Compositions comprising bempedoic acid and a GLP-1 receptor agonist, and combination therapies using bempedoic acid and a GLP-1 receptor agonist.

Abstract

Provided in this disclosure is a method for treating fatty liver and / or hepatic fibrosis by administering a combination of a GLP-1 receptor agonist and bempedoic acid. Also provided in this disclosure is a method for modulating target blood glucose control, hemoglobin A1C levels, body weight, systolic and / or diastolic blood pressure, hepatic fat, ballooning hepatocytes, and / or lobular inflammation by administering a combination of a GLP-1 receptor agonist and bempedoic acid.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits and priority of U.S. Provisional Patent Application No. 63 / 512,395, filed on July 7, 2023, the disclosures of which are incorporated herein by reference in their entirety for all purposes. [Background technology]

[0002] Non-alcoholic fatty liver disease (NAFLD) is estimated to affect 30–40 percent of adults in the United States (Spengler et al. Recommendations for Diagnosis, Referral for Liver Biopsy, and Treatments of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. Mayo Clin. Proc. 2015. 90(9):1233-1246). While the majority of NAFLD cases have little risk of progression, approximately 20 percent of adults with NAFLD develop non-alcoholic steatohepatitis (NASH), a more serious form of NAFLD that poses a greater concern (Spengler et al.). Associated complications and comorbidities of NASH include, but are not limited to, liver fibrosis, cirrhosis, liver cancer, and liver failure (National Institutes of Health). Furthermore, there are currently few approved drug therapies available for the treatment of NASH. Therefore, NASH is a significant health concern.

[0003] Glucagon-like protein-1 (GLP-1) receptor agonists are a class of drugs, some of which are FDA-approved for their usefulness in treating type 2 diabetes, as well as lowering blood glucose levels in patients (e.g., dulaglutide, exenatide, semaglutide, liraglutide, albiglutide, lixisenatide). Semaglutide, the only GLP-1 receptor agonist in this class currently approved for oral administration, has been investigated for the treatment of nonalcoholic steatohepatitis (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 hepatic fibrosis (Newsome et al.).

[0004] Despite the efforts made to date, there remains an unmet need for drug therapies that treat NASH while also improving liver fibrosis. [Overview of the project]

[0005] This disclosure provides combination drug therapies comprising bempedoic acid and a GLP-1 receptor agonist (semaglutide, liraglutide, exenatide, dulaglutide, albiglutide, or lixisenatide). In addition, this disclosure provides a method for treating fatty liver (e.g., non-alcoholic steatohepatitis (NASH)) in subjects requiring treatment using the combination drug therapies described herein. The combination drug therapies described herein are also useful in subjects with fatty liver for one or more of the following: treatment of hepatic fibrosis, regulation of blood glucose control, reduction of hemoglobin A1c (HbA1c) levels in the blood or serum, weight loss, reduction of systolic and / or diastolic blood pressure, reduction of hepatic fat, reduction of ballooning hepatocytes, and reduction of lobular inflammation. The method generally involves administering to the subject an effective dose of bempedoic acid and an effective dose of a GLP-1 receptor agonist described herein.

[0006] In one embodiment, the present disclosure provides a method for treating fatty liver in a patient requiring treatment, comprising administering to the patient an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.

[0007] In another aspect, the present disclosure provides a method for treating hepatic fibrosis in a subject with fatty liver, comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.

[0008] In another aspect, the present disclosure provides a method for regulating blood glucose control in a subject with fatty liver, comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.

[0009] In another aspect, the present disclosure provides a method for reducing the level of hemoglobin A1C (HbA1c) in the blood or serum of a subject with fatty liver, the method comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.

[0010] In another aspect, the present disclosure provides a method for reducing the body weight of a subject with fatty liver, comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.

[0011] In another aspect, the present disclosure provides a method for lowering the systolic and / or diastolic blood pressure of a subject with fatty liver, comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.

[0012] In another aspect, the present disclosure provides a method for reducing hepatic fat in a subject with fatty liver, comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.

[0013] In another aspect, the present disclosure provides a method for reducing ballooning hepatocytes in a subject with fatty liver, comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.

[0014] In another aspect, the present disclosure provides a method for reducing lobular inflammation in a subject with fatty liver, comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.

[0015] In certain embodiments, the fatty liver is NASH.

[0016] In certain embodiments, effective doses of the GLP-1 receptor agonist and bempedoic acid result in lower hbA1c levels in the subject's blood or serum compared to subjects with fatty liver who have not received effective doses of the GLP-1 receptor agonist and bempedoic acid, or who have received effective doses of either (a) the GLP-1 receptor agonist or (b) bempedoic acid. In certain embodiments, effective doses of the GLP-1 receptor agonist and bempedoic acid result in greater weight loss in the subject compared to subjects with fatty liver who have not received effective doses of the GLP-1 receptor agonist and bempedoic acid, or who have received effective doses of either (a) the GLP-1 receptor agonist or (b) bempedoic acid. In certain embodiments, when the GLP-1 receptor agonist and bempedo acid are administered in effective doses, a significant reduction in hepatic fat is observed in subjects with fatty liver compared to subjects who are not administered in effective doses of the GLP-1 receptor agonist and bempedo acid, or subjects who are administered in effective doses of either (a) the GLP-1 receptor agonist or (b) the bempedo acid. In certain embodiments, when the GLP-1 receptor agonist and bempedo acid are administered in effective doses, a significant reduction in hepatic fibrosis is observed in subjects with fatty liver compared to subjects who are not administered in effective doses of the GLP-1 receptor agonist and bempedo acid, or subjects who are administered in effective doses of either (a) the GLP-1 receptor agonist or (b) the bempedo acid.

[0017] 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, administration of an effective dose of the GLP-1 receptor agonist includes administering to the subject about 0.25 mg to about 14 mg of semaglutide. In certain embodiments, administration of an effective dose of the GLP-1 receptor agonist includes parenterally administering to the subject about 0.25 mg to about 1 mg of semaglutide. In certain embodiments, administration of an effective dose of the GLP-1 receptor agonist includes orally administering to the subject about 3 mg to about 14 mg of semaglutide. In certain embodiments, administration of an effective dose of the GLP-1 receptor agonist includes parenterally administering to the subject about 0.6 mg to about 1.8 mg of liraglutide. In certain embodiments, administration of an effective dose of a GLP-1 receptor agonist includes parenterally administering about 2 mg to about 10 mg of exenatide to the subject. In certain embodiments, administration of an effective dose of a GLP-1 receptor agonist includes parenterally administering about 0.75 mg to about 1.5 mg of dulaglutide to the subject. In certain embodiments, administration of an effective dose of a GLP-1 receptor agonist includes parenterally administering about 30 mg to about 50 mg of albiglutide to the subject. In certain embodiments, administration of an effective dose of a GLP-1 receptor agonist includes parenterally administering about 10 mg to about 20 mg of lixisenatide to the subject.

[0018] In another aspect, the present disclosure provides a method for treating fatty liver in a subject receiving a GLP-1 receptor agonist therapy, the method comprising administering an effective amount of bempedoic acid to the subject.

[0019] In another aspect, the present disclosure provides a method for treating hepatic fibrosis in a subject receiving a GLP-1 receptor agonist therapy, the method comprising administering an effective amount of bempedoic acid to the subject.

[0020] In another aspect, the present disclosure provides a method for reducing hepatic fat in a subject receiving a GLP-1 receptor agonist therapy, the method comprising administering an effective amount of bempedoic acid to the subject.

[0021] In another aspect, the present disclosure provides a method for reducing ballooning hepatocytes in a subject receiving a GLP-1 receptor agonist therapy, the method comprising administering an effective amount of bempedoic acid to the subject.

[0022] In another aspect, the present disclosure provides a method for reducing lobular inflammation in a subject receiving a GLP-1 receptor agonist therapy, the method comprising administering an effective amount of bempedoic acid to the subject.

[0023] In certain embodiments, the target is NASH.

[0024] In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 0.25 mg to approximately 14 mg of semaglutide. In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 0.25 mg to approximately 1 mg of semaglutide. In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 3 mg to approximately 14 mg of semaglutide. In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 0.6 mg to approximately 1.8 mg of liraglutide. In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 2 mg to approximately 10 mg of exenatide. In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 0.75 mg to approximately 1.5 mg of dulaglutide. In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 30 mg to 50 mg of albiglutide. In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 10 mg to 20 mg of lixisenatide.

[0025] In certain embodiments, the effective amount of bempedoic acid is from about 120 mg to about 240 mg. In certain embodiments, the effective amount of bempedoic acid is about 180 mg. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] [Figure 1A-1H] Figure 1A shows the percent change in body weight throughout the intervention. Figure 1B shows the percent change in adiposity (post-treatment - pre-treatment) throughout the intervention. Figure 1C shows the intraperitoneal glucose tolerance test (GTT) (1.25 g / kg) over time and the area under the curve (AUC) during a 4-week intervention. Figure 1D shows the intraperitoneal insulin tolerance test (ITT) (1.3 U / kg) over time and the area under the curve (AUC) during a 4-week intervention. Figure 1E shows the intraperitoneal pyruvate tolerance test (PTT) (1.5 g / kg) over time and the area under the curve (AUC) during a 5-week intervention. Figure 1F shows fasting serum insulin collected by tail nick near the end of the intervention (9 weeks). Figure 1G shows fed serum cholesterol obtained from blood drawn by cardiac puncture at sacrifice. Figure 1H shows fasting serum triglycerides. Data are mean ± S.E.M. Colored bars indicate comparison of the group to vehicle. Significance was accepted at p < 0.05 and determined by one-way ANOVA or repeated measures two-way ANOVA with Tukey's post hoc test (where appropriate). White circles are individual mice per group (n = 8 - 9 mice / group). * is P < 0.05, ** is p < 0.01, *** is p < 0.001, **** is p < 0.00 "01. The larger asterisks correspond to Lira and the smaller asterisks correspond to Lira + BemA. Vehicle (subcutaneous treatment with saline every other day), Lira (subcutaneous treatment with 70 μg / kg of liraglutide every other day followed by light off), Lira + BemA (diet containing 10 mg / kg of bempedoic acid and subcutaneous treatment with 70 μg / kg of liraglutide every other day followed by light off). The legend of Figure 1A applies to Figures 1B - 1H.

[0027] [Figure 2A-2I]Figure 2A shows the percentage of liver fat as measured by time-domain NMR. Figure 2B shows liver triglycerides. Figure 2C shows representative micrographs of sections stained with H&E (upper) and sections stained with picrosilius red (PSR, lower) (10×). Figure 2D is a histogram of the histological grade of fatty liver disease. Figure 2E is a histogram of the histological grade of ballooning hepatocytes. Figure 2F is a histogram of the histological grade of lobular inflammation. Figure 2G is a histogram of the composite NAFLD activity score (NAS). Figure 2H shows the percentage of PSR-positive area. Figure 2I shows the percentage of the total that shows the presence of moderate perisinusoidal fibrosis in zone 3. Data are mean ± SEM. Colored bars show group-vehicle comparisons, along with the percentages listed next to the bars. Significance was accepted at p<0.05 and determined by one-way ANOVA and Tukey's post-hoc test, or for histological score analysis, the Kruskal-Wallis test was used in conjunction with Dunn's post-hoc test to correct for multiple comparisons (where appropriate). White circles represent individual mice per group (n=8-9 mice / group). * indicates p<0.05, ** indicates p<0.01, *** indicates p<0.001, and **** indicates p<0.0001. The larger asterisk corresponds to Lira, and the smaller asterisk corresponds to Lira+BemA. Vehicle (subcutaneous treatment with physiological saline every two days), Lira (subcutaneous treatment with 70 μg / kg of liraglutide every two days followed by lights off), Lira+BemA (diet containing 10 mg / kg of bempedoic acid, subcutaneous treatment with 70 μg / kg of liraglutide every two days followed by lights off). The legend in Figure 2A applies to Figures 2B and 2D-2H.

