Methods of treating nash

Abstract

Methods of treating NASH / MASH comprising administering a fatty acid synthesis (FASN) inhibitor and compositions for treating the same are provided herein.

Description

METHODS OF TREATING NASHCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to, and the benefit of, U.S. Provisional Application No. 63 / 623,311, filed January 21, 2024, U.S. Provisional Application No. 63 / 623,515, filed January 22, 2024, and U.S. Provisional Application No. 63 / 721,480, filed November 16, 2024, the contents of each of which are hereby incorporated by reference in its entirety.BACKGROUND

[0002] In 2023, global liver disease medical societies and patient groups formalized the decision to rename non-alcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated steatotic liver disease (MASLD) and nonalcoholic steatohepatitis (NASH) to metabolic dysfunction- associated steatohepatitis (MASH). Additionally, an overarching term, steatotic liver disease (SLD), was established to capture multiple types of liver diseases associated with fat buildup in the liver.

[0003] Increased de novo lipogenesis (DNL) drives the development of nonalcoholic steatohepatitis / metabolic dysfunction- associated steatohepatitis (NASH / MASH) and fatty acid synthase (FASN) is the rate-limiting enzyme in the DNL pathway. FASN inhibition not only reduces liver fat but also acts directly on immune and hepatic stellate cells reducing inflammation and fibrosis. WO2012 / 122391, W02014 / 008197 and W02015 / 105860 describe heterocyclic FASN inhibitors and WO2018 / 089904 describes uses of some of the above-referenced FASN inhibitors for the treatment of NAFLD / MAFLD and NASH / MASH. The content of the above-referenced disclosures is incorporated by reference herein. One of the compounds described in the above-reference applications, Denifanstat (TVB-2640) is a first in class FASN inhibitor that has demonstrated improvements in liver fat and biomarkers associated with inflammation and fibrosis in NASH / MASH trials.

[0004] There is a need for further treatments for NAFLD / MAFLD and NASH / MASH that can improve symptoms and markers of disease, including fibrosis. The embodiments provided for herein satisfy these needs as well as others.SUMMARY

[0005] In some embodiments, methods of treating a subject with NASH / MASH with moderate-to-severe fibrosis are provided. In some embodiments, the methods comprise administering orally to the subject a pharmaceutical composition comprising a compound of 1IPTS / 128851376.1Formula (I), or a pharmaceutically acceptable salt thereof, wherein:Formula (I) is:R1is H, -CN, halogen, C1-C4 straight or branched alkyl, -O-iCi-Cs cycloalkyl), -O-(Ci-C4 straight or branched alkyl) wherein:C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and when R1is not H, -CN or halogen, it is optionally substituted with one, two or three halogens;each R2is independently hydrogen, halogen or C1-C4 straight or branched alkyl; R3is H, -OH, or halogen;R21is H, halogen, C1-C4 straight or branched alkyl, C3-C5 cycloalkyl wherein the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;R22is H, halogen, or C1-C2 alkyl;R24is H, C1-C4 straight or branched alkyl, -(C1-C4 alkyl )t-OH,-(C1-C4 alkyl)t-O-(C3-C5cycloalkyl), -(C1-C4 alkyl)t-(C3-C5cycloalkyl), or-(C1-C4 alkyl)t-O-(Ci-C4 straight or branched alkyl) wherein:the C1-C4 straight or branched alkyl is optionally substituted with one, two or three halogens;t is 0 or 1 ; andthe C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; L1is CR23or N; andR23is H, C1-C4 straight or branched alkyl, -(C1-C4 alkyl )i-OH-(C1-C4 alkyl)v-O-(C3-Cs cycloalkyl), -(C1-C4 alkyl)t-(C3-Cs cycloalkyl), or-(C1-C4 alkyl)v-O-(Ci-C4 straight or branched alkyl) wherein:2IPTS / 128851376.1the C1-C4 straight or branched alkyl is optionally substituted with one, two or three halogens;v is 0 or 1 ; andthe C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom.

[0006] In some embodiments, the subject with NASH / MASH with moderate-to-severe fibrosis is classified as stage F2 or F3 fibrosis. In some embodiments, the subject has a NAFLD / MASLD Activity Score (NAS / MAS) that is equal or greater to 4 prior to administration of the pharmaceutical composition.

[0007] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, Formula (I):R1is H, -CN, halogen, C1-C4 straight or branched alkyl, -O-(C3-Cs cycloalkyl), -O-(Ci-C4 straight or branched alkyl) wherein:C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and when R1is not H, -CN or halogen, it is optionally substituted with one, two or three halogens;each R2is independently hydrogen, halogen or C1-C4 straight or branched alkyl; R3is H, -OH, or halogen;R21is H, halogen, C1-C4 straight or branched alkyl, C3-C5 cycloalkyl wherein the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;R22is H, halogen, or C1-C2 alkyl;R24is H, C1-C4 straight or branched alkyl, -(C1-C4 alkyl)t-OH-(C1-C4 alkyl)t-O-(C3-Cs cycloalkyl), -(C1-C4 alkyl)t-(C3-Cs cycloalkyl), or-(C1-C4 alkyl)t-O-(Ci-C4 straight or branched alkyl) wherein:3IPTS / 128851376.1the C1-C4 straight or branched alkyl is optionally substituted with one, two or three halogens;t is 0 or 1 ;andthe C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; L1is CR23or N;R23is H, C1-C4 straight or branched alkyl, -(C1-C4 alkyl)t-OH.-(C1-C4 alkyl)v-O-(C3-C5 cycloalkyl), -(C1-C4 alkyl)t-(C3-C5 cycloalkyl), or-(C1-C4 alkyl)v-O-(Ci-C4 straight or branched alkyl) wherein:the C1-C4 straight or branched alkyl is optionally substituted with one, two or three halogens; andv is 0 or 1.

[0008] In some embodiments, the compound is(denifanstat), or a pharmaceutically acceptable salt thereof.BRIEF DESCRIPTION OF THE FIGURES

[0009] FIG. 1 shows the primary endpoints and selected secondary endpoints for the FASCINATE- 2 clinical trial.

[0010] FIG. 2 shows the patient disposition for the FASCINATE-2 clinical trial.

[0011] FIG. 3 shows the baseline characteristics of the patients enrolled in the FASCINATE-2 clinical trial.

[0012] FIG. 4 shows effect of denifanstat versus placebo on NAS >2 improvement without worsening of fibrosis, MASH resolution plus NAS >2 improvement without worsening of fibrosis, and MASH resolution without worsening of fibrosis.

[0013] FIG. 5 shows effect of denifanstat versus placebo on >1 improvement in fibrosis without worsening of MASH, >1 improvement in fibrosis without worsening of MASH in subjects with stage F3, and >2 improvement in fibrosis without worsening of MASH in subjects with stage F3.

[0014] FIG. 6 shows effect of denifanstat versus placebo on >1 improvement in GLP1 receptor agonist population, >1 improvement in type 2 diabetes population, and >1 improvement in PNPLA3 1148 carrier population.

[0015] FIG. 7 shows effect of denifanstat versus placebo on antifibrotic activity in F34IPTS / 128851376.1including septa dimensions. Denifanstat showed a strong antifibrotic activity in F3 with a lower rate of progression to cirrhosis than placebo.

[0016] FIG. 8 shows link between zonal parameters and clinical outcomes.

[0017] FIG. 9 shows effect of denifanstat versus placebo in fibrosis improvement by response rate ratios.

[0018] FIG. 10 shows effect of denifanstat versus placebo on number of Peri-Portal Long Strings (PPLS). Denifanstat demonstrated strong effect on number of PPLS’s.

[0019] FIG. 11 shows effect of denifanstat on PPLS’s in a patient with >1 improvement in liver fibrosis score by conventional pathology scoring. Denifanstat showed a strong effect on PPLS’s,.

[0020] FIG. 12 shows effect of denifanstat on PPLS’s in a patient with no change in liver fibrosis score by conventional pathology scoring. Denifanstat showed a strong effect on PPLS’s.

[0021] FIG. 13 shows effect of denifanstat versus placebo on >1 improvement in liver fibrosis in qF4 population (defined by Al).

[0022] FIG. 14 shows qfibrosis data demonstrating strong antifibrotic effect of denifanstat versus placebo.

[0023] FIG. 15 shows qfibrosis data demonstrating strong antifibrotic effect of denifanstat versus placebo.

[0024] FIG. 16 shows effect of denifanstat versus placebo (qfibrosis data by Al-based digital pathology). This data shows patients with a decrease in qfibrosis continuous score (steatosis corrected) based on Al, that are not classified as responders by human / conventional CRN scoring and supports that denifanstat reduced fibrosis, notably in F3 population.

[0025] FIG. 17 shows study in fast-food diet (FFD) induced dyslipidaemia LDL receptor knockout mice with NASH / MASH.

[0026] FIG. 18 shows effect of TVB-3664 on circulating cholesterol and triglycerides in Ldlr- / - NASH / MASH mice.

[0027] FIG. 19 shows effect of TVB-3664 on inflammatory markers related to atherosclerosis in Ldlr- / - NASH / MASH mice.

[0028] FIG. 20 shows effect of TVB-3664 on total atherosclerotic lesion area per crosssection of aortic root in Ldlr- / - NASH / MASH mice.

[0029] FIG. 21 shows effect of TVB-3664 on liver histology in Ldlr- / - NASH / MASH mice.

[0030] FIG. 22 shows effect of denifanstat in patients on GLP-1 therapy at study entry.5IPTS / 128851376.1DETAILED DESCRIPTION

[0031] In certain aspects, the present disclosure provides methods of treating liver disorders, such as, but not limited to NASH / MASH and NAFLD / MASLD, associated with accumulation of fat in the liver (fatty liver disease / steatotic liver disease), liver cirrhosis and / or liver fibrosis and / or for improving liver function comprising administering a compound or compounds as provided for herein to the subject.Definitions

[0032] Chemical moieties referred to as univalent chemical moieties (e.g., alkyl, aryl, etc.) also encompass structurally permissible multivalent moieties, as understood by those skilled in the art. For example, while an “alkyl” moiety generally refers to a monovalent radical (e.g., CH3CH2-), in appropriate circumstances an “alkyl” moiety can also refer to a divalent radical (e.g., -CH2CH2-, which is equivalent to an “alkylene” group). Similarly, under circumstances where a divalent moiety is required, those skilled in the art will understand that the term “aryl” refers to the corresponding divalent arylene group.

[0033] All atoms are understood to have their normal number of valences for bond formation (e.g., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the atom’s oxidation state). On occasion a moiety can be defined, for example, as (A)aB, wherein a is 0 or 1. In such instances, when a is 0 the moiety is B and when a is 1 the moiety is AB.

[0034] Where a substituent can vary in the number of atoms or groups of the same kind (e.g., alkyl groups can be Ci, C2, C3, etc.), the number of repeated atoms or groups can be represented by a range (e.g., C1-C6 alkyl) which includes each and every number in the range and any and all sub ranges. For example, C1-C3 alkyl includes Ci, C2, C3, C1-2, C1-3, and C2-3 alkyl.

[0035] “Alkanoyl” refers to a carbonyl group with a lower alkyl group as a substituent.

[0036] “Alkylamino” refers to an amino group substituted by an alkyl group.

[0037] “Alkoxy” refers to an O-atom substituted by an alkyl group as defined herein, for example, methoxy [-OCH3, a Cialkoxy]. The term “C1-6 alkoxy” encompasses Ci alkoxy, C2 alkoxy, C3 alkoxy, C4 alkoxy, C5 alkoxy, Ce alkoxy, and any sub-range thereof.

[0038] “Alkoxycarbonyl” refers to a carbonyl group with an alkoxy group as a substituent.

[0039] “Alkyl,” “alkenyl,” and “alkynyl,” refer to optionally substituted, straight and branched chain aliphatic groups having from 1 to 30 carbon atoms, or preferably from 1 to 15 carbon atoms, or more preferably from 1 to 6 carbon atoms. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl,6IPTS / 128851376.1pentyl, hexyl, vinyl, allyl, isobutenyl, ethynyl, and propynyl. The term “heteroalkyl” as used herein contemplates an alkyl with one or more heteroatoms.

[0040] “Alkylene” refers to an optionally substituted divalent radical which is a branched or unbranched hydrocarbon fragment containing the specified number of carbon atoms, and having two points of attachment. An example is propylene [-CH2CH2CH2-, a Csalkylene].

[0041] “Amino” refers to the group -NH2.

[0042] “Aryl” refers to optionally substituted aromatic groups which have at least one ring having a conjugated pi electron system and includes carbocyclic aryl, and biaryl groups, all of which can be optionally substituted. Phenyl and naphthyl groups are preferred carbocyclic aryl groups.

[0043] “Aralkyl” or “arylalkyl” refer to alkyl-substituted aryl groups. Examples of aralkyl groups include butylphenyl, propylphenyl, ethylphenyl, methylphenyl, 3, 5 -dimethylphenyl, tert-butylphenyl.O

[0044] “Carbamoyl” as used herein contemplates a group of the structurec2 where in RNis selected from the group consisting of hydrogen, -OH, Ci to C12 alkyl, Ci to C12 heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, sulfonyl, sulfonate and sulfonamide.O II>

[0045] “Carbonyl” refers to a group of the structure C .

[0046] “Cycloalkyl” refers to an optionally substituted ring, which can be saturated or unsaturated and monocyclic, bicyclic, or tricyclic formed entirely from carbon atoms. An example of a cycloalkyl group is the cyclopentenyl group (C5H7-), which is a five carbon (C5) unsaturated cycloalkyl group. In some embodiments, the cycloalkyl is described as optionally including a heteroatom (e.g., an oxygen or nitrogen atom), thereby forming a heterocycle.

[0047] “Heterocycle” refers to an optionally substituted 5- to 7-membered cycloalkyl ring system containing 1, 2 or 3 heteroatoms, which can be the same or different, selected from N, O or S, and optionally containing one double bond.

[0048] “Halogen” refers to a chloro, bromo, fluoro or iodo atom radical. The term “halogen” also contemplates terms “halo” or “halide.”

[0049] “Heteroatom” refers to a non-carbon atom, where boron, nitrogen, oxygen, sulfur and 7IPTS / 128851376.1phosphorus are preferred heteroatoms, with nitrogen, oxygen and sulfur being particularly preferred heteroatoms in the compounds of the present disclosure.

[0050] “Heteroaryl” refers to optionally substituted aryl groups having from 1 to 9 carbon atoms and the remainder of the atoms are heteroatoms, and includes those heterocyclic systems described in “Handbook of Chemistry and Physics,” 49thedition, 1968, R. C. Weast, editor; The Chemical Rubber Co., Cleveland, Ohio. See particularly Section C, Rules for Naming Organic Compounds, B. Fundamental Heterocyclic Systems. Suitable heteroaryls include thienyl, pyrrolyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, pyranyl, tetrazolyl, pyrrolyl, pyrrolinyl, pyridazinyl, triazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, thiadiazolyl, benzothiazolyl, benzothiadiazolyl, and the like.

[0051] An “optionally substituted” moiety can be substituted with from one to four, or preferably from one to three, or more preferably one or two non-hydrogen substituents. Unless otherwise specified, when the substituent is on a carbon, it is selected from the group consisting of -OH, -CN, -NO2, halogen, Ci to C12 alkyl, Ci to C12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, sulfonamide and amino, none of which are further substituted. Unless otherwise specified, when the substituent is on a nitrogen, it is selected from the group consisting of Ci to C12 alkyl, Ci to C12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, sulfonyl, sulfonate and sulfonamide none of which are further substituted.

