WO2025014754A1

WO2025014754A1 - Compositions containing, and combination therapies using bempedoic acid and a glp-1 receptor agonist

Info

Publication number: WO2025014754A1
Application number: PCT/US2024/036741
Authority: WO
Inventors: Stephen L. Pinkosky; Gregory R. Steinberg; Eric Marc-Andre DESJARDINS
Original assignee: Esperion Therapeutics Inc
Current assignee: Esperion Therapeutics Inc
Priority date: 2023-07-07
Filing date: 2024-07-03
Publication date: 2025-01-16
Anticipated expiration: 2026-01-07

Abstract

Provided herein are methods of treating hepatic steatosis and/or liver fibrosis by administering a combination of a GLP-1 receptor agonist and bempedoic acid. Also provided herein are methods of modulating glycemic control, the level of hemoglobin A1C, the body weight, systolic and/or diastolic blood pressure, liver fat, hepatocellular ballooning, and/or lobular inflammation of a subject by administering a combination of a GLP-1 receptor agonist and bempedoic acid.

Description

COMPOSITIONS CONTAINING, AND COMBINATION THERAPIES USING BEMPEDOIC ACID AND A GLP-1 RECEPTOR AGONIST

CROSS REFERENCE TO RELATED APPLICATIONS

[001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63/512,395, filed on July 7, 2023, the disclosure of which is hereby incorporated by reference in its entirety for all purposes.

BACKGROUND

[002] It is estimated that non-alcoholic fatty liver disease (NAFLD) affects between 30 and 40 percent of adults in the United States (Spengler et al. Recommendations for Diagnosis, Referral for Liver Biopsy, and Treatment of Nonalcohol Fatty Liver Disease and Nonalcoholic Slealohepatilis. Mayo Clin. Proc. 2015. 90 (9): 1233-1246). Although the majority of NAFLD cases have little risk progression, about 20 percent of adults with NAFLD have non-alcoholic steatohepatitis (NASH), a more serious form of NAFLD that represents a greater cause for concern (Spengler et al.). Associated complications and comorbidities of NASH include, but are not limited to, fibrosis and cirrhosis of the liver, liver cancer, and liver failure (National Institutes of Health). Moreover, currently there are few approved drug therapies available for the treatment of NASH. As such, NASH represents a significant health concern.

[003] Glucagon-like protein- 1 (GLP-1) receptor agonists are a class of drugs, several members of which are FDA-approved (e.g., dulaglutide, exenatide, semaglutide, liraglutide, albiglutide, lixisenatide), that lower blood sugar in patients and are useful for the treatment of type 2 diabetes. The GLP-1 receptor agonist semaglutide, the only drug of its class currently approved for oral administration, has been investigated in the context of treating NASH (Newsome et al. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. New Eng. J. of Med. 2020). However, semaglutide has not been shown to have a beneficial effect in the management of liver fibrosis (Newsome et al.).

[004] Despite the efforts made to date, there is an unmet need for drug therapies that treat NASH while also improving liver fibrosis.

SUMMARY

[005] The present disclosure provides combination drug therapies comprising bempedoic acid and a GLP- 1 receptor agonist (semaglutide, liraglutide, exenatide, dulaglutide, albiglutide, or lixisenatide). The disclosure additionally provides methods of using the combination drug therapies described herein to treat hepatic steatosis (e.g., non-alcoholic steatohepatitis (NASH)) in a subject in need thereof. The combination drug therapies described herein are also useful for one or more of treating liver fibrosis, modulating glycemic control, reducing the level of hemoglobin A1C (HbAlc) in blood or serum, reducing body weight, reducing the systolic and/or diastolic blood pressure, reducing liver fat, reducing hepatocellular ballooning, and reducing lobular inflammation in a subject with hepatic steatosis. The methods generally comprise administering to the subject an effective amount of bempedoic acid and an effective amount of a GLP- 1 receptor agonist described herein.

[006] In one aspect, provided herein is a method of treating hepatic steatosis in a subject in need thereof, the method comprising administering to the subject an effective amount of a GLP- 1 receptor agonist and an effective amount of bempedoic acid.

[007] In another aspect, provided herein is a method of treating liver fibrosis in a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP- 1 receptor agonist and an effective amount of bempedoic acid.

[008] In another aspect, provided herein is a method of modulating glycemic control in a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP- 1 receptor agonist and an effective amount of bempedoic acid.

[009] In another aspect, provided herein is a method of reducing the level of hemoglobin A1C (HbAlc) in blood or serum of a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP- 1 receptor agonist and an effective amount of bempedoic acid.

[010] In another aspect, provided herein is a method of reducing the body weight of a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP- 1 receptor agonist and an effective amount of bempedoic acid.

[011] In another aspect, provided herein is a method of reducing the systolic and/or diastolic blood pressure of a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.

[012] In another aspect, provided herein is a method of reducing liver fat in a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP- 1 receptor agonist and an effective amount of bempedoic acid. [013] In another aspect, provided herein is a method of reducing hepatocellular ballooning in a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP- 1 receptor agonist and an effective amount of bempedoic acid.

[014] In another aspect, provided herein is a method of reducing lobular inflammation in a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP- 1 receptor agonist and an effective amount of bempedoic acid.

[015] In certain embodiments, the hepatic steatosis is NASH.

[016] In certain embodiments, administration of the effective amounts of the GLP-1 receptor agonist and bempedoic acid lowers the level of hbAlc in blood or serum of the subject below that of a subject with hepatic steatosis, and not receiving the effective amounts of the GLP-1 receptor agonist and bempedoic acid or receiving (a) the effective amount of the GLP-1 receptor agonist or (b) the effective amount of bempedoic acid. In certain embodiments, administration of the effective amounts of the GLP-1 receptor agonist and bempedoic acid results in the subject exhibiting a greater reduction in body weight compared to a subject with hepatic steatosis, and not receiving the effective amounts of the GLP-1 receptor agonist and bempedoic acid or receiving (a) the effective amount of the GLP- 1 receptor agonist or (b) the effective amount of bempedoic acid. In certain embodiments, administration of the effective amounts of the GLP-1 receptor agonist and bempedoic acid results in the subject exhibiting a greater reduction in liver fat compared to a subject with hepatic steatosis, and not receiving the effective amounts of the GLP- 1 receptor agonist and bempedoic acid or receiving (a) the effective amount of the GLP-1 receptor agonist or (b) the effective amount of bempedoic acid. In certain embodiments, administration of the effective amounts of the GLP-1 receptor agonist and bempedoic acid results in the subject exhibiting a greater reduction in liver fibrosis compared to a subject with hepatic steatosis, and not receiving the effective amounts of the GLP-1 receptor agonist and bempedoic acid, or receiving (a) the effective amount of the GLP-1 receptor agonist or (b) the effective amount of bempedoic acid.

[017] In certain embodiments, the GLP-1 receptor agonist is selected from the group consisting of semaglutide, liraglutide, exenatide, dulaglutide, albiglutide, and lixisenatide. In certain embodiments, administering an effective amount of a GLP-1 receptor agonist comprises administering to the subject about 0.25 mg to about 14 mg semaglutide. In certain embodiments, administering an effective amount of a GLP-1 receptor agonist comprises administering parenterally to the subject about 0.25 mg to about 1 mg semaglutide. In certain embodiments, administering an effective amount of a GLP-1 receptor agonist comprises administering orally to the subject about 3 mg to about 14 mg semaglutide. In certain embodiments, administering an effective amount of a GLP-1 receptor agonist comprises administering parenterally to the subject about 0.6 mg to about 1.8 mg liraglutide. In certain embodiments, administering an effective amount of a GLP-1 receptor agonist comprises administering parenterally to the subject about 2 mg to about 10 mg exenatide. In certain embodiments, administering an effective amount of a GLP-1 receptor agonist comprises administering parenterally to the subject about 0.75 mg to about 1.5 mg dulaglutide. In certain embodiments, administering an effective amount of a GLP-1 receptor agonist comprises administering parenterally to the subject about 30 mg to about 50 mg albiglutide. In certain embodiments, administering an effective amount of a GLP-1 receptor agonist comprises administering parenterally to the subject about 10 mg to about 20 mg lixisenatide.

[018] In another aspect, provided herein is a method of treating hepatic steatosis in a subject receiving GLP-1 receptor agonist therapy, the method comprising administering to the subject an effective amount of bempedoic acid.

[019] In another aspect, provided herein is a method of treating liver fibrosis in a subject receiving GLP-1 receptor agonist therapy, the method comprising administering to the subject an effective amount of bempedoic acid.

[020] In another aspect, provided herein is a method of reducing liver fat in a subject receiving GLP-1 receptor agonist therapy, the method comprising administering to the subject an effective amount of bempedoic acid.

[021] In another aspect, provided herein is a method of reducing hepatocellular ballooning in a subject receiving GLP-1 receptor agonist therapy, the method comprising administering to the subject an effective amount of bempedoic acid.

[022] In another aspect, provided herein is a method of reducing lobular inflammation in a subject receiving GLP-1 receptor agonist therapy, the method comprising administering to the subject an effective amount of bempedoic acid.

[023] In certain embodiments, the subject has NASH.

[024] In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 0.25 mg to about 14 mg semaglutide. In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 0.25 mg to about 1 mg semaglutide. In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 3 mg to about 14 mg semaglutide. In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 0.6 mg to about 1.8 mg liraglutide. In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 2 mg to about 10 mg exenatide. In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 0.75 mg to about 1.5 mg dulaglutide. In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 30 mg to about 50 mg albiglutide. In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 10 mg to about 20 mg lixisenatide.

[025] In certain embodiments, the effective amount of bempedoic acid is about 120 mg to about 240 mg. In certain embodiments, the effective amount of bempedoic acid is about 180 mg.

BRIEF DESCRIPTION OF FIGURES

[026] FIG. 1A shows the percent change in body weight and FIG. IB shows the percent change in adiposity (post-pre) throughout intervention. FIG. 1C shows intraperitoneal glucose tolerance test (GTT) (1.25 g/kg) at 4 weeks intervention, FIG. ID shows ip insulin tolerance test (ITT) (1.3 U/kg) at 4 weeks intervention and FIG. IE shows ip pyruvate tolerance test (PTT) (1.5 g/kg) at 5 weeks intervention with time plots and area under the curve (AUC). FIG. IF shows fasted serum insulin collected via tail-nick near-end of intervention (9 weeks). FIG. 1G shows fed serum cholesterol from blood collected by cardiac puncture at sacrifice, and FIG. 1H shows fasted serum triglycerides. Data are means ± S.E.M. Colored bars signify comparisons between groups and Vehicle. Significance was accepted at p < 0.05 and determined via one-way ANOVA or repeated-measures two-way ANOVA with Tukey posthoc, where appropriate. White circles are individual mice per group (n=8-9 mice/group). *P<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Larger asterisks correspond to Lira; smaller asterisks correspond to Lira+BemA. Vehicle (saline treatments subcutaneously every 2 days), Lira (70 pg/kg liraglutide subcutaneously every 2 days before lights out), Lira+BemA (bempedoic acid 10 mg/kg in diet and 70 pg/kg liraglutide subcutaneously every 2 days before lights out). The legend for FIG.

1A applies to FIGs. 1B-1H.

[027] FIG. 2A shows liver fat percentage as measured by time-domain NMR. FIG. 2B shows liver triglycerides. FIG. 2C shows representative micrographs of H&E (top) and picrosirius red (PSR; bottom) stained sections (lOx); FIG. 2D is a histogram of histological grade of liver steatosis, FIG. 2E is a histogram of histological grade of hepatocellular ballooning, FIG. 2F is a histogram of histological grade of lobular inflammation, and FIG. 2G is a histogram of composite NAFLD activity score (NAS). FIG. 2H shows percent positive PSR area; FIG. 21 shows parts of whole indicating presence of moderate, zone 3 perisinusoidal fibrosis. Data are means + S.E.M. Colored bars signify comparisons between groups and Vehicle with percentages listed next to them. Significance was accepted at p < 0.05 and determined via oneway ANOVA with Tukey posthoc or, for histological score analysis, a Kruskal- Wallis test was used with Dunn’s posthoc test to correct for multiple comparisons, where appropriate. White circles are individual mice per group (n=8-9 mice/group). *P<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Larger asterisks correspond to Lira; smaller asterisks correspond to Lira+BemA. Vehicle (saline treatments subcutaneously every 2 days), Lira (70 g/kg liraglutide subcutaneously every 2 days before lights out), Lira+BemA (bempedoic acid 10 mg/kg in diet and 70 pg/kg liraglutide subcutaneously every 2 days before lights out). The legend for FIG. 2A applies to FIGs. 2B and 2D-2H.

[028] FIG. 3A shows signature scores of transcriptional pathways most affected by combination treatment. FIG. 3B shows PCA of control, monotherapy and combination treatment based on pathway signature scores. FIG. 3C shows odds ratio and 95% confidence interval associated with hepatic steatosis, ballooning degeneration, inflammation, fibrosis, NAS, and liver adiposity measurements based on PCI of pathway signature scores. FIG. 3D shows gene expression of hepatic stellate cell markers, and FIG. 3E shows gene expression of chemokines associated with NASH progression.

[029] FIG. 4A shows scaled expression of prognostically significant orthologous genes involved in NASH progression in healthy, NASH/NAFLD patients and experimental cohorts. FIG. 4B shows distribution of disease stages and treatment types in cluster III. FIG. 4C shows PCA of human NASH/NAFLD patients and experimental cohorts based on scaled gene expression. FIG. 4D shows ROC of multivariate logistic regression models using a combination specific gene signature, a smaller subset derived using elastic net regularization, and the 25 -gene signature previously reported by Govaere et al. for the prediction of fibrosis stage > 2 among human NASH/NAFLD patients. FIG. 4E shows classification based on similarity of gene signature expression identifies liver cell types that are differentially expressed between patients classified into the similar or dissimilar classes.

[030] FIG. 5A shows percent change in body weight and FIG. 5B shows percent change in change in adiposity (post-pre) throughout intervention. FIG. 5C shows intraperitoneal glucose tolerance test (GTT) (1.25 g/kg) at 4 weeks intervention, FIG. 5D shows ip insulin tolerance test (ITT) (1.3 U/kg) at 4 weeks intervention and FIG. 5E shows ip pyruvate tolerance test (PTT) (1.5 g/kg) at 5 weeks intervention with time plots and area under the curve (AUC). FIG. 5F shows fasted serum insulin collected via tail-nick near-end of intervention (9 weeks). FIG. 5G shows fed serum cholesterol from blood collected by cardiac puncture at sacrifice, and FIG. 5H shows fasted serum triglycerides. Data are means + S.E.M. Black bars signify comparisons between group and control group (ND). Significance was accepted at p < 0.05 and determined via unpaired t-test or repeated-measures two-way ANOVA with Sidak posthoc, where appropriate. White circles are individual mice per group (n=8-9 mice/group). *P<0.05. ND (or control), ND+BemA (bempedoic acid 10 mg/kg in diet). The legend for FIG. 5A applies to FIGs. 5B-5H.

[031] FIG. 6A shows liver fat percentage as measured by time-domain NMR. FIG. 6B shows liver triglycerides. FIG. 6C shows representative micrographs of H&E (top) and picrosirius red (PSR; bottom) stained sections (lOx); FIG. 6D is a histogram of histological grades of liver steatosis, FIG. 6E is a histogram of histological grades of hepatocellular ballooning, FIG. 6F is a histogram of histological grades of lobular inflammation, and FIG. 6G is a histogram of composite NAFLD activity score (NAS), FIG. 6H shows percent positive PSR area and FIG. 61 shows parts of whole indicating presence of moderate, zone 3 perisinusoidal fibrosis. Data are means + S.E.M. Black bars signify comparisons between group and control group (ND). Significance was accepted at p < 0.05 and determined via unpaired t-test or, for histological score analysis, a Mann- Whitney test was used, where appropriate. *P<0.05, **p<0.01. White circles are individual mice per group (n=8-9 mice/group). ND (or control), ND+BemA (bempedoic acid 10 mg/kg in diet). The legend for FIG. 6A applies to FIGs. 6B and 6D-6I.

[032] FIG. 7A shows number of differentially expressed genes in each treatment group. FIG. 7B shows overlap between significantly downregulated genes and FIG. 7C shows overlap between significantly upregulated genes by combination treatment and genes differentially expressed in all other treatment groups. Horizontal dash indicates genes uniquely regulated by combination treatment. Downward diagonal slash (left to right) indicates genes up or downregulated in all treatment groups. Cross hatch indicates genes upregulated by monotherapy and downregulated by combination treatment. FIG. 7D shows over-represented pathway annotations associated with additively and uniquely downregulated genes by combination treatment.

[033] FIG. 8A shows signature scores of all pathways in the Nanostring nCounter Fibrosis v2 Panel. FIG. 8B shows gene expression of select genes involved in TGFP pathway.

[034] FIG. 9A shows overlap between genes differentially regulated by combination treatment compared to control as well as monotherapy. FIG. 9B shows expression of the 33-gene signature. FIG. 9C shows distribution of disease stages among patients in the similar or dissimilar classes. FIG. 9D shows classification based on similarity of gene signature expression identifies differential expression of hallmark gene sets between the similar and dissimilar classes.

[035] FIG. 10 shows a differential expression analysis comparing liraglutide, bempedoic acid and combination treatment (liraglutide + bempedoic acid) to diseased control.

[036] FIG. 11 shows a downregulated genes and pathway annotations analysis.

[037] FIG. 12 shows a pathway annotation analysis of genes uniquely and additively downregulated by combination treatment (liraglutide + bempedoic acid).

DETAILED DESCRIPTION

[038] As generally described herein, the present disclosure provides methods of treating hepatic steatosis (e.g., non-alcoholic steatohepatitis (NASH)) and liver fibrosis in a subject in need thereof. The methods generally comprise administering to the subject effective amounts of combinations of a GLP-1 receptor agonist (e.g., semaglutide, liraglutide, exenatide, dulaglutide, albiglutide, and lixisenatide) and bempedoic acid. Also provided herein are methods of treating hepatic steatosis (e.g., non-alcoholic steatohepatitis (NASH)) and liver fibrosis in a subject receiving GLP-1 receptor agonist therapy (e.g., semaglutide, liraglutide, exenatide, dulaglutide, albiglutide, and lixisenatide). The methods generally comprise administering to the subject an effective amount of bempedoic acid.

Definitions

[039] To facilitate an understanding of the present disclosure, a number of terms and phrases are defined below.

[040] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[041] Throughout the description, where compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present disclosure that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present disclosure that consist essentially of, or consist of, the recited processing steps.

[042] In the application, where an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components.

[043] Further, it should be understood that elements and/or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present disclosure, whether explicit or implicit herein. For example, where reference is made to a particular compound, that compound can be used in various embodiments of compositions of the present disclosure and/or in methods of the present disclosure, unless otherwise understood from the context. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and disclosure(s). For example, it will be appreciated that all features described and depicted herein can be applicable to all aspects of the disclosure(s) described and depicted herein.

[044] The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article, unless the context is inappropriate. By way of example, “an element” refers to one element or more than one element.

[045] The term “and/or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

[046] It should be understood that the expression “at least one of’ includes individually each of the recited objects after the expression and the various combinations of two or more of the recited objects unless otherwise understood from the context and use. The expression “and/or” in connection with three or more recited objects should be understood to have the same meaning unless otherwise understood from the context.

[047] The use of the term “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context. [048] Where the use of the term “about” is before a quantitative value, the present disclosure also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ±10%, ±5%, ±2%, or ±1% variation from the nominal value unless otherwise indicated or inferred from the context.

[049] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present disclosure remains operable. Moreover, two or more steps or actions may be conducted simultaneously.

[050] At various places in the present specification, variables or parameters are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[051] The use of any and all examples, or exemplary language herein, for example, “such as” or “including,” is intended merely to illustrate better the present disclosure and does not pose a limitation on the scope of the disclosure unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present disclosure.

[052] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.

[053] As used herein, “pharmaceutical composition” or “pharmaceutical formulation” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[054] The phrases “pharmaceutically acceptable” and “pharmacologically acceptable,” as used herein, refer to compounds, molecular entities, compositions, materials, and/or dosage forms that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by regulatory agencies that evaluate the safety and efficacy of pharmaceuticals and drug products, e.g., the U.S. Food and Drug Administration. “Pharmaceutically acceptable” and “pharmacologically acceptable” can mean approved or approvable by a regulatory agency of the federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[055] As used herein, a “compound” (including a specifically named compound, e.g., bempedoic acid or a GLP- 1 receptor agonist described herein) refers to the compound itself and its pharmaceutically acceptable salts unless otherwise understood from the context of the description or expressly limited to one particular form of the compound, e.g., the compound itself, or a pharmaceutically acceptable salt thereof.

[056] As used herein, “pharmaceutically acceptable salt” refers to any salt of an acidic or a basic group that may be present in a compound of the present disclosure (e.g., bempedoic acid or a GLP-1 receptor agonist described herein), which salt is compatible with pharmaceutical administration. For example, one or both of the carboxylic acid groups of bempedoic acid may be ionizable.

[057] As is known to those of skill in the art, “salts” of compounds may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acid. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts.

[058] Examples of bases include, but are not limited to, alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and compounds of formula NWU, wherein W is Ci-4 alkyl, and the like.

