Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
  • A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods

Definitions

• the invention provides methods, compositions, and kits containing a first therapeutic agent that is a substituted 2,3-dimethoxyquinone of Formula I, or a pharmaceutically acceptable salt thereof, for treating patients suffering from diabetic retinopathy, diabetic macular edema, and/or other diabetic retinal disorders and/or other disorders.
• Diabetic retinopathy is a disease of the eye that, if left untreated, can lead to blindness.
• a significant proportion of individuals who suffer from diabetes experience some degree of related retinal damage.
• Existing therapies for diabetic retinopathy are not effective for all patients and/or have undesirable side effects.
• laser photocoagulation produces its effects by creating burns in the tissue of the eye, which can be painful and/or cause certain vision problems (e.g., losses in peripheral, color, and/or night vision).
• Vitrectomy generally proceeds by creating an incision in the surface of the eye (introducing the potential for intraocular infection), and often requires weeks of recovery where the eye must be covered and cannot be used.
• Intravitreal injection of triamcinolone or anti-VEGF medications also carry a risk of intraocular infection, particularly with the need for additional injections over time.
• the invention provides methods, compositions, and kits containing a first therapeutic agent that is a substituted 2,3-dimethoxyquinone of Formula I, or a pharmaceutically acceptable salt thereof, for treating patients suffering from diabetic retinopathy, diabetic macular edema, and/or other diabetic retinal disorders and/or other disorders.
• the methods generally comprise orally administering to a human patient in need thereof an amount of from about 120 mg to about 600 mg per day of a compound of Formula I or a pharmaceutically acceptable salt thereof:
• Exemplary more preferred embodiments comprise orally administering to a human patient in need thereof an amount of from about 480 mg to about 600 mg per day of a compound of Formula I or pharmaceutically acceptable salt thereof.
• Improvement in the patient’s diabetic retinal disorder can be evaluated according to improvement in the patient’s Diabetic Retinopathy Severity Score (DRSS), improvement in the patient’s visual acuity, and other procedures described in the literature. Additional exemplary aspects and embodiments of the invention are described below.
• DRSS Diabetic Retinopathy Severity Score
• One aspect of the invention provides a method of treating a diabetic retinal disease in a human patient.
• the method comprises orally administering to a human patient in need thereof a first therapeutic agent in an amount of from about 480 mg to about 600 mg per day, to thereby treat the diabetic retinal disease, wherein the first therapeutic agent is a compound of Formula I or a pharmaceutically acceptable salt thereof:
• a first dose of the first therapeutic agent and a second dose of the first therapeutic agent are orally administered to the patient on the same day.
• the method further comprises administering to the patient a second therapeutic agent that is a vascular endothelial growth factor inhibitor.
• the diabetic retinal disease is diabetic retinopathy.
• the diabetic retinal disease is diabetic macular edema. Additional features of the method are described in the detailed description.
• Another aspect of the invention provides a method of treating a diabetic retinal disease in a human patient.
• the method comprises orally administering to a human patient in need thereof a first therapeutic agent in an amount of from about 120 mg to about 600 mg per day, to thereby treat the diabetic retinal disease, wherein the first therapeutic agent is a compound of Formula I or a pharmaceutically acceptable salt thereof:
• a first dose of the first therapeutic agent and a second dose of the first therapeutic agent are orally administered to the patient on the same day.
• the method further comprises administering to the patient a second therapeutic agent that is a vascular endothelial growth factor inhibitor.
• the diabetic retinal disease is diabetic retinopathy.
• the pharmaceutical composition is formulated for oral administration.
• 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 comeal graft rejection.
• the method comprises orally administering to a human patient in need thereof a first therapeutic agent in an amount of from about 120 mg to about 600 mg per day, to thereby treat the disease or condition, wherein the first therapeutic agent is a compound of Formula I or a pharmaceutically acceptable salt thereof:
• Figure 1 depicts exemplary diabetic retinopathy severity scores (DRSS) and corresponding descriptions and retinal images.
• DRSS diabetic retinopathy severity scores
• the invention provides methods, compositions, and kits containing a first therapeutic agent that is a substituted 2,3-dimethoxyquinone of Formula I, or a pharmaceutically acceptable salt thereof, for treating patients suffering from diabetic retinopathy, diabetic macular edema, and/or other diabetic retinal disorders and/or other disorders.
• the methods generally comprise orally administering to a human patient in need thereof an amount of from about 120 mg to about 600 mg per day of a compound of Formula I or a pharmaceutically acceptable salt thereof:
• Exemplary more preferred embodiments comprise orally administering to a human patient in need thereof an amount of from about 480 mg to about 600 mg per day of a compound of Formula I or pharmaceutically acceptable salt thereof.
• Improvement in the patient’s diabetic retinal disorder can be evaluated according to improvement in the patient’s Diabetic Retinopathy Severity Score (DRSS), improvement in the patient’s visual acuity, and other procedures described in the literature.
• DRSS Diabetic Retinopathy Severity Score
• Various aspects of the invention are set forth below in sections; however, aspects of the invention described in one particular section are not to be limited to any particular section.
• the term “about” means within 10% of the stated value. In certain embodiments, the value may be within 8%, 6%, 5%, 4%, 2%, or 1% of the stated value.
• the term “patient” refers to organisms to be treated by the methods of the present invention.
• Such organisms preferably include, but are not limited to, mammals (e.g ., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans.