[0052] The term “sulfonamide” as used herein contemplates a group having the structurewherein RNis selected from the group consisting of hydrogen, -OH, Ci to C12 alkyl, Ci to C12 heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and sulfonamide.

[0053] The term “sulfonate” as used herein contemplates a group having the structure8IPTS / 128851376.1wherein Rsis selected from the group consisting of hydrogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkanoyl, or C1-C10 alkoxycarbonyl.

[0054] “Sulfonyl” as used herein alone or as part of another group, refers to an SO2 group. The SO2 moiety is optionally substituted.

[0055] Compounds of the present disclosure can exist as stereoisomers, wherein asymmetric or chiral centers are present. Stereoisomers are designated (R) or (S) depending on the configuration of substituents around the chiral carbon atom. The terms (R) and (S) used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., (1976), 45: 13-30, hereby incorporated by reference. The present disclosure contemplates various stereoisomers and mixtures thereof and are specifically included within the scope of the present disclosure. Stereoisomers include enantiomers, diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.

[0056] Also, moieties disclosed herein which exist in multiple tautomeric forms include all such forms encompassed by a given tautomeric structure.

[0057] Individual atoms in the disclosed compounds may be any isotope of that element. For example hydrogen may be in the form of deuterium.

[0058] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans. It can be material which is not biologically or otherwise undesirable, i.e., the material can be administered to an individual without causing any undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it 9IPTS / 128851376.1is contained.

[0059] The term “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include, for example, acid addition salts and base addition salts.

[0060] “Acid addition salts” according to the present disclosure, are 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, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-l -carboxylic acid), 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like.

[0061] “Base addition salts” according to the present disclosure are 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 ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature can cause a single crystal form to dominate.

[0062] The term “treating” includes the administration of the compounds or agents of as 10IPTS / 128851376.1provided for herein to a subject to prevent or delay, to alleviate, or to arrest or inhibit development of a disease or disorder, including diseases or dissorders associated with accumulation of fat in the liver (fatty liver diseases or disorders) such as NAFLD / MAFLD and NASH / MASH, liver fibrosis and liver cirrhosis. The term “treating” as used herein includes achieving a therapeutic benefit and / or a prophylactic benefit. By therapeutic benefit is meant eradication / normalization or amelioration / improvement / reversal / regression or stabilization / lack of progression of one or more of the physiological symptoms associated with the underlying liver disease.

[0063] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient alone or in combination with other therapies, to provide a therapeutic benefit in the therapeutic treatment of the disease, disorder or condition or to delay or minimize one or more symptoms associated with the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent. In some embodiments, the “term "therapeutically effective amount” refers to asynergistically effective amount or synergistically therapeutic amount.

[0064] "Synergistic" means that the therapeutic effect of FASN inhibitor when administered in combination as described herein with another therapeutic, such as a GLP-1 agonist, is greater than the predicted additive therapeutic effects of the FASN inhibitor and GLP- 1 agonist when administered alone. The “term "synergistically therapeutic amount” or "synergistically effective amount” refers to a less than standard therapeutic amount of one or both drugs, meaning that the amount required for the desired effect is lower than when the drug is used alone.

[0065] A synergistically therapeutic amount also includes cases where one drug is given at a standard therapeutic dose and another drug is administered in a less than standard therapeutic dose. For example, the FASN inhibitor could be given in a therapeutic dose and the GLP- 1 agonist could be given in a standard or less than standard therapeutic dose to provide a synergistic result, or vice versa.

[0066] Except when noted, the terms “subject” or “patient” are used interchangeably and refer to mammals such as human patients and non-human primates, as well as experimental animals such as rabbits, rats, and mice, and other animals. Accordingly, the term “subject” or “patient” as used herein means any mammalian patient or subject to which the compounds as 11IPTS / 128851376.1provided herein can be administered. In one aspect, the subject is a human subject. In some embodiments, methods are provided to identify subject patients for treatment according to the methods provided herein, accepted screening methods are employed to determine risk factors associated with a targeted or suspected disease or condition or to determine the status of an existing disease or condition in a subject. These screening methods include, for example, conventional work-ups to determine risk factors that are associated with the targeted or suspected disease or condition. These and other methods allow the clinician to select patients in need of therapy using the methods, compounds, compositions, and formulations as provided for herein.FASN Pathway Modulators

[0067] One aspect of the present disclosure includes a method of treating diseases associated with accumulation of fat in the liver (fatty liver disease / steatotic liver disease)(e.g., NAFLD / MAFLD, NASH / MASH), cirrhosis and / or liver fibrosis. In some embodiments, the compound is administered with a GLP- 1 agonist. In one aspect, the FASN pathway modulator can be an inhibitor of the fatty acid synthesis pathway. In some embodiments, methods of treating subject with NASH / MASH with moderate-to-severe fibrosis are provided. In some embodiments, the methods comprise administering a FASN inhibitor. In some embodiments, the compound is administered orally. In some embodiments, the inhibitor, such as the compounds provided for herein are administered once daily. In some embodients, the compound is a compound of Formula (I), such as the compounds of Formula (I) provided for herein. In some embodiments, the compound is denifanstat, or a pharmaceutically acceptable salt thereof.

[0068] Examples of inhibitors, such as those of Formula (I) of the fatty acid synthesis pathway that can be used in the methods and compositions of the present disclosure are described below.Compounds of Formula (I)

[0069] In various aspects, compounds of Formula (I) are provided:Formula (I) is:wherein:IPTS / 128851376.1R1is H, -CN, halogen, C1-C4 straight or branched alkyl, -O-iCa-Cs cycloalkyl), -0-(Ci-C4 straight or branched alkyl) wherein:C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and when R1is not H, -CN or halogen, it is optionally substituted with one, two or three halogens;each R2is independently hydrogen, halogen or C1-C4 straight or branched alkyl; R3is H, -OH, or halogen;R21is H, halogen, C1-C4 straight or branched alkyl, C3-C5 cycloalkyl wherein the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;R22is H, halogen, or C1-C2 alkyl;R24is H, C1-C4 straight or branched alkyl, -(C1-C4 alkyl )i-OH-(C1-C4 alkyl)t-O-(C3-C5cycloalkyl), -(C1-C4 alkyl)t-(C3-C5cycloalkyl), or-(C1-C4 alkyl)t-O-(Ci-C4 straight or branched alkyl) wherein:the C1-C4 straight or branched alkyl is optionally substituted with one, two or three halogens;t is 0 or 1 ; andthe C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; L1is CR23or N;R23is H, C1-C4 straight or branched alkyl, -(C1-C4 alkyl)t-OH,-(C1-C4 alkyl)v-O-(C3-C5 cycloalkyl), -(C1-C4 alkyl)t-(C3-C5 cycloalkyl), or-(C1-C4 alkyl)v-O-(Ci-C4 straight or branched alkyl) wherein:the C1-C4 straight or branched alkyl is optionally substituted with one, two or three halogens;v is 0 or 1 ; andthe C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom.

[0070] In some aspects of Formula

[0071] In some aspects of FormulaIPTS / 128851376.1

[0072] In some aspects of Formula (I), R24is C1-C4 straight or branched alkyl, optionally substituted with one, two or three halogens. In some aspects of Formula (I) R24is -Me or -CF3. In some aspects of Formula (I), R24is -Me. In some aspects of Formula (I), R24is -CF3.

[0073] In some aspects of Formula (I), R21is halogen, C1-C4 straight or branched alkyl, C3-Cs cycloalkyl wherein the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom, -S(O)u-(Ci-C4 straight or branched alkyl) wherein u is 0 or 2, or — S(O)u-( C3-C5 cycloalkyl) wherein u is 0 or 2. In some aspects of Formula (I), R21is C1-C4 straight or branched alkyl or C3-C5 cycloalkyl. In some aspects of Formula (I), R21is Me or cyclobutyl. In some aspects of Formula (I), R21is cyclobutyl. In some aspects of Formula (I), R21is -Me.

[0074] In some aspects of Formula (I), R3is H or halogen. In some aspects of Formula (I), R3is H.

[0075] In some aspects of Formula (I), R1is halogen, -CN or C1-C2 haloalkyl. In some aspects of Formula (I), R1is CN.

[0076] In some aspects of Formula (I), L1is N. In some aspects of Formula (I), L1is CR23.

[0077] In some aspects of Formula (I), R22is C1-C2 alkyl. In some aspects of Formula (I), R22is Me.

[0078] In some aspects of Formula (I), R21is C1-C2 alkyl or C3-C5 cycloalkyl and R22is Ci-C2 alkyl. In some aspects of Formula (I), R21is -Me or cyclobutyl and R22is -Me.

[0079] In some aspects of Formula (I), R21is C3-C5 cycloalkyl and R22is C1-C2 alkyl. In some aspects of Formula (I), R21is cyclobutyl and R22is Me.

[0080] In some aspects of Formula (I), R21is C1-C2 alkyl and R22is C1-C2 alkyl. In some aspects of Formula (I), R21is -Me and R22is -Me.

[0081] In some aspects of Formula (I), R23is -(C1-C4 alkyl)v-O-(C3-C5 cycloalkyl), wherein v is 0 or 1. In some aspects, v is 1. In some aspects of Formula (I), R23is CH2-O-CH3.

[0082] In some aspects of Formula (I), R1is -CN, each R2is H, R3is H or F, R21isC1-C4 straight or branched alkyl or C3-C4 cycloalkyl, R22is methyl, R24is C1-C4 straight or branched alkyl, optionally substituted with one, two or three halogens L1is N or CR23, R23is methoxymethyl.

[0083] In some aspects of Formula (I), R1is -CN, each R2is H, R3is H, R21isC1-C4 straight or branched alkyl or C3-C4 cycloalkyl, R22is methyl, R24is C1-C4 straight or branched alkyl, optionally substituted with one, two or three halogens L1is N or CR23, R23is methoxymethyl.

[0084] All aspects of Formula (I) described herein are meant to be combinable with each 14IPTS / 128851376.1other.

[0085] When L1is N, references to Formula (I) are meant to encompass all possible triazole tautomers selected from:

[0086] In some aspects of Formula (I), compounds have a structure selected from the group consisting of:

[0087] Throughout the claims and the specification, references to denifanstat or to thetriazole tautomers, including the tautomer as drawn and any possible alternative triazoleIPTS / 128851376.1denifanstat can be used. In some embodiments, the compound administered to the subject with fibrosis is denifanstat, or a pharmaceutically acceptable salt thereof.

[0088] The compounds of Formula (I) can be prepared as provided for in WO2012 / 122391, W02014 / 008197, W02015 / 105860, and / or WO2018 / 089904, each of which is hereby incorporated by reference in its entirety.Fatty Add Synthesis Pathway

[0089] Various aspects of the present disclosure relate to compositions and methods that modulate the activity of the fatty acid synthesis pathway to treat diseases associated with accumulation of fat in the liver (fatty liver disease / steatotic liver disease) and / or liver fibrosis. The fatty acid synthesis pathway in humans can use four enzymes: 1) acetyl-CoA carboxylase (ACC), which can synthesize malonyl-CoA; 2) malic enzyme, which can produce NADPH; 3) citrate lyase, which can synthesize acetyl-CoA; and 4) fatty acid synthase, which can catalyze NADPH-dependent synthesis of fatty acids (e.g., palmitate) from acetyl-CoA and malonyl-CoA. Palmitate is a building block for additional fatty acids and complex lipids. In various aspects, the present disclosure relates to treatment of diseases associated with accumulation of fat in the liver (fatty liver disease, including NASH / MASH, NAFLD / MAFLD), cirrhosis and / or liver fibrosis.

[0090] The final products of fatty acid synthase are free fatty acids (e.g., palmitate) which can use separate enzymatic derivatization with coenzyme-A for incorporation into other products. In humans, fatty acid synthesis can occur in two sites: the liver, where palmitic acid can be made (Roncari, (1974) Can. J. Biochem., 52:221-230) and lactating mammary gland, where Cio -Ci4 fatty acids can be made (Thompson, et al., (1985) Pediatr. Res., 19:139-143).

[0091] Fatty acids can be synthesized in the cytoplasm from acetyl-CoA. Acetyl-CoA can be generated from pyruvate by pyruvate dehydrogenase (PDH) and by -oxidation of fatty acids in the mitochondria. A “citrate shuttle” can transport acetyl-CoA from the mitochondria to the cytoplasm. Acetyl-CoA can react with oxaloacetate to yield citrate, and a tricarboxylate translocase can transport citrate from the mitochondria to the cytosol. In the cytoplasm, citrate can be cleaved back to oxaloacetate and acetyl-CoA, a reaction that can be catalyzed by ATP-citrate lyase. Oxaloacetate can be converted back to pyruvate for re-entry into mitochondria.

[0092] Acetyl-CoA can be converted to malonyl-CoA. Acetyl-CoA carboxylase (ACC) is a complex multifunctional, biotin-containing, enzyme system that can catalyze carboxylation of acetyl-CoA to malonyl-CoA. This conversion is an irreversible, rate-limiting step in fatty 16IPTS / 128851376.1acid synthesis. ACC can carry out three functions: biotin carboxyl carrier protein, biotin carboxylase and carboxyltransferase. ATP-dependent carboxylation of biotin, a prosthetic group (cofactor) can be followed by transfer of the carboxyl group to acetyl-CoA.

[0093] HCOv + ATP + acetyl-CoA -> ADP + Pi + malonyl-CoA

[0094] There are two ACC forms, alpha and beta, encoded by two different genes ACC-alpha (also known as ACC, ACAC, ACC1 , ACCA, and ACACA) can encode protein highly enriched in lipogenic tissues. Multiple alternatively spliced transcript variants divergent in the sequence and encoding distinct isoforms have been found for this gene. ACC-beta (also known as ACC2, ACCB, HACC275, and ACACB) can encode protein thought to control fatty acid oxidation by means of the ability of malonyl-CoA to inhibit carnitine-palmitoyl-CoA transferase I, the rate-limiting step in fatty acid uptake and oxidation by mitochondria. ACC-beta may be involved in the regulation of fatty acid oxidation, rather than fatty acid biosynthesis. There is evidence for the presence of two ACC-beta isoforms.

[0095] ACC can be regulated by the phosphorylation / dephosphorylation of targeted serine residues. For example, AMP-activated kinase (AMPK) can phosphorylate ACC, and this phosphorylation can inhibit the ability of ACC to produce malonyl-CoA. On ACACA, AMPK can phosphorylate Ser79, Serl200, and Serl215 (Park S.H. et al. (2002) J. Appl. Physiol. 92:2475-82). AMPK can phosphorylate Ser218 on ACACB (Hardie D.G. (1992) Biochim. Biophys. Acta 1123:231-8). Also, cAMP-dependent protein kinase (Protein Kinase A, or PKA) can phosphorylate ACC.

[0096] ACC can be regulated by allosteric transformation by citrate or palmitoyl-CoA. For example, citrate can be a positive effector (i.e. citrate can allosterically activate ACC). Citrate concentration can be high when there is adequate acetyl-CoA entering the Krebs Cycle. Excess acetyl-CoA can then be converted via malonyl-CoA to fatty acids. Palmitoyl-CoA can be a negative effector. Palmitoyl-CoA, which is the product of Fatty Acid Synthase (FASN), can promote the inactive conformation of ACC, which can reduce production of malonyl-CoA (a feedback inhibition process). AMP can regulate fatty acid synthesis by regulating the availability of malonyl-CoA. Insulin binding a receptor can activate a phosphatase to dephosphorylate ACC, which can remove the inhibitory effect.