[059] Examples of salts include, but are not limited, to acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present disclosure compounded with a suitable cation such as Na⁺, K⁺, Ca²⁺, NH4⁺, and NW4⁺ (where W can be a Ci-4 alkyl group), and the like.

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

[061] As used herein, “carrier” refers to a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent such as bempedoic acid, or a pharmaceutically acceptable salt thereof, from one organ, or portion of the body, to another organ, or portion of the body. [062] As used herein, “pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and/or absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, such as a phosphate buffered saline solution, emulsions (e.g., such as an oil/water or water/oil emulsions), lactated Ringer’s solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxypropylmethylcellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the disclosure. For examples of excipients, see Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).

[063] As used herein, “treat,” “treating” or “treatment” includes an action that occurs while a subject (e.g., an adult) is suffering from a specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like), or lessens, reduces, modulates, ameliorates or eliminates a symptom thereof. Treating can be curing, improving, or at least partially ameliorating the disorder. In certain embodiments, treating is curing the disease. [064] As used herein, “reducing” or “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) refers to decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). For example, “reducing” or “reduction” of liver fibrosis may refer to a decrease in the rate of accumulation of fibrotic tissue in the liver, a decrease in the stage of liver fibrosis (e.g., a decrease in the amount of fibrotic tissue in the liver), or reversal/reversion of liver fibrosis

[065] As used herein, “reducing” or “reduction” of an elevated laboratory biomarker/parameter (e.g., HbAlc, LDL-C, etc.) or vital sign (e.g., blood pressure) associated with a disease disclosed herein may refer a decrease in the elevated laboratory biomarker/parameter or vital sign, for example, to a pre-determined clinically relevant endpoint (e.g., a clinically normal level).

[066] As used herein, “subject” and “patient” are used interchangeably and refer to an organism to be treated by the methods and compositions of the present disclosure. Such organisms are preferably a mammal (e.g., human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, and rhesus), and more preferably, a human. In certain embodiments, the subject is an adult human.

[067] As used herein, “solid dosage form” refers to a pharmaceutical dose(s) in solid form, e.g., tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers and chewables.

[068] As used herein, “fixed-dose combination” refers to a form in which the active ingredients (e.g., bempedoic acid and semaglutide) are both administered to a patient simultaneously in the form of a single entity or dosage.

[069] As used herein, “administering” refers to oral administration, administration as a suppository, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By “co- administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g., bempedoic acid and semaglutide). Semaglutide, or a pharmaceutically acceptable salt thereof, can be administered alone or can be co-administered to the patient. Co- administration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation).

[070] As used herein, “disease,” “disorder,” “condition,” or “illness,” can be used interchangeably unless otherwise understood from the context, and refers to a state of being or health status of a patient or subject capable of being treated with a compound, pharmaceutical materials, pharmaceutical composition, or method provided herein. In some embodiments, the combinations described herein comprise reduction or elimination of one or more symptoms of the disease, disorder, condition, or illness e.g., through administration of the combination.

[071] As used herein, “hepatocellular ballooning” may refer to the process of hepatocyte cell death.

[072] As used herein, “lobular inflammation” may refer to the presence of lobular inflammatory foci (grouped inflammatory cells) at microscopic examination of a hematoxylin and eosin (H&E) stained slice of a liver biopsy.

[073] As used herein, “effective amount” or “therapeutically-effective amount” refers to the amount of a compound, a pharmaceutical composition, or a fixed-dose combination (e.g., a fixed-dose combination of the present disclosure) sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.

Abbreviations:

BA bempedoic acid

HDL-C high-density lipoprotein cholesterol

CRP C-reactive protein

GLP-1 glucagon- like protein- 1

LDL-C low-density lipoprotein-cholesterol

NAFLD non-alcoholic fatty liver disease

NASH non-alcoholic steatohepatitis

ND NASH diet

VLDL very-low-density lipoprotein

A 1 c/hb A 1 c glycated hemoglobin hsCRP high-sensitivity C -reactive protein apo B apolipoprotein B apo Al apolipoprotein Al

Bempedoic Acid

[074] Bempedoic acid is a non-statin drug indicated as an adjunct to diet, in combination with other LDL-C lowering therapies, or alone when concomitant LDL-C lowering therapy is not possible, to reduce LDL-C in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH); and/or to reduce the risk of myocardial infarction and coronary revascularization in adults who are unable to take recommended statin therapy (including those not taking a statin) with established cardiovascular disease (CVD) or with a high risk for a CVD event but without established CVD. It functions through inhibition of adenosine triphosphate-citrate lyase (ACL). It behaves as a prodrug in vivo, where it is converted to the active species bempedoic acid-CoA by endogenous liver acyl-Coenzyme (CoA) synthetase (ACS) activity. A specific ACS isozyme, very long-chain acyl-CoA synthetase (ACSVL1), is required to form the active species. Bempedoic acid can also activate the metabolic sensor AMP-activated protein kinase (AMPK).

[075] Bempedoic acid may be represented by the structure of Formula (I):

[076] Bempedoic acid and a process for synthesizing it are disclosed in the U.S. Patent

Nos. 7,335,799 and 11,407,705; and International Publication No. WO 2020/257571 Al, each of which is herein incorporated by reference. Bempedoic acid may also be referred to as ETC- 1002, ESP-55016, or under the tradenames Nexletol® and Nilemdo®.

[077] In various embodiments, bempedoic acid may be used for the treatment and/or prevention of a variety of conditions, diseases and disorders described herein. The methods of treating a condition, disease, or disorder described herein generally comprise administering to a subject in need thereof a therapeutically effective amount of bempedoic acid to treat the condition, disease, or disorder.

[078] In certain embodiments, bempedoic acid may be used for treating hepatic steatosis in a subject in need thereof. In certain embodiments, bempedoic acid may be used for treating liver fibrosis in a subject with hepatic steatosis. In certain embodiments, bempedoic acid may be used for modulating glycemic control in a subject with hepatic steatosis. In certain embodiments, bempedoic acid may be used for reducing the level of hemoglobin A1C (HbAlc) in blood or serum of a subject with hepatic steatosis. In certain embodiments, bempedoic acid may be used for reducing the body weight of a subject with hepatic steatosis. In certain embodiments, bempedoic acid may be used for reducing the systolic and/or diastolic blood pressure of a subject with hepatic steatosis. In certain embodiments, bempedoic acid may be used for reducing liver fat in a subject with hepatic steatosis. In certain embodiments, bempedoic acid may be used for reducing hepatocellular ballooning in a subject with hepatic steatosis. In certain embodiments, bempedoic acid may be used for reducing lobular inflammation in a subject with hepatic steatosis.

[079] In certain embodiments, bempedoic acid may be used in combination with a GLP-1 receptor agonist for treating hepatic steatosis in a subject in need thereof. In certain embodiments, bempedoic acid may be used in combination with a GLP-1 receptor agonist for treating liver fibrosis in a subject with hepatic steatosis. In certain embodiments, bempedoic acid may be used in combination with a GLP-1 receptor agonist for modulating glycemic control in a subject with hepatic steatosis. In certain embodiments, bempedoic acid may be used in combination with a GLP-1 receptor agonist for reducing the level of HbAlc in blood or serum of a subject with hepatic steatosis. In certain embodiments, bempedoic acid may be used in combination with a GLP-1 receptor agonist for reducing the body weight of a subject with hepatic steatosis. In certain embodiments, bempedoic acid may be used in combination with a GLP-1 receptor agonist for reducing the systolic and/or diastolic blood pressure of a subject with hepatic steatosis. In certain embodiments, bempedoic acid may be used in combination with a GLP-1 receptor agonist for reducing liver fat in a subject with hepatic steatosis. In certain embodiments, bempedoic acid may be used in combination with a GLP-1 receptor agonist for reducing hepatocellular ballooning in a subject with hepatic steatosis. In certain embodiments, bempedoic acid may be used in combination with a GLP- 1 receptor agonist for reducing lobular inflammation in a subject with hepatic steatosis.

[080] In certain embodiments, bempedoic acid may be used for treating hepatic steatosis in a subject receiving GLP-1 receptor agonist therapy. In certain embodiments, bempedoic acid may be used for treating liver fibrosis in a subject with hepatic steatosis receiving GLP-1 receptor agonist therapy. In certain embodiments, bempedoic acid may be used for modulating glycemic control in a subject with hepatic steatosis receiving GLP-1 receptor agonist therapy. In certain embodiments, bempedoic acid may be used for reducing the level of HbAlc in blood or serum of a subject with hepatic steatosis receiving GLP-1 receptor agonist therapy. In certain embodiments, bempedoic acid may be used for reducing the body weight of a subject with hepatic steatosis receiving GLP-1 receptor agonist therapy. In certain embodiments, bempedoic acid may be used for reducing the systolic and/or diastolic blood pressure of a subject with hepatic steatosis receiving GLP-1 receptor agonist therapy. In certain embodiments, bempedoic acid may be used for reducing liver fat in a subject with hepatic steatosis receiving GLP-1 receptor agonist therapy. In certain embodiments, bempedoic acid may be used for reducing hepatocellular ballooning in a subject with hepatic steatosis receiving GLP-1 receptor agonist therapy. In certain embodiments, bempedoic acid may be used for reducing lobular inflammation in a subject with hepatic steatosis receiving GLP-1 receptor agonist therapy.

[081] In certain embodiments, the fixed-dose combinations and pharmaceutical formulations disclosed herein comprise a crystalline form of bempedoic acid. As used herein, “crystalline form of bempedoic acid” may refer to a crystalline form of the free acid form of bempedoic acid or a crystalline form of a pharmaceutically acceptable salt of bempedoic acid. See, e.g., International Publication No. WO 2020/257573 Al, which is herein incorporated by reference. [082] In certain embodiments, the fixed-dose combinations and pharmaceutical formulations disclosed herein comprise a high purity crystalline form of bempedoic acid.

[083] In certain embodiments, the fixed-dose combinations and pharmaceutical formulations disclosed herein comprise a pharmaceutical material comprising bempedoic acid.

[084] In various embodiments, a pharmaceutical material generally comprises a crystalline form of bempedoic acid, wherein the pharmaceutical material comprises bempedoic acid, or a pharmaceutically acceptable salt thereof, in an amount greater than 99.0% by weight based on the total weight of the pharmaceutical material. In some embodiments, the amount of bempedoic acid, or a pharmaceutically acceptable salt thereof, in the pharmaceutical material is greater than about 99.1%, greater than about 99.2%, greater than about 99.3%, greater than about 99.4%, greater than about 99.5%, greater than about 99.6%, greater than about 99.7%, greater than about 99.8%, greater than about 99.85%, greater than about 99.9%, greater than about 99.95%, or greater than about 99.98% by weight of the total weight of the pharmaceutical material. In some embodiments, the pharmaceutical material comprises bempedoic acid, or a pharmaceutically acceptable salt thereof, in an amount greater than 99.5% by weight based on the total weight of the pharmaceutical material. In some embodiments, the pharmaceutical material comprises bempedoic acid, or a pharmaceutically acceptable salt thereof, in an amount greater than 99.7% by weight based on the total weight of the pharmaceutical material. In some embodiments, the pharmaceutical material comprises bempedoic acid, or a pharmaceutically acceptable salt thereof, in an amount greater than 99.9% by weight based on the total weight of the pharmaceutical material.

[085] In various embodiments, a pharmaceutical material generally comprises a crystalline form of bempedoic acid, wherein the pharmaceutical material comprises bempedoic acid in an amount greater than 99.0% by weight based on the total weight of the pharmaceutical material. In some embodiments, the amount of bempedoic acid in the pharmaceutical material is greater than about 99.1%, greater than about 99.2%, greater than about 99.3%, greater than about 99.4%, greater than about 99.5%, greater than about 99.6%, greater than about 99.7%, greater than about 99.8%, greater than about 99.85%, greater than about 99.9%, greater than about 99.95%, or greater than about 99.98% by weight of the total weight of the pharmaceutical material. In some embodiments, the pharmaceutical material comprises bempedoic acid in an amount greater than 99.5% by weight based on the total weight of the pharmaceutical material. In some embodiments, the pharmaceutical material comprises bempedoic acid in an amount greater than 99.7% by weight based on the total weight of the pharmaceutical material. In some embodiments, the pharmaceutical material comprises bempedoic acid in an amount greater than 99.9% by weight based on the total weight of the pharmaceutical material.

[086] In certain embodiments, the pharmaceutical material comprises bempedoic acid in an amount of from about 98% to about 102% by weight based on the total weight of the pharmaceutical material (anhydrous, solvent-free basis), as determined by a high-performance liquid chromatography (HPLC) assay.

[087] In certain embodiments, the HPLC assay comprises one or more of:

(i) a Waters XBridge BEH C18 column (4.6 mm i.d. x 150 mm, 2.5 pm);

(ii) a column temperature of about 40 °C;

(iii) a mobile phase comprising about 0.05% phosphoric acid in water/acetonitrile (about 50:50);

(iv) isocratic elution;

(v) a flow rate of about 1.2 mL/minute;

(vi) a sample temperature of ambient temperature;

(vii) detection at 215 nm; and

(viii) the retention time of the compound of Formula (I) is about 4.6 minutes. In some embodiments, the HPLC assay comprises each of the above, i.e., (i)-(viii).

[088] In certain embodiments, the crystalline form of bempedoic acid may be a crystalline form of bempedoic acid as characterized in International Publication Nos. WO 2020/257571 Al and WO 2020/257573 Al, each of which is herein incorporated by reference. A crystalline form of bempedoic acid may be characterized, for example, by an X-ray powder diffraction pattern or peak(s), and/or other characteristic properties such as melting point and hygroscopicity.

Crystalline forms of bempedoic acid may include, but are not limited to, cocrystals (e.g., an aspartame cocrystal and a palmitic acid cocrystal), crystalline salts (e.g., an ammonium salt, a sodium salt, a potassium salt, a calcium salt, a lysine salt, a diethylamine salt, an ethylenediamine salt, a piperazine salt, a betaine salt, a tromethamine salt, and an isonicotinamide salt).

GLP-1 Receptor Agonists

[089] Glucagon- like protein- 1 (GLP-1) receptor agonists are indicated for the treatment of subjects having type 2 diabetes mellitus. They regulate (lower) blood sugar levels by inducing insulin production and inhibiting glucagon. A subject receiving GLP-1 receptor agonist therapy may also lose weight and experience a reduced risk of major adverse cardiovascular events. GLP-1 receptor agonists may be used in the fixed-dose combinations, pharmaceutical compositions, and methods of treatment described herein. In certain embodiments, the GLP-1 receptor agonist is selected from the group consisting of semaglutide, liraglutide, exenatide, dulaglutide, albiglutide, and lixisenatide.

[090] In various embodiments, a GLP-1 receptor agonist may be used for the treatment or prevention of a condition, disease, or disorder described herein. The methods of preventing or treating a disease or disorder generally comprise administering to a subject in need thereof a therapeutically effective amount of a GLP-1 receptor agonist to prevent or treat the disease or disorder.

[091] In certain embodiments, the GLP-1 receptor agonist may be used for treating hepatic steatosis in a subject in need thereof. In certain embodiments, the GLP-1 receptor agonist may be used for treating liver fibrosis in a subject with hepatic steatosis. In certain embodiments, the GLP-1 receptor agonist may be used for modulating glycemic control in a subject with hepatic steatosis. In certain embodiments, the GLP-1 receptor agonist may be used for reducing the level of HbAlc in blood or serum of a subject with hepatic steatosis. In certain embodiments, the GLP- 1 receptor agonist may be used for reducing the body weight of a subject with hepatic steatosis. In certain embodiments, the GLP-1 receptor agonist may be used for reducing the systolic and/or diastolic blood pressure of a subject with hepatic steatosis. In certain embodiments, the GLP-1 receptor agonist may be used for reducing liver fat in a subject with hepatic steatosis. In certain embodiments, the GLP-1 receptor agonist may be used for reducing hepatocellular ballooning in a subject with hepatic steatosis. In certain embodiments, the GLP-1 receptor agonist may be used for reducing lobular inflammation in a subject with hepatic steatosis.

[092] In certain embodiments, the GLP-1 receptor agonist may be used in combination with bempedoic acid for treating hepatic steatosis in a subject in need thereof. In certain embodiments, the GLP-1 receptor agonist may be used in combination with bempedoic acid for treating liver fibrosis in a subject with hepatic steatosis. In certain embodiments, the GLP-1 receptor agonist may be used in combination with bempedoic acid for modulating glycemic control in a subject with hepatic steatosis. In certain embodiments, the GLP-1 receptor agonist may be used in combination with bempedoic acid for reducing the level of HbAlc in blood or serum of a subject with hepatic steatosis. In certain embodiments, the GLP-1 receptor agonist may be used in combination with bempedoic acid for reducing the body weight of a subject with hepatic steatosis. In certain embodiments, the GLP-1 receptor agonist may be used in combination with bempedoic acid for reducing the systolic and/or diastolic blood pressure of a subject with hepatic steatosis. In certain embodiments, the GLP-1 receptor agonist may be used in combination with bempedoic acid for reducing liver fat in a subject with hepatic steatosis. In certain embodiments, the GLP-1 receptor agonist may be used in combination with bempedoic acid for reducing hepatocellular ballooning in a subject with hepatic steatosis. In certain embodiments, the GLP-1 receptor agonist may be used in combination with bempedoic acid for reducing lobular inflammation in a subject with hepatic steatosis.

Semaglutide

[093] In various embodiments, the GLP-1 receptor agonist is semaglutide. Semaglutide may be represented by the structure of Formula (II):

[094] Semaglutide and its methods of use and administration are disclosed in, for example, U.S. Patent Nos. 6,899,699; 7,762,994; 8,114,833; 8,129,343; 8,536,122; 8,579,869; 8,672,898; 8,684,969; 8,920,383; 9,108,002; 9,132,239; 9,457,154; 9,486,588; 9,616,180; 9,687,611; 9,775,953; 9,861,757; 10,220,155; 10,357,616; 10,376,652; 10,335,462; 9,278,123; 10,086,047; and 10,278,923, which are incorporated herein by reference. Semaglutide may be administered as an oral dosage form or as a parenteral dosage form. Semaglutide may also be referred to under the trade names Ozempic® (as a parenteral dosage form) and Rybelsus® (as an oral dosage form).

[095] In various embodiments, semaglutide may be administered to a subject in an amount of about 0.25 mg to about 14 mg, about 1 mg to about 14 mg, about 2 mg to about 14 mg, about 3 mg to about 14 mg, about 4 mg to about 14 mg, about 5 mg to about 14 mg, about 6 mg to about 14 mg, about 7 mg to about 14 mg, about 8 mg to about 14 mg, about 9 mg to about 14 mg, about 10 mg to about 14 mg, about 12 mg to about 14 mg, about 0.25 mg to about 12 mg, about 0.25 mg to about 10 mg, about 0.25 mg to about 9 mg, about 0.25 mg to about 8 mg, about 0.25 mg to about 7 mg, about 0.25 mg to about 6 mg, about 0.25 mg to about 5 mg, about 0.25 mg to about 4 mg, about 0.25 mg to about 3 mg, about 0.25 mg to about 2 mg, about 0.25 mg to about 1 mg, about 1 mg to about 12 mg, about 1 mg to about 10 mg, about 1 mg to about 9 mg, about 1 mg to about 8 mg, about 1 mg to about 7 mg, about 1 mg to about 6 mg, about 1 mg to about 5 mg, about 1 mg to about 4 mg, about 1 mg to about 3 mg, about 1 mg to about 2 mg, about 2 mg to about 12 mg, about 2 mg to about 10 mg, about 2 mg to about 9 mg, about 2 mg to about 8 mg, about 2 mg to about 7 mg, about 2 mg to about 6 mg, about 2 mg to about 5 mg, about 2 mg to about 4 mg, about 2 mg to about 3 mg, about 3 mg to about 12 mg, about 3 mg to about 10 mg, about 3 mg to about 9 mg, about 3 mg to about 8 mg, about 3 mg to about 7 mg, about 3 mg to about 6 mg, about 3 mg to about 5 mg, about 3 mg to about 4 mg, about 4 mg to about 12 mg, about 4 mg to about 10 mg, about 4 mg to about 9 mg, about 4 mg to about 8 mg, about 4 mg to about 7 mg, about 4 mg to about 6 mg, about 4 mg to about 5 mg, about 5 mg to about 12 mg, about 5 mg to about 10 mg, about 5 mg to about 9 mg, about 5 mg to about 8 mg, about 5 mg to about 7 mg, about 5 mg to about 6 mg, about 6 mg to about 12 mg, about 6 mg to about 10 mg, about 6 mg to about 9 mg, about 6 mg to about 8 mg, about 6 mg to about 7 mg, about 7 mg to about 12 mg, about 7 mg to about 10 mg, about 7 mg to about 9 mg, about 7 mg to about 8 mg, about 8 mg to about 12 mg, about 8 mg to about 10 mg, about 8 mg to about 9 mg, about 9 mg to about 12 mg, about 9 mg to about 10 mg, or about 10 mg to about 12 mg. In various embodiments, semaglutide may be administered to a subject in an amount of about 0.25 mg to about 1 mg. In various embodiments, semaglutide may be administered to a subject in an amount of about 3 mg to about 14 mg.

[096] In certain embodiments, semaglutide may be administered to a subject in an amount of about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about

12 mg, about 13 mg, or about 14 mg.

