Methods and compositions for treating diabetic retinopathy and related conditions - Patents.com

Abstract

The present invention provides methods, compositions, and kits comprising a first therapeutic agent that is a substituted 2,3-dimethoxyquinone of formula I or a pharma- ceutically acceptable salt thereof for treating a patient suffering from diabetic retinopathy, diabetic macular edema, and / or other diabetic retinopathy and / or other disorders.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 182,037, filed April 30, 2021, the contents of which are incorporated herein by reference in their entirety.

[0002] The present invention provides methods, compositions, and kits comprising a first therapeutic agent that is a substituted 2,3-dimethoxyquinone of formula I or a pharma- ceutically acceptable salt thereof for treating a patient suffering from diabetic retinopathy, diabetic macular edema, and / or other diabetic retinopathy and / or other disorders. [Background technology]

[0003] Diabetic retinopathy is an eye disease that can lead to blindness if left untreated. A significant percentage of people with diabetes experience some degree of associated retinal damage. Existing treatments for diabetic retinopathy are not effective for all patients and / or have undesirable side effects. For example, laser photocoagulation works by producing burns in the eye tissue, which can be painful and / or cause some visual problems (e.g., reduced peripheral vision, color vision, and / or night vision). Vitrectomy is generally performed by making an incision on the surface of the eye (creating the possibility of intraocular infection) and often requires a recovery period of several weeks during which the eye must be covered and cannot be used. Intravitreal injections of triamcinolone or anti-VEGF drugs also carry the risk of intraocular infection, especially if additional injections are required over time.

[0004] The chemical formula: [ka] The compound (E)-2-((4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dien-1-yl)methylene)undecanoic acid having the formula: is described in WO2009 / 042542. Improved administration procedures for treating diabetic retinopathy, diabetic macular edema and / or other diabetic retinopathy and / or other disorders using the aforementioned compounds would benefit patients.

[0005] The present invention addresses this need and provides other related advantages. Summary of the Invention

[0006] The present invention provides methods, compositions, and kits for treating patients suffering from diabetic retinopathy, diabetic macular edema, and / or other diabetic retinopathy and / or other disorders, comprising a first therapeutic agent that is a substituted 2,3-dimethoxyquinone of formula I, or a pharma- ceutical acceptable salt thereof. The methods generally involve administering a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof to a human patient in need thereof. An exemplary more preferred embodiment includes orally administering to a human patient in need thereof an amount of about 480 mg to about 600 mg per day of a compound of formula I or a pharmaceutically acceptable salt thereof. Improvement in the patient's diabetic retinopathy can be assessed by improvement in the patient's Diabetic Retinopathy Severity Score (DRSS), improvement in the patient's visual acuity, and according to other procedures described in the literature. Additional exemplary aspects and embodiments of the present invention are described below.

[0007] One aspect of the invention provides a method of treating diabetic retinal disease in a human patient. The method includes orally administering to a human patient in need thereof a first therapeutic agent in an amount of about 480 mg to about 600 mg per day, thereby treating diabetic retinal disease, the first therapeutic agent being represented by Formula I: [ka] or a pharma- ceutically acceptable salt thereof. In certain embodiments, the first dose of the first therapeutic agent and the second dose of the first therapeutic agent are orally administered to the patient on the same day. In certain embodiments, the method further comprises administering to the patient a second therapeutic agent that is a vascular endothelial growth factor inhibitor. In certain embodiments, the diabetic retinal disease is diabetic retinopathy. In certain embodiments, the diabetic retinal disease is diabetic macular edema. Additional features of the method are described in the detailed description.

[0008] Another aspect of the invention provides a method of treating diabetic retinal disease in a human patient, the method comprising orally administering to a human patient in need thereof a first therapeutic agent in an amount of about 120 mg to about 600 mg per day, thereby treating diabetic retinal disease, the first therapeutic agent being represented by Formula I: [ka] or a pharma- ceutically acceptable salt thereof. In certain embodiments, the first dose of the first therapeutic agent and the second dose of the first therapeutic agent are orally administered to the patient on the same day. In certain embodiments, the method further comprises administering to the patient a second therapeutic agent that is a vascular endothelial growth factor inhibitor. In certain embodiments, the diabetic retinal disease is diabetic retinopathy. In certain embodiments, the diabetic retinal disease is diabetic macular edema. Additional features of the method are described in the detailed description.

[0009] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of Formula I, or a pharma- ceutical acceptable salt thereof, for use in treating diabetic retinal disease in a human patient according to the methods described herein. Preferably, the pharmaceutical composition is formulated for oral administration.

[0010] Another aspect of the invention provides a method of treating a disease or condition selected from wet age-related macular degeneration, dry age-related macular degeneration, retinal vein occlusion, geographic atrophy, retinal neovascularization, choroidal neovascularization, or corneal graft rejection. The method comprises orally administering to a human patient in need thereof a first therapeutic agent in an amount of about 120 mg to about 600 mg per day, thereby treating the disease or condition, the first therapeutic agent being represented by Formula I: [ka] or a pharma- ceutically acceptable salt thereof. [Brief description of the drawings]

[0011] [Figure 1] 1 shows an exemplary Diabetic Retinopathy Severity Score (DRSS) with corresponding descriptions and retinal images. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The present invention provides methods, compositions, and kits for treating patients suffering from diabetic retinopathy, diabetic macular edema, and / or other diabetic retinopathy and / or other disorders, comprising a first therapeutic agent that is a substituted 2,3-dimethoxyquinone of formula I, or a pharma- ceutical acceptable salt thereof. The methods generally involve administering a compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof to a human patient in need thereof.

[0013] An exemplary more preferred embodiment includes orally administering to a human patient in need thereof a compound of formula I or a pharma- ceutically acceptable salt thereof in an amount of about 480 mg to about 600 mg per day. Improvement in the patient's diabetic retinopathy can be assessed by improvement in the patient's Diabetic Retinopathy Severity Score (DRSS), improvement in the patient's visual acuity, and according to other procedures described in the literature. Various aspects of the invention are described in the following sections, although aspects of the invention described in one particular section should not be limited to any particular section.

[0014] definition To facilitate the understanding of this invention, several terms and phrases are defined below.

[0015] As used herein, the terms "a," "an," and "the" mean "one or more" and include the plural forms unless the context is inappropriate.

[0016] The term "about" means within 10% of a stated value. In certain embodiments, the value may be within 8%, 6%, 5%, 4%, 2%, or 1% of a stated value.

[0017] As used herein, the term "patient" refers to an organism treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murine, simian, equine, bovine, porcine, canine, feline, etc.), and most preferably, humans.

[0018] As used herein, the term "effective amount" refers to an amount of a compound sufficient to produce a beneficial or desired result. Unless otherwise specified, an effective amount can be administered in one or more administrations, applications, or dosages, and is not intended to be limited to a specific formulation or route of administration. As used herein, the term "treating" includes any effect, such as alleviating, reducing, modulating, alleviating, or eliminating, that results in the improvement of a condition, disease, disorder, or the like, or the alleviation of symptoms thereof.

[0019] As used herein, the term "pharmaceutical composition" refers to a combination of an active agent with an inert or active carrier that makes the composition particularly suitable for in vivo or ex vivo therapeutic use.

[0020] As used herein, the term "pharmaceutical acceptable carrier" refers to any of the standard pharmaceutical carriers, such as phosphate buffered saline solution, water, emulsions (such as oil / water or water / oil emulsions), and various types of wetting agents. The composition may also contain stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see Martin in Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] .

[0021] As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention that can provide a compound of the present invention when administered to a subject. As known to those skilled in the art, the "salt" of a compound of the present invention can be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, may be used in the preparation of salts useful as intermediates in obtaining the compounds of the present invention and their pharmaceutically acceptable acid addition salts.

[0022] Examples of bases include, but are not limited to, alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and compounds of the formula NW3, where W is C 1-4 (alkyl) and the like.

[0023] Exemplary salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate (mesylate), 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts are e.g. Na + , NH4 + , and NW4 + (Wherein, W is C 1-4 The anion of a compound of the present invention may be combined with a suitable cation, such as an alkyl group.

[0024] For therapeutic use, the salts of the compounds of the invention are contemplated as pharma-ceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharma-ceutically acceptable compound.

[0025] The term "alkyl" is art-recognized and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In certain embodiments, a straight-chain or branched-chain alkyl group has about 30 or fewer carbon atoms in its backbone (e.g., C1-C5 for straight chain). 30 , C3-C for branched chain 30) or up to about 20. Likewise, cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6 or 7 carbons in the ring structure.

[0026] Throughout this specification, where compositions and kits are described as having, including, or comprising certain components, or processes and methods are described as having, including, or comprising certain steps, it is contemplated that there are additionally compositions and kits of the invention that consist essentially of or consist of the recited components, and processes and methods according to the invention that consist essentially of or consist of the recited process steps.

[0027] Generally, compositions in which percentages are specified are by weight unless otherwise specified. Further, if no definition is accompanied by a variable, the prior definition of that variable takes precedence.

[0028] I. Treatment method The present invention provides a method for treating a patient suffering from diabetic retinopathy, diabetic macular edema and / or other diabetic retinal disorders by orally administering to the human patient a substituted 2,3-dimethoxyquinone of formula I or a pharma- ceutically acceptable salt thereof. The present invention also provides a method for treating a patient suffering from other disorders by administering to the human patient a substituted 2,3-dimethoxyquinone of formula I or a pharma- ceutically acceptable salt thereof. Various aspects and embodiments of the method of treatment are described in the following sections. These sections are arranged for convenience, and the information in one section is not limited to that section and may be applicable to the methods in the other sections.