[0097] The fatty acid synthase gene (also known as FAS, OA-519, SDR27X1; MGC14367; MGC15706; FASN) is involved in fatty acid synthesis. The enzyme encoded by this gene is a multifunctional protein of approximately 272 kDa with multiple domains, each with distinct enzyme activities that can play a role in fatty acid biosynthesis. FASN is an enzyme in the de 17IPTS / 128851376.1novo lipogenesis pathway. FASN can catalyze the synthesis of palmitate from acetyl-CoA and malonyl-CoA, in the presence of NADPH, into long-chain saturated fatty acids. In some cancer cell lines, FASN protein has been found to be fused with estrogen receptor- alpha (ER-alpha), in which the N-terminus of FASN is fused in-frame with the C-terminus of ER-alpha.

[0098] FASN protein can exist in the cytosol as a dimer of identical subunits. FASN consists of three catalytic domains in the N-terminal section (-ketoacyl synthase (KS), malonyl / acetyltransferase (MAT), and dehydrase (DH)). The N-terminal section is separated by a core region of about 600 amino acids from four C-terminal domains (enoyl reductase (ER), -ketoacyl reductase (KR), acyl carrier protein (ACP), and thioesterase (TE)). The crystal structure of a mammalian fatty acid synthase has been reported (Maier T. et al. (2008) Science 321: 1315-1322).

[0099] The enzymatic steps of fatty acid synthesis can involve decarboxylative condensation, reduction, dehydration, and another reduction and can result in a saturated acyl moiety. NADPH can be an electron donor in reductive reactions.Combinations

[0100] The compounds provided for herein can also be administered with an additional therapeutic. The additional therapeutic can be administered concurrently with the compounds of Formula (I) or sequentially. They can also be administered as a combination product, such as a fixed dose combination. However, the compounds of Formula (1) and the additional therapeutic can be administered separately. In some embodiments, the additional therapeutic is a GLP-1 agonist. The GLP-1 agonists can be compounds whose therapeutic activity is related solely / primarily to their GLP-1 agonist activity, as well as compounds with multiple mechanisms of action in addition to GLP-1 agonist activity. GLP-1 agonists include pharmaceutical compositions and dosage forms wherein a compound with GLP- 1 agonist activity is co-formulated with additional therapeutic agents.

[0101] In some aspects, the GLP-1 agonist includes, without limitation, agents selected from single agent GLP-1 receptor agonists, dual GIP / GLP-1 receptor agonists, dual GIP receptor antagonists / GLP-1 receptor agonists, dual Amylin / GLP-1 receptor agonists, dual Glucagon / GLP- 1 receptor agonists and triple Glucagon / GIP / GLP-1 receptor agonists.

[0102] In some aspects, the GLP-1 receptor agonist is a single agent GLP-1 receptor agonist. In some aspects, the single agent GLP-1 receptor agonist is selected from the group consisting of semaglutide, liraglutide, LY3502970 and danuglipron.

[0103] In some aspects, the GLP-1 receptor agonist is a dual GIP / GLP-1 receptor agonist. In 18IPTS / 128851376.1some aspects, the dual GIP / GLP-1 receptor agonist is selected from tirzepatide, CT388 and dapiglutide.

[0104] In some aspects, the GLP-1 receptor agonist is a dual GIP receptor antagonist / GLP- 1 receptor agonist. In some aspects, the dual GIP receptor antagonist / GLP- 1 receptor agonist is AMG133.

[0105] In some aspects, the GLP-1 receptor agonist is a dual Amylin / GLP-1 receptor agonist. In some aspects, the dual Amylin / GLP-1 receptor agonist is Cagri-Sema.

[0106] In some aspects, the GLP-1 receptor agonist is a dual Glucagon / GLP-1 receptor agonist. In some aspects, the dual Glucagon / GLP-1 receptor agonist is selected from the group consisting of BI456906, NN9277, cotadutide and pemvidutide.

[0107] In some aspects, the GLP-1 receptor agonist is a triple Glucagon / GIP / GLP- 1 receptor agonist. In some aspects, the triple Glucagon / GIP / GLP- 1 receptor agonist is retatrutide.

[0108] In some aspects, the GLP-1 receptor agonist includes, without limitation, a GLP-1 agonist selected from the group consisting of semaglutide, liraglutide, danuglipron, LY3502970, AMG-133, CT388, dapiglutide, tirzepatide, cotadutide, pemvidutide, BI456906, NN9277, Cagri-Sema and retatrutide.

[0109] In some aspects, the GLP-1 agonist is semaglutide. In some aspects, the GLP-1 receptor agonist is liraglutide. In some aspects, the GLP-1 receptor agonist is danuglipron. In some aspects, the GLP-1 receptor agonist is LY3502970. In some aspects, the GLP-1 receptor agonist is AMG-133. In some aspects, the GLP-1 receptor agonist is CT388. In some aspects, the GLP-1 receptor agonist is dapiglutide. In some aspects, the GLP-1 receptor agonist is tirzepatide. In some aspects, the GLP-1 receptor agonist is cotadutide. In some aspects, the GLP-1 receptor agonist is pemvidutide. In some aspects, the GLP-1 receptor agonist is BI456906. In some aspects, the GLP-1 receptor agonist is NN9277. In some aspects, the GLP-1 receptor agonist is Cagri-Sema. In some aspects, the GLP-1 receptor agonist is retatrutide.

[0110] The GLP- 1 agonists contemplated in the methods described herein can be administered orally or parenterally (e.g., subcutaneously). For GLP-1 agonists that are approved for at least one indication by the Food and Drug administration, the route of administration can be as described in their FDA-approved label. In some aspects, the GLP-1 agonists are administered orally. In some aspects, the GLP-1 agonists are administered subcutaneously.

[0111] GLP-1 agonists, including the GLP-1 agonists contemplated by the methods described 19IPTS / 128851376.1herein are currently used, and in some cases approved for use by the Food and Drug Administration for two main indications: treatment of Type 2 diabetes (T2D) and weight loss.

[0112] In some aspects of the methods described herein, the GLP- 1 agonists are administered at doses that are equivalent to the doses indicated on their label as maintenance doses for treatment of Type 2 diabetes in adult patients. In some aspects of the methods described herein, the GLP-1 agonists are administered at doses that are lower than the doses indicated on their label as the maintenance dose for treatment of Type 2 diabetes (z.e., doses that represent a certain percentage of the dose indicated on their label as the maintenance dose for the treatment of Type 2 diabetes in adult patients). In some aspects of the methods described herein, the GLP-1 agonist is administered at a dose that is between 10% and 90%, between 20% and 90%, between 30% and 90%, between 40% and 90%, between 50% and 90%, between 60% and 90%, between 70% and 90%, between 80% and 90%, between 10% and 80%, between 20% and 80%, between 30% and 80%, between 40% and 80%, between 50% and 80%, between 60% and 80%, between 70% and 80%, between 10% and 70%, between 20% and 70%, between 30% and 70%, between 40% and 70%, between 50% and 70%, between 60% and 70%, between 10% and 60%, between 20% and 60%, between 30% and 60%, between 40% and 60%, between 50% and 60%, between 10% and 50%, between 20% and 50%, between 30% and 50%, between 40% and 50%, between 10% and 40%, between 20% and 40%, between 30% and 40%, between 10% and 30%, between 20% and 30% and between 10% and 20% of the dose indicated as the maintenance dose for treatment of Type 2 diabetes in adult patients.

[0113] In some aspects, the GLP-1 agonist is administered at a dose that is between 10% and 90% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 20% and 90% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 30% and 90% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 40% and 90% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 50% and 90% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 60% and 90% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some 20IPTS / 128851376.1aspects, the GLP-1 agonist is administered at a dose that is between 70% and 90% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 80% and 90% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 10% and 80% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 20% and 80% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 30% and 80% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 40% and 80% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 50% and 80% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 60% and 80% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 70% and 80% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 10% and 70% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 20% and 70% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 30% and 70% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 40% and 70% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 50% and 70% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 60% and 70% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 10% and 60% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 20% and 60% of the 21IPTS / 128851376.1maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 30% and 60% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 40% and 60% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 50% and 60% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 10% and 50% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 20% and 50% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 30% and 50% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 40% and 50% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 10% and 40% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 20% and 40% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 30% and 40% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 10% and 30% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 20% and 30% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 10% and 20% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects of the methods described herein, the GLP- 1 agonists are administered at doses that equal the doses indicated on their label as the maintenance dose for weight loss in adult patients. In some aspects of the methods described herein, the GLP-1 agonists are administered at doses that are lower than the doses indicated on their label as maintenance doses for weight loss in adult patients (z.e., doses that represent a certain percentage of the dose indicated on their label as the maintenance dose for weight loss in adult patients).22IPTS / 128851376.1

[0114] In some aspects, the GLP-1 agonist is administered at a dose that is between 10% and 90%, between 20% and 90%, between 30% and 90%, between 40% and 90%, between 50% and 90%, between 60% and 90%, between 70% and 90%, between 80% and 90%, between 10% and 80%, between 20% and 80%, between 30% and 80%, between 40% and 80%, between 50% and 80%, between 60% and 80%, between 70% and 80%, between 10% and 70%, between 20% and 70%, between 30% and 70%, between 40% and 70%, between 50% and 70%, between 60% and 70%, between 10% and 60%, between 20% and 60%, between 30% and 60%, between 40% and 60%, between 50% and 60%, between 10% and 50%, between 20% and 50%, between 30% and 50%, between 40% and 50%, between 10% and 40%, between 20% and 40%, between 30% and 40%, between 10% and 30%, between 20% and 30% and between 10% and 20% of the maintenance dose indicated for weight loss in adult patients.

[0115] In some aspects, the GLP-1 agonist is administered at a dose that is between 10% and 90% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 20% and 90% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 30% and 90% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 40% and 90% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 50% and 90% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 60% and 90% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 70% and 90% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 80% and 90% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 10% and 80% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP- 1 agonist is administered at a dose that is between 20% and 80% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 30% and 80% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 40% and 80% of the maintenance dose indicated for weight loss in adult 23IPTS / 128851376.1patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 50% and 80% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP- 1 agonist is administered at a dose that is between 60% and 80% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 70% and 80% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 10% and 70% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 20% and 70% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 30% and 70% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 40% and 70% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 50% and 70% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 60% and 70% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 10% and 60% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 20% and 60% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 30% and 60% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 40% and 60% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP- 1 agonist is administered at a dose that is between 50% and 60% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 10% and 50% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 20% and 50% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 30% and 50% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 40% and 50% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 10% and 40% of the maintenance dose indicated for 24IPTS / 128851376.1weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 20% and 40% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 30% and 40% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 10% and 30% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 20% and 30% of the maintenance dose indicated for weight loss in adult patients. In some aspects, the GLP-1 agonist is administered at a dose that is between 10% and 20% of the maintenance dose indicated for weight loss in adult patients.

[0116] The GLP- 1 agonists can be administered at various dosing frequencies as part of the methods described herein. In certain aspects, the GLP-1 agonists are administered at the frequencies indicated on their labels for the treatment of one of their approved indications. In certain aspects, the GLP-1 agonists are administered at the frequencies indicated on their labels as maintenance regimens for the treatment of type 2 diabetes in adult patients. In certain aspects, the GLP-1 agonists are administered at the frequencies indicated on their labels as maintenance regimens for weight loss in adult patients. In some aspects, the GLP-1 agonists are administered daily (e.g. , once or twice daily) or intermittently (e.g., every other day, on a M / W / F schedule, weekly, biweekly, monthly, bimonthly, etc). In some aspects, the GLP-1 agonists are administered daily (e.g. , once or twice daily). In some aspects, the GLP-1 agonists are administered intermittently (e.g. , every other day, on a M / W / F schedule, weekly, biweekly, monthly, bimonthly, etc).Methods of Use

[0117] In various aspects, the compounds provided for herein can be in the treatment of metabolic diseases, such as NASH / MASH and subjects with NASH / MASH. The compounds can also be used to treat NAFLD / MASLD. Nonalcoholic steatohepatitis / metabolic dysfunction-associated fatty liver disease (NAFLD / MAFLD), a condition in which the liver contains more than 5% fat by weight which is not caused by alcohol consumption, is a disease which currently affects ~20-30% of the US and general western world population, and is associated with a significant increased risk of morbidity extending beyond the liver to cardiovascular disease, chronic kidney disease and malignancy. Obesity and the metabolic syndrome are two key risk factors for NAFLD / MAFLD which are characterized as an imbalance in energy utilization and storage. This imbalance leads to dysregulated metabolic 25IPTS / 128851376.1pathways and inflammatory responses that drive further changes leading to liver damage and comorbid conditions. Along with the progression of metabolic syndrome, NAFLD / MAFLD leads to more advanced liver disease starting with nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH) which can then progress to significant liver diseases including cirrhosis and hepatocellular carcinoma.

[0118] The synthesis of fatty acids in the liver, a pathway termed hepatic de novo lipogenesis (DNL), is increased in subjects with metabolic syndrome and NAFLD / MAFLD. The DNL pathway not only produces fatty acids that contribute to elevated liver stores of triglycerides, but the fatty acids that are produced are saturated fatty acid species, primarily palmitate (C 16:0), which contribute to signaling events that increase liver inflammation. Free palmitate fatty acid has also been implicated in liver inflammation processes such as macrophage recruitment and activation of endoplasmic reticulum stress response.

[0119] In various embodiments, FASN inhibitors can act prophylactically to prevent progression of symptoms of NASH / MASH or the reversal of such symptoms (improvement in symptoms), such as elevated levels of AST and ALT, liver triglycerides and cholesterol, liver steatosis, liver inflammation, liver cell (hepatocyte) ballooning, liver fibrosis, and NAFLD / MAFLD activity score. Thus, the FASN inhibitors can reverse the symptoms of NASH / MASH in models of established NASH / MASH-type disease. This is illustrated, for example, in Example 1, which demonstrates that liver enzymes are reduced, fibrosis is reduced, and cholesterol is reduced in patients that have NASH / MASH and stage F2 or F3 fibrosis and, for example, a NAS of at least 4.

[0120] Accordingly, in various aspects, the present disclosure provides methods for treating NASH / MASH or symptoms of NASH / MASH in a subject, the method comprising administering to a subject in need of such treatment an effective amount of a FASN inhibitor (e.g. a compound of Formula (I), e.g. , denifanstat or TVB-3664). In further aspects, a FASN inhibitor (e.g. a compound of Formula (I), e.g., denifanstat or TVB-3664) can be used for the manufacture of a medicament for treating NASH / MASH or symptoms of NASH / MASH. In further aspects, a FASN inhibitor (e.g. a compound of Formula (I), e.g. , denifanstat or TVB-3664) can be used for treating NASH / MASH or symptoms of NASH / MASH. In some embodiments, the NASH / MASH is established in the subject, and treatment with a FASN inhibitor (e.g. a compound of Formula (I), e.g., denifanstat or TVB-3664) can reduce or eliminate the symptoms and etiology of NASH / MASH, e.g,. general steatosis, steatosis of the liver, steatohepatitis, inflammation, inflammation of the liver, lysosomal acid lipase26IPTS / 128851376.1deficiency, and liver cirrhosis, etc. In some embodiments, the subject / patient is a subject patient with stage F2 or F3 fibrosis and / or a NAS of at least 4. In other embodiments, the treatment is used prophylactically to prevent the on-set of nonalcoholic steatohepatitis / metabolic dysfunction-associated fatty liver disease (NAFLD / MAFLD), the on-set of NASH / MASH, the progression of NAFLD / MAFLD to NASH / MASH or halt progression of NASH / MASH disease. Whether treating prophylactically or established NAFLD / MAFLD or NASH / MASH disease, the treatment of fatty liver disease / steatotic liver disease reduces the risk factors associated with establishment or progressing diabetes, liver cancer, cardiovascular disease, high triglycerides, kidney disease and metabolic syndrome.