• the term “effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results. Unless specified otherwise, an effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.
• composition refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for therapeutic use in vivo or ex vivo.
• the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g ., such as an oil/water or water/oil emulsions), and various types of wetting agents.
• the compositions also can include stabilizers and preservatives.
• stabilizers and adjuvants see Martin in Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA [1975].
• the term “pharmaceutically acceptable salt” refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention which, upon administration to a subject, is capable of providing a compound of this invention.
• salts of the compounds of the present invention may be derived from inorganic or organic acids and bases.
• acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic acid, and the like.
• Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
• bases include, but are not limited to, alkali metals (e.g., sodium) hydroxides, alkaline earth metals (e.g., magnesium), hydroxides, ammonia, and compounds of formula NW3, wherein W is C M alkyl, and the like.
• 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,
• salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable.
• salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
• 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.
• a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), and alternatively, about 20 or fewer.
• 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.
• compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
• compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.
• the invention provides methods for treating patients suffering from diabetic retinopathy, diabetic macular edema, and/or other diabetic retinal disorders by orally administering to a human patient a substituted 2,3-dimethoxyquinone of Formula I, or a pharmaceutically acceptable salt thereof.
• the invention also provides methods for treating patients suffering from other disorders by administering to a human patient a substituted 2,3- dimethoxyquinone of Formula I, or a pharmaceutically acceptable salt thereof.
• Various aspects and embodiments of the therapeutic methods are described in the sections below. The sections are arranged for convenience and information in one section is not to be limited to that section, but may be applied to methods in other sections.
• One aspect of the invention provides a method of treating a 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 from about 480 mg to about 600 mg per day, to thereby treat the diabetic retinal disease, wherein the first therapeutic agent is a compound of Formula I or a pharmaceutically acceptable salt thereof:
• the method may be further characterized by additional features, such as the identity of the first therapeutic agent and the dosing regimen.
• additional features such as the identity of the first therapeutic agent and the dosing regimen.
• the invention embraces all permutations and combinations of these features.
• the method may be further characterized according to the identity of the first therapeutic agent.
• the first therapeutic agent is a compound of Formula I.
• the first therapeutic agent is a pharmaceutically acceptable salt of the compound of Formula I.
• the method may be further characterized according to the dosing regimen.
• a first dose of the first therapeutic agent and a second dose of the first therapeutic agent are orally administered to the patient on the same day.
• the first therapeutic agent is orally administered to a patient only 1 time per day.
• the first therapeutic agent is orally administered to the patient in an amount of about 600 mg per day.
• 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, and then at a time that is from about 8 hours to about 16 hours later about 240 mg of the first therapeutic agent is orally administered to the patient. In certain embodiments, about 360 mg of the first therapeutic agent is orally administered to the patient, and then at a time that is from about 10 hours to about 14 hours later about 240 mg of the first therapeutic agent is orally administered to the patient.
• 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, and then at a time that is from about 8 hours to about 16 hours later about 360 mg of the first therapeutic agent is orally administered to the patient. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient, and then at a time that is from about 10 hours to about 14 hours later about 360 mg of the first therapeutic agent is orally administered to the patient.
• 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, and then at a time that is from about 8 hours to about 16 hours later about 300 mg of the first therapeutic agent is orally administered to the patient. In certain embodiments, about 300 mg of the first therapeutic agent is orally administered to the patient, and then at a time that is from about 10 hours to about 14 hours later about 300 mg of the first therapeutic agent is orally administered to the patient.
• the first therapeutic agent is orally administered to the patient in the reduced-daily amount of about 480 mg per day.
• the first therapeutic agent is orally administered to a patient in an amount of about 480 mg per day.
• 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, and then at a time that is from about 8 hours to about 16 hours later about 240 mg of the first therapeutic agent is orally administered to the patient. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient, and then at a time that is from about 10 hours to about 14 hours later about 240 mg of the first therapeutic agent is orally administered to the patient.
• the first therapeutic agent is orally administered to the patient in the reduced-daily amount of about 300 mg per day. In certain embodiments, the first therapeutic agent is orally administered to the patient in the morning.
• Another aspect of the invention provides a method of treating a 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 from about 120 mg to about 600 mg per day, to thereby treat the diabetic retinal disease, wherein the first therapeutic agent is a compound of Formula I or a pharmaceutically acceptable salt thereof:
• the method may be further characterized by additional features, such as the identity of the first therapeutic agent, the dosing amount, and the dosing regimen.
• the invention embraces all permutations and combinations of these features.
• the method may be further characterized according to the identity of the first therapeutic agent.
• the first therapeutic agent is a compound of Formula I.
• the first therapeutic agent is a pharmaceutically acceptable salt of the compound of Formula I.
• the method may be further characterized according to the dosing amount.
• the first therapeutic agent is orally administered to the patient in an amount of about 300 mg per day.
• the first therapeutic agent is orally administered to the patient in an amount of about 240 mg per day.
• the first therapeutic agent is orally administered to the patient in an amount of about 120 mg per day.
• the method may be further characterized according to the dosing regimen.
• a first dose of the first therapeutic agent and a second dose of the first therapeutic agent are orally administered to the patient on the same day.
• the first therapeutic agent is orally administered to a patient only 1 time per day.
• 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.
