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WO2025217571A1 - Associations à doses fixes d'inhibiteur d'intégrine avec des agonistes de ppar - Google Patents

Associations à doses fixes d'inhibiteur d'intégrine avec des agonistes de ppar

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Publication number
WO2025217571A1
WO2025217571A1 PCT/US2025/024354 US2025024354W WO2025217571A1 WO 2025217571 A1 WO2025217571 A1 WO 2025217571A1 US 2025024354 W US2025024354 W US 2025024354W WO 2025217571 A1 WO2025217571 A1 WO 2025217571A1
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WO
WIPO (PCT)
Prior art keywords
fixed dose
dose combination
pharmaceutically acceptable
acceptable salt
bexotegrast
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/024354
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English (en)
Inventor
Johanna Roberta SCHAUB
Martin L. DECARIS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pliant Therapeutics Inc
Original Assignee
Pliant Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pliant Therapeutics Inc filed Critical Pliant Therapeutics Inc
Publication of WO2025217571A1 publication Critical patent/WO2025217571A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the disclosure relates to, inter alia, use of the integrin inhibitor bexotegrast in combination with PPAR agonists for treatment of liver fibrosis, primary sclerosing cholangitis, or primary biliary cholangitis.
  • Fibrosis a pathologic feature of many diseases, is caused by a dysfunction in the body’s natural ability to repair damaged tissues. If left untreated, fibrosis can result in scarring of vital organs causing irreparable damage and eventual organ failure.
  • PSC Primary sclerosing cholangitis
  • fibrosis that obliterates the bile ducts.
  • the resulting impediment to the flow of bile to the intestines can lead to cirrhosis of the liver and subsequent complications such as liver failure and liver cancer.
  • Bile duct surgery can temporarily open blocked bile ducts, but is not a long-term solution or cure.
  • a liver transplant can result in a positive outcome for resolution of PSC.
  • a suitable organ for transplantation may not be available for a given patient.
  • UDCA Ursodeoxycholic acid
  • a peroxisome proliferator-activated receptor (PPAR) agonist such as an agonist of PPARa, an agonist of PPAR5, or a dual PPARa/5 agonist.
  • PPAR peroxisome proliferator-activated receptor
  • bexotegrast or a pharmaceutically acceptable salt thereof, and fenofibrate, or a pharmaceutically acceptable salt thereof.
  • fixed dose combinations of bexotegrast, or a pharmaceutically acceptable salt thereof, and fenofibrate Further disclosed are fixed dose combinations of bexotegrast, or a pharmaceutically acceptable salt thereof, and elafibranor. Further disclosed are fixed dose combinations of bexotegrast, or a pharmaceutically acceptable salt thereof, and seladelpar.
  • a method of treating a fibrotic disease in an individual comprising administering to the individual a fixed dose combination of bexotegrast, or a pharmaceutically acceptable salt thereof, and fenofibrate, or a pharmaceutically acceptable salt thereof.
  • a method of treating a fibrotic disease in an individual comprising administering to the individual a fixed dose combination of bexotegrast, or a pharmaceutically acceptable salt thereof, and elafibranor, or a pharmaceutically acceptable salt thereof.
  • a fixed dose combination comprising (S)-4-((2- methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and a peroxisome proliferator-activated receptor agonist (PPAR agonist), or a pharmaceutically acceptable salt thereof.
  • the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination can be about 40 mg.
  • the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination can be about 80 mg.
  • the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination can be about 160 mg.
  • the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination can be about 320 mg.
  • the PPAR agonist in the fixed dose combination is an agonist of PPARa.
  • the PPAR agonist can comprise fenofibrate, or a pharmaceutically acceptable salt thereof.
  • the PPAR agonist is fenofibrate, or a pharmaceutically acceptable salt thereof.
  • the PPAR agonist is a choline salt of fenofibrate.
  • the PPAR agonist is fenofibrate.
  • the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination can be about 30 mg, about 40 mg, about 43 mg, about 45 mg, about 48 mg, about 50 mg, about 54 mg, about 67 mg, about 87 mg, about 90 mg, about 100 mg, about 107 mg, about 120 mg, about 130 mg, about 134 mg, about 135 mg, about 145 mg, about 150 mg, about 160 mg, or about 200 mg.
  • the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination can be about 48 mg.
  • the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination can be about 54 mg.
  • the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination can be about 67 mg.
  • the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination can be about 135 mg.
  • the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination can be about 145 mg.
  • the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination can be about 160 mg.
  • the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination can be about 200 mg.
  • the PPAR agonist in the fixed dose combination is a dual PPARa/5 agonist.
  • the PPAR agonist can comprise elafibranor, or a pharmaceutically acceptable salt thereof.
  • the PPAR agonist is elafibranor, or a pharmaceutically acceptable salt thereof.
  • the PPAR agonist is elafibranor.
  • the amount of the elafibranor, or a pharmaceutically acceptable salt thereof, in the fixed dose combination can be about 80 mg.
  • the amount of the elafibranor or a pharmaceutically acceptable salt thereof in the fixed dose combination can be about 120 mg.
  • the PPAR agonist in the fixed dose combination is a PPAR5 agonist.
  • the PPAR agonist can comprise seladelpar, or a pharmaceutically acceptable salt thereof.
  • the PPAR agonist is seladelpar, or a pharmaceutically acceptable salt thereof.
  • the PPAR agonist is a lysine salt of seladelpar.
  • the PPAR agonist is seladelpar.
  • the amount of the seladelpar, or a pharmaceutically acceptable salt thereof, in the fixed dose combination can be about 2 mg.
  • the amount of the seladelpar, or a pharmaceutically acceptable salt thereof, in the fixed dose combination can be about 5 mg.
  • the amount of the seladelpar, or a pharmaceutically acceptable salt thereof, in the fixed dose combination can be about 10 mg.
  • a fixed dose combination comprising a dose selected from Table 1, Table 2, Table 3, Table 4, Table 5, or Table 6. In embodiments, provided is a fixed dose combination comprising a dose selected from Table 1, Table 2, Table 3, Table 4, Table 5, and Table 6.
  • Also provided herein is a fixed dose combination comprising elafibranor and (S)-4-((2- methoxyethyl)(4-(5, 6,7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, for use in the treatment of primary biliary cholangitis in a subject in need thereof.
  • the bexotegrast for use in any of the fixed dose combinations, and methods using the fixed dose combinations, including methods of treatment of disease or methods of treating a subject in need thereof, or use of the fixed dose combinations for treatment of a disease or a subject in need thereof can be a bexotegrast compound, salt, or polymorph disclosed in United States Patent No. 12,018,025, United States Patent No. 10,793,564, United States Patent No. 11,419,869, and United States Patent Application Publication No. US 2023/0028658. The entire contents of each of the preceding patent documents are incorporated herein by reference.
  • the bexotegrast or pharmaceutically acceptable salt thereof is a phosphate salt, a fumarate salt, a naphthalenedisulfonic acid salt, a polymorph (including a crystalline Form I phosphate salt, a crystalline Form IV phosphate salt, a crystalline Form II fumarate salt, and a crystalline Form III naphthalenedisulfonic acid salt), a zwitterionic form, or an amorphous form.
  • the bexotegrast, or pharmaceutically acceptable salt thereof is a phosphate salt.
  • the bexotegrast or pharmaceutically acceptable salt thereof is a Form I phosphate salt.
  • FIG. 1 shows gene expression in precision cut liver slices from a rat bile duct ligation model, after in vitro combination treatment of bexotegrast/elafibranor and bexotegrast/fenofibrate.
  • FIG. 2 shows gene expression in precision cut liver slices from a donor liver from a human with primary sclerosing cholangitis, after in vitro combination treatment of bexotegrast/fenofibrate.
  • FIG. 3 shows gene expression in precision cut liver slices from a rat bile duct ligation model, after in vitro combination treatment of bexotegrast/seladelpar.
  • the present disclosure provides, inter alia, fixed dose combinations of (S)-4-((2- methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, with the peroxisome proliferator-activated receptor (PPAR) agonist fenofibrate, or a pharmaceutically acceptable salt thereof, fixed dose combinations of (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro- l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, with the PPAR
  • Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.
  • description referring to “about X” includes description of “X”.
  • the term “about,” when used in association with a measurement or to modify a parameter or a value or a range of values refers to variations of that measurement, parameter, value, or range of values of +/- 10%, +/- 9%, +/- 8%, +/- 7%, +/- 6%, +/- 5%, +/- 4%, +/- 3%, +/- 2%, or +/- 1%.
