herein, e.g., treatment or administration plans, improves retinal reattachment success rates, improves visual acuity, or stabilizes vision to a greater extent than administration of antagonist A alone or in combination with a VEGF antagonist and / or anti-C5 agent, according to the methods described conventionally.

[0116] In certain embodiments, any method and composition of the present invention may be used to treat or prevent an ophthalmic disease or disorder in a particular subject. For example, in a particular embodiment, a subject treated according to the method herein is defined or identified based on their previous treatment for the disease or disorder, the specific pathology of their disease or disorder being treated, and / or other characteristics. In one embodiment, the subject has a defined phenotype or medical history.

[0117] Accordingly, any method described herein further includes identifying subjects to be treated by determining, for example, whether the subject has previously been administered a VEGF antagonist to treat or prevent the disease or disorder, or whether the subject has previously failed monotherapy with a VEGF antagonist, by asking the subject or their healthcare provider, or by reviewing the subject's medical records.

[0118] In one embodiment, the subject was previously treated with a VEGF antagonist or anti-VEGF monotherapy for any ocular disease or disorder to which a VEGF antagonist is used, or for any ocular disease or disorder described herein (e.g., wet AMD).

[0119] In certain embodiments, the methods and compositions described herein are useful for treating or preventing ophthalmic diseases or disorders in subjects that are anti-VEGF resistant, have been previously administered or treated with anti-VEGF monotherapy and have not responded to anti-VEGF monotherapy, or have not responded well or adequately, and / or have failed monotherapy with a VEGF antagonist. In some embodiments, subjects that have failed monotherapy are anti-VEGF resistant The subjects were of a sexual nature, had complement-mediated inflammation, and / or did not respond well to anti-VEGF monotherapy. In one embodiment, subjects who failed monotherapy with a VEGF antagonist were those who experienced poor visual or anatomical outcomes after treatment or administration with a VEGF antagonist. In one embodiment, subjects did not show improvement in vision or showed a decrease in vision after anti-VEGF monotherapy.

[0120] In certain embodiments, subjects did not respond well or adequately to anti-VEGF monotherapy, as determined by a decline in the subject's vision after anti-VEGF monotherapy or by a lack of significant visual improvement in the subject. In one embodiment, a lack of significant visual improvement in the subject after anti-VEGF monotherapy is determined by the subject's inability to read one or more characters, in some embodiments three or more characters, and in some embodiments fifteen or more characters, on a standardized chart of visual acuity, e.g., the Early Treatment Diabetic Retinopathy Study Research Group (ETDRS) chart ("ETDRS chart"). In some embodiments, the visual acuity test is as described in the Early Treatment Diabetic Retinopathy Study Research Group (ETDRS), Manual of Operations, Baltimore: ETDRS Coordinating Center, University of Maryland. As described herein, it is available from National Technical Information Service, 5285 Port Royal Road, Springfield, VA 22161; Accession No. PB85 223006 / AS; Ferris et al., Am J Ophthalmol 94:91-96, 1982; or Example 4. In some embodiments, the visual acuity test uses one or more charts available from http: / / www.nei.nih.gov / photo / keyword.asp?conditions=Eye+Charts&match=all, for example, ETDRS visual acuity charts 1, 2 and / or R.

[0121] In another embodiment, a subject's visual acuity decline after anti-VEGF monotherapy is determined by the subject's loss of ability to read one or more letters or lines on a standardized visual acuity chart, e.g., an ETDRS chart, from baseline, in some embodiments, three or more letters or lines. In one embodiment, a lack of significant visual acuity improvement in a subject after anti-VEGF monotherapy is determined by the subject's loss of ability to read one or more additional letters, in some embodiments, three or more letters, and in some embodiments, fifteen or more letters on a standardized visual acuity chart, e.g., an ETDRS chart, from baseline. In another embodiment, a lack of significant visual acuity improvement in a subject after anti-VEGF monotherapy is determined by the subject's loss of ability to read one or more additional lines on a standardized visual acuity chart, e.g., an ETDRS chart, from baseline, in some embodiments, three or more lines. In some embodiments, a subject's visual acuity decline or lack of significant visual acuity improvement is determined by anatomical signs of the subject's visual acuity decline or poor treatment response, e.g., persistent leakage, increased bleeding, persistent or increased retinal pigment epithelium (RPE) detachment, signs of neovascularization, or increased neovascularization or abnormal matrix deposition or fibrosis. In certain embodiments, the subject's visual acuity decline or lack of significant visual acuity improvement is determined at 12 or 24 weeks after the start of treatment.

[0122] In certain embodiments, the subject is resistant to VEGF antagonists, such as anti-VEGF monotherapy. In one embodiment, the subject is resistant to VEGF if it has been previously administered with a VEGF antagonist, such as anti-VEGF monotherapy, and it has not resulted in treatment or prevention of an ophthalmic disease or disorder; it has resulted in merely temporary treatment or prevention of an ophthalmic disease or disorder, and the subject has required further treatment or prevention of the ophthalmic disease or disorder; or it has resulted in decreased vision, and the subject has required further treatment or prevention of the ophthalmic disease or disorder.

[0123] In another embodiment, the subject has previously undergone anti-VEGF treatment, such as anti-VEGF monotherapy. A subject is considered to have anti-VEGF resistance if, after treatment or administration, they fail to achieve any improvement in visual acuity or experience a decline in visual acuity. In some embodiments, subjects did not respond well to anti-VEGF treatment. In one embodiment, subjects were administered anti-VEGF treatment for a period of one year or longer. In some such embodiments, subjects require treatment for wet AMD.

[0124] Accordingly, the present invention provides a method for treating, preventing, or stabilizing wet AMD in subjects, such as subjects who have failed monotherapy with VEGF antagonists (e.g., subjects who are anti-VEGF resistant, have complement-mediated inflammation, and / or have not responded well to anti-VEGF monotherapy). In certain embodiments, the method includes determining whether the subject has previously been administered or treated with anti-VEGF monotherapy. In certain embodiments, anti-VEGF monotherapy means the administration of one or more VEGF antagonists alone. In certain embodiments, anti-VEGF monotherapy includes the optional administration of other agents that are not specifically applied to the treatment of an ophthalmic disease or disorder, such as wet AMD.

[0125] In certain embodiments, the methods and compositions described herein are useful for treating or preventing ophthalmic diseases or disorders of a subject that has never been treated before. In some embodiments, a subject is treatment-naive if the subject has not been previously treated for the ophthalmic disease or disorder. In some embodiments, a subject is treatment-naive if the subject has not been previously administered or treated with a VEGF antagonist or anti-VEGF monotherapy ("anti-VEGF treatment-naive"). In certain embodiments, the method further includes determining whether the subject has been previously treated for the ophthalmic disease or disorder, or administered a VEGF antagonist or anti-VEGF monotherapy, for example, by asking the subject or his or her healthcare provider, or by reviewing the subject's medical records. In certain embodiments, anti-VEGF monotherapy means the administration of one or more VEGF antagonists alone. In certain embodiments, anti-VEGF monotherapy includes the optional administration of other agents that are not specifically applied to the treatment of an ophthalmic disease or disorder, such as wet AMD. In some embodiments, the subject is treatment-naive if the subject has not been previously treated for AMD (e.g., wet AMD). In some embodiments, the subject is treatment-naive if the subject has not been previously treated for AMD (e.g., wet AMD) in either eye, or has not received any conventional treatment. In yet another embodiment, the subject is treatment-naive if the subject has not been previously treated for AMD (e.g., wet AMD; e.g., in either eye), or has not received any conventional treatment, except for one or more oral supplements of vitamins and minerals. In some embodiments, the subject is treatment-naive if the subject has not been previously administered a therapeutic agent used for the treatment of AMD (e.g., wet AMD).

[0126] In certain embodiments, the subject has complement-mediated inflammation. In certain embodiments, the subject is resistant to anti-VEGF and has complement-mediated inflammation. In certain embodiments, the complement-mediated inflammation is present in the subject's eye. In certain embodiments, the complement-mediated inflammation is due to a previous administration of anti-VEGF monotherapy. In other embodiments, the subject has been diagnosed with or is diagnosed with complement-mediated inflammation. In yet another embodiment, the subject has not adequately responded to anti-VEGF monotherapy and is diagnosed with or is diagnosed with complement-mediated inflammation. In certain embodiments, the complement-mediated inflammation is diagnosed in the subject using a genetic screening method. Such genetic screening methods are known to those skilled in the art and include, but are not limited to, screening for mutations in complement genes, such as complement factor H (CFH), CFI, CFHR5, and MCP, BF, and C2 genes.

[0127] In certain embodiments, the methods and compositions described herein are useful for treating or preventing an ophthalmic disease or disorder in a subject newly diagnosed with the ophthalmic disease or disorder. In some embodiments, the subject is newly diagnosed with the ophthalmic disease or disorder in which the subject had not been previously diagnosed. In some embodiments, the subject is newly diagnosed with age-related macular degeneration. In some embodiments, the subject is newly diagnosed with dry age-related macular degeneration. In some embodiments, the subject is newly diagnosed with wet AMD. In certain embodiments, the method further includes determining whether the subject has been previously diagnosed with the ophthalmic disease or disorder, for example, by asking the subject or his or her healthcare provider, or by reviewing the subject's medical records.

[0128] In some embodiments of the present invention, the methods and compositions described herein are useful for treating or preventing ophthalmic diseases or disorders that are neovascular diseases. In other embodiments of the present invention, the ophthalmic diseases or disorders result in retinal edema. Exemplary ophthalmic diseases or disorders that can be treated or prevented are described herein.

[0129] Treatment or prevention of age-related macular degeneration

[0130] In one embodiment, the ophthalmic disease or disorder treated or prevented by any method or composition described herein is age-related macular degeneration. Visual changes that may be associated with macular degeneration include distortion and / or blind spots (scotoma) detected using Amsler charts, changes in dark adaptation (diagnosis of rod cell health) or changes in color interpretation (diagnosis of retinal cone cell health), or decreased visual acuity. Examples of age-related macular degeneration include non-neovascular (also known as "dry type") and neovascular (also known as "wet type" or "exudative type") macular degeneration.

[0131] In one embodiment, dry age-related macular degeneration is associated with the formation of drusen. In one embodiment, treating or preventing dry age-related macular degeneration involves treating or preventing abnormalities of the retinal pigment epithelium and / or the underlying vascular system known as the choriocapilary. Examples of abnormalities of the retinal pigment epithelium include geographic atrophy, non-geographic atrophy, focal depigmentation, and focal hyperpigmentation. In another embodiment, treating or preventing wet age-related macular degeneration involves treating or preventing choroidal neovascularization or pigment epithelial detachment.

[0132] In one embodiment, the present invention provides a method for treating or preventing wet age-related macular degeneration. Another aspect of the present invention is a method for treating, preventing, or inhibiting a choroidal neovascular complex of interest, for example, for inhibiting the formation or growth of a choroidal neovascular complex.

[0133] In another aspect of the present invention, the present invention provides a method for treating or preventing choroidal neovascularization in a subject. In some embodiments, the choroidal neovascularization is subfoveal choroidal neovascularization. In some embodiments, the subfoveal choroidal neovascularization is associated with age-related macular degeneration. In one embodiment, the subfoveal choroidal neovascularization is secondary to exudative AMD. In other embodiments, the subfoveal choroidal neovascularization is present in a subject having exudative AMD, and in other embodiments, the subfoveal choroidal neovascularization is present in a subject not having exudative AMD. In some embodiments, the subfoveal choroidal neovascularization is secondary to inflammatory, traumatic, myopic, idiopathic, or neoplastic disease of the macula.

[0134] In some embodiments, wet age-related macular degeneration is determined by fundus angiography, known as fluorescein angiography, according to the appearance of its choroidal neovascularization (CNV), cla CNVs are classified as classic, occult, or mixed (classic and occult) type. The classification of classic, occult, or mixed (classic and occult) CNVs can be based on the time, intensity, and definition level of pigment appearance, and leakage from the CNV, as assessed by fluorescein angiography. In some embodiments, the subject has a classic CNV (e.g., pure classic) or a mixed CNV (predominantly or minimally classic CNV). In some embodiments, the subject has an occult CNV (e.g., pure occult CNV).

[0135] Administration of antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist and / or anti-C5 agent may have a synergistic effect in the treatment or prevention of classic or occult CNV. For example, administration of both antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist may improve vision and stabilize vision to a greater extent than the additive effect of antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist together. In another example, administration of both antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist may reduce CNV or inhibit CNV growth to a greater extent than the administration of antagonist A or another pharmaceutically acceptable salt thereof or a VEGF antagonist alone. In some embodiments, administration of both antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist can reduce CNV over a shorter timeframe, at a lower dose, or at a lower frequency compared to administration of antagonist A or another pharmaceutically acceptable salt thereof or a VEGF antagonist alone. In some embodiments, administration of both antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist can reduce CNV or inhibit CNV growth to a greater extent than the additive effect of both antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist. In some embodiments, administration of both antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist can reduce CNV over a shorter timeframe, at a lower dose, or at a lower frequency compared to the additive timeframe, dose, or frequency of administration of both antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist.

[0136] In one embodiment, the present invention provides a method for treating, preventing, or stabilizing non-exudative ("dry") AMD. In one embodiment, antagonist A or another pharmaceutically acceptable salt thereof, an anti-C5 agent, a combination of antagonist A or another pharmaceutically acceptable salt thereof and an anti-C5 agent, or a combination of an anti-C5 agent and a VEGF antagonist is administered in an amount effective in maintaining or reducing the level of drusen (e.g., quantity, size, number, area and / or form) (e.g., size, number, area and / or form) compared to the target drusen level before administration of antagonist A or another pharmaceutically acceptable salt thereof, an anti-C5 agent, a combination of antagonist A or another pharmaceutically acceptable salt thereof and an anti-C5 agent, or (or) a combination of an anti-C5 agent and a VEGF antagonist. In certain embodiments, the level of drusen is reduced by at least or about 5%, at least or about 10%, at least or about 20%, at least or about 30%, at least or about 40%, or at least or about 50%.

[0137] In some embodiments, antagonist A or another pharmaceutically acceptable salt thereof, an anti-C5 agent, a combination of antagonist A or another pharmaceutically acceptable salt thereof and an anti-C5 agent, or a combination of an anti-C5 agent and a VEGF antagonist are effective in inhibiting, delaying, or preventing the progression of non-exudative AMD to geographic atrophy (GA). It is administered in a dose. GA is a progressive form of non-exudative AMD. In other embodiments, antagonist A or another pharmaceutically acceptable salt thereof and / or anti-C5 agent or a pharmaceutically acceptable salt thereof is administered in a dose effective to reduce the growth or area of ​​GA lesions over time compared to that of subjects not receiving antagonist A or another pharmaceutically acceptable salt thereof and / or anti-C5 agent. In other embodiments, anti-C5 agent or a pharmaceutically acceptable salt thereof and a VEGF antagonist are administered in a dose effective to reduce the growth or area of ​​GA lesions over time compared to that of subjects not receiving the anti-C5 agent and / or VEGF antagonist. In certain embodiments, the change in the area or growth of geographic atrophy lesions over time is reduced by at least or about 5%, at least or about 10%, at least or about 20%, at least or about 30%, at least or about 40%, or at least or about 50%. Methods for identifying and evaluating the size of geographic lesions are known to those skilled in the art, and include autofluorescence imaging and optical coherence tomography.

[0138] In certain embodiments, the present invention treats subjects whose non-exudative AMD has transformed into exudative AMD, for example, when new blood vessels invade the retina above them. The present invention further provides methods for treating, preventing, or stabilizing drusen retinopathy secondary to complement-mediated immune disorders, including drusen retinopathy secondary to membranoproliferative glomerulonephritis type II. In some embodiments, antagonist A or another pharmaceutically acceptable salt thereof and / or anti-C5 agent and / or VEGF antagonist is administered in an amount effective in reducing retinal drusen levels in subjects having or diagnosed with membranoproliferative glomerulonephritis type II or exudative AMD, compared to the level of retinal drusen prior to administration of antagonist A or another pharmaceutically acceptable salt thereof and / or anti-C5 agent and / or VEGF antagonist. In a particular embodiment, the level of drusen is reduced by at least or about 5%, at least or about 10%, at least or about 20%, at least or about 30%, at least or about 40%, or at least or about 50%.

[0139] In one embodiment, the ophthalmic disease or disorder is polypoid choroidal vasculopathy (PCV), which is a variant of wet AMD.

[0140] Treatment or prevention of symptoms associated with choroidal neovascularization

[0141] In one embodiment, an ophthalmic disease or disorder is a symptom associated with choroidal neovascularization. Examples of symptoms associated with choroidal neovascularization include degenerative, inflammatory, traumatic, or idiopathic symptoms. Treating or preventing degenerative disorders associated with choroidal neovascularization also includes treating or preventing heredodegerative disorders. Examples of heredodegerative disorders include vitiligo macular degeneration, macular retina, and optic disc drusen. Examples of degenerative symptoms associated with choroidal neovascularization include myopic degeneration or retinal pigment streaks. In some embodiments, treating or preventing inflammatory disorders associated with choroidal neovascularization includes treating or preventing ocular histoplasmosis, multifocal choroiditis, creeping choroiditis, toxoplasmosis, toxocariasis, rubella, Vogt-Koyanagi-Harada syndrome, Behçet's syndrome, or sympathetic ophthalmia. In some embodiments, treating or preventing traumatic injury associated with choroidal neovascularization includes treating or preventing traumatic symptoms caused by choroidal rupture or severe photocoagulation.

[0142] Treatment or prevention of proliferative retinopathy

[0143] A particular aspect of the present invention provides methods and compositions for treating or preventing proliferative vitreoretinopathy (PVR). In some embodiments, PVR is in a moderate form. In other embodiments, PVR is a severe form. In some embodiments, PVR is a recurrent form. In one embodiment, a subject with PVR also has or had retinal detachment, or the subject has PVR associated with retinal detachment, or has PVR-related scarring (e.g., scarring resulting from PVR, e.g., retinal scarring). In some embodiments, PVR is characterized based on the retinal morphology and the location of scar tissue, for example, as shown in Table 2 (Lean J et al., Classification of proliferative vitreoretinopathy used in the silicone (See study. The Silicone study group. Ophthalmology 1989;96:765-771). Any of these categories or types of PVR can be treated or prevented in accordance with the present invention.

[0144] [Table 1]

[0145] The present invention's method for treating PVR may further include administering other agents useful for treating PVR, such as corticosteroids; anti-cancer agents such as 5-fluorouracil; colchicine; retinoids; heparin; and epidermal growth factor receptor (EGFR) inhibitors, such as gefitinib or erlotinib.

[0146] Another aspect of the present invention is a method for treating or preventing proliferative retinopathy, for example, related to PVR (e.g., treating or preventing the ocular pathological conditions of proliferative retinopathy), such as proliferative diabetic retinopathy, sickle cell retinopathy, post-traumatic retinopathy, hyperviscosity syndrome, aortic arch syndrome, ocular ischemic syndrome, carotid-cavernous sinus fistula, multiple sclerosis, retinal vasculitis, systemic lupus erythematosus, arteriolar inflammation with SS-A autoantibodies, acute multifocal hemorrhagic vasculitis, infection-related vasculitis, vasculitis due to Behçet's disease, sarcoidosis, coagulation disorders, sickle hemoglobin disorders, AC and C-β thalassemia, microvascular hyaline degeneration, incontinentia pigmenti, Eels' disease, retinal artery branch occlusion or retinal vein branch occlusion, frostbite branch vasculitis, idiopathic retinal vasculitis, Methods for treating or preventing aneurysms, optic retinitis, retinal embolism, retinopathy of prematurity, uveitis, ciliary body squamous inflammation, acute retinal necrosis, birdshot chorioretinopathy, chronic retinal detachment, choroidal melanoma, radiation retinopathy, familial exudative vitreoretinopathy, inherited retinal venous beading, retinal schizophrenia, retinitis pigmentosa, or autosomal dominant vitreoretinopathy.

[0147] Another aspect of the present invention is a method for treating or preventing a disease or condition that causes proliferative retinopathy or PVR. In one embodiment, the method is to treat or prevent post-retinal detachment (e.g., causing or resulting in PVR). In another embodiment, the method is to treat or prevent proliferative diabetic retinopathy (e.g., causing or resulting in PVR) or sickle cell retinopathy (e.g., causing or resulting in PVR), as well as scarring caused by one or more of these disorders.