[0029] A. First Method One aspect of the invention is a method of treating diabetic retinal disease in a human patient comprising orally administering to a human patient in need thereof a first therapeutic agent in an amount of about 480 mg to about 600 mg per day, thereby treating diabetic retinal disease, wherein the first therapeutic agent is a compound represented by Formula I: [ka] or a pharma- ceutically acceptable salt thereof.

[0030] The method may be further characterized by additional features, such as the identity of the first therapeutic agent and the dosing regimen. The invention encompasses all permutations and combinations of these features.

[0031] Thus, the method can be further characterized according to the nature of the first therapeutic agent.For example, in certain embodiments, the first therapeutic agent is a compound of formula I.In certain embodiments, the first therapeutic agent is a pharma- ceutically acceptable salt of the compound of formula I.

[0032] The method can be further characterized according to the administration regimen.For example, in certain embodiments, the first dose of the first therapeutic agent and the second dose of the first therapeutic agent are orally administered to the patient on the same day.In certain embodiments, the first therapeutic agent is orally administered to the patient only once a day.

[0033] In certain embodiments, the first therapeutic agent is orally administered to the patient in an amount of about 600 mg per day.

[0034] In certain embodiments, about 360 mg of the first therapeutic agent is orally administered to the patient in the morning and about 240 mg of the first therapeutic agent is orally administered to the patient in the evening. In certain embodiments, about 360 mg of the first therapeutic agent is orally administered to the patient, followed by about 8 hours to about 16 hours later about 240 mg of the first therapeutic agent. In certain embodiments, about 360 mg of the first therapeutic agent is orally administered to the patient, followed by about 10 hours to about 14 hours later about 240 mg of the first therapeutic agent.

[0035] In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient in the morning and about 360 mg of the first therapeutic agent is orally administered to the patient in the evening. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient, followed by about 8 hours to about 16 hours later about 360 mg of the first therapeutic agent. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient, followed by about 10 hours to about 14 hours later about 360 mg of the first therapeutic agent.

[0036] In certain embodiments, about 300 mg of the first therapeutic agent is orally administered to the patient in the morning and about 300 mg of the first therapeutic agent is orally administered to the patient in the evening. In certain embodiments, about 300 mg of the first therapeutic agent is orally administered to the patient, followed by about 8 hours to about 16 hours later about 300 mg of the first therapeutic agent. In certain embodiments, about 300 mg of the first therapeutic agent is orally administered to the patient, followed by about 10 hours to about 14 hours later about 300 mg of the first therapeutic agent.

[0037] In certain embodiments, if the patient experiences an adverse event from the first therapeutic agent, the first therapeutic agent is orally administered to the patient at a reduced daily dose of about 480 mg per day for at least two days thereafter.

[0038] In certain embodiments, the first therapeutic agent is orally administered to the patient in an amount of about 480 mg per day.

[0039] In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient in the morning and about 240 mg of the first therapeutic agent is orally administered to the patient in the evening. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient, followed by about 8 hours to about 16 hours later about 240 mg of the first therapeutic agent. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient, followed by about 10 hours to about 14 hours later about 240 mg of the first therapeutic agent.

[0040] In certain embodiments, if the patient experiences an adverse event from the first therapeutic agent, the first therapeutic agent is orally administered to the patient at a reduced daily dose of about 300 mg per day for at least two days thereafter, hi certain embodiments, the first therapeutic agent is orally administered to the patient in the morning.

[0041] B. Second Method Another aspect of the invention is a method of treating diabetic retinal disease in a human patient comprising orally administering to a human patient in need thereof a first therapeutic agent in an amount of about 120 mg to about 600 mg per day, thereby treating diabetic retinal disease, wherein the first therapeutic agent is a compound represented by Formula I: [ka] or a pharma- ceutically acceptable salt thereof.

[0042] The method may be further characterized by additional features such as the identity of the first therapeutic agent, dosage, and administration regimen. The invention encompasses all permutations and combinations of these features.

[0043] Thus, the method can be further characterized according to the nature of the first therapeutic agent.For example, in certain embodiments, the first therapeutic agent is a compound of formula I.In certain embodiments, the first therapeutic agent is a pharma- ceutically acceptable salt of the compound of formula I.

[0044] The method can be further characterized according to dosage.For example, in certain embodiments, the first therapeutic agent is orally administered to the patient in an amount of about 300mg per day.In certain embodiments, the first therapeutic agent is orally administered to the patient in an amount of about 240mg per day.In certain embodiments, the first therapeutic agent is orally administered to the patient in an amount of about 120mg per day.

[0045] The method can be further characterized according to the administration regimen.For example, in certain embodiments, the first dose of the first therapeutic agent and the second dose of the first therapeutic agent are orally administered to the patient on the same day.In certain embodiments, the first therapeutic agent is orally administered to the patient only once a day.

[0046] In certain embodiments, the first therapeutic agent is orally administered to the patient in the morning. In certain embodiments, the first therapeutic agent is orally administered to the patient in the evening.

[0047] C. The third method One aspect of the invention is a method of reducing angiogenesis in retinal tissue in a human patient suffering from diabetic retinal disease, comprising orally administering to a human patient in need thereof a first therapeutic agent in an amount of about 480 mg to about 600 mg per day to reduce angiogenesis in retinal tissue, wherein the first therapeutic agent is a compound represented by Formula I: [ka] or a pharma- ceutically acceptable salt thereof.

[0048] The method may be further characterized by additional features, such as the identity of the first therapeutic agent and the dosing regimen. The invention encompasses all permutations and combinations of these features.

[0049] Thus, the method can be further characterized according to the nature of the first therapeutic agent.For example, in certain embodiments, the first therapeutic agent is a compound of formula I.In certain embodiments, the first therapeutic agent is a pharma- ceutically acceptable salt of the compound of formula I.

[0050] The method can be further characterized according to the administration regimen.For example, in certain embodiments, the first dose of the first therapeutic agent and the second dose of the first therapeutic agent are orally administered to the patient on the same day.In certain embodiments, the first therapeutic agent is orally administered to the patient only once a day.

[0051] In certain embodiments, the first therapeutic agent is orally administered to the patient in an amount of about 600 mg per day.

[0052] In certain embodiments, about 360 mg of the first therapeutic agent is orally administered to the patient in the morning and about 240 mg of the first therapeutic agent is orally administered to the patient in the evening. In certain embodiments, about 360 mg of the first therapeutic agent is orally administered to the patient, followed by about 8 hours to about 16 hours later about 240 mg of the first therapeutic agent. In certain embodiments, about 360 mg of the first therapeutic agent is orally administered to the patient, followed by about 10 hours to about 14 hours later about 240 mg of the first therapeutic agent.

[0053] In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient in the morning and about 360 mg of the first therapeutic agent is orally administered to the patient in the evening. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient, followed by about 8 hours to about 16 hours later about 360 mg of the first therapeutic agent. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient, followed by about 10 hours to about 14 hours later about 360 mg of the first therapeutic agent.

[0054] In certain embodiments, about 300 mg of the first therapeutic agent is orally administered to the patient in the morning and about 300 mg of the first therapeutic agent is orally administered to the patient in the evening. In certain embodiments, about 300 mg of the first therapeutic agent is orally administered to the patient, followed by about 8 hours to about 16 hours later about 300 mg of the first therapeutic agent. In certain embodiments, about 300 mg of the first therapeutic agent is orally administered to the patient, followed by about 10 hours to about 14 hours later about 300 mg of the first therapeutic agent.

[0055] In certain embodiments, if the patient experiences an adverse event from the first therapeutic agent, the first therapeutic agent is orally administered to the patient at a reduced daily dose of about 480 mg per day for at least two days thereafter.

[0056] In certain embodiments, the first therapeutic agent is orally administered to the patient in an amount of about 480 mg per day.

[0057] In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient in the morning and about 240 mg of the first therapeutic agent is orally administered to the patient in the evening. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient, followed by about 8 hours to about 16 hours later about 240 mg of the first therapeutic agent. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient, followed by about 10 hours to about 14 hours later about 240 mg of the first therapeutic agent.

[0058] In certain embodiments, if the patient experiences an adverse event from the first therapeutic agent, the first therapeutic agent is orally administered to the patient at a reduced daily dose of about 300 mg per day for at least two days thereafter, hi certain embodiments, the first therapeutic agent is orally administered to the patient in the morning.

[0059] D. The fourth method Another aspect of the invention is a method of reducing angiogenesis in retinal tissue in a human patient suffering from diabetic retinal disease, comprising orally administering to a human patient in need thereof a first therapeutic agent in an amount of about 120 mg to about 600 mg per day to reduce angiogenesis in retinal tissue, wherein the first therapeutic agent is a compound represented by Formula I: [ka] or a pharma- ceutically acceptable salt thereof.

[0060] The method may be further characterized by additional features such as the identity of the first therapeutic agent, dosage, and administration regimen. The invention encompasses all permutations and combinations of these features.

[0061] Thus, the method can be further characterized according to the nature of the first therapeutic agent.For example, in certain embodiments, the first therapeutic agent is a compound of formula I.In certain embodiments, the first therapeutic agent is a pharma- ceutically acceptable salt of the compound of formula I.

[0062] The method can be further characterized according to dosage.For example, in certain embodiments, the first therapeutic agent is orally administered to the patient in an amount of about 300mg per day.In certain embodiments, the first therapeutic agent is orally administered to the patient in an amount of about 240mg per day.In certain embodiments, the first therapeutic agent is orally administered to the patient in an amount of about 120mg per day.