[097] In various embodiments, semaglutide, as an oral dosage form, may be administered to a subject in an amount of about 3 mg to about 14 mg, about 4 mg to about 14, about 5 mg to about 14 mg, about 6 mg to about 14 mg, about 7 mg to about 14 mg, about 8 mg to about 14 mg, about 9 mg to about 14 mg, about 10 mg to about 14 mg, about 11 mg to about 14 mg, about 12 mg to about 14 mg, about 13 mg to about 14 mg, about 3 mg to about 13 mg, about 3 mg to about 12 mg, about 3 mg to about 11 mg, about 3 mg to about 10 mg, about 3 mg to about 9 mg, about 3 mg to about 8 mg, about 3 mg to about 7 mg, about 3 mg to about 6 mg, about 3 mg to about 5 mg, about 3 mg to about 4 mg, about 4 mg to about 13 mg, about 4 mg to about 12 mg, about 4 mg to about 11 mg, about 4 mg to about 10 mg, about 4 mg to about 9 mg, about 4 mg to about 8 mg, about 4 mg to about 7 mg, about 4 mg to about 6 mg, about 4 mg to about 5 mg, about 5 mg to about 13 mg, about 5 mg to about 12 mg, about 5 mg to about 11 mg, about 5 mg to about 10 mg, about 5 mg to about 9 mg, about 5 mg to about 8 mg, about 5 mg to about 7 mg, about 5 mg to about 6 mg, about 6 mg to about 13 mg, about 6 mg to about 12 mg, about 6 mg to about 11 mg, about 6 mg to about 10 mg, about 6 mg to about 9 mg, about 6 mg to about 8 mg, about 6 mg to about 7 mg, about 7 mg to about 13 mg, about 7 mg to about 12 mg, about 7 mg to about 11 mg, about 7 mg to about 10 mg, about 7 mg to about 9 mg, about 7 mg to about 8 mg, about 8 mg to about 13 mg, about 7 mg to about 12 mg, about 7 mg to about 11 mg, about 7 mg to about 10 mg, about 7 mg to about 9 mg, about 7 mg to about 8 mg, about 8 mg to about

13 mg, about 8 mg to about 12 mg, about 8 mg to about 1 1 mg, about 8 mg to about 10 mg, about 8 mg to about 9 mg, about 9 mg to about 13 mg, about 9 mg to about 12 mg, about 9 mg to about 11 mg, about 9 mg to about 10 mg, about 10 mg to about 13 mg, about 10 mg to about 12 mg, about 10 mg to about 11 mg, about 11 mg to about 13 mg, about 11 mg to about 12 mg, or about 12 mg to about 13 mg. In various embodiments, semaglutide, as an oral dosage form, may be administered to a subject in an amount of about 3 mg to about 14 mg.

[098] In certain embodiments, semaglutide, as an oral dosage form, may be administered to a subject in an amount of about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, or about 14 mg.

[099] In various embodiments, semaglutide, as a parenteral dosage form, may be administered to a subject in an amount of about 0.25 mg to about 1 mg, about 0.3 mg to about 1 mg, about 0.4 mg to about 1 mg, about 0.5 mg to about 1 mg, about 0.6 mg to about 1 mg, about 0.7 mg to about 1 mg, about 0.8 mg to about 1 mg, about 0.9 mg to about 1 mg, about 0.25 mg to about 0.9 mg, about 0.25 mg to about 0.8 mg, about 0.25 mg to about 0.7 mg, about 0.25 mg to about 0.6 mg, about 0.25 mg to about 0.5 mg, about 0.25 mg to about 0.4 mg, about 0.25 mg to about 0.3 mg, about 0.3 mg to about 0.9 mg, about 0.3 mg to about 0.8 mg, about 0.3 mg to about 0.7 mg, about 0.3 mg to about 0.6 mg, about 0.3 mg to about 0.5 mg, about 0.3 mg to about 0.4 mg, about 0.4 mg to about 0.9 mg, about 0.4 mg to about 0.8 mg, about 0.4 mg to about 0.7 mg, about 0.4 mg to about 0.6 mg, about 0.4 mg to about 0.5 mg, about 0.5 mg to about 0.9 mg, about 0.5 mg to about 0.8 mg, about 0.5 mg to about 0.7 mg, about 0.5 mg to about 0.6 mg, about 0.6 mg to about 0.9 mg, about 0.6 mg to about 0.8 mg, about 0.6 mg to about 0.7 mg, about 0.7 mg to about 0.9 mg, about 0.7 mg to about 0.8 mg, or about 0.8 mg to about 0.9 mg. In certain embodiments, semaglutide, as a parenteral dosage form, may be administered to a subject in an amount of about 0.25 mg to about 1 mg.

[0100] In certain embodiments, semaglutide, as a parenteral dosage form, may be administered to a subject in an amount of about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, or about 1 mg.

[0101] In various embodiments, semaglutide may be used for the treatment or prevention of a condition, disease, or disorder described herein. The methods of preventing or treating a disease or disorder generally comprise administering to a subject in need thereof a therapeutically effective amount of semaglutide to prevent or treat the disease or disorder.

[0102] In certain embodiments, semaglutide may be used for treating hepatic steatosis in a subject in need thereof. In certain embodiments, semaglutide may be used for treating liver fibrosis in a subject with hepatic steatosis. In certain embodiments, semaglutide may be used for modulating glycemic control in a subject with hepatic steatosis. In certain embodiments, semaglutide may be used for reducing the level of HbAlc in blood or serum of a subject with hepatic steatosis. In certain embodiments, semaglutide may be used for reducing the body weight of a subject with hepatic steatosis. In certain embodiments, semaglutide may be used for reducing the systolic and/or diastolic blood pressure of a subject with hepatic steatosis. In certain embodiments, semaglutide may be used for reducing liver fat in a subject with hepatic steatosis. In certain embodiments, semaglutide may be used for reducing hepatocellular ballooning in a subject with hepatic steatosis. In certain embodiments, semaglutide may be used for reducing lobular inflammation in a subject with hepatic steatosis.

[0103] In certain embodiments, semaglutide may be used in combination with bempedoic acid for treating hepatic steatosis in a subject in need thereof. In certain embodiments, semaglutide may be used in combination with bempedoic acid for treating liver fibrosis in a subject with hepatic steatosis. In certain embodiments, semaglutide may be used in combination with bempedoic acid for modulating glycemic control in a subject with hepatic steatosis. In certain embodiments, semaglutide may be used in combination with bempedoic acid for reducing the level of HbAlc in blood or serum of a subject with hepatic steatosis. In certain embodiments, semaglutide may be used in combination with bempedoic acid for reducing the body weight of a subject with hepatic steatosis. In certain embodiments, semaglutide may be used in combination with bempedoic acid for reducing the systolic and/or diastolic blood pressure of a subject with hepatic steatosis. In certain embodiments, semaglutide may be used in combination with bempedoic acid for reducing liver fat in a subject with hepatic steatosis. In certain embodiments, semaglutide may be used in combination with bempedoic acid for reducing hepatocellular ballooning in a subject with hepatic steatosis. In certain embodiments, semaglutide may be used in combination with bempedoic acid for reducing lobular inflammation in a subject with hepatic steatosis.

Liraslulide

[0104] In various embodiments, the GLP-1 receptor agonist is liraglutide. Liraglutide may be represented by the structure of Formula (III):

[0105] Liraglutide and its methods of use and administration are disclosed in, for example, U.S. Patent Nos. 6,268,343; 7,762,994; 8,114,833; 8,846,618; 8,579,869; 9,265,893; and 9,968,659, which are incorporated herein by reference. Liraglutide may be administered as a parenteral dosage form. Liraglutide may also be referred to under the trade names Victoza® and Saxenda®.

[0106] In various embodiments, liraglutide may be administered to a subject in an amount of about 0.6 mg to about 1.8 mg, about 0.8 mg to about 1.8 mg, about 1 mg to about 1.8 mg, about 1.2 mg to about 1.8 mg, about 1.4 mg to about 1.8 mg, about 1.6 mg to about 1.8 mg, about 0.6 mg to about 1.6 mg, about 0.6 mg to about 1.4 mg, about 0.6 mg to about 1.2 mg, about 0.6 mg to about 1 mg, or about 0.6 mg to about 0.8 mg, about 0.8 mg to about 1.6 mg, about 0.8 mg to about 1.4 mg, about 0.8 mg to about 1.2 mg, about 0.8 mg to about 1 mg, about 1 mg to about 1.6 mg, about 1 mg to about 1.4 mg, about 1 mg to about 1.2 mg, about 1.2 mg to about 1.6 mg, about 1.2 mg to about 1.4 mg, or about 1.4 mg to about 1.6 mg. In certain embodiments, liraglutide may be administered to a subject in an amount of about 0.6 mg to about 1.8 mg. [0107] In certain embodiments, liraglutide may be administered to a subject in an amount of about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, or about 1.8 mg. [0108] In various embodiments, liraglutide may be used for the treatment or prevention of a condition, disease, or disorder described herein. The methods of preventing or treating a disease or disorder generally comprise administering to a subject in need thereof a therapeutically effective amount of liraglutide to prevent or treat the disease or disorder.

[0109] In certain embodiments, liraglutide may be used for treating hepatic steatosis in a subject in need thereof. In certain embodiments, liraglutide may be used for treating liver fibrosis in a subject with hepatic steatosis. In certain embodiments, liraglutide may be used for modulating glycemic control in a subject with hepatic steatosis. In certain embodiments, liraglutide may be used for reducing the level of HbAlc in blood or serum of a subject with hepatic steatosis. In certain embodiments, liraglutide may be used for reducing the body weight of a subject with hepatic steatosis. In certain embodiments, liraglutide may be used for reducing the systolic and/or diastolic blood pressure of a subject with hepatic steatosis. In certain embodiments, liraglutide may be used for reducing liver fat in a subject with hepatic steatosis. In certain embodiments, liraglutide may be used for reducing hepatocellular ballooning in a subject with hepatic steatosis. In certain embodiments, liraglutide may be used for reducing lobular inflammation in a subject with hepatic steatosis.

[0110] In certain embodiments, liraglutide may be used in combination with bempedoic acid for treating hepatic steatosis in a subject in need thereof. In certain embodiments, liraglutide may be used in combination with bempedoic acid for treating liver fibrosis in a subject with hepatic steatosis. In certain embodiments, liraglutide may be used in combination with bempedoic acid for modulating glycemic control in a subject with hepatic steatosis. In certain embodiments, liraglutide may be used in combination with bempedoic acid for reducing the level of HbAlc in blood or serum of a subject with hepatic steatosis. In certain embodiments, liraglutide may be used in combination with bempedoic acid for reducing the body weight of a subject with hepatic steatosis. In certain embodiments, liraglutide may be used in combination with bempedoic acid for reducing the systolic and/or diastolic blood pressure of a subject with hepatic steatosis. In certain embodiments, liraglutide may be used in combination with bempedoic acid for reducing liver fat in a subject with hepatic steatosis. In certain embodiments, liraglutide may be used in combination with bempedoic acid for reducing hepatocellular ballooning in a subject with hepatic steatosis. In certain embodiments, liraglutide may be used in combination with bempedoic acid for reducing lobular inflammation in a subject with hepatic steatosis.

Exenatide

[0111] In various embodiments, the GLP-1 receptor agonist is exenatide. Exenatide may be represented by the structure of Formula (IV):

[0112] Exenatide and its methods of use and administration are disclosed in, for example, U.S. Patent Nos. 5,424,286; 6,902,744; 6,924,264; 7,157,555; 7,220,721; and 7,223,725, which are incorporated herein by reference. Exenatide may be administered as a parenteral dosage form. Exenatide may also be referred to under the trade names Byetta® and Bydureon®.

[0113] In various embodiments, exenatide may be administered to a subject in an amount of about 2 mg to about 10 mg, about 3 mg to about 10 mg, about 4 mg to about 10 mg, about 5 mg to about 10 mg, about 6 mg to about 10 mg, about 7 mg to about 10 mg, about 8 mg to about 10 mg, about 9 mg to about 10 mg, about 2 mg to about 9 mg, about 2 mg to about 8 mg, about 2 mg to about 7 mg, about 2 mg to about 6 mg, about 2 mg to about 5 mg, about 2 mg to about 4 mg, about 2 mg to about 3 mg, about 3 mg to about 9 mg, about 3 mg to about 8 mg, about 3 mg to about 7 mg, about 3 mg to about 6 mg, about 3 mg to about 5 mg, about 3 mg to about 4 mg, about 4 mg to about 9 mg, about 4 mg to about 8 mg, about 4 mg to about 7 mg, about 4 mg to about 6 mg, about 4 mg to about 5 mg, about 5 mg to about 9 mg, about 5 mg to about 8 mg, about 5 mg to about 7 mg, about 5 mg to about 6 mg, about 6 mg to about 9 mg, about 6 mg to about 8 mg, about 6 mg to about 7 mg, about 7 mg to about 9 mg, about 7 mg to about 8 mg, or about 8 mg to about 9 mg. In certain embodiments, exenatide may be administered to a subject in an amount of about 2 mg to about 10 mg.

[0114] In certain embodiments, exenatide may be administered to a subject in an amount of about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg.

[0115] In various embodiments, exenatide may be used for the treatment or prevention of a condition, disease, or disorder described herein. The methods of preventing or treating a disease or disorder generally comprise administering to a subject in need thereof a therapeutically effective amount of exenatide to prevent or treat the disease or disorder.

[0116] In certain embodiments, exenatide may be used for treating hepatic steatosis in a subject in need thereof. In certain embodiments, exenatide may be used for treating liver fibrosis in a subject with hepatic steatosis. In certain embodiments, exenatide may be used for modulating glycemic control in a subject with hepatic steatosis. In certain embodiments, exenatide may be used for reducing the level of HbAlc in blood or serum of a subject with hepatic steatosis. In certain embodiments, exenatide may be used for reducing the body weight of a subject with hepatic steatosis. In certain embodiments, exenatide may be used for reducing the systolic and/or diastolic blood pressure of a subject with hepatic steatosis. In certain embodiments, exenatide may be used for reducing liver fat in a subject with hepatic steatosis. In certain embodiments, exenatide may be used for reducing hepatocellular ballooning in a subject with hepatic steatosis. In certain embodiments, exenatide may be used for reducing lobular inflammation in a subject with hepatic steatosis.

[0117] In certain embodiments, exenatide may be used in combination with bempedoic acid for treating hepatic steatosis in a subject in need thereof. In certain embodiments, exenatide may be used in combination with bempedoic acid for treating liver fibrosis in a subject with hepatic steatosis. In certain embodiments, exenatide may be used in combination with bempedoic acid for modulating glycemic control in a subject with hepatic steatosis. In certain embodiments, exenatide may be used in combination with bempedoic acid for reducing the level of HbAlc in blood or serum of a subject with hepatic steatosis. In certain embodiments, exenatide may be used in combination with bempedoic acid for reducing the body weight of a subject with hepatic steatosis. In certain embodiments, exenatide may be used in combination with bempedoic acid for reducing the systolic and/or diastolic blood pressure of a subject with hepatic steatosis. In certain embodiments, exenatide may be used in combination with bempedoic acid for reducing liver fat in a subject with hepatic steatosis. In certain embodiments, exenatide may be used in combination with bempedoic acid for reducing hepatocellular ballooning in a subject with hepatic steatosis. In certain embodiments, exenatide may be used in combination with bempedoic acid for reducing lobular inflammation in a subject with hepatic steatosis.

Dulaglutide

[0118] In various embodiments of the present disclosure, the GLP- 1 receptor agonist is dulaglutide. Dulaglutide is a human GLP- 1 receptor agonist which comprises a dimer of a GLP- 1 analog fused at its C-terminus via a peptide linker to the N-terminus of an analog of an Fc portion of an immunoglobulin, and is identified by CAS registry number 923950-08-7.

Dulaglutide may be represented by SEQ ID NO 1 :

SEQ ID NO 1 :

HGEGTFTSDVSSYLEEQAAKEFIAWLVKGGGGGGGSGGGGSGGGGSAESKYGPPCPPC PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNA KTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG

[0119] Dulaglutide and its methods of use and administration are disclosed in, for example, U.S. Patent No. 7,452,966 and Canadian publication CA3056663A1, which are incorporated herein by reference. Dulaglutide may be administered as a parenteral dosage form. Dulaglutide may also be referred to as LY-2189265 and under the trade name Trulicity®.

[0120] In various embodiments, dulaglutide may be administered to a subject in an amount of about 0.75 mg to about 1.5 mg, about 1 mg to about 1.5 mg, about 1.25 mg to about 1.5 mg, about 0.75 mg to about 1.25 mg, about 0.75 mg to about 1 mg, or about 1 mg to about 1.25 mg. In certain embodiments, dulaglutide may be administered to a subject in an amount of about 0.75 mg to about 1.5 mg.

[0121] In certain embodiments, dulaglutide may be administered to a subject in an amount of about 0.75 mg, about 1 mg, about 1.25 mg, or about 1.5 mg.

[0122] In various embodiments, dulaglutide may be used for the treatment or prevention of a condition, disease, or disorder described herein. The methods of preventing or treating a disease or disorder generally comprise administering to a subject in need thereof a therapeutically effective amount of dulaglutide to prevent or treat the disease or disorder.

[0123] In certain embodiments, dulaglutide may be used for treating hepatic steatosis in a subject in need thereof. In certain embodiments, dulaglutide may be used for treating liver fibrosis in a subject with hepatic steatosis. In certain embodiments, dulaglutide may be used for modulating glycemic control in a subject with hepatic steatosis. In certain embodiments, dulaglutide may be used for reducing the level of HbAlc in blood or serum of a subject with hepatic steatosis. In certain embodiments, dulaglutide may be used for reducing the body weight of a subject with hepatic steatosis. In certain embodiments, dulaglutide may be used for reducing the systolic and/or diastolic blood pressure of a subject with hepatic steatosis. In certain embodiments, dulaglutide may be used for reducing liver fat in a subject with hepatic steatosis. In certain embodiments, dulaglutide may be used for reducing hepatocellular ballooning in a subject with hepatic steatosis. In certain embodiments, dulaglutide may be used for reducing lobular inflammation in a subject with hepatic steatosis.

[0124] In certain embodiments, dulaglutide may be used in combination with bempedoic acid for treating hepatic steatosis in a subject in need thereof. In certain embodiments, dulaglutide may be used in combination with bempedoic acid for treating liver fibrosis in a subject with hepatic steatosis. In certain embodiments, dulaglutide may be used in combination with bempedoic acid for modulating glycemic control in a subject with hepatic steatosis. In certain embodiments, dulaglutide may be used in combination with bempedoic acid for reducing the level of HbAlc in blood or serum of a subject with hepatic steatosis. In certain embodiments, dulaglutide may be used in combination with bempedoic acid for reducing the body weight of a subject with hepatic steatosis. In certain embodiments, dulaglutide may be used in combination with bempedoic acid for reducing the systolic and/or diastolic blood pressure of a subject with hepatic steatosis. In certain embodiments, dulaglutide may be used in combination with bempedoic acid for reducing liver fat in a subject with hepatic steatosis. In certain embodiments, dulaglutide may be used in combination with bempedoic acid for reducing hepatocellular ballooning in a subject with hepatic steatosis. In certain embodiments, dulaglutide may be used in combination with bempedoic acid for reducing lobular inflammation in a subject with hepatic steatosis.

Albislutide

[0125] In some embodiments of the present disclosure, the GLP-1 receptor agonist is albiglutide. Albiglutide may be represented by the structure of Formula (V):

[0126] Albiglutide and its methods of use and administration are disclosed in, for example, European Patent No. EP2373681B 1, which is incorporated herein by reference. Albiglutide may be administered as a parenteral dosage form. Albiglutide may also be referred to as GSK- 716155 and under the trade names Eperzan® and Tanzeum®.

[0127] In various embodiments, albiglutide may be administered to a subject in an amount of about 30 mg to about 50 mg, about 32 mg to about 50 mg, about 34 mg to about 50 mg, about 36 mg to about 50 mg, about 38 mg to about 50 mg, about 40 mg to about 50 mg, about 42 mg to about 50 mg, about 44 mg to about 50 mg, about 46 mg to about 50 mg, about 48 mg to about 50 mg, about 30 mg to about 48 mg, about 30 mg to about 46 mg, about 30 mg to about 44 mg, about 30 mg to about 42 mg, about 30 mg to about 40 mg, about 30 mg to about 38 mg, about 30 mg to about 36 mg, about 30 mg to about 34 mg, about 30 mg to about 32 mg, about 32 mg to about 48 mg, about 32 mg to about 46 mg, about 32 mg to about 44 mg, about 32 mg to about 42 mg, about 32 mg to about 40 mg, about 32 mg to about 38 mg, about 32 mg to about 36 mg, about 32 mg to about 34 mg, about 34 mg to about 48 mg, about 34 mg to about 46 mg, about 34 mg to about 44 mg, about 34 mg to about 42 mg, about 34 mg to about 40 mg, about 34 mg to about 38 mg, about 34 mg to about 36 mg, about 36 mg to about 48 mg, about 36 mg to about 46 mg, about 36 mg to about 44 mg, about 36 mg to about 42 mg, about 36 mg to about 40 mg, about 36 mg to about 38 mg, about 38 mg to about 48 mg, about 38 mg to about 46 mg, about 38 mg to about 44 mg, about 38 mg to about 42 mg, about 38 mg to about 40 mg, about 40 mg to about 48 mg, about 40 mg to about 46 mg, about 40 mg to about 44 mg, about 40 mg to about 42 mg, about 42 mg to about 48 mg, about 42 mg to about 46 mg, about 42 mg to about 44 mg, about 44 mg to about 48 mg, about 44 mg to about 46 mg, or about 46 mg to about 48 mg. In certain embodiments, albiglutide may be administered to a subject in an amount of about 30 mg to about 50 mg.