[0148] Treatment or prevention of glaucoma

[0149] In one embodiment, the ophthalmological disease or disorder is glaucoma. In one embodiment, glaucoma is open-angle glaucoma, primary open-angle glaucoma, secondary open-angle glaucoma, closed-angle glaucoma, glaucoma associated with diabetes, glaucoma associated with diabetic retinopathy, closed-angle glaucoma, narrow-angle glaucoma, or acute glaucoma.

[0150] Treatment or prevention of tumors

[0151] In one embodiment, the ophthalmic disease or disorder is a tumor. Examples of tumors include eyelid tumors, conjunctival tumors, choroidal tumors, iris tumors, optic nerve tumors, retinal tumors, invasive intraocular tumors, or orbital tumors. Examples of eyelid tumors include basal cell carcinoma, squamous carcinoma, sebaceous carcinoma, malignant melanoma, capillary hemangioma, sweat gland cyst, nevus, or seborrheic keratoma. Examples of conjunctival tumors include Kaposi's sarcoma of the conjunctiva, squamous carcinoma, neoplasm of the conjunctiva, epibulbar dermoid, lymphoma of the conjunctiva, melanoma, pinguecula, or pterygium. Examples of choroidal tumors include choroidal nevus, choroidal hemangioma, metastatic choroidal tumor, choroidal osteoma, choroidal melanoma, ciliary melanoma, or nevus of Ota. Examples of iris tumors include metastatic anterior uveal tumor, iris cyst, iris melanoma, iris melanoma, or cholesteatoma of the iris. Examples of optic nerve tumors include optic nerve melanoma, optic nerve sheath meningioma, choroidal melanoma of the optic nerve, or metastatic periapillary tumor with optic neuropathy. Examples of retinal tumors include retinal pigment epithelium (RPE) hypertrophy, RPE adenoma, RPE carcinoma, retinoblastoma, or RPE hamartoma. In some embodiments, the present invention provides methods for inhibiting retinal pigment epithelium (RPE) or glial cells, such as inhibiting the migration of RPE or glial cells. Examples of invasive intraocular tumors include chronic lymphocytic leukemia, invasive choroidopathy, or intraocular lymphoma. Examples of orbital tumors include adenoid cystic carcinoma of the lacrimal gland, cavernous hemangioma of the orbit, lymphangioma of the orbit, mucocele of the orbit, orbital pseudotumor, orbital rhabdomyosarcoma, periorbital hemangioma in children, or sclerosing orbital pseudotumor.

[0152] Another aspect of the present invention is a method for treating or preventing von Hippel-Lindau (VHL) disease (for example, treating or preventing vision loss associated with VHL disease). In some embodiments, VHL disease is characterized by a tumor. The tumor may be malignant or benign. In another embodiment, the method treats or prevents an intraocular benign or malignant tumor (e.g., an ocular tumor) or cyst (e.g., an ocular cyst) associated with VHL. In some embodiments, the tumor is a hemangioma. In some embodiments, the tumor is a von Hippel hemangioma or a retinal capillary hemangioma (e.g., a peripapillary hemangioma).

[0153] In some embodiments, subjects with VHL disease lack the protein "pVHL".

[0154] In some embodiments, VHL disease is severe (for example, subjects with severe VHL disease have lesions that cannot be effectively treated with non-pharmacological therapies (e.g., laser or cryotherapy). For example, the lesions are located on or adjacent to important nerve structures (e.g., optic nerve, macula, palpebral-macular bundle) that can be damaged by laser or cryotherapy).

[0155] In some embodiments, methods for treating or preventing VHL disease include treating ocular or non-ocular conditions of VHL (e.g., benign or malignant tumors or cysts of the kidneys, adrenal glands, pancreas, brain, spinal cord, inner ear, epididymis, or broad ligament of the uterus).

[0156] In some embodiments, the subject being treated has a family history of VHL disease or one or more of the following: retinal capillary angiomas (RCH), spinal hemangioblastoma or cerebellar hemangioblastoma, pheochromocytoma, multiple pancreatic cysts, epididymal or broad ligament cystadenoma, multiple renal cysts, and renal cell carcinoma. In some embodiments, the subject has one or more of the following prior to age 60: RCH, spinal hemangioblastoma and cerebellar hemangioblastoma, pheochromocytoma, multiple pancreatic cysts, epididymal or broad ligament cystadenoma, multiple renal cysts, or renal cell carcinoma. In some embodiments, the subject has two or more hemangioblastomas of the retina or brain, or one hemangioblastoma associated with a visceral condition such as a renal or pancreatic cyst; renal cell carcinoma; adrenal or extraadrenal pheochromocytoma; endolymphatic sac tumor; papillary cystadenoma of the epididymis or broad ligament; or neuroendocrine tumor of the pancreas. In some embodiments, the subject has a pathogenic germline mutation within the VHL gene.

[0157] In some embodiments, the subject has RCH exhibiting, for example, associated intraretinal or subretinal exudation or lipid deposition (which may reflect ongoing vascular dysfunction and not secondary residual changes from previous treatment or coexistent retinal traction); increased tumor size compared to a previous point in time as assessed by fundus photography or fluorescein angiography (FA); associated intraretinal, subretinal, or preretinal hemorrhage not secondary to previous treatment as assessed by fundus photography or FA; the appearance of new afferent artery vessels or greater dilation or tortuosity of existing afferent artery vessels compared to a previous point in time; and / or activity such as vitreous cells or opacities indicating vitreous exudation, in the absence of other ocular features that may be contributing to such findings. In some embodiments, the subject has RCH that is not readily treatable with cryotherapy or thermal laser due to its size, posterior location, poor previous response to conventional therapy, or other factors.

[0158] In some embodiments, the methods or compositions of the present invention are used to treat or prevent complications of VHL, visual impairment (e.g., caused by VHL), or fibrous complications of VHL (e.g., fibrous meningioma). In certain embodiments, the methods or compositions of the present invention are used to treat the pathological condition of VHL as vascular proliferation, often involving fine, superficial, peripapillary vessels, associated with proliferation of vascular connective tissue and epiretinal membrane formation.

[0159] Treatment or prevention of scarring or fibrosis

[0160] Another aspect of the present invention provides methods for treating, inhibiting, or preventing scarring or fibrosis (e.g., scarring or fibrosis is located beneath the macula of the retina). In some embodiments, the scarring is scarring of vascular connective tissue (e.g., within the retina). In some embodiments, the fibrosis is hepatic fibrosis, pulmonary fibrosis, or renal fibrosis. In some embodiments, the fibrosis is ocular fibrosis. In some embodiments, the fibrosis is subretinal fibrosis (e.g., associated with neovascular AMD). In some embodiments, the subretinal fibrosis is neovascular It is not associated with tubular AMD. In some embodiments, the fibrosis is subfoveal fibrosis. In some embodiments, the subfoveal fibrosis is accompanied by retinal atrophy. In some embodiments, the subfoveal or subretinal fibrosis develops after administration of a VEGF antagonist, e.g., anti-VEGF monotherapy.

[0161] In some embodiments, scarring occurs as a result of or after glaucoma surgery, such as trabeculectomy, filtration surgery (including partial thickness filtering surgery), glaucoma filtration procedures, minimally invasive glaucoma surgery, glaucoma valve implantation, glaucoma seton surgery, glaucoma tube shunt surgery, glaucoma stent placement, or simultaneous cataract and glaucoma surgery. In some embodiments, the methods of the present invention are useful for treating or preventing scarring (e.g., which may result in scar-associated proliferation) associated with or resulting from glaucoma surgery. In some embodiments, the scarring is subretinal scarring. In some embodiments, the scarring is subretinal scarring that occurs after choroidal neovascular regression.

[0162] In certain embodiments, a method for treating, inhibiting, or preventing subretinal fibrosis (e.g., reducing the formation of subretinal fibrosis) comprises administering an effective amount of antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist to a subject in need thereof. In some embodiments, the subject has or has been diagnosed with AMD (e.g., wet AMD). In some embodiments, the subject has or has been diagnosed with progressive wet AMD.

[0163] Treatment or prevention of other ophthalmic diseases and disorders

[0164] In certain embodiments, ophthalmic diseases or disorders include cataracts (e.g., age-related cataracts), diabetic macula edema, macular telangiectasia (e.g., type 1 or type 2 macular telangiectasia), atrophic macular degeneration, chorioretinopathy (e.g., central serous chorioretinopathy), inflammatory retinal vascular disorders, pathological retinal angiogenesis, age-related maculopathy, retinoblastoma, pseudoxanthoma elasticum, vitreous retinal diseases, choroidal and subretinal neovascularization, central serous chorioretinopathy, ischemic retinopathy, hypertensive retinopathy or diabetic retinopathy (e.g., non-proliferative or proliferative diabetic retinopathy, e.g., macular edema or macular ischemia), retinopathy of prematurity (e.g., associated with abnormal growth of blood vessels in the vascular bed supporting the developing retina), venous occlusion (e.g., retinal vein occlusion, retinal vein branch occlusion or intraretinal These include cardiovenous occlusion, arterial occlusion (e.g., branch retinal artery occlusion (BRAO), central retinal artery occlusion, or ocular ischemic syndrome), central serous chorioretinopathy (CSC), cystoid macular edema (CME) (e.g., developing in the central retina or macula, or developing after cataract surgery), peripheral telangiectasia (e.g., characterized by dilated and tortuosic retinal vessels and multiple aneurysms, idiopathic JXT, Leber miliary artery aneurysm, or Coats disease), retinal microaneurysms, retinal hemangioma, radiation-induced retinopathy (RIRP), or iris rubeosis (e.g., associated with neovascular glaucoma, diabetic retinopathy, central retinal vein occlusion, ocular ischemic syndrome, or chronic retinal detachment).

[0165] In other embodiments, the ophthalmic disease or disorder is sickle cell disease (SCD), anemia, or sickle cell retinopathy (e.g., non-neovascular or non-proliferative ocular conditions). In some embodiments, the treatment or prevention of vascular occlusion or hemolysis associated with SCD is performed. In some embodiments, the ocular conditions of SCD include vascular occlusion in the conjunctiva, iris, retina, or choroid. Non-neovascular or non-proliferative ocular conditions may include conjunctival vascular occlusion that deforms smooth vessels into comma-shaped fragments, iris atrophy, retinal "salmon patch" hemorrhage, retinal pigment changes, and other abnormalities of the retinal vascular system, macula, choroid, and optic disc. In some embodiments, neovascular or proliferative ocular conditions necessarily include vitreous hemorrhage, retinal detachment, and abnormal proliferation of vascular lamellae that can lead to epiretinal membranes, resulting in decreased vision. Therefore, this method further includes performing other procedures such as diaartemy, cryotherapy, laser photocoagulation, or surgery (e.g., vitrectomy).

[0166] In one embodiment, the ophthalmic disease or disorder is a symptom associated with peripheral retinal neovascularization. Examples of symptoms associated with peripheral retinal neovascularization include ischemic vascular disease, potentially ischemic inflammatory disease, incontinentia pigmenti, retinitis pigmentosa, retinolysis, or chronic retinal detachment.

[0167] Examples of ischemic vascular diseases include proliferative diabetic retinopathy, retinal vein branch occlusion, retinal artery branch occlusion, carotid-cavernous sinus fistula, sickle hemoglobin disorder, non-sickle hemoglobin disorder, IRVAN syndrome (retinal vasculitis characterized by idiopathic retinal vasculitis, aneurysms, and optic neuroretinitis), retinal embolism, retinopathy of prematurity, familial exudative vitreoretinopathy, hyperviscosity syndrome, aortic arch syndrome, or Eels' disease. Examples of sickle hemoglobin disorders include SS hemoglobin disorder and SC hemoglobin disorder. Examples of non-sickle hemoglobin disorders include AC hemoglobin disorder and AS hemoglobin disorder. Examples of hyperviscosity syndrome include leukemia, Waldenström macroglobulinemia, multiple myeloma, polycythemia, or myeloproliferative disorders.

[0168] In some embodiments, treating or preventing inflammatory diseases that may be ischemic includes treating or preventing retinal vasculitis associated with systemic diseases, retinal vasculitis associated with infectious agents, uveitis, or birdshot retinopathy. Examples of systemic diseases include systemic lupus erythematosus, Behçet's disease, inflammatory bowel disease, sarcoidosis, multiple sclerosis, Wegener's granulomatosis, and polyarteritis nodosa. Examples of infectious agents include bacterial agents that cause syphilis, tuberculosis, Lyme disease, or cat scratch disease, viruses such as herpesviruses, or parasites such as canine roundworms or Toxoplasma. Examples of uveitis include ciliary vasculitis or Fuchs' uveitis syndrome.

[0169] Compositions for therapeutic or prophylactic administration

[0170] Antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist, or an anti-C5 agent may be administered as a component of a composition further comprising a pharmaceutically acceptable carrier or vehicle, such as a pharmaceutical composition. In certain embodiments, each therapeutic agent is administered to a subject in a separate composition. However, in other embodiments, two or more therapeutic agents may be administered to a subject in the same composition. In one embodiment, the composition of the present invention comprises an effective amount of antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist, and / or an anti-C5 agent and a pharmaceutically acceptable carrier or vehicle. In another embodiment, a composition comprising antagonist A or another pharmaceutically acceptable salt thereof and another composition comprising a VEGF antagonist is administered. In some embodiments, another composition comprising an anti-C5 agent is administered. In some embodiments, a composition comprising antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist is administered. In some embodiments, another composition comprising an anti-C5 agent is also administered.

[0171] The administration of each antagonist may be by any preferred method that results in an amount of antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist, and / or an anti-C5 agent effective for the treatment or prevention of ophthalmic diseases or disorders. Each antagonist can be mixed with a suitable carrier material, for example, and generally exists in an amount of 1 to 95% by weight of the total weight of the composition. The composition may be provided in a dosage form suitable for ocular, oral, parenteral (e.g., intravenous, intramuscular, subcutaneous), rectal, transdermal, nasal, or inhalation administration. In one embodiment, the composition is in a form suitable for direct injection into the eye. The composition may be, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams It may be in the form of ointments, plasters, delivery devices, suppositories, enemas, injections, grafts, sprays, infusions, or aerosols. A pharmaceutical composition containing one or more antagonists may be formulated according to conventional pharmaceutical practices (see, for example, Remington: The Science and Practice of Pharmacy, (20th edition), edited by ARGennaro, 2000, Lippincott Williams & Wilkins, Philadelphia, Pennsylvania, and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and JCBoylan, 1988–2002, Marcel Dekker, New York).

[0172] In one useful embodiment, the compositions of the present invention are administered parenterally (e.g., by intramuscular, intraperitoneal, intravenous, intraocular, intravitreous, retrobulbar, subconjunctival, subocular sheath, or subcutaneous injection or implant) or systemically. Formulations for parenteral or systemic administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Various aqueous carriers, such as water, buffer water, saline, and the like, can be used. Examples of other suitable vehicles include injectable organic esters such as polypropylene glycol, polyethylene glycol, vegetable oils, gelatin, hydrogels, hydrogenated naphalene, and ethyl oleate. Such formulations may also contain auxiliary substances such as preservatives, humectants, buffers, emulsifiers, and / or dispersants. Biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the active ingredient.

[0173] Alternatively, the composition may be administered by oral ingestion. Compositions intended for oral use may be prepared in solid or liquid form according to any method known in the art for the manufacture of pharmaceutical compositions.

[0174] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. Generally, these pharmaceutical formulations contain active ingredients mixed with non-toxic, pharmaceutically acceptable excipients. These may include inert diluents such as calcium carbonate, sodium carbonate, lactose, sucrose, glucose, mannitol, cellulose, starch, calcium phosphate, sodium phosphate, and kaolin. Binders, buffers, and / or lubricants (e.g., magnesium stearate) may also be used. Tablets and pills may optionally be formulated with enteric coatings. Compositions may optionally contain sweeteners, flavorings, colorants, fragrances, and preservatives to provide a more palatable formulation.

[0175] Compositions useful for ophthalmic applications include tablets containing one or more antagonists mixed with pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose and sorbitol), lubricants, flow promoters, and anti-adhesion agents (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc).

[0176] The antagonists of the present invention may be mixed together or dispensed in tablets or other vehicles. In one example, the first antagonist is contained inside the tablet, and the second antagonist is located on the outside such that a substantial portion of the second antagonist is released before the release of the first antagonist. If desired, the antagonists in tablet form may be administered using a drug delivery device (see below).

[0177] For example, the compositions of the present invention can be administered intraocularly by intravitreal injection into the eye, as well as by subconjunctival and subtonon's capsule injection. Other routes of administration include transscleral, retrobulbar, intraperitoneal, intramuscular, and intravenous. Alternatively, the compositions may be administered using a drug delivery device or intraocular implant (see below). It is possible.

[0178] In one embodiment, antagonist A or another pharmaceutically acceptable salt thereof or a VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept, pegaptanib sodium, or ESBA1008) is administered intravitreally using a 30-gauge or 27-gauge needle. In some embodiments, a 0.5-inch needle is used. In one embodiment, antagonist A or another pharmaceutically acceptable salt thereof is administered intravitreally using a 30-gauge 0.5-inch needle, and a VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept, pegaptanib sodium, or ESBA1008) is administered intravitreally using a 27-gauge needle. In some embodiments, 50 μL (1.5 mg in 0.05 mL) of antagonist A or another pharmaceutically acceptable salt thereof is administered intravitreally using a 30-gauge 0.5-inch needle, and 50 μL of a VEGF antagonist (e.g., 0.5 mg ranibizumab, 1.25 mg bevacizumab, or 2.0 mg aflibercept) is administered intravitreously using a 27-gauge needle.

[0179] Liquid formulations for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and soft gelatin capsules. These formulations may contain inert diluents commonly used in the field, such as water and oily media, and may also include auxiliary agents such as wetting agents, emulsifiers, and suspending agents.

[0180] In some cases, the composition may also be administered topically, for example by patch, or by direct application to areas such as the epidermis or eyes that are susceptible to or affected by neovascular disease, or by iontophoresis.

[0181] In one embodiment, the composition may contain one or more pharmaceutically acceptable excipients. In one embodiment, the excipients for a composition containing an antagonist may include, but are not limited to, buffers, nonionic surfactants, preservatives, isotonic agents, sugars, amino acids, and pH adjusters. Suitable buffers include, but are not limited to, monobasic sodium phosphate, dibasic sodium 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 isotonic 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 one embodiment, the pH adjuster or agent is present in an amount effective to provide a pH of about 3 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 one embodiment, the composition does not contain a preservative. In another embodiment, the composition does not contain an antimicrobial agent. In another embodiment, the composition does not contain a bacteriostatic agent. Suitable excipients for VEGF antagonists include those described in U.S. Patent No. 7,365,166, the contents of which are incorporated herein by reference in their entirety.

[0182] In one embodiment, the composition is in the form of an aqueous solution suitable for injection. In one embodiment, the composition comprises antagonist A or another pharmaceutically acceptable salt thereof, a buffer, a pH adjuster, and water for injection. In another embodiment, the composition comprises antagonist A or another pharmaceutically acceptable salt thereof, monobasic sodium phosphate, dibasic sodium phosphate, sodium chloride, hydrochloric acid, and sodium hydroxide.

[0183] In one embodiment, the composition comprises a VEGF antagonist, a buffer, a sugar, a nonionic surfactant, and water for injection. In another embodiment, the composition comprises a VEGF antagonist, monobasic sodium phosphate, dibasic sodium phosphate, α,α-trehalose dihydrate, and polysorbate 20. In one embodiment, the composition comprises a VEGF antagonist, a buffer, a pH adjuster, an isotonic agent, and water suitable for injection. In another embodiment, the composition comprises a VEGF antagonist, monobasic sodium phosphate, dibasic sodium phosphate, sodium chloride, hydrochloric acid, and sodium hydroxide. In one embodiment, the VEGF antagonist is a PEGylated anti-VEGF aptamer, such as pegaptanib sodium.