[0063] The method can be further characterized according to the administration regimen.For example, in certain embodiments, the first dose of the first therapeutic agent and the second dose of the first therapeutic agent are orally administered to the patient on the same day.In certain embodiments, the first therapeutic agent is orally administered to the patient only once a day.

[0064] In certain embodiments, the first therapeutic agent is orally administered to the patient in the morning. In certain embodiments, the first therapeutic agent is orally administered to the patient in the evening.

[0065] E. The fifth method One aspect of the invention is a method of reducing HIF-1α and / or NF-κB activity in a human patient suffering from diabetic retinal disease, comprising orally administering to a human patient in need thereof a first therapeutic agent in an amount of about 480 mg to about 600 mg per day to reduce HIF-1α and / or NF-κB activity, wherein the first therapeutic agent is an amino acid sequence represented by Formula I: [ka] or a pharma- ceutically acceptable salt thereof.

[0066] The method may be further characterized by additional features, such as the identity of the first therapeutic agent and the dosing regimen. The invention encompasses all permutations and combinations of these features.

[0067] Thus, the method can be further characterized according to the nature of the first therapeutic agent.For example, in certain embodiments, the first therapeutic agent is a compound of formula I.In certain embodiments, the first therapeutic agent is a pharma- ceutically acceptable salt of the compound of formula I.

[0068] The method can be further characterized according to the administration regimen.For example, in certain embodiments, the first dose of the first therapeutic agent and the second dose of the first therapeutic agent are orally administered to the patient on the same day.In certain embodiments, the first therapeutic agent is orally administered to the patient only once a day.

[0069] In certain embodiments, the first therapeutic agent is orally administered to the patient in an amount of about 600 mg per day.

[0070] In certain embodiments, about 360 mg of the first therapeutic agent is orally administered to the patient in the morning and about 240 mg of the first therapeutic agent is orally administered to the patient in the evening. In certain embodiments, about 360 mg of the first therapeutic agent is orally administered to the patient, followed by about 8 hours to about 16 hours later about 240 mg of the first therapeutic agent. In certain embodiments, about 360 mg of the first therapeutic agent is orally administered to the patient, followed by about 10 hours to about 14 hours later about 240 mg of the first therapeutic agent.

[0071] In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient in the morning and about 360 mg of the first therapeutic agent is orally administered to the patient in the evening. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient, followed by about 8 hours to about 16 hours later about 360 mg of the first therapeutic agent. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient, followed by about 10 hours to about 14 hours later about 360 mg of the first therapeutic agent.

[0072] In certain embodiments, about 300 mg of the first therapeutic agent is orally administered to the patient in the morning and about 300 mg of the first therapeutic agent is orally administered to the patient in the evening. In certain embodiments, about 300 mg of the first therapeutic agent is orally administered to the patient, followed by about 8 hours to about 16 hours later about 300 mg of the first therapeutic agent. In certain embodiments, about 300 mg of the first therapeutic agent is orally administered to the patient, followed by about 10 hours to about 14 hours later about 300 mg of the first therapeutic agent.

[0073] In certain embodiments, if the patient experiences an adverse event from the first therapeutic agent, the first therapeutic agent is orally administered to the patient at a reduced daily dose of about 480 mg per day for at least two days thereafter.

[0074] In certain embodiments, the first therapeutic agent is orally administered to the patient in an amount of about 480 mg per day.

[0075] In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient in the morning and about 240 mg of the first therapeutic agent is orally administered to the patient in the evening. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient, followed by about 8 hours to about 16 hours later about 240 mg of the first therapeutic agent. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient, followed by about 10 hours to about 14 hours later about 240 mg of the first therapeutic agent.

[0076] In certain embodiments, if the patient experiences an adverse event from the first therapeutic agent, the first therapeutic agent is orally administered to the patient at a reduced daily dose of about 300 mg per day for at least two days thereafter, hi certain embodiments, the first therapeutic agent is orally administered to the patient in the morning.

[0077] F. Method 6 One aspect of the invention is a method of reducing HIF-1α and / or NF-κB activity in a human patient suffering from diabetic retinal disease, comprising orally administering to a human patient in need thereof a first therapeutic agent in an amount of about 120 mg to about 600 mg per day to reduce HIF-1α and / or NF-κB activity, wherein the first therapeutic agent is an amino acid sequence represented by Formula I: [ka] or a pharma- ceutically acceptable salt thereof.

[0078] The method may be further characterized by additional features such as the identity of the first therapeutic agent, dosage, and administration regimen. The invention encompasses all permutations and combinations of these features.

[0079] Thus, the method can be further characterized according to the nature of the first therapeutic agent.For example, in certain embodiments, the first therapeutic agent is a compound of formula I.In certain embodiments, the first therapeutic agent is a pharma- ceutically acceptable salt of the compound of formula I.

[0080] The method can be further characterized according to dosage.For example, in certain embodiments, the first therapeutic agent is orally administered to the patient in an amount of about 300mg per day.In certain embodiments, the first therapeutic agent is orally administered to the patient in an amount of about 240mg per day.In certain embodiments, the first therapeutic agent is orally administered to the patient in an amount of about 120mg per day.

[0081] The method can be further characterized according to the administration regimen.For example, in certain embodiments, the first dose of the first therapeutic agent and the second dose of the first therapeutic agent are orally administered to the patient on the same day.In certain embodiments, the first therapeutic agent is orally administered to the patient only once a day.

[0082] In certain embodiments, the first therapeutic agent is orally administered to the patient in the morning. In certain embodiments, the first therapeutic agent is orally administered to the patient in the evening.

[0083] G. Seventh Method One aspect of the invention is a method of treating a disease or condition in a human patient comprising administering a first therapeutic agent to a human patient in need thereof, thereby treating the disease or condition, wherein the first therapeutic agent has a structure represented by Formula I: [ka] or a pharma- ceutically acceptable salt thereof.

[0084] The method may be further characterized by additional features such as the nature of the disease or condition, the nature of the first therapeutic agent, the dosage, and the administration regimen. The invention encompasses all permutations and combinations of these features.

[0085] Thus, the method can be further characterized according to the nature of the disease or condition. In certain embodiments, the disease or condition is selected from wet age-related macular degeneration, dry age-related macular degeneration, retinal vein occlusion, geographic atrophy, retinal neovascularization, choroidal neovascularization, or corneal graft rejection. In certain embodiments, the disease or condition is wet age-related macular degeneration. In certain embodiments, the disease or condition is dry age-related macular degeneration. In certain embodiments, the disease or condition is retinal vein occlusion. In certain embodiments, the disease or condition is geographic atrophy. In certain embodiments, the disease or condition is retinal neovascularization. In certain embodiments, the disease or condition is choroidal neovascularization. In certain embodiments, the disease or condition is corneal graft rejection.

[0086] In certain embodiments, the disease or condition is an eye tumor. In certain embodiments, the disease or condition is a solid tumor. In certain embodiments, the disease or condition is a cancer caused by human myeloid leukemia monocytic cell line (THP-1). In certain embodiments, the disease or condition is Barrett's esophagus (BE). In certain embodiments, the disease or condition is metaplastic Barrett's esophagus (BE). In certain embodiments, the disease or condition is esophageal adenocarcinoma.

[0087] In certain embodiments, the disease or condition is dry eye disease, uveitis, liver disease (e.g., hepatitis, NASH, or alcoholic steatosis), thyroid eye disease, sickle cell retinopathy, chemotherapy-induced peripheral neuropathy, irritable bowel syndrome, stroke, gastrointestinal dysfunction, or chronic gastroesophageal reflux disease (GERD). In certain embodiments, the disease or condition is an inflammatory skin disorder. In certain embodiments, the disease or condition is psoriasis, atopic dermatitis, or rosacea. In certain embodiments, the disease or condition is dry eye disease. In certain embodiments, the disease or condition is uveitis. In certain embodiments, the disease or condition is liver disease (e.g., hepatitis, NASH, or alcoholic steatosis). In certain embodiments, the disease or condition is thyroid eye disease. In certain embodiments, the disease or condition is an inherited retinal disease (e.g., retinitis pigmentosa, choroideremia, Stargardt's disease, cone-rod dystrophy, or Leber's congenital amaurosis). In certain embodiments, the disease or condition is sickle cell retinopathy. In certain embodiments, the disease or condition is chemotherapy-induced peripheral neuropathy. In certain embodiments, the disease or condition is irritable bowel syndrome. In certain embodiments, the disease or condition is stroke. In certain embodiments, the disease or condition is gastrointestinal dysfunction. In certain embodiments, the disease or condition is chronic gastroesophageal reflux disease (GERD).

[0088] In certain embodiments, the disease or condition is diabetic retinal disease.

[0089] As mentioned above, the method can be further characterized according to the nature of the first therapeutic agent.For example, in certain embodiments, the first therapeutic agent is a compound of formula I.In certain embodiments, the first therapeutic agent is a pharma- ceutically acceptable salt of the compound of formula I.

[0090] The method may be further characterized according to the dosage. For example, in certain embodiments, the first therapeutic agent is orally administered to the patient in an amount of about 120 mg to about 600 mg per day. In certain embodiments, the first therapeutic agent is orally administered to the patient in an amount of about 480 mg to about 600 mg per day. In certain embodiments, the first therapeutic agent is orally administered to the patient in an amount of about 600 mg per day. In certain embodiments, the first therapeutic agent is orally administered to the patient in an amount of about 480 mg per day. In certain embodiments, the first therapeutic agent is orally administered to the patient in an amount of about 300 mg per day. In certain embodiments, the first therapeutic agent is orally administered to the patient in an amount of about 240 mg per day. In certain embodiments, the first therapeutic agent is orally administered to the patient in an amount of about 120 mg per day.