• One aspect of the invention provides a method of reducing angiogenesis in retinal tissue in a human patient suffering from a diabetic retinal disease, comprising orally administering to a human patient in need thereof a first therapeutic agent in an amount of from about 480 mg to about 600 mg per day, to reduce angiogenesis in retinal tissue, wherein the first therapeutic agent is a compound of Formula I or a pharmaceutically acceptable salt thereof:
• the method may be further characterized by additional features, such as the identity of the first therapeutic agent and the dosing regimen.
• additional features such as the identity of the first therapeutic agent and the dosing regimen.
• the invention embraces all permutations and combinations of these features.
• the method may be further characterized according to the identity of the first therapeutic agent.
• the first therapeutic agent is a compound of Formula I.
• the first therapeutic agent is a pharmaceutically acceptable salt of the compound of Formula I.
• the method may be further characterized according to the dosing regimen.
• a first dose of the first therapeutic agent and a second dose of the first therapeutic agent are orally administered to the patient on the same day.
• the first therapeutic agent is orally administered to a patient only 1 time per day.
• the first therapeutic agent is orally administered to the patient in an amount of about 600 mg per day.
• 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, and then at a time that is from about 8 hours to about 16 hours later about 240 mg of the first therapeutic agent is orally administered to the patient. In certain embodiments, about 360 mg of the first therapeutic agent is orally administered to the patient, and then at a time that is from about 10 hours to about 14 hours later about 240 mg of the first therapeutic agent is orally administered to the patient.
• 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, and then at a time that is from about 8 hours to about 16 hours later about 360 mg of the first therapeutic agent is orally administered to the patient. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient, and then at a time that is from about 10 hours to about 14 hours later about 360 mg of the first therapeutic agent is orally administered to the patient.
• 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, and then at a time that is from about 8 hours to about 16 hours later about 300 mg of the first therapeutic agent is orally administered to the patient. In certain embodiments, about 300 mg of the first therapeutic agent is orally administered to the patient, and then at a time that is from about 10 hours to about 14 hours later about 300 mg of the first therapeutic agent is orally administered to the patient.
• the first therapeutic agent is orally administered to the patient in the reduced-daily amount of about 480 mg per day.
• the first therapeutic agent is orally administered to a patient in an amount of about 480 mg per day.
• 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, and then at a time that is from about 8 hours to about 16 hours later about 240 mg of the first therapeutic agent is orally administered to the patient. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient, and then at a time that is from about 10 hours to about 14 hours later about 240 mg of the first therapeutic agent is orally administered to the patient.
• the first therapeutic agent is orally administered to the patient in the reduced-daily amount of about 300 mg per day. In certain embodiments, the first therapeutic agent is orally administered to the patient in the morning.
• Another aspect of the invention provides a method of reducing angiogenesis in retinal tissue in a human patient suffering from a diabetic retinal disease, comprising orally administering to a human patient in need thereof a first therapeutic agent in an amount of from about 120 mg to about 600 mg per day, to reduce angiogenesis in retinal tissue, wherein the first therapeutic agent is a compound of Formula I or a pharmaceutically acceptable salt thereof:
• the method may be further characterized by additional features, such as the identity of the first therapeutic agent, the dosing amount, and the dosing regimen.
• additional features such as the identity of the first therapeutic agent, the dosing amount, and the dosing regimen.
• the invention embraces all permutations and combinations of these features.
• the method may be further characterized according to the identity of the first therapeutic agent.
• the first therapeutic agent is a compound of Formula I.
• the first therapeutic agent is a pharmaceutically acceptable salt of the compound of Formula I.
• the method may be further characterized according to the dosing amount.
• the first therapeutic agent is orally administered to the patient in an amount of about 300 mg per day.
• the first therapeutic agent is orally administered to the patient in an amount of about 240 mg per day.
• the first therapeutic agent is orally administered to the patient in an amount of about 120 mg per day.
• the method may be further characterized according to the dosing regimen.
• a first dose of the first therapeutic agent and a second dose of the first therapeutic agent are orally administered to the patient on the same day.
• the first therapeutic agent is orally administered to a patient only 1 time per day.
• 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. E. Fifth Method
• One aspect of the invention provides a method of reducing the activity of HIF-la and/or NF-KB in a human patient suffering from a diabetic retinal disease, comprising orally administering to a human patient in need thereof a first therapeutic agent in an amount of from about 480 mg to about 600 mg per day, to reduce the activity of HIF-Ia and/or NF-KB, wherein the first therapeutic agent is a compound of Formula I or a pharmaceutically acceptable salt thereof:
• the method may be further characterized by additional features, such as the identity of the first therapeutic agent and the dosing regimen.
• additional features such as the identity of the first therapeutic agent and the dosing regimen.
• the invention embraces all permutations and combinations of these features.
• the method may be further characterized according to the identity of the first therapeutic agent.
• the first therapeutic agent is a compound of Formula I.
• the first therapeutic agent is a pharmaceutically acceptable salt of the compound of Formula I.
• the method may be further characterized according to the dosing regimen.
• a first dose of the first therapeutic agent and a second dose of the first therapeutic agent are orally administered to the patient on the same day.
• the first therapeutic agent is orally administered to a patient only 1 time per day.
• the first therapeutic agent is orally administered to the patient in an amount of about 600 mg per day.