[0184] In another embodiment, the VEGF antagonist is ranibizumab, bevacizumab, aflibercept, or ESBA1008. The present invention provides pharmaceutically acceptable salts of antagonists. The antagonists of the present invention may have sufficient basic functional groups to react with any number of inorganic and organic acids to form pharmaceutically acceptable salts. pharmaceutically acceptable acid addition salts are formed from pharmaceutically acceptable acids known in the art. Such salts include pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2-19 (1977) and The Handbook of Pharmaceutical salts; Properties, Selection, and Use. PHStahl and CG Wermuth (ED.s), Verlag, Zurich (Switzerland) 2002, which are incorporated herein by reference in their entirety.

[0185] Examples of pharmaceutically acceptable salts include sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acidic phosphates, isonicotinates, lactates, salicylates, acidic citrates, tartrates, oleates, tannates, pantothenates, bitartrates, ascorbic acid, succinates, maleates, gentisinates, fumarates, glucons, glucarones, sugars, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, camphor sulfons, pamoates, phenyl acetate, trifluoroacetates, acrylates, chlorobenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, methylbenzoates, o-acetoxybenzoates, and naphthalene-2. Examples include benzoates, isobutyrates, phenylbutyrates, α-hydroxybutyrates, butyn-1,4-dicarboxylates, hexyn-1,4-dicarboxylates, caprinates, caprylates, cinnamates, glycolates, heptanoates, hipruates, malates, hydroxymaleates, malons, mandelic acid, mesylates, nicotinates, phthalates, teraphthalates, propiolates, propions, phenylpropions, sebacinates, suberates, p-bromobenzenesulfonates, chlorobenzenesulfonates, ethylsulfonates, 2-hydroxyethylsulfonates, methylsulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, naphthalene-1,5-sulfonates, xylenesulfonates, and tartrates. The term "pharmaceutically acceptable salt" refers to a salt of the antagonist of the present invention that contains a hydrate of the compound of the present invention and has an acidic functional group such as a carboxylic acid functional group or a hydrogen phosphate functional group, and a base.Suitable bases include alkali metal hydroxides such as sodium, potassium, and lithium; alkaline earth metal hydroxides such as calcium and magnesium; hydroxides of other metals such as aluminum and zinc; ammonia; and organic amines, such as unsubstituted or hydroxysubstituted 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. Examples of pharmaceutically acceptable salts include, but are not limited to, 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. In one embodiment, the pharmaceutically acceptable salt is a sodium salt. In another embodiment, the pharmaceutically acceptable salt is a per-sodium salt.

[0186] The present invention further provides a composition comprising antagonist A or another pharmaceutically acceptable salt thereof. In one embodiment, the composition of the present invention comprises, per approximately 1 mL, approximately 30.0 mg of antagonist A or another pharmaceutically acceptable salt thereof, approximately 0.3 mg of monobasic sodium phosphate monohydrate, approximately 2.1 mg of dibasic sodium phosphate heptahydrate, and approximately 9.0 mg of sodium chloride. In some embodiments, hydrochloric acid and / or sodium hydroxide are present as needed to adjust the pH of the composition. In some embodiments, the pH is approximately pH 5.5 to approximately pH 7.5 or approximately pH 6.0.

[0187] In some embodiments, the composition comprises about 3% (w / v) antagonist A or another pharmaceutically acceptable salt thereof, about 0.03% (w / v) monobasic sodium phosphate monohydrate, about 0.2% (w / v) dibasic sodium phosphate heptahydrate, about 0.9% (w / v) sodium chloride, and about 95.9% (w / v) water. In some embodiments, hydrochloric acid and / or sodium hydroxide are present as needed to adjust the pH of the composition. In some embodiments, the pH is about pH 5.5 to about pH 7.5 or about pH 6.0.

[0188] In certain embodiments, the concentrations of antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008, or pegaptanib sodium), and / or an anti-C5 agent (e.g., ARC1905 or a pharmaceutically acceptable salt thereof) in the composition are from about 0.002 mg / mL to about 50 mg / mL. In some embodiments, the concentrations of antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008, or pegaptanib sodium), and / or an anti-C5 agent (e.g., ARC1905 or a pharmaceutically acceptable salt thereof) in the composition are less than or equal to 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 certain embodiments, the concentrations of antagonist A or another pharmaceutically acceptable salt thereof, VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008, or pegaptanib sodium), and / or anti-C5 agent (e.g., ARC1905 or a pharmaceutically acceptable salt thereof) in the composition range from about 0.3 mg / mL to about 100 mg / mL, about 0.3 mg / mL to about 50 mg / mL, about 0.3 mg / mL to about 40 mg / mL, about 0.3 mg / mL to about 30 mg / mL, about 0.3 to about 25 mg / mL, and about 0.3 mg / mL. The recommended dosages are approximately 20 mg / mL from 0.3 mg / mL to 15 mg / mL, approximately 10 mg / mL from 0.3 mg / mL to 100 mg / mL, approximately 50 mg / mL from 1 mg / mL to 40 mg / mL, approximately 30 mg / mL from 1 mg / mL to 25 mg / mL, approximately 20 mg / mL from 1 mg / mL to 15 mg / mL, approximately 1 mg / mL to 10 mg / mL, approximately 5 mg / mL to 100 mg / mL, or approximately 5 mg / mL to 50 mg / mL.

[0189] In certain embodiments, the method of the present invention involves administering antagonist A and optionally one or both of a VEGF antagonist and an anti-C5 agent as components of a pharmaceutical composition. The present invention provides a composition comprising: (a) an antagonist A or another pharmaceutically acceptable salt thereof; and (b) a VEGF antagonist or a pharmaceutically acceptable salt thereof. In certain embodiments, the composition further comprises an effective amount of an anti-C5 agent or a pharmaceutically acceptable salt thereof. In some embodiments, the composition stabilizes one or more of the antagonist A or another pharmaceutically acceptable salt thereof, the VEGF antagonist, and the anti-C5 agent. In certain embodiments, the antagonist A or another pharmaceutically acceptable salt thereof, the VEGF antagonist, and / or the anti-C5 agent do not adversely affect the activity of other activators present in the composition. In certain embodiments, at least about 90% of one or more activators in the composition, e.g., antagonist A or another pharmaceutically acceptable salt thereof, the VEGF antagonist, or the anti-C5 agent, are chemically stable when the composition is stored at a temperature of about 2.0°C to about 8.0°C for at least about 12 weeks.

[0190] In certain embodiments, antagonist A or another pharmaceutically acceptable salt thereof, VEGF antagonist, or anti-C5 agent is chemically stable when it does not show signs of degradation or modification resulting in the formation of new chemical components. In certain embodiments, antagonist A or another pharmaceutically acceptable salt thereof, VEGF antagonist, or anti-C5 agent is chemically stable when at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99% of antagonist A or another pharmaceutically acceptable salt thereof, VEGF antagonist, or anti-C5 agent does not show signs of degradation or modification resulting in the formation of new chemical components, for example, when stored at a temperature of about 2.0°C to about 8.0°C for at least about 12 weeks.

[0191] In certain embodiments, antagonist A or another pharmaceutically acceptable salt thereof does not adversely affect the activity of a VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept, pegaptanib sodium, or ESBA1008) or ARC1905 or a pharmaceutically acceptable salt thereof. In certain embodiments, ARC1905 or a pharmaceutically acceptable salt thereof does not adversely affect the activity of antagonist A or another pharmaceutically acceptable salt thereof, or a VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept, pegaptanib sodium, or ESBA1008).

[0192] In certain embodiments, the composition comprises antagonist A or another pharmaceutically acceptable salt thereof; and ranibizumab, bevacizumab, aflibercept, pegaptanib sodium, or ESBA1008, or a pharmaceutically acceptable salt thereof, wherein the composition is physically or chemically stable at a specific pH with respect to both activators or is suitable for parenteral administration. In certain embodiments, the composition comprises antagonist A or another pharmaceutically acceptable salt thereof; ranibizumab, bevacizumab, aflibercept, pegaptanib sodium, or ESBA1008, or a pharmaceutically acceptable salt thereof; and ARC1905, or a pharmaceutically acceptable salt thereof, wherein the composition is physically or chemically stable at a specific pH with respect to all activators or is suitable for parenteral administration. In certain embodiments, the composition contains at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99% of all activators present in the composition, i.e., antagonist A or another pharmaceutically acceptable salt thereof, VEGF antagonist, and anti-C5 agent (if present), which can be detected by visual inspection of color or transparency, or by ultraviolet light scattering or size exclusion chromatography. Physically stable if it does not show signs of aggregation, precipitation, or denaturation when measured by (SEC) or differential scanning calorimetry (DSC).

[0193] In certain embodiments, the compositions of the present invention are considered physically stable if the average number of particles detected after storage, as measured by the light-shielded particle counting method described in (788) Particulate Matter in Injections, Revised Bulletin, Official, October 1, 2011, by the American Pharmacopeia, does not exceed approximately 50 particles / mL, where the particle diameter is > approximately 10 μm, and does not exceed 5 particles / mL, where the particle diameter is > 25 μm.

[0194] In certain embodiments, the composition is considered physically stable if the average number of particles detected after storage, as measured by the microscopic particle counting method described in (788) Particulate Matter in Injections, Revised Bulletin, Official, October 1, 2011, by the American Pharmacopeia, is not greater than 50 particles / mL, where the particle diameter is >approximately 10 μm; not greater than 5 particles / mL, where the particle diameter is >25 μm; or not greater than 2 particles / mL, where the particle diameter is >50 μm.

[0195] In certain embodiments, the composition comprises antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008, or pegaptanib sodium), and optionally, an anti-C5 agent (e.g., ARC1905 or a pharmaceutically acceptable salt thereof), and is chemically stable for at least 8 weeks or at least 12 weeks at 25°C or at least 12 weeks or at least 16 weeks or at least 24 weeks at 4°C. In certain embodiments, at least 80% of each antagonist A or another pharmaceutically acceptable salt thereof, the VEGF antagonist, and the anti-C5 agent (if present) do not show signs of degradation or modification resulting in the formation of new chemical components under at least one of these conditions.

[0196] In certain embodiments, the composition comprises: (1) antagonist A or another pharmaceutically acceptable salt thereof; (2) VEGF antagonist; optionally, (3) anti-C5 agent; (4) buffering agent; optionally, (5) osmotic tension modifier; and optionally, (6) surfactant. In certain embodiments of such compositions, the buffering agent is an acetate, phosphate, tris or histidine buffering agent, or a mixture thereof; the osmotic tension modifier is sodium chloride, mannitol, sorbitol, or trehalose, or a mixture thereof; the surfactant is polysorbate 20. In various embodiments, antagonist A or another pharmaceutically acceptable salt thereof is present in the composition of the present invention at a concentration of about 0.1 mg / mL to about 200 mg / mL; the VEGF antagonist is present at a concentration of about 0.1 mg / mL to about 200 mg / mL. If present, anti-C5 agents are present at concentrations ranging from approximately 0.1 mg / mL to approximately 200 mg / mL. Buffering agents are present at concentrations ranging from approximately 1 mM to approximately 200 mM; osmotic tension regulators are present at concentrations ranging from approximately 10 mM to approximately 200 mM (sodium chloride), approximately 1% to approximately 10% (w / v) (sorbitol), or approximately 1% to approximately 20% (w / v) (trehalose); surfactants, if present, are present at concentrations ranging from approximately 0.005% to approximately 0.05% or approximately 0.001% to approximately 0.05%.

[0197] In certain embodiments, the ratio of the concentration of antagonist A or another pharmaceutically acceptable salt present in the composition (mass of antagonist A or another pharmaceutically acceptable salt of the composition, minus its R group / volume) to the concentration of a VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept, pegaptanib sodium, or ESBA1008), ARC1905, or a pharmaceutically acceptable salt thereof (mass / volume of the composition) is less than 25.0 or less, less than 10.0 or less, less than 9.0, or less than 8.0, or less than 7.0, or less than 6.0, or less than 5.0, or less than 4.0, or less than 3.0, or less than 2.0, or less than 1.0, or less. The R group of antagonist A is shown in Figure 1. In certain embodiments, the ratio of the concentration of antagonist A or another pharmaceutically acceptable salt present in the composition (mass of antagonist A or another pharmaceutically acceptable salt of the composition, minus its R group / volume) to the concentration of a VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept, pegaptanib sodium, or ESBA1008), ARC1905, or a pharmaceutically acceptable salt thereof (mass / volume of the composition) is in the range of about 1 to about 10, about 2 to about 5, about 3, about 4, or about 5. In certain embodiments, the composition comprises antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept, pegaptanib sodium, or ESBA1008), and ARC1905 or a pharmaceutically acceptable salt thereof.

[0198] In one particular embodiment, the composition comprises an antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008, or pegaptanib sodium), and optionally, an anti-C5 agent (e.g., ARC1905 or a pharmaceutically acceptable salt thereof), wherein the ratio of the concentration of the PDGF antagonist to the concentration of the VEGF antagonist (and / or anti-C5 agent) is less than 2; the composition further comprises sodium chloride at a concentration of about 10 mM to about 200 mM, histidine at a concentration of about 1 mM to about 100 mM, and polysorbate (e.g., polysorbate 20) at a concentration of about 0.005% to about 0.05%, where the pH of the composition is about 5.5 to about 7.0.

[0199] In certain embodiments, the composition comprises one or more osmotic tension modifiers, surfactants, and buffers suitable for achieving or maintaining a specific pH or suitable for parenteral administration. Suitable buffers include those described herein, as well as others known in the art, such as Good Buffer, e.g., MES.

[0200] In certain embodiments, the composition comprises an antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008, or pegaptanib sodium), and an osmotic tension modifier which is sorbitol or sodium chloride, or a mixture thereof. In certain embodiments, the composition further comprises an anti-C5 agent (e.g., ARC1905, or a pharmaceutically acceptable salt thereof). In certain embodiments, the osmotic tension modifier is sorbitol, and the pH of the composition is about 5.0 to about 8.0, about 5.0 to about 7.0, about 6.0, or about 7.0. In certain embodiments, the osmotic tension modifier is sodium chloride, and the pH of the composition is about 5.0 to about 8.0, about 5.0 to about 7.0, about 5.5 to about 7.5, about 6.0 to about 8.0, about 8.0, about 7.0, or about 6.0. In certain embodiments, the osmotic tension modifier is sorbitol in concentrations of about 1% to about 10% (w / v), or about 1% (w / v), about 2% (w / v), about 3% (w / v), about 4% (w / v), about 5% (w / v), about 6% (w / v), about 7% (w / v), about 8% (w / v), about 9% (w / v), or about 10% (w / v). In certain embodiments, the osmotic tension modifier is sodium chloride in concentrations of about 10 mM to about 200 mM, about 50 mM to about 200 mM, about 75 mM to about 200 mM, about 50 mM to about 150 mM, about 100 mM, about 110 mM, about 120 mM, about 130 mM, about 140 mM, or about 150 mM. In one embodiment, the osmotic tension modifier is sodium chloride at a concentration of approximately 130 mM. In other embodiments, the osmotic tension modifier is sodium chloride at a concentration of approximately 75 mM or approximately 120 mM. Regarding the concentration of the osmotic tension modifier, "mM" refers to millimoles of the osmotic tension modifier per liter of composition.

[0201] In certain embodiments, the composition comprises an antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008, or pegaptanib sodium), and a buffer that can achieve or maintain the pH of the composition within a desired range. In certain embodiments, the composition further comprises an anti-C5 agent (e.g., ARC1905 or a pharmaceutically acceptable salt thereof). In certain embodiments, the composition comprises histidine (e.g., L-histidine or a pharmaceutically acceptable salt thereof) or phosphoric acid as a buffer, e.g., sodium phosphate, potassium phosphate, or both. In certain embodiments, the buffer is present in concentrations of about 1 mM to about 200 mM, about 1 mM to about 150 mM, about 1 mM to about 20 mM, about 1 mM to about 10 mM, about 2 mM to about 100 mM, about 2 mM to about 20 mM, about 5 mM to about 20 mM, or about 10 mM. In certain embodiments, the pH of the buffer composition is about 5.0 to about 8.0, about 5.0 to about 7.0, about 5.5 to about 7.5, about 5.5 to about 7.0, or about 6.0. In one embodiment, the buffer composition has a pH of about 5.5 to about 7.0. In certain embodiments, the buffer contains histidine at concentrations of about 1 mM to about 200 mM, about 1 mM to about 150 mM, about 2 mM to about 100 mM, about 5 mM to about 20 mM, or about 10 mM, and the buffer composition has a pH of about 5.5 to about 7.0, or about 6.0. In certain embodiments, the buffer contains histidine at a concentration of about 10 mM, and the pH of the histidine buffer composition is about 6.0. With respect to buffer concentration, "mM" refers to millimoles of buffer (e.g., histidine) per liter of composition.

[0202] In certain embodiments, the composition comprises an antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008, or pegaptanib sodium), and a buffer containing phosphate alone or in combination with histidine. In certain embodiments, the composition further comprises an anti-C5 agent (e.g., ARC1905 or a pharmaceutically acceptable salt thereof). The phosphate buffer may be, for example, a sodium phosphate or potassium phosphate buffer. In certain embodiments, the buffer contains phosphoric acid at concentrations of about 1 mM to about 200 mM, about 1 mM to about 50 mM, about 2 mM to about 200 mM, about 2 mM to about 50 mM, about 5 mM to about 200 mM, about 5 mM to about 100 mM, about 5 mM to about 50 mM, about 10 mM to about 150 mM, about 10 mM to about 100 mM, about 5 mM, about 10 mM, about 25 mM, or about 50 mM. In certain embodiments, the pH of the buffer composition is about 5.0 to about 8.0, about 6.0 to about 8.0, about 5.5 to about 7.5, about 5.5 to about 7.0, about 6.0, about 7.0, or about 8.0. In one embodiment, the buffer contains phosphoric acid, and the buffer composition has a pH of about 6.0 to about 8.0. In a particular embodiment, the buffer contains phosphoric acid at concentrations of about 5 mM to about 200 mM, about 5 mM to about 150 mM, about 5 mM to about 100 mM, about 5 mM, about 8 mM, about 10 mM, about 25 mM, or about 50 mM, and the buffer composition has a pH of about 5.5 to about 7.5, about 5.5 to about 7.0, or about 6.0. In a particular embodiment, the buffer contains phosphoric acid at a concentration of about 10 mM, and the buffer composition has a pH of about 6.2.

[0203] In certain embodiments, the composition comprises an antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008, or pegaptanib sodium), and a surfactant. In certain embodiments, the composition further comprises an anti-C5 agent (e.g., ARC1905 or a pharmaceutically acceptable salt thereof). In certain embodiments, the surfactant is polysorbate 20 in concentrations of about 0.001% (w / v) to about 0.05% (w / v), about 0.002% (w / v) to about 0.05% (w / v), about 0.005% (w / v) to about 0.05% (w / v), about 0.01% (w / v) to about 0.05% (w / v), or about 0.02% (w / v).

[0204] In one embodiment, the composition comprises an antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008, or pegaptanib sodium), histidine, and NaCl. In certain embodiments, the composition further comprises an anti-C5 agent (e.g., ARC1905 or a pharmaceutically acceptable salt thereof). The composition may further comprise a polysorbate.

[0205] In certain embodiments, the composition comprises an effective amount of: (a) an antagonist A or another pharmaceutically acceptable salt thereof in an amount of about 0.3 mg / mL to about 30 mg / mL; (b) a VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008, or pegaptanib sodium) in an amount of about 0.5 mg / mL to about 20 mg / mL; and (c) a buffer that can achieve or maintain the pH of the composition at about pH 5.0 to about pH 8.0; and (d) one or both of an osmotic tension modifier. In certain embodiments, the composition further comprises (e) an anti-C5 agent (e.g., ARC1905 or a pharmaceutically acceptable salt thereof) in an amount of about 0.3 mg / mL to about 30 mg / mL. In certain embodiments, the buffer is about 1 mM to about 20 mM L-histidine or about 1 mM to about 20 mM sodium phosphate, and the osmotic tension modifier is about 10 mM to about 200 mM NaCl, about 1% to about 20% (w / v) sorbitol, or about 1% to about 20% (w / v) trehalose. In certain embodiments, the composition further comprises (f) about 0.001% (w / v) to about 0.05% (w / v) of a surfactant.