[0091] The method can be further characterized according to the administration regimen.For example, in certain embodiments, the first dose of the first therapeutic agent and the second dose of the first therapeutic agent are orally administered to the patient on the same day.In certain embodiments, the first therapeutic agent is orally administered to the patient only once a day.

[0092] In certain embodiments, the first therapeutic agent is orally administered to the patient in the morning. In certain embodiments, the first therapeutic agent is orally administered to the patient in the evening.

[0093] In certain embodiments, about 360 mg of the first therapeutic agent is orally administered to the patient in the morning and about 240 mg of the first therapeutic agent is orally administered to the patient in the evening. In certain embodiments, about 360 mg of the first therapeutic agent is orally administered to the patient, followed by about 8 hours to about 16 hours later about 240 mg of the first therapeutic agent. In certain embodiments, about 360 mg of the first therapeutic agent is orally administered to the patient, followed by about 10 hours to about 14 hours later about 240 mg of the first therapeutic agent.

[0094] In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient in the morning and about 360 mg of the first therapeutic agent is orally administered to the patient in the evening. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient, followed by about 8 hours to about 16 hours later about 360 mg of the first therapeutic agent. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient, followed by about 10 hours to about 14 hours later about 360 mg of the first therapeutic agent.

[0095] In certain embodiments, about 300 mg of the first therapeutic agent is orally administered to the patient in the morning and about 300 mg of the first therapeutic agent is orally administered to the patient in the evening. In certain embodiments, about 300 mg of the first therapeutic agent is orally administered to the patient, followed by about 8 hours to about 16 hours later about 300 mg of the first therapeutic agent. In certain embodiments, about 300 mg of the first therapeutic agent is orally administered to the patient, followed by about 10 hours to about 14 hours later about 300 mg of the first therapeutic agent.

[0096] In certain embodiments, if the patient experiences an adverse event from the first therapeutic agent, the first therapeutic agent is orally administered to the patient at a reduced daily dose of about 480 mg per day for at least two days thereafter.

[0097] In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient in the morning and about 240 mg of the first therapeutic agent is orally administered to the patient in the evening. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient, followed by about 8 hours to about 16 hours later about 240 mg of the first therapeutic agent. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient, followed by about 10 hours to about 14 hours later about 240 mg of the first therapeutic agent.

[0098] In certain embodiments, if the patient experiences an adverse event from the first therapeutic agent, the first therapeutic agent is orally administered to the patient at a reduced daily dose of about 300 mg per day for at least two days thereafter, hi certain embodiments, the first therapeutic agent is orally administered to the patient in the morning.

[0099] Combinations of the embodiments described herein above are part of the present invention.For example, in certain embodiments, the present invention provides a method for treating a disease or condition selected from wet age-related macular degeneration, dry age-related macular degeneration, retinal vein occlusion, geographic atrophy, retinal neovascularization, choroidal neovascularization, or corneal graft rejection, comprising orally administering a first therapeutic agent in an amount of about 120 mg to about 600 mg per day to a human patient in need thereof, thereby treating the disease or condition, wherein the first therapeutic agent is a compound represented by Formula I: [ka] or a pharma- ceutically acceptable salt thereof.

[0100] H. General Considerations Regarding Treatment Methods General considerations that may be applied to the therapeutic methods described herein (e.g., the methods described in Part A and Part G above) are provided below, including, for example, the duration of daily oral administration of the first therapeutic agent, the characteristics of the disease or condition being treated (e.g., the characteristics of diabetic retinal disease), and the characteristics of the human patient. A more detailed description of such characteristics is provided below. The present invention encompasses all permutations and combinations of these characteristics.

[0101] Duration of daily administration of the first therapeutic agent The method may be further characterized according to the duration of daily oral administration of the first therapeutic agent. For example, in certain embodiments, the amount of the first therapeutic agent is orally administered to the patient daily for at least 1 week. In certain embodiments, the amount of the first therapeutic agent is orally administered to the patient daily for at least 2 weeks. In certain embodiments, the amount of the first therapeutic agent is orally administered to the patient daily for at least 4 weeks. In certain embodiments, the amount of the first therapeutic agent is orally administered to the patient daily for at least 6 weeks. In certain embodiments, the amount of the first therapeutic agent is orally administered to the patient daily for at least 8 weeks. In certain embodiments, the amount of the first therapeutic agent is orally administered to the patient daily for at least 10 weeks. In certain embodiments, the amount of the first therapeutic agent is orally administered to the patient daily for at least 12 weeks. In certain embodiments, the amount of the first therapeutic agent is orally administered to the patient daily for at least 24 weeks. In certain embodiments, the amount of the first therapeutic agent is administered orally to the patient daily for at least 30, 32, 34, 36, 38 40, 42, 44, 46, 48, 50, or 52 weeks.

[0102] Characteristics of diabetic retinal disease The method may be further characterized according to the characteristics of the diabetic retinal disease. For example, in certain embodiments, the diabetic retinal disease is diabetic retinopathy. In certain embodiments, the diabetic retinopathy is mild diabetic retinopathy. In certain embodiments, the diabetic retinopathy is moderate diabetic retinopathy. In certain embodiments, the diabetic retinopathy is semi-severe to severe diabetic retinopathy. In certain embodiments, the diabetic retinopathy is non-proliferative diabetic retinopathy. In certain embodiments, the diabetic retinopathy is proliferative diabetic retinopathy.

[0103] In certain embodiments, the diabetic retinal disease is diabetic macular edema.

[0104] Additional Considerations The method may be further characterized according to additional considerations, such as the form in which the first therapeutic agent is administered, the characteristics of the human patient, and the amelioration of diabetic retinal disease achieved by the method.

[0105] For example, in certain embodiments, the first therapeutic agent is orally administered to the patient in the form of a sustained release pharmaceutical composition. In certain embodiments, the first therapeutic agent is orally administered to the patient in the form of a sustained release pharmaceutical composition that provides release of the first therapeutic agent over a period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours. In certain embodiments, the first therapeutic agent is orally administered to the patient in the form of an immediate release pharmaceutical composition. Pharmaceutical compositions are described in more detail in Section III below.

[0106] In certain embodiments, the human patient is an adult human patient.

[0107] In certain embodiments, the method is further characterized according to the improvement of diabetic retinopathy severity score.For example, in certain embodiments, the patient experiences a 5, 10, 15, 20, 25, 30, 35, or 40 point reduction in diabetic retinopathy severity score by the method.In certain embodiments, the patient experiences at least a 2-step reduction in diabetic retinopathy severity score by the method.In certain embodiments, the patient experiences at least a 3-step reduction in diabetic retinopathy severity score by the method.In certain embodiments, the patient experiences at least a 4-step reduction in diabetic retinopathy severity score by the method.

[0108] In certain embodiments, the method is further characterized according to the improvement of best-corrected visual acuity. For example, in certain embodiments, the patient experiences at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% improvement in best-corrected visual acuity by the method. In certain embodiments, the patient experiences at least 2, 4, 6, 8, 10, 12, 14, 16, or 18 letters improvement in best-corrected visual acuity by the method. Best-corrected visual acuity can be measured according to methods known in the art, for example, using a standard ETDRS illumination chart (wall-mounted or stand) at 4m. Alternatively, best-corrected visual acuity can be measured using a Snellen chart.

[0109] In certain embodiments, the method is further characterized according to the effect on diabetic symptoms. In certain embodiments, the method reduces diabetic symptoms. In certain embodiments, the method reduces any renal damage experienced by the patient. In certain embodiments, the method reduces any renal damage experienced by the patient by at least 5, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 50, 60, 70, 80, or 90%. The reduction in renal damage is compared to that experienced by a comparable patient who is not treated by the method with the first therapeutic agent.

[0110] In certain embodiments, the method achieves neuroprotection.

[0111] In certain embodiments, the method is further characterized by the first therapeutic agent increasing the plasma concentration of alanine aminotransferase by no more than 5%. In certain embodiments, the method is further characterized by the first therapeutic agent increasing the plasma concentration of alanine aminotransferase by no more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 15 percent.

[0112] In certain embodiments, the method is further characterized by the feature that the first therapeutic agent results in a decrease in the plasma concentration of alanine aminotransferase, hi certain embodiments, the decrease is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 15 percent.

[0113] In certain embodiments, the method is further characterized by the first therapeutic agent increasing the plasma concentration of aspartate aminotransferase by no more than 5%. In certain embodiments, the method is further characterized by the first therapeutic agent increasing the plasma concentration of aspartate aminotransferase by no more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 15 percent.

[0114] In certain embodiments, the method is further characterized by the feature that the first therapeutic agent results in a decrease in the plasma concentration of aspartate aminotransferase, hi certain embodiments, the decrease is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 15 percent.

[0115] In certain embodiments, the method is further characterized by the patient experiencing a decline in glomerular filtration rate of no more than 15%. In certain embodiments, the method is further characterized by the patient experiencing a decline in glomerular filtration rate of no more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 15 percent.

[0116] In certain embodiments, the method is further characterized by the occurrence of any eye disorder due to the first therapeutic agent occurring at a frequency of no more than 1 patient per 10 patients receiving the same treatment. In certain embodiments, the method is further characterized by the occurrence of any eye disorder due to the first therapeutic agent occurring at a frequency of no more than 1 patient per 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, or 40 patients receiving the same treatment.