[0121] Accordingly, in some embodiments, the present disclosure provides a method of treating nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH) comprising administering to the subject in need thereof a FASN inhibitor (e.g. a compound of Formula (I), e.g. , denifanstat or TVB-3664), wherein the method comprises improving or reversing at least one symptom of established nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH). In some embodiments, the method comprises preventing the progression of at least one symptom of nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH). In some embodiments, the symptom is selected from elevated levels of AST; elevated levels of ALT; elevated levels of liver triglycerides; elevated levels of cholesterol; liver steatosis; liver inflammation; liver cell (hepatocyte) ballooning; liver fibrosis; and NAFLD / MAFLD activity score. In some embodiments, the symptoms are reversed or attenuated after 52 weeks of treatment with the compounds provided for herein. In some embodiments, the compound is administered once a day. In some embodiments, the subject / patient is administered 50 mg of the compound once a day for at least 52 weeks.

[0122] In some embodiments, the present disclosure provides methods for reducing fibrotic gene expression in a subject (e.g., in the subject’s liver cells), the method comprising administering to a subject in need of such treatment an effective amount of a FASN inhibitor (e.g. a compound of Formula (I), e.g. , denifanstat or TVB-3664). In further aspects, a FASN inhibitor (e.g. a compound of Formula (I), e.g., denifanstat or TVB-3664) can be used for the manufacture of a medicament for reducing fibrotic gene expression (e.g., in liver cells). In further aspects, a FASN inhibitor (e.g. a compound of Formula (I), e.g. , denifanstat or TVB-3664) can be used for reducing fibrotic gene expression (e.g., in liver cells).

[0123] Cardiovascular disease is closely linked to the progression of metabolic syndrome.27IPTS / 128851376.1However, NAFLD / MAFLD is also a strong predictor of cardiovascular disease, such as increased risk of carotid atherosclerotic plaques and endothelial dysfunction, which is independent of the existence of metabolic syndrome (Francis W. B., et. als., “De novo lipogenesis in the liver in health and disease: more than just a shunting yard for glucose.” Biol. Rev. (2016), 91, pp. 452-468). NAFLD / MAFLD has also been implicated as an independent factor contributing to the development of type 2 diabetes. The rate of incidence of pre-diabetes or type 2 diabetes is 2.6 times higher in individuals with NAFLD / MAFLD, suggesting an independent role in the pathogenesis of type 2 diabetes beyond initial insulin resistance (Francis W. B., Biol. Rev. (2016), pp. 452-468; Bae, J. C., et. als., “Combined effect of nonalcoholic fatty liver disease and impaired fasting glucose on the development of type 2 diabetes.” Diabetes Care, 2011, 34, 727-729). Therefore DNL is an important pathway for therapeutic intervention to reduce the consequences associated with metabolic syndrome and NAFLD / MAFLD (Bae, J. C., Diabetes Care, 2011, 727-729).

[0124] The FASN inhibitors provided for herein can be used to treat various aspects of metabolic syndrome including nonalcoholic liver disease (NAFLD / MAFLD) and the more advanced disease, nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH). If left untreated, these liver dysfunction disease states can progress to significant liver diseases, including liver cirrhosis, a state in which the liver shows steatosis, inflammation, fibrosis, steatohepatitis, and may progress to liver cancer (hepatocellular carcinoma). Liver cirrhosis can have direct health consequences due to the liver dysfunction including spider angiomata or spider nevi, palmar erythema, gynecomastia, hypogonadism, ascites, fetor hepaticus, jaundice, portal hypertension which causes splenomegaly, esophageal varices, caput medusa, hepatic encephalopathy, and acute kidney injury (particularly hepatorenal syndrome). In some embodiments, the FASN inhibitors of the present disclosure can be used to treat metabolic syndrome, nonalcoholic liver disease (NAFLD / MAFLD), nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH), liver cirrhosis, liver fibrosis, and / or liver cancer (hepatocellular carcinoma).

[0125] In another embodiment, the present disclosure relates to a method of treating nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis nonalcoholic fatty acid disease (NAFLD / MAFLD) with a FASN inhibitor (e.g., a compound of Formula (I), e.g., denifanstat or TVB-3664, or a pharmaceutically acceptable salt thereof).

[0126] In various aspects, the FASN inhibitor (e.g. , a compound of Formula (I), e.g. ,28IPTS / 128851376.1denifanstat or TVB-3664, or a pharmaceutically acceptable salt thereof) is useful in the treatment of metabolic syndrome. In some embodiments, the present disclosure relates to a method of treating metabolic syndrome with a FASN inhibitor (e.g., a compound of Formula (I), e.g., denifanstat or TVB-3664, or a pharmaceutically acceptable salt thereof).

[0127] In various aspects, the FASN inhibitor (e.g. , a compound of Formula (I), e.g. , denifanstat or TVB-3664, or a pharmaceutically acceptable salt thereof) is useful in the treatment of liver fibrosis in a subject with fibrosis characterized as stage F2 or F3 and / or a NAS of at least 4. In one embodiment, the present disclosure relates to a method of treating liver fibrosis a FASN inhibitor (e.g. , a compound of Formula (I), e.g. , denifanstat or TVB-3664, or a pharmaceutically acceptable salt thereof). In some embodiments, a subject sees an improvement in the NAS / MAS score of at least 2 or more after 52 weeks of treatment. The treatment can be, for example, taking 50 mg of the compound once daily for 52 weeks.

[0128] In some embodiments, the disclosed FASN inhibitors (i.e. , a compound of Formula (I), e.g., denifanstat or TVB-3664) may also be used in combination with one or more antifibrosis treatment agents in the treatment condition related to NASH, fatty liver or metabolic syndrome. Such anti-fibrosis treatment agents include, but are not limited to, (1) Inhibitors of C-C chemokine receptors or dual inhibitor of C-C chemokine receptor type 2 (CCR2) and C-C chemokine receptor type 5 (CCR5) pathways, e.g., Cenicriviroc; (2) Galectin antagonists or galectin-3 antagonist, e.g. , GR-MD-02; (3) Angiotensin receptor blockers (ARB) which disrupt the reninangiotensin system, e.g., Losartan; (4) Lysyloxidase-Like 2 (LOXL2) inhibitors, e.g., Simtuzumab; and (5) Mediators of fibrosis, e.g. , Vitamin A, Vitamin C, and Vitamin D.

[0129] In some aspects, embodiments provided herein relate to a method of treating fatty liver disease / steatotic liver disease in a subject in need thereof, such as a subject with stage F2 or F3 fibrosis with a NAS of at least 4, the method comprising administering to the subject a FASN inhibitor (e.g. , a compound of Formula (I), e.g., denifanstat or TVB-3664, or a pharmaceutically acceptable salt thereof). In some embodiments, a subject sees an improvement in the NAS / MAS score of at least 2 or more after 52 weeks of treatment. The treatment can be, for example, taking 50 mg of the compound once daily for 52 weeks.

[0130] In some aspects, embodiments provided herein relate to a method of treating nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis nonalcoholic fatty acid disease (NAFLD / MAFLD) in a subject in need thereof, such as a subject with stage F2 or F3 fibrosis with a NAS of at least 4, the method comprising administering to the subject 29IPTS / 128851376.1a FASN inhibitor (e.g. , a compound of Formula (I), e.g., denifanstat or TVB-3664, or a pharmaceutically acceptable salt thereof). In some embodiments, a subject sees an improvement in the NAS / MAS score of at least 2 or more after 52 weeks of treatment. The treatment can be, for example, taking 50 mg of the compound once daily for 52 weeks.

[0131] In some aspects, embodiments provided herein relate to a method of treating nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH) in a subject in need thereof, such as a subject with stage F2 or F3 fibrosis with a NAS of at least 4, the method comprising administering to the subject a FASN inhibitor (e.g. , a compound of Formula (I), e.g. , denifanstat or TVB-3664, or a pharmaceutically acceptable salt thereof). In some embodiments, a subject sees an improvement in the NAS / MAS score of at least 2 or more after 52 weeks of treatment. The treatment can be, for example, taking 50 mg of the compound once daily for 52 weeks.

[0132] In some aspects, embodiments provided herein relate to a method of treating liver cirrhosis in a subject in need thereof, such as a subject with stage F2 or F3 fibrosis with a NAS of at least 4, the method comprising administering to the subject a FASN inhibitor (e.g. , a compound of Formula (I), e.g., denifanstat or TVB-3664, or a pharmaceutically acceptable salt thereof). In some embodiments, a subject sees an improvement in the NAS / MAS score of at least 2 or more after 52 weeks of treatment. The treatment can be, for example, taking 50 mg of the compound once daily for 52 weeks.

[0133] In some aspects, embodiments provided herein relate to a method of treating liver fibrosis in a subject in need thereof, such as a subject with stage F2 or F3 fibrosis with a NAS of at least 4, the method comprising administering to the subject a FASN inhibitor (e.g. , a compound of Formula (I), e.g. , denifanstat or TVB-3664, or a pharmaceutically acceptable salt thereof). In some embodiments, a subject sees an improvement in the NAS / MAS score of at least 2 or more after 52 weeks of treatment. The treatment can be, for example, taking 50 mg of the compound once daily for 52 weeks.

[0134] In some aspects, embodiments provided herein relate to a method of treating liver cancer (e.g. , hepatocellular carcinoma) in a subject in need thereof, such as a subject with stage F2 or F3 fibrosis and / or a NAS / MAS score of at least 4, the method comprising administering to the subject a FASN inhibitor (e.g. , a compound of Formula (I) or a pharmaceutically acceptable salt thereof). In some embodiments, a subject sees an improvement in the NAS / MAS score of at least 2 or more after 52 weeks of treatment. The treatment can be, for example, taking 50 mg of the compound once daily for 52 weeks.30IPTS / 128851376.1

[0135] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I) wherein:Formula (I) is:"R1is H, -CN, halogen, C1-C4 straight or branched alkyl, -O-iCi-Cs cycloalkyl), -O-(Ci-C4 straight or branched alkyl) wherein:C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and when R1is not H, -CN or halogen, it is optionally substituted with one, two or three halogens;each R2is independently hydrogen, halogen or C1-C4 straight or branched alkyl; R3is H, -OH, or halogen;R21is H, halogen, C1-C4 straight or branched alkyl, C3-C5 cycloalkyl wherein the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;R22is H, halogen, or C1-C2 alkyl;R24is H, C1-C4 straight or branched alkyl, -(C1-C4 alkyl)t-OH.-(C1-C4 alkyl)t-O-(C3-C5 cycloalkyl), -(C1-C4 alkyl)t-(C3-C5 cycloalkyl), or-(C1-C4 alkyl)t-O-(Ci-C4 straight or branched alkyl) wherein:the C1-C4 straight or branched alkyl is optionally substituted with one, two or three halogens;t is 0 or 1 ; andthe C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; L1is CR23or N;R23is H, C1-C4 straight or branched alkyl, -(C1-C4 alkyl)t-OH-(C1-C4 alkyl)v-O-(C3-Cs cycloalkyl), -(C1-C4 alkyl)t-(C3-C5 cycloalkyl), or-(C1-C4 alkyl)v-O-(Ci-C4 straight or branched alkyl) wherein:the C1-C4 straight or branched alkyl is optionally substituted with one, two or three halogens;v is 0 or 1 ; andthe C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom.

[0136] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I) wherein L-Ar is

[0137] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I) wherein L-Ar is

[0138] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein R24is Ci-C4 straight or branched alkyl, optionally substituted with one, two or three halogens. In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein R24is -Me or -CF3. In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein R24is -Me. In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein R24is -CF3.

[0139] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein R21is halogen, C1-C4 straight or branched alkyl, C3-C5 cycloalkyl wherein the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom, -S(O)u-(Ci-C4 straight or branched alkyl) wherein u is 0 or 2, or -S(O)u-( C3-C5 cycloalkyl) wherein u is 0 or 2. In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein R21is C1-C4 straight or branched alkyl or C3-C5 cycloalkyl. In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein R21is Me or cyclobutyl. In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein R21is cyclobutyl. In some embodiments of the methodsIPTS / 128851376.1provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein R21is -Me.

[0140] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein R3is H or halogen. In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein R3is H.

[0141] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein R1is halogen, -CN or C1-C2 haloalkyl. In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein R1is CN.

[0142] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein L1is N. In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein, L1is CR23.

[0143] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein R22is Ci-C2 alkyl. In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein R22is Me.

[0144] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein R21is Ci-C2 alkyl or C3-C5 cycloalkyl and R22is C1-C2 alkyl. In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein R21is -Me or cyclobutyl and R22is -Me.

[0145] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein R21is C3-Cs cycloalkyl and R22is C1-C2 alkyl. In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein R21is cyclobutyl and R22is Me.

[0146] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein R21is Ci- 33IPTS / 128851376.1C-2 alkyl and R22is C1-C2 alkyl. In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein R21is -Me and R22is -Me.

[0147] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein R23is -(C1-C4 alkyl)v-O-(C3-Cs cycloalkyl), wherein v is 0 or 1. In some aspects, v is 1. In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein R23is CH2-O-CH3.

[0148] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein R1is -CN, each R2is H, R3is H or F, R21is C1-C4 straight or branched alkyl or C3-C4 cycloalkyl, R22is methyl, R24is C1-C4 straight or branched alkyl, optionally substituted with one, two or three halogens L1is N or CR23, R23is methoxymethyl.

[0149] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein, R1is -CN, each R2is H, R3is H, R21is C1-C4 straight or branched alkyl or C3-C4 cycloalkyl, R22is methyl, R24is C1-C4 straight or branched alkyl, optionally substituted with one, two or three halogens L1is N or CR23, R23is methoxymethyl.

[0150] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound of Formula (I), wherein compounds have a structure selected from the group consisting of:

[0151] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is denifanstat or a pharmaceutically acceptable salt thereof, including all possible tautomers of denifanstat.IPTS / 128851376.1

[0152] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is TVB-3664 or a pharmaceutically acceptable salt thereof. Reducing the activity of the fatty acid synthesis pathway, e.g., FASN gene expression or FASN protein activity, is also referred to as “inhibiting” the fatty acid synthesis pathway, e.g., FASN gene expression or FASN protein activity. The term “inhibits” and its grammatical conjugations, such as “inhibitory,” do not require complete inhibition, but refer to a reduction in fatty acid synthesis activity, e.g., FASN gene expression or FASN protein activity. In another aspect, such reduction is by at least 50%, at least 75%, at least 90%, and can be by at least 95% of the activity of the enzyme in the absence of the inhibitory effect, e.g., in the absence of an inhibitor. Conversely, the phrase “does not inhibit” and its grammatical conjugations refer to situations where there is less than 20%, less than 10%, and can be less than 5%, of reduction in enzyme activity in the presence of the agent. Further the phrase “does not substantially inhibit” and its grammatical conjugations refer to situations where there is less than 30%, less than 20%, and in some aspects less than 10% of reduction in enzyme activity in the presence of the agent.