• 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, and then at a time that is from about 8 hours to about 16 hours later about 240 mg of the first therapeutic agent is orally administered to the patient. In certain embodiments, about 360 mg of the first therapeutic agent is orally administered to the patient, and then at a time that is from about 10 hours to about 14 hours later about 240 mg of the first therapeutic agent is orally administered to the patient.
• 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, and then at a time that is from about 8 hours to about 16 hours later about 360 mg of the first therapeutic agent is orally administered to the patient. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient, and then at a time that is from about 10 hours to about 14 hours later about 360 mg of the first therapeutic agent is orally administered to the patient.
• 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, and then at a time that is from about 8 hours to about 16 hours later about 300 mg of the first therapeutic agent is orally administered to the patient. In certain embodiments, about 300 mg of the first therapeutic agent is orally administered to the patient, and then at a time that is from about 10 hours to about 14 hours later about 300 mg of the first therapeutic agent is orally administered to the patient.
• the first therapeutic agent is orally administered to the patient in the reduced-daily amount of about 480 mg per day.
• the first therapeutic agent is orally administered to a patient in an amount of about 480 mg per day.
• 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, and then at a time that is from about 8 hours to about 16 hours later about 240 mg of the first therapeutic agent is orally administered to the patient. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient, and then at a time that is from about 10 hours to about 14 hours later about 240 mg of the first therapeutic agent is orally administered to the patient.
• the first therapeutic agent is orally administered to the patient in the reduced-daily amount of about 300 mg per day. In certain embodiments, the first therapeutic agent is orally administered to the patient in the morning.
• One aspect of the invention provides a method of reducing the activity of HIF-la and/or NF-KB in a human patient suffering from a diabetic retinal disease, comprising orally administering to a human patient in need thereof a first therapeutic agent in an amount of from about 120 mg to about 600 mg per day, to reduce the activity of HIF-Ia and/or NF-KB, wherein the first therapeutic agent is a compound of Formula I or a pharmaceutically acceptable salt thereof:
• the method may be further characterized by additional features, such as the identity of the first therapeutic agent, the dosing amount, and the dosing regimen.
• additional features such as the identity of the first therapeutic agent, the dosing amount, and the dosing regimen.
• the invention embraces all permutations and combinations of these features.
• the method may be further characterized according to the identity of the first therapeutic agent.
• the first therapeutic agent is a compound of Formula I.
• the first therapeutic agent is a pharmaceutically acceptable salt of the compound of Formula I.
• the method may be further characterized according to the dosing amount.
• the first therapeutic agent is orally administered to the patient in an amount of about 300 mg per day.
• the first therapeutic agent is orally administered to the patient in an amount of about 240 mg per day.
• the first therapeutic agent is orally administered to the patient in an amount of about 120 mg per day.
• the method may be further characterized according to the dosing regimen.
• a first dose of the first therapeutic agent and a second dose of the first therapeutic agent are orally administered to the patient on the same day.
• the first therapeutic agent is orally administered to a patient only 1 time per day.
• 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.
• One aspect of the invention provides a method of treating a disease or condition in a human patient, comprising administering to a human patient in need thereof a first therapeutic agent to thereby treat the disease or condition, wherein the first therapeutic agent is a compound of Formula I or a pharmaceutically acceptable salt thereof:
• the method may be further characterized by additional features, such as the identity of the disease or condition, the identity of the first therapeutic agent, the dosing amount, and the dosing regimen.
• additional features such as the identity of the disease or condition, the identity of the first therapeutic agent, the dosing amount, and the dosing regimen.
• the invention embraces all permutations and combinations of these features.
• the method may be further characterized according to the identity the disease or condition.
• 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.
• the disease or condition is wet age-related macular degeneration.
• the disease or condition is dry age-related macular degeneration.
• the disease or condition is retinal vein occlusion.
• the disease or condition is geographic atrophy.
• the disease or condition is retinal neovascularization.
• the disease or condition is choroidal neovascularization.
• the disease or condition is comeal graft rejection.
• the disease or condition is ocular oncology. In certain embodiments, the disease or condition is a solid tumor. In certain embodiments, the disease or condition is a cancer due to human myeloid leukemia mononuclear 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 an esophageal adenocarcinoma.
• 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, gastro-intestinal disfunction, or chronic gastroesophageal reflux disease (GERD).
• the disease or condition is an inflammatory skin disorder.
• the disease or condition is psoriasis, atopic dermatitis, or rosacea.
• the disease or condition is dry eye disease.
• the disease or condition is uveitis.
• 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 inherited retinal diseases (e.g., retinitis pigmentosa, choroideremia, Stargardt disease, cone-rod dystrophy, or Leber 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 gastro intestinal disfunction. In certain embodiments, the disease or condition is chronic gastroesophageal reflux disease (GERD).
• GGID chronic gastroesophageal reflux disease
• the disease or condition is diabetic retinal disease.
• the method may be further characterized according to the identity of the first therapeutic agent.
• the first therapeutic agent is a compound of Formula I.
• the first therapeutic agent is a pharmaceutically acceptable salt of the compound of Formula I.
• the method may be further characterized according to the dosing amount.
• the first therapeutic agent is orally administered to the patient in an amount of from about 120 mg to about 600 mg per day.
• the first therapeutic agent is orally administered to the patient in an amount of from about 480 mg to about 600 mg per day.
• the first therapeutic agent is orally administered to the patient in an amount of about 600 mg per day.
• the first therapeutic agent is orally administered to the patient in an amount of about 480 mg per day.