[0117] In certain embodiments, the method is further characterized by the occurrence of any eye disorder due to the first therapeutic agent occurring at a frequency of no more than 1 patient per 20 patients receiving the same treatment. In certain embodiments, the method is further characterized by the occurrence of any eye disorder due to the first therapeutic agent occurring at a frequency of no more than 1 patient per 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, or 40 patients receiving the same treatment.

[0118] In certain embodiments, the method is further characterized by the occurrence of any gastrointestinal disorder due to the first therapeutic agent occurring at a frequency of no more than 1 patient per 10 patients receiving the same treatment. In certain embodiments, the method is further characterized by the occurrence of any gastrointestinal disorder due to the first therapeutic agent occurring at a frequency of no more than 1 patient per 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, or 40 patients receiving the same treatment.

[0119] In certain embodiments, the method is further characterized by the occurrence of any nervous system disorder due to the first therapeutic agent occurring at a frequency of no more than 1 patient per 20 patients receiving the same treatment. In certain embodiments, the method is further characterized by the occurrence of any nervous system disorder due to the first therapeutic agent occurring at a frequency of no more than 1 patient per 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, or 40 patients receiving the same treatment.

[0120] Another aspect of the present invention provides the use of a first therapeutic agent as described herein in the manufacture of a medicament.In certain embodiments, the medicament is for treating a disorder as described herein, for example, for treating diabetic retinopathy, diabetic macular edema, and / or other diabetic retinal disorders.

[0121] Another aspect of the present invention provides for the use of a first therapeutic agent described herein to treat a medical disorder, e.g., a medical disorder described herein, e.g., to treat diabetic retinopathy, diabetic macular edema, and / or other diabetic retinopathy.

[0122] II. Combination Therapy Another aspect of the present invention provides combination therapy.The first, second, third, fourth, fifth, sixth and seventh treatment methods described herein above can optionally further comprise administering one or more second therapeutic agents to patient.For example, in certain embodiments, the method further comprises administering a second therapeutic agent for treating diabetic retinal disease to patient.

[0123] In certain embodiments, the second therapeutic agent is an anti-inflammatory agent, an anti-angiogenic agent, a tyrosine kinase inhibitor, an angiopoietin 2 inhibitor, and / or a vascular endothelial growth factor inhibitor. In certain embodiments, the second therapeutic agent is a vascular endothelial growth factor inhibitor. In certain embodiments, the vascular endothelial growth factor inhibitor is sorafenib, sunitinib, pazopanib, bevacizumab, ranibizumab, aflibercept, nilotinib, or dasatinib. In certain embodiments, the vascular endothelial growth factor inhibitor is a bispecific antibody. In certain embodiments, the anti-inflammatory agent is a corticosteroid. In certain embodiments, the second therapeutic agent is a VEGF inhibitor, an mTor inhibitor, a VEGFR2 phosphorylating agent, a tyrosine kinase inhibitor, an IGF-1R inhibitor, a nicotinic acetylcholine receptor antagonist, a selective glycation inhibitor, a corticosteroid, an NSAID, a flavonoid, a TNFα inhibitor, a PKC inhibitor, an aldose reductase, a PARP inhibitor, a reactive oxygen species inhibitor, an AT-I receptor modulator, an AT-II receptor modular, a rho-associated protein kinase inhibitor, a protease inhibitor, a nitric oxide synthase inhibitor, an AGE inhibitor, or a PPAR gamma upregulator.

[0124] In certain embodiments, the second therapeutic agent is an immuno-oncology therapy, a Car-t therapy, a Crispr therapy, a BTK modulator, a bcl-2 modulator, a stat-3 modulator, a KRAS modulator, a PD1 modulator, and / or a DNA repair agent.In certain embodiments, the second therapeutic agent is a bone marrow transplant or related transplant.In certain embodiments, the modulator is an inhibitor.

[0125] In certain embodiments, the method further comprises administering to the patient a second therapeutic agent that is an anti-inflammatory agent, an anti-angiogenic agent, a tyrosine kinase inhibitor, an angiopoietin 2 inhibitor, and / or a vascular endothelial growth factor inhibitor. In certain embodiments, the method further comprises administering to the patient a second therapeutic agent that is a vascular endothelial growth factor inhibitor. In certain embodiments, the vascular endothelial growth factor inhibitor is sorafenib, sunitinib, pazopanib, bevacizumab, ranibizumab, aflibercept, nilotinib, or dasatinib. In certain embodiments, the vascular endothelial growth factor inhibitor is a bispecific antibody. In certain embodiments, the anti-inflammatory agent is a corticosteroid.

[0126] In certain embodiments,

[0127] In certain embodiments, the first therapeutic agent is the only therapeutic agent administered to the human patient for treating diabetic retinal disease.

[0128] In certain embodiments, such as when treating an inflammatory skin disease, the second therapeutic agent is an immunosuppressant, an anti-inflammatory agent, phototherapy (e.g., sunlight, UVA, UVB, psoralen UVA, or excimer laser), a retinoid, a corticosteroid, a vitamin D analog, a calcineurin inhibitor, salicylic acid, anthralin, coal tar, or Geckerman therapy (e.g., light and coal tar).

[0129] The second therapeutic agent and optional additional therapeutic agent may be administered separately from the compound or composition of the present invention as part of a multiple dose regimen. Alternatively, the second therapeutic agent and optional additional therapeutic agent may be part of a single dosage form mixed with the compound of the present invention in a single composition. When administered as a multiple dose regimen, the second therapeutic agent and optional additional therapeutic agent and the compound or composition of the present invention may be administered simultaneously, sequentially, or within a period of time between doses, for example, within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours between doses. In some embodiments, the second therapeutic agent and optional additional therapeutic agent and the compound or composition of the present invention are administered as a multiple dose regimen with more than 24 hours between doses.

[0130] III. Pharmaceutical Compositions As mentioned above, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of one or more of the above compounds, formulated with one or more pharma- ceutically acceptable carriers (excipients) and / or diluents. Pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for oral administration, such as drenches (aqueous or non-aqueous solutions or suspensions), tablets, such as those intended for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue.

[0131] Wetting agents, emulsifying agents and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

[0132] Examples of pharma- ceutically acceptable antioxidants include (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) fat-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0133] The preparations can be conveniently provided in unit dosage form and can be prepared by any method well known in the art of pharmacy. The amount of active ingredient that can be combined with carrier materials to produce a single dosage form varies depending on the host treated, the particular mode of administration. The amount of active ingredient that can be combined with carrier materials to produce a single dosage form will generally be the amount of compound that produces a therapeutic effect. Generally, out of 100 percent, this amount will range from about 0.1 percent to about 99 percent of active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent.

[0134] In certain embodiments, a formulation of the invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents such as bile acids, and polymeric carriers such as polyesters and polyanhydrides, and a compound of the invention, hi certain embodiments, the formulation renders the compound of the invention orally bioavailable.

[0135] The method of preparing these formulations or compositions includes the step of bringing the compound of the present invention into association with carrier and optionally one or more accessory ingredients.In general, the formulation is prepared by uniformly and intimately bringing the compound of the present invention into association with liquid carrier or finely divided solid carrier or both, and then, if necessary, shaping the product.

[0136] Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, sweetened tablets (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion, or an elixir or syrup, or a pastille (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or a mouthwash, each containing a predetermined amount of a compound of the present invention as the active ingredient. The compounds of the present invention may also be administered as a bolus, electuary, or paste.

[0137] In the solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, lozenges, etc.), the active ingredient is mixed with one or more pharma- ceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarders, such as glycerol, ... agents, such as paraffin, (6) absorption enhancers, such as quaternary ammonium compounds, and surfactants, such as poloxamers and sodium lauryl sulfate, (7) wetting agents, such as cetyl alcohol, glycerol monostearate, and nonionic surfactants, (8) absorbents, such as kaolin and bentonite clay, (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof, (10) coloring agents, and (11) controlled release agents, such as crospovidone or ethylcellulose. In the case of capsules, tablets, and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard shell gelatin capsules, using such excipients as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0138] Tablets can be made by compression or molding, optionally with one or more accessory ingredients.Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents, or dispersants.Molded tablets can be made by molding a mixture of powdered compound moistened with an inert liquid diluent in a suitable machine.

[0139] Tablets, as well as other solid dosage forms of the pharmaceutical composition of the present invention, such as dragees, capsules, pills, and granules, may be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may also be formulated to sustain or control release the active ingredient therein, for example, using hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres in various proportions to provide a desired release profile. They may also be formulated for rapid release, for example, lyophilized. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or other sterile injectable medium immediately before use. These compositions may optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only or preferentially in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0140] The liquid dosage form for oral administration of the compound of the present invention includes pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.In addition to active ingredient, liquid dosage form can contain inert diluent commonly used in the art, such as water or other solvent, solubilizer and emulsifier, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (specifically cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid ester of sorbitan, and mixtures thereof.

[0141] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.

[0142] Suspensions may contain, in addition to the active compounds, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0143] Suitable examples of aqueous and non-aqueous carriers that can be used in the pharmaceutical composition of the present invention include water, ethanol, polyol (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oil such as olive oil, and injectable organic ester such as ethyl oleate.Proper fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersion, and by using surfactants.

[0144] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms on the subject compounds can be ensured by including various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, etc., in the compositions.