  • “about X” includes and describes X +/- 10%, +/- 9%, +/- 8%, +/- 7%, +/- 6%, +/- 5%, +/- 4%, +/- 3%, +/- 2%, or +/- 1% of X.
  • the term “about” refers to variations of +/- 5%, +/- 4%, +/- 3%, +/- 2%, or +/- 1%.
  • the term “about” refers to variations of +/- 2% or +/- 1%.
  • the term “about” refers to variations of +/- 2%.
  • the term “about” refers to variations of +/- 1%.
  • an individual intends a mammal, including but not limited to a primate, human, bovine, horse, feline, canine, or rodent. In one variation, the individual is a human.
  • treatment is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread of the disease, delaying the occurrence or recurrence of the disease, delay or slowing the progression of the disease, ameliorating the disease state, providing a remission (whether partial or total) of the disease, decreasing the dose of one or more other medications required to treat the disease, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
  • treatment is a reduction of pathological consequence of fibrosis. The methods disclosed herein contemplate any one or more of these aspects of treatment.
  • additive effect refers to the effect produced by two or more therapeutic agents administered in combination, which is equal to the mathematical sum of the effects of each individual therapeutic agent when administered separately.
  • therapeutic agents A and B produce an additive effect when the effect of their combination is equal to the sum of: (the effect achieved by therapeutic agent A alone) + (the effect achieved by therapeutic agent B alone).
  • two or more therapeutic agents produce an “antagonistic effect” when the total effect of the combination is less than the sum of each individual agent administered separately.
  • “synergistic effect” refers to the effect produced by two or more therapeutic agents administered in combination, which is greater than the mathematical sum of the effects of each individual therapeutic agent when administered separately.
  • therapeutic agents A and B produce a synergistic effect when the effect of their combination is greater than the sum of: (the effect achieved by therapeutic agent A alone) + (the effect achieved by therapeutic agent B alone).
  • an effective amount intends such amount of a compound disclosed herein which should be effective in a given therapeutic form.
  • an effective amount may be in one or more doses, z.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint.
  • An effective amount may be considered in the context of administering one or more therapeutic agents (e.g., a compound, or pharmaceutically acceptable salt thereof), and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.
  • Suitable doses of any of the co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.
  • a “therapeutically effective amount” refers to an amount of a compound or salt thereof (e.g., pharmaceutically acceptable salt thereof) sufficient to produce a desired therapeutic outcome.
  • unit dosage form refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredients calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • controlled release refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate, z.e., with a “controlled release” formulation, administration does not result in immediate release of the drug into an absorption pool.
  • the term encompasses depot formulations designed to gradually release the drug compound over an extended period of time.
  • Controlled release formulations can include a wide variety of drug delivery systems, generally involving mixing the drug compound with carriers, polymers or other compounds having the desired release characteristics (e.g, pH-dependent or non-pH-dependent solubility, different degrees of water solubility, and the like) and formulating the mixture according to the desired route of delivery e.g., coated capsules, implantable reservoirs, injectable solutions containing biodegradable capsules, and the like).
  • desired release characteristics e.g, pH-dependent or non-pH-dependent solubility, different degrees of water solubility, and the like
  • composition refers to the combination of an active agent with an excipient or a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
  • Pharmaceutical compositions may be prepared by known pharmaceutical methods. Suitable compositions, excipients, or carriers can be found, e.g., in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21 st ed. (2005), which is incorporated herein by reference in its entirety.
  • pharmaceutically acceptable or “pharmacologically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
  • “Pharmaceutically acceptable salts” are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an individual. See, e.g., Handbook of Pharmaceutical Salts Properties, Selection, and Use, International Union of Pure and Applied Chemistry, John Wiley & Sons (2008), hereby incorporated by reference in its entirety.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid, and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base.
  • Acceptable organic bases include choline, ethanolamine, diethanolamine, triethanolamine, and the like.
  • Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
  • Pharmaceutically acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound disclosed herein in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification.
  • excipient means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound disclosed herein as an active ingredient. See, e.g., Handbook of Pharmaceutical Excipients. 6 th Edition, Pharmaceutical Press (2008), hereby incorporated by reference in its entirety.
  • excipient including without limitation, any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent.
  • substantially pure intends a composition that contains no more than about 5% impurity, such as a composition comprising less than about 4%, about 3%, about 2%, about 1%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% impurity.
  • aspects and embodiments described herein as “comprising” include “consisting of’ and “consisting essentially of’ embodiments.
  • the term “comprise” or variations such as “comprises” or “comprising,” will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. It is understood that aspects and embodiments described herein as “comprising” include “consisting of’ and “consisting essentially of’ embodiments.
  • composition when a composition is described as “consisting essentially of’ the listed components, the composition contains the components expressly listed, and may contain other components which do not substantially affect the disease or condition being treated such as trace impurities. However, the composition either does not contain any other components which do substantially affect the disease or condition being treated other than those components expressly listed; or, if the composition does contain extra components other than those listed which substantially affect the disease or condition being treated, the composition does not contain a sufficient concentration or amount of those extra components to substantially affect the disease or condition being treated.
  • the method contains the steps listed, and may contain other steps that do not substantially affect the disease or condition being treated, but the method does not contain any other steps which substantially affect the disease or condition being treated other than those steps expressly listed.
  • Blood level concentrations of drug substances and other substances in a subject can be measured in plasma or serum, as appropriate. Where a level of a substance is indicated as measured in plasma, the level can also be measured in serum if such a measurement is suitably accurate. Where a level of a substance is indicated as measured in serum, the level can also be measured in plasma if such a measurement is suitably accurate.
  • the disclosure also includes all salts of compounds referred to herein, such as pharmaceutically acceptable salts.
  • the disclosure also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of the compounds described. Unless stereochemistry is explicitly indicated in a chemical structure or name, the structure or name is intended to embrace all possible stereoisomers of a compound depicted. In addition, where a specific stereochemical form is depicted, it is understood that other stereochemical forms are also described and embraced.
  • compositions comprising a compound of the disclosure are also intended.
  • Compositions comprising a mixture of compounds of the disclosure in any ratio are also embraced, including mixtures of two or more stereochemical forms of a compound in any ratio, such that racemic, non- racemic, enantioenriched and scalemic mixtures of a compound are embraced.
  • Articles of manufacture comprising a compound as disclosed herein, or a salt or solvate thereof, in a suitable container are provided.
  • the container may be a vial, jar, ampoule, preloaded syringe, i.v. bag, and the like.
  • the compounds detailed herein are orally bioavailable.
  • the compounds may also be formulated for parenteral (e.g., intravenous) administration.
  • One or several compounds described herein can be used in the preparation of a medicament by combining the compound or compounds as an active ingredient with a pharmacologically acceptable carrier, which are known in the art.
  • a pharmacologically acceptable carrier which are known in the art.
  • the carrier may be in various forms.
  • PPAR Peroxisome proliferator-activated receptor
  • the fixed dose combinations comprise peroxisome proliferator-activated receptor (PPAR) agonists as one active component of the combination.
  • PPAR peroxisome proliferator-activated receptor
  • Fenofibrate is an activator of PPAR-alpha.
  • Elafibranor is a PPAR-alpha/delta dual agonist.
  • Seladelpar is a PPAR-delta agonist.
  • compositions of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (bexotegrast) and pharmaceutically acceptable salts thereof, with peroxisome proliferator-activated receptor agonists and pharmaceutically acceptable salts thereof, are embraced by this disclosure.
  • the disclosure includes pharmaceutical compositions comprising such compounds or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid.
  • compositions according to the disclosure may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.
  • the pharmaceutical composition is a composition for controlled release of any of the compounds detailed herein.
  • compositions comprising compounds in substantially pure forms are detailed herein.
  • compositions may have no more than about 5% impurity, wherein the impurity denotes a compound other than the active compounds comprising the majority of the composition or a pharmaceutically acceptable salt thereof, and other than the pharmaceutical excipients used in the composition.
  • compositions containing bexotegrast, or a pharmaceutically acceptable salt thereof, a peroxisome proliferator-activated receptor agonist or a pharmaceutically acceptable salt thereof, and one or more excipients may contains no more than about 5% impurity, wherein the impurity denotes a compound other than bexotegrast or a pharmaceutically acceptable salt thereof, other than a peroxisome proliferator- activated receptor agonist and pharmaceutically acceptable salts thereof, and other than an excipient.
  • compositions may have no more than about 4% impurity.
  • compositions may contain no more than about 3% impurity.
  • compositions may contain no more than about 2% impurity.