[0028] [Figure 3A] The signature scores of transcriptional pathways particularly affected by combination therapy are shown. [Figure 3B] This describes PCA for control, monotherapy, and combination therapy, showing PCA based on pathway signature scores. [Figure 3C]The odds ratios and 95% confidence intervals associated with measurements of fatty liver, balloonoid malformation, inflammation, fibrosis, NAS, and hepatic steatosis are shown, based on the PC1 of the pathway signature score. [Figure 3D] This shows the gene expression of hepatic stellate cell markers associated with NASH progression. [Figure 3E] This shows gene expression of chemokines associated with NASH progression.

[0029] [Figure 4A] Healthy patients, NASH / NAFLD patients, and experimental cohorts exhibit scaled expression of prognostically significant orthologous genes involved in NASH progression. [Figure 4B] This shows the distribution of disease stages and treatment types in Cluster III. [Figure 4C] This shows PCA of human NASH / NAFLD patients and experimental cohorts, representing PCA based on scaled gene expression. [Figure 4D] Regarding the prediction of fibrosis stage 2 or higher, we present the ROC of a multivariate logistic regression model using combination-specific gene signatures (a smaller subset derived using elastic net normalization) and 25 gene signatures previously reported by Govaere et al. in human NASH / NAFLD patients. [Figure 4E] Classification based on the similarity of gene signature expression indicates the identification of differentially expressed hepatocyte types among patients classified into similar or different classes.

[0030] [Figure 5A-5H]Figure 5A shows the percentage change in body weight throughout the intervention. Figure 5B shows the percentage change in hyperlipidemia (post-treatment - pre-treatment) throughout the intervention. Figure 5C shows the intraperitoneal glucose tolerance test (GTT) (1.25 g / kg) (time plot and area under the curve (AUC)) for the 4-week intervention. Figure 5D shows the intraperitoneal insulin tolerance test (ITT) (1.3 U / kg) (time plot and area under the curve (AUC)) for the 4-week intervention. Figure 5E shows the intraperitoneal pyruvate tolerance test (PTT) (1.5 g / kg) (time plot and area under the curve (AUC)) for the 5-week intervention. Figure 5F shows fasting serum insulin collected by making a tail wound near the end of the intervention (9 weeks). Figure 5G shows satiety serum cholesterol obtained from blood collected by cardiac puncture at the time of euthanasia. Figure 5H shows fasting serum triglycerides. Data are mean ± SEM. Black bars indicate a comparison between the group and the control group (ND). Significance is accepted at p<0.05 and determined by independent t-tests or repeated measures two-way ANOVA and Sidak post-hoc tests (where appropriate). White circles represent individual mice per group (n=8-9 mice / group). * indicates P<0.05, ND (or control), or ND+BemA (bempedoic acid 10 mg / kg in diet). Apply the legend from Figure 5A to Figures 5B-5H.

[0031] [Figure 6A-6I]Figure 6A shows the percentage of liver fat as measured by time-domain NMR. Figure 6B shows liver triglycerides. Figure 6C shows representative micrographs (10×) of sections stained with H&E (upper) and sections stained with picrosilius red (PSR, lower). Figure 6D is a histogram of the histological grades of fatty liver disease. Figure 6E is a histogram of the histological grades of ballooning hepatocytes. Figure 6F is a histogram of the histological grades of lobular inflammation. Figure 6G is a histogram of the composite NAFLD activity score (NAS). Figure 6H shows the percentage of PSR-positive area. Figure 6I shows the proportion of the total that shows the presence of moderate perisinusoidal fibrosis in zone 3. Data are mean ± SEM. Black bars indicate the comparison between the group and the control group (ND). Significance was accepted at p<0.05 and determined by independent t-tests, or, for histological score analysis, by the Mann-Whitney test (where appropriate). * indicates p<0.05, and ** indicates p<0.01. White circles represent individual mice in each group (n=8-9 mice / group). ND (or control), ND+BemA (bempedoic acid 10 mg / kg in diet). The legend in Figure 6A applies to Figures 6B and 6D-6I.

[0032] [Figure 7A] This shows the number of genes that were differentially expressed in each treatment group. [Figure 7B] Significant duplication is observed between downregulated genes. [Figure 7C] This chart shows the overlap between genes significantly upregulated by combination therapy and genes differentially expressed in all other treatment groups. Horizontal dash symbols indicate genes specifically regulated by combination therapy. Downward diagonal lines (from left to right) indicate genes upregulated or downregulated in all treatment groups. Crossover patterns indicate genes upregulated by monotherapy and downregulated by combination therapy. [Figure 7D]This shows over-annotated pathways associated with genes that were additively and uniquely downregulated by combination therapy.

[0033] [Figure 8A] This shows the signature scores for all pathways in the Nanostring nCounter Fibrosis v2 Panel. [Figure 8B] This shows the gene expression of specific genes involved in the TGFβ pathway.

[0034] [Figure 9A] Compared to control and monotherapy, combination therapy shows differentially regulated intergenetic duplication. [Figure 9B] It shows the expression of 33 gene signatures. [Figure 9C] This shows the distribution of disease stages among patients in similar or different classes. [Figure 9D] This study demonstrates that classification based on the similarity of gene signature expression can identify differential expression of Hallmark gene sets between similar and different classes.

[0035] [Figure 10] This paper presents differential expression analyses comparing liraglutide, bempedoic acid, and combination therapy (liraglutide + bempedoic acid) with disease controls.

[0036] [Figure 11] Downregulation gene and pathway annotation analysis is shown.

[0037] [Figure 12] This shows pathway annotation analysis of genes that were uniquely and additively downregulated by combination therapy (liraglutide + bempedoic acid). [Modes for carrying out the invention]

[0038] As generally described herein, this disclosure provides a method for treating fatty liver (e.g., non-alcoholic steatohepatitis (NASH)) and hepatic fibrosis in subjects requiring treatment. The method generally involves administering to the subject an effective dose of a combination of a GLP-1 receptor agonist (e.g., semaglutide, liraglutide, exenatide, dulaglutide, albiglutide, and lixisenatide) and bempedoic acid. Also provided in this disclosure is a method for treating fatty liver (e.g., non-alcoholic steatohepatitis (NASH)) and hepatic fibrosis in subjects receiving GLP-1 receptor agonist therapy (e.g., semaglutide, liraglutide, exenatide, dulaglutide, albiglutide, and lixisenatide). The method generally involves administering to the subject an effective dose of bempedoic acid.

[0039] definition To facilitate understanding of this disclosure, several terms and phrases are defined below.

[0040] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art in which this disclosure pertains. Abbreviations used herein have their conventional meanings in the fields of chemistry and biology. The chemical structures and formulas defined herein are constructed in accordance with the standard rules of chemical valencies known in the field of chemistry.

[0041] Throughout this Specification, where compositions and kits are described as having, including, or comprising certain components, or where processes and methods are described as having, including, or comprising certain steps, it is intended that, in addition to those, there exist compositions and kits of the Disclosure that are essentially composed of or comprise the listed components, and processes and methods of the Disclosure that are essentially composed of or comprise the listed process steps.

[0042] Where it is stated in this application that an element or component is included in and / or selected from a list of enumerated elements or components, it should be understood that the element or component may be any one of the enumerated elements or components, or it may be selected from a group consisting of two or more of the enumerated elements or components.

[0043] Furthermore, it should be understood that the elements and / or features of the compositions or methods described herein can be combined in various ways, whether expressly or implicitly, without departing from the spirit and scope of this disclosure. For example, where a particular compound is referred to, unless otherwise understood from the context, that compound can be used in various embodiments and / or methods of the compositions of this disclosure. In other words, while embodiments are described and depicted within this application in a manner that allows for the writing and depiction of an obvious and concise application, it will be apparent that embodiments may be combined or separated in various ways without departing from this teaching and disclosure. For example, it will be apparent that all features described and depicted herein can be applied to all embodiments of the disclosure described and depicted herein.

[0044] The articles “a” and “an” are used in this disclosure to refer to one or more (i.e., at least one) grammatical objects of the articles, unless the context is inappropriate. For example, “(an) element” refers to one or more elements.

[0045] Unless otherwise indicated, the term "and / or" is used in this disclosure to mean either "and" or "or".

[0046] The expression "at least one of ~" should be understood to include each of the items listed after it, and any various combinations of two or more of the listed items, unless otherwise understood from the context and usage. The expression "and / or" relating to three or more listed items should be understood to have the same meaning unless otherwise understood from the context.

[0047] The use of the terms “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including their grammatical equivalents, should generally be understood as open-ended and non-limiting, not excluding, for example, additional unmentioned elements or processes, unless specifically indicated otherwise or understood from the context.

[0048] Where the term "approximately" is used before a quantitative value, this disclosure also includes that specific quantitative value itself, unless otherwise specifically indicated. As used herein, the term "approximately" means a variation of ±10%, ±5%, ±2%, or ±1% from the nominal value, unless otherwise indicated or inferred from the context.

[0049] As long as this disclosure remains implementable, please understand that the order of the processes or the order in which specific actions are performed is not important. Furthermore, two or more processes or actions may be performed simultaneously.

[0050] In various places in this specification, variables or parameters are disclosed in groups or ranges. This description is specifically intended to include any individual partial combination of elements of such groups and ranges. For example, integers in the range of 0 to 40 are specifically intended to 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 individually, and integers in the range of 1 to 20 are specifically intended to disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 individually.

[0051] Unless specifically requested, any use of example or illustrative language in this specification, such as “such as” or “including,” is intended solely to better describe this disclosure and not to limit its scope. No language in this specification should be construed as indicating any unrequested element as essential for the implementation of this disclosure.

[0052] As a general rule, compositions for which percentages are specified are based on weight unless otherwise specified. Furthermore, if a variable element is not defined, the previous definition of that variable element takes precedence.

[0053] As used herein, “pharmaceutical composition” or “pharmaceutical preparation” refers to a combination of an activator and a carrier (an inactive or active carrier) that makes the composition particularly suitable for use in in vivo or ex vivo diagnostic or therapeutic applications.

[0054] As used herein, the terms “pharmaceutically acceptable” and “pharmacologically acceptable” refer to compounds, molecular entities, compositions, materials and / or dosage forms that, when administered appropriately to animals or humans, do not cause adverse reactions, allergic reactions or other unwanted reactions. For administration to humans, preparations must meet the standards of sterility, pyrogenicity, and general safety and purity as required by regulatory authorities that evaluate the safety and efficacy of pharmaceuticals and drugs, such as the U.S. Food and Drug Administration. “pharmaceutically acceptable” and “pharmacologically acceptable” may mean that they are approved or authorized by federal or state regulatory authorities or corresponding agencies in countries other than the United States, or that they are listed in the United States Pharmacopeia or other generally accepted pharmacopoeias for use in animals, and more specifically, in humans.