[0153] Increasing the activity of the fatty acid synthesis pathway, e.g., FASN gene expression or FASN protein activity, is also referred to as “activating” the fatty acid synthesis pathway, e.g., FASN gene expression or FASN protein activity. The term “activated” and its grammatical conjugations, such as “activating,” do not require complete activation, but refer to an increase in fatty acid synthesis pathway activity, e.g., FASN gene expression or FASN protein activity. In another aspect such increase is by at least 50%, at least 75%, at least 90%, and can be by at least 95% of the activity of the enzyme in the absence of the activation effect, e.g., in the absence of an activator. Conversely, the phrase “does not activate” and its grammatical conjugations refer to situations where there is less than 20%, less than 10%, and can be less than 5%, of an increase in enzyme activity in the presence of the agent. Further the phrase “does not substantially activate” and its grammatical conjugations refer to situations where there is less than 30%, less than 20%, and in another aspect less than 10% of an increase in enzyme activity in the presence of the agent.

[0154] The ability to reduce enzyme activity is a measure of the potency or the activity of an agent, or combination of agents, towards or against the enzyme. Potency can be measured by cell free, whole cell and / or in vivo assays in terms of IC50, Ki and / or ED50 values. An IC50 value represents the concentration of an agent required to inhibit enzyme activity by half (50%) under a given set of conditions. A Ki value represents the equilibrium affinity constant 35IPTS / 128851376.1for the binding of an inhibiting agent to the enzyme. An ED50 value represents the dose of an agent required to effect a half-maximal response in a biological assay. Further details of these measures will be appreciated by those of ordinary skill in the art, and can be found in standard texts on biochemistry, enzymology, and the like.

[0155] Also provided herein are kits that can be used to treat diseases associated with accumulation of fat in the liver (fatty liver diseases / steatotic liver diseases). These kits comprise an agent or combination of agents that inhibit the fatty acid synthesis pathway, e.g., FASN gene expression or FASN protein activity, and optionally instructions teaching the use of the kit according to the various methods and approaches described herein. Such kits can also include information, such as scientific literature references, package insert materials, clinical trial results, and / or summaries of these and the like, which indicate or establish the activities and / or advantages of the agent. Such information can be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials. Kits described herein can be provided, marketed and / or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like.

[0156] As used herein, “NAS” refers to NAFLD activity score and “MAS” refers to MASLD activity score, which is a scoring system to characterize a subjects liver and disease state. A subject is analyzed according to different criteria, such as listed in the table below and the sum of the numbers in the right column that are assigned to such subject is the subject’s NAS. As provided for in Example 1 , the subjects tested in the clinical trial all had a NAS of at least 4.Table 1. NAS / MAS and Fibrosis Stage Evaluation Guidelines<>><>36IPTS / 128851376.1

[0157] The fibrosis stages listed in the table above is not incorporated into the NAS, but is used to stage the level of fibrosis in the subject. A subject can be characterized as stage F0 (no fibrosis), Fl, F2, F3, or F4 (e.g., cirrhosis). For example, the fibrosis stages are defined by Kleiner et al. (Hepatology 2005, 41(6): 1313-21) and are the following: Stage 0 -> no fibrosis; Stage 1perisinusoidal or periportal fibrosis, Stage 1A -> mild, zone 3, perisinusoidal fibrosis, Stage IB -> moderate, zone 3, perisinusoidal fibrosis, Stage 1Cportal / periportal fibrosis; Stage 2 -> perisinusoidal and portal / periportal fibrosis; Stage 3bridging fibrosis; Stage 4 - cirrhosis.

[0158] An improvement in NAS can be found after being treated with the compounds and compositions provided for herein. Additionally, other biomarkers of liver and cardiovascular health can also be improved. The NAS is also described in U.S. Patent No. 11 ,034,690, which is hereby incorporated by reference in its entirety. NAS is also described in 13. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313-21, which is hereby incorporated by reference in its entirety.

[0159] Thus, in some embodiments, methods of treating subject with NASH / MASH with moderate-to-severe fibrosis are provided. In some embodiments, the methods comprise administering orally to the subject a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as provided for herein. In some embodiments, the pharmaceutical composition comprises about 25 mg to about 100 mg, about 30 mg to about 70 mg, about 40 mg to about 60 mg, about 45 mg to about 55 mg, or about 50 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises 50 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0160] In some embodiments, the subject with NASH / MASH with moderate-to-severe 37IPTS / 128851376.1fibrosis is classified as stage F2 or F3 fibrosis.

[0161] In some embodiments, the subject has a NAFLD / MASLD Activity Score (NAS / MAS) that is equal or greater to 4 prior to administration of the pharmaceutical composition.

[0162] In some embodiments, the subject with NASH / MASH with moderate-to-severe fibrosis is a biopsy confirmed subject with NASH / MASH with moderate-to-severe fibrosis.

[0163] In some embodiments, the subject has a reduction in NAS after 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, or 52 weeks of administration of the pharmaceutical composition to the subject. In some embodiments, the subject has a reduction in NAS after 26 and / or 52 weeks of administration of the pharmaceutical composition to the subject. In some embodiments, the subject has > 2-point reduction in NAS.

[0164] In some embodiments, the fibrosis in the subject does not worsen after administration of the pharmaceutical composition. In some embodiments, the fibrosis is improved after administration of the pharmaceutical composition. In some embodiments, the administration of the pharmaceutical composition to the subject results in NASH / MASH resolution. In some embodiments, the NASH / MASH resolution occurs without worsening of fibrosis and with >2 -point reduction in NAS. In some embodiments, after administration of the pharmaceutical composition the subject has at least 2-point decrease in NAS without worsening of fibrosis.

[0165] In some embodiments, the subject has a decrease in LDL in the serum of the subject after administration of the pharmaceutical composition. In some embodiments, the LDL is decreased from about 0.5 to about 20 mg / dL, about 5 to about 20 mg / dL, about 10 to about 20 mg / dL, about 15 to about 20 mg / dL, about 17 to about 20 mg / dL, about 18 to about 20 mg / dL, about 19 to about 20 mg / dL, or about 19 mg / dL. In the subject has a baseline LDL-C greater than about 100 mg / dL.

[0166] In some embodiments, the subject has at least 30% a relative reduction of liver fat at the after at least 26 or 52 weeks of treatment.

[0167] In some embodiments, the ALT (Alanine Aminotransferase Activity) in the subject is reduced from about 20 to about 35%, about 25 to about 35%, about 28 to about 32%, at least 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

[0168] In some embodiments, the enhanced liver fibrosis score (ELF) is reduced in the subjects. In some embodiments, the score is decreased by at least, or about, 0.2, 0.3, 0.4, or 0.5. In some embodiments, the ELF is decreased about 0.4 to about 0.5 after 26 and / or 5238IPTS / 128851376.1weeks. The ELF test is a noninvasive blood-derived panel of biomarkers consisting of 3 components: type III procollagen peptide, hyaluronic acid, and tissue inhibitor of metalloproteinase- 1. (see, for example, www.fda.gov / media / 135355 / download and Younossi et al, Performance of the Enhanced Liver Fibrosis Test to Estimate Advanced Fibrosis, Among Patients With Nonalcoholic Fatty Liver DiseaseJAMA Network Open.2021;4(9):e2123923. doi:10.1001 / jamanetworkopen.2021.23923, each of which is hereby incorporated by reference in its entirety.

[0169] In some embodiments, the FAST score is decreased as compared to baseline in the subjects. In some embodiments, the score is decreased at least, or about, 0.2 or 0.3 compared to baseline after 26 and / or 52 weeks of treatment. The FibroScan-AST (FAST) score is a non-invasive identification of patients with non-alcoholic steatohepatitis with significant activity and fibrosis and is described, for example, in Newsome P.et al., FibroScan-AST (FAST) score for the non-invasive identification of patients with non-alcoholic steatohepatitis with significant activity and fibrosis: a prospective derivation and global validation study. Lancet Gastroenterol Hepatol. 2020;5:362-373, which is incorporated by reference in its entirety.

[0170] In some embodiments, the fibrosis is measured or detected using co-localized images generated by second harmonic generation and two photon emission. One example of such method can be found in U.S. Application Publication No. US20180024064, which is hereby incorporated by reference in its entirety. In some embodiments, the method comprises, a method of image generating and analyzing for quantifying collagen fibers in a biological test specimen comprising: irradiating an interested region of the test specimen using an electromagnetic light source through an optical assembly at an excitation wavelength, the irradiated test specimen having excitable materials and optically non-linear materials in the collagen fibers respectively leading to concurrent emission of a first electromagnetic signal caused by two-photon excitation (TPE) and a second electromagnetic signal as a result of second harmonic generation (SHG); manipulating the first and second electromagnetic signals emitted from the test specimen through the optical assembly; recording the manipulated first and the second electromagnetic signals through one or more sensors; using the concurrently recorded first and second electromagnetic signals to generate a co-localized image having a set of image properties and being indicative of spatial distribution of the collagen fibers in the interested region; and quantifying one or more scalar features and distribution features of the co-localized image to generate quantified result for each scalar 39IPTS / 128851376.1and / or distribution feature, and deposition of collagen fibers in the test specimen using the quantified results for the extracted scalar and distribution features.

[0171] In some embodiments, the distribution features of the co-localized image are any one or combinations of intensity of the second electromagnetic signal, distribution of the second electromagnetic signal, gray level co-occurrence matrix (GLCM), thickness of collagen fiber, length of the collagen fibers, orientation of the collagen fibers, and straightness of the collagen fibers.

[0172] In some embodiments, the scalar features of the co-localized image are any one or combinations of collagen proportion ratio, total average collagen, complexity of collagen fibers, and fragment average ratio of the collagen fibers.

[0173] In some embodiments, the method further comprises the step of calculating at least one of mean, variance, skewness, kurtosis, energy and entropy for each of the distribution features.

[0174] In some embodiments, the method further comprises the step of deriving an absolute total average collagen by way of subjecting the co-localized image to multiple iterations of enhancement that each iteration of enhancement corresponds to a quotient of enhancement including N-fold amplification of the default pixel intensity of the co-localized image, calculating total average collagen for each iteration, generating a graft with the calculated total average collagen plotting against the quotient of enhancement, identifying a inflexion point from the plotted graph, and referring the total average collagen on the graph corresponding to the identified inflexion point to derive the absolute total average collagen, wherein N is 0.1 to 100.

[0175] In some embodiments, the method further comprises the step of identifying collagen fibers associated to blood vessels of the test specimen generated in the co-localized image and excluding the identified collagen fibers associated to blood vessels in deriving the absolute total average collagen.

[0176] In some embodiments, the method further comprises the step of mapping the generated graph against a standard graph calculated from a non-diseased specimen and deriving a prognosis towards a diseased state associated to the test specimen based upon relative distance between the mapped generated graph and the standard graph, wherein the generated and standard graphs are line graph.

[0177] In some embodiments, the method further comprises the step of deriving a prognosis towards a diseased state associated to the test specimen based upon a distance of the inflexion 40IPTS / 128851376.1point of the generated graph in relation to a standard graph calculated from a non-diseased specimen.

[0178] In some embodiments, the excitation wavelength is 700 to 850 nm.

[0179] In some embodiments, the biological test specimen is trimmed to a thickness of 1 to 5 pm and free from any staining.Formulations, Routes of Administration, and Effective Doses

[0180] In some embodiments, embodiments are provided that relate to formulations, routes of administration and effective doses for pharmaceutical compositions comprising an agent or combination of agents as provided for herein. Such pharmaceutical compositions can be used in the methods provided for herein.

[0181] Compounds and compositions provided herein can be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, transdermal patch, pulmonary, vaginal, suppository, or parenteral (including intramuscular, intraarterial, intrathecal, intradermal, intraperitoneal, subcutaneous and intravenous) administration or in a form suitable for administration by aerosolization, inhalation or insufflation. General information on drug delivery systems can be found in Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (Lippencott Williams & Wilkins, Baltimore Md. (1999).

[0182] In various aspects, the pharmaceutical composition includes carriers and excipients (including but not limited to buffers, carbohydrates, mannitol, proteins, polypeptides or amino acids such as glycine, antioxidants, bacteriostats, chelating agents, suspending agents, thickening agents and / or preservatives), water, oils including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like, saline solutions, aqueous dextrose and glycerol solutions, flavoring agents, coloring agents, detackifiers and other acceptable additives, adjuvants, or binders, other pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH buffering agents, tonicity adjusting agents, emulsifying agents, wetting agents and the like. Examples of excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. In another aspect, the pharmaceutical preparation is substantially free of preservatives. In another aspect, the pharmaceutical preparation can contain at least one preservative. General methodology on pharmaceutical dosage forms is found in Ansel et al., Pharmaceutical 41IPTS / 128851376.1Dosage Forms and Drug Delivery Systems (Lippencott Williams & Wilkins, Baltimore Md. (1999)). It will be recognized that, while any suitable carrier known to those of ordinary skill in the art can be employed to administer the compositions and compounds provided for herein, the type of carrier will vary depending on the mode of administration.

[0183] Compounds can also be encapsulated within liposomes using well-known technology. Biodegradable microspheres can also be employed as carriers for the pharmaceutical compositions as provided for herein. Suitable biodegradable microspheres are disclosed, for example, in U.S. Pat. Nos. 4,897,268; 5,075,109; 5,928,647; 5,811,128; 5,820,883;5,853,763; 5,814,344 and 5,942,252.

[0184] The compound can be administered in liposomes or microspheres (or microparticles). Methods for preparing liposomes and microspheres for administration to a patient are well known to those of skill in the art. U.S. Pat. No. 4,789,734, the contents of which are hereby incorporated by reference, describes methods for encapsulating biological materials in liposomes. Essentially, the material is dissolved in an aqueous solution, the appropriate phospholipids and lipids added, along with surfactants if required, and the material dialyzed or sonicated, as necessary. A review of known methods is provided by G. Gregoriadis, Chapter 14, “Liposomes,” Drug Carriers in Biology and Medicine, pp. 2. sup.87-341 (Academic Press, 1979).

[0185] Microspheres formed of polymers or proteins are well known to those skilled in the art, and can be tailored for passage through the gastrointestinal tract directly into the blood stream. Alternatively, the compound can be incorporated and the microspheres, or composite of microspheres, implanted for slow release over a period of time ranging from days to months. See, for example, U.S. Pat. Nos. 4,906,474, 4,925,673 and 3,625,214, and Jein, TIPS 19:155-157 (1998), the contents of which are hereby incorporated by reference.

[0186] The concentration of drug can be adjusted, the pH of the solution buffered and the isotonicity adjusted to be compatible with intravenous injection, as is well known in the art.

[0187] The compounds as provided for herein can be formulated as a sterile solution or suspension, in suitable vehicles, well known in the art. The pharmaceutical compositions can be sterilized by conventional, well-known sterilization techniques, or can be sterile filtered. The resulting aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile solution prior to administration. Suitable formulations and additional carriers are described in Remington “The Science and Practice of Pharmacy” (20thEd., Lippincott Williams & Wilkins, Baltimore MD), the teachings of which 42IPTS / 128851376.1are incorporated by reference in their entirety herein.