[0128] In certain embodiments, albiglutide may be administered to a subject in an amount of about 30 mg, about 32 mg, about 34 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 mg, or about 50 mg.

[0129] In various embodiments, albiglutide may be used for the treatment or prevention of a condition, disease, or disorder described herein. The methods of preventing or treating a disease or disorder generally comprise administering to a subject in need thereof a therapeutically effective amount of albiglutide to prevent or treat the disease or disorder.

[0130] In certain embodiments, albiglutide may be used for treating hepatic steatosis in a subject in need thereof. In certain embodiments, albiglutide may be used for treating liver fibrosis in a subject with hepatic steatosis. In certain embodiments, albiglutide may be used for modulating glycemic control in a subject with hepatic steatosis. In certain embodiments, albiglutide may be used for reducing the level of HbAlc in blood or serum of a subject with hepatic steatosis. In certain embodiments, albiglutide may be used for reducing the body weight of a subject with hepatic steatosis. In certain embodiments, albiglutide may be used for reducing the systolic and/or diastolic blood pressure of a subject with hepatic steatosis. In certain embodiments, albiglutide may be used for reducing liver fat in a subject with hepatic steatosis. In certain embodiments, albiglutide may be used for reducing hepatocellular ballooning in a subject with hepatic steatosis. In certain embodiments, albiglutide may be used for reducing lobular inflammation in a subject with hepatic steatosis.

[0131] In certain embodiments, albiglutide may be used in combination with bempedoic acid for treating hepatic steatosis in a subject in need thereof. In certain embodiments, albiglutide may be used in combination with bempedoic acid for treating liver fibrosis in a subject with hepatic steatosis. In certain embodiments, albiglutide may be used in combination with bempedoic acid for modulating glycemic control in a subject with hepatic steatosis. In certain embodiments, albiglutide may be used in combination with bempedoic acid for reducing the level of HbAlc in blood or serum of a subject with hepatic steatosis. In certain embodiments, albiglutide may be used in combination with bempedoic acid for reducing the body weight of a subject with hepatic steatosis. In certain embodiments, albiglutide may be used in combination with bempedoic acid for reducing the systolic and/or diastolic blood pressure of a subject with hepatic steatosis. In certain embodiments, albiglutide may be used in combination with bempedoic acid for reducing liver fat in a subject with hepatic steatosis. In certain embodiments, albiglutide may be used in combination with bempedoic acid for reducing hepatocellular ballooning in a subject with hepatic steatosis. In certain embodiments, albiglutide may be used in combination with bempedoic acid for reducing lobular inflammation in a subject with hepatic steatosis.

Lixisenatide

[0132] In various embodiments, the GLP-1 receptor agonist is lixisenatide. Lixisenatide may be represented by the structure of Formula (VI):

[0133] Lixisenatide and its methods of use and administration are disclosed in, for example, International Publication No. WO 2001/04156 Al, which is incorporated herein by reference. Lixisenatide may be administered as a parenteral dosage form. Lixisenatide may also be referred to under the trade names Lyxumia® and Adlyxin®.

[0134] In various embodiments, lixisenatide may be administered to a subject in an amount of about 10 mg to about 20 mg, about 11 mg to about 20 mg, about 12 mg to about 20 mg, about 13 mg to about 20 mg, about 14 mg to about 20 mg, about 15 mg to about 20 mg, about 16 mg to about 20 mg, about 17 mg to about 20 mg, about 18 mg to about 20 mg, about 19 mg to about 20 mg, about 10 mg to about 19 mg, about 10 mg to about 18 mg, about 10 mg to about 17 mg, about 10 mg to about 16 mg, about 10 mg to about 15 mg, about 10 mg to about 14 mg, about 10 mg to about 13 mg, about 10 mg to about 12 mg, about 10 mg to about 11 mg, about 11 mg to about 19 mg, about 11 mg to about 18 mg, about 11 mg to about 17 mg, about 11 mg to about 16 mg, about 11 mg to about 15 mg, about 11 mg to about 14 mg, about 11 mg to about 13 mg, about 11 mg to about 12 mg, about 12 mg to about 19 mg, about 12 mg to about 18 mg, about 12 mg to about 17 mg, about 12 mg to about 16 mg, about 12 mg to about 15 mg, about 12 mg to about 14 mg, about 12 mg to about 13 mg, about 13 mg to about 19 mg, about 13 mg to about 18 mg, about 13 mg to about 17 mg, about 13 mg to about 16 mg, about 13 mg to about 15 mg, about 13 mg to about 14 mg, about 14 mg to about 19 mg, about 14 mg to about 18 mg, about 14 mg to about 17 mg, about 14 mg to about 16 mg, about 14 mg to about 15 mg, about 15 mg to about 19 mg, about 15 mg to about 18 mg, about 15 mg to about 17 mg, about 15 mg to about 16 mg, about 16 mg to about 19 mg, about 16 mg to about 18 mg, about 16 mg to about 17 mg, about 17 mg to about 19 mg, about 17 mg to about 18 mg, or about 18 mg to about 19 mg. In certain embodiments, lixisenatide may be administered to a subject in an amount of about 10 mg to about 20 mg. [0135] In certain embodiments, lixisenatide may administered to a subject in an amount of about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg.

[0136] In various embodiments, lixisenatide may be used for the treatment or prevention of a condition, disease, or disorder described herein. The methods of preventing or treating a disease or disorder generally comprise administering to a subject in need thereof a therapeutically effective amount of lixisenatide to prevent or treat the disease or disorder.

[0137] In certain embodiments, lixisenatide may be used for treating hepatic steatosis in a subject in need thereof. In certain embodiments, lixisenatide may be used for treating liver fibrosis in a subject with hepatic steatosis. In certain embodiments, lixisenatide may be used for modulating glycemic control in a subject with hepatic steatosis. In certain embodiments, lixisenatide may be used for reducing the level of HbAlc in blood or serum of a subject with hepatic steatosis. In certain embodiments, lixisenatide may be used for reducing the body weight of a subject with hepatic steatosis. In certain embodiments, lixisenatide may be used for reducing the systolic and/or diastolic blood pressure of a subject with hepatic steatosis. In certain embodiments, lixisenatide may be used for reducing liver fat in a subject with hepatic steatosis. In certain embodiments, lixisenatide may be used for reducing hepatocellular ballooning in a subject with hepatic steatosis. In certain embodiments, lixisenatide may be used for reducing lobular inflammation in a subject with hepatic steatosis.

[0138] In certain embodiments, lixisenatide may be used in combination with bempedoic acid for treating hepatic steatosis in a subject in need thereof. In certain embodiments, lixisenatide may be used in combination with bempedoic acid for treating liver fibrosis in a subject with hepatic steatosis. In certain embodiments, lixisenatide may be used in combination with bempedoic acid for modulating glycemic control in a subject with hepatic steatosis. In certain embodiments, lixisenatide may he used in combination with bempedoic acid for reducing the level of HbAlc in blood or serum of a subject with hepatic steatosis. In certain embodiments, lixisenatide may be used in combination with bempedoic acid for reducing the body weight of a subject with hepatic steatosis. In certain embodiments, lixisenatide may be used in combination with bempedoic acid for reducing the systolic and/or diastolic blood pressure of a subject with hepatic steatosis. In certain embodiments, lixisenatide may be used in combination with bempedoic acid for reducing liver fat in a subject with hepatic steatosis. In certain embodiments, lixisenatide may be used in combination with bempedoic acid for reducing hepatocellular ballooning in a subject with hepatic steatosis. In certain embodiments, lixisenatide may be used in combination with bempedoic acid for reducing lobular inflammation in a subject with hepatic steatosis.

Fixed-Dose Combinations

[0139] In one aspect, disclosed herein are fixed-dose combinations generally comprising bempedoic acid and a GLP-1 receptor agonist. In various embodiments, a fixed-dose combination described herein is a solid dosage form comprising bempedoic acid and the GLP- 1 receptor agonist.

[0140] In various embodiments, a fixed-dose combination described herein is a solid dosage form comprising a pharmaceutical composition comprising bempedoic acid and semaglutide described herein.

[0141] In certain embodiments, the GLP-1 receptor agonist is semaglutide.

[0142] In various embodiments, provided herein is a fixed-dose combination comprising bempedoic acid and semaglutide.

[0143] In various embodiments, a fixed-dose combination described herein is a solid dosage form comprising bempedoic acid and semaglutide.

[0144] In certain embodiments, the fixed-dose combination comprises about 30 mg to about 300 mg, about 60 mg to about 300 mg, about 90 mg to about 300 mg, about 120 mg to about 300 mg, about 150 mg to about 300 mg, about 180 mg to about 300 mg, about 210 mg to about 300 mg, about 240 mg to about 300 mg, about 270 mg to about 300 mg, about 30 mg to about 270 mg, about 30 mg to about 240 mg, about 30 mg to about 210 mg, about 30 mg to about 180 mg, about 30 mg to about 150 mg, about 30 mg to about 120 mg, about 30 mg to about 90 mg, about 30 mg to about 60 mg, about 60 mg to about 270 mg, about 60 mg to about 240 mg, about 60 mg to about 210 mg, about 60 mg to about 180 mg, about 60 mg to about 150 mg, about 60 mg to about 120 mg, about 60 mg to about 90 mg, about 90 mg to about 270 mg, about 90 mg to about 240 mg, about 90 mg to about 210 mg, about 90 mg to about 180 mg, about 90 mg to about 150 mg, about 90 mg to about 120 mg, about 120 mg to about 270 mg, about 120 mg to about 240 mg, about 120 mg to about 210 mg, about 120 mg to about 180 mg, about 120 mg to about 150 mg, about 150 mg to about 270 mg, about 150 mg to about 240 mg, about 150 mg to about 210 mg, about 150 mg to about 180 mg, about 180 mg to about 270 mg, about 180 mg to about 240 mg, about 180 mg to about 210 mg, about 210 mg to about 270 mg, about 210 mg to about 240 mg, or about 240 mg to about 270 mg bempedoic acid. In certain embodiments, the fixed-dose combination comprises about 120 mg to about 240 mg bempedoic acid. [0145] In certain embodiments, the fixed-dose combination comprises about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, or about 300 mg bempedoic acid, In certain embodiments, the fixed-dose combination comprises about 120 mg bempedoic acid, In certain embodiments, the fixed-dose combination comprises about 180 mg bempedoic acid, In certain embodiments, the fixed-dose combination comprises about 240 mg bempedoic acid.

[0146] In certain embodiments, the fixed-dose combination comprises about 1 mg to about 30 mg, about 2 mg to about 30 mg, about 3 mg to about 30 mg, about 4 mg to about 30 mg, about 6 mg to about 30 mg, about 8 mg to about 30 mg, about 10 mg to about 30 mg, about 12 mg to about 30 mg, about 14 mg to about 30 mg, about 16 mg to about 30 mg, about 20 mg to about 30 mg, about 25 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 1 mg to about 16 mg, about 1 mg to about 14 mg, about 1 mg to about 12 mg, about 1 mg to about 10 mg, about 1 mg to about 8 mg, about 1 mg to about 6 mg, about 1 mg to about 4 mg, about 1 mg to about 3 mg, about 1 mg to about 2 mg, about 2 mg to about 25 mg, about 2 mg to about 20 mg, about 2 mg to about 16 mg, about 2 mg to about 14 mg, about 2 mg to about 12 mg, about 2 mg to about 10 mg, about 2 mg to about 8 mg, about 2 mg to about 6 mg, about 2 mg to about 4 mg, about 2 mg to about 3 mg, about 3 mg to about 25 mg, about 3 mg to about 20 mg, about 3 mg to about 16 mg, about 3 mg to about 14 mg, about 3 mg to about 12 mg, about 3 mg to about 10 mg, about 3 mg to about 8 mg, about 3 mg to about 6 mg, about 3 mg to about 4 mg, about 4 mg to about 25 mg, about 4 mg to about 20 mg, about 4 mg to about 16 mg, about 4 mg to about 14 mg, about 4 mg to about 12 mg, about 4 mg to about 10 mg, about 4 mg to about 8 mg, about 4 mg to about 6 mg, about 6 mg to about 25 mg, about 6 mg to about 20 mg, about 6 mg to about 16 mg, about 6 mg to about 14 mg, about 6 mg to about 12 mg, about 6 mg to about 10 mg, about 6 mg to about 8 mg, about 8 mg to about 25 mg, about 8 mg to about 20 mg, about 8 mg to about 16 mg, about 8 mg to about 14 mg, about 8 mg to about 12 mg, about 8 mg to about 10 mg, about 10 mg to about 25 mg, about 10 mg to about 20 mg, about 10 mg to about 16 mg, about 10 mg to about 14 mg, about 10 mg to about 12 mg, about 12 mg to about 25 mg, about 12 mg to about 20 mg, about 12 mg to about 16 mg, about 12 mg to about 14 mg, about 14 mg to about 25 mg, about 14 mg to about 20 mg, about 14 mg to about 16 mg, about 16 mg to about 25 mg, about 16 mg to about 20 mg, or about 20 mg to about 25 mg semaglutide. In certain embodiments, the fixed-dose combination comprises about 3 mg to about 14 mg semaglutide.

[0147] In some embodiments, the fixed-dose combination comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, or about 30 mg semaglutide. In certain embodiments, the fixed dose combination comprises about 3 mg semaglutide. In certain embodiments, the fixed-dose combination comprises about 7 mg semaglutide. In certain embodiments, the fixed-dose combination comprises about 14 mg semaglutide.

[0148] In various embodiments, a fixed-dose combination comprises about 120 mg to about 240 mg bempedoic acid and about 3 mg to about 14 mg semaglutide.

[0149] In certain embodiments, a fixed-dose combination described herein comprises about 180 mg bempedoic acid and about 3 mg semaglutide. In certain embodiments, a fixed-dose combination described herein comprises about 180 mg bempedoic acid and about 7 mg semaglutide. In certain embodiments, a fixed-dose combination described herein comprises comprising about 180 mg bempedoic acid and about 14 mg semaglutide.

[0150] In some embodiments, the fixed-dose combinations disclosed herein are formulated for oral delivery. In some embodiments, the fixed-dose combinations disclosed herein are formulated as an oral dosage form. Examples of oral dosage forms include, but are not limited to a drench, a tablet, a capsule, a softgel capsule, a cachet, a pill, an emulsion, a lozenge, a solution, a suspension, a bolus, a powder, an elixir or syrup, a pastille, a mouthwash, a granule, or a paste for application to the tongue. In some embodiments, the fixed-dose combination is formulated as a tablet.

[0151] In various embodiments, the fixed-dose combinations described herein may be used for the treatment or prevention of a condition, disease, or disorder described herein. The methods of preventing or treating a disease or disorder generally comprise administering to a subject in need thereof a fixed-dose combination described herein comprising therapeutically effective amounts of bempedoic acid and the GLP-1 receptor agonist (e.g., semaglutide) to prevent or treat the disease or disorder.

[0152] In certain embodiments, the fixed-dose combinations described herein may be used for treating hepatic steatosis in a subject in need thereof. In certain embodiments, the fixed-dose combinations described herein may be used for treating liver fibrosis in a subject with hepatic steatosis. In certain embodiments, the fixed-dose combinations described herein may be used for modulating glycemic control in a subject with hepatic steatosis. In certain embodiments, the fixed-dose combinations described herein may be used for reducing the level of HbAlc in blood or serum of a subject with hepatic steatosis. In certain embodiments, the fixed-dose combinations described herein may be used for reducing the body weight of a subject with hepatic steatosis. In certain embodiments, the fixed-dose combinations described herein may be used for reducing the systolic and/or diastolic blood pressure of a subject with hepatic steatosis. In certain embodiments, the fixed-dose combinations described herein may be used for reducing liver fat in a subject with hepatic steatosis. In certain embodiments, the fixed-dose combinations described herein may be used for reducing hepatocellular ballooning in a subject with hepatic steatosis. In certain embodiments, the fixed-dose combinations described herein may be used for reducing lobular inflammation in a subject with hepatic steatosis.

Pharmaceutical Compositions

( 1 ) Bempedoic Acid

[0153] In one aspect, provided herein are pharmaceutical compositions generally comprising bempedoic acid, and one or more pharmaceutically acceptable excipients.

[0154] In certain embodiments, the one or more pharmaceutically acceptable excipients is selected from the group consisting of colloidal silicon dioxide, a hydroxyl propyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, and combinations thereof.

[0155] In various embodiments, provided herein is a pharmaceutical formulation comprising bempedoic acid, colloidal silicon dioxide, hydroxyl propyl cellulose, lactose monohydrate, magnesium stearate, microcrystal] ine cellulose, and sodium starch glycolate.

[0156] In certain embodiments, the amount of bempedoic acid in the pharmaceutical formulation is about 45% (w/w) to about 55% (w/w). In certain embodiments, the amount of bempedoic acid in the pharmaceutical formulation is about 45% (w/w), about 46% (w/w), about 47% (w/w), about 48% (w/w), about 49% (w/w), about 50% (w/w), about 51% (w/w), about 52% (w/w), about 53% (w/w), about 54% (w/w), or about 55% (w/w). In certain embodiments, the amount of bempedoic acid in the pharmaceutical formulation is about 47% (w/w). In certain embodiments, the amount of bempedoic acid in the pharmaceutical formulation is about 48% (w/w). In certain embodiments, the amount of bempedoic acid in the pharmaceutical formulation is about 49% (w/w). In certain embodiments, the amount of bempedoic acid in the pharmaceutical formulation is about 50% (w/w). In certain embodiments, the amount of bempedoic acid in the pharmaceutical formulation is about 51% (w/w). In certain embodiments, the amount of bempedoic acid in the pharmaceutical formulation is about 52% (w/w).

[0157] In certain embodiments, the amount of bempedoic acid in the pharmaceutical formulation is about 180 mg. In certain embodiments, the amount of bempedoic acid in the pharmaceutical formulation is 180 mg.

[0158] In certain embodiments, the amount of colloidal silicon dioxide in the pharmaceutical formulation is about 1% (w/w) to about 2% (w/w). In certain embodiments, the amount of colloidal silicon dioxide in the pharmaceutical formulation is about 1% (w/w), about 1.1% (w/w), about 1.2% (w/w), about 1.3% (w/w), about 1.4% (w/w), about 1.5% (w/w), about 1.6% (w/w), about 1.7% (w/w), about 1.8% (w/w), about 1.9% (w/w), or about 2% (w/w). In certain embodiments, the amount of colloidal silicon dioxide in the pharmaceutical formulation is about 1% (w/w). In certain embodiments, the amount of colloidal silicon dioxide in the pharmaceutical formulation is about 1.1% (w/w). In certain embodiments, the amount of colloidal silicon dioxide in the pharmaceutical formulation is about 1.2% (w/w). In certain embodiments, the amount of colloidal silicon dioxide in the pharmaceutical formulation is about 1.3% (w/w). In certain embodiments, the amount of colloidal silicon dioxide in the pharmaceutical formulation is about 1.4% (w/w). In certain embodiments, the amount of colloidal silicon dioxide in the pharmaceutical formulation is about 1.5% (w/w).

[0159] In certain embodiments, the amount of colloidal silicon dioxide in the pharmaceutical formulation is about 3 mg to about 6 mg. In certain embodiments, the amount of colloidal silicon dioxide in the pharmaceutical formulation is about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, or about 6 mg. In certain embodiments, the amount of colloidal silicon dioxide in the pharmaceutical formulation is about 3 mg. In certain embodiments, the amount of colloidal silicon dioxide in the pharmaceutical formulation is about

3.5 mg. In certain embodiments, the amount of colloidal silicon dioxide in the pharmaceutical formulation is about 4 mg. In certain embodiments, the amount of colloidal silicon dioxide in the pharmaceutical formulation is about 4.5 mg. In certain embodiments, the amount of colloidal silicon dioxide in the pharmaceutical formulation is about 5 mg. In certain embodiments, the amount of colloidal silicon dioxide in the pharmaceutical formulation is about

5.5 mg. In certain embodiments, the amount of colloidal silicon dioxide in the pharmaceutical formulation is about 6 mg. [0160] In certain embodiments, the amount of the hydroxyl propyl cellulose in the pharmaceutical formulation is about 3% (w/w) to about 5% (w/w). In certain embodiments, the amount of the hydroxyl propyl cellulose in the pharmaceutical formulation is about 3% (w/w), about 3.1% (w/w), about 3.2% (w/w), about 3.3% (w/w), about 3.4% (w/w), about 3.5% (w/w), about 3.6% (w/w), about 3.7% (w/w), about 3.8% (w/w), about 3.9% (w/w), about 4% (w/w), about 4.1% (w/w), about 4.2% (w/w), about 4.3% (w/w), about 4.4% (w/w), about 4.5% (w/w), about 4.6% (w/w), about 4.7% (w/w), about 4.8% (w/w), about 4.9% (w/w), or about 5% (w/w). In certain embodiments, the amount of the hydroxyl propyl cellulose in the pharmaceutical formulation is about 4.6% (w/w). In certain embodiments, the amount of the hydroxyl propyl cellulose in the pharmaceutical formulation is about 4.7% (w/w). In certain embodiments, the amount of the hydroxyl propyl cellulose in the pharmaceutical formulation is about 4.8% (w/w). In certain embodiments, the amount of the hydroxyl propyl cellulose in the pharmaceutical formulation is about 4.9% (w/w). In certain embodiments, the amount of the hydroxyl propyl cellulose in the pharmaceutical formulation is about 5.0% (w/w).