[0055] As used herein, “compound” (including a specifically named compound, e.g., bempedoic acid or a GLP-1 receptor agonist as described herein) means the compound itself and its pharmaceutically acceptable salts, unless otherwise understood in the context of this description or expressly limited to a particular form of the compound, e.g., the compound itself or a pharmaceutically acceptable salt thereof.

[0056] As used herein, “pharmaceutically acceptable salt” means any salt of an acidic or basic group that may be present in the compounds of this disclosure (e.g., bempedoic acid or GLP-1 receptor agonists as described herein) that is suitable for pharmacopoeial administration. For example, one or both of the carboxylic acid groups of bempedoic acid may be ionic.

[0057] As is known to those skilled 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 acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Other acids, such as oxalic acid, which are themselves pharmaceutically unacceptable, may be used in preparing salts that are useful as intermediate products in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts.

[0058] Examples of bases include alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and formula NW4. + The compound (wherein W is C) 1-4 Examples include alkyl groups, but are not limited to these.

[0059] Examples of salts include, but are not limited to, acetate, adipine, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Other examples of salts include appropriate cations, such as Na. + , K + Ca 2+ NH4 + and NW4 + (In the formula, W is C1-4 Examples include anions of the compounds of this disclosure that are combined with alkyl groups.

[0060] For therapeutic use, salts of the compounds of this disclosure are intended to be pharmaceutically acceptable. However, pharmaceutically unacceptable acid and base salts may also be used, for example, in the preparation or purification of pharmaceutically acceptable compounds.

[0061] As used herein, “carrier” means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulant, that carries a pharmaceutical agent, such as pempedoic acid or a pharmaceutically acceptable salt thereof, or is involved in transporting it from one organ or part of the body to another organ or part of the body.

[0062] As used herein, “pharmaceutically acceptable excipients” means substances that can be included in the compositions of this disclosure without causing serious and harmful toxic effects to the patient, and which assist in the administration and / or absorption of the activator to the subject. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, ordinary saline, e.g., phosphate-buffered saline, emulsions (e.g., oil / water emulsion or water / oil emulsion), Ringer's lactate solution, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (e.g., Ringer's solution), alcohols, oils, gelatin, glycans, e.g., lactose, amylose or starch, fatty acid esters, hydroxypropyl methylcellulose, polyvinyl pyrrolidine, pigments, and the like. Such preparations can be sterilized and, if desired, mixed with excipients such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts to affect osmotic pressure, buffers, colorants, and / or aromatics, which do not react adversely with the compounds of the Disclosure. For examples of excipients, see Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).

[0063] As used herein, “to treat,” “to treat,” or “to treat” includes any action taken while a subject (e.g., an adult) is suffering from a particular disease, disorder, or condition that reduces the severity of the disease, disorder, or condition, or delays or slows the progression of the disease, disorder, or condition (e.g., inhibiting, reducing, regulating, improving, or eliminating the condition, disease, disorder, etc.), or inhibiting, reducing, regulating, improving, or eliminating the symptoms thereof. Treatment may be to cure, improve, or at least partially improve the disorder. In certain embodiments, treatment is to cure the disease.

[0064] As used herein, “reduction” or “reduction” (and grammatically equivalent terms) of one or more symptoms means reducing the severity or frequency of the symptom(s) or eliminating the symptom(s). For example, “reduction” or “reduction” of hepatic fibrosis may mean a decrease in the rate of accumulation of fibrous tissue in the liver, a decrease in the stage of hepatic fibrosis (e.g., a decrease in the amount of fibrous tissue in the liver), or a reversal of hepatic fibrosis.

[0065] As used herein, “reducing” or “reducing” an increase in a biomarker / parameter (e.g., HbA1c, LDL-C, etc.) or vital sign (e.g., blood pressure) in a test that is associated with a disease disclosed herein may mean that the increase in the biomarker / parameter or vital sign in the test is reduced, for example, to a predetermined clinically significant endpoint (e.g., a clinically normal level).

[0066] As used herein, “subject” and “patient” are used synonymously and refer to the organism to be treated by the methods and compositions of this disclosure. Such organisms are preferably mammals (e.g., humans, mice, rats, guinea pigs, dogs, cats, horses, cattle, pigs, or non-human primates, e.g., monkeys, chimpanzees, baboons, and rhesus macaques), and more preferably humans. In certain embodiments, the subject is an adult human.

[0067] As used herein, “solid dosage form” refers to a drug administration agent in solid form, such as tablets, capsules, granules, powders, sachets, reconstituted powders, dry powder inhalants, and chewable tablets.

[0068] As used herein, “fixed-dose combination” refers to a form in which both active ingredients (e.g., bempedoic acid and semaglutide) are administered to the patient simultaneously in the form of a single entity or a single dose.

[0069] As used herein, “administering” refers to oral administration, suppository administration, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intrafocal administration, intrathecal administration, intracranial administration, intranasal administration, or subcutaneous administration, or implantation of a sustained-release device, such as a mini osmotic pump. Administration is by any route, including parenteral and transmucosal routes (e.g., oral, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal routes). Examples of parenteral administration include intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intracavitary, and intracranial administration. Other delivery methods include, but are not limited to, liposomal formulations, intravenous infusion, and transdermal patches. "Concomitant administration" means administering the composition described herein concurrently with, immediately before or immediately after, the administration of one or more additional therapeutic agents (e.g., bempedoic acid and semaglutide). Semaglutide or a pharmaceutically acceptable salt thereof may be administered to the patient alone or in combination. Concomitant administration is intended to include administering the compound individually or in combination (two or more compounds or agents) simultaneously or sequentially. Thus, the preparation may also be combined with other active substances (e.g., to reduce metabolic degradation) if desired.

[0070] As used herein, “disease,” “disorder,” “condition,” or “illness” can be used synonymously unless otherwise understood from the context, and refer to the state or health condition of a patient or subject that can be treated with the compounds, medicinal materials, medicinal compositions, or methods provided herein. In some embodiments, the combinations described herein include, for example, the alleviation or elimination of one or more symptoms of the disease, disorder, condition, or illness of the disclosure through the administration of such combination.

[0071] As used herein, “balloon-like enlargement of hepatocytes” may refer to the process of hepatocyte death.

[0072] As used herein, "lobular inflammation" may refer to the presence of lobular inflammatory foci (clusters of inflammatory cells) as observed under a microscope in slices of liver biopsy specimens stained with hematoxylin and eosin (H&E).

[0073] As used herein, “effective dose” or “therapeutic effective dose” refers to the amount of a compound, pharmaceutical composition, or combination of fixed doses (e.g., the combination of fixed doses in this disclosure) that is sufficient to produce a beneficial or desired result. An effective dose may be administered in one or more doses, topical applications, or prescriptions and is not intended to be limited to any particular formulation or route of administration. Abbreviation: 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 A1c / hbA1c: Glycated hemoglobin hsCRP: Highly sensitive C-reactive protein apoB: Apolipoprotein B apo A1: Apolipoprotein A1

[0074] Bempedoic acid Bempedoic acid is a non-statin drug indicated for use in adults with primary hyperoxaluria (including heterozygous familial hypercholesterolemia (HeFH)) to lower LDL-C, and / or as a dietary adjunct in adults who are unable to receive recommended statin therapy (including statin-free therapy), have established cardiovascular disease (CVD) or are at high risk of CVD events, but do not have established CVD, to reduce the risk of myocardial infarction and coronary revascularization, in combination with other LDL-C lowering therapies, or alone when combination LDL-C lowering therapy is not possible. Bempedoic acid functions through the inhibition of adenosine triphosphate-citrate lyase (ACL). In vivo, bempedoic acid behaves as a prodrug, in which case its active species, bempedoic acid-CoA, is converted by endogenous hepatic acyl-coenzyme (CoA) synthetase (ACS) activity. To form this active species, a specific ACS isozyme, very long-chain acyl-CoA synthetase (ACSVL1), is required. Bempedoic acid can also activate AMP-activated protein kinase (AMPK), a metabolic sensor.

[0075] Bempedoic acid may be represented by the structure shown in formula (I) below. TIFF2026522971000002.tif43164

[0076] Bempedoic acid and its synthesis process are disclosed in U.S. Patent Nos. 7,335,799 and 11,407,705, and International Publication No. WO2020 / 257571A1, each of which is incorporated herein by reference. Bempedoic acid may also be referred to by the trademarks ETC-1002, ESP-55016, or Nexletol® and Nilemdo®.

[0077] In various embodiments, bempedoic acid may be used to treat and / or prevent the various conditions, diseases, and disorders described herein. Methods for treating the conditions, diseases, or disorders described herein generally involve administering a therapeutically effective amount of bempedoic acid to a subject in need of treatment to treat the condition, disease, or disorder.

[0078] In certain embodiments, bempedoic acid may be used to treat fatty liver in subjects requiring treatment. In certain embodiments, bempedoic acid may be used to treat hepatic fibrosis in subjects with fatty liver. In certain embodiments, bempedoic acid may be used to regulate blood glucose control in subjects with fatty liver. In certain embodiments, bempedoic acid may be used to lower hemoglobin A1c (HbA1c) levels in the blood or serum of subjects with fatty liver. In certain embodiments, bempedoic acid may be used to reduce the body weight of subjects with fatty liver. In certain embodiments, bempedoic acid may be used to lower the systolic and / or diastolic blood pressure of subjects with fatty liver. In certain embodiments, bempedoic acid may be used to reduce hepatic fat in subjects with fatty liver. In certain embodiments, bempedoic acid may be used to reduce ballooning hepatocytes in subjects with fatty liver. In certain embodiments, bempedoic acid may be used to reduce lobular inflammation in subjects with fatty liver.

[0079] In certain embodiments, bempedoic acid may be used in combination with a GLP-1 receptor agonist to treat fatty liver in subjects requiring treatment. In certain embodiments, bempedoic acid may be used in combination with a GLP-1 receptor agonist to treat hepatic fibrosis in subjects with fatty liver. In certain embodiments, bempedoic acid may be used in combination with a GLP-1 receptor agonist to modulate blood glucose control in subjects with fatty liver. In certain embodiments, bempedoic acid may be used in combination with a GLP-1 receptor agonist to lower HbA1c levels in the blood or serum of subjects with fatty liver. In certain embodiments, bempedoic acid may be used in combination with a GLP-1 receptor agonist to reduce body weight in subjects with fatty liver. In certain embodiments, bempedoic acid may be used in combination with a GLP-1 receptor agonist to lower systolic and / or diastolic blood pressure in subjects with fatty liver. In certain embodiments, bempedoic acid may be used in combination with a GLP-1 receptor agonist to reduce hepatic fat in subjects with fatty liver. In certain embodiments, bempedoic acid may be used in combination with a GLP-1 receptor agonist to reduce ballooning hepatocytes in subjects with fatty liver. In certain embodiments, bempedoic acid may be used in combination with a GLP-1 receptor agonist to reduce lobular inflammation in subjects with fatty liver.