[0145] In certain embodiments, the pharmaceutical composition may be in the form of a cream, colloid, suspension, spray, gel, lotion, ointment, foam, or solution. In certain embodiments, the pharmaceutical composition may be in the form of a solution for injection. In certain embodiments, the pharmaceutical composition may be in the form of a solution for subcutaneous injection.

[0146] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.

[0147] The selected dosage level will depend on a variety of factors, including the activity of the particular compound of the invention or its esters, salts, or amides employed, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound employed, the rate and extent of absorption, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health, and past medical history of the patient being treated, and similar factors well known in the medical arts.

[0148] Generally, the suitable daily dose of the compound of the present invention is the amount of compound that is the lowest effective dose to produce therapeutic effect.Such effective dose generally depends on the above-mentioned factors.When the compound described herein is used in combination with another drug (for example, as a sensitizing agent), the effective amount may be less than when the drug is used alone.

[0149] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.

[0150] The present invention further provides unit dosage forms (eg, tablets or capsules) containing a therapeutically effective amount of a compound described herein for treating a medical disorder described herein.

[0151] IV. Medical Kit Another aspect of the invention provides medical kits that include, for example, (i) a therapeutic agent described herein and (ii) instructions for treating diabetic retinopathy, diabetic macular edema, and / or other diabetic retinal disorders according to the methods described herein. EXAMPLES

[0152] The invention having been generally described herein will be more readily understood by reference to the following examples, which are included merely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to be limiting of the invention.

[0153] Example 1 - Treatment of Non-Proliferative and Mild Proliferative Diabetic Retinopathy The ability of compound 1 to treat non-proliferative diabetic retinopathy (NPDR) and mild proliferative diabetic retinopathy (PDR) can be evaluated following a clinical trial in which patients suffering from non-proliferative diabetic retinopathy or mild proliferative diabetic retinopathy are orally administered compound 1. Compound 1 has the chemical name (E)-2-((4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dien-1-yl)methylene)undecanoic acid and the following chemical formula: [ka] It is expressed as:

[0154] The study will be structured as a placebo-controlled, double-blind, randomized, Phase 2 study to evaluate the safety and efficacy of Compound 1 administered twice daily for 24 weeks in approximately 100 subjects with subsevere-to-severe NPDR (Diabetic Retinopathy Severity Score [DRSS] levels 47 or 53, see Figure 1) or mild PDR (DRSS level 61). The study will involve 1:1 randomization (placebo:compound 1). Randomization will be stratified by level of disease severity (NPDR or PDR). Subjects with mild PDR will be capped at 20% in each group. Efficacy assessments at 12 and / or 24 weeks will include DRSS, diabetic macular edema (DME) involving the fovea, moderate PDR, or PDR-related adverse events (AEs), best-corrected visual acuity (BCVA), and central retinal thickness (CST). Further experimental procedures and results are described below.

[0155] Part I - Experimental Procedure Subject participation was scheduled for a total of approximately 26 weeks, with five clinic visits, four safety telephone checks, and one follow-up telephone visit, summarized below. Screening Visit 1 (up to 7 days prior to the Baseline Visit) Eligibility Assessment / Baseline Visit 2 (Day 1) Treatment-study period (24 weeks) o Treatment Visit 4 (Week 4), Visit 6 (Week 12), and Visit 9 (Week 24) Telephone safety checks at Visit 3 (Week 1), Visit 5 (Week 8), Visit 7 (Week 16), and Visit 8 (Week 20) Telephone follow-up visit 10 (2 days)

[0156] Human subjects will be screened for possible enrollment and, if eligible, will be enrolled in the study. The inclusion and exclusion criteria for this study are listed below. Human subjects may be eligible in either eye. The eligible eye with the higher DRSS will be designated as the study eye for efficacy analysis of the primary endpoint. If the upper limit of PDR is reached, the study eye may be the eye with the lower DRSS if the other eye has mild PDR. If the DRSS of both eyes is the same, the eye with the worse BCVA will be selected as the study eye. If the DRSS and BCVA are equal in both eyes, the study eye will be the right eye. Selection Criteria ·Males or non-pregnant women aged 18 or older. Patients with diabetic retinopathy classified as at least semi-severe to severe NPDR or mild PDR (equivalent to DRSS 47, 53, or 61 and confirmed by a central reading center) in at least one eye in which panretinal laser photocoagulation (PRP) and intravitreal injection of anti-VEGF agents can be safely postponed for at least 6 months in the opinion of the investigator. - Patients must have BCVA of 60 letters or more (Snellen equivalent 20 / 63 or more) in the study eye as assessed by the Early Treatment Diabetic Retinopathy Trial (ETDRS) protocol letter score. - Those whose ocular media is sufficiently transparent, whose pupils are appropriately dilated, whose fixation is sufficient, and whose high-quality fundus photographs can be taken with both eyes. -Those who can fully cooperate with ophthalmologic visual function tests and anatomical evaluations. Body mass index (BMI) between 18 and 40 kg / m 2 Those who are within. ·Able and willing to provide signed informed consent and comply with study instructions. -Able to administer the study drug orally by themselves or by a caregiver throughout the study period. Exclusion Criteria – Eye-related -Retinopathy due to causes other than diabetes. Subjects with diabetic macular edema (DME) involving the fovea, defined as a central subfield thickness (CST) ≥ 300 μm on SD-OCT, or intraretinal or subretinal exudate in the central subfield. DME involving the fovea in the fellow eye is permitted. Intravitreal injection of anti-VEGF agents in the fellow eye is not excluded. Prior treatments in the study eye and excluded concomitant medications / treatments: o Subjects who have had focal or grid laser photocoagulation within the past year or have ever received PRP. o Subjects who have received systemic or intravitreal anti-VEGF therapy within the past 6 months or who, in the opinion of the investigator, may require treatment during the study. -Subjects who have had steroids such as triamcinolone and dexamethasone implanted into their eyes within the past 6 months. - Subjects who have had fluocinolone implanted within the past 3 years. - Subjects with clinically significant ocular disease in either eye that, in the opinion of the investigator, is likely to interfere with the study procedures and visual acuity measurements (e.g., cataract, pseudophakia without evidence of posterior capsule opacification, glaucoma, corneal edema, uveitis, severe keratoconjunctivitis sicca). - Subjects with other macular or retinal vascular diseases such as age-related macular degeneration, pattern dystrophy, choroidal neovascularization due to any cause, retinal vein occlusion, or retinal artery occlusion in the test eye. -Persons with active vitreous hemorrhage in either eye that may prevent adequate clinical imaging. - Subjects with a history of retinal detachment or full-thickness macular hole in the study eye. -Uncontrolled glaucoma (defined as cup-to-distal ratio >0.7 and intraocular pressure (IOP) >25mmHg) in either eye with or without topical antihypertensive eye drops; treatment for ocular hypertension or controlled glaucoma is not an exclusion criterion. -Subjects who have undergone open eye surgery such as cataract surgery in the study eye within 3 months prior to Day 1. -Subjects who had undergone yttrium aluminum garnet (YAG) posterior capsulotomy in the study eye within the past 30 days. - Subjects whose test eye is aphakic. -Patients with a history of pars plana vitrectomy in the study eye. -Preretinal membrane, posterior vitreous traction, and / or vitreomacular traction in the study eye as determined by the investigator to be significant. -Persons with active uveitis and / or vitritis in either eye. -Subjects with a history of idiopathic or autoimmune-related uveitis in either eye. -People with active infection in either eye, such as infectious conjunctivitis, keratitis, scleritis, or endophthalmitis. Exclusion criteria - whole body · Individuals with poorly controlled diabetes mellitus defined as hemoglobin A1c (HbA1c) ≥ 12.0%, or HbA1c < 12.0% and uncontrolled diabetes mellitus, or no available HbA1c. -Those known to be immunocompromised or receiving immunosuppressive therapy. Any illness or medical condition which, in the opinion of the Investigator, may prevent the subject from successfully participating in the study or which may confound the results of the study. -Subjects with clinically significant systemic illness (e.g., uncontrolled diabetes mellitus, myasthenia gravis, cancer, hepatic, renal, endocrine, or cardiovascular disorders) that the investigator believes may interfere with the study. -Those with Modification of Diet in Renal Disease (MDRD) estimated glomerular filtration rate (eGFR) less than 30mL / min or creatinine greater than 4mg / dL. -People with a history of allergic reactions to the investigational product or any of its ingredients. - Subjects whose resting heart rate (HR) at the screening visit is outside the prescribed range of 50-110 beats per minute. If the HR is outside the prescribed range, it may be repeated only once after at least 5 minutes of rest in a seated position. - Subjects with hypertension at the time of the screening visit, with resting diastolic blood pressure (BP) >110mmHg or systolic blood pressure (BP) >180mmHg. If BP is outside the prescribed range, it may be repeated only once after at least 5 minutes of rest in a seated position. · Anyone with a history of chronic liver disease or elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) consistent with such a diagnosis (i.e., AST or ALT > 2 × upper limit of normal). Participated in an investigational drug clinical trial within 30 days prior to screening, or will participate in any other investigational drug or device clinical trial within 30 days of completion of the trial. Women of childbearing potential who are pregnant, nursing, planning to become pregnant, or not using a medically acceptable form of contraception. All women of childbearing potential must have a negative urine pregnancy test result at Visit 1 / Screening and must not intend to become pregnant during the study.

[0157] Patients with DME in the fellow eye were eligible to be enrolled in the study, but DME involving the fovea in the study eye was excluded.