[0161] In certain embodiments, the amount of the hydroxyl propyl cellulose in the pharmaceutical formulation is about 10 mg to about 20 mg. In certain embodiments, the amount of the hydroxyl propyl cellulose in the pharmaceutical formulation is about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg. In certain embodiments, the amount of the hydroxyl propyl cellulose in the pharmaceutical formulation is about 10 mg. In certain embodiments, the amount of the hydroxyl propyl cellulose in the pharmaceutical formulation is about 11 mg. In certain embodiments, the amount of the hydroxyl propyl cellulose in the pharmaceutical formulation is about 12 mg. In certain embodiments, the amount of the hydroxyl propyl cellulose in the pharmaceutical formulation is about 13 mg. In certain embodiments, the amount of the hydroxy] propyl cellulose in the pharmaceutical formulation is about 14 mg. In certain embodiments, the amount of the hydroxyl propyl cellulose in the pharmaceutical formulation is about 15 mg. In certain embodiments, the amount of the hydroxyl propyl cellulose in the pharmaceutical formulation is about 16 mg.

[0162] In certain embodiments, the amount of lactose monohydrate in the pharmaceutical formulation is about 8% (w/w) to about 20% (w/w). In certain embodiments, the amount of lactose monohydrate in the pharmaceutical formulation is about 8% (w/w), about 9% (w/w), about 10% (w/w), about 11% (w/w), about 12% (w/w), about 13% (w/w), about 14% (w/w), about 15% (w/w), about 16% (w/w), about 17% (w/w), about 18% (w/w), about 19% (w/w), or about 20% (w/w). In certain embodiments, the amount of lactose monohydrate in the pharmaceutical formulation is about 8% (w/w). In certain embodiments, the amount of lactose monohydrate in the pharmaceutical formulation is about 9% (w/w). In certain embodiments, the amount of lactose monohydrate in the pharmaceutical formulation is about 10% (w/w). In certain embodiments, the amount of lactose monohydrate in the pharmaceutical formulation is about 11 % (w/w). In certain embodiments, the amount of lactose monohydrate in the pharmaceutical formulation is about 17% (w/w). In certain embodiments, the amount of lactose monohydrate in the pharmaceutical formulation is about 18% (w/w). In certain embodiments, the amount of lactose monohydrate in the pharmaceutical formulation is about 19% (w/w). In certain embodiments, the amount of lactose monohydrate in the pharmaceutical formulation is about 20% (w/w).

[0163] In certain embodiments, the amount of lactose monohydrate in the pharmaceutical formulation is about 20 mg to about 50 mg. In certain embodiments, the amount of lactose monohydrate in the pharmaceutical formulation is about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg. In certain embodiments, the amount of lactose monohydrate in the pharmaceutical formulation is about 20 mg. In certain embodiments, the amount of lactose monohydrate in the pharmaceutical formulation is about 25 mg. In certain embodiments, the amount of lactose monohydrate in the pharmaceutical formulation is about 30 mg. In certain embodiments, the amount of lactose monohydrate in the pharmaceutical formulation is about 35 mg.

[0164] In certain embodiments, the amount of magnesium stearate in the pharmaceutical formulation is about 1% (w/w) to about 3% (w/w). In certain embodiments, the amount of magnesium stearate in the pharmaceutical formulation is about 1% (w/w), about 1.1% (w/w), about 1.2% (w/w), about 1.3% (w/w), about 1.4% (w/w), about 1.5% (w/w), about 1.6% (w/w), about 1 .7% (w/w), about 1.8% (w/w), about 1 .9% (w/w), about 2% (w/w), about 2.1 % (w/w), about 2.2% (w/w), about 2.3% (w/w), about 2.4% (w/w), about 2.5% (w/w), about 2.6% (w/w), about 2.7% (w/w), about 2.8% (w/w), about 2.9% (w/w), or about 3% (w/w). In certain embodiments, the amount of magnesium stearate in the pharmaceutical formulation is about 2.7% (w/w). In certain embodiments, the amount of magnesium stearate in the pharmaceutical formulation is about 2.8% (w/w). In certain embodiments, the amount of magnesium stearate in the pharmaceutical formulation is about 2.9% (w/w). In certain embodiments, the amount of magnesium stearate in the pharmaceutical formulation is about 3% (w/w). [0165] In certain embodiments, the amount of the magnesium stearate in the pharmaceutical formulation is about 2 mg to about 10 mg. In certain embodiments, the amount of the magnesium stearate in the pharmaceutical formulation is about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg. In certain embodiments, the amount of the magnesium stearate in the pharmaceutical formulation is about 5 mg. In certain embodiments, the amount of the magnesium stearate in the pharmaceutical formulation is about 6 mg. In certain embodiments, the amount of the magnesium stearate in the pharmaceutical formulation is about 7 mg. In certain embodiments, the amount of the magnesium stearate in the pharmaceutical formulation is about 8 mg. In certain embodiments, the amount of the magnesium stearate in the pharmaceutical formulation is about 9 mg.

[0166] In certain embodiments, the amount of the microcrystalline cellulose in the pharmaceutical formulation is about 15% (w/w) to about 20% (w/w). In certain embodiments, the amount of the microcrystalline cellulose in the pharmaceutical formulation is about 15% (w/w), about 16% (w/w), about 17% (w/w), about 18% (w/w), about 19% (w/w), or about 20% (w/w). In certain embodiments, the amount of the microcrystalline cellulose in the pharmaceutical formulation is about 17% (w/w). In certain embodiments, the amount of the microcrystalline cellulose in the pharmaceutical formulation is about 18% (w/w). In certain embodiments, the amount of the microcrystalline cellulose in the pharmaceutical formulation is about 19% (w/w). In certain embodiments, the amount of the microcrystalline cellulose in the pharmaceutical formulation is about 20% (w/w).

[0167] In certain embodiments, the amount of the microcrystalline cellulose in the pharmaceutical formulation is about 55 mg to about 65 mg. In certain embodiments, the amount of the microcrystalline cellulose in the pharmaceutical formulation is about 55 mg, about 55.5 mg, about 56 mg, about 56.5 mg, about 57 mg, about 57.5 mg, about 58 mg, about 58.5 mg, about 59 mg, about 59.5 mg, about 60 mg, about 60.5 mg, about 61 mg, about 61 .5 mg, about 62 mg, about 62.5 mg, about 63 mg, about 63.5 mg, about 64 mg, about 64.5 mg, or about 65 mg. In certain embodiments, the amount of the microcrystalline cellulose in the pharmaceutical formulation is about 62 mg. In certain embodiments, the amount of the microcrystalline cellulose in the pharmaceutical formulation is about 62.5 mg. In certain embodiments, the amount of the microcrystalline cellulose in the pharmaceutical formulation is about 63 mg. In certain embodiments, the amount of the microcrystalline cellulose in the pharmaceutical formulation is about 63.5 mg. In certain embodiments, the amount of the microcrystalline cellulose in the pharmaceutical formulation is about 64 mg. In certain embodiments, the amount of the microcrystalline cellulose in the pharmaceutical formulation is about 64.5 mg. In certain embodiments, the amount of the microcrystalline cellulose in the pharmaceutical formulation is about 65 mg.

[0168] In certain embodiments, the amount of sodium starch glycolate in the pharmaceutical formulation is about 6.5% (w/w) to about 7.5% (w/w). In certain embodiments, the amount of sodium starch glycolate in the pharmaceutical formulation is about 6.5% (w/w), about 6.6% (w/w), about 6.7% (w/w), about 6.8% (w/w), about 6.9% (w/w), about 7% (w/w), about 7.1% (w/w), about 7.2% (w/w), about 7.3% (w/w), about 7.4% (w/w), or about 7.5% (w/w). In certain embodiments, the amount of sodium starch glycolate in the pharmaceutical formulation is about 6.8% (w/w). In certain embodiments, the amount of sodium starch glycolate in the pharmaceutical formulation is about 6.9% (w/w). In certain embodiments, the amount of sodium starch glycolate in the pharmaceutical formulation is about 7% (w/w). In certain embodiments, the amount of sodium starch glycolate in the pharmaceutical formulation is about 7.1% (w/w). In certain embodiments, the amount of sodium starch glycolate in the pharmaceutical formulation is about 7.2% (w/w). In certain embodiments, the amount of sodium starch glycolate in the pharmaceutical formulation is about 7.3% (w/w).

[0169] In certain embodiments, the amount of sodium starch glycolate in the pharmaceutical formulation is about 20 mg to about 30 mg. In certain embodiments, the amount of sodium starch glycolate in the pharmaceutical formulation is about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, or about 30 mg. In certain embodiments, the amount of sodium starch glycolate in the pharmaceutical formulation is about 22 mg. In certain embodiments, the amount of sodium starch glycolate in the pharmaceutical formulation is about 23 mg. In certain embodiments, the amount of sodium starch glycolate in the pharmaceutical formulation is about 24 mg. In certain embodiments, the amount of sodium starch glycolate in the pharmaceutical formulation is about 25 mg. In certain embodiments, the amount of sodium starch glycolate in the pharmaceutical formulation is about 26 mg. In certain embodiments, the amount of sodium starch glycolate in the pharmaceutical formulation is about 27 mg.

[0170] In various embodiments, provided herein is a pharmaceutical formulation comprising

(i) about 45% (w/w) to about 55% (w/w) bempedoic acid;

(ii) about 1% (w/w) to about 2% (w/w) colloidal silicon dioxide;

(iii) about 3% (w/w) to about 5% (w/w) of a hydroxy propyl cellulose;

(iv) about 8% (w/w) to about 20% (w/w) lactose monohydrate; (v) about 1% (w/w) to about 3% (w/w) magnesium stearate;

(vi) about 15% (w/w) to about 20% (w/w) a microcrystalline cellulose; and

(vii) about 6.5% (w/w) to about 7.5% (w/w) sodium starch glycolate.

[0171] In various embodiments, provided herein is a pharmaceutical formulation comprising

(1) 180 mg bempedoic acid;

(ii) about 3 mg to about 6 mg colloidal silicon dioxide;

(iii) about 10 mg to about 20 mg of a hydroxy propyl cellulose;

(iv) about 20 mg to about 80 mg lactose monohydrate;

(v) about 2 mg to about 10 mg magnesium stearate;

(vi) about 55 mg to about 65 mg a microcrystalline cellulose; and

(vii) about 20 mg to about 30 mg sodium starch glycolate.

[0172] In certain embodiments, the pharmaceutical formulation further comprises a coating. In certain embodiments, the coating comprises Opadry White 85F18422. In certain embodiments, the coating comprises Opadry AMB II Blue.

[0173] In certain embodiments, the pharmaceutical compositions comprising bempedoic acid described herein are formulated for oral delivery. In certain embodiments, the pharmaceutical compositions comprising bempedoic acid are formulated as a tablet.

(2) Bempedoic Acid and Semaglutide

[0174] In another aspect, provided herein are pharmaceutical compositions generally comprising bempedoic acid, semaglutide, and one or more pharmaceutically acceptable excipients.

[0175] In certain embodiments, the pharmaceutical composition comprises about 30 mg to about 300 mg, about 60 mg to about 300 mg, about 90 mg to about 300 mg, about 120 mg to about 300 mg, about 150 mg to about 300 mg, about 180 mg to about 300 mg, about 210 mg to about 300 mg, about 240 mg to about 300 mg, about 270 mg to about 300 mg, about 30 mg to about 270 mg, about 30 mg to about 240 mg, about 30 mg to about 210 mg, about 30 mg to about 180 mg, about 30 mg to about 150 mg, about 30 mg to about 120 mg, about 30 mg to about 90 mg, about 30 mg to about 60 mg, about 60 mg to about 270 mg, about 60 mg to about 240 mg, about 60 mg to about 210 mg, about 60 mg to about 180 mg, about 60 mg to about 150 mg, about 60 mg to about 120 mg, about 60 mg to about 90 mg, about 90 mg to about 270 mg, about 90 mg to about 240 mg, about 90 mg to about 210 mg, about 90 mg to about 180 mg, about 90 mg to about 150 mg, about 90 mg to about 120 mg, about 120 mg to about 270 mg, about 120 mg to about 240 mg, about 120 mg to about 210 mg, about 120 mg to about 180 mg, about 120 mg to about 150 mg, about 150 mg to about 270 mg, about 150 mg to about 240 mg, about 150 mg to about 210 mg, about 150 mg to about 180 mg, about 180 mg to about 270 mg, about 180 mg to about 240 mg, about 180 mg to about 210 mg, about 210 mg to about 270 mg, about 210 mg to about 240 mg, or about 240 mg to about 270 mg bempedoic acid. In certain embodiments, the pharmaceutical composition comprises about 120 mg to about 240 mg bempedoic acid.

[0176] In certain embodiments, the pharmaceutical composition comprises about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 1 10 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, or about 300 mg bempedoic acid. In certain embodiments, the pharmaceutical composition comprises about 180 mg bempedoic acid.

[0177] In certain embodiments, the pharmaceutical composition comprises about 1 mg to about 30 mg, about 2 mg to about 30 mg, about 3 mg to about 30 mg, about 4 mg to about 30 mg, about 6 mg to about 30 mg, about 8 mg to about 30 mg, about 10 mg to about 30 mg, about 12 mg to about 30 mg, about 14 mg to about 30 mg, about 16 mg to about 30 mg, about 20 mg to about 30 mg, about 25 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 1 mg to about 16 mg, about 1 mg to about 14 mg, about 1 mg to about 12 mg, about 1 mg to about 10 mg, about 1 mg to about 8 mg, about 1 mg to about 6 mg, about 1 mg to about 4 mg, about 1 mg to about 3 mg, about 1 mg to about 2 mg, about 2 mg to about 25 mg, about 2 mg to about 20 mg, about 2 mg to about 16 mg, about 2 mg to about 14 mg, about 2 mg to about 12 mg, about 2 mg to about 10 mg, about 2 mg to about 8 mg, about 2 mg to about 6 mg, about 2 mg to about 4 mg, about 2 mg to about 3 mg, about 3 mg to about 25 mg, about 3 mg to about 20 mg, about 3 mg to about 16 mg, about 3 mg to about 14 mg, about 3 mg to about 12 mg, about 3 mg to about 10 mg, about 3 mg to about 8 mg, about 3 mg to about 6 mg, about 3 mg to about 4 mg, about 4 mg to about 25 mg, about 4 mg to about 20 mg, about 4 mg to about 16 mg, about 4 mg to about 14 mg, about 4 mg to about 12 mg, about 4 mg to about 10 mg, about 4 mg to about 8 mg, about 4 mg to about 6 mg, about 6 mg to about 25 mg, about 6 mg to about 20 mg, about 6 mg to about 16 mg, about 6 mg to about 14 mg, about 6 mg to about 12 mg, about 6 mg to about 10 mg, about 6 mg to about 8 mg, about 8 mg to about 25 mg, about 8 mg to about 20 mg, about 8 mg to about 16 mg, about 8 mg to about 14 mg, about 8 mg to about 12 mg, about 8 mg to about 10 mg, about 10 mg to about 25 mg, about 10 mg to about 20 mg, about 10 mg to about 16 mg, about 10 mg to about 14 mg, about 10 mg to about 12 mg, about 12 mg to about 25 mg, about 12 mg to about 20 mg, about 12 mg to about 16 mg, about 12 mg to about 14 mg, about 14 mg to about 25 mg, about 14 mg to about 20 mg, about 14 mg to about 16 mg, about 16 mg to about 25 mg, about 16 mg to about 20 mg, or about 20 mg to about 25 mg semaglutide. In certain embodiments, the fixed-dose combination comprises about 3 mg to about 14 mg semaglutide.

[0178] In certain embodiments, the pharmaceutical composition comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, or about 30 mg semaglutide. In certain embodiments, the pharmaceutical composition comprises about 3 mg semaglutide. In certain embodiments, the pharmaceutical composition comprises about 7 mg semaglutide. In certain embodiments, the pharmaceutical composition comprises about 14 mg semaglutide.

[0179] In various embodiments, provided herein is a pharmaceutical composition comprising about 120 mg to about 240 mg bempedoic acid, about 3 mg to about 14 mg semaglutide, and one or more pharmaceutically acceptable excipients.

[0180] In various embodiments, provided herein is a pharmaceutical composition comprising about 180 mg bempedoic acid, about 3 mg semaglutide, and one or more pharmaceutically acceptable excipients.

[0181] In various embodiments, provided herein is a pharmaceutical composition comprising about 180 mg bempedoic acid, about 7 mg semaglutide, and one or more pharmaceutically acceptable excipients.

[0182] In various embodiments, provided herein is a pharmaceutical composition comprising about 180 mg bempedoic acid, about 14 mg semaglutide, and one or more pharmaceutically acceptable excipients.

[0183] The amounts of the compounds of bempedoic acid and semaglutide present in a pharmaceutical composition described herein may vary depending upon the subject being treated and/or the particular mode of administration.

[0184] In certain embodiments, the amounts of bempedoic acid and semaglutide that can be combined with a pharmaceutically acceptable excipient to produce a pharmaceutical composition described herein will generally be amounts of bempedoic acid and semaglutide that produce a therapeutic effect. [0185] Pharmaceutically acceptable excipients contemplated to be useful in the preparation of pharmaceutical compositions comprising bempedoic acid and semaglutide include, but are not limited to, a filler or extender, a sweetening agent, a binder, a humectant, a disintegrating agent, a preservative, a perfuming agent, a flavoring agent, an antioxidant, a solution retarding agent, an absorption accelerator, a wetting agent, an absorbent, a lubricant, a coloring agent, and a controlled release agent. In some embodiments, the pharmaceutical compositions may comprise a buffering agent. In some embodiments, the pharmaceutical compositions may comprise one or more excipients selected from lactose, a milk sugar, a high molecular weight polyethylene glycol and combinations thereof.

[0186] In certain embodiments, a pharmaceutical composition comprising bempedoic acid and semaglutide described herein may further comprise one or more pharmaceutically acceptable excipients selected from the group consisting of a cyclodextrin, a cellulose, a liposome, a micelle forming agent, and a polymeric carrier. In some embodiments, the pharmaceutical compositions may comprise an antibacterial agent, an antifungal agent, or combinations thereof. Examples of antibacterial and antifungal agents include, but are not limited to, paraben, chlorobutanol, phenol and sorbic acid. In some embodiments, the pharmaceutical compositions may comprise an isotonic agent.

[0187] In some embodiments, the pharmaceutical compositions comprising bempedoic acid and semaglutide described herein are formulated for oral delivery. In some embodiments, the pharmaceutical compositions are formulated as an oral dosage form. In some embodiments, the pharmaceutical compositions are formulated as a tablet.

( 3 ) Dosage Forms

[0188] In another aspect, provided herein are solid dosage forms comprising a pharmaceutical formulation described herein. In certain embodiments, the solid dosage forms described herein may be used for oral administration. In certain embodiments, the solid dosage form is a tablet. In certain embodiments, the solid dosage form is a capsule.

[0189] In various embodiments, the pharmaceutical formulations described herein are formulated as an oral dosage form. Examples of oral dosage forms include, but are not limited to a drench, a tablet, a capsule, a softgel capsule, a cachet, a pill, an emulsion, a lozenge, a solution, a suspension, a bolus, a powder, an elixir or syrup, a pastille, a mouthwash, a granule, or a paste for application to the tongue. In some embodiments, the pharmaceutical formulation is formulated as a tablet. (4) Uses

[0190] In certain embodiments, the pharmaceutical compositions described herein may be used for treating hepatic steatosis in a subject in need thereof. In certain embodiments, the pharmaceutical compositions described herein may be used for treating liver fibrosis in a subject with hepatic steatosis. In certain embodiments, the pharmaceutical compositions described herein may be used for modulating glycemic control in a subject with hepatic steatosis. In certain embodiments, the pharmaceutical compositions described herein may be used for reducing the level of HbAlc in blood or serum of a subject with hepatic steatosis. In certain embodiments, the pharmaceutical compositions described herein may be used for reducing the body weight of a subject with hepatic steatosis. In certain embodiments, the pharmaceutical compositions described herein may be used for reducing the systolic and/or diastolic blood pressure of a subject with hepatic steatosis. In certain embodiments, the pharmaceutical compositions described herein may be used for reducing liver fat in a subject with hepatic steatosis. In certain embodiments, the pharmaceutical compositions described herein may be used for reducing hepatocellular ballooning in a subject with hepatic steatosis. In certain embodiments, the pharmaceutical compositions described herein may be used for reducing lobular inflammation in a subject with hepatic steatosis.

Methods of Use and Treatments

[0191] Provided herein are methods of treating hepatic steatosis in a subject in need thereof. The methods generally comprise administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.