[0080] In certain embodiments, bempedoic acid may be used to treat fatty liver in subjects receiving GLP-1 receptor agonist therapy. In certain embodiments, bempedoic acid may be used to treat hepatic fibrosis in subjects with fatty liver who are receiving GLP-1 receptor agonist therapy. In certain embodiments, bempedoic acid may be used to regulate blood glucose control in subjects with fatty liver who are receiving GLP-1 receptor agonist therapy. In certain embodiments, bempedoic acid may be used to lower HbA1c levels in the blood or serum of subjects with fatty liver who are receiving GLP-1 receptor agonist therapy. In certain embodiments, bempedoic acid may be used to reduce body weight in subjects with fatty liver who are receiving GLP-1 receptor agonist therapy. In certain embodiments, bempedoic acid may be used to lower the systolic and / or diastolic blood pressure of subjects with fatty liver who are being treated with GLP-1 receptor agonist therapy. In certain embodiments, bempedoic acid may be used to reduce hepatic fat in subjects with fatty liver who are being treated with GLP-1 receptor agonist therapy. In certain embodiments, bempedoic acid may be used to reduce ballooning hepatocytes in subjects with fatty liver who are being treated with GLP-1 receptor agonist therapy. In certain embodiments, bempedoic acid may be used to reduce lobular inflammation in subjects with fatty liver who are being treated with GLP-1 receptor agonist therapy.

[0081] In certain embodiments, the fixed-dose combinations and pharmaceutical formulations disclosed herein include 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, for example, International Publication WO2020 / 257573A1 (incorporated herein by reference).

[0082] In certain embodiments, the fixed-dose combinations and pharmaceutical formulations disclosed herein include a high-purity crystalline form of bempedoic acid.

[0083] In certain embodiments, the fixed-dose combinations and pharmaceutical formulations disclosed herein include pharmaceutical materials containing bempedoic acid.

[0084] In various embodiments, the pharmaceutical material generally contains bempedoic acid in a crystalline form, in which case the pharmaceutical material contains bempedoic acid or a pharmaceutically acceptable salt thereof in an amount greater than 99.0% by weight of 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 contains bempedoic acid or a pharmaceutically acceptable salt thereof in an amount greater than 99.5% by weight of the total weight of the pharmaceutical material. In some embodiments, the pharmaceutical material contains bempedoic acid or a pharmaceutically acceptable salt thereof in an amount exceeding 99.7% by weight of the total weight of the pharmaceutical material. In some embodiments, the pharmaceutical material contains bempedoic acid or a pharmaceutically acceptable salt thereof in an amount exceeding 99.9% by weight of the total weight of the pharmaceutical material.

[0085] In various embodiments, the pharmaceutical material generally contains bempedoic acid in a crystalline form, in which case the pharmaceutical material contains bempedoic acid in an amount greater than 99.0% by weight of the total weight of the pharmaceutical material. In some embodiments, the amount of bempedoic acid in the pharmaceutical material is about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.85%, about 99.9%, about 99.95%, or about 99.98% by weight of the total weight of the pharmaceutical material. In some embodiments, the pharmaceutical material contains bempedoic acid in an amount greater than 99.5% by weight of the total weight of the pharmaceutical material. In some embodiments, the pharmaceutical material contains bempedoic acid in an amount greater than 99.7% by weight of the total weight of the pharmaceutical material. In some embodiments, the pharmaceutical material contains bempedoic acid in an amount exceeding 99.9% by weight of the total weight of the pharmaceutical material.

[0086] In certain embodiments, the pharmaceutical material contains bempedoic acid in an amount of approximately 98% to approximately 102% by weight of the total weight of the pharmaceutical material (anhydrous, solvent-free basis), as determined by a high-performance liquid chromatography (HPLC) assay.

[0087] In certain embodiments, the HPLC assay includes one or more of the following: (i) Waters XBridge BEH C18 column (4.6mm (id) x 150mm, 2.5pm) (ii) Column temperature: approximately 40°C (iii) Mobile phase containing approximately 0.05% phosphoric acid in water / acetonitrile (approximately 50:50) (iv) Isocratic elution (v)Flow rate: approx. 1.2mL / min (vi) Sample temperature: Ambient temperature (vii) Detected at 215nm (viii) The retention time of the compound of formula (I) is approximately 4.6 minutes. In some embodiments, the HPLC assay includes each of the above, i.e., (i) to (viii).

[0088] In certain embodiments, the crystalline form of bempedoic acid may be one of those characterized in International Publication Nos. WO2020 / 257571A1 and WO2020 / 257573A1 (each of which is incorporated herein by reference). The crystalline form of bempedoic acid may be characterized, for example, by the pattern or peak(s) of powder X-ray diffraction and / or other characteristic properties, such as melting point and hygroscopicity. Examples of crystalline forms of bempedoic acid include, but are not limited to, cocrystals (e.g., aspartame cocrystals and palmitic acid cocrystals) and salt crystals (e.g., ammonium salts, sodium salts, potassium salts, calcium salts, lysine salts, diethylamine salts, ethylenediamine salts, piperazine salts, betaine salts, tromethamine salts and isonicotinamide salts).

[0089] GLP-1 receptor agonist Glucagon-like protein-1 (GLP-1) receptor agonists are indicated for the treatment of subjects with type 2 diabetes mellitus. GLP-1 receptor agonists regulate (lower) blood glucose levels by inducing insulin production and inhibiting glucagon. Subjects receiving GLP-1 receptor agonist therapy may experience weight loss and a reduced risk of major adverse cardiovascular events. GLP-1 receptor agonists may be used in fixed-dose combinations, pharmaceutical compositions, and therapeutic methods as described herein. In certain embodiments, the GLP-1 receptor agonist is selected from the group consisting of semaglutide, liraglutide, exenatide, dulaglutide, albiglutide, and lixisenatide.

[0090] In various embodiments, GLP-1 receptor agonists may be used to treat or prevent conditions, diseases, or disorders described herein. Methods for preventing or treating a disease or disorder generally involve administering a therapeutically effective dose of a GLP-1 receptor agonist to a subject in need of such prevention or treatment to prevent or treat the disease or disorder.

[0091] In certain embodiments, the GLP-1 receptor agonist may be used to treat fatty liver in subjects requiring treatment. In certain embodiments, the GLP-1 receptor agonist may be used to treat hepatic fibrosis in subjects with fatty liver. In certain embodiments, the GLP-1 receptor agonist may be used to regulate blood glucose control in subjects with fatty liver. In certain embodiments, the GLP-1 receptor agonist may be used to lower HbA1c levels in the blood or serum of subjects with fatty liver. In certain embodiments, the GLP-1 receptor agonist may be used to reduce body weight in subjects with fatty liver. In certain embodiments, the GLP-1 receptor agonist may be used to lower systolic and / or diastolic blood pressure in subjects with fatty liver. In certain embodiments, the GLP-1 receptor agonist may be used to reduce hepatic fat in subjects with fatty liver. In certain embodiments, the GLP-1 receptor agonist may be used to reduce ballooning hepatocytes in subjects with fatty liver. In certain embodiments, the GLP-1 receptor agonist may be used to reduce lobular inflammation in subjects with fatty liver.

[0092] In certain embodiments, the GLP-1 receptor agonist may be used in combination with bempedo acid to treat fatty liver in subjects requiring treatment. In certain embodiments, the GLP-1 receptor agonist may be used in combination with bempedo acid to treat hepatic fibrosis in subjects with fatty liver. In certain embodiments, the GLP-1 receptor agonist may be used in combination with bempedo acid to regulate blood glucose control in subjects with fatty liver. In certain embodiments, the GLP-1 receptor agonist may be used in combination with bempedo acid to lower HbA1c levels in the blood or serum of subjects with fatty liver. In certain embodiments, the GLP-1 receptor agonist may be used in combination with bempedo acid to reduce the body weight of subjects with fatty liver. In certain embodiments, the GLP-1 receptor agonist may be used in combination with bempedo acid to lower the systolic and / or diastolic blood pressure of subjects with fatty liver. In certain embodiments, the GLP-1 receptor agonist may be used in combination with bempedoic acid to reduce hepatic fat in subjects with fatty liver. In certain embodiments, the GLP-1 receptor agonist may be used in combination with bempedoic acid to reduce ballooning hepatocytes in subjects with fatty liver. In certain embodiments, the GLP-1 receptor agonist may be used in combination with bempedoic acid to reduce lobular inflammation in subjects with fatty liver.

[0093] Semaglutide In various embodiments, the GLP-1 receptor agonist is semaglutide. Semaglutide may be represented by the structure of formula (II) below. TIFF2026522971000003.tif33164

[0094] Semaglutide, as well as its methods of use and administration, are, 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, and 9 Semaglutide is disclosed in Patent Nos. 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 in oral or parenteral dosage forms. Semaglutide may be referred to by the trademarks Ozempic® (parenteral dosage form) and Rybelsus® (oral dosage form).

[0095] In various embodiments, semaglutide is administered to the target population in doses of approximately 0.25 mg to 14 mg, 1 mg to 14 mg, 2 mg to 14 mg, 3 mg to 14 mg, 4 mg to 14 mg, 5 mg to 14 mg, 6 mg to 14 mg, 7 mg to 14 mg, 8 mg to 14 mg, 9 mg to 14 mg, 10 mg to 14 mg, 12 mg to 14 mg, 0.25 mg to 12 mg, 0.25 mg to 10 mg, 0.25 mg to 9 mg, 0.25 mg to 8 mg, and 0.25 mg to 14 mg. Approximately 7 mg, approximately 0.25 mg to approximately 6 mg, approximately 0.25 mg to approximately 5 mg, approximately 0.25 mg to approximately 4 mg, approximately 0.25 mg to approximately 3 mg, approximately 0.25 mg to approximately 2 mg, approximately 0.25 mg to approximately 1 mg, approximately 1 mg to approximately 12 mg, approximately 1 mg to approximately 10 mg, approximately 1 mg Approximately 9 mg, approximately 1 mg to approximately 8 mg, approximately 1 mg to approximately 7 mg, approximately 1 mg to approximately 6 mg, approximately 1 mg to approximately 5 mg, approximately 1 mg to approximately 4 mg, approximately 1 mg to approximately 3 mg, approximately 1 mg to approximately 2 mg, approximately 2 mg to approximately 12 mg, approximately 2 mg to approximately 10 mg, approximately 2 mg to approximately 9 mg, approximately 2 mg ~about 8mg, about 2mg to about 7mg, about 2mg to about 6mg, about 2mg to about 5mg, about 2mg to about 4mg, about 2mg to about 3mg, about 3mg to about 12mg, about 3mg to about 10mg, about 3mg to about 9mg, about 3mg to about 8mg, about 3mg to about 7mg, about 3 mg~6mg, 3mg~5mg, 3mg~4mg, 4mg~12mg, 4mg~10mg, 4mg~9mg, 4mg~8mg, 4mg~7mg, 4mg~6mg, 4mg~5mg, 5mg~12mg, Semaglutide may be administered in amounts of approximately 5mg to 10mg, 5mg to 9mg, 5mg to 8mg, 5mg to 7mg, 5mg to 6mg, 6mg to 12mg, 6mg to 10mg, 6mg to 9mg, 6mg to 8mg, 6mg to 7mg, 7mg to 12mg, 7mg to 10mg, 7mg to 9mg, 7mg to 8mg, 8mg to 12mg, 8mg to 10mg, 8mg to 9mg, 9mg to 12mg, 9mg to 10mg, or 10mg to 12mg. In various embodiments, semaglutide may be administered to the subject in amounts of approximately 0.25mg to 1mg. In various embodiments, semaglutide may be administered to the subject in amounts of approximately 3mg to 14mg.