[0158] Subjects are screened at Visit 1, and those who successfully meet the eligibility requirements return to the site for an eligibility / baseline visit (Visit 2 / Day 1), where they undergo a series of safety and clinical laboratory assessments and are issued study medication. Subjects then return to the site at Visit 4 (Week 4), Visit 6 (Week 12), and Visit 9 (Week 24) for safety and efficacy assessments. Between these site visits, subjects are called at Visit 3 (Week 1), Visit 5 (Week 8), Visit 7 (Week 16), and Visit 8 (Week 20) ​​for safety assessments, including AEs, concomitant medications, and medication management.

[0159] Study medication will be initially dispensed at Visit 2 (Day 1), then at Visit 4 (Week 4) and Visit 6 (Week 12) at the site. Subjects will bring all unused study medication to each site visit for medication management. Study medication will be collected at the site at Visit 9 (Week 24). A follow-up phone call will be conducted 1 week after Visit 9 (Week 24) for AE and concomitant medication assessment.

[0160] At Screening (Visit 1, Day -7 to Day -1): A member of the testing center staff will interview the individual regarding their eligibility to take part in the study and will sign an informed consent form if the subject wishes to continue. Screening initiation involves assignment of a subject identification number, explanation of the study, and a review of medical and ophthalmologic history, demographics, and prior / concomitant medications. This is followed by a physical examination, measurement of HR / BP, and, for women of childbearing potential, a urine pregnancy test. This is followed by measuring BCVA, SD-OCT (for CST) and color fundus photography (for DRSS). DRSS eligibility is determined by a central reading center using 7-field or 4-widefield fundus photography. The central reading center also determines CST eligibility using SD-OCT. BCVA (distance) can be measured using a standard ETDRS illumination chart (wall-mounted or stand) at 4m. This will be followed by blood chemistry and hematology evaluation, ophthalmologic examination including biomicroscopy and direct or indirect ophthalmoscopy, IOP assessment, eGFR, and evaluation of AEs.

[0161] If the subject meets all eligibility criteria (including DRSS and SD-OCT), BCVA, DRSS, CST, and other safety assessments performed at screening will become baseline values ​​and the subject will be asked to return for an eligibility visit.

[0162] Eligibility Assessment / Baseline (Visit 2, Day 1): Randomly assign subjects to studies. -Treatment will be provided according to the treatment group to which the subject is randomly assigned. Blood samples will be collected pre-dose to obtain baseline levels and exploratory biomarker treatment (i.e., cytokine and Ref-1 levels) will be performed at Visit 9 (Week 24) to evaluate pharmacodynamic properties. Subjects will be instructed to take three tablets of study medication (APX3330 or placebo) each morning and two tablets each evening. Study medication should be taken at approximately the same time each day, with or without food.

[0163] Safety checks by telephone will be conducted at Visit 3 (Week 1 ± 2 days), Visit 5 (Week 8 ± 2 days), Visit 7 (Week 16 ± 2 days), and Visit 8 (Week 20 ± 2 days). Safety assessments will include review of compliance, concomitant medications, AEs, and a home urine pregnancy test (for women of reproductive potential only).

[0164] At the first treatment visit (Visit 4, Week 4 ± 2 days), subjects will return to the site for a battery of safety and efficacy assessments including: medication management, concomitant medications, urine pregnancy test (women of childbearing potential only), HR / BP / vital signs, BCVA (ETDRS), biomicroscopy, ophthalmoscopy, IOP, and AEs. After completion of the assessments, the used medication kit will be collected for administration (counting the number of unused tablets) and a new study medication kit will be issued.

[0165] At the second treatment visit (Visit 6, Week 12 ± 2 days), subjects will return to the site for a battery of safety and efficacy assessments including: medication management, concomitant medications, urine pregnancy test (women of reproductive potential only), HR / BP / vital signs, BCVA (ETDRS), DRSS, CST (SD-OCT), blood draws for PK, blood chemistry, hematology, biomicroscopy, ophthalmoscopy, IOP, eGFR, and AEs. After completion of the assessments, the used drug kit will be collected for administration (counting the number of unused tablets) and a new study drug kit will be issued.

[0166] At the third treatment visit (Visit 9, Week 24 ± 2 days), subjects return to the site for a battery of safety and efficacy assessments including: medication management, concomitant medications, urine pregnancy test (women of reproductive potential only), physical examination, HR / BP / vital signs, BCVA (ETDRS), DRSS, CST (SD-OCT), blood chemistry, hematology, biomicroscopy, ophthalmoscopy, IOP, eGFR, AEs, and blood draws for exploratory biomarkers (ELISA, cytokine panel, comprehensive metabolic panel). Visit 9 (Week 24) marks the end of the treatment period. Study drug is returned for study administration (counting unused tablets) and no further study drug is issued.

[0167] A telephone follow-up call will be conducted at Visit 10 (Week 25 ± 2 days) to assess concomitant medications and AEs.

[0168] Study subjects will receive the study medication as described in Table 1 according to the treatment group to which they are assigned. Subjects will be instructed to take the study medication at approximately the same time each day and that the medication may be taken with or without food. Study medications are listed in Table 2. [Table 1] [Table 2]

[0169] Any subject will be permitted to voluntarily withdraw from the study at any time without retaliation. A non-completer is defined as a subject who withdraws from the study voluntarily or at the discretion of the Investigator and / or Medical Monitor before completing all study procedures required by the protocol.

[0170] If a subject considers discontinuing the study due to an AE, the investigator may suggest an alternative dose reduction from 600 mg to 480 mg per day (2 tablets in the morning and 2 tablets in the evening).

[0171] Efficacy and safety evaluation – endpoints and measurement procedures The primary efficacy endpoint was the proportion of subjects achieving ≥2-grade improvement in DRSS in the study eye at Week 24. Secondary efficacy endpoints included: The proportion of subjects whose DRSS scores (see Figure 1) improved or worsened by 1 or more grades, 2 or more grades, 3 or more grades, and 4 or more grades at Weeks 12 and 24, Mean change from baseline in DRSS at week 24, The proportion of subjects who were free of DME involving the fovea or moderate PDR or PDR-related AEs during the study at Weeks 12 and 24; Mean change from baseline in BCVA at week 24, and - Mean change from baseline in CST.

[0172] Primary and secondary endpoints will be assessed in the study eye, fellow eye, all eligible eyes (study eye and fellow eye that meet all study eye eligibility criteria), and any eye (i.e., best response). All efficacy endpoints will also be analyzed by modified intention-to-treat (mITT) and per protocol (PP) populations. Other subpopulations may be identified and analyzed.

[0173] Exploratory efficacy endpoints included: The relationship between Compound 1 in plasma measured at Week 12 and the change from baseline in DRSS in the study eye at Weeks 12 and 24; Mean change from baseline in plasma Ref-1 levels at week 24, Mean change from baseline in cytokine levels at week 24, The relationship between plasma Ref-1 levels and the change from baseline in DRSS in the study eye at week 24. The relationship between plasma cytokine levels at week 24 and the change from baseline in DRSS in the study eye.

[0174] Measurements will be determined as follows, and every effort will be made to have the same person perform the measurements at all time points and visits. DRSS is measured using 7-field or 4-widefield color fundus photographs. CST is measured using SD-OCT. · BCVA is measured at 4m (characters) using a standard ETDRS chart.

[0175] For pharmacokinetic analysis, blood samples will be collected prior to and 3 hours after the morning dose at Visit 6 (Week 12 ± 2 days) to establish Compound 1 drug levels in approximately 25-30 subjects at a subset of clinical sites. These subjects will be instructed to delay dosing with study drug in the morning on the day of this visit so that they can receive study drug at the site. To establish steady-state drug levels, 5 mL of blood will be collected immediately prior to dosing. A second 5 mL sample will be collected 3 hours later to establish C max Establish drug levels. Analysis of plasma samples for compound 1 concentration measurements will be performed by a central PK laboratory using validated liquid chromatography mass spectrometry and liquid chromatography tandem mass spectrometry (LC-MS / MS) methods.

[0176] Safety endpoints included: - incidence and severity of systemic and ocular AEs; Changes from baseline in body systems assessments, -Changes from baseline in vital sign measurements; Changes from baseline in laboratory test results (blood chemistry, hematology), Change from baseline in intraocular pressure (IOP), -Changes from baseline in slit lamp examination parameters, Change from baseline in dilated ophthalmoscopic parameters, Proportion of subjects who experienced a loss of ≥10 letters of BCVA compared to baseline at Weeks 12 and 24, Proportion of subjects who progressed to DME involving the fovea (eligible for rescue treatment at weeks 12 and 24); The proportion of subjects whose DRSS worsened by ≥2 grades in the study eye at Weeks 12 and 24, The proportion of subjects who developed anterior segment neovascularization at weeks 12 and 24, Proportion of subjects who were rescued at investigator discretion (intravitreal anti-VEGF injections, laser PRP, topical / lattice laser treatment, or surgery [vitrectomy]) at Weeks 12 and 24, and -Change from baseline in estimated glomerular filtration rate (eGFR) at weeks 12 and 24.

[0177] Efficacy and safety evaluation – general analysis procedure Analysis populations included: Modified Intention-to-Treat (mITT): mITT includes all randomized subjects who received at least one dose of study treatment and at least one post-dose efficacy measurement. mITT is used to analyze efficacy endpoints. Per Protocol Population (PP): The PP population includes all subjects in the mITT who received less than 20% of the planned dose and who have no major protocol deviations that would have a significant impact on treatment outcomes. The PP population will be used for the primary endpoint analysis and efficacy endpoints will be analyzed. All Randomized Set (ARP): The ARP includes all randomized subjects. This set is also known as the Intent-to-Treat (ITT) set. The ARP is used for efficacy confirmation analyses. Safety Population (SP): The SP includes all randomized subjects who received at least one dose of study treatment. The SP will be used to summarize safety items.