  • compositions may contain no more than about 1% impurity. In one embodiment, compositions may contain no more than about 0.5% impurity. In one embodiment, compositions may contain no more than about 0.4% impurity. In one embodiment, compositions may contain no more than about 0.3% impurity. In one embodiment, compositions may contain no more than about 0.2% impurity. In one embodiment, compositions may contain no more than about 0.1% impurity.
  • the fixed dose combinations detailed herein may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form.
  • oral e.g., nasal, sublingual, vaginal, buccal or rectal
  • parenteral e.g., intramuscular, subcutaneous or intravenous
  • topical or transdermal delivery form e.g., topical or transdermal delivery form.
  • suitable carriers may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.
  • suitable carriers include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices),
  • the fixed dose combinations as described herein can be used in the preparation of a formulation, such as a pharmaceutical formulation.
  • a formulation such as a pharmaceutical formulation.
  • the carrier may be in various forms.
  • pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
  • Formulations comprising the fixed dose combinations may also contain other substances which have valuable therapeutic properties.
  • Pharmaceutical formulations may be prepared by known pharmaceutical methods.
  • the composition is for use as a human or veterinary medicament.
  • the composition is for use in a method described herein.
  • the composition is for use in the treatment of a disease or disorder described herein.
  • Fixed dose combinations and compositions as disclosed herein such as a pharmaceutical composition containing a fixed dose combination as provided herein and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein.
  • the fixed dose combinations and compositions may also be used in in vitro methods, such as in vitro methods of administering a fixed dose combination or composition to cells for screening purposes and/or for conducting quality control assays.
  • the fixed dose combinations and compositions are used to treat and/or ameliorate a disease in a human who has, or who is suspected of having a disease.
  • the human has liver fibrosis.
  • the human is suspected of having liver fibrosis.
  • the human has primary sclerosing cholangitis.
  • the human is suspected of having primary sclerosing cholangitis.
  • the human has primary biliary cholangitis.
  • the human is suspected of having primary biliary cholangitis.
  • the human has one or more of the following risk factors for fibrosis prior to a first administration of the fixed dose combinations as disclosed herein: an enhanced liver fibrosis score greater than or equal to about 7.7; a transient elastography measurement between about 7.7 kPa and about 14.4 kPa; a magnetic resonance elastography measurement between about 2.4 kPa and about 4.9 kPa, and a historical liver biopsy indicating fibrosis.
  • the bexotegrast, or pharmaceutically acceptable salt thereof, used in the fixed dose combinations is a phosphate salt, a polymorph (including crystalline Form I phosphate salt, crystalline Form IV phosphate salt, crystalline Form II fumarate salt, and crystalline Form III naphthalenedisulfonic acid salt), a zwitterionic form, or an amorphous form.
  • the bexotegrast, or pharmaceutically acceptable salt thereof is a phosphate salt.
  • the bexotegrast or pharmaceutically acceptable salt thereof is Form I phosphate salt. Salts and polymorphs of bexotegrast are disclosed in United States Patent No. 12,018,025, incorporated by reference herein in its entirety.
  • administration of the fixed dose combinations or composition is added on to a patient’s existing therapeutic regimen.
  • the patient is treatment-naive prior to administration of the fixed dose combinations or composition.
  • the administration can be oral administration.
  • the administration can be administration daily, such as once daily, twice daily, three times daily, or four times daily.
  • the administration is for about 12 weeks. In embodiments, the administration is for at least about 12 weeks.
  • the methods may include inhibiting the activity of avPi and avPe integrin in a human.
  • the methods may include administering to the human an amount of the compound, or a pharmaceutically acceptable salt thereof, effective to modulate the activity of avPi and avPe, the human being in need of treatment for liver fibrosis, primary sclerosing cholangitis, or primary biliary cholangitis.
  • bexotegrast, or a pharmaceutically acceptable salt thereof, and fenofibrate in the manufacture of a fixed dose combination medicament for the treatment of liver fibrosis, primary sclerosing cholangitis, or primary biliary cholangitis.
  • bexotegrast or a pharmaceutically acceptable salt thereof, and elafibranor, or a pharmaceutically acceptable salt thereof, in the manufacture of a fixed dose combination medicament for the treatment of liver fibrosis, primary sclerosing cholangitis, or primary biliary cholangitis.
  • bexotegrast or a pharmaceutically acceptable salt thereof, and elafibranor, in the manufacture of a fixed dose combination medicament for the treatment of liver fibrosis, primary sclerosing cholangitis, or primary biliary cholangitis.
  • bexotegrast, or a pharmaceutically acceptable salt thereof, and seladelpar in the manufacture of a fixed dose combination medicament for the treatment of liver fibrosis, primary sclerosing cholangitis, or primary biliary cholangitis.
  • Also provided herein is a fixed dose combination comprising elafibranor and (S)-4-((2- methoxyethyl)(4-(5, 6,7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, for use in the treatment of primary biliary cholangitis in a subject in need thereof.
  • the fixed dose combinations can have the amounts of bexotegrast and fenofibrate, or the amounts of bexotegrast and elafibranor, or the amounts of bexotegrast and seladelpar, or about the amounts of bexotegrast and fenofibrate, or about the amounts of bexotegrast and elafibranor, or about the amounts of bexotegrast and seladelpar, as listed in the following tables: Table 1, Table 2, Table 3, Table 4, Table 5, and Table 6.
  • the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is from about 20 mg to about 640 mg. In some embodiments, the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is from about 40 mg to about 320 mg.
  • the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 20mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about 500 mg, or about 600 mg.
  • the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 20 mg. In some embodiments, the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 40 mg. In some embodiments, the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 80 mg. In some embodiments, the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 100 mg. In some embodiments, the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 120 mg.
  • the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 160 mg. In some embodiments, the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 320 mg.
  • the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is 20 mg. In some embodiments, the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is 40 mg. In some embodiments, the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is 80 mg. In some embodiments, the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is 100 mg. In some embodiments, the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is 120 mg.
  • the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is 160 mg. In some embodiments, the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is 320 mg. [0068] In some embodiments, the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is from about 30 mg to about 200 mg.
  • the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 30 mg, about 40 mg, about 43 mg, about 45 mg, about 48 mg, about 50 mg, about 54 mg, about 67 mg, about 87 mg, about 90 mg, about 100 mg, about 107 mg, about 120 mg, about 130 mg, about 134 mg, about 135 mg, about 145 mg, about 150 mg, about 160 mg, or about 200 mg.
  • the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 48 mg. In some embodiments, the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 54 mg. In some embodiments, the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 67 mg. In some embodiments, the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 135 mg. In some embodiments, the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 145 mg.
  • the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 160 mg. In some embodiments, the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 200 mg.
  • the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is 48 mg. In some embodiments, the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is 54 mg. In some embodiments, the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is 67 mg. In some embodiments, the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is 135 mg. In some embodiments, the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is 145 mg.
  • the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is 160 mg. In some embodiments, the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is 200 mg.
  • the amount of elafibranor, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is from about 1 mg to about 150 mg. In some embodiments, the amount of elafibranor, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is from about 70 mg to about 130 mg.
  • the amount of elafibranor, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, or about 130 mg.
  • the amount of elafibranor, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 70 mg. In some embodiments, the amount of elafibranor, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 80 mg. In some embodiments, the amount of elafibranor, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 100 mg. In some embodiments, the amount of elafibranor, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 120 mg.
  • the amount of elafibranor, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is 70 mg. In some embodiments, the amount of elafibranor, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is 80 mg. In some embodiments, the amount of elafibranor, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is 100 mg. In some embodiments, the amount of elafibranor, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is 120 mg.
  • the amount of seladelpar, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is from about 1 mg to about 20 mg. In some embodiments, the amount of seladelpar, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is from about 2 mg to about 10 mg.
  • the amount of seladelpar, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 12 mg, about 15 mg, or about 20 mg.
  • the amount of seladelpar, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 1 mg. In some embodiments, the amount of seladelpar, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 2 mg. In some embodiments, the amount of seladelpar, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 5 mg. In some embodiments, the amount of seladelpar, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 10 mg.
  • the amount of seladelpar, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is 1 mg. In some embodiments, the amount of seladelpar, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is 2 mg. In some embodiments, the amount of seladelpar, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is 5 mg. In some embodiments, the amount of seladelpar, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is 10 mg.
  • the weight of a pharmaceutically acceptable salt is adjusted to administer the same amount of active agent as would be administered if the non-salt compound were used.
  • a fixed dose combination comprises 45 mg of fenofibrate, with a molecular weight of 360.8, and the fenofibrate is provided as choline fenofibrate (the choline salt of fenofibrate) with a molecular weight of 421.9, then to provide 45 mg (0.125 mmol) of fenofibrate equivalent, 52.6 mg of choline fenofibrate would be used in the fixed dose combination.