[0192] Also provided herein are methods of treating a subject with hepatic steatosis, the methods generally comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid, wherein the treating comprises one or more of treating liver fibrosis, modulating glycemic control, reducing the level of HbAlc in blood or serum, reducing body weight, reducing the systolic and/or diastolic blood pressure, reducing liver fat, reducing hepatocellular ballooning, and reducing lobular inflammation in the subject.

[0193] Also provided herein are methods of treating hepatic steatosis in a subject receiving GLP-1 receptor agonist therapy, the methods generally comprising administering to the subject an effective amount of bempedoic acid. [0194] Also provided herein are methods of treating a subject with hepatic steatosis receiving GLP-1 receptor agonist therapy, the methods generally comprising administering to the subject an effective amount of bempedoic acid, wherein the treating comprises one or more of treating liver fibrosis, modulating glycemic control, reducing the level of HbAlc in blood or serum, reducing body weight, reducing the systolic and/or diastolic blood pressure, reducing liver fat, reducing hepatocellular ballooning, and reducing lobular inflammation in the subject.

[0195] In various embodiments, provided herein is a method of treating hepatic steatosis in a subject in need thereof, the method comprising administering to the subject an effective amount of a GLP- 1 receptor agonist and an effective amount of bempedoic acid.

[0196] In various embodiments, provided herein is a method of treating liver fibrosis in a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP- 1 receptor agonist and an effective amount of bempedoic acid.

[0197] In various embodiments, provided herein is a method of modulating glycemic control in a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP- 1 receptor agonist and an effective amount of bempedoic acid.

[0198] In various embodiments, provided herein is a method of reducing the level of HbAlc in blood or serum of a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.

[0199] In various embodiments, provided herein is a method of reducing the body weight of a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP- 1 receptor agonist and an effective amount of bempedoic acid.

[0200] In various embodiments, provided herein is a method of reducing the systolic and/or diastolic blood pressure of a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.

[0201] In various embodiments, provided herein is a method of reducing liver fat in a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP- 1 receptor agonist and an effective amount of bempedoic acid.

[0202] In various embodiments, provided herein is a method of reducing hepatocellular ballooning in a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid. [0203] In various embodiments, provided herein is a method of reducing lobular inflammation in a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP- 1 receptor agonist and an effective amount of bempedoic acid.

[0204] In certain embodiments, the hepatic steatosis is non-alcoholic steatohepatitis (NASH). [0205] In certain embodiments, administration of the effective amounts of the GLP-1 receptor agonist and bempedoic acid lowers the level of hbAlc in blood or serum of the subject below that of a subject with hepatic steatosis, and not receiving the effective amounts of the GLP-1 receptor agonist and bempedoic acid or receiving (a) the effective amount of the GLP- 1 receptor agonist or (b) the effective amount of bempedoic acid.

[0206] In certain embodiments, administration of the effective amounts of the GLP-1 receptor agonist and bempedoic acid results in the subject exhibiting a greater reduction in body weight compared to a subject with hepatic steatosis, and not receiving the effective amounts of the GLP-1 receptor agonist and bempedoic acid or receiving (a) the effective amount of the GLP-1 receptor agonist or (b) the effective amount of bempedoic acid.

[0207] In certain embodiments, administration of the effective amounts of the GLP-1 receptor agonist and bempedoic acid results in the subject exhibiting a greater reduction in liver fat compared to a subject with hepatic steatosis, and not receiving the effective amounts of the GLP-1 receptor agonist and bempedoic acid or receiving (a) the effective amount of the GLP-1 receptor agonist or (b) the effective amount of bempedoic acid.

[0208] In certain embodiments, administration of the effective amounts of the GLP-1 receptor agonist and bempedoic acid results in the subject exhibiting a greater reduction in liver fibrosis compared to a subject with hepatic steatosis, and not receiving the effective amounts of the GLP- 1 receptor agonist and bempedoic acid, or receiving (a) the effective amount of the GLP- 1 receptor agonist or (b) the effective amount of bempedoic acid.

[0209] In some embodiments, administration of the effective amounts of the GLP- 1 receptor agonist and bempedoic acid lowers the level of apolipoprotein B (apo B) in blood or serum of the subject below that of a subject not receiving the effective amounts of the GLP-1 receptor agonist and bempedoic acid, or receiving (a) the effective amount of the GLP- 1 receptor agonist or (b) the effective amount of bempedoic acid.

[0210] In some embodiments, administration of the effective amounts of the GLP-1 receptor agonist and bempedoic acid lowers the level of non-high-density lipoprotein cholesterol in blood or serum of the subject below that of a subject not receiving the effective amounts of the GLP-1 receptor agonist and bempedoic acid, or receiving (a) the effective amount of the GLP-1 receptor agonist or (b) the effective amount of bempedoic acid.

[0211] In some embodiments, administration of the effective amounts of the GLP-1 receptor agonist and bempedoic acid lowers the level of triglycerides in blood or serum of the subject below that of a subject not receiving the effective amounts of the GLP-1 receptor agonist and bempedoic acid, or receiving (a) the effective amount of the GLP- 1 receptor agonist or (b) the effective amount of bempedoic acid.

[0212] In some embodiments, administration of the effective amounts of the GLP-1 receptor agonist and bempedoic acid lowers the LDL particle number in blood or serum of the subject below that of a subject not receiving the effective amounts of the GLP-1 receptor agonist and bempedoic acid, or receiving (a) the effective amount of the GLP-1 receptor agonist or (b) the effective amount of bempedoic acid.

[0213] In some embodiments, administration of the effective amounts of the GLP-1 receptor agonist and bempedoic acid decreases the size of VLDL particles in blood or serum of the subject below that of a subject not receiving the effective amounts of the GLP-1 receptor agonist and bempedoic acid, or receiving (a) the effective amount of the GLP- 1 receptor agonist or (b) the effective amount of bempedoic acid.

[0214] In some embodiments, administration of the effective amounts of the GLP-1 receptor agonist and bempedoic acid decreases the number of VLDL particles in blood or serum of the subject below that of a subject not receiving the effective amounts of the GLP-1 receptor agonist and bempedoic acid, or receiving (a) the effective amount of the GLP- 1 receptor agonist or (b) the effective amount of bempedoic acid.

[0215] In some embodiments, administration of the effective amounts of the GLP-1 receptor agonist and bempedoic acid increases the level of apolipoprotein Al (apo Al) in blood or serum of the subject above that of a subject not receiving the effective amounts of the GLP-1 receptor agonist and bempedoic acid, or receiving (a) the effective amount of the GLP- 1 receptor agonist or (b) the effective amount of bempedoic acid.

[0216] In some embodiments, administration of the effective amounts of the GLP-1 receptor agonist and bempedoic acid does not change the level of apolipoprotein Al (apo Al) in blood or serum of the subject compared to that of a subject not receiving the effective amounts of the GLP-1 receptor agonist and bempedoic acid, or receiving (a) the effective amount of the GLP-1 receptor agonist or (b) the effective amount of bempedoic acid. [0217] In some embodiments, administration of the effective amounts of the GLP-1 receptor agonist and bempedoic acid decreases the level of apolipoprotein Al (apo Al) in blood or serum of the subject below that of a subject not receiving the effective amounts of the GLP-1 receptor agonist and bempedoic acid, or receiving (a) the effective amount of the GLP- 1 receptor agonist or (b) the effective amount of bempedoic acid.

[0218] In some embodiments, administration of the effective amount of a GLP-1 receptor agonist and the effective amount of bempedoic acid to the subject reduces the liver fibrosis score by 1 point or more. In some embodiments, administration of the effective amount of a GLP-1 receptor agonist and the effective amount of bempedoic acid to the subject reduces the liver fibrosis score by 2 points. In some embodiments, administration of the effective amount of a GLP- 1 receptor agonist and the effective amount of bempedoic acid to the subject reduces the liver fibrosis score by 3 points.

[0219] In some embodiments, administering the effective amount of the GLP-1 receptor agonist and the effective amount of bempedoic acid to the subject reduces hepatic fat content by about 20 to about 70 percent, about 20 to about 65 percent, about 20 to about 60 percent, about 20 to about 55 percent, about 20 to about 45 percent, about 20 to about 40 percent, about 20 to about 35 percent, about 20 to about 30 percent, about 20 to about 25 percent, about 10 to about 60 percent, about 10 to about 55 percent, about 10 to about 50 percent, about 10 to about 45 percent, about 10 to about 40 percent, about 10 to about 35 percent, about 10 to about 30 percent, about 10 to about 25 percent, about 10 to about 20 percent, or about 10 to about 15 percent. In certain embodiments, the administration of effective amounts of the GLP-1 receptor agonist and bempedoic acid reduces hepatic fat content by greater than 30%, 35%, 40%, 45%, 50%, 55%, 60% or 65%. Hepatic fat content may be measured in a subject by magnetic resonance spectroscopy or biopsy.

[0220] In some embodiments, administration of the effective amount of the GLP-1 receptor agonist and the effective amount of bempedoic acid reduces the mean body weight of the subject by about 1 to about 20 kg, about 1 to about 18 kg, about 1 to about 16 kg, about 1 to about 14 kg, about 1 to about 12 kg, about 1 to about 10 kg, about 1 to about 8 kg, about 1 to about 6 kg, about 1 to about 3 kg, about 2 to about 20 kg, about 2 to about 18 kg, about 2 to about 16 kg, about 2 to about 14 kg, about 2 to about 12 kg, about 2 to about 10 kg, about 2 to about 8 kg, about 2 to about 6 kg, about 2 to about 4 kg, about 3 to about 15 kg, about 3 to about 13 kg, about 3 to about 11 kg, about 3 to about 9 kg, about 3 to about 7 kg, about 3 to about 5 kg, about 3 to about 4 kg, about 6 to about 20 kg, about 6 to about 18 kg, about 6 to about 16 kg, about 6 to about 14 kg, about 6 to about 12 kg, about 6 to about 10 kg, or about 6 to about 8 kg. In certain embodiments, the administration of effective amounts of the GLP-1 receptor agonist and bempedoic acid to the subject reduces mean body weight of the subject by at least 8 kg, 10 kg, 12 kg, 14 kg, 16 kg, 18 kg, or 20 kg. In certain embodiments, for example, in each of the foregoing embodiments, the subject has diabetes (e.g., type 2 diabetes) and/or a baseline body mass index (BMI) of > 30 kg/m².

[0221] In some embodiments, administration of the effective amount of the GLP-1 receptor agonist and the effective amount of bempedoic acid lowers the level of HbAlc in blood or serum of the subject by about 0.5 to about 6 percent, about 0.5 to about 5.5 percent, about 0.5 to about 5 percent, about 0.5 to about 4.5 percent, about 0.5 to about 4 percent, about 0.5 to about 3.5 percent, about 0.5 to about 3 percent, about 0.5 to about 2.5 percent, about 0.5 to about 2.0 percent, about 0.5 to about 1.8 percent, about 0.8 to about 6 percent, about 0.8 to about 5.5 percent, by about 0.8 to about 5 percent, about 0.8 to about 4.5 percent, about 0.8 to about 4 percent, about 0.8 to about 3.5 percent, about 0.8 to about 3 percent, about 0.8 to about 2.5 percent, about 0.8 to about 2 percent, about 0.8 to about 1.5 percent, or about 0.8 to about 1.2 percent. In certain embodiments, the administration of effective amounts of the GLP-1 receptor agonist and bempedoic acid to the subject reduces the level of HbAlc by greater than 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, or 6%.

[0222] In some embodiments, administration of the effective amount of the GLP-1 receptor agonist and the effective amount of bempedoic acid reduces the systolic blood pressure of the subject by about 1 to about 18 mmHg, about 1 to about 17 mmHg, about 1 to about 16 mmHg, about 1 to about 15 mmHg, about 1 to about 14 mmHg, about 1 to about 13 mmHg, about 1 to about 12 mmHg, about 1 to about 11 mmHg, about 1 to about 10 mmHg, about 1 to about 9 mmHg, about 1 to about 8 mmHg, about 1 to about 7 mmHg, about 1 to about 6 mmHg, about 1 to about 5 mmHg, about 2 to about 18 mmHg, about 2 to about 17 mmHg, about 2 to about 16 mmHg, about 2 to about 15 mmHg, about 2 to about 14 mmHg, about 2 to about 13 mmHg, about 2 to about 12 mmHg, about 2 to about 11 mmHg, about 2 to about 10 mmHg, about 2 to about 9 mmHg, about 2 to about 8 mmHg, about 2 to about 7 mmHg, about 2 to about 6 mmHg, about 2 to about 5 mmHg, about 3 to about 18 mmHg, about 3 to about 17 mmHg, about 3 to about 16 mmHg, about 3 to about 15 mmHg, about 3 to about 14 mmHg, about 3 to about 13 mmHg, about 3 to about 12 mmHg, about 3 to about 11 mmHg, about 3 to about 10 mmHg, about 3 to about 9 mmHg, about 3 to about 8 mmHg, about 3 to about 7 mmHg, about 3 to about 6 mmHg, or about 3 to about 5 mmHg. In certain embodiments, the administration of effective amounts of the GLP-1 receptor agonist and bempedoic acid to the subject reduces the systolic blood pressure of the subject by at least 5 mmHg, 6 mmHg, 7 mmHg, 8 mmHg, 9 mmHg, 10 mmHg, 11 mmHg, 12 mmHg, 13 mmHg, 14 mmHg, 15 mmHg, 16 mmHg, 17 mmHg, or 18 mmHg. In certain embodiments, for example, in each of the foregoing embodiments, the subject has a baseline systolic blood pressure > 130 mg.

[0223] In some embodiments, administration of the effective amounts of the GLP-1 receptor agonist and bempedoic acid reduces the lobular inflammation score of the subject by 1 point. In some embodiments, administration of the effective amounts of the GLP-1 receptor agonist and bempedoic acid reduces the lobular inflammation score of the subject by 2 points. In some embodiments, administration of the effective amounts of the GLP-1 receptor agonist and bempedoic acid reduces the lobular inflammation score of the subject by 3 points.

[0224] In certain embodiments, the effective amount of the GLP-1 receptor agonist is administered to the subject orally. In certain embodiments, the effective amount of the GLP-1 receptor agonist is administered to the subject parenterally. Parenteral delivery may be performed by subcutaneous, intramuscular, intraperitoneal, or intravenous injection by means of a syringe, optionally a pen-like syringe. In certain embodiments, parenteral delivery is performed by means of an infusion pump.

[0225] In certain embodiments, the effective amount of the GLP-1 receptor agonist is administered to the subject one, two, three, four, or fives times daily. In certain embodiments, the effective amount of the GLP-1 receptor agonist is administered to the subject once daily. In certain embodiments, the effective amount of the GLP-1 receptor agonist is administered to the subject twice daily.

[0226] In certain embodiments, the effective amount of the GLP-1 receptor agonist is administered to the subject one, two, three, four, five, six, or seven times weekly. In certain embodiments, the effective amount of the GLP- 1 receptor agonist is administered to the subject once weekly.

[0227] In certain embodiments, the GLP-1 receptor agonist is selected from the group consisting of semaglutide, liraglutide, exenatide, dulaglutide, albiglutide, and lixisenatide. In certain embodiments, the GLP-1 receptor agonist is semaglutide. In certain embodiments, the GLP-1 receptor agonist is liraglutide. In certain embodiments, the GLP-1 receptor agonist is exenatide. In certain embodiments, the GLP-1 receptor agonist is dulaglutide. In certain embodiments, the GLP-1 receptor agonist is albiglutide. In certain embodiments, the GLP-1 receptor agonist is lixisenatide. [0228] In certain embodiments, administering the effective amount of the GLP-1 receptor agonist comprises administering to the subject about 0.25 mg to about 14 mg semaglutide. In certain embodiments, administering the effective amount of the GLP-1 receptor agonist comprises administering parenterally to the subject about 0.25 mg to about 1 mg semaglutide. In certain embodiments, administering the effective amount of the GLP-1 receptor agonist comprises administering parenterally to the subject about 0.25 mg to about 1 mg semaglutide once weekly. In certain embodiments, administering the effective amount of the GLP-1 receptor agonist comprises administering orally to the subject about 3 mg to about 14 mg semaglutide. In certain embodiments, administering the effective amount of the GLP-1 receptor agonist comprises administering orally to the subject about 3 mg to about 14 mg semaglutide once daily. [0229] In certain embodiments, administering the effective amount of the GLP-1 receptor agonist comprises administering parenterally to the subject about 0.6 mg to about 1.8 mg liraglutide. In certain embodiments, administering the effective amount of the GLP-1 receptor agonist comprises administering parenterally to the subject about 0.6 mg to about 1.8 mg liraglutide once daily.

[0230] In certain embodiments, administering the effective amount of the GLP-1 receptor agonist comprises administering parenterally to the subject about 2 mg to about 10 mg exenatide. In certain embodiments, administering the effective amount of the GLP-1 receptor agonist comprises administering parenterally to the subject about 2 mg to about 10 mg exenatide twice daily.

[0231] In certain embodiments, administering the effective amount of the GLP-1 receptor agonist comprises administering parenterally to the subject about 0.75 mg to about 1.5 mg dulaglutide. In certain embodiments, administering the effective amount of the GLP-1 receptor agonist comprises administering parenterally to the subject about 0.75 mg to about 1.5 mg dulaglutide once weekly.

[0232] In certain embodiments, administering the effective amount of the GLP-1 receptor agonist comprises administering parenterally to the subject about 30 mg to about 50 mg albiglutide. In certain embodiments, administering the effective amount of the GLP-1 receptor agonist comprises administering parenterally to the subject about 30 mg to about 50 mg albiglutide once weekly.

[0233] In certain embodiments, administering the effective amount of the GLP-1 receptor agonist comprises administering parenterally to the subject about 10 mg to about 20 mg lixisenatide. In certain embodiments, administering the effective amount of the GLP-1 receptor agonist comprises administering parenterally to the subject about 10 mg to about 20 mg lixisenatide once daily.

[0234] In various embodiments, provided herein is a method of treating hepatic steatosis in a subject receiving GLP-1 receptor agonist therapy, the method comprising administering to the subject an effective amount of bempedoic acid.

[0235] In various embodiments, provided herein is a method of treating liver fibrosis in a subject receiving GLP-1 receptor agonist therapy, the method comprising administering to the subject an effective amount of bempedoic acid.

[0236] In various embodiments, provided herein is a method of modulating glycemic control in a subject with hepatic steatosis receiving GLP-1 receptor agonist therapy, the method comprising administering to the subject an effective amount of bempedoic acid.

[0237] In various embodiments, provided herein is a method of reducing the level of HbAlc in blood or serum of a subject with hepatic steatosis receiving GLP-1 receptor agonist therapy, the method comprising administering to the subject an effective amount of bempedoic acid.

[0238] In various embodiments, provided herein is a method of reducing the body weight of a subject with hepatic steatosis receiving GLP-1 receptor agonist therapy, the method comprising administering to the subject an effective amount of bempedoic acid.

[0239] In various embodiments, provided herein is a method of reducing the systolic and/or diastolic blood pressure of a subject with hepatic steatosis receiving GLP-1 receptor agonist therapy, the method comprising administering to the subject an effective amount of bempedoic acid.

[0240] In various embodiments, provided herein is a method of reducing liver fat in a subject receiving GLP-1 receptor agonist therapy, the method comprising administering to the subject an effective amount of bempedoic acid.

[0241] In various embodiments, provided herein is a method of reducing hepatocellular ballooning in a subject receiving GLP-1 receptor agonist therapy, the method comprising administering to the subject an effective amount of bempedoic acid.

[0242] In various embodiments, provided herein is a method of reducing lobular inflammation in a subject receiving GLP-1 receptor agonist therapy, the method comprising administering to the subject an effective amount of bempedoic acid.

[0243] In certain embodiments, the subject has NASH.

[0244] In certain embodiments, administration of the effective amount of bempedoic acid lowers the level of hbAlc in blood or serum of the subject receiving GLP-1 receptor agonist therapy below that of a subject with hepatic steatosis, and not receiving the effective amount of bempedoic acid and the GLP- 1 receptor agonist therapy or receiving (a) the GLP- 1 receptor agonist therapy or (b) the effective amount of bempedoic acid.

[0245] In certain embodiments, administration of the effective amount of bempedoic acid results in the subject receiving GLP-1 receptor agonist therapy exhibiting a greater reduction in body weight compared to a subject with hepatic steatosis, and not receiving the effective amount of bempedoic acid and the GLP- 1 receptor agonist therapy or receiving (a) the GLP- 1 receptor agonist therapy or (b) the effective amount of bempedoic acid.

[0246] In certain embodiments, administration of the effective amount of bempedoic acid results in the subject receiving GLP-1 receptor agonist therapy exhibiting a greater reduction in liver fat compared to a subject with hepatic steatosis, and not receiving the effective amount of bempedoic acid and the GLP- 1 receptor agonist therapy or receiving (a) the GLP- 1 receptor agonist therapy or (b) the effective amount of bempedoic acid.

[0247] In certain embodiments, administration of the effective amount of bempedoic acid results in the subject receiving GLP-1 receptor agonist therapy exhibiting a greater reduction in liver fibrosis compared to a subject with hepatic steatosis, and not receiving the effective amount of bempedoic acid and the GLP- 1 receptor agonist therapy, or receiving (a) the GLP- 1 receptor agonist therapy or (b) the effective amount of bempedoic acid.