[0206] In certain embodiments, the composition comprises (a) an antagonist A or another pharmaceutically acceptable salt thereof in an amount of about 0.3 mg / mL to about 30 mg / mL; and (b) a VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008, or pegaptanib sodium) in an amount of about 0.5 mg / mL to about 20 mg / mL. In certain embodiments, the composition further comprises (c) an anti-C5 agent (e.g., ARC1905 or a pharmaceutically acceptable salt thereof) in an amount of about 0.3 mg / mL to about 30 mg / mL. In certain embodiments, any of these compositions further comprises (d) L-histidine in an amount of about 1 mM to about 20 mM; and (e) one or both of NaCl in an amount of about 10 mM to about 200 mM. In further embodiments, the composition further comprises (f) about 0.001% (w / v) to about 0.05% (w / v) of a surfactant (optionally being a polysorbate). In certain embodiments, the composition comprises (a) about 0.3 mg / mL to about 30 mg / mL of antagonist A or another pharmaceutically acceptable salt thereof; (b) about 0.5 mg / mL to about 20 mg / mL of a VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008, or pegaptanib sodium); (c) about 1 mM to about 20 mM of L-histidine; and (d) about 10 mM to about 200 mM of NaCl, where the pH of the composition is about pH 5.0 to about pH 7.0. In certain embodiments, the composition further comprises (e) about 0.3 mg / mL to about 30 mg / mL of an anti-C5 agent (e.g., ARC1905 or a pharmaceutically acceptable salt thereof). In certain embodiments, the composition further comprises (f) about 0.01% (w / v) polysorbate 20.

[0207] In certain embodiments, the composition comprises (a) an antagonist A or another pharmaceutically acceptable salt thereof in an amount of about 1.0 mg / mL to about 100 mg / mL, or about 5.0 mg / mL to about 50 mg / mL; and (b) a VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008, or pegaptanib sodium) in an amount of about 1.0 mg / mL to about 50 mg / mL. In certain embodiments, the composition further comprises (c) an anti-C5 agent (e.g., ARC1905 or a pharmaceutically acceptable salt thereof) in an amount of about 1.0 mg / mL to about 100 mg / mL. In other embodiments, any composition further comprises (d) L-histidine in an amount of about 1 mM to about 20 mM; and (e) one or both of NaCl in an amount of about 10 mM to about 200 mM. In further embodiments, any composition may contain (f) about 0.001% (w / v) to about 0.05% (w / v) of surfactant (optionally selected to contain It further includes (that which is resorbable).

[0208] In certain embodiments, the composition comprises (a) an antagonist A or another pharmaceutically acceptable salt thereof in an amount of about 0.3 mg / mL to about 30 mg / mL; (b) a VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008, or pegaptanib sodium) in an amount of about 0.5 mg / mL to about 20 mg / mL; and (c) a buffer that can achieve or maintain the pH of the composition between about pH 5.0 and about pH 8.0; and (d) one or both of an osmotic tension modifier. In certain embodiments, the composition further comprises an anti-C5 agent (e.g., ARC1905 or a pharmaceutically acceptable salt thereof) in an amount of about 0.3 mg / mL to about 30 mg / mL. In certain embodiments, the buffer, if present, is about 1 mM to about 20 mM L-histidine or about 1 mM to about 20 mM sodium phosphate; the osmotic tension modifier, if present, is about 10 mM to about 200 mM NaCl, about 1% to about 20% (w / v) sorbitol, or about 1% to about 20% (w / v) trehalose. In certain embodiments, the buffer is about 1 mM to about 20 mM L-histidine; the osmotic tension modifier is about 10 mM to about 200 mM NaCl, where the pH of the composition is about pH 5.0 to about pH 7.0.

[0209] Any composition may also contain surfactants, for example, about 0.001% (w / v) to about 0.05% (w / v) of surfactant.

[0210] In certain embodiments, the composition comprises (a) an antagonist A or another pharmaceutically acceptable salt thereof in an amount of about 3 mg / mL to about 90 mg / mL; (b) a VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008, or pegaptanib sodium) in an amount of about 1.0 mg / mL to about 30 mg / mL; and (c) a buffer that can achieve or maintain the pH of the composition between about pH 5.0 and about pH 8.0; and (d) one or both of an osmotic tension modifier. In certain embodiments, any composition further comprises (e) an anti-C5 agent (e.g., ARC1905 or a pharmaceutically acceptable salt thereof) in an amount of about 3 mg / mL to about 90 mg / mL. In certain embodiments, the buffer, if present, comprises about 1 mM to about 100 mM sodium phosphate or about 1.0 mM to about 10 mM histidine HCl; the osmotic tension modifier, if present, is about 0.5% (w / v) to about 10% (w / v) trehalose.

[0211] In certain embodiments, the composition of the present invention comprises (a) about 0.3 mg / mL to about 30 mg / mL of antagonist A or another pharmaceutically acceptable salt thereof; (b) about 0.5 mg / mL to about 20 mg / mL of ranibizumab or a pharmaceutically acceptable salt thereof; and (c) a buffer that can achieve or maintain the pH of the composition at about pH 5.0 to about pH 8.0; and (d) one or both of an osmotic tension modifier. In certain embodiments, the buffer is about 1 mM to about 20 mM of L-histidine or about 1 mM to about 20 mM of sodium phosphate, and the osmotic tension modifier is about 10 mM to about 200 mM of NaCl, about 1% to about 20% (w / v) of sorbitol, or about 1% to about 20% (w / v) of trehalose. In certain embodiments, the composition of the present invention further comprises (e) about 0.001% (w / v) to about 0.05% (w / v) of a surfactant. In certain embodiments, the composition further comprises (f) an anti-C5 agent, another PDGF antagonist, or another VEGF antagonist. In certain embodiments, the anti-C5 agent is ARC186, ARC187, or ARC1905, and the other VEGF antagonist is bevacizumab or aflibercept.

[0212] In certain embodiments, the composition of the present invention comprises (a) an antagonist A or another pharmaceutically acceptable salt thereof in an amount of about 0.3 mg / mL to about 30 mg / mL; and (b) bevacizumab or a pharmaceutically acceptable salt thereof in an amount of about 0.5 mg / mL to about 25 mg / mL; and: (c) a buffer that can achieve or maintain the pH of the composition between approximately pH 5.0 and approximately pH 8.0; and (d) one or both of an osmotic tension modifier. In certain embodiments, the buffer is approximately 5 mM to approximately 200 mM sodium phosphate or approximately 5 mM to approximately 200 mM Tris.HCl, and the osmotic tension modifier is approximately 10 mM to approximately 200 mM NaCl, approximately 1% to approximately 20% (w / v) sorbitol, or approximately 1% to approximately 20% (w / v) trehalose. In certain embodiments, the composition of the present invention further comprises (e) approximately 0.001% (w / v) to approximately 0.05% (w / v) a surfactant. In certain embodiments, the composition further comprises (f) an anti-C5 agent, another PDGF antagonist, and / or another VEGF antagonist. In certain embodiments, the anti-C5 agent is ARC186, ARC187, or ARC1905, and the other VEGF antagonist is ranibizumab or aflibercept.

[0213] In certain embodiments, the composition of the present invention comprises (a) about 0.3 mg / mL to about 30 mg / mL of antagonist A or another pharmaceutically acceptable salt thereof; (b) about 5 mg / mL to about 40 mg / mL of aflibercept or a pharmaceutically acceptable salt thereof; and (c) a buffer that can achieve or maintain the pH of the composition between about pH 5.0 and about pH 8.0; (d) an osmotic tension modifier; and (e) one or more of 0 to about 10% (w / v) sucrose. In certain embodiments, the buffer is about 5 mM to about 50 mM of phosphate, and the osmotic tension modifier is about 10 mM to about 200 mM of NaCl. In certain embodiments, the composition of the present invention further comprises (f) about 0.001% (w / v) to about 0.05% (w / v) of a surfactant. In certain embodiments, the composition further comprises (g) an anti-C5 agent, another PDGF antagonist, and / or another VEGF antagonist. In certain embodiments, the anti-C5 agent is ARC186, ARC187, or ARC1905, and the other VEGF antagonist is ranibizumab or bevacizumab.

[0214] In certain embodiments, the composition of the present invention comprises (a) an antagonist A or another pharmaceutically acceptable salt thereof in an amount of about 3 mg / mL to about 90 mg / mL; (b) ranibizumab or another pharmaceutically acceptable salt thereof in an amount of about 1.0 mg / mL to about 30 mg / mL; and (c) a buffer that can achieve or maintain the pH of the composition at about pH 5.0 to about pH 8.0; and (d) one or both of an osmotic tension modifier. In certain embodiments, the buffer comprises about 1 mM to about 100 mM sodium phosphate or about 1.0 mM to about 10 mM histidineHCl, and the osmotic tension modifier is about 0.5% (w / v) to about 10% (w / v) trehalose. In certain embodiments, the composition further comprises (e) an anti-C5 agent, another PDGF antagonist, and / or another VEGF antagonist. In certain embodiments, the anti-C5 agent is ARC186, ARC187, or ARC1905, and the other VEGF antagonist is bevacizumab or aflibercept.

[0215] Exemplary compositions include F1 to F31 as shown in Tables 3 and 4. Exemplary compositions are also described in PCT application publication WO2013 / 181495. Any of these compositions may further contain an anti-C5 agent, such as ARC1905 or a pharmaceutically acceptable salt thereof.

[0216] [Table 2]

[0217] [Table 3]

[0218] Dosage and Administration

[0219] The methods and compositions according to the present invention can be administered alone or in combination with other treatments and can be provided at home, in a clinic, medical practice, hospital outpatient clinic, or hospital. Treatment may be initiated in a hospital so that a physician can closely observe the effects of the treatment and make any necessary adjustments. The duration of administration may depend on the type of ophthalmic disease or disorder being treated or prevented, the age and condition of the subject, the stage and type of the disease or disorder of the subject, and how the subject responds to the treatment. Furthermore, subjects at higher risk of developing ophthalmic disease or disorder (e.g., diabetic patients) may receive treatment to inhibit or delay the onset of symptoms. In one embodiment, the methods or compositions of the present invention allow for the administration of relatively low doses of each antagonist.

[0220] The dosage and frequency of administration of each antagonist can be controlled independently. For example, one antagonist may be administered three times a day, while another antagonist is administered once a day. Administration can be carried out in on / off cycles, including rest periods, to allow the subject's body time to recover from any side effects. Antagonists may also be present in the same composition.

[0221] In other embodiments, antagonist A or another pharmaceutically acceptable salt thereof and optionally a VEGF antagonist and / or anti-C5 agent are administered before, during, and / or after another procedure. In one embodiment, antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist and / or anti-C5 agent are administered simultaneously, for example in a co-formulation, before, during, and / or after the other procedure. In other embodiments, antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist are administered sequentially before, during, and / or after the other procedure. In some embodiments, antagonist A or another pharmaceutically acceptable salt thereof is administered before the administration of the VEGF antagonist. In other embodiments, antagonist A or another pharmaceutically acceptable salt thereof is administered following the administration of the VEGF antagonist. In some embodiments, the other procedure is surgery. Other treatments include gas retinal reattachment, laser retinal reattachment, scleral buckling, and transciliary vitrectomy (PPV), laser photocoagulation, or cryotherapy.

[0222] Administration of the compositions disclosed herein in conjunction with the implementation of another treatment can improve retinal reattachment success rates, improve visual acuity, reduce choroidal neovascularization, or stabilize vision to a greater extent than the other treatment alone. For example, in some embodiments, administration of antagonist A or another pharmaceutically acceptable salt thereof and the implementation of another treatment can improve retinal reattachment success rates, improve visual acuity, or stabilize vision to a greater extent than the additive effect of antagonist A or another pharmaceutically acceptable salt thereof and the implementation of the other treatment. In some embodiments, the synergistic effect is to reduce tumor size or growth (e.g., treating or preventing VHL disease, retinal capillary angiomas, or von Hippel angiomas). In some embodiments, the synergistic effect is to reduce or inhibit scarring or fibrosis (e.g., ocular scarring of fibrosis such as subretinal fibrosis).

[0223] Administration of both antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist can improve retinal reattachment success rates, improve visual acuity, or stabilize vision to a greater extent than administration of antagonist A or another pharmaceutically acceptable salt thereof or a VEGF antagonist alone. In some embodiments, administration of antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist can have a synergistic effect in the treatment or prevention of ophthalmic diseases or disorders. For example, administration of both antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist can improve retinal reattachment success rates, improve visual acuity, or stabilize vision to a greater extent than administration of antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist. The combined effect of both administrations may improve retinal reattachment success rates, improve visual acuity, or stabilize vision to a greater extent than the additive effect of both administrations. In some embodiments, the synergistic effect is to reduce tumor size or growth (e.g., treating or preventing VHL disease, retinal capillary hemangioma, or von Hippel hemangioma). In some embodiments, the synergistic effect is to reduce or inhibit scarring or fibrosis (e.g., fibrotic ocular scarring such as subretinal fibrosis).

[0224] In some embodiments, the method comprises administering antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist, and an anti-C5 agent, wherein two or more of the antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist, and an anti-C5 agent are present in the same composition. In certain embodiments, a PDGF antagonist and a VEGF antagonist are present in the same composition; in certain embodiments, antagonist A or another pharmaceutically acceptable salt thereof and an anti-C5 agent are present in the same composition; and in certain embodiments, a VEGF antagonist and an anti-C5 agent are present in the same composition. In some embodiments, all three of the antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist, and an anti-C5 agent are present in the same composition.

[0225] In some embodiments, antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist, and an anti-C5 agent are administered sequentially. In one embodiment, antagonist A or another pharmaceutically acceptable salt thereof is administered before the VEGF antagonist or the anti-C5 agent. In one embodiment, the VEGF antagonist is administered before antagonist A or another pharmaceutically acceptable salt thereof or the anti-C5 agent. In one embodiment, the anti-C5 agent is administered before the VEGF antagonist or antagonist A or another pharmaceutically acceptable salt thereof. In one embodiment, antagonist A or another pharmaceutically acceptable salt thereof is administered before the VEGF antagonist and the anti-C5 agent. In one embodiment, the VEGF antagonist is administered before antagonist A or another pharmaceutically acceptable salt thereof and the anti-C5 agent (he-C5 agent). In one embodiment, the anti-C5 agent is administered before the VEGF antagonist and the PDGF antagonist.

[0226] In a particular embodiment, the subject is administered two or more activators (e.g., antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist) in an alternating dosing schedule, where one or more of the two or more activators are administered before another one or more of the two or more activators are administered to the subject.

[0227] In certain embodiments, one or more activators are administered at least one day before one or more other activators. Accordingly, in some embodiments, the method of the present invention comprises administering, on one or more days, an antagonist A or another pharmaceutically acceptable salt thereof, one or more VEGF antagonists, or one or more anti-C5 agents.

[0228] In one embodiment, the order of administration is: antagonist A or another pharmaceutically acceptable salt thereof, followed by the VEGF antagonist, followed by the anti-C5 agent. In another embodiment, the order of administration is: antagonist A or another pharmaceutically acceptable salt thereof, followed by the anti-C5 agent, followed by the VEGF antagonist. In another embodiment, the order of administration is: VEGF antagonist, followed by the anti-C5 agent, followed by antagonist A or another pharmaceutically acceptable salt thereof. In yet another embodiment, the order of administration is: VEGF antagonist, followed by antagonist A or another pharmaceutically acceptable salt thereof, followed by the anti-C5 agent. In yet another embodiment, the order of administration is: anti-C5 agent, followed by antagonist A or another pharmaceutically acceptable salt thereof, followed by the VEGF antagonist. In this embodiment, the order of administration is: anti-C5 agent, followed by a VEGF antagonist, followed by a PDGF antagonist.

[0229] In some embodiments, antagonist A or another pharmaceutically acceptable salt thereof and the VEGF antagonist are administered simultaneously, and the anti-C5 agent is administered before or after the administration of the PDGF antagonist and the VEGF antagonist. In some embodiments, antagonist A or another pharmaceutically acceptable salt thereof and the anti-C5 agent are administered simultaneously, and the VEGF antagonist is administered before or after the administration of antagonist A or another pharmaceutically acceptable salt thereof and the VEGF antagonist. In some embodiments, the VEGF antagonist and the anti-C5 agent are administered simultaneously, and antagonist A or another pharmaceutically acceptable salt thereof is administered before or after the administration of the anti-C5 agent and the VEGF antagonist.

[0230] In other embodiments, the order of administration is: antagonist A or another pharmaceutically acceptable salt thereof, followed by the VEGF antagonist and the anti-C5 agent, where the VEGF antagonist and the anti-C5 agent are present in the same composition. In yet another embodiment, the order of administration is: VEGF antagonist, followed by the anti-C5 agent and antagonist A or another pharmaceutically acceptable salt thereof, where the anti-C5 agent and the PDGF antagonist are present in the same composition. In yet another embodiment, the order of administration is: anti-C5 agent, followed by antagonist A or another pharmaceutically acceptable salt thereof and the VEGF antagonist, where the PDGF antagonist and the VEGF antagonist are present in the same composition.

[0231] In other embodiments, the order of administration is: antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist, where antagonist A or another pharmaceutically acceptable salt thereof and the VEGF antagonist are present in the same composition, followed by the anti-C5 agent. In another embodiment, the order of administration is: antagonist A or another pharmaceutically acceptable salt thereof and an anti-C5 agent, where antagonist A or another pharmaceutically acceptable salt thereof and the anti-C5 agent are present in the same composition, followed by the VEGF antagonist. In another embodiment, the order of administration is: VEGF antagonist and an anti-C5 agent, where VEGF antagonist and the anti-C5 agent are present in the same composition, followed by antagonist A or another pharmaceutically acceptable salt thereof.

[0232] For example, antagonist A or another pharmaceutically acceptable salt thereof may be administered before or after administration of a VEGF antagonist and / or an anti-C5 agent; a VEGF antagonist may be administered before or after administration of antagonist A or another pharmaceutically acceptable salt thereof and / or an anti-C5 agent; or an anti-C5 agent may be administered before or after administration of antagonist A or another pharmaceutically acceptable salt thereof and / or a VEGF antagonist.

[0233] In some embodiments, the method of the present invention includes administering the first drug before administering the second drug. In some embodiments, the method of the present invention includes administering the first drug before administering the second drug, and administering the second drug before administering the third drug.

[0234] In some embodiments, the method of the present invention includes administering the first drug and the second drug simultaneously. In some embodiments, the method of the present invention includes administering the first drug and the second drug simultaneously before administering the third drug.

[0235] In some embodiments, the method of the present invention includes administering the first drug before simultaneously administering the second and third drugs.

[0236] In some embodiments, the method of the present invention includes the simultaneous administration of a first drug, a second drug, and a third drug.

[0237] Examples of the first, second, and third drug groups are shown below in Tables 5 and 6.

[0238] [Table 4]

[0239] [Table 5]

[0240] In some embodiments, the method of the present invention comprises administering antagonist A or another pharmaceutically acceptable salt thereof and two or more VEGF antagonists. In some embodiments, the method of the present invention comprises administering antagonist A or another pharmaceutically acceptable salt thereof and two or more anti-C5 agents. In some embodiments, the method of the present invention comprises administering a VEGF antagonist and two or more anti-C5 agents.

[0241] In some embodiments, the method of the present invention includes administering antagonist A or another pharmaceutically acceptable salt thereof before administering two or more VEGF antagonists. In some embodiments, the method of the present invention includes administering antagonist A or another pharmaceutically acceptable salt thereof before administering the first VEGF antagonist, and administering the first VEGF antagonist before administering the second VEGF antagonist.

[0242] In some embodiments, the method of the present invention involves co-administering antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist. In some embodiments, the method of the present invention involves co-administering antagonist A or another pharmaceutically acceptable salt thereof and a primary VEGF antagonist before administering a secondary VEGF antagonist.

[0243] In some embodiments, the method of the present invention includes administering antagonist A or another pharmaceutically acceptable salt thereof before the co-administration of the primary VEGF antagonist and the secondary VEGF antagonist.

[0244] In some embodiments, the method of the present invention involves the simultaneous administration of antagonist A or another pharmaceutically acceptable salt thereof, a primary VEGF antagonist, and a secondary VEGF antagonist.

[0245] In some embodiments, the method of the present invention includes administering a VEGF antagonist before administering two PDGF antagonists (e.g., antagonist A or another pharmaceutically acceptable salt thereof and another PDGF antagonist). In some embodiments, the method of the present invention includes administering a VEGF antagonist before administering a first PDGF antagonist, and administering a first PDGF antagonist before administering a second PDGF antagonist.