[0096] In certain embodiments, semaglutide may be administered to subjects in amounts of approximately 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, or 14 mg.

[0097] In various embodiments, semaglutide is available in oral dosage forms for the target population at approximately 3 mg to 14 mg, 4 mg to 14 mg, 5 mg to 14 mg, 6 mg to 14 mg, 7 mg to 14 mg, 8 mg to 14 mg, 9 mg to 14 mg, 10 mg to 14 mg, 11 mg to 14 mg, 12 mg to 14 mg, 13 mg to 14 mg, 3 mg to 13 mg, 3 mg to 12 mg, 3 mg to 11 mg, 3 mg to 10 mg, and 3 mg to 14 mg. 9mg, about 3mg to about 8mg, about 3mg to about 7mg, about 3mg to about 6mg, about 3mg to about 5mg, about 3mg to about 4mg, about 4mg to about 13mg, about 4mg to about 12mg, about 4mg to about 11mg, about 4mg to about 10mg, about 4mg ~9mg, 4mg~8mg, 4mg~7mg, 4mg~6mg, 4mg~5mg, 5mg~13mg, 5mg~12mg, 5mg~11mg, 5mg~10mg, 5mg~9mg, 5m g ~ about 8 mg, about 5 mg - about 7 mg, about 5 mg - about 6 mg, about 6 mg - about 13 mg, about 6 mg - about 12 mg, about 6 mg - about 11 mg, about 6 mg - about 10 mg, about 6 mg - about 9 mg, about 6 mg - about 8 mg, about 6 mg - about 7 mg, about 7mg to about 13mg, about 7mg to about 12mg, about 7mg to about 11mg, about 7mg to about 10mg, about 7mg to about 9mg, about 7mg to about 8mg, about 8mg to about 13mg, about 7mg to about 12mg, about 7mg to about 11mg, about 7mg to about 1 Semaglutide may be administered in amounts of 0 mg, approximately 7 mg to 9 mg, approximately 7 mg to 8 mg, approximately 8 mg to 13 mg, approximately 8 mg to 12 mg, approximately 8 mg to 11 mg, approximately 8 mg to 10 mg, approximately 8 mg to 9 mg, approximately 9 mg to 13 mg, approximately 9 mg to 12 mg, approximately 9 mg to 11 mg, approximately 9 mg to 10 mg, approximately 10 mg to 13 mg, approximately 10 mg to 12 mg, approximately 10 mg to 11 mg, approximately 11 mg to 13 mg, approximately 11 mg to 12 mg, or approximately 12 mg to 13 mg. In various embodiments, semaglutide may be administered orally to the subject in amounts of approximately 3 mg to 14 mg.

[0098] In certain embodiments, semaglutide may be administered orally to subjects in amounts of approximately 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, or 14 mg.

[0099] In various embodiments, semaglutide is administered as a parenteral dosage form in doses of approximately 0.25 mg to 1 mg, 0.3 mg to 1 mg, 0.4 mg to 1 mg, 0.5 mg to 1 mg, 0.6 mg to 1 mg, 0.7 mg to 1 mg, 0.8 mg to 1 mg, 0.9 mg to 1 mg, 0.25 mg to 0.9 mg, 0.25 mg to 0.8 mg, 0.25 mg to 0.7 mg, 0.25 mg to 0.6 mg, 0.25 mg to 0.5 mg, 0.25 mg to 0.4 mg, 0.25 mg to 0.3 mg, 0.3 mg to 0.9 mg, 0.3 mg to 0.8 mg, and 0.3 mg to 0.3 mg. It may be administered in amounts of approximately 0.7 mg, approximately 0.3 mg to approximately 0.6 mg, approximately 0.3 mg to approximately 0.5 mg, approximately 0.3 mg to approximately 0.4 mg, approximately 0.4 mg to approximately 0.9 mg, approximately 0.4 mg to approximately 0.8 mg, approximately 0.4 mg to approximately 0.7 mg, approximately 0.4 mg to approximately 0.6 mg, approximately 0.4 mg to approximately 0.5 mg, approximately 0.5 mg to approximately 0.9 mg, approximately 0.5 mg to approximately 0.8 mg, approximately 0.5 mg to approximately 0.7 mg, approximately 0.5 mg to approximately 0.6 mg, approximately 0.6 mg to approximately 0.9 mg, approximately 0.6 mg to approximately 0.8 mg, approximately 0.6 mg to approximately 0.7 mg, approximately 0.7 mg to approximately 0.9 mg, approximately 0.7 mg to approximately 0.8 mg, or approximately 0.8 mg to approximately 0.9 mg. In certain embodiments, semaglutide may be administered to the subject in a parenteral dosage form at a dose of approximately 0.25 mg to approximately 1 mg.

[0100] In certain embodiments, semaglutide may be administered to subjects in parenteral dosage forms at doses of approximately 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, or 1 mg.

[0101] In various embodiments, semaglutide may be used to treat or prevent conditions, diseases, or disorders described herein. Methods for preventing or treating diseases or disorders generally involve administering a therapeutically effective amount of semaglutide to a subject in need of treatment to prevent or treat the disease or disorder.

[0102] In certain embodiments, semaglutide may be used to treat fatty liver in subjects requiring treatment. In certain embodiments, semaglutide may be used to treat hepatic fibrosis in subjects with fatty liver. In certain embodiments, semaglutide may be used to regulate blood glucose control in subjects with fatty liver. In certain embodiments, semaglutide may be used to lower HbA1c levels in the blood or serum of subjects with fatty liver. In certain embodiments, semaglutide may be used to reduce body weight in subjects with fatty liver. In certain embodiments, semaglutide may be used to lower systolic and / or diastolic blood pressure in subjects with fatty liver. In certain embodiments, semaglutide may be used to reduce hepatic fat in subjects with fatty liver. In certain embodiments, semaglutide may be used to reduce ballooning hepatocytes in subjects with fatty liver. In certain embodiments, semaglutide may be used to reduce lobular inflammation in subjects with fatty liver.

[0103] In certain embodiments, semaglutide may be used in combination with bempedo acid to treat fatty liver in subjects requiring treatment. In certain embodiments, semaglutide may be used in combination with bempedo acid to treat hepatic fibrosis in subjects with fatty liver. In certain embodiments, semaglutide may be used in combination with bempedo acid to regulate blood glucose control in subjects with fatty liver. In certain embodiments, semaglutide may be used in combination with bempedo acid to lower HbA1c levels in the blood or serum of subjects with fatty liver. In certain embodiments, semaglutide may be used in combination with bempedo acid to reduce body weight in subjects with fatty liver. In certain embodiments, semaglutide may be used in combination with bempedo acid to lower systolic and / or diastolic blood pressure in subjects with fatty liver. In certain embodiments, semaglutide may be used in combination with bempedo acid to reduce hepatic fat in subjects with fatty liver. In certain embodiments, semaglutide may be used in combination with bempedoic acid to reduce ballooning hepatocytes in subjects with fatty liver disease. In certain embodiments, semaglutide may be used in combination with bempedoic acid to reduce lobular inflammation in subjects with fatty liver disease.

[0104] Liraglutide In various embodiments, the GLP-1 receptor agonist is liraglutide. Liraglutide may be represented by the structure of formula (III) below. JPEG2026522971000004.jpg33164

[0105] Liraglutide, as well as methods of use and administration thereof, are disclosed, for example, in U.S. Patents 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 in parenteral dosage form. Liraglutide may also be referred to by the trademarks Victoza® and Saxenda®.

[0106] In various embodiments, liraglutide is administered to the target in doses of approximately 0.6 mg to 1.8 mg, 0.8 mg to 1.8 mg, 1 mg to 1.8 mg, 1.2 mg to 1.8 mg, 1.4 mg to 1.8 mg, 1.6 mg to 1.8 mg, 0.6 mg to 1.6 mg, 0.6 mg to 1.4 mg, 0.6 mg to 1.2 mg, and 0.6 mg to 1 mg. It may be administered in amounts of approximately 0.6 mg to approximately 0.8 mg, approximately 0.8 mg to approximately 1.6 mg, approximately 0.8 mg to approximately 1.4 mg, approximately 0.8 mg to approximately 1.2 mg, approximately 0.8 mg to approximately 1 mg, approximately 1 mg to approximately 1.6 mg, approximately 1 mg to approximately 1.4 mg, approximately 1 mg to approximately 1.2 mg, approximately 1.2 mg to approximately 1.6 mg, approximately 1.2 mg to approximately 1.4 mg, or approximately 1.4 mg to approximately 1.6 mg. In a particular embodiment, liraglutide may be administered to the subject in amounts of approximately 0.6 mg to approximately 1.8 mg.

[0107] In certain embodiments, liraglutide may be administered to the subject in amounts of approximately 0.6 mg, approximately 0.7 mg, approximately 0.8 mg, approximately 0.9 mg, approximately 1.0 mg, approximately 1.1 mg, approximately 1.2 mg, approximately 1.3 mg, approximately 1.4 mg, approximately 1.5 mg, approximately 1.6 mg, approximately 1.7 mg, or approximately 1.8 mg.

[0108] In various embodiments, liraglutide may be used to treat or prevent conditions, diseases, or disorders described herein. Methods for preventing or treating diseases or disorders generally involve administering a therapeutically effective amount of liraglutide to a subject in need of prevention or treatment to prevent or treat the disease or disorder.

[0109] In certain embodiments, liraglutide may be used to treat fatty liver in subjects requiring treatment. In certain embodiments, liraglutide may be used to treat hepatic fibrosis in subjects with fatty liver. In certain embodiments, liraglutide may be used to regulate blood glucose control in subjects with fatty liver. In certain embodiments, liraglutide may be used to lower HbA1c levels in the blood or serum of subjects with fatty liver. In certain embodiments, liraglutide may be used to reduce body weight in subjects with fatty liver. In certain embodiments, liraglutide may be used to lower systolic and / or diastolic blood pressure in subjects with fatty liver. In certain embodiments, liraglutide may be used to reduce hepatic fat in subjects with fatty liver. In certain embodiments, liraglutide may be used to reduce ballooning hepatocytes in subjects with fatty liver. In certain embodiments, liraglutide may be used to reduce lobular inflammation in subjects with fatty liver.

[0110] In certain embodiments, liraglutide may be used in combination with bempedo acid to treat fatty liver in subjects requiring treatment. In certain embodiments, liraglutide may be used in combination with bempedo acid to treat hepatic fibrosis in subjects with fatty liver. In certain embodiments, liraglutide may be used in combination with bempedo acid to regulate blood glucose control in subjects with fatty liver. In certain embodiments, liraglutide may be used in combination with bempedo acid to lower HbA1c levels in the blood or serum of subjects with fatty liver. In certain embodiments, liraglutide may be used in combination with bempedo acid to reduce body weight in subjects with fatty liver. In certain embodiments, liraglutide may be used in combination with bempedo acid to lower systolic and / or diastolic blood pressure in subjects with fatty liver. In certain embodiments, liraglutide may be used in combination with bempedo acid to reduce hepatic fat in subjects with fatty liver. In certain embodiments, liraglutide may be used in combination with bempedoic acid to reduce ballooning hepatocytes in subjects with fatty liver disease. In certain embodiments, liraglutide may be used in combination with bempedoic acid to reduce lobular inflammation in subjects with fatty liver disease.