[0178] Part II - Results Provided below is data regarding the safety of Compound 1 administered orally to patients according to the study protocol described herein. The data are from 100 patients enrolled in the study. Patients enrolled in the study were randomized 1:1 to receive placebo or Compound 1 according to the study protocol described above. The safety data below is a combination of the results for patients who received placebo and those who received Compound 1. The results indicate that Compound 1 administered according to the study protocol had a favorable safety profile in the patient population enrolled in this study.

[0179] Table 3 below provides the results of an analysis of alanine aminotransferase concentrations in the blood of subjects. [Table 3]

[0180] Comparing data obtained at week 12 for 50 subjects, the mean concentration of alanine aminotransferase in the subjects' blood showed a change of -0.8 IU / L compared to the mean concentration of alanine aminotransferase in the subjects' blood at baseline, which corresponds to a 3.6% decrease in the mean concentration of alanine aminotransferase in the subjects' blood at week 12 compared to the mean concentration of alanine aminotransferase in the subjects' blood at baseline.

[0181] Comparing data obtained at week 24 for 22 subjects, the mean concentration of alanine aminotransferase in the subjects' blood showed a change of -2.1 IU / L compared to the mean concentration of alanine aminotransferase in the subjects' blood at baseline, which corresponds to a 9.4% decrease in the mean concentration of alanine aminotransferase in the subjects' blood at week 24 compared to the mean concentration of alanine aminotransferase in the subjects' blood at baseline.

[0182] Table 4 below provides the results of an analysis of aspartate aminotransferase concentrations in the blood of subjects. [Table 4]

[0183] Comparing data obtained at week 12 for 50 subjects, the mean concentration of aspartate aminotransferase in the subjects' blood showed a change of -0.5 IU / L compared to the mean concentration of aspartate aminotransferase in the subjects' blood at baseline, which corresponds to a 3% decrease in the mean concentration of aspartate aminotransferase in the subjects' blood at week 12 compared to the mean concentration of aspartate aminotransferase in the subjects' blood at baseline.

[0184] Comparing data obtained at week 24 for 22 subjects, the mean concentration of aspartate aminotransferase in the subjects' blood showed a change of -1.8 IU / L compared to the mean concentration of aspartate aminotransferase in the subjects' blood at baseline, which corresponds to a 9% decrease in the mean concentration of aspartate aminotransferase in the subjects' blood at week 24 compared to the mean concentration of aspartate aminotransferase in the subjects' blood at baseline.

[0185] Table 5 below provides the results of an analysis of the glomerular filtration rates of the subjects. [Table 5]

[0186] Comparing data obtained at week 12 for 47 subjects, the subjects' mean glomerular filtration rate was -2.24 mL / min / 1.73 m compared with the subjects' mean glomerular filtration rate at baseline. 2 This corresponds to a 2% decrease in the subjects' mean glomerular filtration rate at Week 12 compared to the subjects' mean glomerular filtration rate at baseline.

[0187] Comparing data obtained at week 24 for 21 subjects, the subjects' mean glomerular filtration rate was -9.84 mL / min / 1.73 m compared with the subjects' mean glomerular filtration rate at baseline. 2 This corresponds to an 11% decrease in the subjects' mean glomerular filtration rate at Week 24 compared to the subjects' mean glomerular filtration rate at baseline.

[0188] Table 6 below provides the results of the subject heart rate analysis. [Table 6]

[0189] Comparing data obtained at week 12 for 62 subjects, the subjects' average heart rate showed a change of +0.9 beats / min compared to the subjects' average heart rate at baseline, which corresponds to a 1% increase in the subjects' average heart rate at week 12 compared to the subjects' average heart rate at baseline.

[0190] Comparing data obtained at week 24 for 27 subjects, the subjects' average heart rate showed a change of +4.3 beats / min compared to the subjects' average heart rate at baseline, which corresponds to a 6% increase in the subjects' average heart rate at week 24 compared to the subjects' average heart rate at baseline.

[0191] Table 7 below provides the results of the analysis of the subjects' systolic blood pressure. [Table 7]

[0192] Comparing data obtained at week 12 for 62 subjects, the subjects' mean systolic blood pressure showed a change of -4.7 mmHg compared to the subjects' mean systolic blood pressure at baseline, which corresponds to a 3% decrease in the subjects' mean systolic blood pressure at week 12 compared to the subjects' mean systolic blood pressure at baseline.

[0193] Comparing data obtained at week 24 for 27 subjects, the subjects' mean systolic blood pressure showed a change of -0.7 mmHg compared to the subjects' mean systolic blood pressure at baseline, which corresponds to a 1% decrease in the subjects' mean systolic blood pressure at week 24 compared to the subjects' mean systolic blood pressure at baseline.

[0194] Table 8 below provides the analysis of the subjects' diastolic blood pressure. [Table 8]

[0195] Comparing data obtained at week 12 for 62 subjects, the subjects' mean diastolic blood pressure showed a change of -2.8 mmHg compared to the subjects' mean diastolic blood pressure at baseline, which corresponds to a 3% decrease in the subjects' mean diastolic blood pressure at week 12 compared to the subjects' mean diastolic blood pressure at baseline.

[0196] Comparing data obtained at week 24 for 27 subjects, the subjects' mean diastolic blood pressure showed a change of +1 mmHg compared to the subjects' mean diastolic blood pressure at baseline, which corresponds to a 1% increase in the subjects' mean diastolic blood pressure at week 24 compared to the subjects' mean diastolic blood pressure at baseline.

[0197] Table 9 below summarizes the occurrence of adverse events across the 100 subjects enrolled in the study, combining the results for patients who received placebo and those who received Compound 1. Of these 100 subjects, 41 subjects reported at least one treatment-emergent adverse event. A total of 83 treatment-emergent adverse events were observed across the 100 subjects enrolled in the study. Subjects who reported multiple treatment-emergent adverse events are counted only once within the organ system class in Table 9. [Table 9]

[0198] Incorporation by Reference The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.

[0199] Equivalent The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics.The foregoing embodiments are therefore to be considered in all respects as illustrative rather than limiting the invention described herein.The scope of the present invention is therefore indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. 1. A pharmaceutical composition for treating diabetic retinal disease in a human patient comprising a first therapeutic agent, the first therapeutic agent being adapted to be orally administered to the human patient in an amount of about 480 mg to about 600 mg per day, the first therapeutic agent being represented by Formula I: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof.

2. 10. The pharmaceutical composition of claim 1, wherein the first dose of the first therapeutic agent and the second dose of the first therapeutic agent are adapted to be orally administered to the patient on the same day.

3. 10. The pharmaceutical composition of claim 1, wherein the first therapeutic agent is adapted to be orally administered to the patient in an amount of about 600 mg per day.

4. 10. The pharmaceutical composition of claim 1, wherein about 300 mg of the first therapeutic agent is orally administered to the patient in the morning and about 300 mg of the first therapeutic agent is orally administered to the patient in the evening.

5. 10. The pharmaceutical composition of claim 1, wherein about 300 mg of the first therapeutic agent is orally administered to the patient, followed by about 8 to about 16 hours later, at a time point where about 300 mg of the first therapeutic agent is orally administered to the patient.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein if the patient experiences an adverse event due to the first therapeutic agent, the first therapeutic agent is orally administered to the patient at a reduced daily dose of about 480 mg per day for at least two days thereafter.

7. The pharmaceutical composition of any one of claims 1 to 5, wherein the amount of said first therapeutic agent is administered orally to said patient daily for at least 4 weeks.

8. The pharmaceutical composition of any one of claims 1 to 5, wherein the amount of said first therapeutic agent is administered orally to said patient daily for at least 24 weeks.

9. The pharmaceutical composition according to any one of claims 1 to 5, wherein the diabetic retinal disease is diabetic retinopathy.

10. The pharmaceutical composition according to claim 6 , wherein the diabetic retinal disease is diabetic retinopathy.

11. The pharmaceutical composition according to claim 9, wherein the diabetic retinopathy is mild diabetic retinopathy.

12. The pharmaceutical composition according to claim 9, wherein the diabetic retinopathy is moderate diabetic retinopathy.

13. The pharmaceutical composition according to claim 9, wherein the diabetic retinopathy is semi-severe to severe diabetic retinopathy.

14. The pharmaceutical composition according to claim 9, wherein the diabetic retinopathy is non-proliferative diabetic retinopathy.

15. The pharmaceutical composition according to claim 9, wherein the diabetic retinopathy is proliferative diabetic retinopathy.

16. The pharmaceutical composition according to any one of claims 1 to 5, wherein the human patient is an adult patient.

17. 1. A pharmaceutical composition comprising a first therapeutic agent, the pharmaceutical composition being for treating a disease or condition selected from wet age-related macular degeneration, dry age-related macular degeneration, retinal vein occlusion, geographic atrophy, retinal neovascularization, choroidal neovascularization, or corneal graft rejection, the first therapeutic agent being adapted to be orally administered to a human patient in need of such treatment in an amount of about 120 mg to about 600 mg per day, the first therapeutic agent being a compound represented by Formula I: 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof.

18. 20. The pharmaceutical composition of claim 17, wherein the first therapeutic agent is adapted to be orally administered to the patient in an amount of about 600 mg per day.

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