• the first therapeutic agent is orally administered to the patient in an amount of about 300 mg per day.
• the first therapeutic agent is orally administered to the patient in an amount of about 240 mg per day.
• the first therapeutic agent is orally administered to the patient in an amount of about 120 mg per day.
• the method may be further characterized according to the dosing regimen.
• a first dose of the first therapeutic agent and a second dose of the first therapeutic agent are orally administered to the patient on the same day.
• the first therapeutic agent is orally administered to a patient only 1 time per day.
• 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.
• 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, and then at a time that is from about 8 hours to about 16 hours later about 240 mg of the first therapeutic agent is orally administered to the patient. In certain embodiments, about 360 mg of the first therapeutic agent is orally administered to the patient, and then at a time that is from about 10 hours to about 14 hours later about 240 mg of the first therapeutic agent is orally administered to the patient.
• 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, and then at a time that is from about 8 hours to about 16 hours later about 360 mg of the first therapeutic agent is orally administered to the patient. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient, and then at a time that is from about 10 hours to about 14 hours later about 360 mg of the first therapeutic agent is orally administered to the patient.
• 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, and then at a time that is from about 8 hours to about 16 hours later about 300 mg of the first therapeutic agent is orally administered to the patient. In certain embodiments, about 300 mg of the first therapeutic agent is orally administered to the patient, and then at a time that is from about 10 hours to about 14 hours later about 300 mg of the first therapeutic agent is orally administered to the patient.
• the first therapeutic agent is orally administered to the patient in the reduced-daily amount of about 480 mg per day.
• 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, and then at a time that is from about 8 hours to about 16 hours later about 240 mg of the first therapeutic agent is orally administered to the patient. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the patient, and then at a time that is from about 10 hours to about 14 hours later about 240 mg of the first therapeutic agent is orally administered to the patient.
• the first therapeutic agent is orally administered to the patient in the reduced-daily amount of about 300 mg per day. In certain embodiments, the first therapeutic agent is orally administered to the patient in the morning.
• 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 comeal graft rejection, wherein the comprises orally administering to a human patient in need thereof a first therapeutic agent in an amount of from about 120 mg to about 600 mg per day, to thereby treat the disease or disease or condition, wherein the first therapeutic agent is a compound of Formula I or a pharmaceutically acceptable salt thereof:
• the methods may be further characterized according to the duration of daily oral administration of the first therapeutic agent.
• the amount of the first therapeutic agent is orally administered to the patient daily for at least 1 week.
• the amount of the first therapeutic agent is orally administered to the patient daily for at least 2 weeks.
• the amount of the first therapeutic agent is orally administered to the patient daily for at least 4 weeks.
• the amount of the first therapeutic agent is orally administered to the patient daily for at least 6 weeks.
• the amount of the first therapeutic agent is orally administered to the patient daily for at least 8 weeks.
• the amount of the first therapeutic agent is orally administered to the patient daily for at least 10 weeks.
• 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 orally administered to the patient daily for at least 30, 32, 34, 36, 38 40, 42, 44, 46, 48, 50, or 52 weeks.
• the methods may be further characterized according to characteristics of the diabetic retinal disease.
• the diabetic retinal disease is diabetic retinopathy.
• the diabetic retinopathy is mild diabetic retinopathy.
• the diabetic retinopathy is moderate diabetic retinopathy.
• the diabetic retinopathy is moderately severe to severe diabetic retinopathy.
• the diabetic retinopathy is non-proliferative diabetic retinopathy.
• the diabetic retinopathy is proliferative diabetic retinopathy.
• the diabetic retinal disease is diabetic macular edema.
• the methods may be further characterized according to additional considerations, such as the form in which the first therapeutic agent is administered, identity of the human patient, and improvement in diabetic retinal disease achieved by the method.
• the first therapeutic agent is orally administered to the patient in the form of an extended-release pharmaceutical composition
• the first therapeutic agent is orally administered to the patient in the form of an extended-release pharmaceutical composition that provides release of the first therapeutic agent for duration of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours.
• the first therapeutic agent is orally administered to the patient in the form of an immediate- release pharmaceutical composition.
• the human patient is an adult human patient.
• the method is further characterized according to the improvement in diabetic retinopathy severity score.
• the patient experiences a reduction of at 5, 10, 15, 20, 25, 30, 35, or 40 points in the diabetic retinopathy severity score due to the method.
• the patient experiences at least a two-step reduction in diabetic retinopathy severity score due to the method.
• the patient experiences at least a three-step reduction in diabetic retinopathy severity score due to the method.
• the method is further characterized according to the improvement in best-corrected visual acuity.
• the patient experiences an improvement of at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% in best-corrected visual acuity due to the method.
• the patient experiences an improvement of at least 2, 4, 6, 8, 10, 12, 14, 16, or 18 letters in best- corrected visual acuity due to the method.
• Best-corrected visual acuity can be measured according to methods known in the art, for example, with a Standard ETDRS illuminated chart (on wall or stand) at 4 m. Alternatively, best-corrected visual acuity can be measured using a Snellen chart.
• the method is further characterized according to impact on a symptom of diabetes.
• the method reduces a symptom of diabetes.
• the method reduces any renal impairment experienced by the patient.
• the method reduces any renal impairment 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 percent. The said reduction in renal impairment is relative to that experienced by a comparable patient that has not received therapy according to the method using the first therapeutic agent.