  • the amount of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin- 4-ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof refers to the amount of (S)-4-((2-methoxyethyl)(4- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid free base equivalents present in the composition.
  • the corresponding amount of pharmaceutically acceptable salt may be determined based on the form of (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro- l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin- 4-ylamino)butanoic acid used.
  • the fixed dose combinations may include the amounts of bexotegrast and PPAR agonist in a percentage range about any of the individual values in milligrams herein, for example, any percentage range independently selected from one of, or one of about: ⁇ 1%, ⁇ 2%, ⁇ 2.5%, ⁇ 5%, ⁇ 7.5%, or ⁇ 10%.
  • the range may be, or be about, ⁇ 1%.
  • the range may be, or be about, ⁇ 2%.
  • the range may be, or be about, ⁇ 2.5%.
  • the range may be, or be about, ⁇ 5%.
  • the range may be, or be about, ⁇ 7.5%.
  • the range may be, or be about, ⁇ 10%.
  • the subject to be treated with a fixed dose combination as disclosed herein is undergoing concurrent treatment with standard of care therapy for liver fibrosis.
  • the subject is undergoing concurrent treatment with another therapeutic for liver fibrosis.
  • the subject is not undergoing concurrent treatment with standard of care therapy for liver fibrosis.
  • the subject is not undergoing concurrent treatment with another therapeutic for liver fibrosis.
  • the subject to be treated with a fixed dose combination as disclosed herein is undergoing concurrent treatment with standard of care therapy for primary sclerosing cholangitis.
  • the subject is undergoing concurrent treatment with another therapeutic for primary sclerosing cholangitis.
  • the subject is not undergoing concurrent treatment with standard of care therapy for primary sclerosing cholangitis.
  • the subject is not undergoing concurrent treatment with another therapeutic for primary sclerosing cholangitis.
  • standard of care therapy for primary sclerosing cholangitis comprises administration of ursodeoxycholic acid to the subject.
  • the subject to be treated with a fixed dose combination as disclosed herein is undergoing concurrent treatment with standard of care therapy for primary biliary cholangitis.
  • the subject is undergoing concurrent treatment with another therapeutic for primary biliary cholangitis.
  • the subject is not undergoing concurrent treatment with standard of care therapy for primary biliary cholangitis.
  • the subject is not undergoing concurrent treatment with another therapeutic for primary biliary cholangitis.
  • standard of care therapy for primary biliary cholangitis comprises administration of ursodeoxycholic acid to the subject.
  • the subject has liver cirrhosis.
  • the subject with liver cirrhosis has Child-Pugh score A or Child-Pugh score B.
  • Liver cirrhosis is defined as compensated or decompensated and further classified using the Child-Pugh system which is well known to individuals skilled in the art. Cirrhosis patients are classified on the basis of certain clinical parameters. Child Pugh A patients are compensated and may display minimal obvious symptoms. Patients classified as Child Pugh B or Child Pugh C are decompensated and can exhibit outward symptoms such as ascites.
  • the Child-Pugh score consists of five clinical features including ascites, hepatic encephalopathy, albumin, total bilirubin, and PT-INR (Prothrombin Time - International Normalized Ratio) and is used to assess the prognosis of chronic liver disease and cirrhosis. Each component is given a numerical score from 1 to 3 and added to provide total scores ranging from 5 to 15. The higher the score, the worse the prognosis is for the patient. Patients with a total score of 5-6 are classified as Child Pugh A. Patients with a total score of 7-9 are classified as Child Pugh B. Patients with a total score of 10-15 are the most ill and are classified as Child Pugh C (see Pugh R.N. et al.
  • the subject has Child-Pugh score A. In some embodiments, the subject has Child-Pugh score B.
  • the subject has moderate hepatic impairment. In some embodiments, the subject with moderate hepatic impairment has Child-Pugh score B.
  • the subject has or is at risk of decompensated cirrhosis, liver cirrhosis progression, or portal hypertension.
  • the subject has or is at risk of decompensated cirrhosis.
  • Decompensated cirrhosis is defined as acute deterioration in liver function that is characterized by at least one clinical complication, such as ascites, hepatic encephalopathy, gastrointestinal bleeding, and jaundice (see D’Amico et al., Journal of Hepatology, Volume 76, Issue 1, 202 - 207, herein incorporated by reference in its entirety).
  • the subject has or is at risk of liver cirrhosis progression.
  • Liver cirrhosis progression refers to the transition from compensated (i.e., Child Pugh A) to decompensated cirrhosis (Child Pugh B or C), and is characterized by worsening of liver damage leading to severe scarring and permanent damage of liver tissue.
  • the subject has or is at risk of portal hypertension.
  • Portal hypertension is defined as increased portal venous pressure, with a hepatic venous pressure gradient greater than 5 mm Hg.
  • a fixed dose combination as disclosed herein is the only therapy specific for a liver disorder (that is, the only liver-specific therapy) administered to the subject, such as a subject with a fibrotic liver disease, for example, primary sclerosing cholangitis or primary biliary cholangitis.
  • a fixed dose combination as disclosed herein may be administered without administration of ursodeoxycholic acid, or a pharmaceutically acceptable salt thereof, or any other therapy specific for a fibrotic liver disorder.
  • a fixed dose combination as disclosed herein may be administered without administration of ursodeoxycholic acid, or a pharmaceutically acceptable salt thereof, or any other therapy specific for primary sclerosing cholangitis.
  • a fixed dose combination as disclosed herein may be administered without administration of ursodeoxycholic acid, or a pharmaceutically acceptable salt thereof, or any other therapy specific for primary biliary cholangitis.
  • Subjects may be taking medications for reasons other than treatment of liver disorders, or which are not specific for liver disorders, such as over-the counter treatments, including, but not limited to, vitamins, minerals, or ibuprofen, or prescription treatments such as drugs to treat diabetes, high blood pressure, or other disorders.
  • the fixed dose combination is dosed BID (twice a day) or QD (once a day). In some embodiments, the fixed dose combination is dosed for at least about 4 weeks. In some embodiments, the fixed dose combination is dosed for at least about 8 weeks. In some embodiments, the fixed dose combination is dosed for at least about 12 weeks. In some embodiments, the fixed dose combination is dosed for at least about 24 weeks. In some embodiments, the fixed dose combination is dosed for between at least about 4 weeks to at least about 12 weeks. In some embodiments, the fixed dose combination is dosed for between at least about 4 weeks to at least about 24 weeks.
  • a method of reducing alkaline phosphatase (ALP) levels in a human in need thereof comprising administering to the subject a fixed dose combination as disclosed herein whereby the level of ALP is reduced.
  • a method of reducing alkaline phosphatase (ALP) levels in a human in need thereof comprising administering to the subject a fixed dose combination as disclosed herein whereby the level of ALP is reduced as compared to a human who has not been administered a fixed dose combination as disclosed herein.
  • ALP ranges for healthy individuals are provided in Table M-2 below. Table M-2
  • administration of a fixed dose combination as disclosed herein to the human results in an amelioration in alkaline phosphatase level in the human.
  • administration of a fixed dose combination as disclosed herein to the human results in an amelioration in alkaline phosphatase level in the human as compared to a human who has not been administered a fixed dose combination as disclosed herein.
  • administration of a fixed dose combination as disclosed herein to the human results in a reduction in alkaline phosphatase level in the human.
  • administration of a fixed dose combination as disclosed herein to the human results in a reduction in alkaline phosphatase level in the human as compared to a human who has not been administered a fixed dose combination as disclosed herein.
  • administration of a fixed dose combination as disclosed herein to the human results in a change in alkaline phosphatase level in the human.
  • the alkaline phosphatase level is above an upper limit of normal prior to a first administration of a fixed dose combination as disclosed herein to the human.
  • the human has liver fibrosis.
  • the human is suspected of having liver fibrosis.
  • the human has primary sclerosing cholangitis.
  • the human is suspected of having primary sclerosing cholangitis. In embodiments, the human is at risk for moderate to severe fibrosis. In embodiments, the human has one or more of the following risk factors for fibrosis prior to a first administration of a fixed dose combination as disclosed herein: an enhanced liver fibrosis score greater than or equal to about 7.7; a transient elastography measurement between about 7.7 kPa and about 14.4 kPa; a magnetic resonance elastography measurement between about 2.4 kPa and about 4.9 kPa, and a historical liver biopsy indicating fibrosis.
  • a method of stabilizing or decreasing total bilirubin in a human in need thereof comprising administering a fixed dose combination as disclosed herein to the human in need thereof.