[0246] In some embodiments, the method of the present invention comprises co-administering a VEGF antagonist and antagonist A or another pharmaceutically acceptable salt thereof. In some embodiments, the method of the present invention comprises co-administering a VEGF antagonist and a first PDGF antagonist before administering a second PDGF antagonist.

[0247] In some embodiments, the method of the present invention comprises administering a VEGF antagonist before co-administering a first PDGF antagonist and a second PDGF antagonist.

[0248] In some embodiments, the method of the present invention comprises co-administering a VEGF antagonist, a first PDGF antagonist and a second PDGF antagonist.

[0249] In some embodiments, the method of the present invention comprises administering antagonist A or another pharmaceutically acceptable salt thereof before administering two or more anti-C5 agents. In some embodiments, the method of the present invention comprises administering antagonist A or another pharmaceutically acceptable salt thereof before administering a first anti-C5 agent, and administering the first anti-C5 agent before administering a second anti-C5 agent.

[0250] In some embodiments, the method of the present invention comprises co-administering antagonist A or another pharmaceutically acceptable salt thereof and an anti-C5 agent. In some embodiments, the method of the present invention comprises co-administering antagonist A or another pharmaceutically acceptable salt thereof and a first anti-C5 agent before administering a second anti-C5 agent.

[0251] In some embodiments, the method of the present invention comprises antagonist A or another pharmaceutically acceptable salt thereof before co-administering a first anti-C5 agent and a second anti-C5 agent.

[0252] In some embodiments, the method of the present invention involves the simultaneous administration of an antagonist A or another pharmaceutically acceptable salt thereof, a first anti-C5 agent, and a second anti-C5 agent.

[0253] In some embodiments, the method of the present invention includes administering an anti-C5 agent before administering two or more PDGF antagonists. In some embodiments, the method of the present invention includes administering an anti-C5 agent before administering a first PDGF antagonist, and administering a first PDGF antagonist before administering a second PDGF antagonist.

[0254] In some embodiments, the method of the present invention involves co-administering an anti-C5 agent and antagonist A or another pharmaceutically acceptable salt thereof. In some embodiments, the method of the present invention involves co-administering an anti-C5 agent and a primary PDGF antagonist before administering a secondary PDGF antagonist.

[0255] In some embodiments, the method of the present invention includes administering the anti-C5 agent before the simultaneous administration of the first PDGF antagonist and the second PDGF antagonist.

[0256] In some embodiments, the method of the present invention includes the simultaneous administration of an anti-C5 agent, a primary PDGF antagonist, and a secondary PDGF antagonist.

[0257] In some embodiments, the method of the present invention includes administering a VEGF antagonist before administering two or more anti-C5 agents. In some embodiments, the method of the present invention includes administering a VEGF antagonist before administering a first anti-C5 agent, and administering a first anti-C5 agent before administering a second anti-C5 agent.

[0258] In some embodiments, the method of the present invention includes co-administration of a VEGF antagonist and an anti-C5 agent. In some embodiments, the method of the present invention includes co-administration of a VEGF antagonist and a first anti-C5 agent before administration of a second anti-C5 agent.

[0259] In some embodiments, the method of the present invention includes administering a VEGF antagonist before the simultaneous administration of a first anti-C5 agent and a second anti-C5 agent.

[0260] In some embodiments, the method of the present invention includes the simultaneous administration of a VEGF antagonist, a first anti-C5 agent, and a second anti-C5 agent.

[0261] In some embodiments, the method of the present invention includes administering an anti-C5 agent before administering two or more VEGF antagonists. In some embodiments, the method of the present invention includes administering an anti-C5 agent before administering a first VEGF antagonist, and administering a first VEGF antagonist before administering a second VEGF antagonist.

[0262] In some embodiments, the method of the present invention includes the co-administration of an anti-C5 agent and a VEGF antagonist. In some embodiments, the method of the present invention includes the co-administration of an anti-C5 agent and a first VEGF antagonist before the administration of a second VEGF antagonist.

[0263] In some embodiments, the method of the present invention includes administering the anti-C5 agent before the simultaneous administration of the primary VEGF antagonist and the secondary VEGF antagonist.

[0264] In some embodiments, the method of the present invention includes the simultaneous administration of an anti-C5 agent, a primary VEGF antagonist, and a secondary VEGF antagonist.

[0265] In some embodiments, the first agent and the second agent are PDGF antagonists, which may be the same or different. In some embodiments, the first agent and the second agent are VEGF antagonists, which may be the same or different. In some embodiments, the first agent and the second agent are anti-C5 agents, which may be the same or different.

[0266] In some embodiments, the first agent and the third agent are PDGF antagonists, which may be the same or different. In some embodiments, the first agent and the third agent are VEGF antagonists, which may be the same or different. In some embodiments, the first agent and the third agent are anti-C5 agents, which may be the same or different.

[0267] In some embodiments, the second agent and the third agent are PDGF antagonists, which may be the same or different. In some embodiments, the second agent and the third agent are VEGF antagonists, which may be the same or different. In some embodiments, the second agent and the third agent are anti-C5 agents, which may be the same or different.

[0268] Exemplary groups of the first agent, the second agent, and the third agent are shown below in Tables 7, 8, 9, and 10.

[0269] [Table 6]

[0270] [Table 7]

[0271] [Table 8-1]

[0272] [Table 8-2]

[0273] [Table 8-3]

[0274] [Table 9]

[0275] In one embodiment, two or more drugs are administered simultaneously. In one embodiment, the two or more drugs administered simultaneously are present in the same composition. In another embodiment, the two or more drugs administered simultaneously are present in separate compositions.

[0276] In a particular embodiment, the time between the administration of the first drug and the administration of the second drug is at least 1 minute, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 30 minutes, or at least 1 hour. In a particular embodiment, the time between the administration of the first drug and the administration of the second drug is between 1 minute and 2 hours, 5 minutes and 2 hours, 10 minutes and 2 hours, 15 minutes and 2 hours, 30 minutes and 2 hours, 45 minutes and 2 hours, 1 hour and 2 hours, or 30 minutes and 1 hour. In a particular embodiment, the time between the administration of the first drug and the administration of the second drug is about 1 minute, about 2 minutes, about 3 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 90 minutes, or about 120 minutes. In a particular embodiment, the second drug is administered within 90 days, 30 days, 10 days, 5 days, 2 days, 1 day, 24 hours, 1 hour, 30 minutes, 10 minutes, 5 minutes, or 1 minute after the administration of the second drug.

[0277] In certain embodiments, the time between the administration of the second drug and the administration of the third drug is at least 1 minute, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 30 minutes, or at least 1 hour. In certain embodiments, the time between the administration of the second drug and the administration of the third drug is between 1 minute and 2 hours, 5 minutes and 2 hours, 10 minutes and 2 hours, 15 minutes and 2 hours, 30 minutes and 2 hours, 45 minutes and 2 hours, 1 hour and 2 hours, or 30 minutes and 1 hour. In certain embodiments, the time between the administration of the second drug and the administration of the third drug is about 1 minute, about 2 minutes, about 3 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 90 minutes, or about 120 minutes. In a particular embodiment, the third drug is administered within 90 days, 30 days, 10 days, 5 days, 2 days, 1 day, 24 hours, 1 hour, 30 minutes, 10 minutes, 5 minutes, or 1 minute after the administration of the second drug.

[0278] In certain embodiments, the time between the simultaneous administration of the first and second drugs and the administration of the third drug is at least 1 minute, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 30 minutes, or at least 1 hour. In certain embodiments, the time between the simultaneous administration of the first and second drugs and the administration of the third drug is between 1 minute and 2 hours, 5 minutes and 2 hours, 10 minutes and 2 hours, 15 minutes and 2 hours, 30 minutes and 2 hours, 45 minutes and 2 hours, 1 hour and 2 hours, or 30 minutes and 1 hour. In certain embodiments, the time from the simultaneous administration of the first and second drugs to the administration of the third drug is about 1 minute, about 2 minutes, about 3 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 90 minutes, or about 120 minutes. In a particular embodiment, the administration of the third drug is within 90 days, 30 days, 10 days, 5 days, 2 days, 1 day, 24 hours, 1 hour, 30 minutes, 10 minutes, 5 minutes, or 1 minute of simultaneous administration of the first and second drugs.

[0279] In certain embodiments, the time from administration of the first drug to simultaneous administration of the second and third drugs is at least 1 minute, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 30 minutes, or at least 1 hour. In certain embodiments, the time from administration of the first drug to simultaneous administration of the second and third drugs is between 1 minute and 2 hours, 5 minutes and 2 hours, 10 minutes and 2 hours, 15 minutes and 2 hours, 30 minutes and 2 hours, 45 minutes and 2 hours, 1 hour and 2 hours, or 30 minutes and 1 hour. In certain embodiments, the time from administration of the first drug to simultaneous administration of the second and third drugs is about 1 minute, about 2 minutes, about 3 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 90 minutes, or about 120 minutes. In terms of administration methods, simultaneous administration of the second and third drugs is permitted within 90 days, 30 days, 10 days, 5 days, 2 days, 1 day, 24 hours, 1 hour, 30 minutes, 10 minutes, 5 minutes, or 1 minute of administration of the first drug.

[0280] The administration of two or more, for example, three or more, activators (e.g., antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist, and an anti-C5 agent) may have a synergistic effect in treating or preventing a disease or disorder, such as an ophthalmic disease or disorder. For example, the administration of antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist, and an anti-C5 agent (or any two of these activators) may improve the success rate of retinal reattachment, improve visual acuity, reduce choroidal neovascularization, or stabilize vision to a greater extent than the additive effect of the activators alone.

[0281] In certain embodiments, the present invention provides a method for treating or preventing an ophthalmic disease or disorder, comprising administering one or more, in some embodiments two or more or three or more activators, to a subject in need thereof via an instrument. In other embodiments, the method further comprises performing surgery on the subject. In other embodiments, the method further comprises administering another activator, such as an anti-cancer agent, including but not limited to any of those described herein. In certain embodiments, the method further comprises administering another activator and performing surgery on the subject.

[0282] In some embodiments, administering antagonist A or another pharmaceutically acceptable salt thereof, and optionally a VEGF antagonist and / or anti-C5 agent to a subject results in visual improvements, such as increased visual acuity. In some embodiments, subjects experienced moderate visual acuity loss at week 24, defined as a decrease of 15 letters or more from baseline on the ETDRS visual acuity test, prior to treatment with antagonist A or another pharmaceutically acceptable salt thereof.

[0283] In some embodiments, the visual acuity test is as described in the Early Treatment Diabetic Retinopathy Study Research Group (ETDRS), Manual of Operations, Baltimore: ETDRS Coordinating Center, University of Maryland; available from National Technical Information Service, 5285 Port Royal Road, Springfield, VA22161; Accession No. PB85223006 / AS; Ferris et al., Am J Ophthalmol 94:91-96, 1982; or Example 4. In some embodiments, the visual acuity test uses one or more charts available from http: / / www.nei.nih.gov / photo / keyword.asp?conditions=Eye+Charts&match=all, e.g., ETDRS Visual Acuity Charts 1, 2 and / or R.

[0284] In other embodiments, administration of antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist results in a reduction of ocular adverse events, a reduction in RCH size (e.g., measured by fundus photography and FA), a reduction in exudation (measured by fundus photography, OCT, and FA), or a reduction in epiretinal proliferation or retinal traction (assessed by fundus photography) compared to subjects who do not receive antagonist A or another pharmaceutically acceptable salt thereof. In some embodiments, the subjects do not require excision of RCH or ocular surgery, and the method is not included.

[0285] In some embodiments, the target is an antagonist A or another pharmaceutically acceptable salt thereof, and optionally a VEGF antagonist and / or an anti-C5 agent. Compared to the vision of subjects not administered antagonist A or another pharmaceutically acceptable salt thereof, or compared to subjects administered anti-VEGF monotherapy, this results in an improvement in vision independent of baseline lesion size or baseline vision. In some embodiments, administration of antagonist A or another pharmaceutically acceptable salt thereof, and optionally a VEGF antagonist and / or anti-C5 agent to subjects results in subjects having visual acuity of 20 / 40 or better, or 20 / 25 or better. In some embodiments, administration of antagonist A or another pharmaceutically acceptable salt thereof, and optionally a VEGF antagonist and / or anti-C5 agent to subjects results in an increased reduction in CNV size in subjects compared to CNV size in patients not administered antagonist A or another pharmaceutically acceptable salt thereof, or compared to subjects administered anti-VEGF monotherapy. In some embodiments, administration of antagonist A or another pharmaceutically acceptable salt thereof, and optionally a VEGF antagonist and / or anti-C5 agent to a subject results in a reduction in CNV size (e.g., a reduction in optic disc area (DA) size). In some embodiments, administration of antagonist A or another pharmaceutically acceptable salt thereof, and optionally a VEGF antagonist and / or anti-C5 agent to a subject results in an increased reduction in DA size compared to patients who did not receive antagonist A or another pharmaceutically acceptable salt thereof, or compared to subjects who received anti-VEGF monotherapy. In some embodiments, the increased reduction in CNV size is observed in subjects with a small baseline CNV, e.g., 1.62 DA (optic disc area) or less. In some embodiments, the increased reduction in CNV size (e.g., in optic disc area) is observed in subjects with a large baseline CNV, e.g., greater than 1.62 DA. In some embodiments, neovascular regression is induced by targeting an antagonist A or another pharmaceutically acceptable salt thereof, and optionally a VEGF antagonist and / or an anti-C5 agent.In some embodiments, administration of antagonist A or another pharmaceutically acceptable salt thereof, and optionally a VEGF antagonist and / or anti-C5 agent to a subject results in a reduction of neovascularization compared to that occurring in subjects not administered antagonist A or another pharmaceutically acceptable salt thereof, or compared to subjects administered anti-VEGF monotherapy. In some embodiments, the reduction of neovascularization is anti-fibrotic. In some embodiments, administration of antagonist A or another pharmaceutically acceptable salt thereof, and optionally a VEGF antagonist and / or anti-C5 agent to a subject results in a reduction or absence of hyperintensity images, e.g., subretinal hyperintensity images, e.g., a reduction in the size of subretinal hyperintensity images (SHRMs) as demonstrated by spectral-domain optical coherence tomography (SD-OCT). In some embodiments, administration of antagonist A or another pharmaceutically acceptable salt thereof, and optionally a VEGF antagonist and / or anti-C5 agent to a subject results in an increased resolution of hyperintensity images, such as subretinal hyperintensity images, compared to, for example, a subject not administered antagonist A or another pharmaceutically acceptable salt thereof, or compared to a subject administered a VEGF antagonist, anti-VEGF drug monotherapy, and / or anti-C5 agent.

[0286] In some embodiments, subjects with improved vision have an improvement of 3, 4, or 5 lines or more in visual acuity. In one embodiment, the subject's visual acuity is determined using a protocol such as the Early Treatment Diabetic Retinopathy Study Research Group (ETDRS) or the Age-Related Eye Disease Study (AREDS) protocol. In some embodiments, visual acuity is measured using a modified ETDRS and / or AREDS protocol, such as the visual acuity measurement described by Ferris et al., Am J Ophthalmol 94:91-96, 1982. In some embodiments, visual acuity is measured using the Early Treatment Diabetic Retinopathy Study Research Group (ETDRS), Manual of Operations, Baltimore: ETDRS Coordinator The visual acuity is measured as described in the ting Center, University of Maryland. It is available from the National Technical Information Service, 5285 Port Royal Road, Springfield, VA22161; Accession No. PB85 223006 / AS as described herein. In other embodiments, the visual acuity is measured as described in Example 4 below. In some embodiments, the visual acuity is measured using one or more charts available from http: / / www.nei.nih.gov / photo / keyword.asp?conditions=Eye+Charts&match=all, e.g., ETDRS visual acuity charts 1, 2 and / or R.

[0287] In one embodiment, the visual acuity of the subject is determined by one or more of the following steps: (1) measuring the best corrected visual acuity (BCVA) with the required overt refraction; (2) measuring the corrected visual acuity with conditional overt refraction; or (3) measuring the corrected visual acuity without overt refraction.

[0288] In one embodiment, each PDGF and VEGF antagonist is administered in an effective amount to treat or prevent an ophthalmic disease or disorder. The amount of antagonist mixed with the carrier material to produce a single dose can vary depending on the subject being treated and the specific mode of administration.

[0289] The dosage of each antagonist may depend on several factors, including the severity of the symptoms, whether the symptoms should be treated or prevented, age, weight, and the health of the person being treated. In addition, genomic pharmacological information (the influence of genotype on the pharmacokinetic, pharmacodynamic, or efficacy profile of the treatment) for a particular patient may influence the dosage used. Furthermore, precise individual dosages may be adjusted to some extent depending on various factors, including the specific combination of antagonists administered, the timing of administration, the route of administration, the nature of the formulation, the elimination rate, the specific ophthalmic disease or disorder being treated, the severity of the disorder, and the anatomical location of neovascular disease. Some variation in dosage can be expected.

[0290] Generally, when administered orally to a subject, the dose of the antagonist of the present invention is typically 0.001 mg / kg / day to 100 mg / kg / day, 0.01 mg / kg / day to 50 mg / kg / day, or 0.1 mg / kg / day to 10 mg / kg / day. Generally, when administered orally to humans, the dose of the antagonist of the present invention is typically 0.001 mg to 300 mg per day, 1 mg to 200 mg per day, or 5 mg to 50 mg per day. A maximum dose of 200 mg per day may be required. For parenteral injection administration of the antagonist of the present invention, the dose is typically 0.1 mg to 250 mg per day, 1 mg to 20 mg per day, or 3 mg to 5 mg per day. Injections may be given up to four times per day. In some embodiments, the dosage of PDGF or VEGF antagonist for use in the present invention is typically 0.1 mg to 1500 mg per day, or 0.5 mg to 10 mg per day, or 0.5 mg to 5 mg per day. Doses up to a maximum of 3000 mg per day can be administered.

[0291] In some embodiments, for parenteral injection administration of three activators (e.g., antagonist A or another pharmaceutically acceptable salt thereof, VEGF antagonist, and anti-C5 agent or other combination disclosed herein), the doses of each PDGF antagonist, VEGF antagonist, and anti-C5 agent are typically 0.1 mg to 250 mg per day, 1 mg to 20 mg per day, or 3 mg to 5 mg per day. Injections may be given up to four times per day. Generally, when administered parenterally, the doses of antagonist A or another pharmaceutically acceptable salt thereof, VEGF antagonist, or anti-C5 agent are typically 0.1 mg to 1500 mg per day, or 1 The dosage is 0.5 mg to 10 mg per day, or 0.5 mg to 5 mg per day. A maximum daily dose of at least 3000 mg may be administered.

[0292] In some embodiments in which antagonist A or another pharmaceutically acceptable salt thereof, VEGF antagonist and / or anti-C5 agent is administered ophthalmologically to humans, for example intravitreally, the doses of each antagonist A or another pharmaceutically acceptable salt thereof, VEGF antagonist and anti-C5 agent are typically 0.003 mg to 5.0 mg / eye / administer, or 0.03 mg to 3.0 mg / eye / administer, or 0.1 mg to 1.0 mg / eye / administer. In one embodiment, the doses of each antagonist A or another pharmaceutically acceptable salt thereof, VEGF antagonist and anti-C5 agent are about 0.03 mg, about 0.3 mg, about 0.5 mg, about 1.0 mg, about 1.25 mg, about 1.5 mg, about 2.0 mg or about 3.0 mg / eye. In one embodiment, the dose of antagonist A or another pharmaceutically acceptable salt thereof is about 0.03 mg, about 0.3 mg, about 0.5 mg, about 1.0 mg, about 1.25 mg, about 1.5 mg, about 2.0 mg, about 3.0 mg, or about 4.0 mg / eye. In another embodiment, the dose of a VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008, or pegaptanib sodium) is about 0.03 mg, about 0.3 mg, about 0.5 mg, about 1.0 mg, about 1.25 mg, about 1.5 mg, about 1.65 mg, about 2.0 mg, about 3.0 mg, or about 4.0 mg / eye. In another embodiment, the dose of the anti-C5 agent (e.g., ARC1905 or a pharmaceutically acceptable salt thereof) is about 0.03 mg, about 0.3 mg, about 0.5 mg, about 1.0 mg, about 1.25 mg, about 1.5 mg, about 1.65 mg, about 2.0 mg, about 3.0 mg, or about 4.0 mg / eye.