• the method achieves a neuroprotective effect.
• the method is further characterized by the feature that any increase in blood plasma concentration of alanine aminotransferase due to the first therapeutic agent is no greater than 5%.
• the method is further characterized by the feature that any increase in blood plasma concentration of alanine aminotransferase due to the first therapeutic agent is no greater than 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 15 percent.
• the method is further characterized by the feature it results in a reduction in blood plasma concentration of alanine aminotransferase due to the first therapeutic agent.
• the reduction is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
• the method is further characterized by the feature that any increase in blood plasma concentration of aspartate aminotransferase due to the first therapeutic agent is no greater than 5%. In certain embodiments, the method is further characterized by the feature that any increase in blood plasma concentration of aspartate aminotransferase due to the first therapeutic agent is no greater than 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 15 percent.
• the method is further characterized by the feature it results in a reduction in blood plasma concentration of aspartate aminotransferase due to the first therapeutic agent.
• the reduction is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
• the method is further characterized by the feature that any reduction in glomerular filtration rate in the patient is no greater than 15%. In certain embodiments, the method is further characterized by the feature that any reduction in glomerular filtration rate in the patient is no greater than 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 15 percent.
• the method is further characterized by the feature that the incidence of any eye disorder due to the first therapeutic agent occurs no more frequently than one patient for every ten patients subjected to the same treatment. In certain embodiments, the method is further characterized by the feature that the incidence of any eye disorder due to the first therapeutic agent occurs no more frequently than one patient for every 10, 12, 14, 16, 18,
• the method is further characterized by the feature that the incidence of any eye disorder due to the first therapeutic agent occurs no more frequently than one patient for every twenty patients subjected to the same treatment. In certain embodiments, the method is further characterized by the feature that the incidence of any eye disorder due to the first therapeutic agent occurs no more frequently than one patient for every 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, or 40 patients subjected to the same treatment.
• the method is further characterized by the feature that the incidence of any gastrointestinal disorder due to the first therapeutic agent occurs no more frequently than one patient for every ten patients subjected to the same treatment. In certain embodiments, the method is further characterized by the feature that the incidence of any gastrointestinal disorder due to the first therapeutic agent occurs no more frequently than one patient for every 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, or 40 patients subjected to the same treatment.
• the method is further characterized by the feature that the incidence of any nervous system disorder due to the first therapeutic agent occurs no more frequently than one patient for every twenty patients subjected to the same treatment. In certain embodiments, the method is further characterized by the feature that the incidence of any nervous system disorder due to the first therapeutic agent occurs no more frequently than one patient for every 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, or 40 patients subjected to the same treatment.
• Another aspect of the invention provides for the use of the first therapeutic agent described herein in the manufacture of a medicament.
• the medicament is for treating a disorder described herein, for example, for treating diabetic retinopathy, diabetic macular edema, and/or other diabetic retinal disorders.
• Another aspect of the invention provides for the use of the first therapeutic agent described herein for treating a medical disorder, such as a medical disorder described herein, for example, for treating diabetic retinopathy, diabetic macular edema, and/or other diabetic retinal disorders.
• a medical disorder such as a medical disorder described herein, for example, for treating diabetic retinopathy, diabetic macular edema, and/or other diabetic retinal disorders.
• Another aspect of the invention provides for combination therapy.
• Second, Third, Fourth, Fifth, Sixth, and Seventh Therapeutic Methods described hereinabove may optionally further comprise administering one or more second therapeutic agents to the patient.
• the method further comprises administering to the patient a second therapeutic agent for treating diabetic retinal disease.
• the second therapeutic agent that is an anti-inflammatory agent, anti-angiogenic agent, tyrosine kinase inhibitor, angiopoietin-2 inhibitor, and/or vascular endothelial growth factor inhibitor.
• the second therapeutic agent is a vascular endothelial growth factor inhibitor.
• the vascular endothelial growth factor inhibitor is sorafenib, sunitinib, pazopanib, bevacizumab, ranibizumab, aflibercept, nilotinib, or dasatinib.
• the vascular endothelial growth factor inhibitor is a bispecific antibody.
• the anti-inflammatory agent is a corticosteroid.
• the second therapeutic agent is a VEGF inhibitor, mTor inhibitor, VEGFR2 phosphorylation agent, tyrosine kinase inhibitor, IGF-1R inhibitor, nicotinic acetylcholine receptor antagonist, selective inhibitor of glycation, corticosteroid, NSAID, flavonoid, TNF alpha inhibitor, PKC inhibitor, aldose reductase, PARP inhibitor, reactive oxygen species inhibitor, AT-I Receptor modulator, AT-II receptor modular, rho associated protein kinase inhibitor, protease inhibitor, nitric oxide synthase inhibitor, AGE inhibitor, or PPAR-gamma up-regulator.
• the second therapeutic agent is an immunoncology 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.
• the second therapeutic agent is a bone marrow transplant or related transplant.
• the modulator is an inhibitor.
• the method further comprises administering to the patient a second therapeutic agent that is an anti-inflammatory agent, anti- angiogenic agent, tyrosine kinase inhibitor, angiopoietin-2 inhibitor, and/or vascular endothelial growth factor inhibitor.
• the method further comprises administering to the patient a second therapeutic agent that is a vascular endothelial growth factor inhibitor.