[0248] In some embodiments, administration of the effective amount of bempedoic acid lowers the level of apolipoprotein B (apo B) in blood or serum of the subject receiving GLP-1 receptor agonist therapy below that of a subject not receiving the effective amount of bempedoic acid and the GLP-1 receptor agonist therapy, or receiving (a) the GLP-1 receptor agonist therapy or (b) the effective amount of bempedoic acid.

[0249] In some embodiments, administration of the effective amount of bempedoic acid lowers the level of non-high-density lipoprotein cholesterol in blood or serum of the subject receiving GLP-1 receptor agonist therapy below that of a subject not receiving the effective amount of bempedoic acid and the GLP- 1 receptor agonist therapy, or receiving (a) the GLP- 1 receptor agonist therapy or (b) the effective amount of bempedoic acid.

[0250] In some embodiments, administration of the effective amount of bempedoic acid lowers the level of triglycerides in blood or serum of the subject receiving GLP- 1 receptor agonist therapy below that of a subject not receiving the effective amount of bempedoic acid and the GLP-1 receptor agonist therapy, or receiving (a) the GLP-1 receptor agonist therapy or (b) the effective amount of bempedoic acid. [0251] In some embodiments, administration of the effective amount of bempedoic acid lowers the LDL particle number in blood or serum of the subject receiving GLP-1 receptor agonist therapy below that of a subject not receiving the effective amount of bempedoic acid and the GLP-1 receptor agonist therapy, or receiving (a) the GLP-1 receptor agonist therapy or (b) the effective amount of bempedoic acid.

[0252] In some embodiments, administration of the effective amount of bempedoic acid decreases the size of VLDL particles in blood or serum of the subject receiving GLP-1 receptor agonist therapy below that of a subject not receiving the effective amount of bempedoic acid and the GLP-1 receptor agonist therapy, or receiving (a) the GLP-1 receptor agonist therapy or (b) the effective amount of bempedoic acid.

[0253] In some embodiments, administration of the effective amount of bempedoic acid decreases the number of VLDL particles in blood or serum of the subject receiving GLP-1 receptor agonist therapy below that of a subject not receiving the effective amount of bempedoic acid and the GLP-1 receptor agonist therapy, or receiving (a) the GLP-1 receptor agonist therapy or (b) the effective amount of bempedoic acid.

[0254] In some embodiments, administration of the effective amount of bempedoic acid increases the level of apolipoprotein Al (apo Al) in blood or serum of the subject receiving GLP-1 receptor agonist therapy above that of a subject not receiving the effective amount of bempedoic acid and the GLP- 1 receptor agonist therapy, or receiving (a) the GLP- 1 receptor agonist therapy or (b) the effective amount of bempedoic acid.

[0255] In some embodiments, administration of the effective amount of bempedoic acid does not change the level of apolipoprotein Al (apo Al) in blood or serum of the subject receiving GLP-1 receptor agonist therapy compared to that of a subject not receiving the effective amount of bempedoic acid, or receiving (a) the GLP- 1 receptor agonist therapy or (b) the effective amount of bempedoic acid.

[0256] In some embodiments, administration of the effective amount of bempedoic acid decreases the level of apolipoprotein Al (apo Al) in blood or serum of the subject receiving GLP-1 receptor agonist therapy below that of a subject not receiving the effective amount of bempedoic acid and the GLP- 1 receptor agonist therapy, or receiving (a) the GLP- 1 receptor agonist therapy or (b) the effective amount of bempedoic acid.

[0257] In certain embodiments, the GLP-1 receptor agonist therapy is administered to the subject orally. In certain embodiments, the GLP-1 receptor agonist therapy is administered to the subject parenterally. Parenteral delivery may be performed by subcutaneous, intramuscular, intraperitoneal, or intravenous injection by means of a syringe, optionally a pen-like syringe. In certain embodiments, parenteral delivery is performed by means of an infusion pump.

[0258] In certain embodiments, the GLP-1 receptor agonist therapy is administered to the subject one, two, three, four, or five times daily. In certain embodiments, the GLP-1 receptor agonist therapy is administered to the subject once daily. In certain embodiments, the GLP-1 receptor agonist therapy is administered to the subject twice daily.

[0259] In certain embodiments, the GLP-1 receptor agonist therapy is administered to the subject one, two, three, four, five, six, or seven times weekly. In certain embodiments, the GLP-

1 receptor agonist therapy is administered to the subject once weekly.

[0260] In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 0.25 mg to about 14 mg semaglutide. In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 0.25 mg to about 1 mg semaglutide. In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 0.25 mg to about 1 mg semaglutide parenterally. In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 0.25 mg to about 1 mg semaglutide parenterally, once weekly. In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 3 mg to about 14 mg semaglutide. In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 3 mg to about 14 mg semaglutide orally. In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 3 mg to about 14 mg semaglutide orally, once daily.

[0261] In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 0.6 mg to about 1.8 mg liraglutide. In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 0.6 mg to about 1.8 mg liraglutide parenterally. In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 0.6 mg to about 1.8 mg liraglutide parenterally, once daily.

[0262] In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 2 mg to about 10 mg exenatide. In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 2 mg to about 10 mg exenatide parenterally. In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about

2 mg to about 10 mg exenatide parenterally, twice daily.

[0263] In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 0.75 mg to about 1.5 mg dulaglutide. In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 0.75 mg to about 1.5 mg dulaglutide parenterally. In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 0.75 mg to about 1.5 mg dulaglutide parenterally, once weekly.

[0264] In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 30 mg to about 50 mg albiglutide. In certain embodiments, the subject receiving GLP- 1 receptor agonist therapy is receiving about 30 mg to about 50 mg albiglutide parenterally. In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 30 mg to about 50 mg albiglutide parenterally, once weekly.

[0265] In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 10 mg to about 20 mg lixisenatide. In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 10 mg to about 20 mg lixisenatide parenterally. In certain embodiments, the subject receiving GLP-1 receptor agonist therapy is receiving about 10 mg to about 20 mg lixisenatide parenterally, once daily.

[0266] In certain embodiments, the effective amount of bempedoic acid is about 120 mg to about 240 mg. In certain embodiments, the effective amount of bempedoic acid is about 180 mg.

[0267] In certain embodiments, the effective amount of bempedoic acid is administered to the subject one, two, three, four, or five times daily. In certain embodiments, the effective amount of bempedoic acid is administered to the subject once daily.

[0268] In certain embodiments, the effective amount of bempedoic acid is administered to the subject orally. In certain embodiments, the effective amount of bempedoic acid is administered to the subject orally, once daily.

[0269] In some embodiments, the methods described herein lower LDL-C in the blood or serum of the subject. In some embodiments, the methods described herein lower systolic and/or diastolic blood pressure in the subject. In some embodiments, the methods described herein lower uric acid in the blood or serum of the subject. In some embodiments, the methods described herein lower hsCRP in the blood or serum of the subject. In some embodiments, the methods described herein lower the body weight of the subject. In some embodiments, the methods described herein reduce the risk of atherosclerotic cardiovascular disease in the subject. In some embodiments, the methods described herein lower the level of hbAlc in the blood or serum of the subject.

[0270] In some embodiments, the methods described herein lower the level of apolipoprotein B (apo B) in blood or serum of the subject below that of a subject not receiving the combination of GLP-1 receptor agonist and bempedoic acid. In some embodiments, the methods described herein lower the level of non-high-density lipoprotein cholesterol in blood or serum of the subject below that of a subject not receiving the combination of GLP-1 receptor agonist and bempedoic acid. In some embodiments, the methods described herein lower the level of triglycerides in blood or serum of the subject below that of a subject not receiving the combination of GLP-1 receptor agonist and bempedoic acid. In some embodiments, the methods described herein lower the LDL particle number in blood or serum of the subject below that of a subject not receiving the combination of GLP-1 receptor agonist and bempedoic acid. In some embodiments, the methods described herein decrease the size of VLDL particles in blood or serum of the subject below that of a subject not receiving the combination of GLP-1 receptor agonist and bempedoic acid. In some embodiments, the methods described herein decrease the number of VLDL particles in blood or serum of the subject below that of a subject not receiving the combination of GLP- 1 receptor agonist and bempedoic acid. In some embodiments, the methods described herein increase the level of apolipoprotein Al (apo Al) in blood or serum of the subject above that of a subject not receiving the combination of GLP-1 receptor agonist and bempedoic acid. In some embodiments, the methods described herein do not change the level of apolipoprotein Al (apo Al) in blood or serum of the subject compared to that of a subject not receiving the combination of GLP-1 receptor agonist and bempedoic acid. In some embodiments, the methods described herein decrease the level of apolipoprotein Al (apo Al) in blood or serum of the subject below that of a subject not receiving the combination of GLP- 1 receptor agonist and bempedoic acid.

EXAMPLES

[0271] Below are examples of specific embodiments for carrying out the present disclosure. The examples are offered for illustrative purposes only, and are not intended to limit the scope of the present disclosure in any way.

[0272] Any terms not directly defined herein shall be understood to have the meanings commonly associated with them as understood within the art of the disclosure. Certain terms are discussed herein to provide additional guidance to the practitioner in describing the compositions, devices, methods and the like of aspects of the disclosure, and how to make or use them. It will be appreciated that the same thing may be said in more than one way. Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein. No significance is to be placed upon whether or not a term is elaborated or discussed herein. Some synonyms or substitutable methods, materials and the like are provided. Recital of one or a few synonyms or equivalents does not exclude use of other synonyms or equivalents, unless it is explicitly stated. Use of examples, including examples of terms, is for illustrative purposes only and does not limit the scope and meaning of the aspects of the disclosure herein.

Example 1 - Study to Evaluate the Effect of Bempedoic Acid and Liraglutide Combination in a Murine Model of Metabolic- Associated Steatohepatitis and Hepatic Fibrosis

(1) Methods

Animals

[0273] All in vivo experiments were approved by the McMaster University Animal Ethics Committee and conducted under the Canadian guidelines for animal research. Male mice with a C57BL/6J background were purchased from Jackson Laboratories at 6-7 weeks of age. Mice were housed 3-5 per cage in a controlled environment; 12-hour light/dark cycle, given food and water ad libitum, and enrichment provided. At 8 weeks of age, mice were moved into specificpathogen free (SPF) microisolators in a room maintained at ~29 °C and fed a high-fat, high- fructose diet (NASH Diet; ND; 40% fat from mostly palm, 20% fructose, 0.02% cholesterol). Due to fructose being supplemented in the diet, diet was changed every few weeks. 16 weeks later, mice were grouped by matching body weight and adiposity randomly and placed on respective interventional arms. Adiposity was assessed based on time-domain NMR using a Bruker Minispec LF90II. Control mice were continued on diet alone, vehicle-treated mice (Vehicle) were given subcutaneous saline injections every second day 1-2 hrs before the dark cycle, bempedoic acid-treated mice (BemA) had the drug supplemented in the diet at a dose of 10 mg/kg, liraglutide-treated mice (Lira) were given subcutaneous injections of Victoza® diluted in saline to a dose of 70 pg/kg every second day 1-2 hrs before the dark cycle, and combination-treated mice (Lira+BemA) were given subcutaneous injections of Victoza® diluted in saline to a dose of 70 pg/kg every second day 1-2 hrs before the dark cycle with bempedoic acid supplemented in the diet at a dose of 10 mg/kg. After 9 weeks of treatment, all mice were sacrificed in the fed state between 09:00 and 11 :00 hrs, using a ketamine/xylazine mixture to sedate mice before collecting blood via cardiac puncture. Mice were presumed dead by exsanguination and cervical dislocation was performed as a secondary measure. Metabolic Testing

[0274] Metabolic tests were performed between 4 and 9 weeks of intervention, in respective order below. Intraperitoneal glucose (ipGTT; 1.25 g/kg) and insulin (ipITT; 1.3 U/kg) tolerance tests were performed in 6-hour fasted mice, with fasting starting at 07:00 hrs and basal values being tested at 13:00 hrs. Intraperitoneal pyruvate tolerance tests (ipPTT; 1.5 g/kg) were performed in 15-hour fasted mice, with fasting occurring overnight and basal values being evaluated at 09:00hrs. Fasting blood glucose and serums were collected in 6-hour fasted mice, mimicking ipGTT and ipITT times. Blood collection for these tests were obtained via tail-nick.

Liver Lipid Analysis

[0275] Liver fat percentage was assessed based on time-domain NMR using a Broker Minispec LF90II. Briefly, ~3O-5O mg tissue chips were obtained on dry ice, given 10 minutes to thaw on ice and given 10 minutes to equilibrate at room temperature before being placed in biopsy tubes purchased from Broker. Liver triglycerides were assessed using the Cayman Chemicals Triglyceride Colorimetric Assay kit (Item no. 10010303). Briefly, 10-20 mg of frozen liver was immediately homogenized in 400 pL of diluted NP40 substitute assay reagent. The manufacturer’s instructions were followed for all other aspects of the assay.

Histology

[0276] Tissues were fixed in 10% neutral buffered formalin for 48 hrs before being stored in 70% ethanol. The medial lobe of the liver was processed, paraffin embedded, serially sectioned, and stained with haemotoxylin and eosin (H&E), Masson’s Trichrome, and picrosirius red (PSR) by the McMaster Immunology Research Centre’s core histology facility. Images were acquired by a Nikon 90i Eclipse upright microscope. Liver histology scores were obtained by a blinded pathologist who utilized descriptions as documented by Kleiner and colleagues as their basis (Kleiner et al. 2005). NAFLD activity scores were compiled by the sum of scores: liver steatosis, lobular inflammation, and hepatocellular ballooning, as assessed using H&E-stained slides. Fibrosis scores were obtained by the assessment of both Masson’s Trichrome and PSR- stained slides.

RNA Isolation and Analysis

[0277] Liver tissue (~15 mg) was lysed in 1 mL TRIzol reagent (Invitrogen) using ceramic beads and a Precellys 24 homogenizer (Berlin Technologies). Samples were spun down for 10 mins at 12 000 g at 4 °C. 200 pL of chloroform was added and shaken vigorously before spinning samples again at same settings. Supernatant was placed in new tubes and an equal amount of 70% ethanol was added then vortexed. Solutions were loaded onto RNeasy columns and manufacturer’s instructions were followed (Qiagen).

NanoString Gene Expression Analysis

[0278] For NanoString analysis, 4-5 RNA samples per group were inspected by a BioAnalyzer quality control test. The McMaster Genomics Facility ran an nCounter Fibrosis v2 Panel (NanoString Technologies) containing 760 target genes as well as a CustomSet Panel consisting of 22 orthologous mus musculus genes that correspond to the 25 -gene NASH severity signature described by Govaere and colleagues. (Govaere et al.; Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis.-, Sci. Transl. Med.; 2020; 12(572): 1-18) Gene expression data was normalized and log-transformed prior to differential gene expression analysis and pathway signature score computation using NanoString Technologies’ nSolver 4.0 software (version 4.0.70) and the embedded PLAGE algorithm.

[0279] Uniquely regulated genes were defined as differentially expressed genes (FDR < 0.05) between control and combination treatment but not monotherapy. Additively regulated genes were defined as differentially expressed genes (FDR < 0.05) exhibiting the largest fold change between control and combination treatment compared to monotherapy. Combination specific signature was derived based on the overlap between uniquely and additively regulated genes and differential expression (p- value < 0.05) between combination treatment and monotherapy. An elastic net regularization model with 10-fold cross validation was used to further identify a subset of genes associated with fibrosis stages > 2 in a cohort of 216 human NAFLD/NASH patients using methods implemented in caret v6.0.93 and glmnet v4.1 .6.Pathway overrepresentation was determined by tabulating the pathway annotations associated with genes in the unique and additive gene sets. Statistical significance was computed using Chi-square test.

RNA-Seq Analysis

[0280] Patient derived RNA-Seq data was obtained from GEO repository GSE135251 and processed for quality control, alignment, and count as described previously (Govaere et al. 2020). Variance stabilizing transformation was applied to compute relative mRNA abundance using DESeq2 vl.36.0. Integrated Human and Mouse Gene Expression Analysis

[0281] Gene expression data derived from NanoString and DESeq2 analyses underwent logscale and z-score transformation prior to integration with human data. PCA and hierarchical clustering using Pearson correlation, as implemented in stats v4.2.2, were applied to integrated gene expression data to assess sample similarity between treatment cohorts and human NASH/NAFLD disease stages.

[0282] Multivariate logistic regression, as implemented in the caret v6.0.93, using the combination treatment specific gene signatures and the 25-gene signature reported by Govaere et al. were used to predict advanced fibrosis stages in patients. AUROC scores were computed to assess the predictive performance of each gene signature using methods implemented in pROC vl.18.0.

[0283] Classification of patients based on similarity to the combination specific gene signature was computed using Nearest Template Prediction as implemented in GenePattern. (Hoshida Y. ; Nearest template prediction: A single-sample-based flexible class prediction with confidence assessment.-, PLoS One.; 2010; 5(11): 1-8) The gene set associated with the similar class is defined as upregulated genes within the combination specific gene signature. The gene set associated with the dissimilar class is defined as downregulated genes within the combination specific gene signature. Only patients with statistically significant classification (p-value < 0.05) were included in downstream analyses.

[0284] ssGSEA was performed as implemented in GenePattern. Log-transformed gene expression along with hallmark gene sets and Aizarani liver cell type gene sets derived from MSIgDB were used as the respective inputs for ssGSEA. Differential ssGSEA scores were computed using T-test followed by FDR adjustment and significance was defined as FDR < 0.05.

Serum Measurements

[0285] Serum insulin was assessed in 6-hour fasted samples using the manufacturer’s instructions for the Ultra-Sensitive Mouse Insulin ELISA kit (Crystal Chem, Catalog # 90080). Fed serum samples were assessed using the manufacturer’ s instructions for: cholesterol E (Fujifilm, No. 999-02601) triglycerides (Cayman Chemicals, Item no. 10010303), non-esterified fatty acids (Fujifilm, NEFA-HR (2), 999-34691, 991-34891, 993-35191), ALT (Cohesion, #CAK1002), AST (Cohesion #CAK1004), Serum Amyloid A (R&D Systems, MSAA00), and sPLA2 (Cayman Chemical, Item No. 765001-96). ProCartaPlex Mouse kits from ThermoFisher were used to measure CRP and CXCL10 on a Bio-Rad Bio-Plex Reader.

Statistics

[0286] All other statistical analyses not previously specified using R packages or GenePattern softwares were performed using GraphPad Prism 9. Values throughout the illustrations are shown as means + S.E.M. with p-values reported in the graphs. Colored bars signify comparisons between groups (with respective colors) and control groups (both ND and ND+Veh). Significance was accepted at p < 0.05 and determined via unpaired t-tests, one-way or repeated-measures two-way ANOVA with Tukey or Sidak’s posthoc, where appropriate. For histological score analysis, a Kruskal- Wallis test or Mann- Whitney tests were used - these are nonparametric tests, with the Kruskal-Wallis test comparing the rank of each column with every other column, and correcting for multiple comparisons using Dunn’s posthoc test. White circles are individual mice per group (n=8-9 mice/group).

(2) Results

Combination of Liraglutide and Bempedoic Acid Reduces Body Weight, Adiposity, Glucose Intolerance, Insulin Resistance, and Serum Cholesterol

[0287] Housing C57BL6J mice at thermoneutrality and feeding a diet high-in fat and fructose leads to metabolic, pathological and transcriptional characteristics similar to human NASH. (Morrow MR et al.; Inhibition of ATP -citrate lyase improves NASH, liver fibrosis, and dyslipidemia.', Cell Metab.; 2022; 34(6): 919-936.e8.) Using this diet and housing paradigm, after 16 weeks, mice were assigned to interventional arms by matching body weight and adiposity so there were no differences at the start of the treatment period which continued for 9 weeks.

[0288] Bempedoic acid (BemA) did not alter body weight, adiposity, glucose tolerance, insulin sensitivity, pyruvate tolerance (a measure of hepatic gluconeogenesis), or fasting serum insulin or triglyceride levels, but did reduce serum cholesterol (FIGs. 5A-5H). Despite similar adiposity and glucose homeostasis, BemA reduced liver fat percentage, pathological scoring of liver steatosis, hepatocellular ballooning, and the NAFLD activity composite (FIGs. 6A-6G). Importantly, BemA also reduced percent fibrosis area assessed using picrosirius red (PSR) (FIG. 6H). These data indicate that, consistent with previous studies using thermoneutral housing but a shorter duration of dietary intervention before initiating treatment (10 vs. 16 wks in the current study), BemA reduces liver steatosis, ballooning and fibrosis independently of changes in body mass or adiposity.