[0188] In some aspects, each of the agents described herein (e.g., FASN inhibitors of Formula (I), e.g. , denifanstat or TVB-3664, or pharmaceutically acceptable salts thereof, GLP- 1 agonists) can be provided alone or in combination with each other and / or with one or more other agents. In some aspects, the FASN inhibitor and / or one or more additional therapeutics (e.g., GLP-1 agonists) are provided as a fixed dose combination (i.e., a combination comprising a fixed dose of the FASN inhibitor and a fixed dose of one or more GLP-1 agonists formulated together in the same dosage unit e.g., in one cream, suppository, tablet, capsule, aerosol spray, solution for parenteral administration, or packet of powder to be dissolved in a beverage or in a carrier vehicle for parenteral administration. In some aspects, the FASN inhibitor and one or more GLP-1 agonists are provided as separate dosage units (e.g. , two creams, two suppositories, two tablets, two solutions or suspensions for parenteral (e.g., intramuscular, intravenous, subcutaneous) administration, two packets of powder to be dissolved in a beverage or in a carrier vehicle for parenteral (e.g. , intramuscular, intravenous, subcutaneous) administration, one tablet and one solution or suspension for parenteral (e.g., intramuscular, intravenous, subcutaneous) administration, one tablet and one packet of powder to be dissolved in a beverage or in a carrier vehicle for parenteral (e.g., intramuscular, intravenous, subcutaneous) administration, wherein the two dosage units can be administered concurrently or separately. In some aspects, the dosage units are administered concurrently. In some aspects, the dosage units are administered sequentially. In some aspects, the dosage units are administered on the same dosing schedule. In some aspects, the dosage units are administered on different dosing schedules (e.g., the FASN inhibitor may be administered on a daily dosing schedule and the GLP-1 agonist may be administered on a weekly dosing schedule). The term “pharmaceutically acceptable salt” means those salts which retain the biological effectiveness and properties of the agents used as provided for herein, and which are not biologically or otherwise undesirable. For example, a pharmaceutically acceptable salt would not interfere with the beneficial effect of an agent as provided for herein, for example, in inhibiting the fatty acid synthesis pathway, e.g., inhibiting FASN gene expression or FASN protein activity.

[0189] Typical salts are those of the inorganic ions, such as, for example, sodium, potassium, calcium, magnesium ions, and the like. Such salts include salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic 43IPTS / 128851376.1acid, mandelic acid, malic acid, citric acid, tartaric acid or maleic acid. In addition, if the agent(s) contain a carboxy group or other acidic group, it can be converted into a pharmaceutically acceptable addition salt with inorganic or organic bases. Examples of suitable bases include sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine , dicyclohexyl-amine, ethanolamine, diethanolamine, triethanolamine, and the like.

[0190] A pharmaceutically acceptable ester or amide refers to those which retain biological effectiveness and properties of the agents provided for herein, and which are not biologically or otherwise undesirable. For example, the ester or amide does not interfere with the beneficial effect of an agent as provided for herein, for example, in inhibiting the fatty acid synthesis pathway, e.g., inhibiting FASN gene expression or FASN protein activity. Typical esters include ethyl, methyl, isobutyl, ethylene glycol, and the like. Typical amides include unsubstituted amides, alkyl amides, dialkyl amides, and the like.

[0191] In another aspect, an agent can be administered in combination with one or more other compounds, forms, and / or agents, e.g., as described above. Pharmaceutical compositions comprising combinations of a fatty acid synthesis pathway inhibitor e.g., an inhibitor or FASN gene expression or FASN protein activity with one or more other active agents can be formulated to comprise certain molar ratios. For example, molar ratios of about 99:1 to about 1:99 of a fatty acid synthesis pathway inhibitor e.g., an inhibitor of FASN gene expression or FASN protein activity, to the other active agent can be used. In some subset of the aspects, the range of molar ratios of fatty acid synthesis pathway inhibitor e.g., an inhibitor of FASN gene expression or FASN protein activity: other active agent is selected from about 80:20 to about 20:80; about 75:25 to about 25:75, about 70:30 to about 30:70, about 66:33 to about 33:66, about 60:40 to about 40:60; about 50:50; and about 90:10 to about 10:90. The molar ratio of a fatty acid synthesis pathway inhibitor e.g., an inhibitor of FASN gene expression or FASN protein activity: other active agent can be about 1 :9, and in another aspect can be about 1:1. The two agents, forms and / or compounds can be formulated together, in the same dosage unit e.g., in one cream, suppository, tablet, capsule, or packet of powder to be dissolved in a beverage; or each agent, form, and / or compound can be formulated in separate units, e.g., two creams, suppositories, tablets, two capsules, a tablet and a liquid for dissolving the tablet, an aerosol spray a packet of powder and a liquid for dissolving the powder, etc.

[0192] If necessary or desirable, the agents and / or combinations of agents can be administered with still other agents. The choice of agents that can be coadministered with the 44IPTS / 128851376.1agents and / or combinations of agents as provided for herein can depend, at least in part, on the condition being treated. As provided for herein, they can be GLP modulating compounds, some of which are described herein. In certain aspects, the FASN inhibitor and GLP-1 compounds of the present disclosure can be administered in combination with a known cancer therapeutic, for example as part of a method for treating liver cancer (e.g., hepatocellular carcinoma). For example, the compounds can be administered in combination with paclitaxel (commercially available as Taxol, Bristol-Myers Squibb), doxorubicin (also known under the trade name Adriamycin), vincristine (known under the trade names Oncovin, Vincasar PES, and Vincrex), actinomycin D, altretamine, asparaginase, bleomycin, busulphan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, hydroxyurea, idarubicin, ifosfamide, irinotecan, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitozantrone, oxaliplatin, procarbazine, steroids, streptozocin, taxotere, tamozolomide, thioguanine, thiotepa, tomudex, topotecan, treosulfan, UFT (uracil-tegufur), vinblastine, and vindesine, or the like.

[0193] The agent(s) (or pharmaceutically acceptable salts, esters or amides thereof) can be administered per se or in the form of a pharmaceutical composition wherein the active agent(s) is in an admixture or mixture with one or more pharmaceutically acceptable carriers. A pharmaceutical composition, as used herein, can be any composition prepared for administration to a subject. Pharmaceutical compositions for use in accordance with methods or other compounds provided for herein can be formulated in conventional manner using one or more physiologically acceptable carriers, comprising excipients, diluents, and / or auxiliaries, e.g., which facilitate processing of the active agents into preparations that can be administered. Proper formulation can depend at least in part upon the route of administration chosen. The agent(s) (compounds) as provided for herein, or pharmaceutically acceptable salts, esters, or amides thereof, can be delivered to a patient using a number of routes or modes of administration, including oral, buccal, topical, rectal, transdermal, transmucosal, subcutaneous, intravenous, and intramuscular applications, as well as by inhalation. In some embodiments, the route of administration is oral administration.

[0194] For oral administration, the agents can be formulated readily by combining the active agent(s) with pharmaceutically acceptable carriers well known in the art. Such carriers enable the agent(s) to be formulated as tablets, including chewable tablets, pills, dragees, capsules, lozenges, hard candy, liquids, gels, syrups, slurries, powders, suspensions, elixirs, wafers, and 45IPTS / 128851376.1the like, for oral ingestion by a patient to be treated. Such formulations can comprise pharmaceutically acceptable carriers including solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. A solid carrier can be one or more substances which can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about one (1) to about seventy (70) percent of the active compound. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. In some embodiments, the agent(s) will be included at concentration levels ranging from about 0.5%, about 5%, about 10%, about 20%, or about 30% to about 50%, about 60%, about 70%, about 80% or about 90% by weight of the total composition of oral dosage forms, in an amount sufficient to provide a desired unit of dosage.

[0195] Aqueous suspensions for oral use can contain agent(s) as provided for herein with pharmaceutically acceptable excipients, such as a suspending agent (e.g., methyl cellulose), a wetting agent (e.g., lecithin, lysolecithin and / or a long-chain fatty alcohol), as well as coloring agents, preservatives, flavoring agents, and the like.

[0196] In another aspect, oils or non-aqueous solvents can be required to bring the agents into solution, due to, for example, the presence of large lipophilic moieties. Alternatively, emulsions, suspensions, or other preparations, for example, liposomal preparations, can be used. With respect to liposomal preparations, any known methods for preparing liposomes for treatment of a condition can be used. See, for example, Bangham et al., J. Mol. Biol. 23: 238-252 (1965) and Szoka et al., Proc. Natl Acad. Sci. USA 75: 4194-4198 (1978), incorporated herein by reference. Ligands can also be attached to the liposomes to direct these compositions to particular sites of action. Agents as provided for herein can also be integrated into foodstuffs, e.g., cream cheese, butter, salad dressing, or ice cream to facilitate solubilization, administration, and / or compliance in certain patient populations.

[0197] Pharmaceutical preparations for oral use can be obtained as a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in 46IPTS / 128851376.1particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; flavoring elements, cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinyl pyrrolidone (PVP). If desired, disintegrating agents can be added, such as the crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. The agents can also be formulated as a sustained release preparation.

[0198] Dragee cores can be provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.

[0199] Pharmaceutical preparations that can be used orally include pushfit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The pushfit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active agents can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration should be in dosages suitable for administration.

[0200] Other forms suitable for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations. Emulsions can be prepared in solutions, for example, in aqueous propylene glycol solutions or can contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. Suitable fillers or carriers with which the compositions can be administered include agar, alcohol, fats, lactose, starch, cellulose derivatives, polysaccharides, polyvinylpyrrolidone, silica, sterile saline and 47IPTS / 128851376.1the like, or mixtures thereof used in suitable amounts. Solid form preparations include solutions, suspensions, and emulsions, and can contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0201] A syrup or suspension can be made by adding the active compound to a concentrated, aqueous solution of a sugar, e.g., sucrose, to which can also be added any accessory ingredients. Such accessory ingredients can include flavoring, an agent to retard crystallization of the sugar or an agent to increase the solubility of any other ingredient, e.g., as a polyhydric alcohol, for example, glycerol or sorbitol.

[0202] When formulating compounds as provided for herein for oral administration, it can be desirable to utilize gastroretentive formulations to enhance absorption from the gastrointestinal (GI) tract. A formulation which is retained in the stomach for several hours can release the compound or compounds slowly and provide a sustained release that can be used in methods as provided for herein. Disclosure of such gastro-retentive formulations are found in Klausner, E.A.; Lavy, E.; Barta, M.; Cserepes, E.; Friedman, M.; Hoffman, A. 2003 “Novel gastroretentive dosage forms: evaluation of gastroretentivity and its effect on levodopa in humans.” Pharm. Res. 20, 1466-73, Hoffman, A.; Stepensky, D.; Lavy, E.; Eyal, S. Klausner, E.; Friedman, M. 2004 “Pharmacokinetic and pharmacodynamic aspects of gastroretentive dosage forms” Int. J. Pharm. 11, 141-53, Streubel, A.; Siepmann, J.;Bodmeier, R.; 2006 “Gastroretentive drug delivery systems” Exp. Opin. Drug Deliver. 3, 217-3, and Chavanpatil, M.D.; Jain, P.; Chaudhari, S.; Shear, R.; Vavia, P.R. “Novel sustained release, swellable and bioadhesive gastroretentive drug delivery system for olfoxacin” Int. J. Pharm. 2006 epub March 24. Expandable, floating and bioadhesive techniques can be utilized to maximize absorption of the compounds and compositions provided for herein.

[0203] The compounds and compositions provided for herein can be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and can be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol.

[0204] For injectable formulations, the vehicle can be chosen from those known in art to be suitable, including aqueous solutions or oil suspensions, or emulsions, with sesame oil, com 48IPTS / 128851376.1oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. The formulation can also comprise polymer compositions which are biocompatible, biodegradable, such as poly(lactic-co-glycolic)acid. These materials can be made into micro or nanospheres, loaded with drug and further coated or derivatized to provide superior sustained release performance. Vehicles suitable for periocular or intraocular injection include, for example, suspensions of therapeutic agent in injection grade water, liposomes and vehicles suitable for lipophilic substances. Other vehicles for periocular or intraocular injection are well known in the art.

[0205] In a preferred aspect, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition can also include a solubilizing agent and a local anesthetic such as lidocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.

[0206] When administration is by injection, the active compound can be formulated in aqueous solutions, specifically in physiologically compatible buffers such as Hanks solution, Ringer’s solution, or physiological saline buffer. The solution can contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active compound can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. In another aspect, the pharmaceutical composition does not comprise an adjuvant or any other substance added to enhance the immune response stimulated by the peptide. In another aspect, the pharmaceutical composition comprises a substance that inhibits an immune response to the peptide. Methods of formulation are known in the art, for example, as disclosed in Remington’s Pharmaceutical Sciences, latest edition, Mack Publishing Co., Easton P.

[0207] In addition to the formulations described previously, the agents can also be formulated as a depot preparation. Such long acting formulations can be administered by 49IPTS / 128851376.1implantation or transcutaneous delivery (for example subcutaneously or intramuscularly), intramuscular injection or use of a transdermal patch. Thus, for example, the agents can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0208] Lubricants which can be used to form pharmaceutical compositions and dosage forms of comprising the compounds and compositions provided for herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof. A lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.

[0209] In some aspects, the FASN inhibitor is administered at a dose of 10-100 mg. In some aspects, the FASN inhibitor is administered at a dose of 10-90 mg. In some aspects, the FASN inhibitor is administered at a dose of 10-80 mg. In some aspects, the FASN inhibitor is administered at a dose of 10-70 mg. In some aspects, the FASN inhibitor is administered at a dose of 10-60 mg. In some aspects, the FASN inhibitor is administered at a dose of 10-50 mg. In some aspects, the FASN inhibitor is administered at a dose of 10-40 mg. In some aspects, the FASN inhibitor is administered at a dose of 10-30 mg. In some aspects, the FASN inhibitor is administered at a dose of 10-20 mg. In some aspects, the FASN inhibitor is administered at a dose of 20-100 mg. In some aspects, the FASN inhibitor is administered at a dose of 20-90 mg. In some aspects, the FASN inhibitor is administered at a dose of 20-80 mg. In some aspects, the FASN inhibitor is administered at a dose of 20-70 mg. In some aspects, the FASN inhibitor is administered at a dose of 20-60 mg. In some aspects, the FASN inhibitor is administered at a dose of 20-50 mg. In some aspects, the FASN inhibitor is administered at a dose of 20-40 mg. In some aspects, the FASN inhibitor is administered at a dose of 20-30 mg. In some aspects, the FASN inhibitor is administered at a dose of 30-100 mg. In some aspects, the FASN inhibitor is administered at a dose of 30-90 mg. In some aspects, the FASN inhibitor is administered at a dose of 30-80 mg. In some aspects, the FASN inhibitor is administered at a dose of 30-70 mg. In some aspects, the FASN inhibitor is administered at a dose of 30-60 mg. In some aspects, the FASN inhibitor is administered at a 50IPTS / 128851376.1dose of 30-50 mg. In some aspects, the FASN inhibitor is administered at a dose of 30-40 mg. In some aspects, the FASN inhibitor is administered at a dose of 40-100 mg. In some aspects, the FASN inhibitor is administered at a dose of 40-90 mg. In some aspects, the FASN inhibitor is administered at a dose of 40-80 mg. In some aspects, the FASN inhibitor is administered at a dose of 40-70 mg. In some aspects, the FASN inhibitor is administered at a dose of 40-60 mg. In some aspects, the FASN inhibitor is administered at a dose of 40-50 mg. In some aspects, the FASN inhibitor is administered at a dose of 50-100 mg. In some aspects, the FASN inhibitor is administered at a dose of 50-90 mg. In some aspects, the FASN inhibitor is administered at a dose of 50-80 mg. In some aspects, the FASN inhibitor is administered at a dose of 50-70 mg. In some aspects, the FASN inhibitor is administered at a dose of 50-60 mg. In some aspects, the FASN inhibitor is administered at a dose of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg or 100 mg.