  • a method of stabilizing or decreasing total bilirubin in a human in need thereof comprising administering a fixed dose combination as disclosed herein to the human in need thereof, as compared to a human who has not been administered a fixed dose combination as disclosed herein.
  • the human has liver fibrosis.
  • the human is suspected of having liver fibrosis.
  • the human has primary sclerosing cholangitis.
  • the human is suspected of having primary sclerosing cholangitis.
  • the human has primary biliary cholangitis. In embodiments, the human is suspected of having primary biliary cholangitis. In embodiments, the human is at risk for moderate to severe fibrosis. In embodiments, the human has one or more of the following risk factors for fibrosis prior to a first administration of a fixed dose combination as disclosed herein: an enhanced liver fibrosis score greater than or equal to about 7.7; a transient elastography measurement between about 7.7 kPa and about 14.4 kPa; a magnetic resonance elastography measurement between about 2.4 kPa and about 4.9 kPa, and a historical liver biopsy indicating fibrosis.
  • Transient elastography utilizes an ultrasound shear wave to assess the elasticity of the liver, that is, how “stiff’ the liver tissue is. Fibrosis causes stiffening or hardening of tissue, and TE can be used to diagnose fibrosis and determine the degree of fibrosis.
  • the FIBROSCAN device FIBROSCAN is a registered trademark of ECHOSENS, Paris, France, for medical equipment and software
  • FIBROSCAN is a registered trademark of ECHOSENS, Paris, France, for medical equipment and software
  • a method of ameliorating the transient elastography measurement in a human in need thereof comprising administering a fixed dose combination as disclosed herein to the human.
  • a method of ameliorating the transient elastography measurement in a human in need thereof comprising administering a fixed dose combination as disclosed herein to the human as compared to a human who has not been administered a fixed dose combination as disclosed herein.
  • a method of changing the transient elastography measurement in a human in need thereof comprising administering a fixed dose combination as disclosed herein to the human.
  • a method of changing the transient elastography measurement in a human in need thereof comprising administering a fixed dose combination as disclosed herein to the human as compared to a human who has not been administered a fixed dose combination as disclosed herein.
  • a method of decreasing the transient elastography measurement in a human in need thereof comprising administering a fixed dose combination as disclosed herein to the human.
  • a method of decreasing the transient elastography measurement in a human in need thereof comprising administering a fixed dose combination as disclosed herein to the human as compared to a human who has not been administered a fixed dose combination as disclosed herein.
  • the human has liver fibrosis.
  • the human is suspected of having liver fibrosis. In embodiments, the human has primary sclerosing cholangitis. In embodiments, the human is suspected of having primary sclerosing cholangitis. In embodiments, the human has primary biliary cholangitis. In embodiments, the human is suspected of having primary biliary cholangitis. In embodiments, the human is at risk for moderate to severe fibrosis.
  • the human has one or more of the following risk factors for fibrosis prior to a first administration of a fixed dose combination as disclosed herein: an enhanced liver fibrosis score greater than or equal to about 7.7; a transient elastography measurement between about 7.7 kPa and about 14.4 kPa; a magnetic resonance elastography measurement between about 2.4 kPa and about 4.9 kPa, and a historical liver biopsy indicating fibrosis.
  • a method of reducing itch or pruritus (chronic itching). Itch severity can be quantified on a 0-10 scale using the Peak Pruritus Numerical Rating Scale (NRS), where 0 is “no itch” and 10 is “worst imaginable itch” over the past 24 hours (Yosipovitch et al., British Journal of Dermatology (2019) 181 :761-769, incorporated by reference herein in its entirety).
  • a method of reducing pruritis in a human who has fibrotic liver disease comprising administering to the human a fixed dose combination as disclosed herein.
  • a method of reducing (e.g., ameliorating) pruritis in a human who has fibrotic liver disease comprising administering to the human a fixed dose combination as disclosed herein, as compared to a human who has not been administered a fixed dose combination as disclosed herein.
  • a method of reducing pruritis in a human who has fibrotic liver disease comprising administering to the human a fixed dose combination as disclosed herein, as compared to a human who has not been administered a fixed dose combination as disclosed herein.
  • a method of ameliorating pruritis in a human who has primary sclerosing cholangitis comprising administering to the human a fixed dose combination as disclosed herein, as compared to a human who has not been administered a fixed dose combination as disclosed herein.
  • a method of treating primary biliary cholangitis by inhibiting both avPe integrin and avPi integrin in a subject in need thereof comprising administering a fixed dose combination as disclosed herein, wherein the administering is not accompanied by a serious adverse event.
  • the administering is not accompanied by a serious adverse event, wherein the serious adverse event is life-threatening (e.g., its occurrence places the subject at immediate risk of death); results in death; requires inpatient hospitalization (i.e., admission, overnight stay) or prolongs existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect/miscarriage; or is an important medical event (e.g., is considered to be clinically significant and may jeopardize the subject, or when medical or surgical intervention may be required to prevent one of the outcomes listed above).
  • life-threatening e.g., its occurrence places the subject at immediate risk of death
  • results in death i.e., admission, overnight stay
  • results in persistent or significant disability/incapacity results in persistent or significant disability/incapacity
  • is an important medical event e.g., is considered to be clinically significant and may jeopardize the subject
  • a method of slowing the clinical progression of primary sclerosing cholangitis in a human who has primary sclerosing cholangitis and is at risk for moderate to severe liver fibrosis comprising administering to the subject a fixed dose combination as disclosed herein.
  • a method of slowing the clinical progression of primary sclerosing cholangitis in a human who has primary sclerosing cholangitis and is at risk for moderate to severe liver fibrosis comprising administering to the subject a fixed dose combination as disclosed herein, as compared to a human who has not been administered a fixed dose combination as disclosed herein.
  • a method of slowing the clinical progression of primary sclerosing cholangitis in a human who has primary sclerosing cholangitis and is at risk for moderate to severe liver fibrosis comprising administering to the subject a fixed dose combination as disclosed herein, as compared to a human who has not been administered a fixed dose combination as disclosed herein, or compared to a human who has been administered a placebo.
  • the clinical progression at two years following a first administration of a fixed dose combination as disclosed herein to the human is slowed as compared to a subject who has not been administered a fixed dose combination as disclosed herein.
  • hepatocyte function is improved, by administration of a fixed dose combination as disclosed herein to the human.
  • the improvement in hepatocyte function can be measured by contrast MRI.
  • bile flow is improved, by administration of a fixed dose combination as disclosed herein to the human.
  • the improvement in bile flow can be measured by excretory function MRI.
  • the subject who has been administered a fixed dose combination as disclosed herein is a human. In some embodiments, the subject is being treated with an additional therapeutic. In some embodiments, the subject who has been administered a fixed dose combination as disclosed herein is concurrently being treated with a standard medical therapy or a standard of care. In some embodiments, the subject who has been administered a fixed dose combination as disclosed herein is concurrently being treated with a standard medical therapy or a standard of care, wherein the standard medical therapy or standard of care comprises administration of ursodeoxycholic acid (UDCA), or a pharmaceutically acceptable salt thereof.
  • UDCA ursodeoxycholic acid
  • the subject who has been administered a fixed dose combination as disclosed herein has not been previously treated with a standard medical therapy or a standard of care for a liver disorder. In some embodiments, the subject who has been administered a fixed dose combination as disclosed herein has not been previously treated with a standard medical therapy or a standard of care for a liver disorder, wherein the standard medical therapy or standard of care comprises administration of ursodeoxycholic acid (UDCA), or a pharmaceutically acceptable salt thereof.
  • UDCA ursodeoxycholic acid
  • the subject who has been administered a fixed dose combination as disclosed herein is not being concurrently treated with an additional therapeutic. In some embodiments, the subject who has been administered a fixed dose combination as disclosed herein is not being concurrently treated with a standard medical therapy or a standard of care.
  • the subject who has been administered a fixed dose combination as disclosed herein is not being concurrently treated with a standard medical therapy or a standard of care, wherein the standard medical therapy or standard of care comprises administration of ursodeoxycholic acid (UDCA), or a pharmaceutically acceptable salt thereof.
  • the subject is not administered any treatment for a liver disorder other than a fixed dose combination as disclosed herein.
  • Also provided herein is a method of treating liver fibrosis in a subject in need thereof, comprising administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and a peroxisome proliferator-activated receptor agonist (PPAR agonist) or a pharmaceutically acceptable salt thereof.