[0111] Exenatide In various embodiments, the GLP-1 receptor agonist is exenatide. Exenatide may be represented by the structure of formula (IV) below. JPEG2026522971000005.jpg48164

[0112] Exenatide, as well as methods of use and administration thereof, are disclosed, for example, in U.S. Patents No. 5,424,286, No. 6,902,744, No. 6,924,264, No. 7,157,555, No. 7,220,721 and No. 7,223,725, which are incorporated herein by reference. Exenatide may be administered in parenteral dosage form. Exenatide may also be referred to by the trademarks Byetta® and Bydureon®.

[0113] In various embodiments, exenatide is administered to subjects in doses of approximately 2 mg to 10 mg, 3 mg to 10 mg, 4 mg to 10 mg, 5 mg to 10 mg, 6 mg to 10 mg, 7 mg to 10 mg, 8 mg to 10 mg, 9 mg to 10 mg, 2 mg to 9 mg, 2 mg to 8 mg, 2 mg to 7 mg, 2 mg to 6 mg, 2 mg to 5 mg, 2 mg to 4 mg, 2 mg to 3 mg, 3 mg to 9 mg, and 3 mg to 8 mg. Exenatide may be administered in amounts of approximately 3mg to 7mg, 3mg to 6mg, 3mg to 5mg, 3mg to 4mg, 4mg to 9mg, 4mg to 8mg, 4mg to 7mg, 4mg to 6mg, 4mg to 5mg, 5mg to 9mg, 5mg to 8mg, 5mg to 7mg, 5mg to 6mg, 6mg to 9mg, 6mg to 8mg, 6mg to 7mg, 7mg to 9mg, 7mg to 8mg, or 8mg to 9mg. In certain embodiments, exenatide may be administered to the subject in amounts of approximately 2mg to 10mg.

[0114] In certain embodiments, exenatide may be administered to subjects in amounts of approximately 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg.

[0115] In various embodiments, exenatide may be used to treat or prevent the conditions, diseases, or disorders described herein. Methods for preventing or treating a disease or disorder generally involve administering a therapeutically effective dose of exenatide to a subject in need of prevention or treatment to prevent or treat the disease or disorder.

[0116] In certain embodiments, exenatide may be used to treat fatty liver in subjects requiring treatment. In certain embodiments, exenatide may be used to treat hepatic fibrosis in subjects with fatty liver. In certain embodiments, exenatide may be used to regulate blood glucose control in subjects with fatty liver. In certain embodiments, exenatide may be used to lower HbA1c levels in the blood or serum of subjects with fatty liver. In certain embodiments, exenatide may be used to reduce body weight in subjects with fatty liver. In certain embodiments, exenatide may be used to lower systolic and / or diastolic blood pressure in subjects with fatty liver. In certain embodiments, exenatide may be used to reduce hepatic fat in subjects with fatty liver. In certain embodiments, exenatide may be used to reduce ballooning hepatocytes in subjects with fatty liver. In certain embodiments, exenatide may be used to reduce lobular inflammation in subjects with fatty liver.

[0117] In certain embodiments, exenatide may be used in combination with bempedo acid to treat fatty liver in subjects requiring treatment. In certain embodiments, exenatide may be used in combination with bempedo acid to treat hepatic fibrosis in subjects with fatty liver. In certain embodiments, exenatide may be used in combination with bempedo acid to regulate blood glucose control in subjects with fatty liver. In certain embodiments, exenatide may be used in combination with bempedo acid to lower HbA1c levels in the blood or serum of subjects with fatty liver. In certain embodiments, exenatide may be used in combination with bempedo acid to reduce body weight in subjects with fatty liver. In certain embodiments, exenatide may be used in combination with bempedo acid to lower systolic and / or diastolic blood pressure in subjects with fatty liver. In certain embodiments, exenatide may be used in combination with bempedo acid to reduce hepatic fat in subjects with fatty liver. In certain embodiments, exenatide may be used in combination with bempedoic acid to reduce ballooning hepatocytes in subjects with fatty liver disease. In certain embodiments, exenatide may be used in combination with bempedoic acid to reduce lobular inflammation in subjects with fatty liver disease.

[0118] dulaglutide In various embodiments of this disclosure, the GLP-1 receptor agonist is dulaglutide. Dulaglutide is a human GLP-1 receptor agonist comprising a dimer of a GLP-1 analog fused to the N-terminus of an immunoglobulin Fc moiety analog via a peptide linker at its C-terminus, and is identified by CAS registry number 923950-08-7. Dulaglutide may be represented by the following SEQ ID NO: 1. Sequence ID 1: HGEGTFTSDVSSYLEEQAAKEFIAWLVKGGGGGGGSGGGGGSGGGGSAESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTV LHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG

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

[0120] In various embodiments, dulaglutide may be administered to the subject in amounts of approximately 0.75 mg to approximately 1.5 mg, approximately 1 mg to approximately 1.5 mg, approximately 1.25 mg to approximately 1.5 mg, approximately 0.75 mg to approximately 1.25 mg, approximately 0.75 mg to approximately 1 mg, or approximately 1 mg to approximately 1.25 mg. In a particular embodiment, dulaglutide may be administered to the subject in amounts of approximately 0.75 mg to approximately 1.5 mg.

[0121] In certain embodiments, dulaglutide may be administered to the subject in amounts of approximately 0.75 mg, approximately 1 mg, approximately 1.25 mg, or approximately 1.5 mg.

[0122] In various embodiments, dulaglutide may be used to treat or prevent conditions, diseases, or disorders described herein. Methods for preventing or treating diseases or disorders generally involve administering a therapeutically effective dose of dulaglutide to a subject requiring treatment to prevent or treat the disease or disorder.

[0123] In certain embodiments, dulaglutide may be used to treat fatty liver in subjects requiring treatment. In certain embodiments, dulaglutide may be used to treat hepatic fibrosis in subjects with fatty liver. In certain embodiments, dulaglutide may be used to regulate blood glucose control in subjects with fatty liver. In certain embodiments, dulaglutide may be used to lower HbA1c levels in the blood or serum of subjects with fatty liver. In certain embodiments, dulaglutide may be used to reduce body weight in subjects with fatty liver. In certain embodiments, dulaglutide may be used to lower systolic and / or diastolic blood pressure in subjects with fatty liver. In certain embodiments, dulaglutide may be used to reduce hepatic fat in subjects with fatty liver. In certain embodiments, dulaglutide may be used to reduce ballooning hepatocytes in subjects with fatty liver. In certain embodiments, dulaglutide may be used to reduce lobular inflammation in subjects with fatty liver.

[0124] In certain embodiments, dulaglutide may be used in combination with bempedoic acid to treat fatty liver in subjects requiring treatment. In certain embodiments, dulaglutide may be used in combination with bempedoic acid to treat hepatic fibrosis in subjects with fatty liver. In certain embodiments, dulaglutide may be used in combination with bempedoic acid to regulate blood glucose control in subjects with fatty liver. In certain embodiments, dulaglutide may be used in combination with bempedoic acid to lower HbA1c levels in the blood or serum of subjects with fatty liver. In certain embodiments, dulaglutide may be used in combination with bempedoic acid to reduce body weight in subjects with fatty liver. In certain embodiments, dulaglutide may be used in combination with bempedoic acid to lower systolic and / or diastolic blood pressure in subjects with fatty liver. In certain embodiments, dulaglutide may be used in combination with bempedoic acid to reduce hepatic fat in subjects with fatty liver. In certain embodiments, dulaglutide may be used in combination with bempedoic acid to reduce ballooning hepatocytes in subjects with fatty liver disease. In certain embodiments, dulaglutide may be used in combination with bempedoic acid to reduce lobular inflammation in subjects with fatty liver disease.

[0125] Albiglutide In some embodiments of this disclosure, the GLP-1 receptor agonist is albiglutide. Albiglutide may be represented by the structure of formula (V) below. JPEG2026522971000006.jpg33164

[0126] Albiglutide, as well as methods of use and administration thereof, are disclosed, for example, in European Patent No. EP2373681B1, which is incorporated herein by reference. Albiglutide may be administered in parenteral dosage form. Albiglutide may also be referred to as GSK-716155, and by the trademarks Eperzan® and Tanzeum®.

[0127] In various embodiments, albiglutide is administered to the target population in doses of approximately 30 mg to 50 mg, approximately 32 mg to 50 mg, approximately 34 mg to 50 mg, approximately 36 mg to 50 mg, approximately 38 mg to 50 mg, approximately 40 mg to 50 mg, approximately 42 mg to 50 mg, approximately 44 mg to 50 mg, approximately 46 mg to 50 mg, approximately 48 mg to 50 mg, approximately 30 mg to 48 mg, approximately 30 mg to 46 mg, and approximately 30 mg to 50 mg. Approximately 44 mg, approximately 30 mg to approximately 42 mg, approximately 30 mg to approximately 40 mg, approximately 30 mg to approximately 38 mg, approximately 30 mg to approximately 36 mg, approximately 30 mg to approximately 34 mg, approximately 30 mg to approximately 32 mg, approximately 32 mg to approximately 48 mg, about 32mg to about 46mg, about 32mg to about 44mg, about 32mg to about 42mg, about 32mg to about 40mg, about 32mg to about 38mg, about 32mg to about 36mg, about 32mg to about 34mg, Approximately 34mg to approximately 48mg, approximately 34mg to approximately 46mg, approximately 34mg to approximately 44mg, approximately 34mg to approximately 42mg, approximately 34mg to approximately 40mg, approximately 34mg to approximately 38mg, approximately 34mg to approximately 36mg, approximately 3 6mg to about 48mg, about 36mg to about 46mg, about 36mg to about 44mg, about 36mg to about 42mg, about 36mg to about 40mg, about 36mg to about 38mg, about 38mg to about 48mg, about 38mg It may be administered in amounts of approximately 46 mg, approximately 38 mg to approximately 44 mg, approximately 38 mg to approximately 42 mg, approximately 38 mg to approximately 40 mg, approximately 40 mg to approximately 48 mg, approximately 40 mg to approximately 46 mg, approximately 40 mg to approximately 44 mg, approximately 40 mg to approximately 42 mg, approximately 42 mg to approximately 48 mg, approximately 42 mg to approximately 46 mg, approximately 42 mg to approximately 44 mg, approximately 44 mg to approximately 48 mg, approximately 44 mg to approximately 46 mg, or approximately 46 mg to approximately 48 mg. In certain embodiments, albiglutide may be administered to the subject in amounts of approximately 30 mg to approximately 50 mg.

[0128] In certain embodiments, albiglutide may be administered to subjects in amounts of approximately 30 mg, approximately 32 mg, approximately 34 mg, approximately 36 mg, approximately 38 mg, approximately 40 mg, approximately 42 mg, approximately 44 mg, approximately 46 mg, approximately 48 mg, or approximately 50 mg.

[0129] In various embodiments, albiglutide may be used to treat or prevent conditions, diseases, or disorders described herein. Methods for preventing or treating diseases or disorders generally involve administering a therapeutically effective amount of albiglutide to a subject in need of prevention or treatment to prevent or treat the disease or disorder.