[0210] In some aspects, the FASN inhibitor is administered at a dose of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg.

[0211] In some aspects, the FASN inhibitor is administered at a dose of 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg.

[0212] In some aspects, the FASN inhibitor is administered at a dose of 10 mg. In some aspects, the FASN inhibitor is administered at a dose of 15 mg. In some aspects, the FASN inhibitor is administered at a dose of 20 mg. In some aspects, the FASN inhibitor is administered at a dose of 25 mg. In some aspects, the FASN inhibitor is administered at a dose of 30 mg. In some aspects, the FASN inhibitor is administered at a dose of 35 mg. In some aspects, the FASN inhibitor is administered at a dose of 40 mg. In some aspects, the FASN inhibitor is administered at a dose of 45 mg. In some aspects, the FASN inhibitor is administered at a dose of 50 mg. In some aspects, the FASN inhibitor is administered at a dose of 55 mg. In some aspects, the FASN inhibitor is administered at a dose of 60 mg. In some aspects, the FASN inhibitor is administered at a dose of 65 mg. In some aspects, the FASN inhibitor is administered at a dose of 70 mg. In some aspects, the FASN inhibitor is administered at a dose of 75 mg. In some aspects, the FASN inhibitor is administered at a dose of 80 mg. In some aspects, the FASN inhibitor is administered at a dose of 85 mg. In some aspects, the FASN inhibitor is administered at a dose of 90 mg. In some aspects, the FASN inhibitor is administered at a dose of 95 mg. In some aspects, the FASN inhibitor is administered at a dose of 100 mg.51IPTS / 128851376.1

[0213] In some aspects, the FASN inhibitor is administered once or twice daily. In some aspects, the FASN inhibitor is administered once daily. In some aspects, the FASN inhibitor is administered twice daily. In some aspects, the FASN inhibitor is administered intermittently, for example administration once every two days, every three days, every five days, once a week, once or twice a month, and the like. . In some aspects, the FASN inhibitor is administered three times a week. In some aspects, the FASN inhibitor is administered on an on / off / on / off / on / off / off schedule (e.g., a Monday, Wednesday, Friday schedule. In some aspects, the FASN inhibitor is administered twice a week. In some aspects, the FASN inhibitor is administered once a week. In some aspects, the FASN inhibitor is administered orally.

[0214] In some aspects, the FASN inhibitor if administered with an additional therapeutic, such a GLP-1 agonist, are administered as a fixed-dose combination. In some aspects, the FASN inhibitor and the GLP-1 agonist are administered as separate dosage units. In some aspects, the FASN inhibitor and the GLP-1 agonist are administered concurrently. In some aspects, the FASN inhibitor and the GLP-1 agonist are administered sequentially. In some aspects, the FASN inhibitor and the GLP-1 agonist are administered on the same dosing schedule. In some aspects, the FASN inhibitor and the GLP-1 agonist are administered on different dosing schedules. In another aspect, the amount, forms, and / or amounts of the different agents and / or forms can be varied at different times of administration.

[0215] The following examples are illustrative, but not limiting, of the compounds, compositions and methods described herein. Other suitable modifications and adaptations known to those skilled in the art are within the scope of the following embodiments.EXAMPLESExample 1. Denifanstat achieved statistically significant results on primary and multiple secondary endpoints at week 52 in a clinical trial of 168 NASH patients with stage F2 or F3 fibrosis.

[0216] The Phase 2b FASCINATE-2 clinical trial was a phase 2b 52-week randomized, double-blind, placebo-controlled trial that evaluated the safety and histological impact of denifanstat compared to placebo in 168 biopsy-confirmed NASH patients with moderate-to-severe fibrosis (stage F2 or F3) with NAS >4 with at least a score of 1 in each of steatosis, lobular inflammation and hepatocyte ballooning (FIG. 1). Patients were randomized 2:1 to receive 50 mg denifanstat or placebo, taken orally once daily. An end-of-trial biopsy was 52IPTS / 128851376.1assessed by a central pathologist for histological endpoints. Liver biopsies were also analyzed using Al-based digital pathology. Pre- and post-treatment biopsies were available for 126 patients.

[0217] The disposition of patients enrolled in the study is shown in FIG. 2. The baseline characteristics of the patients enrolled in the study are shown in FIG. 3.

[0218] No treatment-related serious adverse events (SAEs) were observed, and the majority of adverse events (AEs) were mild to moderate in nature (Grades 1 and 2). There were no Grade >3 treatment-related AEs. The most common treatment-related AEs by system organ class (observed in >5% of patients in the study) were eye disorders (denifanstat 15.2%, placebo 16.1%), gastrointestinal disorders (denifanstat 11.6%, placebo 8.9%), and skin and subcutaneous tissue disorders (denifanstat 22.3%, placebo 7.1%). The incidence of treatment emergent adverse events (TEAEs) leading to treatment discontinuation was 19.6% in the denifanstat group compared to 5.4% in placebo.

[0219] In this trial, denifanstat, an oral, selective FASN inhibitor, showed statistically significant improvements relative to placebo on both of the primary endpoints of NASH resolution without worsening of fibrosis with >2-point reduction in NAS, and >2-point reduction in NAS without worsening of fibrosis. Denifanstat-treated patients also showed statistically significant fibrosis improvement by > 1 stage with no worsening of NASH, and a greater proportion of MRI-derived proton density fat fraction (MRI-PDFF) >30% responders relative to placebo.

[0220] Statistical significance achieved in primary endpoints and improvements across secondary endpoints at week 52 of denifanstat treatment. Specifically, the primary endpoints that were achieved were: a) NASH resolution without worsening of fibrosis with >2-point reduction in NAS (NAFLD Activity Score) in 36% of denifanstat-treated patients vs 13% with placebo (p=0.002); b) >2-point reduction in NAS without worsening of fibrosis in 52% of denifanstat-treated patients vs 20% with placebo (p=0.0001). Multiple secondary endpoints were also achieved, including: a) Fibrosis improvement by > 1 stage with no worsening of NASH in 41% of denifanstat-treated patients vs 18% with placebo (p=0.005); b) NASH resolution with no worsening of fibrosis in 38% of denifanstat-treated patients vs 16% with placebo (p=0.002); and MRI-PDFF decline from baseline >30% (responders) in 65% of denifanstat-treated patients vs 21% with placebo (p<0.0001). Statistically significant improvements in additional markers of liver health, including artificial intelligence (Al) digital pathology-based fibrosis assessment, FAST Score, and ALT, and numerical53IPTS / 128851376.1improvements in LDL were also observed.

[0221] The results are summarized in the following table and FIGs. 4-7.Table 2.>>>< <>

[0222] Stain-free imaging using second- harmonic generation (SHG) / two-photon excitation fluorescence (TPEF) microscopy with artificial intelligence (Al) analysis provides a visual mapping of hepatic collagen and allows quantitative detailed measurement of collagen and fibrosis patterns and qualities. This can provide further insights into subtle changes in fibrosis -related parameters that conventional liver microscopy by traditional pathology approaches lacks.

[0223] Unstained liver biopsy sections were imaged using second-harmonic generation / two-photon excitation fluorescence (TPEF)microscopy. This is an Al-based digital pathology 54IPTS / 128851376.1platform conducted by Histolndex.

[0224] Published data show that several indices that include these parameters have been linked to clinical outcomes in the SteatoSITE UK dataset whereby patients with higher scores had higher mortality (left panel, FIG. 8) or liver decompensation (right panel, FIG. 8) than patients with low scores (from Kendall TJ et al. Liver Int. 2024;44:2511-2516). This indicates that results from this Al-based platform can directly predict clinical endpoints.

[0225] Denifanstat decreased fibrotic activity in the portal and peri-portal regions of the liver (FIG. 9). This was statistically significant versus placebo. Specifically when periportal strings (a fibrosis parameter) were measured, denifanstat showed a decreased signal not only in patients who had a fibrosis improvement by 1 stage or more by traditional pathology as defined by NASH CRN criteria, but also in patients that did not show a change in stage, or showed worsening by traditional pathology (FIG. 10, FIG. 11, and FIG. 12). These changes were statistically significant versus placebo. The Al-based method provides higher granularity and indicates that denifanstat via its anti-fibrotic activity favorably alters fibrosis features that are part of composite scores that have been shown to correlate with poor outcome (Kendall et al.).

[0226] Additional results are summarized in FIGs. 13-16.Example 2. TVB-3664 reduced atherosclerosis development in diet-induced dyslipidaemia LDL receptor knockout mice with NASH.

[0227] Male Ldlr- / -. Leiden mice were fed with fast-food diet (FFD) for 18 weeks to induce dyslipidaemia, atherosclerosis and MASH features, and treated with TVB-3664 (a surrogate FASN inhibitor for denifanstat, 5 mg / kg, PO, QD) for 10 weeks (FIG. 17). Endpoints included plasma lipids, lipoprotein profile, inflammatory marker profile, liver histology and histological analysis of atherosclerosis in the aortic root (lesion area and severity according to the AHA score in 4 cross sections, TNO, Netherlands).

[0228] Results from this study are summarized in FIGs. 18-21.

[0229] Denifanstat has shown promise on LDL-C lowering and liver histological improvements in MASH patients in Phase 2b FASCINATE-2 study. FASN inhibitor not only reduced circulating cholesterol but also decreased the development of atherosclerosis and improved liver histology in a mouse model of dyslipidaemia and NASH. FASN inhibitor also decreased inflammation by reducing several circulating inflammatory markers, such as CCL4 and CXCL2, in Ldlr- / - NASH mice.

[0230] These results suggest that a FASN inhibitor like denifanstat could provide benefit in 55IPTS / 128851376.1cardiovascular as well as liver health, supporting clinical evaluation of denifanstat for long term outcomes in NASH patients.

[0231] These results demonstrate the therapeutically effective use of denifanstat in treating patients with NASH patients with stage F2 or F3 fibrosis and a NAS of at least 4.Example 3. Patient Subset on Stable GLPl-Receptor Agonists (GLP1-RA) at Baseline: Liver Biopsy Denifanstat Improves NASH Resolution and Fibrosis.

[0232] An analysis was undertaken of the patients from the trial described in Example 1 to determine what affect, if any, the combination of a GLP-1 receptor agonist (RA) and denifanstat had on NASH resolution and fibrosis. The data analyzed were patients who were on stable GLP 1 therapy at study entry. In the absence of denifanstat, there was no evidence of NASH resolution or improvement of fibrosis. In the patients that had both denifanstat and GLP-1 therapy, there was a statistically significant improvement in fibrosis response.Specifically, there was resolution of NASH without worsening of fibrosis in 42% of the patients (n=12) on a combination of GLP-1 therapy and denifanstat as compared to 0% of those patients on placebo and GLP-1 therapy (n=4). Additionally, improvement in liver fibrosis > 1 stage without worsening of NASH was also observed in 42% of the patients (n=12) on a combination of GLP-1 therapy and denifanstat as compared to 0% of those patients on placebo and GLP-1 therapy (n=4). This data is illustrated in FIG. 22.

[0233] This data demonstrates that the combination of GLP- 1 receptor agonists and denifanstat leads to the resolution of NASH and improvement in fibrosis in patients on taking both therapeutics and that the combination, based on this subset of patients in this clinical trial, suggests a synergistic effect, which could not have been predicted for these secondary endpoints.INCORPORATION BY REFERENCE

[0234] This specification contains numerous citations to patents, patent applications, and publications. Each is hereby incorporated by reference for all purposes.56IPTS / 128851376.1

Claims

CLAIMS1. A method of treating a subject with NASH / MASH with moderate-to- severe fibrosis, the method comprising administering orally to the subject a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein:Formula (I) is:R1is H, -CN, halogen, C1-C4 straight or branched alkyl, -O-iCi-Cs cycloalkyl), -O-(Ci-C4 straight or branched alkyl) wherein:C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and when R1is not H, -CN or halogen, it is optionally substituted with one, two or three halogens;each R2is independently hydrogen, halogen or C1-C4 straight or branched alkyl; R3is H, -OH, or halogen;R21is H, halogen, C1-C4 straight or branched alkyl, C3-C5 cycloalkyl wherein the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;R22is H, halogen, or C1-C2 alkyl;R24is H, C1-C4 straight or branched alkyl, -(C1-C4 alkyl)t-OH.-(C1-C4 alkyl)t-O-(C3-Cs cycloalkyl), -(C1-C4 alkyl)t-(C3-C5 cycloalkyl), or-(C1-C4 alkyl)t-O-(Ci-C4 straight or branched alkyl) whereinthe C1-C4 straight or branched alkyl is optionally substituted with one, two or three halogens;t is 0 or 1 ;the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; L1is CR23or N;57IPTS / 128851376.1R23is H, C1-C4 straight or branched alkyl, -(C1-C4 alkyl)t-OH.-(C1-C4 alkyl)v-O-(C3-Cs cycloalkyl), -(C1-C4 alkyl)t-(C3-Cs cycloalkyl), or-(C1-C4 alkyl)v-O-(Ci-C4 straight or branched alkyl) wherein:the C1-C4 straight or branched alkyl is optionally substituted with one, two or three halogens;v is 0 or 1 ;the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom.

2. A method of reducing fibrosis (e.g., 1 stage or 2 stage) in a subject with NASH / MASH with moderate-to- severe fibrosis, the method comprising administering orally to the subject a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein:Formula (I) is:R1is H, -CN, halogen, C1-C4 straight or branched alkyl, -O-(C3-Cs cycloalkyl), -O-(Ci-C4 straight or branched alkyl) wherein:C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and when R1is not H, -CN or halogen, it is optionally substituted with one, two or three halogens;each R2is independently hydrogen, halogen or C1-C4 straight or branched alkyl; R3is H, -OH, or halogen;R21is H, halogen, C1-C4 straight or branched alkyl, C3-C5 cycloalkyl wherein the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;R22is H, halogen, or C1-C2 alkyl;58IPTS / 128851376.1R24is H, C1-C4 straight or branched alkyl, -(C1-C4 alkyl)t-OH.-(C1-C4 alkyl)t-O-(C3-Cs cycloalkyl), -(C1-C4 alkyl)t-(C3-C5 cycloalkyl), or-(C1-C4 alkyl)t-O-(Ci-C4 straight or branched alkyl) whereinthe C1-C4 straight or branched alkyl is optionally substituted with one, two or three halogens;t is 0 or 1 ;the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; L1is CR23or N;R23is H, C1-C4 straight or branched alkyl, -(C1-C4 alkyl)t-OH,-(C1-C4 alkyl)v-O-(C3-Cs cycloalkyl), -(C1-C4 alkyl)t-(C3-Cs cycloalkyl), or-(C1-C4 alkyl)v-O-(Ci-C4 straight or branched alkyl) wherein:the C1-C4 straight or branched alkyl is optionally substituted with one, two or three halogens;v is 0 or 1 ;the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom.