  • PPAR agonist peroxisome proliferator-activated receptor agonist
  • Also provided herein is a method of treating primary sclerosing cholangitis in a subject in need thereof, comprising administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and a peroxisome proliferator-activated receptor agonist (PPAR agonist) or a pharmaceutically acceptable salt thereof.
  • PPAR agonist peroxisome proliferator-activated receptor agonist
  • Also provided herein is a method of treating primary biliary cholangitis in a subject in need thereof, comprising administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and a peroxisome proliferator-activated receptor agonist (PPAR agonist), or a pharmaceutically acceptable salt thereof.
  • PPAR agonist peroxisome proliferator-activated receptor agonist
  • [OHl] Also provided herein is a fixed dose combination comprising (S)-4-((2-methoxyethyl)(4- (5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (bexotegrast) or a pharmaceutically acceptable salt thereof, and a peroxisome proliferator-activated receptor agonist (PPAR agonist), or a pharmaceutically acceptable salt thereof for use in the treatment of liver fibrosis, primary sclerosing cholangitis, or primary biliary cholangitis.
  • the PPAR agonist is fenofibrate.
  • the PPAR agonist is elafibranor.
  • the PPAR agonist is seladelpar.
  • a fixed dose combination comprising (S)-4-((2-methoxyethyl)(4- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and a peroxisome proliferator- activated receptor agonist (PPAR agonist) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treatment of liver fibrosis, primary sclerosing cholangitis, or primary biliary cholangitis.
  • PPAR agonist peroxisome proliferator- activated receptor agonist
  • the PPAR agonist is fenofibrate. In some embodiments, the PPAR agonist is elafibranor. In some embodiments, the PPAR agonist is seladelpar. [0113] Also provided herein is a fixed dose combination comprising elafibranor and (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof for use in treating primary biliary cholangitis.
  • the PPAR agonist is selected from the group consisting of elafibranor, fenofibrate, and seladelpar, or pharmaceutically acceptable salts thereof. In some embodiments, the PPAR agonist is elafibranor, or a pharmaceutically acceptable salt thereof. In some embodiments, the PPAR agonist is elafibranor. In some embodiments, the PPAR agonist is fenofibrate, or a pharmaceutically acceptable salt thereof. In some embodiments, the PPAR agonist is fenofibrate. In some embodiments, the PPAR agonist is a choline salt of fenofibrate.
  • the PPAR agonist is seladelpar, or a pharmaceutically acceptable salt thereof. In some embodiments, the PPAR agonist is seladelpar. In some embodiments, the PPAR agonist is a lysine salt of seladelpar.
  • Also provided herein is a method of lowering gene expression of at least one of COL3A1, CTHRC1, or PDGFRB in a subject comprising administering to the subject a fixed dose combination comprising (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and elafibranor, or a pharmaceutically acceptable salt thereof.
  • Also provided herein is a method of lowering gene expression of at least one of COL3A1, CTHRC1, and PDGFRB in a subject comprising administering to the subject a fixed dose combination comprising (S)-4-((2 -methoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and elafibranor, or a pharmaceutically acceptable salt thereof.
  • administering to a subject a fixed dose combination comprising (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-1, 8-naphthyri din-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and elafibranor, or a pharmaceutically acceptable salt thereof, results in a synergistic effect in lowering gene expression of at least one of COL3A1, CTHRC1, and PDGFRB in the subject.
  • Also provided herein is a method of increasing gene expression of at least one of ACOX1 or PDK4 in a subject comprising administering to the subject a fixed dose combination comprising (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and elafibranor, or a pharmaceutically acceptable salt thereof.
  • Also provided herein is a method of increasing gene expression of at least one of ACOX1 and PDK4 in a subject comprising administering to the subject a fixed dose combination comprising (S)-4-((2- methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and elafibranor, or a pharmaceutically acceptable salt thereof.
  • administering to a subject a fixed dose combination comprising (S)-4-((2- methoxy ethyl)(4-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and elafibranor, or a pharmaceutically acceptable salt thereof, results in a synergistic effect in increasing gene expression of at least one of AC0X1 and PDK4 in the subject.
  • the fixed dose combination comprises a phosphate salt of bexotegrast and elafibranor.
  • Also provided herein is a method of lowering gene expression of at least one of CXCL1, PPARD, COL1A1, ACTA2, COL1A2, COL3A1, CTHRC1, PDGFRB, TGFB1, TIMP1, or SERPINE1 in a subject comprising administering to the subject a fixed dose combination comprising (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and fenofibrate, or a pharmaceutically acceptable salt thereof.
  • Also provided herein is a method of lowering gene expression of at least one of CXCL1, PPARD, COL1 Al, ACTA2, COL1 A2, COL3A1, CTHRC1, PDGFRB, TGFB1, TIMP1, and SERPINE1 in a subject comprising administering to the subject a fixed dose combination comprising (S)-4-((2-methoxyethyl)(4- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and fenofibrate, or a pharmaceutically acceptable salt thereof.
  • administering to a subject a fixed dose combination comprising (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and fenofibrate, or a pharmaceutically acceptable salt thereof, results in a synergistic effect in lowering gene expression of at least one of CXCL1, PPARD, COL1 Al, ACTA2, COL1A2, COL3A1, CTHRC1, PDGFRB, TGFB1, TIMP1, and SERPINE1 in the subject.
  • Also provided herein is a method of lowering gene expression of at least one of CXCL1, PPARD, COL1 Al, ACTA2, COL1 A2, or SERPINE1 in a subject comprising administering to the subject a fixed dose combination comprising (S)-4-((2-methoxyethyl)(4-(5, 6,7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and fenofibrate, or a pharmaceutically acceptable salt thereof.
  • Also provided herein is a method of lowering gene expression of at least one of CXCL1, PPARD, COL1A1, ACTA2, COL1A2, and SERPINE1 in a subject comprising administering to the subject a fixed dose combination comprising (S)-4-((2 -methoxy ethyl)(4-(5, 6,7, 8-tetrahydro- l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and fenofibrate, or a pharmaceutically acceptable salt thereof.
  • administering to a subject a fixed dose combination comprising (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and fenofibrate, or a pharmaceutically acceptable salt thereof, results in a synergistic effect in lowering gene expression of at least one of CXCL1, PPARD, C0L1A1, ACTA2, COL1 A2, and SERPINE1 in the subject.
  • Also provided herein is a method of increasing gene expression of at least one of AC0X1, PDK4, ABCB11, or ABCB4 in a subject comprising administering to the subject a fixed dose combination comprising (S)-4-((2- methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and fenofibrate, or a pharmaceutically acceptable salt thereof.
  • Also provided herein is a method of increasing gene expression of at least one of AC0X1, PDK4, ABCB1 1, and ABCB4 in a subject comprising administering to the subject a fixed dose combination comprising (S)-4-((2- methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and fenofibrate, or a pharmaceutically acceptable salt thereof.
  • administering to a subject a fixed dose combination comprising (S)-4-((2- methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and fenofibrate, or a pharmaceutically acceptable salt thereof, results in a synergistic effect in increasing gene expression of at least one of AC0X1, PDK4, ABCB11, and ABCB4 in the subject.
  • the fixed dose combination comprises a phosphate salt of bexotegrast and fenofibrate. In some embodiments, the fixed dose combination comprises a phosphate salt of bexotegrast and a choline salt of fenofibrate.
  • Also provided herein is a method of lowering gene expression of at least one of COL3A1, CTHRC1, PDGFRB, or TIMP1, in a subject comprising administering to the subject a fixed dose combination comprising (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and seladelpar, or a pharmaceutically acceptable salt thereof.
  • Also provided herein is a method of lowering gene expression of at least one of COL3A1, CTHRC1, PDGFRB, and TIMP1, in a subject comprising administering to the subject a fixed dose combination comprising (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and seladelpar, or a pharmaceutically acceptable salt thereof.
  • administering to a subject a fixed dose combination comprising (S)-4-((2 -methoxy ethyl)(4- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and seladelpar, or a pharmaceutically acceptable salt thereof, results in a synergistic effect in lowering gene expression of at least one of C0L3A1, CTHRC1, PDGFRB, and TIMP1, in the subject.
  • the fixed dose combination comprises a phosphate salt of bexotegrast and seladelpar.
  • the method comprising administering to the subject a fixed dose combination as disclosed herein is not accompanied by a serious adverse event.
  • the method comprising administering to the subject a fixed dose combination as disclosed herein is not accompanied by a serious adverse event, wherein the serious adverse event is life- threatening (e.g., its occurrence places the subject at immediate risk of death); results in death; requires inpatient hospitalization (i.e., admission, overnight stay) or prolongs existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect/miscarriage; or is an important medical event (e.g., is considered to be clinically significant and may jeopardize the subject, or when medical or surgical intervention may be required to prevent one of the outcomes listed above).