• the vascular endothelial growth factor inhibitor is sorafenib, sunitinib, pazopanib, bevacizumab, ranibizumab, aflibercept, nilotinib, or dasatinib.
• the vascular endothelial growth factor inhibitor is a bispecific antibody.
• the anti inflammatory agent is a corticosteroid.
• the first therapeutic agent is the only therapeutic agent for treating diabetic retinal disease that is administered to the human patient.
• the second therapeutic agent is an immunosuppressant, anti-inflammatory agent, light therapy (e.g., sunlight, UVA, UVB, Psoralen UVA, or Excimer laser), a retinoid, a corticosteroid, a Vitamin D analogue, a calcineurin inhibitor, salicylic acid, anthralin, coal tar, or Goeckerman therapy (e.g., light and coal tar).
• light therapy e.g., sunlight, UVA, UVB, Psoralen UVA, or Excimer laser
• a retinoid e.g., a corticosteroid
• a Vitamin D analogue e.g., a calcineurin inhibitor
• salicylic acid e.g., anthralin
• coal tar e.g., calcineurin inhibitor
• Goeckerman therapy e.g., light and coal tar
• the second therapeutic agent and optionally additional therapeutic agents may be administered separately from a compound or composition of the invention, as part of a multiple dosage regimen.
• the second therapeutic agent and optionally additional therapeutic agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition.
• the second therapeutic agent and optionally additional therapeutic agents and a compound or composition of the invention may be administered simultaneously, sequentially or within a period of time from one another, 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 from one another.
• the second therapeutic agent and optionally additional therapeutic agents and a compound or composition of the invention are administered as a multiple dosage regimen more than 24 hours apart.
• the invention provides pharmaceutical compositions, which comprise a therapeutically effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
• the pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue.
• wetting agents, emulsifiers and lubricants 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 compositions.
• antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
• water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
• oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
• the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
• the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
• the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
• a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and poly anhydrides; and a compound of the present invention.
• an aforementioned formulation renders orally bioavailable a compound of the present invention.
• Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
• Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
• a compound of the present invention may also be administered as a bolus, electuary or paste.
• the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such
• compositions may also comprise buffering agents.
• Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
• a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
• Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
• the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried.
• compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
• These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
• embedding compositions which can be used include polymeric substances and waxes.
• the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
• Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents
• the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
• adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
• Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
• suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
• aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
• polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
• vegetable oils such as olive oil
• injectable organic esters such as ethyl oleate.
• Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
• compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions.
• the pharmaceutical composition may be in the form of a cream, colloidal, suspension, spray, gel, lotion, ointment, foam, or solution.
• the pharmaceutical composition may be in the form of a solution for injection.
• the pharmaceutical composition may be in the form of a solution for sub cutaneous injection.
• Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
• the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
• a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. When the compounds described herein are co-administered with another agent (e.g., as sensitizing agents), the effective amount may be less than when the agent is used alone.
• 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.
• the invention further provides a unit dosage form (such as a tablet or capsule) comprising a compound described herein in a therapeutically effective amount for the treatment of a medical disorder described herein.
• a unit dosage form such as a tablet or capsule
• Another aspect of the invention provides a medical kit comprising, 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 methods described herein.
• Compound 1 to treat non-proliferative diabetic retinopathy (NPDR) and mild proliferative diabetic retinopathy (PDR) may be evaluated according to a clinical study in which Compound 1 is orally administered to patients suffering from non-proliferative diabetic retinopathy or mild proliferative diabetic retinopathy.
• Compound 1 has the chemical name (£)- 2- ((4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4-dien-l-yl)methylene)undecanoic acid, and is depicted by the following chemical formula:
• the study is to be configured as a placebo-controlled, double-masked, randomized, Phase 2 study in approximately 100 subjects with moderately severe to severe NPDR (diabetic retinopathy severity score [DRSS] Level 47 or 53, see Figure 1) or mild PDR (DRSS Level 61), evaluating safety and efficacy following administration of Compound 1 twice daily for 24 weeks.
• the study will have a 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% for each arm.
• Efficacy evaluations at 12 and/or 24 weeks will include DRSS, center- involved diabetic macular edema (DME), moderate PDR or PDR-related adverse events (AEs), best-corrected visual acuity (BCVA), and central subfield thickness (CST). Further experimental procedures and results are described below.
• DME center- involved diabetic macular edema
• AEs moderate PDR or PDR-related adverse events
• BCVA best-corrected visual acuity
• CST central subfield thickness
• Human subjects will be screened for potential enrollment and, if qualified, enrolled in the study. Inclusion criteria and exclusion criteria for the study are set forth below. Human subjects can qualify in either eye.
• the eligible eye with the higher DRSS will be designated as the study eye for the primary endpoint efficacy analysis. If the PDR cap is reached, the study eye may be an eye with the lower DRSS, if the other eye has mild PDR. If both eyes have the same DRSS, the eye with the worse BCVA will be selected as the study eye. If the DRSS and BCVA are equivalent between both eyes, the study eye will be the right eye.
• PRP panretinal laser photocoagulation
• Body mass index (BMI) between 18 and 40 kg/m 2 , inclusive.
• DME center-involved diabetic macular edema
• CST central subfield thickness
• Uncontrolled glaucoma in either eye defined as advanced cup-to-disc ratio > 0.7 and intraocular pressure (IOP) > 25 mmHg, with or without topical antihypertensive eye drops; treatment of ocular hypertension or controlled glaucoma are not criteria for exclusion.