3. A method of reducing fibrosis as measured by Al digital pathology in a subject with NASH / MASH with moderate-to- severe fibrosis, the method comprising administering orally to the subject a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein:Formula (I) is:R1is H, -CN, halogen, C1-C4 straight or branched alkyl, -O-(C3-Cs cycloalkyl), -O-(Ci-C4 straight or branched alkyl) wherein:C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and59IPTS / 128851376.1when R1is not H, -CN or halogen, it is optionally substituted with one, two or three halogens;each R2is independently hydrogen, halogen or C1-C4 straight or branched alkyl; R3is H, -OH, or halogen;R21is H, halogen, C1-C4 straight or branched alkyl, C3-C5 cycloalkyl wherein the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;R22is H, halogen, or C1-C2 alkyl;R24is H, C1-C4 straight or branched alkyl, -(C1-C4 alkyl )i-OH-(C1-C4 alkyl)t-O-(C3-Cs cycloalkyl), -(C1-C4 alkyl)t-(C3-Cs cycloalkyl), or-(C1-C4 alkyl)t-O-(Ci-C4 straight or branched alkyl) whereinthe C1-C4 straight or branched alkyl is optionally substituted with one, two or three halogens;t is 0 or 1 ;the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; L1is CR23or N;R23is H, C1-C4 straight or branched alkyl, -(C1-C4 alkyl)t-OH.-(C1-C4 alkyl)v-O-(C3-C5 cycloalkyl), -(C1-C4 alkyl)t-(C3-Cs cycloalkyl), or-(C1-C4 alkyl)v-O-(Ci-C4 straight or branched alkyl) wherein:the C1-C4 straight or branched alkyl is optionally substituted with one, two or three halogens;v is 0 or 1 ;the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom.

4. A method of treating a subject with NASH / MASH with atherosclerosis or a method of reducing atherosclerosis in a subject with NASH / MASH, the method comprising administering orally to the subject a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein:Formula (I) is:<wherein:60IPTS / 128851376.1R1is H, -CN, halogen, C1-C4 straight or branched alkyl, -O-iCi-Cs cycloalkyl), -0-(Ci-C4 straight or branched alkyl) wherein:C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and when R1is not H, -CN or halogen, it is optionally substituted with one, two or three halogens;each R2is independently hydrogen, halogen or C1-C4 straight or branched alkyl; R3is H, -OH, or halogen;R21is H, halogen, C1-C4 straight or branched alkyl, C3-C5 cycloalkyl wherein the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;R22is H, halogen, or C1-C2 alkyl;R24is H, C1-C4 straight or branched alkyl, -(C1-C4 alkyl )i-OH-(C1-C4 alkyl)t-O-(C3-C5cycloalkyl), -(C1-C4 alkyl)t-(C3-C5cycloalkyl), or-(C1-C4 alkyl)t-O-(Ci-C4 straight or branched alkyl) whereinthe C1-C4 straight or branched alkyl is optionally substituted with one, two or three halogens;t is 0 or 1 ;the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; L1is CR23or N;R23is H, C1-C4 straight or branched alkyl, -(C1-C4 alkyl)t-OH,-(C1-C4 alkyl)v-O-(C3-C5 cycloalkyl), -(C1-C4 alkyl)t-(C3-Cs cycloalkyl), or-(C1-C4 alkyl)v-O-(Ci-C4 straight or branched alkyl) wherein:the C1-C4 straight or branched alkyl is optionally substituted with one, two or three halogens;v is 0 or 1 ;the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom.

5. The method of claim 4, wherein the subject is a subject with NASH / MASH with moderate-to-severe fibrosis.61IPTS / 128851376.

16. The method of any one of claims 1-5, wherein the pharmaceutical composition comprises about 25 mg to about 100 mg, about 30 mg to about 70 mg, about 40 mg to about 60 mg, about 45 mg to about 55 mg, or about 50 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

7. The method of any one of claims 1-6, wherein the subject with NASH / MASH with moderate-to-severe fibrosis is classified as stage F2 or F3 fibrosis.

8. The method of any one of claims 1-7, wherein the subject has a NAFLD / MASLD Activity Score (NAS / MAS) that is equal or greater to 4 prior to administration of the pharmaceutical composition.

9. The method of any one of claims 1-8, wherein the subject with NASH / MASH with moderate-to-severe fibrosis is a biopsy confirmed subject with NASH / MASH with moderate-to-severe fibrosis.

10. The method of any one of claims 1-9, wherein the pharmaceutical composition is administered once a day to the subject.

11. The method of any one of claims 1-10, wherein the pharmaceutical composition is administered once a day to the subject for at about, or at least 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 or 52 weeks.

12. The method of any one of claims 1-11, wherein the subject has a reduction in NAS / MAS after 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, or 52 weeks of administration of the pharmaceutical composition to the subject.

13. The method of any one of claims 1-11, wherein the subject has a reduction in NAS / MAS after 4, after 52 weeks of administration of the pharmaceutical composition to the subject.

14. The method of claims 12 or 1 , wherein the subject has > 2-point reduction in NAS / MAS.

15. The method of any one of claims 1-14, wherein the fibrosis in the subject does not worsen after administration of the pharmaceutical composition.62IPTS / 128851376.

116. The method of any one of claims 1-15, wherein the administration of the pharmaceutical composition to the subject results in NASH / MASH resolution.

17. The method of claim 16, wherein the subject has NASH / MASH resolution without worsening of fibrosis with >2 -point reduction in NAS / MAS.

18. The method of any one of claims 1-17, wherein after administration of the pharmaceutical composition the subject has at least 2-point decrease in NAS / MAS without worsening of fibrosis.

19. The method of any one of claims 1-18, wherein the subject has a decrease in LDL in the serum of the subject after administration of the pharmaceutical composition.

20. The method of claim 19, wherein the LDL is decreased from about 0.5 to about 20 mg / dL, about 5 to about 20 mg / dL, about 10 to about 20 mg / dL, about 15 to about 20 mg / dL, about 17 to about 20 mg / dL, about 18 to about 20 mg / dL, about 19 to about 20 mg / dL, or about 19 mg / dL.

21. The method of claim 20, where in the subject has a baseline LDL-C greater than about 100 mg / dL.

22. The method of any one of claims 1-21, wherein the subject has at least 30% a relative reduction of liver fat after 26 or 52 weeks of treatment .

23. The method of any one of claims 1-22, wherein the ALT in the subject is reduced from about 20 to about 35%, about 25 to about 35%, about 28 to about 32%, at least 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

24. The method of any one of claims 1-23, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof:Formula (I):IPTS / 128851376.1R1is H, -CN, halogen, C1-C4 straight or branched alkyl, -O-iCi-Cs cycloalkyl), -0-(Ci-C4 straight or branched alkyl) wherein:C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and when R1is not H, -CN or halogen, it is optionally substituted with one, two or three halogens;each R2is independently hydrogen, halogen or C1-C4 straight or branched alkyl; R3is H, -OH, or halogen;R21is H, halogen, C1-C4 straight or branched alkyl, C3-C5 cycloalkyl wherein the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;R22is H, halogen, or C1-C2 alkyl;R24is H, C1-C4 straight or branched alkyl, -(C1-C4 alkyl )i-OH-(C1-C4 alkyl)t-O-(C3-C5cycloalkyl), -(C1-C4 alkyl)t-(C3-C5cycloalkyl), or-(C1-C4 alkyl)t-O-(Ci-C4 straight or branched alkyl) whereinthe C1-C4 straight or branched alkyl is optionally substituted with one, two or three halogens;t is 0 or 1 ;the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; L1is CR23or N;R23is H, C1-C4 straight or branched alkyl, -(C1-C4 alkyl)t-OH,-(C1-C4 alkyl)v-O-(C3-C5 cycloalkyl), -(C1-C4 alkyl)t-(C3-Cs cycloalkyl), or-(C1-C4 alkyl)v-O-(Ci-C4 straight or branched alkyl) wherein:the C1-C4 straight or branched alkyl is optionally substituted with one, two or three halogens;v is 0 or 1.

25. The method of any one of claims 1-24, wherein the compound is:64IPTS / 128851376.1(denifanstat),or a pharmaceutically acceptable salt there of; or< " " " ""or pharmaceutically acceptable salt thereof.

26. The method of any one of the preceding claims, wherein the method further comprises a liver biopsy before, after, or during the administration of the compound.

27. The method of any one of the preceding claims, wherein the method further comprises administering to the subject a therapeutically effective amount of a glucagon- like peptide 1 (GLP-1) agonist.

28. The method of any one of the preceding claims, wherein the pharmaceutical composition is a solid dosage form.

29. The method of claim 28, wherein the solid dosage form is a tablet, caplet, capsule, and the like.

30. A pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for: a) treating a subject with NASH / MASH with moderate-to-severe fibrosis, b) reducing fibrosis (e.g., 1 stage or 2 stage) in a subject with NASH, or c) reducing fibrosis as measured by Al digital pathology, wherein:Formula (I) is:wherein:IPTS / 128851376.1R1is H, -CN, halogen, C1-C4 straight or branched alkyl, -O-(C3-C5 cycloalkyl), -0-(Ci-C4 straight or branched alkyl) wherein:C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and when R1is not H, -CN or halogen, it is optionally substituted with one, two or three halogens;each R2is independently hydrogen, halogen or C1-C4 straight or branched alkyl; R3is H, -OH, or halogen;R21is H, halogen, C1-C4 straight or branched alkyl, C3-C5 cycloalkyl wherein the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;R22is H, halogen, or C1-C2 alkyl;R24is H, C1-C4 straight or branched alkyl, -(C1-C4 alkyl )i-OH-(C1-C4 alkyl)t-O-(C3-C5cycloalkyl), -(C1-C4 alkyl)t-(C3-C5cycloalkyl), or-(C1-C4 alkyl)t-O-(Ci-C4 straight or branched alkyl) whereinthe C1-C4 straight or branched alkyl is optionally substituted with one, two or three halogens;t is 0 or 1 ;the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; L1is CR23or N;R23is H, C1-C4 straight or branched alkyl, -(C1-C4 alkyl)t-OH,-(C1-C4 alkyl)v-O-(C3-C5 cycloalkyl), -(C1-C4 alkyl)t-(C3-Cs cycloalkyl), or-(C1-C4 alkyl)v-O-(Ci-C4 straight or branched alkyl) wherein:the C1-C4 straight or branched alkyl is optionally substituted with one, two or three halogens;v is 0 or 1 ;the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom.

31. The composition of claim 30, wherein the pharmaceutical composition comprises about 25 mg to about 100 mg, about 30 mg to about 70 mg, about 40 mg to about 60 mg,66IPTS / 128851376.1about 45 mg to about 55 mg, or about 50 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

32. The composition of claims 30 or 31, wherein the subject with NASH / MASH with moderate-to-severe fibrosis is classified as stage F2 or F3 fibrosis.

33. The composition of any one of claims 30-32, wherein the subject has a NAFLD / MASLD Activity Score (NAS / MAS) that is equal or greater to 4.

34. The composition of any one of claims 30-33, wherein the subject with NASH / MASH with moderate-to-severe fibrosis is a biopsy confirmed subject with NASH / MASH with moderate-to-severe fibrosis.

35. The composition of any one of claims 30-34, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, :Formula (I):R1is H, -CN, halogen, C1-C4 straight or branched alkyl, -O-(C3-Cs cycloalkyl), -O-(Ci-C4 straight or branched alkyl) wherein:C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and when R1is not H, -CN or halogen, it is optionally substituted with one, two or three halogens;each R2is independently hydrogen, halogen or C1-C4 straight or branched alkyl; R3is H, -OH, or halogen;R21is H, halogen, C1-C4 straight or branched alkyl, C3-C5 cycloalkyl wherein the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;R22is H, halogen, or C1-C2 alkyl;R24is H, C1-C4 straight or branched alkyl, -(C1-C4 alkyl)t-OH.-(C1-C4 alkyl)t-O-(C3-Cs cycloalkyl), -(C1-C4 alkyl)t-(C3-C5 cycloalkyl), or-(C1-C4 alkyl)t-O-(Ci-C4 straight or branched alkyl) whereinthe C1-C4 straight or branched alkyl is optionally substituted with one, two or three halogens;t is 0 or 1 ;the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; L1is CR23or N;R23is H, C1-C4 straight or branched alkyl, -(C1-C4 alkyl)t-OH,-(C1-C4 alkyl)v-O-(C3-Cs cycloalkyl), -(C1-C4 alkyl)t-(C3-C5 cycloalkyl), or-(C1-C4 alkyl)v-O-(Ci-C4 straight or branched alkyl) wherein:the C1-C4 straight or branched alkyl is optionally substituted with one, two or three halogens;v is 0 or 1.

36. The composition of any one of claims 30-35, wherein the compound is:"(denifanstat),or a pharmaceutically acceptable salt there of; oror pharmaceutically acceptable salt thereof.

37. The pharmaceutical composition of any one of claims 30-36, wherein the pharmaceutical composition is a solid dosage form.

38. The pharmaceutical composition of claim 37, wherein the solid dosage form is a tablet, caplet, capsule, and the like.IPTS / 128851376.

139. A method of treating a subject with NASH / MASH with moderate-to- severe fibrosis, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase inhibitor of Formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a glucagon-like peptide 1 (GLP-1) agonist, wherein:Formula (I) is:R1is H, -CN, halogen, C1-C4 straight or branched alkyl, -O-(C3-Cs cycloalkyl), -0-(Ci-C4 straight or branched alkyl) wherein:C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and when R1is not H, -CN or halogen, it is optionally substituted with one, two or three halogens;each R2is independently hydrogen, halogen or C1-C4 straight or branched alkyl; R3is H, -OH, or halogen;R21is H, halogen, C1-C4 straight or branched alkyl, C3-C5 cycloalkyl wherein the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;R22is H, halogen, or C1-C2 alkyl;R24is H, C1-C4 straight or branched alkyl, -(C1-C4 alkyl)t-OH.-(C1-C4 alkyl)t-O-(C3-Cs cycloalkyl), -(C1-C4 alkyl)t-(C3-Cs cycloalkyl), or-(C1-C4 alkyl)t-O-(Ci-C4 straight or branched alkyl) whereinthe C1-C4 straight or branched alkyl is optionally substituted with one, two or three halogens;t is 0 or 1 ;the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; L1is CR23or N;IPTS / 128851376.1R23is H, C1-C4 straight or branched alkyl, -(C1-C4 alkyl)t-OH.-(C1-C4 alkyl)v-O-(C3-Cs cycloalkyl), -(C1-C4 alkyl)t-(C3-Cs cycloalkyl), or-(C1-C4 alkyl)v-O-(Ci-C4 straight or branched alkyl) wherein:the C1-C4 straight or branched alkyl is optionally substituted with one, two or three halogens;v is 0 or 1 ;the C3-C5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom.

40. The method of claim 39, wherein the subject has an improvement in liver fibrosis > 1 stage without worsening of NASH / MASH.

41. The method of claim 39, wherein the subject has resolution of NASH / MASH without worsening of fibrosis.

42. The method of any one of claims 39-41 , wherein the pharmaceutical composition comprises about 25 mg to about 100 mg, about 30 mg to about 70 mg, about 40 mg to about 60 mg, about 45 mg to about 55 mg, or about 50 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

43. The method of any one of claims 39-42, wherein the subject with NASH / MASH with moderate-to-severe fibrosis is classified as stage F2 or F3 fibrosis.

44. The method of any one of claims 39-43, wherein the subject has a NAFLD / MASLD Activity Score (NAS) that is equal or greater to 4 prior to administration of the pharmaceutical composition.

45. The method of any one of claims 39-44, wherein the pharmaceutical composition is administered once a day to the subject.

46. The method of any one of claims 39-45, wherein the compound is denifanstat, or a pharmaceutically acceptable salt thereof.

47. The method of any one of claims 39-46, wherein the GLP-1 agonist is semaglutide, liraglutide, danuglipron, LY3502970, AMG-133, CT388, dapiglutide, tirzepatide, cotadutide, pemvidutide, BI456906, NN9277, Cagri-Sema or retatrutide, or other GLP-1 agonist as provided for herein.70IPTS / 128851376.1

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