  • Salts and polymorphs of bexotegrast are disclosed in United States Patent No. 12,018,025, incorporated by reference herein in its entirety, and can be produced by the processes therein.
  • the methods herein employ a crystalline form of bexotegrast.
  • Crystalline forms of bexotegrast include the Form I phosphate salt, the Form II fumarate salt, the Form III 1,5-naphthalenedisulfonate salt, and the Form IV mixed isopropyl alcohol and water phosphate salt.
  • the crystalline form is selected from the group consisting of the Form I phosphate salt, the Form II fumarate salt, the Form III 1,5- naphthalenedisulfonate salt, and the Form IV mixed isopropyl alcohol and water phosphate salt.
  • the crystalline form is the Form I or Form IV phosphate salt.
  • the crystalline form is selected from the group consisting of the Form I phosphate salt, the Form II fumarate salt, the Form III 1,5-naphthalenedisulfonate salt, and the Form IV mixed isopropyl alcohol and water phosphate salt.
  • the crystalline form is the Form I phosphate salt.
  • the crystalline form is the Form II fumarate salt.
  • the crystalline form is the Form III 1,5-naphthalenedisulfonate salt. In some embodiments, the crystalline form is the Form IV mixed isopropyl alcohol and water phosphate salt. United States Patent No. 12,018,025 is hereby incorporated herein by reference in its entirety.
  • kits for carrying out the methods as disclosed herein which comprise one or more fixed dose combinations described herein, or a pharmacological composition comprising a fixed dose combination described herein.
  • the kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for use in the treatment of a fibrotic liver disease, primary sclerosing cholangitis, or primary biliary cholangitis.
  • Kits generally comprise suitable packaging.
  • the kits may comprise one or more containers comprising a fixed dose combination as described herein.
  • One or more components of a kit may be sterile and/or may be contained within sterile packaging.
  • kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or subunit doses.
  • kits may be provided that contain sufficient dosages of a fixed dose combination as described herein (e.g., a therapeutically effective amount) and/or a second pharmaceutically active compound useful for a disease detailed herein (e.g., liver fibrosis) to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more.
  • Kits may also include multiple unit doses of the fixed dose combinations as described herein and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).
  • kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component s) of the methods of the present disclosure.
  • the instructions included with the kit generally include information as to the components and their administration to an individual.
  • kits may optionally further comprise instructions for daily administration of the fixed dose combination to an individual in need thereof, such as instructions for administration of the fixed dose combination to an individual in need thereof one, two, three, or four times daily.
  • the kits comprise instructions for administration of the fixed dose combination to an individual in need thereof once daily.
  • Embodiment Al A fixed dose combination comprising (S)-4-((2-methoxyethyl)(4- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and a peroxisome proliferator- activated receptor agonist (PPAR agonist), or a pharmaceutically acceptable salt thereof.
  • PPAR agonist peroxisome proliferator- activated receptor agonist
  • Embodiment A2 The fixed dose combination of embodiment Al, wherein the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 40 mg.
  • Embodiment A3 The fixed dose combination of embodiment Al, wherein the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 80 mg.
  • Embodiment A4 The fixed dose combination of embodiment Al, wherein the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 160 mg.
  • Embodiment A5 The fixed dose combination of embodiment Al, wherein the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 320 mg.
  • Embodiment A6 The fixed dose combination of any one of embodiments A1-A5, wherein the PPAR agonist is an agonist of PPARa.
  • Embodiment A7 The fixed dose combination of any one of embodiments A1-A6, wherein the PPAR agonist comprises fenofibrate, or a pharmaceutically acceptable salt thereof.
  • Embodiment A8 The fixed dose combination of embodiment A7, wherein the amount of fenofibrate, or pharmaceutically acceptable salt thereof, in the fixed dose combination is about 30 mg, about 40 mg, about 43 mg, about 45 mg, about 48 mg, about 50 mg, about 54 mg, about 67 mg, about 87 mg, about 90 mg, about 100 mg, about 107 mg, about 120 mg, about 130 mg, about 134 mg, about 135 mg, about 145 mg, about 150 mg, about 160 mg, or about 200 mg.
  • Embodiment A9 The fixed dose combination of embodiment A7, wherein the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 48 mg.
  • Embodiment A10 The fixed dose combination of embodiment A7, wherein the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 54 mg.
  • Embodiment Al 1. The fixed dose combination of embodiment A7, wherein the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 67 mg.
  • Embodiment A12 The fixed dose combination of embodiment A7, wherein the amount of fenofibrate or a pharmaceutically acceptable salt thereof in the fixed dose combination is about 135 mg.
  • Embodiment Al 3 The fixed dose combination of embodiment A7, wherein the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 145 mg.
  • Embodiment A14 The fixed dose combination of embodiment A7, wherein the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 160 mg.
  • Embodiment Al 5 The fixed dose combination of embodiment A7, wherein the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 200 mg.
  • Embodiment Al 6 The fixed dose combination of any one of embodiments A1-A6, wherein the PPAR agonist is a dual PPARa/5 agonist.
  • Embodiment A17 The fixed dose combination of any one of embodiments A1-A6 or
  • the PPAR agonist comprises elafibranor, or a pharmaceutically acceptable salt thereof
  • Embodiment A18 The fixed dose combination of embodiment A17, wherein the amount of the elafibranor, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 80 mg.
  • Embodiment Al 9 The fixed dose combination of embodiment Al 7, wherein the amount of the elafibranor, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 120 mg.
  • Embodiment A20 The fixed dose combination of embodiment Al, comprising a dose selected from Table 1, Table 2, Table 3, or Table 4.
  • Embodiment A21 A method of treating liver fibrosis in a subject in need thereof, comprising administering the fixed dose combination of any one of embodiments A1-A20 to the subject.
  • Embodiment A22 A method of treating primary sclerosing cholangitis in a subject in need thereof, comprising administering the fixed dose combination of any one of embodiments Al- A20 to the subject.
  • Embodiment A23 A method of treating primary biliary cholangitis in a subject in need thereof, comprising administering the fixed dose combination of any one of embodiments A1-A20 to the subject.
  • Embodiment A24 The fixed dose combination of any one of embodiments A1-A20 for use in treating liver fibrosis.
  • Embodiment A25 The fixed dose combination of any one of embodiments A1-A20 for use in treating primary sclerosing cholangitis.
  • Embodiment A26 The fixed dose combination of any one of embodiments A1-A20 for use in treating primary biliary cholangitis.
  • Embodiment B A fixed dose combination comprising (S)-4-((2-methoxyethyl)(4- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and a peroxisome proliferator- activated receptor agonist (PPAR agonist), or a pharmaceutically acceptable salt thereof.
  • PPAR agonist peroxisome proliferator- activated receptor agonist
  • Embodiment B2 The fixed dose combination of embodiment Bl, wherein the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 40 mg.
  • Embodiment B3 The fixed dose combination of embodiment Bl, wherein the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 80 mg.
  • Embodiment B4 The fixed dose combination of embodiment Bl, wherein the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 160 mg.
  • Embodiment B5. The fixed dose combination of embodiment Bl, wherein the amount of bexotegrast, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 320 mg.
  • Embodiment B6 The fixed dose combination of any one of embodiments B1-B5, wherein the bexotegrast is a phosphate salt.
  • Embodiment B7 The fixed dose combination of any one of embodiments B1-B6, wherein the PPAR agonist is an agonist of PPARa.
  • Embodiment B8 The fixed dose combination of any one of embodiments B1-B7, wherein the PPAR agonist is fenofibrate, or a pharmaceutically acceptable salt thereof.
  • Embodiment B9 The fixed dose combination of embodiment B8, wherein the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 30 mg, about 40 mg, about 43 mg, about 45 mg, about 48 mg, about 50 mg, about 54 mg, about 67 mg, about 87 mg, about 90 mg, about 100 mg, about 107 mg, about 120 mg, about 130 mg, about
  • Embodiment B10 The fixed dose combination of embodiment B9, wherein the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 48 mg.
  • Embodiment B 11 The fixed dose combination of embodiment B9, wherein the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 54 mg.
  • Embodiment B 12 The fixed dose combination of embodiment B9, wherein the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 67 mg.
  • Embodiment B 13 The fixed dose combination of embodiment B9, wherein the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about
  • Embodiment B 14 The fixed dose combination of embodiment B9, wherein the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 145 mg.
  • Embodiment Bl 5.
  • the fixed dose combination of embodiment B9, wherein the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 160 mg.