[0293] In certain embodiments in which the subject is administered both antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist, and optionally an anti-C5 agent, the dose of antagonist A or another pharmaceutically acceptable salt thereof is about 1.5 mg, and the dose of the VEGF antagonist (e.g., ranibizumab) is about 0.5 mg. In certain embodiments in which the subject is administered both antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist, the dose of antagonist A or another pharmaceutically acceptable salt thereof is about 3.0 mg, and the dose of the VEGF antagonist (e.g., ranibizumab) is about 0.5 mg. In certain embodiments, subjects are administered both antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist, where the dose of antagonist A or another pharmaceutically acceptable salt thereof is approximately 1.5 mg and the dose of the VEGF antagonist (e.g., bevacizumab) is approximately 1.25 mg. In certain embodiments, subjects are administered both antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist, where the dose of antagonist A or another pharmaceutically acceptable salt thereof is approximately 3.0 mg and the dose of the VEGF antagonist (e.g., bevacizumab) is approximately 1.25 mg. In certain embodiments, the subject is administered both antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist, where the dose of antagonist A or another pharmaceutically acceptable salt thereof is about 1.5 mg and the dose of the VEGF antagonist (e.g., aflibercept) is about 2.0 mg. In certain embodiments, the subject is administered both antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist, where the dose of antagonist A or another pharmaceutically acceptable salt thereof is about 3.0 mg and the dose of the VEGF antagonist (e.g., aflibercept) is about 2.0 mg.In certain embodiments, the subject is administered both antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist, where the dose of antagonist A or another pharmaceutically acceptable salt thereof is about 1.5 mg and the dose of the VEGF antagonist, for example, pegaptanib sodium, is about 1.65 mg. In certain embodiments, the subject is antagonist A or another pharmaceutically acceptable salt thereof. Both a pharmaceutically acceptable salt and a VEGF antagonist were administered, with the dose of antagonist A or another pharmaceutically acceptable salt thereof being approximately 3.0 mg, and the dose of the VEGF antagonist, such as pegaptanib sodium, being approximately 1.65 mg.

[0294] The dosage can be administered in the range of approximately 0.01 mL / eye to approximately 0.2 mL / eye, or approximately 0.03 mL / eye to approximately 0.15 mL / eye, or approximately 0.05 mL / eye to approximately 0.10 mL / eye.

[0295] Antagonist A or a pharmaceutically acceptable salt thereof can be delivered intravitreously at a maximum dose of approximately 30 mg / mL using an injection volume of up to 100 μL.

[0296] Table 11 shows exemplary antagonist A / VEGF antagonist combinations and their dosages.

[0297] [Table 10]

[0298] In certain embodiments in which the subject is administered the anti-C5 agent in combination with antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist, the anti-C5 agent may be administered in doses of about 0.03 mg, about 0.3 mg, about 0.5 mg, about 1.0 mg, about 1.25 mg, about 1.5 mg, about 2.0 mg, or about 3.0 mg / eye.

[0299] In certain embodiments, the ocular dose of a composition containing an anti-C5 aptamer, such as ARC1905 and ARC187, or a pharmaceutically acceptable salt thereof, may range from about 0.01 mg to about 5 mg / eye or from about 0.1 mg to about 3 mg / eye. For example, the ocular dose of a composition containing ARC1905, ARC187, or a pharmaceutically acceptable salt thereof may be about 0.01 mg, about 0.03 mg, about 0.05 mg, about 0.1 mg, about 0.3 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, or about 5 mg. Such doses may be administered to the eye, for example, by intravitreal injection, on an optional basis, weekly, bi-weekly, monthly, or quarterly. It may be administered by a sustained-release device or formulation. In some embodiments, an anti-C5 aptamer (e.g., ARC1905, ARC187, or a pharmaceutically acceptable salt thereof) may be administered in multiple injections (e.g., intravitreal injection) at varying time intervals over a period of several months. In certain such embodiments, the initial injections received earlier in the treatment plan are divided at shorter intervals than the injections received later in the treatment plan. For example, a single-dosage plan particularly useful in methods for treating, preventing, or stabilizing AMD (e.g., non-wet AMD or geographic atrophy) includes administering an initial injection of an anti-C5 aptamer (e.g., ARC1905, ARC187, or a pharmaceutically acceptable salt thereof) on a monthly basis at the start of treatment (e.g., the first two, three, four, or five injections) and subsequent injections at longer intervals (e.g., every three, four, five, or six months). For example, the first three injections of anti-C5 aptamer are administered monthly to the subject, while the fourth and fifth injections are administered three or four months after the previous injection. The interval between anti-C5 aptamer injections may be adjusted based on the subject's response to the treatment, measured, for example, by changes in the size of geographic atrophic lesions or improvement or stabilization of visual acuity.

[0300] In some embodiments, the anti-C5 aptamer is administered to the subject together with a VEGF antagonist, where the dose of the anti-C5 aptamer is approximately 0.03 mg and the dose of the VEGF antagonist, such as ranibizumab, is approximately 0.5 mg. In a particular embodiment, the subject is administered both the anti-C5 aptamer and the VEGF antagonist, where the dose of the anti-C5 aptamer is approximately 1.0 mg and the dose of the VEGF antagonist, such as ranibizumab, is approximately 0.5 mg. In a particular embodiment, the subject is administered both the anti-C5 aptamer and the VEGF antagonist, where the dose of the anti-C5 aptamer is approximately 2.0 mg and the dose of the VEGF antagonist, such as ranibizumab, is approximately 0.5 mg.

[0301] In some embodiments, an anti-C5 aptamer is administered to the subject together with a VEGF antagonist, where the dose of the anti-C5 aptamer is approximately 0.03 mg and the dose of the VEGF antagonist, such as bevacizumab, is approximately 1.25 mg. In a particular embodiment, the subject is administered both an anti-C5 aptamer and a VEGF antagonist, where the dose of the anti-C5 aptamer is approximately 1.0 mg and the dose of the VEGF antagonist, such as bevacizumab, is approximately 1.25 mg. In a particular embodiment, the subject is administered both an anti-C5 aptamer and a VEGF antagonist, where the dose of the anti-C5 aptamer is approximately 2.0 mg and the dose of the VEGF antagonist, such as bevacizumab, is approximately 1.25 mg.

[0302] In some embodiments, the anti-C5 aptamer is administered to the subject together with a VEGF antagonist, where the dose of the anti-C5 aptamer is approximately 0.03 mg and the dose of the VEGF antagonist, such as aflibercept, is approximately 2.0 mg. In a particular embodiment, the subject is administered both the anti-C5 aptamer and the VEGF antagonist, where the dose of the anti-C5 aptamer is approximately 1.0 mg and the dose of the VEGF antagonist, such as aflibercept, is approximately 2.0 mg. In a particular embodiment, the subject is administered both the anti-C5 aptamer and the VEGF antagonist, where the dose of the anti-C5 aptamer is approximately 2.0 mg and the dose of the VEGF antagonist, such as aflibercept, is approximately 2.0 mg.

[0303] Each antagonist can be administered independently, 1 to 4 times a day, or 1 to 4 times a month, or 1 to 6 times a year, or once every 2, 3, 4, or 5 years. Administration can span a period of 1 day or 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, or even the patient's lifetime. In one embodiment, administration is performed once a month for 3 months. Chronic, long-term administration will likely be observed in many cases. The dosage may be administered as a single dose or in multiple divided doses. Generally, the desired dosage should be administered at predetermined intervals over a long period, usually for at least several weeks or months, but longer-term administration of several months, years or more may be required.

[0304] In addition to treating pre-existing ophthalmic diseases and disorders, compositions may be administered prophylactically to prevent or delay the onset of these diseases and disorders. The term “prevention” includes inhibiting or delaying the onset or progression of a disease or disorder. For prophylactic use, compositions may be administered to patients who are susceptible to or otherwise at risk of certain ophthalmic diseases or disorders.

[0305] In one embodiment, antagonist A or another pharmaceutically acceptable salt thereof and VEGF antagonist are administered to subjects requiring treatment with them, typically in the form of an injectable pharmaceutical composition. Antagonist A or another pharmaceutically acceptable salt thereof and VEGF antagonist can be administered in a separate composition or in a pharmaceutical composition containing both PDGF antagonist and VEGF antagonist. Administration can be done by injection, for example, by intraocular injection, or by using a drug delivery device. Parenteral, systemic, or transdermal administration is also within the scope of the present invention. Administration of antagonist A or another pharmaceutically acceptable salt thereof and VEGF antagonist can be chronological or simultaneous. When administered sequentially, the respective routes of administration can be the same or different. In one embodiment, antagonist A or another pharmaceutically acceptable salt thereof is administered within 90 days, 30 days, 10 days, 5 days, 24 hours, 1 hour, 30 minutes, 10 minutes, 5 minutes, or 1 minute prior to the administration of the VEGF antagonist. When antagonist A or another pharmaceutically acceptable salt thereof is administered prior to the VEGF antagonist, the VEGF antagonist is administered in an amount and time such that the total amount of antagonist A or another pharmaceutically acceptable salt thereof and the VEGF antagonist is effective in treating or preventing an ophthalmic disease or disorder. When the VEGF antagonist is administered prior to antagonist A or another pharmaceutically acceptable salt thereof, antagonist A or another pharmaceutically acceptable salt thereof is administered in an amount and time such that the total amount of antagonist A or another pharmaceutically acceptable salt thereof and the VEGF antagonist is effective in treating or preventing an ophthalmic disease or disorder.

[0306] In one embodiment, antagonist A or another pharmaceutically acceptable salt thereof or a VEGF antagonist (e.g., ranibizumab, bevacizumab, pegaptanib sodium, ESBA1008, or aflibercept) is administered intravitreally using a 30-gauge or 27-gauge needle. In some embodiments, a 0.5-inch needle is used. In one embodiment, antagonist A or another pharmaceutically acceptable salt thereof is administered intravitreally using a 30-gauge 0.5-inch needle, and a VEGF antagonist (e.g., ranibizumab, bevacizumab, pegaptanib sodium, ESBA1008, or aflibercept) is administered intravitreally using a 27-gauge needle. In some embodiments, 50 μL (1.5 mg in 0.05 mL) of antagonist A or another pharmaceutically acceptable salt thereof is administered intravitreously using a 30-gauge 0.5-inch needle, and 50 μL (0.5 mg in 0.05 mL) of a VEGF antagonist (e.g., ranibizumab, bevacizumab, pegaptanib sodium, or aflibercept) is administered intravitreously using a 27-gauge needle.

[0307] In certain embodiments in which antagonist A or another pharmaceutically acceptable salt thereof is used in combination with a VEGF antagonist such as ranibizumab, bevacizumab, ESBA1008, pegaptanib sodium, or aflibercept, one of these two drugs is administered first to the subject. Then the other drug is administered to the subject. In certain embodiments, both drugs are administered to the same eye of the subject. In certain embodiments, both drugs are administered to both eyes of the subject. The two drugs may be administered to the eyes in either order; that is, antagonist A or another pharmaceutically acceptable salt thereof may be administered first, followed by the VEGF antagonist, or the VEGF antagonist may be administered first, followed by antagonist A or another pharmaceutically acceptable salt thereof. The second drug may be administered immediately after the first drug, or the second drug may be administered some time after the first drug.

[0308] In a particular embodiment, the time between the administration of the first drug and the administration of the second drug is at least 1 minute, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 30 minutes, or at least 1 hour. In a particular embodiment, the time between the administration of the first drug and the administration of the second drug is between 1 minute and 2 hours, 5 minutes and 2 hours, 10 minutes and 2 hours, 15 minutes and 2 hours, 30 minutes and 2 hours, 45 minutes and 2 hours, 1 hour and 2 hours, or 30 minutes and 1 hour. In a particular embodiment, the time between the administration of the first drug and the administration of the second drug is about 1 minute, about 2 minutes, about 3 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 90 minutes, or about 120 minutes.

[0309] In certain embodiments, the present invention provides a method for treating or preventing any ophthalmic disease described herein, comprising providing an antagonist A or another pharmaceutically acceptable salt thereof to a subject in need thereof at a first time point, and providing a VEGF antagonist, such as aflibercept, bevacizumab, ranibizumab, ESBA1008, or pegaptanib sodium, to the subject at a second time point, wherein the amount of time between the first and second time points is about 1 minute, about 2 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 90 minutes, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days.

[0310] In certain embodiments, antagonist A or another pharmaceutically acceptable salt thereof and the VEGF antagonist are administered intravitreously. In certain embodiments, about 1.5 mg or 3.0 mg of antagonist A or another pharmaceutically acceptable salt thereof is administered into the eye, and about 0.5 mg, about 1.25 mg, about 1.65 mg, or about 2.0 mg of the VEGF antagonist is administered into the eye. In some embodiments, the VEGF antagonist is administered intravitreously about 30 minutes after the intravitreous administration of antagonist A or another pharmaceutically acceptable salt thereof. In some embodiments, antagonist A or another pharmaceutically acceptable salt thereof is administered intravitreously about 30 minutes after the intravitreous administration of the VEGF antagonist.

[0311] In one embodiment, a VEGF antagonist is administered to at least one eye of the subject, and approximately one hour after the administration of the VEGF antagonist, antagonist A or another pharmaceutically acceptable salt thereof is administered to the same eye. In another embodiment, antagonist A or another pharmaceutically acceptable salt thereof is administered to at least one eye of the subject, and approximately one hour after the administration of the PDGF antagonist, VEGF antagonist is administered to the same eye.

[0312] In certain embodiments, the PDGF antagonist and VEGF antagonist are present in amounts of approximately 50 μL or less, approximately 60 μL or less, approximately 70 μL or less, approximately 80 μL or less, approximately 90 μL or less, approximately 100 μL or less, approximately 120 μL or less, approximately 150 μL or less, or approximately 200 μL or less. The full total dose is administered to each eye.

[0313] In certain embodiments, antagonist A or another pharmaceutically acceptable salt thereof, VEGF antagonist, and anti-C5 agent are administered intraocularly, for example, intravitreally. In certain embodiments, antagonist A or another pharmaceutically acceptable salt thereof, VEGF antagonist, and anti-C5 agent are administered to mammals by a single injection, for example, a single intraocular or intravitreal injection. In certain embodiments, antagonist A or another pharmaceutically acceptable salt thereof, VEGF antagonist, and anti-C5 agent are administered sequentially. In certain embodiments, two or more antagonist A or another pharmaceutically acceptable salt thereof, VEGF antagonist, and anti-C5 agent are administered simultaneously, for example, in the same composition. In certain embodiments, one of antagonist A or another pharmaceutically acceptable salt thereof, VEGF antagonist, and anti-C5 agent is administered, and within about 30 seconds, one or two others are administered thereafter. In certain embodiments, all three agents—antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist, and an anti-C5 agent—are administered within approximately 30 seconds or 1 minute of each other. In other embodiments, one of the agents—antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist, and an anti-C5 agent—is administered, and one or both of the other are administered approximately 1 minute, 2 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 90 minutes, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 3 days, 4 days, 5 days, 6 days, or 7 days later. In other embodiments, one or two of antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist, and an anti-C5 agent are administered, the other being administered approximately 1 minute, 2 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 90 minutes, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 3 days, 4 days, 5 days, 6 days, or 7 days later.In one particular embodiment, one of a PDGF antagonist, a VEGF antagonist, and an anti-C5 agent is administered; another is administered in approximately 1 minute, 2 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 90 minutes, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 3 days, approximately One dose is administered after 4 days, approximately 5 days, approximately 6 days, or approximately 7 days; the remaining dose is administered after approximately 1 minute, approximately 2 minutes, approximately 5 minutes, approximately 10 minutes, approximately 15 minutes, approximately 20 minutes, approximately 25 minutes, approximately 30 minutes, approximately 40 minutes, approximately 50 minutes, approximately 60 minutes, approximately 90 minutes, approximately 2 hours, approximately 4 hours, approximately 6 hours, approximately 8 hours, approximately 12 hours, approximately 24 hours, approximately 36 hours, approximately 48 hours, approximately 3 days, approximately 4 days, approximately 5 days, approximately 6 days, or approximately 7 days. In certain embodiments in which two of the same composition are present: antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist, and an anti-C5 agent, the composition is administered, and the PDGF antagonist, VEGF antagonist, or anti-C5 agent not present in the composition is administered after about 1 minute, about 2 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 90 minutes, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days. In other embodiments in which two of the same composition are present: antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist, and an anti-C5 agent, antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist, or an anti-C5 agent that is not present in the composition is administered, and the composition is administered after about 1 minute, about 2 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 90 minutes, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days.

[0314] In certain embodiments, antagonist A or another pharmaceutically acceptable salt thereof, for example, antagonist A or another pharmaceutically acceptable salt thereof, is administered at intervals of approximately 24 hours for 2, 3, 4, 5, 6, or 7 days or more. A VEGF antagonist, such as aflibercept, bevacizumab, ESBA1008, pegaptanib sodium, or ranimizumab, is administered approximately 48 hours after the first dose of antagonist A or another pharmaceutically acceptable salt thereof. In certain embodiments, antagonist A or another pharmaceutically acceptable salt thereof is administered on each of the four consecutive days, i.e., on days 1, 2, 3, and 4, while the VEGF antagonist (e.g., bevacizumab, ranimizumab, ESBA1008, pegaptanib sodium, or aflibercept) is administered on day 3. In certain embodiments, a composition comprising antagonist A or another pharmaceutically acceptable salt thereof, for example, antagonist A or another pharmaceutically acceptable salt thereof, is administered to a subject, and a composition comprising a VEGF antagonist is administered to the subject about 48 hours later.

[0315] In one embodiment, approximately 50 mg / kg of antagonist A or another pharmaceutically acceptable salt thereof (e.g., antagonist A or another pharmaceutically acceptable salt thereof) is administered, for example, intraperitoneally on days 1, 2, 3, and 4, and approximately 1 mg / kg of a VEGF antagonist (e.g., bevacizumab, ranibizumab, ESBA1008, pegaptanib sodium, or aflibercept) is administered on day 3. In another embodiment, approximately 50 mg / kg of antagonist A or another pharmaceutically acceptable salt thereof (e.g., antagonist A or another pharmaceutically acceptable salt thereof) is administered on days 1, 2, 3, and 4, and approximately 5 mg / kg of a VEGF antagonist (e.g., bevacizumab, ranibizumab, ESBA1008, pegaptanib sodium, or aflibercept) is administered on day 3.

[0316] In one embodiment, approximately 50 mg / kg of antagonist A or another pharmaceutically acceptable salt thereof is administered on days 1, 2, 3, and 4, and approximately 1 mg / kg of aflibercept is administered on day 3. In another embodiment, approximately 50 mg / kg of antagonist A or another pharmaceutically acceptable salt thereof is administered on days 1, 2, 3, and 4, and approximately 5 mg / kg of aflibercept is administered on day 3.

[0317] In one embodiment, approximately 0.03 mg, approximately 0.3 mg, approximately 0.5 mg, approximately 1.0 mg, approximately 1.5 mg, or approximately 3.0 mg of antagonist A or another pharmaceutically acceptable salt thereof (e.g., antagonist A or another pharmaceutically acceptable salt thereof) is administered intravitreously on days 1, 2, 3, and 4, and approximately 0.5 mg, approximately 1.0 mg, approximately 1.5 mg, approximately 1.65 mg, approximately 3.0 mg, or approximately 4.0 mg of a VEGF antagonist (e.g., bevacizumab, ranibizumab, ESBA1008, pegaptanib sodium, or aflibercept) is administered intravitreously on day 3. In one embodiment, approximately 0.3 mg or approximately 1.5 mg of antagonist A or another pharmaceutically acceptable salt thereof is administered intravitreously on days 1, 2, 3, and 4, and approximately 0.5 mg of ranibizumab is administered intravitreously on day 3. In one embodiment, approximately 0.3 mg or approximately 1.5 mg of antagonist A or another pharmaceutically acceptable salt thereof is administered intravitreously on days 1, 2, 3, and 4, and approximately 1.25 mg of bevacizumab is administered intravitreously on day 3. In one embodiment, approximately 0.3 mg or approximately 1.5 mg of antagonist A or another pharmaceutically acceptable salt thereof is administered intravitreously on days 1, 2, 3, and 4, and approximately 2.0 mg of aflibercept is administered intravitreously on day 3. In one embodiment, approximately 0.3 mg or approximately 1.5 mg of antagonist A or another pharmaceutically acceptable salt thereof is administered intravitreously on days 1, 2, 3, and 4, and approximately 1.65 mg of pegaptanib sodium is administered intravitreously on day 3.