[0130] In certain embodiments, albiglutide may be used to treat fatty liver in subjects requiring treatment. In certain embodiments, albiglutide may be used to treat hepatic fibrosis in subjects with fatty liver. In certain embodiments, albiglutide may be used to regulate blood glucose control in subjects with fatty liver. In certain embodiments, albiglutide may be used to lower HbA1c levels in the blood or serum of subjects with fatty liver. In certain embodiments, albiglutide may be used to reduce body weight in subjects with fatty liver. In certain embodiments, albiglutide may be used to lower systolic and / or diastolic blood pressure in subjects with fatty liver. In certain embodiments, albiglutide may be used to reduce hepatic fat in subjects with fatty liver. In certain embodiments, albiglutide may be used to reduce ballooning hepatocytes in subjects with fatty liver. In certain embodiments, albiglutide may be used to reduce lobular inflammation in subjects with fatty liver.

[0131] In certain embodiments, albiglutide may be used in combination with bempedo acid to treat fatty liver in subjects requiring treatment. In certain embodiments, albiglutide may be used in combination with bempedo acid to treat hepatic fibrosis in subjects with fatty liver. In certain embodiments, albiglutide may be used in combination with bempedo acid to regulate blood glucose control in subjects with fatty liver. In certain embodiments, albiglutide may be used in combination with bempedo acid to lower HbA1c levels in the blood or serum of subjects with fatty liver. In certain embodiments, albiglutide may be used in combination with bempedo acid to reduce body weight in subjects with fatty liver. In certain embodiments, albiglutide may be used in combination with bempedo acid to lower systolic and / or diastolic blood pressure in subjects with fatty liver. In certain embodiments, albiglutide may be used in combination with bempedo acid to reduce hepatic fat in subjects with fatty liver. In certain embodiments, albiglutide may be used in combination with bempedoic acid to reduce ballooning hepatocytes in subjects with fatty liver disease. In certain embodiments, albiglutide may be used in combination with bempedoic acid to reduce lobular inflammation in subjects with fatty liver disease.

[0132] Lixisenatide In various embodiments, the GLP-1 receptor agonist is lixisenatide. Lixisenatide may be represented by the structure of formula (VI) below. JPEG2026522971000007.jpg74164

[0133] Lixisenatide, as well as methods of use and administration thereof, are disclosed, for example, in International Publication No. WO2001 / 04156A1, which is incorporated herein by reference. Lixisenatide may be administered in parenteral dosage form. Lixisenatide may also be referred to by the trademarks Lyxumia® and Adlyxin®.

[0134] In various embodiments, lixisenatide is administered to subjects in doses of approximately 10 mg to 20 mg, 11 mg to 20 mg, 12 mg to 20 mg, 13 mg to 20 mg, 14 mg to 20 mg, 15 mg to 20 mg, 16 mg to 20 mg, 17 mg to 20 mg, 18 mg to 20 mg, 19 mg to 20 mg, 10 mg to 19 mg, 10 mg to 18 mg, and 10 mg to 20 mg. Approximately 17mg, approximately 10mg to approximately 16mg, approximately 10mg to approximately 15mg, approximately 10mg to approximately 14mg, approximately 10mg to approximately 13mg, approximately 10mg to approximately 12mg, approximately 10mg to approximately 11mg, approximately 11mg to approximately 19mg, approximately 11mg to approximately 18mg, approximately 11mg to approximately 17mg, approximately 11mg to approximately 16mg, approximately 11mg to approximately 15mg, approximately 11mg to approximately 14mg, approximately 11mg to approximately 13mg, approximately 11mg to approximately 12mg, Approximately 12mg to 19mg, approximately 12mg to 18mg, approximately 12mg to 17mg, approximately 12mg to 16mg, approximately 12mg to 15mg, approximately 12mg to 14mg, approximately 12mg to 13mg, approximately 13mg to 19mg, approximately 13mg to 18mg, approximately 13mg to 17mg, approximately 13mg to 16mg, approximately 13mg to 15mg, approximately 13mg to 14mg, approximately 14mg to 19mg, approximately 14mg It may be administered in amounts of approximately 18 mg, 14 mg to 17 mg, 14 mg to 16 mg, 14 mg to 15 mg, 15 mg to 19 mg, 15 mg to 18 mg, 15 mg to 17 mg, 15 mg to 16 mg, 16 mg to 19 mg, 16 mg to 18 mg, 16 mg to 17 mg, 17 mg to 19 mg, 17 mg to 18 mg, or 18 mg to 19 mg. In certain embodiments, lixisenatide may be administered to the subject in amounts of approximately 10 mg to 20 mg.

[0135] In certain embodiments, lixisenatide may be administered to the subject in amounts of approximately 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg.

[0136] In various embodiments, lixisenatide may be used to treat or prevent conditions, diseases, or disorders described herein. Methods for preventing or treating diseases or disorders generally involve administering a therapeutically effective amount of lixisenatide to a subject in need of prevention or treatment to prevent or treat the disease or disorder.

[0137] In certain embodiments, lixisenatide may be used to treat fatty liver in subjects requiring treatment. In certain embodiments, lixisenatide may be used to treat hepatic fibrosis in subjects with fatty liver. In certain embodiments, lixisenatide may be used to regulate blood glucose control in subjects with fatty liver. In certain embodiments, lixisenatide may be used to lower HbA1c levels in the blood or serum of subjects with fatty liver. In certain embodiments, lixisenatide may be used to reduce body weight in subjects with fatty liver. In certain embodiments, lixisenatide may be used to lower systolic and / or diastolic blood pressure in subjects with fatty liver. In certain embodiments, lixisenatide may be used to reduce hepatic fat in subjects with fatty liver. In certain embodiments, lixisenatide may be used to reduce ballooning hepatocytes in subjects with fatty liver. In certain embodiments, lixisenatide may be used to reduce lobular inflammation in subjects with fatty liver.

[0138] In certain embodiments, lixisenatide may be used in combination with bempedo acid to treat fatty liver in subjects requiring treatment. In certain embodiments, lixisenatide may be used in combination with bempedo acid to treat hepatic fibrosis in subjects with fatty liver. In certain embodiments, lixisenatide may be used in combination with bempedo acid to regulate blood glucose control in subjects with fatty liver. In certain embodiments, lixisenatide may be used in combination with bempedo acid to lower HbA1c levels in the blood or serum of subjects with fatty liver. In certain embodiments, lixisenatide may be used in combination with bempedo acid to reduce body weight in subjects with fatty liver. In certain embodiments, lixisenatide may be used in combination with bempedo acid to lower systolic and / or diastolic blood pressure in subjects with fatty liver. In certain embodiments, lixisenatide may be used in combination with bempedo acid to reduce hepatic fat in subjects with fatty liver. In certain embodiments, lixisenatide may be used in combination with bempedoic acid to reduce ballooning hepatocytes in subjects with fatty liver disease. In certain embodiments, lixisenatide may be used in combination with bempedoic acid to reduce lobular inflammation in subjects with fatty liver disease.

[0139] combination of fixed doses In one embodiment, the present disclosure provides a fixed-dose combination generally comprising bempedoic acid and a GLP-1 receptor agonist. In various embodiments, the fixed-dose combination described herein is a solid dosage form comprising bempedoic acid and the GLP-1 receptor agonist.

[0140] In various embodiments, the fixed-dose combinations described herein are solid dosage forms comprising a pharmaceutical composition containing bempedoic acid and the semaglutide described herein.

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

[0142] In various embodiments, the present disclosure provides a fixed-dose combination comprising bempedoic acid and semaglutide.

[0143] In various embodiments, the fixed-dose combinations described herein are solid dosage forms comprising bempedoic acid and semaglutide.

[0144] In certain embodiments, the combination of fixed doses of pempedoic acid is approximately 30 mg to 300 mg, approximately 60 mg to 300 mg, approximately 90 mg to 300 mg, approximately 120 mg to 300 mg, approximately 150 mg to 300 mg, approximately 180 mg to 300 mg, approximately 210 mg to 300 mg, approximately 240 mg to 300 mg, approximately 270 mg to 300 mg, and approximately 30 mg to Approximately 270mg, approximately 30mg to approximately 240mg, approximately 30mg to approximately 210mg, approximately 30mg to approximately 180mg, approximately 30mg to approximately 150mg, approximately 30mg to approximately 120mg, approximately 30mg to approximately 90mg, about 30mg to about 60mg, about 60mg to about 270mg, about 60mg to about 240mg, about 60mg to about 210mg, about 60mg to about 180mg, about 60mg to about 150m g, about 60mg to about 120mg, about 60mg to about 90mg, about 90mg to about 270mg, about 90mg to about 240mg, about 90mg to about 210mg, about 90mg to about 180mg, Approximately 90mg to approximately 150mg, approximately 90mg to approximately 120mg, approximately 120mg to approximately 270mg, approximately 120mg to approximately 240mg, approximately 120mg to approximately 210mg, approximately 120mg to approximately 180m g contains approximately 120 mg to 150 mg, approximately 150 mg to 270 mg, approximately 150 mg to 240 mg, approximately 150 mg to 210 mg, approximately 150 mg to 180 mg, approximately 180 mg to 270 mg, approximately 180 mg to 240 mg, approximately 180 mg to 210 mg, approximately 210 mg to 270 mg, approximately 210 mg to 240 mg, or approximately 240 mg to 270 mg. In certain embodiments, the fixed dose combination contains approximately 120 mg to 240 mg of bempedoic acid.

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

[0146] In a particular embodiment, the fixed dose combinations of semaglutide are approximately 1 mg to 30 mg, approximately 2 mg to 30 mg, approximately 3 mg to 30 mg, approximately 4 mg to 30 mg, approximately 6 mg to 30 mg, approximately 8 mg to 30 mg, approximately 10 mg to 30 mg, approximately 12 mg to 30 mg, approximately 14 mg to 30 mg, approximately 16 mg to 30 mg, approximately 20 mg to 30 mg, approximately 25 mg to 30 mg, approximately 1 mg to 25 mg, approximately 1 mg to 20 mg, approximately 1 mg to 16 mg, approximately 1 mg to 14 mg, approximately 1 mg to 12 mg, Approximately 1 mg to approximately 10 mg, approximately 1 mg to approximately 8 mg, approximately 1 mg to approximately 6 mg, approximately 1 mg to approximately 4 mg, approximately 1 mg to approximately 3 mg, approximately 1 mg to approximately 2 mg, approximately 2 mg to approximately 25 mg, approximately 2 mg to approximately 20 mg, approximately 2 mg to approximately 16 mg, approximately 2 mg to approximately 14 mg, approximately 2 mg to approximately 1 2mg, about 2mg to about 10mg, about 2mg to about 8mg, about 2mg to about 6mg, about 2mg to about 4mg, about 2mg to about 3mg, about 3mg to about 25mg, about 3mg to about 20mg, about 3mg to about 16mg, about 3mg to about 14mg, about 3mg to about 12mg, about 3m g ~ about 10mg, about 3mg - about 8mg, about 3mg - about 6mg, about 3mg - about 4mg, about 4mg - about 25mg, about 4mg - about 20mg, about 4mg - about 16mg, about 4mg - about 14mg, about 4mg - about 12mg, about 4mg - about 10mg, about 4mg - about 8m g, about 4mg to about 6mg, about 6mg to about 25mg, about 6mg to about 20mg, about 6mg to about 16mg, about 6mg to about 14mg, about 6mg to about 12mg, about 6mg to about 10mg, about 6mg to about 8mg, about 8mg to about 25mg, about 8mg to about 20mg, about 8m g-approximately 16 mg, approximately 8 mg-approximately 14 mg, approximately 8 mg-approximately 12 mg, approximately 8 mg-approximately 10 mg, approximately 10 mg-approximately 25 mg, approximately 10 mg-approximately 20 mg, approximately 10 mg-approximately 16 mg, approximately 10 mg-approximately 14 mg, approximately 10 mg-approximately 12 mg, approximately 12 mg-approximately 25 mg, approximately 12 mg-approximately 20 mg, approximately 12 mg-approximately 16 mg, approximately 12 mg-approximately 14 mg, approximately 14 mg-approximately 25 mg, approximately 14 mg-approximately 20 mg, approximately 14 mg-approximately 16 mg, approximately 16 mg-approximately 25 mg, approximately 16 mg-approximately 20 mg, or approximately 20 mg-approximately 25 mg. In certain embodiments, the fixed dose combination contains approximately 3 mg-approximately 14 mg of semaglutide.