  • Embodiment Bl 6.
  • the fixed dose combination of embodiment B9, wherein the amount of fenofibrate, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 200 mg.
  • Embodiment Bl 7. The fixed dose combination of any one of embodiments B8-B16, wherein the PPAR agonist is a choline salt of fenofibrate.
  • Embodiment Bl 8. The fixed dose combination of any one of embodiments B8-B16, wherein the PPAR agonist is fenofibrate.
  • Embodiment Bl 9. The fixed dose combination of any one of embodiments B1-B7, wherein the PPAR agonist is a dual PPARa/5 agonist.
  • Embodiment B20 The fixed dose combination of any one of embodiments B1-B7 or Bl 9, wherein the PPAR agonist is elafibranor, or a pharmaceutically acceptable salt thereof.
  • Embodiment B21 The fixed dose combination of embodiment B20, wherein the amount of elafibranor, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 80 mg.
  • Embodiment B22 The fixed dose combination of embodiment B20, wherein the amount of elafibranor, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 120 mg.
  • Embodiment B23 The fixed dose combination of any one of embodiments B20-B22, wherein the PPAR agonist is elafibranor.
  • Embodiment B24 The fixed dose combination of any one of embodiments B1-B6, wherein the PPAR agonist is a PPAR5 agonist.
  • Embodiment B25 The fixed dose combination of embodiment B24, wherein the PPAR agonist is seladelpar, or a pharmaceutically acceptable salt thereof.
  • Embodiment B26 The fixed dose combination of embodiment B25, wherein the amount of seladelpar, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 2 mg.
  • Embodiment B27 The fixed dose combination of embodiment B25, wherein the amount of seladelpar, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 5 mg.
  • Embodiment B28 The fixed dose combination of embodiment B25, wherein the amount of seladelpar, or a pharmaceutically acceptable salt thereof, in the fixed dose combination is about 10 mg.
  • Embodiment B29 The fixed dose combination of any one of embodiments B25-B28, wherein the PPAR agonist is seladelpar.
  • Embodiment B30 The fixed dose combination of any one of embodiments B25-B28, wherein the PPAR agonist is a lysine salt of seladelpar.
  • Embodiment B31 The fixed dose combination of embodiment Bl, comprising a dose combination selected from dose combinations in Table 1, Table 2, Table 3, Table 4, Table 5, or Table 6.
  • Embodiment B32 A method of treating liver fibrosis in a subject in need thereof, comprising administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and a peroxisome proliferator-activated receptor agonist (PPAR agonist), or a pharmaceutically acceptable salt thereof.
  • PPAR agonist peroxisome proliferator-activated receptor agonist
  • Embodiment B33 A method of treating primary sclerosing cholangitis in a subject in need thereof, comprising administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and a peroxisome proliferator-activated receptor agonist (PPAR agonist), or a pharmaceutically acceptable salt thereof.
  • PPAR agonist peroxisome proliferator-activated receptor agonist
  • Embodiment B34 A method of treating primary biliary cholangitis in a subject in need thereof, comprising administering (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin- 2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (bexotegrast), or a pharmaceutically acceptable salt thereof, and a peroxisome proliferator-activated receptor agonist (PPAR agonist) or a pharmaceutically acceptable salt thereof.
  • PPAR agonist peroxisome proliferator-activated receptor agonist
  • Embodiment B35 The method of any one of embodiments B32-B34, wherein the PPAR agonist is elafibranor, or a pharmaceutically acceptable salt thereof.
  • Embodiment B36 The method of any one of embodiments B32-B34, wherein the PPAR agonist is fenofibrate, or a pharmaceutically acceptable salt thereof.
  • Embodiment B37 The method of any one of embodiments B32-B34, wherein the PPAR agonist is seladelpar, or a pharmaceutically acceptable salt thereof.
  • Embodiment B38 A method of treating liver fibrosis in a subject in need thereof, comprising administering the fixed dose combination of any one of embodiments B1-B31 to the subject.
  • Embodiment B39 A method of treating primary sclerosing cholangitis in a subject in need thereof, comprising administering the fixed dose combination of any one of embodiments Bl- B31 to the subject.
  • Embodiment B40 A method of treating primary biliary cholangitis in a subject in need thereof, comprising administering the fixed dose combination of any one of embodiments Bl -B31 to the subject.
  • Embodiment B41 The fixed dose combination of any one of embodiments B1-B31 for use in treating liver fibrosis.
  • Embodiment B42 The fixed dose combination of any one of embodiments B1-B31 for use in treating primary sclerosing cholangitis.
  • Embodiment B43 The fixed dose combination of any one of embodiments B1-B31 for use in treating primary biliary cholangitis.
  • Embodiment B44 Use of a fixed dose combination of any one of embodiments Bl -31 for the manufacture of a fixed dose combination medicament for the treatment of liver fibrosis.
  • Embodiment B45 Use of a fixed dose combination of any one of embodiments Bl -31 for the manufacture of a fixed dose combination medicament for the treatment of primary sclerosing cholangitis.
  • Embodiment B46 Use of a fixed dose combination of any one of embodiments Bl -31 for the manufacture of a fixed dose combination medicament for the treatment of primary biliary cholangitis.
  • RNA- compatible tissue lysate was generated from slices and gene expression was determined using a custom gene panel on a NanoString nCounter MAX system. mRNA counts were normalized to housekeeping genes and expression relative to the vehicle control group from the same rat/human liver was reported.
  • Example B-l Fixed-dose Combination (bexotegrast + fenofibrate and bexotegrast + elafibranor) in Rat Bile Duct Ligation Model
  • the combination of bexotegrast and fenofibrate or elafibranor affected both fibrogenic and cholestasis gene expression by producing consistent antifibrotic and anti-cholestatic changes.
  • the combination of bexotegrast and elafibranor produced a synergistic effect compared to the sum of bexotegrast administered alone and elafibranor administered alone in lowering the gene expression of each of COL3A1, CTHRC1, and PDGFRB.
  • Table B-l summarizes the effects of the fixed dose combinations shown in FIG. 1.
  • the numerical data represent the log2 fold change of averaged values.
  • Example B-2 Fixed-dose Combination (bexotegrast + fenofibrate) in Human Precision-Cut Liver Slices
  • PCLivS Precision cut liver slices
  • Table B-2 summarizes the effects of the fixed dose combinations shown in FIG. 2.
  • the numerical data represent the log2 fold change of averaged values.
  • Example B-3 Fixed-dose Combination (bexotegrast + seladelpar) in Rat Bile Duct Ligation Model
  • Table B-3 summarizes the effects of the fixed dose combinations shown in FIG. 3. The numerical data represent the log2 fold change of averaged values. Table B-3

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Abstract

La divulgation concerne des associations à doses fixes de l'inhibiteur d'intégrine bexotégrast (acide (S)-4-((2-méthoxyéthyl) (4- (5,6,7,8-tétrahydro-1,8-naphtyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoïque) avec des agonistes du récepteur activé par les proliférateurs de peroxysomes (agonistes de PPAR), et des méthodes de traitement d'un sujet pour une maladie fibrotique hépatique, telle qu'une cholangite sclérosante primitive ou une cholangite biliaire primaire, par administration des associations à doses fixes.
PCT/US2025/024354 2024-04-12 2025-04-11 Associations à doses fixes d'inhibiteur d'intégrine avec des agonistes de ppar Pending WO2025217571A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180333396A1 (en) * 2014-06-13 2018-11-22 Inventiva Ppar compounds for use in the treatment of fibrotic diseases
US20200121625A1 (en) * 2017-04-18 2020-04-23 Genfit Combination of elafibranor or derivatives thereof with an anti-nash, anti-fibrotic or anti-cholestatic agent
US20220177468A1 (en) * 2020-11-19 2022-06-09 Pliant Therapeutics, Inc. Integrin inhibitor and uses thereof
US20230060422A1 (en) * 2019-12-20 2023-03-02 Novartis Ag Combination treatment of liver diseases using integrin inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180333396A1 (en) * 2014-06-13 2018-11-22 Inventiva Ppar compounds for use in the treatment of fibrotic diseases
US20200121625A1 (en) * 2017-04-18 2020-04-23 Genfit Combination of elafibranor or derivatives thereof with an anti-nash, anti-fibrotic or anti-cholestatic agent
US20230060422A1 (en) * 2019-12-20 2023-03-02 Novartis Ag Combination treatment of liver diseases using integrin inhibitors
US20220177468A1 (en) * 2020-11-19 2022-06-09 Pliant Therapeutics, Inc. Integrin inhibitor and uses thereof

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