• IOP intraocular pressure
• YAG Yttrium aluminum garnet
• Active infection in either eye including infectious conjunctivitis, keratitis, scleritis, or endophthalmitis.
• HbAlc hemoglobin Ale
• Clinically significant systemic disease e.g., uncontrolled diabetes, myasthenia gravis, cancer, hepatic, renal, endocrine, or cardiovascular disorders
• systemic disease e.g., uncontrolled diabetes, myasthenia gravis, cancer, hepatic, renal, endocrine, or cardiovascular disorders
• HR Resting heart rate outside the specified range of 50-110 beats per minute at the Screening Visit. HR may be repeated only once if outside the specified range following at least a 5-minute rest period in the sitting position.
• BP may be repeated only once if outside the specified range following at least a 5-minute rest period in the sitting position.
• ALT alanine aminotransferase
• AST aspartate aminotransferase
• Subjects will be screened at Visit 1 and those successfully completing eligibility requirements will return to site for their Qualification/Baseline Visit (Visit 2/Day 1) where they will undergo a set of safety and lab test assessments and study medication will be dispensed. Subjects will then return to site at Visit 4 (Week 4), Visit 6 (Week 12) and Visit 9 (Week 24) for safety and efficacy assessments. In between these site visits, subjects will be contacted by telephone on Visit 3 (Week 1), Visit 5 (Week 8), Visit 7 (Week 16), and Visit 8 (Week 20) for a safety assessment to include AEs, concomitant medications, and drug accountability.
• Study medication will be dispensed initially at Visit 2 (Day 1) and 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 drug accountability. Study medication will be collected at site during Visit 9 (Week 24). A follow-up Phone Call will be conducted one week after Visit 9 (Week 24) for AE and concomitant medication assessments.
• the start of Screening includes the assignment of a subject identification number, an explanation of the study, a medical and ophthalmic history, demographics, and a review of prior/concomitant medications.
• BCVA will be measured and SD-OCT (for CST) and color fundus photographs (for DRSS) will be performed.
• DRSS eligibility will be determined by a central reading center with 7-field or 4-wide field fundus photography. The central reading center will also determine CST eligibility with SD-OCT.
• BCVA (distance) can be measured with a Standard ETDRS illuminated chart (on wall or stand) at 4 m.
• assessments of blood chemistry and hematology ophthalmic examination that includes biomicroscopy and direct or indirect ophthalmoscopy, IOP assessment, eGFR, and AEs.
• BCVA, DRSS, CST and other safety assessments performed at Screening will be the baseline values, and the subject will be asked to return for their Qualification Visit.
• Study medication APX3330 or placebo
• Study medication should be taken at approximately the same time each day and may be taken with or without food.
• HR/B P/vital signs BCVA (ETDRS), DRSS, CST (SD-OCT), blood draw for PK, blood chemistry, blood hematology, biomicroscopy, ophthalmoscopy, IOP, eGFR, and AEs.
• a telephone follow-up call will be conducted for Visit 10 (Week 25 + 2 Days) to evaluate concomitant medications and AEs.
• Study subjects will receive study medication as set forth in Table 1 according to the Treatment Group to which the subject is assigned. Subjects will be instructed to take study medication at approximately the same time each day, and the medication may be taken with or without food. Study medication is listed in Table 2.
• Any subject is permitted to voluntarily withdraw from the study at any time without prejudice.
• a non-completing subject is defined as one who exited the study by their own volition or at the discretion of the Investigator and/or the Medical Monitor prior to completing all of the study procedures required in the protocol.
• the Investigator may offer a dose reduction from 600 mg to 480 mg per day as an alternative (2 tablets every morning and 2 tablets every evening).
• the primary efficacy endpoint will be the percent of subjects with a > 2-step improvement in DRSS in the study eye at Week 24. Secondary efficacy endpoints will include:
• Exploratory efficacy endpoints will include:
• Measurements will be determined as follows, where every effort will be made to have the same person perform the measurements at all timepoints and at all visits:
• BCVA will be measured by Standard ETDRS chart at 4 m (letters).
• Safety endpoints will include:
• IOP intraocular pressure
• Analysis populations will include:
• the mITT will include all randomized subjects who received at least one dose of study treatment and at least one post-dose efficacy measurement. The mITT will be used to analyze efficacy endpoints.
• Per Protocol Population The PP population will include all subjects in the mITT who have missed less than 20% of expected doses and do not have any major protocol deviations considered to have significant impact on treatment outcome. The PP population will be used for primary endpoint analysis and to analyze efficacy endpoints.
• ARP All Randomized Population
• ITT Intent-to-Treat
• SP Safety Population
• the SP will include all randomized subjects who have received at least one dose of study treatment.
• the SP will be used to summarize safety variables.
• Table 4 below provides results from analysis of concentration of aspartate aminotransferase in subjects' blood.
• Table 5 provides results from analysis of glomerular filtration rate of subjects.
• Table 6 below provides results from analysis of heart rate of subjects. Table 6.
• Table 7 provides results from analysis of systolic blood pressure of subjects.
• Table 9 below provides a summary of occurrence of adverse events across 100 subjects enrolled in the study, which is the combined results from patients that received placebo and those that 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 from the 100 subject enrolled in the study. A subject reporting more than one treatment-emergent adverse event is only counted once within the System Organ Class in Table 9.

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