[0318] In some embodiments, antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist are administered over six treatments, every four weeks or every 30 days. In some embodiments, the VEGF antagonist is ranibizumab. In some embodiments, 0.3 mg of antagonist A or another pharmaceutically acceptable salt thereof and 0.5 mg of ranibizumab are administered over six treatments, every four weeks or every 30 days. In some embodiments, 1.5 mg of antagonist A or another pharmaceutically acceptable salt thereof and 0.5 mg of ranibizumab are administered over six treatments, every four weeks or every 30 days.

[0319] In some embodiments, 0.3 mg of antagonist A or another pharmaceutically acceptable salt thereof and 1.25 mg of bevacizumab, 2.0 mg of aflibercept, or 1.65 mg of pegaptanib sodium are administered over six treatments, every four weeks or every 30 days. In some embodiments, 1.5 mg of antagonist A or another pharmaceutically acceptable salt thereof and 1.25 mg of bevacizumab, 2.0 mg of aflibercept, or 1.65 mg of pegaptanib sodium are administered over six treatments, every four weeks or every 30 days.

[0320] In some embodiments, the method involves administering antagonist A or another pharmaceutically acceptable salt thereof, bevacizumab, and aflibercept. In some embodiments, the method involves administering antagonist A or another pharmaceutically acceptable salt thereof, bevacizumab, and aflibercept over six treatments every four weeks or every 30 days. In some embodiments, the method involves administering 1.5 mg of antagonist A or another pharmaceutically acceptable salt thereof, 1.25 mg of bevacizumab, and 2 mg of aflibercept. In some embodiments, the method involves administering 1.5 mg of antagonist A or another pharmaceutically acceptable salt thereof, 1.25 mg of bevacizumab, and 2 mg of aflibercept over six treatments every four weeks or every 30 days.

[0321] In some embodiments, the method comprises administering to a subject in need (a) an antagonist A or another pharmaceutically acceptable salt thereof and (b) a VEGF antagonist, wherein (a) and (b) are administered in amounts effective to treat or prevent an ocular condition (e.g., wet AMD), and such administrations occur once every 1 month ± approximately 7 days for 12 consecutive months.

[0322] In some embodiments, the method comprises administering to a subject in need (a) an antagonist A or another pharmaceutically acceptable salt thereof and (b) a VEGF antagonist, wherein (a) and (b) are administered in amounts effective to treat or prevent an ocular condition (e.g., wet AMD), and such administration occurs once every 1 month ± approximately 7 days for a first 12 consecutive months, and immediately thereafter, starting in the second month of a second 12 consecutive months, once every 2 months ± approximately 7 days for a second 12 consecutive months.

[0323] In some embodiments, the method also provided herein comprises administering to a subject requiring it (a) an antagonist A or another pharmaceutically acceptable salt thereof and (b) a VEGF antagonist, wherein (a) and (b) are administered in amounts effective to treat or prevent an ocular condition (e.g., wet AMD), and such administration occurs once every 1 month ± approximately 7 days for 24 consecutive months.

[0324] In some embodiments, the method comprises administering to a subject in need (a) an antagonist A or another pharmaceutically acceptable salt thereof and (b) a VEGF antagonist, wherein (a) and (b) are administered in amounts effective to treat or prevent an ocular condition (e.g., wet AMD), and such administration is once every 1 month ± approximately 7 days for 3 consecutive months, and immediately thereafter, starting in the second month of 12 consecutive months, once every 2 months ± approximately 7 days for 12 consecutive months. It occurs over several months.

[0325] In some embodiments, the method includes, for example, sequential, sequential and discontinuous procedures and / or re-procedures for the treatment or prevention of wet AMD or subfoveal neovascular AMD. In some embodiments, sequential procedures include administering antagonist A or another pharmaceutically acceptable salt thereof and an anti-VEGF agent monthly (±7 days) for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive months. In some embodiments, antagonist A or a pharmaceutically acceptable salt thereof is administered within approximately 1 minute, 2 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 90 minutes, 2 hours, 4 hours, 6 hours, 8 hours, or 12 hours of administration of the VEGF antagonist. In some embodiments, the VEGF antagonist is administered before the administration of antagonist A or a pharmaceutically acceptable salt thereof. In other embodiments, antagonist A or a pharmaceutically acceptable salt thereof is administered before the administration of the VEGF antagonist. In some embodiments, antagonist A or a pharmaceutically acceptable salt thereof and the VEGF antagonist are administered as a co-formulation. In some embodiments, the amount of antagonist A or a pharmaceutically acceptable salt thereof administered is about 1.5 mg / eye, and the amount of VEGF antagonist administered is about 0.5 mg / eye (e.g., ranibizumab), about 1.25 mg / eye (e.g., bevacizumab), about 1.65 mg / eye (e.g., pegaptanib sodium), or about 2.0 mg / eye (e.g., aflibercept).

[0326] In some embodiments, the method further includes measuring the subject's visual acuity. In some embodiments, the subject's visual acuity is measured once every 1 month ± approximately 7 days. In some embodiments, visual acuity is considered stable when it is stable over three consecutive months. In some embodiments, visual acuity is considered stable when, in the two most recent months of each of the three consecutive months, the visual acuity is within 5 ETDRS characters (better or worse) of the subject's visual acuity in the first month of the three consecutive months (i.e., the month immediately preceding the first month of the subsequent two consecutive months).

[0327] In some embodiments, the subject is administered according to the method of the present invention until the subject's visual acuity stabilizes. In some embodiments, the subject is administered according to the method of the present invention until the subject's visual acuity stabilizes over three consecutive months. In some embodiments, the subject is administered according to the method of the present invention until the subject's visual acuity in each of the two most recent months of the three consecutive months is ≤ 5 ETDRS letter difference from the subject's visual acuity in the first month of the three consecutive months. In some embodiments, the subject is administered according to the method of the present invention until the subject no longer experiences novel significant intraretinal or subretinal hemorrhage or an increase of ≥ 50 μm in the foveal intraretinal fluid. In some embodiments, the subject is administered according to the method of the present invention until the subject's visual acuity in each of the two most recent months of the three consecutive months is ≤ 5 ETDRS letter difference from the subject's visual acuity in the first month of the three consecutive months, and the subject no longer experiences novel significant intraretinal or subretinal hemorrhage or an increase of ≥ 50 μm in the foveal intraretinal fluid.

[0328] In some embodiments, the discontinuous treatment is administered after the continuous treatment, and the discontinuous treatment is administered at the physician's discretion, and the subject has stabilized vision determined by the difference of ≤5 ETDRS characters in the subject's visual acuity after the continuous and discontinuous treatments.

[0329] In some embodiments, subjects who have a visual acuity decrease of >5 ETDRS characters since the previous monthly assessment, a new significant intraretinal or subretinal hemorrhage, and / or an increase of ≥50 μm in foveal intraretinal fluid are retreated.

[0330] In some embodiments, a continuous method is used to treat or prevent wet AMD by using antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist. The method comprises administering an effective dose, which is given once every 1 month ± approximately 7 days for 12 consecutive months. In some embodiments, the method further comprises measuring the subject's visual acuity 1 month ± approximately 7 days immediately following the 12 consecutive months, wherein the subject's visual acuity measured in the 12th month of the 12 consecutive months and in the month immediately following the 12th month is ≤ 5 ETDRS character difference from the subject's visual acuity measured in the 11th month of the 12 consecutive months.

[0331] In some embodiments, the method further includes measuring the subject's visual acuity once every 1 month ± approximately 7 days for each additional 11 consecutive months. In some embodiments, the subject's visual acuity measured in any two consecutive months of the additional 11 consecutive months is ≤ 5 ETDRS character difference from the subject's visual acuity measured in the month immediately preceding those two consecutive months.

[0332] In some embodiments, if the visual acuity of a subject measured in the 12th month of a 12-month consecutive period and in the month immediately following the 12-month consecutive period is not ≤ 5 ETDRS character difference from the visual acuity of the subject measured in the 11th month of the 12-month consecutive period, the subject is retreated. In some embodiments, retreatment includes administering antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist to the patient in the month immediately following a 12-month consecutive period in an amount effective to treat or prevent wet AMD, until the visual acuity of the subject for any two subsequent consecutive months is ≤ 5 ETDRS character difference from the visual acuity of the subject measured in the month immediately following the first month of the two subsequent consecutive months; measuring the patient's visual acuity for one month, ± approximately 7 days, immediately following the month immediately following the 12-month consecutive period; and administering antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist to the subject in an amount effective to treat or prevent wet AMD in each subsequent month. In some embodiments, the total number of elapsed months does not exceed 24.

[0333] In some embodiments, the method includes administering antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist to the subject in the month immediately following a 12-month period in an amount effective to treat or prevent wet AMD, until the subject's visual acuity measured in the month immediately following a 12-month period is less than 5 ETDRS letter difference in the subject's visual acuity measured in the 12th month of the 12-month period, and not solely attributable to newly diagnosed foveal atrophy or worsened translucent opacity; and further administering (a) and (b) to the subject in the month immediately following each subsequent month in an amount effective to treat or prevent wet AMD. In some embodiments, the total number of elapsed months does not exceed 24.

[0334] In some embodiments, where a subject exhibits intraretinal or subretinal hemorrhage or an increase in foveal intraretinal fluid ≥ 50 μm within one month, ± approximately 7 days, immediately following 12 consecutive months, the method comprises administering antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist to the subject in an amount effective to treat or prevent wet AMD in the month immediately following 12 consecutive months until the subject's visual acuity for any two subsequent consecutive months differs by ≤ 5 ETDRS letters from the subject's visual acuity measured in the month immediately preceding the first month of the two subsequent consecutive months; and further comprising administering (a) and (b) to the subject in an amount effective to treat or prevent wet AMD in each subsequent month. In some embodiments, the total number of elapsed months does not exceed 24.

[0335] The present invention also provides a method comprising administering antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist intravitreously once every 1 month ± approximately 7 days for a first 12 consecutive months, and immediately thereafter, starting in the second month of a second 12 consecutive months, once every 2 months ± approximately 7 days for a second 12 consecutive months. In some embodiments, antagonist A or a pharmaceutically acceptable salt thereof is administered approximately 1 minute, 2 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, and 30 minutes after administration of the VEGF antagonist. The administration is performed within minutes, approximately 40 minutes, 50 minutes, 60 minutes, 90 minutes, approximately 2 hours, approximately 4 hours, approximately 6 hours, approximately 8 hours, and approximately 12 hours. In some embodiments, the VEGF antagonist is administered before the administration of antagonist A or a pharmaceutically acceptable salt thereof. In other embodiments, antagonist A or a pharmaceutically acceptable salt thereof is administered before the administration of the VEGF antagonist. In some embodiments, antagonist A or a pharmaceutically acceptable salt thereof and the VEGF antagonist are administered as a co-formulation. In some embodiments, the amount of antagonist A or a pharmaceutically acceptable salt thereof administered is about 1.5 mg / eye, and the amount of VEGF antagonist administered is about 0.5 mg / eye (e.g., ranibizumab), about 1.25 mg / eye (e.g., bevacizumab), about 1.65 mg / eye (e.g., pegaptanib sodium), or about 2.0 mg / eye (e.g., aflibercept).

[0336] In some embodiments, the method further includes measuring the subject's visual acuity once every 1 month ± approximately 7 days during the first 12 consecutive months and the second 12 consecutive months. In some embodiments, the subject's visual acuity measured in any one of the 1st, 3rd, 5th, 7th, 9th, and 11th months of the second consecutive 12 months was reduced by at least 5 ETDRS characters compared to the patient's visual acuity measured in the month immediately preceding the 1st, 3rd, 5th, 7th, 9th, and 11th months of the second consecutive 12 months.

[0337] In some embodiments, the method further comprises administering to a subject a certain amount of antagonist A or a pharmaceutically acceptable salt thereof and a VEGF antagonist effective to treat or prevent wet AMD in the month in which the subject's visual acuity measured in the patient's visual acuity in the preceding month was reduced by at least 5 ETDRS letters.

[0338] In some embodiments, the method further comprises administering antagonist A or a pharmaceutically acceptable salt thereof and a VEGF antagonist at any one of the 1st, 3rd, 5th, 7th, 9th, and 11th months of a second consecutive 12-month period.

[0339] In some embodiments, the reduction in visual acuity is simply due to newly diagnosed foveal atrophy or opaque transparent media.

[0340] In some embodiments, the subject represents an increase of ≥50 μm in intraretinal or subretinal hemorrhage or foveal intraretinal fluid at any one of months 1, 3, 5, 7, 9, and 11 of a second consecutive 12-month period.

[0341] In some embodiments, the method further comprises administering antagonist A or a pharmaceutically acceptable salt thereof and a VEGF antagonist in months in which the subject exhibits an increase of ≥50 μm in intraretinal or subretinal hemorrhage or foveal intraretinal fluid.

[0342] Methods are also provided herein that include administering antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist intravitreously once every 1 month ± approximately 7 days for 24 consecutive months. In other embodiments, antagonist A or another pharmaceutically acceptable salt thereof and a VEGF antagonist are administered intravitreously once a month for 3 months, and then every month for 21 months. In some embodiments, antagonist A or a pharmaceutically acceptable salt thereof is administered within approximately 1 minute, 2 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 90 minutes, 2 hours, 4 hours, 6 hours, 8 hours, and 12 hours of administration of the VEGF antagonist. In some embodiments, the VEGF antagonist is administered prior to the administration of antagonist A or a pharmaceutically acceptable salt thereof. In other embodiments, antagonist A or a pharmaceutically acceptable salt thereof is administered before administration of the VEGF antagonist. In some embodiments, antagonist A or a pharmaceutically acceptable salt thereof and VEGF A The antagonist is administered as a co-formulation. In some embodiments, the amount of antagonist A or a pharmaceutically acceptable salt thereof administered is about 1.5 mg / eye, and the amount of VEGF antagonist administered is about 0.5 mg / eye (e.g., ranibizumab), about 1.25 mg / eye (e.g., bevacizumab), about 1.65 mg / eye (e.g., pegaptanib sodium), or about 2.0 mg / eye (e.g., aflibercept).

[0343] In some embodiments, the method comprises administering to a subject in need (a) an antagonist A or another pharmaceutically acceptable salt thereof, and (b) a VEGF antagonist, wherein (a) and (b) are administered in amounts effective to treat or prevent an ophthalmic disease or disorder (e.g., wet AMD), the administration occurring once every 1 month ± approximately 7 days over a first administration period of at least 3 consecutive months, thereafter administering (a) and (b) at a frequency of at least 1 month ± approximately 7 days over a second administration period, starting 2 months ± approximately 7 days after the last month of the first administration period in which (a) and (b) were administered. In some embodiments, the first administration period extends for at least 6 consecutive months. In some embodiments, the VEGF antagonist is ranibizumab or bevacizumab, and (a) and (b) are administered once every 1 month ± approximately 7 days during the second administration period, which is at least 9 months.

[0344] In some embodiments, the method further includes measuring the subject's visual acuity on a day prior to and within about one month of administration of (a) and (b). In some embodiments, the method further includes administering (a) and (b) to the subject in amounts effective to treat or prevent an ophthalmic disease or disorder (e.g., wet AMD) until the subject's visual acuity for any two consecutive months is less than 5 ETDRS letter difference from the subject's visual acuity measured in the month immediately preceding the first month of the two consecutive months.

[0345] In some embodiments, the method further comprises administering (a) and (b) to a subject every month in amounts effective for treating or preventing an ophthalmic disease or disorder (e.g., wet AMD) until the visual acuity of the subject in any two consecutive visual acuity assessments is no longer ≤ 5 ETDRS character difference from the visual acuity of the subject measured in the visual acuity assessment immediately preceding the first assessment in the two consecutive visual acuity assessments.

[0346] In other embodiments, the method further comprises administering (a) and (b) to a subject monthly in amounts effective to treat or prevent an ophthalmic disease or disorder (e.g., wet AMD) until the subject's visual acuity for any two consecutive months is less than 5 ETDRS letter difference in the subject's visual acuity measured in the month immediately preceding the first month of the two consecutive months.

[0347] In some embodiments, the method comprises administering to a subject in need (a) an antagonist A or another pharmaceutically acceptable salt thereof and (b) aflibercept, wherein (a) and (b) are administered in amounts effective for treating or preventing an ophthalmic disease or disorder (e.g., wet AMD), the administration occurring once every 1 month ± approximately 7 days over a first administration period of at least 3 consecutive months, thereafter administering (a) and (b) at a frequency of at least every 1 month ± approximately 7 days over a second administration period, starting 2 months ± approximately 7 days after the last month of the first administration period in which (a) and (b) were administered.

[0348] In some embodiments, the subject has an increase of ≥50 μm in intraretinal or subretinal hemorrhage or foveal intraretinal fluid immediately following the second administration period, within one month ± approximately 7 days. In some embodiments, the method involves administering (a) and (b) to the subject at doses effective to treat or prevent wet AMD, starting in the month immediately following the second administration period, within approximately 7 days each month, until the subject's visual acuity measured in any two consecutive months following 12 consecutive months is ≤5 ETDRS letter difference from the subject's visual acuity measured in the month immediately preceding the first month of those two consecutive months. It also includes.

[0349] In some embodiments, the total number of months elapsed during the treatment does not exceed 24.

[0350] The pharmaceutical compositions according to the present invention can be formulated using controlled-release formulations to release antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist, or an anti-C5 agent substantially immediately upon administration or at any predetermined time after administration. For example, the pharmaceutical compositions can be provided in a sustained-release form. The use of immediate or sustained-release compositions depends on the nature of the symptoms being treated. If the symptoms consist of acute disorders, treatment using immediate-release forms may be used in conjunction with long-release compositions. For certain prophylactic or long-term treatments, sustained-release compositions may also be suitable.

[0351] In controlled-release formulations, administration of one or both antagonists or anti-C5 agents means that the antagonist, alone or in combination, (i) has a narrow therapeutic coefficient (e.g., a small difference between the plasma concentration leading to adverse side effects or toxic reactions and the plasma concentration leading to therapeutic effects; typically, the therapeutic coefficient, TI, is the median lethal dose (LD). 50 ) vs. half effective dose (ED 50 (ii) defined as the ratio of; (ii) a narrow absorption window in the gastrointestinal tract; (iii) having a short biological half-life and requiring frequent dosing during the day to maintain plasma levels at therapeutic levels, it can be useful.

[0352] Many strategies can be explored to obtain controlled release, where the rate of release exceeds the rate of degradation or metabolism of the therapeutic antagonist. For example, controlled release can be achieved by the appropriate selection of formulation parameters and components, including, for example, suitable controlled-release compositions and coatings. Examples include single-unit or multiple-unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes. Methods for preparing such sustained-release or controlled-release formulations are well known in the art.

[0353] Antagonist A or another pharmaceutically acceptable salt thereof, VEGF antagonist, or anti-C5 agent may also be delivered using a drug delivery device such as an implant. Such implants may be biodegradable and / or biocompatible, or non-biodegradable. The implant may be permeable to antagonist A or another pharmaceutically acceptable salt thereof, VEGF antagonist, or anti-C5 agent. The ophthalmic drug delivery device may be inserted into an ocular chamber, such as the anterior or posterior chamber, or implanted in or on an avascular region outside the sclera, suprachoroidal space, or vitreous humor. In one embodiment, the implant may be positioned on an avascular region, such as on the sclera, to allow transcleral diffusion of antagonist A or another pharmaceutically acceptable salt thereof, VEGF antagonist, or anti-C5 agent to the desired site of treatment, e.g., the intraocular lumen and macula of the eye. Furthermore, the site of transscleral diffusion can be proximal to the site of neovascularization, for example, proximal to the macula. Preferred drug delivery devices are described, for example, in U.S. Publications 2008 / 0286334;2008 / 0145406;2007 / 0184089;2006 / 0233860;2005 / 0244500;2005 / 0244471; and 2005 / 0244462, and U.S. Patents 6,808,719 and 5,322,691, the contents of which are incorporated herein by reference in whole.