[0289] Large reductions in body mass can resolve NASH in rodents. GLP-1R agonists such as liraglutide (Lira) dose-dependently suppress appetite and body mass and can, at high doses, reduce body mass by greater than 50% over 10 weeks of treatment. Therefore, to enhance potential translatability of Lira to treatment of NASH in humans, a dose and frequency of administration was utilized that resulted in similar reductions in body mass/adiposity observed in participants within clinical trials where 5-10% weight loss is observed. (Armstrong MJ et al.; Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): A multicentre, double-blind, randomised, placebo-controlled phase 2 study.', Lancet.; 2016; 387(10019): 679-90) Treatment of mice with liraglutide (Lira) reduced body mass by 6% at 9 weeks of treatment and this effect was not altered by the addition of BemA (Lira+BemA) (FIGs. 1 and IB). Compared to vehicle control mice, Lira and Lira+BemA improved glucose tolerance (FIG. 1C) and insulin sensitivity (FIG. ID) but did not alter pyruvate tolerance (FIG. IE). Lira lowered fasting insulin levels (FIG. IF), and this effect was maintained by the addition of BemA. Lira lowered serum cholesterol levels (FIG. 1G), and there was tendency for this effect to be enhanced with the addition of BemA. Serum triglycerides (FIG. 1H) were unchanged in either Lira or Lira+BemA combination groups.

Combination of Liraglutide and Bempedoic Acid Results in Additive Benefits in Liver Steatosis, Ballooning, and Fibrosis

[0290] In comparison to the vehicle group, Lira and Lira+BemA reduced percent liver fat by 36 and 47%, respectively (FIG. 2A), and triglycerides by 69 and 81% respectively (FIG. 2B). Consistent with these observations, steatosis scores from H&E sections were reduced with Lira (63%) and Lira+BemA treatments (74%) (FIGs. 2C and 2D). Hepatocellular ballooning scores were reduced with Lira by 56% and Lira+BemA by 94% (FIGs. 2C and 2E). Lira and Lira+BemA reduced lobular inflammation score to a similar degree (—50%) (FIGs. 2C and 2F). In sum, the NAFLD activity score (NAS) was reduced by 56% by Lira and by 75% by Lira+BemA (NAS: FIG. 2G). Importantly, Lira and Lira+BemA treatment groups reduced fibrosis area assessed using PSR (40 and 44%, respectively) (FIGs. 2C and 2H) and had fewer (Lira 1 of 9) or no (Lira+BemA 0 of 9) moderate zone 3, perisinusoidal fibrosis (1C) compared to vehicle-treated mice (4 of 8) (FIGs. 2C and 21). Lastly, serum markers of liver inflammation/damage including alanine transaminase (ALT), aspartate aminotransferase (AST), serum amyloid A (SAA), the C-X-C motif chemokine ligand 10 (CXCL10), c-reactive protein (CRP) and secreted phospholipase A2 (sPLA2) were measured. BemA reduced ALT, AST and CXCL10, however, these effects were blunted with Lira. BemA also reduced SAA, CRP and sPLA2 effects that were maintained (SAA, CRP), or were enhanced (sPLA2) with Lira+BemA treatment (Table 1).

ALT=Alanine transaminase, AST=Aspartate aminotransferase (AST), SAA=Serum amyloid A

CXCL10=C-X-C motif chemokine ligand 10, also known as interferon gamma-induced protein 10 (IP- 10), CRP=C- reactive protein, sPLA2=secretory phospholipase A2. P values reported are based on comparisons used throughout the remainder of manuscript - unpaired t-test between Control and BemA, One-Way ANOVA with Tukey posthoc between Vehicle, Lira, Lira+BemA. Significance was accepted at p<0.05. * indicates a significant difference p<0.05 between Lira and Lira+BemA.

[0291] Collectively, Lira+BemA led to greater percent reductions and lower p-values for steatosis, ballooning, NAS, PSR and sPLA2 compared to Lira monotherapy, suggesting there may be additive effects towards improving liver pathology.

Targeted Gene Expression Profiling Identifies Additive Downregulation of Fibrosis-Related Molecular Pathways That Are Predictive of NASH Resolution

[0292] To determine the transcriptional differences between the treatment cohorts, the expression of 760 genes implicated in 49 fibrosis related pathways using the nCounter Fibrosis v2 Panel was examined. Differential expression analysis comparing liraglutide, bempedoic acid and combination treatment to diseased control yielded 249, 132, and 263 genes respectively (FIG. 7A and FIG. 10). Combination treatment resulted in the greatest number of downregulated genes, significantly reducing the expression of 172 genes compared to 97 and 86 by Lira and Bern A alone. Of these, 56 genes were uniquely altered by combination treatment, 113 genes overlapped between all treatment cohorts and 3 genes were upregulated by Lira but downregulated in the combination cohort (FIG. 7B and FIG. 11). Conversely, 8 genes were uniquely upregulated by combination treatment (FIG. 7C). Over-representation analysis of the uniquely downregulated and overlapping genes, which is defined as additive if the effect size is largest in the combination treatment cohort, identified seven disease processes of interest related to inflammation, fibrosis, and wound healing (FIG. 7D and FIG. 12). A more comprehensive parallel approach was then employed using PLAGE to identify pathway level alterations induced by combination treatment and to assess their predictivity of phenotype observations (FIG. 8A). (Tomfohr et al.; Pathway level analysis of gene expression using singular value decomposition', BMC Bioinformatics; 2005; 6: 1-11) Combination treatment led to reductions across 17 pathways with hierarchical clustering identifying reductions in overarching disease processes related to fibrosis (e.g., collagen biosynthesis & modification, myofibroblast regulation), inflammation (e.g., chemokine signaling, cytokine signaling) and wound healing (e.g., phagocytic cell function, angiogenesis) which was consistent with pathway annotation analysis (FIG. 3A).

[0293] To assess gene set association with phenotype observations, disease outcome measurements were regressed on the first principal component (PCI) of the 17 gene sets (FIG. 3B) most affected by combination treatment relative to monotherapy. This demonstrates a significant predictive relationship between PCI increment and hepatic steatosis, inflammation, fibrosis, adiposity, and NAS resolution (FIG. 3C). Hierarchical clustering grouped the selected gene sets into fibrosis, inflammation, and wound healing related disease processes, consistent with over-representation analysis using differentially expressed genes.

[0294] Hepatic stellate cells are critical for driving liver fibrosis and therefore the expression of key markers implicated in NASH progression were explored. (Payen et al. ; Single-cell RNA sequencing of human liver reveals hepatic stellate cell heterogeneity.', JHEP Reports [Internet].; 2021; 3(3): 100278.) Consistently, markers of activated stellate cells (Collal, Colla2, ColSal, Lox, Timpl ) were significantly reduced in the Lira+BemA treatment groups to a greater extent than monotherapies of Lira or BemA (FIG. 3D). Interestingly, BemA appeared to counteract Lira-induced upregulation of TGFP effectors, including Smad3, a transcription factor critical for upregulating fibrotic pathways in NASH (FIG. 8B). Moreover, combination therapy generally reduced the expression of several chemokines implicated in NASH progression greater than Lira or BemA treatment alone (FIG. 3E). Collectively, these data indicate that combination therapy with Lira+BemA induces an anti-fibrotic and anti-inflammatory gene-expression profile that is predictive of reduced liver pathology (steatosis, ballooning, and fibrosis).

Combination Treatment Induces a Prognostically Favorable Gene Expression Profile That Most Closely Resembles Those from Healthy Human Liver Biopsies

[0295] In humans a 25-gene signature has been established to be predictive of NASH severity (Govaere et al. 2020). Therefore, to contextualize the clinical significance of the experimental therapies, an integrative analysis combining the expression data of 22 orthologous genes derived from the treatment cohorts with the expression data derived from 216 NAFLD/NASH patients was performed. Combination treatment significantly downregulated the expression of 13 genes in this prognostic signature. Hierarchical clustering using Pearson correlation reveals four clusters with differential compositions of healthy individuals, patients with pre-fibrotic (NAFLD, F0-F1) or fibrotic (F2-F4) disease and the experimental cohorts (FIG. 4A). Cluster II exhibits the most clinically benign phenotype. 80% of healthy individuals in the patient derived dataset are represented in this cluster compared to 7.55%, 1.85% and 0% of patients with F2, F3 and F4 stages of disease (FIG. 4B). It was found that 4 out of 6 of the combination treatment samples colocalized in this cluster while monotherapy treatment samples are mostly grouped in clusters I and II which exhibit more advanced disease. Using PCA, the progressive resolution of NASH in human patients on PCI is shown (FIG. 4C). Mapping the control, monotherapy, and combination treatment cohorts with human NASH disease stages further supports the increased transcriptional similarity between healthy individuals and combination treatment samples beyond what can be achieved using Lira and BemA alone.

[0296] Classification of patients into disease subtypes based on their expression of pre-defined gene signatures can inform risk stratification and elucidate molecular characteristics between disease subtypes. Recent studies have similarly utilized treatment specific gene signatures to classify patients exhibiting similar or dissimilar gene expression profiles into treatment responsive or non-responsive subtypes. (Torrens et al.; Immunomodulatory Effects of Lenvatinib Plus Anti-Programmed Cell Death Protein 1 in Mice and Rationale for Patient Enrichment in Hepatocellular Carcinoma.', Hepatology.; 2021 ; 74(5):2652-69. Geeleher et al.; Clinical drug response can be predicted using baseline gene expression levels and in vitro drug sensitivity in cell lines. Genome Biol.; 2014; 15(3): 1-12.) This analysis may provide preliminary evidence informing clinical translation and elucidate molecular differences driving therapeutic response in patients. As such, a combination treatment specific gene signature was derived by filtering for genes that were differentially regulated by combination treatment both when compared to control and monotherapy (FIG. 9A).

[0297] To determine the prognostic significance of this gene signature, its predictive performance using multivariate logistic regression was compared to the reference gene signature derived by Govaere et al. in the human NAFLD/NASH cohort. For the prediction of fibrosis stage > 2, the complete signature and a subset derived using elastic net regularization achieved area under receiver operating curve (AUROC) scores of 0.899 and 0.893 which approximates the score of 0.922 achieved by the reference signature (FIG. 4D). Among the signature genes, AXL, SLC2A2, CYBB, DOCK2, C3AR1, CYFIP1 and LEPR were significantly associated with advanced fibrosis in the multivariate model. Subsequently, Nearest Template Prediction was utilized to classify patients based on their expression similarity to the treatment signature. (Hoshida; Nearest template prediction: A single-sample-based flexible class prediction with confidence assessment. PLoS One; 2010; 5(11): 1—8). Patients classified as similar predominantly exhibited pre-fibrotic stages of disease (NAFLD and F0-F1) whereas those classified as dissimilar were enriched for fibrotic stages (F2 - F4) (FIG. 9C). Single sample GSEA (ssGSEA) of hallmark gene sets and liver cell types reveal a favorable transcriptional profile for NASH resolution. Patients in the similar class exhibit significant downregulation of fibrosis, inflammation, and cellular damage related gene sets while pathways related to fatty acid metabolism, oxidative phosphorylation and DNA repair are significantly upregulated (FIG. 9D). Correspondingly, liver cell type analysis based on markers derived from the human liver cell atlas (Aizarani et al.; A human liver cell atlas reveals heterogeneity and epithelial progenitors.', Nature.; 2019; 572(7768): 199-204) reveals significant downregulation of all non-parenchymal liver cell types including hepatic stellate cells, liver sinusoidal endothelial cells and, conversely, upregulation of hepatocytes (FIG. 9B and FIG. 4E). Overall, the gene expression pattern identified in patients who exhibit a similar gene signature profile as combination treatment supports fibrosis, steatosis, and inflammation resolution among NAFLD/NASH patients.

(3) Conclusions

[0298] It was found that, in a diet-induced NASH mouse model housed at thermoneutrality, adding bempedoic acid as a combinatorial therapy to the GLP-1R agonist liraglutide yields additional benefits in treating NASH and hepatic fibrosis in comparison to liraglutide alone. These two treatments were chosen as they have distinct targets, have good safety profiles, and have the potential to concomitantly treat separate comorbidities associated with NAFLD. In this study, liraglutide caused reductions in body weight, adiposity, glucose intolerance, and insulin resistance, while bempedoic acid treatment resulted in reductions in total cholesterol. These data indicate that the interventions were effective at treating the associated comorbidities of obesity and insulin resistance, as well as hypercholesterolemia, respectively.

[0299] As de novo lipogenesis (DNL) is a major player in the accumulation of intrahepatic triglycerides in NAFLD (Loomba et al.; Mechanisms and disease consequences of nonalcoholic fatty liver disease.', Cell [Internet]; 2021 ; 184(10):2537-64. Donnelly et al.; Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.', J Clin Invest.; 2005; 115(5): 1343— 51), targeting ACLY - an enzyme upstream from acetyl-CoA carboxylase (ACC) - with the inhibitor bempedoic acid presents an opportunity to reduce fatty acid and cholesterol synthesis within the liver. (Morrow et al.; Inhibition of ATP- citrate lyase improves NASH, liver fibrosis, and dyslipidemia.', Cell Metab.; 2022; 34(6):919- 936. e8.) In the current study, significant reductions in liver fat percentage, triglycerides, and steatosis scores with both bempedoic acid and liraglutide treatments on their own were found. With their combination, more profound reductions in liver fat percentage and triglycerides were found. Importantly, these changes did not result in elevated serum triglycerides.

[0300] As distinguishable by its suffix, the prominent feature differentiating steatohepatitis from simple liver steatosis is the development of inflammation. The transcriptome analysis indicates a unique cluster with which the combination of both bempedoic acid and liraglutide significantly reduced markers of inflammation as characterized by cytokine and chemokine signaling, the adenosine pathway, TLR and NF-KB signaling, phagocytic cell function, neutrophil degranulation, and interferon signaling. Furthermore, the reductions in inflammatory markers within the liver were more broadly apparent in the measurements of systemic markers of inflammation in serum as shown by large reductions in CRP and SAA.

[0301] Perhaps most importantly, in this study, it was found that combining bempedoic acid with liraglutide resulted in reductions in fibrosis. These pathological findings were supported by transcriptome data indicating combination therapy reduced extracellular matrix synthesis, epithelial-to-mesenchymal transition, myofibroblast regulation, focal adhesion kinase, and collagen biosynthesis and modification. This is of great importance as, to date, neither liraglutide or semaglutide have shown efficacy at reducing fibrosis stage in patients with NASH. Furthermore, the analyses revealed that a potentially unique effect of bempedoic acid may be due to its effects on countering Lira-induced increases in the TGF-R activated transcription factor Smad3, which is a critical driver of fibrosis. (Schwabe et al.; Mechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis .; Gastroenterology [Internet]. 2020;158(7): 1913- 28.) As the GLP-1R is not expressed on hepatic stellate cells (Yabut and Drucker.; Glucagon- like Peptide-1 Receptor-based Therapeutics for Metabolic Liver Disease. Endocr Rev.

2022;(July):l-19), and bempedoic acid treatment attenuates TGF-P-mediated activation of both murine and human stellate cells in vitro (Morrow et al.; 2022), this direct effect on hepatic stellate cells may be important for reducing fibrosis.

[0302] In summary, this study illustrates additive benefits when combining bempedoic acid and liraglutide treatments in a mouse model of metabolic-associated NASH and fibrosis.

INCORPORATION BY REFERENCE

[0303] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.

EQUIVALENTS

[0304] The disclosure may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the disclosure described herein. Scope of the disclosure is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

CLAIMS We claim:

1. A method of treating hepatic steatosis in a subject in need thereof, the method comprising administering to the subject an effective amount of a GLP- 1 receptor agonist and an effective amount of bempedoic acid.

2. A method of treating liver fibrosis in a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.

3. A method of modulating glycemic control in a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.

4. A method of reducing the level of hemoglobin A1C (HbAlc) in blood or serum of a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP- 1 receptor agonist and an effective amount of bempedoic acid.

5. A method of reducing the body weight of a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.

6. A method of reducing the systolic and/or diastolic blood pressure of a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.

7. A method of reducing liver fat in a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP- 1 receptor agonist and an effective amount of bempedoic acid.

8. A method of reducing hepatocellular ballooning in a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.

9. A method of reducing lobular inflammation in a subject with hepatic steatosis, the method comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.

10. The method of any one of claims 1-9, wherein the hepatic steatosis is non-alcoholic steatohepatitis (NASH).

11. The method of any one of claims 1-10, wherein administration of the effective amounts of the GLP-1 receptor agonist and bempedoic acid lowers the level of hbAlc in blood or serum of the subject below that of a subject with hepatic steatosis, and not receiving the effective amounts of the GLP- 1 receptor agonist and bempedoic acid or receiving (a) the effective amount of the GLP-1 receptor agonist or (b) the effective amount of bempedoic acid.

12. The method of any one of claims 1-11 wherein administration of the effective amounts of the GLP-1 receptor agonist and bempedoic acid results in the subject exhibiting a greater reduction in body weight compared to a subject with hepatic steatosis, and not receiving the effective amounts of the GLP- 1 receptor agonist and bempedoic acid or receiving (a) the effective amount of the GLP- 1 receptor agonist or (b) the effective amount of bempedoic acid.

13. The method of any one of claims 1-12, wherein administration of the effective amounts of the GLP- 1 receptor agonist and bempedoic acid results in the subject exhibiting a greater reduction in liver fat compared to a subject with hepatic steatosis, and not receiving the effective amounts of the GLP-1 receptor agonist and bempedoic acid or receiving (a) the effective amount of the GLP- 1 receptor agonist or (b) the effective amount of bempedoic acid.

14. The method of any one of claims 1-13, wherein administration of the effective amounts of the GLP-1 receptor agonist and bempedoic acid results in the subject exhibiting a greater reduction in liver fibrosis compared to a subject with hepatic steatosis, and not receiving the effective amounts of the GLP-1 receptor agonist and bempedoic acid, or receiving (a) the effective amount of the GLP- 1 receptor agonist or (b) the effective amount of bempedoic acid.

15. The method of any one of claims 1-14, wherein the GLP-1 receptor agonist is selected from the group consisting of semaglutide, liraglutide, exenatide, dulaglutide, albiglutide, and lixisenatide.

16. The method of any one of claims 1-15, wherein administering an effective amount of a GLP-1 receptor agonist comprises administering to the subject about 0.25 mg to about 14 mg semaglutide.

17. The method of any one of claims 1-16, wherein administering an effective amount of a GLP-1 receptor agonist comprises administering parenterally to the subject about 0.25 mg to about 1 mg semaglutide.

18. The method of any one of claims 1-16, wherein administering an effective amount of a GLP-1 receptor agonist comprises administering orally to the subject about 3 mg to about 14 mg semaglutide.

19. The method of any one of claims 1- 15, wherein administering an effective amount of a GLP-1 receptor agonist comprises administering parenterally to the subject about 0.6 mg to about 1.8 mg liraglutide.

20. The method of any one of claims 1-15, wherein administering an effective amount of a GLP-1 receptor agonist comprises administering parenterally to the subject about 2 mg to about 10 mg exenatide.

21. The method of any one of claims 1-15, wherein administering an effective amount of a GLP- 1 receptor agonist comprises administering parenterally to the subject about 0.75 mg to about 1.5 mg dulaglutide.

22. The method of any one of claims 1-15, wherein administering an effective amount of a GLP-1 receptor agonist comprises administering parenterally to the subject about 30 mg to about 50 mg albiglutide.

23. The method of any one of claims 1-15, wherein administering an effective amount of a GLP-1 receptor agonist comprises administering parenterally to the subject about 10 mg to about 20 mg lixisenatide.

24. A method of treating hepatic steatosis in a subject receiving GLP-1 receptor agonist therapy, the method comprising administering to the subject an effective amount of bempedoic acid.

25. A method of treating liver fibrosis in a subject receiving GLP-1 receptor agonist therapy, the method comprising administering to the subject an effective amount of bempedoic acid.

26. A method of reducing liver fat in a subject receiving GLP- 1 receptor agonist therapy, the method comprising administering to the subject an effective amount of bempedoic acid.

27. A method of reducing hepatocellular ballooning in a subject receiving GLP-1 receptor agonist therapy, the method comprising administering to the subject an effective amount of bempedoic acid.

28. A method of reducing lobular inflammation in a subject receiving GLP- 1 receptor agonist therapy, the method comprising administering to the subject an effective amount of bempedoic acid.

29. The method of any one of claims 24-30, wherein the subject has non-alcoholic steatohepatitis (NASH).

30. The method of any one of claims 24-29, wherein the subject receiving GLP-1 receptor agonist therapy is receiving about 0.25 mg to about 14 mg semaglutide.

31. The method of any one of claims 24-30, wherein the subject receiving GLP-1 receptor agonist therapy is receiving about 0.25 mg to about 1 mg semaglutide.

32. The method of any one of claims 24-30, wherein the subject receiving GLP-1 receptor agonist therapy is receiving about 3 mg to about 14 mg semaglutide.

33. The method of any one of claims 24-29, wherein the subject receiving GLP-1 receptor agonist therapy is receiving about 0.6 mg to about 1.8 mg liraglutide.

34. The method of any one of claims 24-29, wherein the subject receiving GLP-1 receptor agonist therapy is receiving about 2 mg to about 10 mg exenatide.

35. The method of any one of claims 24-29, wherein the subject receiving GLP-1 receptor agonist therapy is receiving about 0.75 mg to about 1.5 mg dulaglutide.

36. The method of any one of claims 24-29, wherein the subject receiving GLP-1 receptor agonist therapy is receiving about 30 mg to about 50 mg albiglutide.

37. The method of any one of claims 24-29, wherein the subject receiving GLP-1 receptor agonist therapy is receiving about 10 mg to about 20 mg lixisenatide.

38. The method of any one of claims 1-37, wherein the effective amount of bempedoic acid is about 120 mg to about 240 mg.

39. The method of any one of claims 1 -38, wherein the effective amount of bempedoic acid is about 180 mg.