[0354] In one embodiment, the implant comprises antagonist A or another pharmaceutically acceptable salt thereof and / or VEGF antagonist dispersed within a biodegradable polymer matrix. The matrix is ​​PLGA (polylactic acid-polyglycolic acid copolymer), polymers with ester-terminated capped polymers, polymers with acid-terminated capped polymers, or mixtures thereof. Compounds may be included. In another embodiment, the implant comprises antagonist A or another pharmaceutically acceptable salt thereof and / or a VEGF antagonist, a surfactant, and a lipophilic compound. The lipophilic compound may be present in an amount of about 80–99% by weight of the implant. Suitable lipophilic compounds include, but are not limited to, glyceryl palmitostearate, diethylene glycol monostearate, propylene glycol monostearate, glyceryl monostearate, glyceryl monolinoleate, glyceryl monooleate, glyceryl monopalmitate, glyceryl monolaurate, glyceryl dilaurate, glyceryl monomyristate, glyceryl dimyristate, glyceryl monopalmitate, glyceryl dipalmitate, glyceryl monostearate, glyceryl distearate, glyceryl monooleate, glyceryl dioleate, glyceryl monolinoleate, glyceryl dilinoleate, glyceryl monoarachidate, glyceryl diarachidate, glyceryl monobehenate, glyceryl dibehenate, and mixtures thereof. In another embodiment, the implant comprises antagonist A or another pharmaceutically acceptable salt thereof and / or VEGF antagonist housed in a hollow sleeve. PDGF antagonists or VEGF antagonists, or both, are delivered to the eye by inserting a sleeve into the eye, releasing the implant from the sleeve into the eye, and then removing the sleeve from the eye. An example of such a delivery device is described in U.S. Publication 2005 / 0244462, which is incorporated herein by reference in its entirety.

[0355] In one embodiment, the implant is a flexible ocular implantable device suitable for controlled, sustained intraocular release of antagonist A or another pharmaceutically acceptable salt thereof and / or a VEGF antagonist. In one embodiment, the device comprises an elongated body of a polymer material in the form of a rod or tube containing antagonist A or another pharmaceutically acceptable salt thereof, a VEGF antagonist, or both, accompanied by at least two anchoring projections extending radially outward from the body. The device may have a length of at least 8 mm, and the diameter of its body portion including the projections does not exceed 1.9 mm. The mechanism of sustained release can be, for example, by diffusion, infiltration, or bioerosion. The implantable device can be inserted into the superior or inferior conjunctival sac (formix) of the eye independently of eye movement, thanks to the anatomical structure of the conjunctival sac. The projections can be of various shapes, such as ribs, screws, depressions or ridges, truncated conical segments, or braided segments. In a further embodiment, the polymer material for the body is selected to expand in a liquid environment. Therefore, smaller initial-size devices may be employed. The implantable device may be sized or constructed such that, upon insertion into the superior or inferior conjunctival sac, it remains outside the field of view so as to remain well-retained in the correct location over a long period of use and not be perceived by the recipient. The device may be retained in the superior or inferior conjunctival sac for 7 to 14 days or longer. An example of such a device is described in U.S. Patent No. 5,322,691, which is incorporated herein by reference in its entirety.

[0356] kit

[0357] The present invention relates to a kit comprising one or more pharmaceutical compositions and instructions for use thereof. At least two antagonists can be formulated together or in separate compositions in individual doses. Antagonists are also useful when formulated as pharmaceutically acceptable salts. In one embodiment, the kit comprises a composition comprising antagonist A or another pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, and another composition comprising a VEGF antagonist and a pharmaceutically acceptable carrier or vehicle. In another embodiment, the kit comprises a composition comprising a VEGF antagonist, antagonist A or another pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle. Each kit composition can be contained in a container. In some embodiments, the kit comprises an anti-C5 agent.

[0358] The kit may include (1) a certain amount of antagonist A or another pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, vehicle, or diluent in a first unit dosage form; (2) a certain amount of VEGF antagonist and a pharmaceutically acceptable carrier, vehicle, or diluent in a second unit dosage form; and (3) a container. The container may be used to separate the components and may include, for example, a divided bottle or a divided foil box. The separated antagonist compositions may, if necessary, be contained in a single, undivided container. In some embodiments, the kit includes an anti-C5 agent.

[0359] The kit also includes instructions for administering the antagonist. The kit is particularly advantageous when the separated components are administered in different dosage forms, at different dose levels, or when individual antagonist dose settings are desired. Examples Example 1: Combination therapy of antagonist A and ranibizumab to treat subfoveal neovascular lesions secondary to neovascular age-related macular degeneration (NVAMD).

[0360] In this study, 449 subjects with subfoveal neovascular lesions secondary to NVAMD were treated with ranibizumab (Lucentis (登録商標) Participants received intravitreal injections of antagonist A (marketed by Genentech, South San Francisco, California) in combination with the drug administered as [product name]. Antagonist A was injected as the formulation shown in Table 12. The primary efficacy endpoint in this study was the mean change from baseline in visual acuity at the 24-week visit. As specified in the analysis plan, the Hochberg procedure (Hochberg, Y. (1988). A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 75, 800-802) was used to explain the comparison of multiple doses.

[0361] The subjects were randomized in a 1:1:1 ratio to the groups shown in Table 13.

[0362] [Table 11]

[0363] [Table 12]

[0364] Combination therapy demonstrated superior average visual acuity improvement compared to eyes treated with anti-VEGF monotherapy. Subjects treated with Lucentis® and either 1.5 mg / eye or 0.3 mg / eye of antagonist A were compared with Lucentis®. Compared to treatment with ntis® alone, it showed an increase in visual acuity (Figure 2). Treatment with 1.5 mg / eye of antagonist A and 0.5 mg of Lucentis showed an increase in visual acuity. (登録商標)The combination therapy met the pre-specified alpha-protective primary endpoint of superiority in mean change in visual acuity compared to ranibizumab monotherapy from baseline to week 24 (10.6 ETDRS letters compared to 6.5 letters at week 24, p=0.019, representing a 62% additional benefit). (Figure 3) Subjects treated with Lucentis® and either 1.5 mg or 0.3 mg of antagonist A showed a comparative benefit of 62% from baseline compared to treatment with Lucentis® monotherapy.

[0365] In addition, the mean changes in vision over time demonstrated the benefit of the combination therapy at each measurement point over 24 weeks (Figure 4). This benefit persisted throughout the study, demonstrating increased differentiation of the curves at the end of the study.

[0366] Treatment with 0.5 mg of Lucentis® and either 1.5 mg or 0.3 mg of antagonist A in patients with wet AMD also showed increased efficacy compared to patients treated with Lucentis® alone, independently of baseline lesion size or visual appearance (Figures 5A and 5B).

[0367] As shown in Figure 6A and Table 14, for multiple treatment endpoints at week 24, a higher percentage (%) of subjects in the combination therapy (1.5 mg) group achieved improved visual outcomes compared to subjects in the ranibizumab monotherapy group.

[0368] [Table 13]

[0369] Furthermore, as shown in Figure 6B and Table 15, at week 24, fewer subjects in the combination therapy (1.5 mg) group demonstrated a decline in visual acuity compared to the number of subjects in the ranibizumab monotherapy group.

[0370] [Table 14]

[0371] Subjects treated with Lucentis® and 1.5 mg of antagonist A showed improved final visual acuity compared to subjects treated with Lucentis® monotherapy (Figure 7). Subjects in the combination therapy (1.5 mg) group also showed increased reductions in CNV size in both small and large baseline CNVs compared to subjects in the ranibizumab monotherapy group (Figures 8A and 8B).

[0372] The combination therapy was well tolerated. A total of 4431 intravitreal injections were administered (1776 doses of antagonist A and Lucentis). (登録商標) Following 2655 doses, there were no events of endophthalmitis, retinal detachment, retinal tear, or iatrogenic traumatic cataract. As predicted, the increase in mean intraocular pressure (IOP) after each intravitreal injection was consistent with the volume effect. However, mean IOP in all groups returned to pre-injection levels by the next visit, including at the end of the study. The systemic safety profile of the combination therapy was similar to that of ranibizumab monotherapy.

[0373] The results of this clinical trial demonstrate that combination therapy with antagonist A and ranibizumab is statistically significantly more effective than Lucentis® (ranibizumab) monotherapy for treating wet AMD. Example 2: ARC1905 for the treatment of wet AMD

[0374] Forty-three patients with subfoveal neovascular AMD received ARC1905 (0.3 mg / eye, 1 mg / eye, or 2 mg / eye) once monthly for six months in combination with Lucentis. The mean change in visual acuity at week 24 was an increase of +13.6, +11.7, and +15.3 letters for the 0.3 mg, 1 mg, and 2 mg doses, respectively. Furthermore, 46%, 47%, and 60% of patients improved their visual acuity on three or more lines with the 0.3 mg, 1 mg, and 2 mg doses, respectively. Example 3: ARC1905 for the treatment and prevention of dry AMD

[0375] Forty-seven patients with dry AMD participated in a 36-week treatment period, receiving five intravitreal injections of either 0.3 mg / eye or 1.0 mg / eye of ARC1905. Figure 9 shows the mean change in geographic atrophy (GA) lesion area measured at week 24 in patients with dry AMD treated with either 0.3 mg or 1.0 mg of ARC1905 at weeks 0, 4, and 8. Figure 10 shows the results for two patients treated with either 0.3 mg or 1.0 mg of ARC1905 at weeks 0, 4, 8, 24, and 36. The mean change in GA lesions in patients with dry AMD, measured at weeks 4 and 48, is shown. The results demonstrate a dose-dependent reduction in GA lesion growth, indicating that ARC1905 can slow the progression of GA in patients with non-exudative AMD. Example 4: Visual acuity test using ETDRS chart

[0376] Best corrected visual acuity was measured using standard charts, lighting, and procedures. Best correction is determined by careful refraction at the time of the visit.

[0377] Chart 1 (Figure 11) is used to test the visual acuity of the right eye. Chart 2 (Figure 12) is used to test the left eye. Chart R (Figure 13) is used to test refraction. The subject does not look at any of the charts before the test.

[0378] A distance of 4 meters is maintained between the subject's eye and the visual acuity chart. With the box light off, a light of 15-foot candle (161.4 lux) or less is cast onto the center of the chart. The room is set up for visual acuity testing to measure the amount of light, but the box light remains off. The light meter is placed on the fourth line from the top of the chart, with its back facing the chart, and the reading is taken. If multiple lanes are available for visual acuity testing, the visual acuity of each individual subject should be measured in the same lane at each visit. If different lanes are used for visual acuity testing, they should each meet the same criteria.

[0379] Use a retroilluminated ETDRS chart. The lightbox is either wall-mounted or stand-mounted (available from Lighthouse Low Vision Services). The lightbox is mounted at a height of 49 ± 2 inches from the floor, with the top of the third line of text above the floor.

[0380] The vision lightbox is equipped with two 20-watt fluorescent tubes (available from General Electric Cool Daylight) and a ballast that partially covers the tubes. Since the illumination of the fluorescent tubes typically decreases by 5% during the first 100 hours and another 5% during the next 2000 hours, keep new tubes for 4 consecutive days (96 hours) and replace them once a year.

[0381] Attach a sticker to the back of the lightbox to indicate the date the current tube was installed. A spare set of burned-in bulbs is available.

[0382] Each tube is partially covered by a 14-inch windowed sleeve that opens at the rear. This acts as a baffle to reduce illumination. Each sleeve is positioned centered on the tube with the opening facing the rear.

[0383] Even if refraction is performed at 1 meter, all eyes are first examined at 4 meters. The subject sits comfortably directly in front of the chart so that the eyes remain at a distance of 4 meters. The examination begins with the right eye. The subject's left eye is occluded. A folded tissue or eye pad, lightly taped over the eye behind the eyepiece frame, serves as an effective occluder, allowing for out-of-center fixation without inadvertent use of the covered eye. After the right eye is examined, the right eye is occluded before Chart 2 is presented for the examination of the left eye.

[0384] The lens correction from the subjective refraction test is within the scope of the eye examination frame worn by the subject.

[0385] Participants are asked to read the letters slowly, at approximately one letter per second. They are told they only have one chance to read each letter on the chart. If you are unsure, encourage them to try to guess the subject.

[0386] The subject begins by reading the top line of the chart and continues reading all the letters on each smaller line from left to right along each line. The examiner circles all correctly read letters and totals each line and column on the data collection form (0 if no letters are correct). An X is placed next to any letters that were misread. Letters that were not attempted to be guessed are not circled. When the subject reaches a level where they cannot guess, the examiner may end the test under the condition that the subject made an error in their previous guess, which clearly indicates that the best visual acuity has been achieved.

[0387] If the subject is unable to read at least 20 characters on the chart at 4.0 meters, the subject is tested at 1.0 meter. The distance from the subject to the chart should be measured again using a rigid 1-meter rod. The distance is measured from the outer corner of the eye to the center of the fourth character (right eye) or second character (left eye) on the third line of the chart. The spherical correction in the optometry frame should be adjusted by adding +0.75 to compensate for the closer testing distance. The subject may fix, turn, or shake their head eccentrically to improve their visual acuity. If this is done, the examiner ensures that one eye remains occluded both centrally and peripherally, and that the subject does not move forward in the chair. When testing at 1 meter, particular care must be taken to ensure that the subject does not move forward. The subject is asked to blink.

[0388] The inspector does not tell the subject whether the letters were correctly identified. They may encourage the subject with neutral comments such as "Good," "Next," or "OK."

[0389] The inspector should not stand near the chart during the inspection. The inspector should focus their attention on the subject and the data collection form. If the subject is having difficulty identifying the next line to read, the inspector may go to the chart, point out the next line to read, and then move away from the chart.

[0390] When visual acuity can be measured at 4.0 meters (i.e., 20 or more letters are read at 4 meters), the visual acuity score for that eye is recorded as the number of correctly read letters + 30. The subject gains confidence in 30 letters at 1 meter, even if they do not need to read them. Alternatively, the visual acuity score is the number of letters correctly read at 1.0 meter + the number of letters read at 4 meters, if any. If no letters are correctly read at either 4.0 meters or 1 meter, the visual acuity score is recorded as 0. Built-in by reference

[0391] All publications and patent applications disclosed herein are incorporated by reference to the same extent as when each individual publication or patent application is specifically and individually incorporated by reference herein.

Claims

1. A method for treating or preventing wet age-related macular degeneration (wet AMD), comprising administering to a subject in need (a) an antagonist A or another pharmaceutically acceptable salt thereof and (b) a VEGF antagonist, wherein (a) and (b) are administered in amounts effective for treating or preventing wet AMD, the administration occurring once every 1 month ± approximately 7 days over a first administration period of at least 3 consecutive months, and thereafter administering (a) and (b) at a frequency of at least every 1 month ± approximately 7 days over a second administration period, starting 2 months ± approximately 7 days after the last month of the first administration period in which (a) and (b) were administered.

2. The method according to claim 1, wherein (a) and (b) are administered within approximately 60 minutes of each other.

3. The method according to claim 1, wherein the VEGF antagonist is ranibizumab, bevacizumab, pegaptanib sodium, ESBA1008, or aflibercept.

4. The method according to claim 1, wherein the VEGF antagonist is ranibizumab or bevacizumab, and (a) and (b) are administered once every 1 month ± approximately 7 days during the second administration period, and the second administration period is at least approximately 9 months.

5. The method according to claim 4, further comprising measuring the visual acuity of the subject.

6. The method of claim 5, further comprising administering (a) and (b) to the subject in amounts effective for treating or preventing wet AMD until the visual acuity of the subject for the two most recent months of any three consecutive months is less than 5 ETDRS letter differences from the visual acuity of the subject in the first month of the three consecutive months.

7. The method according to claim 5, further comprising administering (a) and (b) to the subject every month in an amount effective to treat or prevent wet AMD, wherein the visual acuity of the subject in the two most recent months of any three consecutive months is less than 5 ETDRS letter differences from the visual acuity of the subject in the first month of the three consecutive months.

8. The method according to claim 7, further comprising administering (a) and (b) to the subject monthly in amounts effective for treating or preventing wet AMD, until the subject's visual acuity for the two most recent months of any three consecutive months is less than 5 ETDRS letter differences from the subject's visual acuity for the first month of the three consecutive months.

9. The method according to claim 1, wherein the VEGF antagonist is aflibercept.

10. The method according to claim 1, wherein the total number of months does not exceed 24.

11. The method according to claim 4, wherein the subject has an increase of ≥50 μm in intraretinal or subretinal hemorrhage or foveal intraretinal fluid for approximately 7 days, ± 1 month immediately following the second administration period.

12. The method according to claim 11, further comprising administering (a) and (b) to the subject in amounts effective for treating or preventing wet AMD, starting in the month immediately following the second administration period, for approximately 7 days ± each month, until the subject's visual acuity for the two most recent months of any three consecutive months following the 12 consecutive months is less than 5 ETDRS letter differences from the subject's visual acuity in the first month of the three consecutive months.

13. The method according to claim 12, wherein the total number of months does not exceed 24.

14. The method according to claim 1, wherein antagonist A or another pharmaceutically acceptable salt thereof is administered intravitreously at a dose of about 1.5 mg / eye.

15. The method according to claim 4, wherein the VEGF antagonist is bevacizumab, and is administered intravitreously at a dose of approximately 1.25 mg / eye.

16. The method according to claim 9, wherein the VEGF antagonist is administered intravitreously at a dose of approximately 2 mg / eye.

17. The method according to claim 4, wherein the VEGF antagonist is ranibizumab, and is administered intravitreously at a dose of approximately 0.5 mg / eye.

18. The method according to claim 1, further comprising administering an anti-C5 agent.

19. The method according to claim 1, further comprising administering (a) and (b) in months in which the subject has an increase of ≥ 50 μm in intraretinal or subretinal hemorrhage or foveal intraretinal fluid.

20. A method for treating or preventing subretinal fibrosis, comprising (a) administering to a subject in need thereof an amount effective for treating or preventing subretinal fibrosis:

21. The method according to claim 20, further comprising administering (b) a VEGF antagonist to the subject, wherein (a) and (b) are administered in amounts effective for treating or preventing subretinal fibrosis.

22. The method according to claim 20, wherein the subject has wet age-related macular degeneration (wet AMD).

23. The method according to claim 22, wherein the subretinal fibrosis is associated with the wet type AMD.

24. The method according to claim 20, wherein administration of antagonist A or another pharmaceutically acceptable salt thereof results in a reduction in the size of subretinal hyperintensity images (SHRMs) as demonstrated by spectral domain optical coherence tomography (SD-OCT), or results in stabilization of the vision of the subject.

25. The method according to claim 20, wherein antagonist A or another pharmaceutically acceptable salt thereof is administered intravitreously at a dose of about 1.5 mg / eye.

26. The method according to claim 21, wherein the VEGF antagonist is bevacizumab, ranibizumab, aflibercept, pegaptanib sodium, or ESBA1008.

27. The method according to claim 26, wherein the VEGF antagonist is bevacizumab, and is administered intravitreously at a dose of approximately 1.25 mg / eye.

28. The method according to claim 26, wherein the VEGF antagonist is aflibercept and is administered intravitreously at a dose of approximately 2 mg / eye.

29. The aforementioned VEGF antagonist is ranibizumab, administered intravitreously at a dose of approximately 0.5 mg / eye. The method according to claim 26, which is administered.

30. The method according to claim 21, further comprising administering an anti-C5 agent.

31. A method for treating or preventing von Hippel-Lindau (VHL) disease, comprising administering to a subject in need thereof an antagonist A or another pharmaceutically acceptable salt thereof in an amount effective for treating or preventing VHL disease.

32. The method according to claim 31, further comprising administering a VEGF antagonist.

33. The method according to claim 31, wherein antagonist A or another pharmaceutically acceptable salt thereof is administered intravitreously at a dose of about 1.5 mg / eye.

34. The method according to claim 32, wherein the VEGF antagonist is bevacizumab and is administered intravitreously at a dose of approximately 1.25 mg / eye.

35. The method according to claim 32, wherein the VEGF antagonist is aflibercept and is administered intravitreously at a dose of approximately 2 mg / eye.

36. The method according to claim 32, wherein the VEGF antagonist is ranibizumab, and is administered intravitreously at a dose of approximately 0.5 mg / eye.

37. The method according to claim 32, further comprising administering an anti-C5 agent.

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