[0147] In some embodiments, the fixed dose combination contains 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 of semaglutide. In certain embodiments, the fixed dose combination contains about 3 mg of semaglutide. In certain embodiments, the fixed dose combination contains about 7 mg of semaglutide. In certain embodiments, the fixed dose combination contains about 14 mg of semaglutide.

[0148] In various embodiments, the fixed dose combination includes approximately 120 mg to 240 mg of bempedoic acid and approximately 3 mg to 14 mg of semaglutide.

[0149] In certain embodiments, the fixed-dose combination described herein comprises about 180 mg of bempedoic acid and about 3 mg of semaglutide. In certain embodiments, the fixed-dose combination described herein comprises about 180 mg of bempedoic acid and about 7 mg of semaglutide. In certain embodiments, the fixed-dose combination described herein comprises about 180 mg of bempedoic acid and about 14 mg of 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 oral dosage forms. Examples of oral dosage forms include, but are not limited to, drenches, tablets, capsules, softgel capsules, cachets, pills, emulsions, lozenges, solutions, suspensions, boluses, powders, elixirs or syrups, sachets, mouthwashes, granules, or pastes for application to the tongue. In some embodiments, the fixed-dose combinations are formulated as tablets.

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

[0152] In certain embodiments, the fixed-dose combinations described herein may be used to treat fatty liver in subjects requiring treatment. In certain embodiments, the fixed-dose combinations described herein may be used to treat hepatic fibrosis in subjects with fatty liver. In certain embodiments, the fixed-dose combinations described herein may be used to regulate blood glucose control in subjects with fatty liver. In certain embodiments, the fixed-dose combinations described herein may be used to lower HbA1c levels in the blood or serum of subjects with fatty liver. In certain embodiments, the fixed-dose combinations described herein may be used to reduce body weight in subjects with fatty liver. In certain embodiments, the fixed-dose combinations described herein may be used to lower systolic and / or diastolic blood pressure in subjects with fatty liver. In certain embodiments, the fixed-dose combinations described herein may be used to reduce hepatic fat in subjects with fatty liver. In certain embodiments, the fixed-dose combinations described herein may be used to reduce ballooning hepatocytes in subjects with fatty liver. In certain embodiments, the fixed-dose combinations described herein may be used to reduce lobular inflammation in subjects with fatty liver.

[0153] Pharmaceutical composition (1) Bempedoic acid In one embodiment, the present disclosure provides a pharmaceutical composition generally comprising bempedoic acid and one or more pharmaceutically acceptable excipients.

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

[0155] In various embodiments, the present disclosure provides a pharmaceutical formulation comprising bempedoic acid, colloidal silicon dioxide, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.

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

[0157] In certain embodiments, the amount of bempedo acid in the pharmaceutical formulation is approximately 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 approximately 1.2% (w / w). In certain embodiments, the amount of colloidal silicon dioxide in the pharmaceutical formulation is approximately 1.3% (w / w). In certain embodiments, the amount of colloidal silicon dioxide in the pharmaceutical formulation is approximately 1.4% (w / w). In certain embodiments, the amount of colloidal silicon dioxide in the pharmaceutical formulation is approximately 1.5% (w / w).

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

[0160] In certain embodiments, the amount of hydroxypropylcellulose in the pharmaceutical formulation is approximately 3% (w / w) to approximately 5% (w / w). In certain embodiments, the amount of hydroxypropylcellulose in the pharmaceutical formulation is approximately 3% (w / w), approximately 3.1% (w / w), approximately 3.2% (w / w), approximately 3.3% (w / w), approximately 3.4% (w / w), approximately 3.5% (w / w), approximately 3.6% (w / w), approximately 3.7% (w / w), approximately 3.8% (w / w), approximately 3.9% (w / w), approximately 4% (w / w), approximately 4.1% (w / w), approximately 4.2% (w / w), approximately 4.3% (w / w), approximately 4.4% (w / w), approximately 4.5% (w / w), approximately 4.6% (w / w), approximately 4.7% (w / w), approximately 4.8% (w / w), approximately 4.9% (w / w), or approximately 5% (w / w). In certain embodiments, the amount of hydroxypropyl cellulose in the pharmaceutical formulation is approximately 4.6% (w / w). In certain embodiments, the amount of hydroxypropyl cellulose in the pharmaceutical formulation is approximately 4.7% (w / w). In certain embodiments, the amount of hydroxypropyl cellulose in the pharmaceutical formulation is approximately 4.8% (w / w). In certain embodiments, the amount of hydroxypropyl cellulose in the pharmaceutical formulation is approximately 4.9% (w / w). In certain embodiments, the amount of hydroxypropyl cellulose in the pharmaceutical formulation is approximately 5.0% (w / w).

[0161] In certain embodiments, the amount of hydroxypropyl cellulose in the pharmaceutical formulation is approximately 10 mg to approximately 20 mg. In certain embodiments, the amount of hydroxypropyl cellulose in the pharmaceutical formulation is approximately 10 mg, approximately 11 mg, approximately 12 mg, approximately 13 mg, approximately 14 mg, approximately 15 mg, approximately 16 mg, approximately 17 mg, approximately 18 mg, approximately 19 mg, or approximately 20 mg. In certain embodiments, the amount of hydroxypropyl cellulose in the pharmaceutical formulation is approximately 10 mg. In certain embodiments, the amount of hydroxypropyl cellulose in the pharmaceutical formulation is approximately 11 mg. In certain embodiments, the amount of hydroxypropyl cellulose in the pharmaceutical formulation is approximately 12 mg. In certain embodiments, the amount of hydroxypropyl cellulose in the pharmaceutical formulation is approximately 13 mg. In certain embodiments, the amount of hydroxypropyl cellulose in the pharmaceutical formulation is approximately 14 mg. In certain embodiments, the amount of hydroxypropyl cellulose in the pharmaceutical formulation is approximately 15 mg. In certain embodiments, the amount of hydroxypropyl cellulose in the pharmaceutical formulation is approximately 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 approximately 10% (w / w). In certain embodiments, the amount of lactose monohydrate in the pharmaceutical formulation is approximately 11% (w / w). In certain embodiments, the amount of lactose monohydrate in the pharmaceutical formulation is approximately 17% (w / w). In certain embodiments, the amount of lactose monohydrate in the pharmaceutical formulation is approximately 18% (w / w). In certain embodiments, the amount of lactose monohydrate in the pharmaceutical formulation is approximately 19% (w / w). In certain embodiments, the amount of lactose monohydrate in the pharmaceutical formulation is approximately 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 approximately 1% (w / w) to approximately 3% (w / w). In certain embodiments, the amount of magnesium stearate in the pharmaceutical formulation is approximately 1% (w / w), approximately 1.1% (w / w), approximately 1.2% (w / w), approximately 1.3% (w / w), approximately 1.4% (w / w), approximately 1.5% (w / w), approximately 1.6% (w / w), approximately 1.7% (w / w), approximately 1.8% (w / w), approximately 1.9% (w / w), approximately 2% (w / w), approximately 2.1% (w / w), approximately 2.2% (w / w), approximately 2.3% (w / w), approximately 2.4% (w / w), approximately 2.5% (w / w), approximately 2.6% (w / w), approximately 2.7% (w / w), approximately 2.8% (w / w), approximately 2.9% (w / w), or approximately 3% (w / w). In certain embodiments, the amount of magnesium stearate in the pharmaceutical formulation is approximately 2.7% (w / w). In certain embodiments, the amount of magnesium stearate in the pharmaceutical formulation is approximately 2.8% (w / w). In certain embodiments, the amount of magnesium stearate in the pharmaceutical formulation is approximately 2.9% (w / w). In certain embodiments, the amount of magnesium stearate in the pharmaceutical formulation is approximately 3% (w / w).

[0165] In certain embodiments, the amount of magnesium stearate in the pharmaceutical formulation is approximately 2 mg to approximately 10 mg. In certain embodiments, the amount of magnesium stearate in the pharmaceutical formulation is approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 6 mg, approximately 7 mg, approximately 8 mg, approximately 9 mg, or approximately 10 mg. In certain embodiments, the amount of magnesium stearate in the pharmaceutical formulation is approximately 5 mg. In certain embodiments, the amount of magnesium stearate in the pharmaceutical formulation is approximately 6 mg. In certain embodiments, the amount of magnesium stearate in the pharmaceutical formulation is approximately 7 mg. In certain embodiments, the amount of magnesium stearate in the pharmaceutical formulation is approximately 8 mg. In certain embodiments, the amount of magnesium stearate in the pharmaceutical formulation is approximately 9 mg.

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

[0167] In certain embodiments, the amount of microcrystalline cellulose in the pharmaceutical formulation is approximately 55 mg to approximately 65 mg. In certain embodiments, the amount of microcrystalline cellulose in the pharmaceutical formulation is approximately 55 mg, approximately 55.5 mg, approximately 56 mg, approximately 56.5 mg, approximately 57 mg, approximately 57.5 mg, approximately 58 mg, approximately 58.5 mg, approximately 59 mg, approximately 59.5 mg, approximately 60 mg, approximately 60.5 mg, approximately 61 mg, approximately 61.5 mg, approximately 62 mg, approximately 62.5 mg, approximately 63 mg, approximately 63.5 mg, approximately 64 mg, approximately 64.5 mg, or approximately 65 mg. In certain embodiments, the amount of microcrystalline cellulose in the pharmaceutical formulation is approximately 62 mg. In certain embodiments, the amount of microcrystalline cellulose in the pharmaceutical formulation is approximately 62.5 mg. In certain embodiments, the amount of microcrystalline cellulose in the pharmaceutical formulation is approximately 63 mg. In certain embodiments, the amount of microcrystalline cellulose in the pharmaceutical formulation is approximately 63.5 mg. In certain embodiments, the amount of microcrystalline cellulose in the pharmaceutical formulation is approximately 64 mg. In certain embodiments, the amount of microcrystalline cellulose in the pharmaceutical formulation is approximately 64.5 mg. In certain embodiments, the amount of microcrystalline cellulose in the pharmaceutical formulation is approximately 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 approximately 7% (w / w). In certain embodiments, the amount of sodium starch glycolate in the pharmaceutical formulation is approximately 7.1% (w / w). In certain embodiments, the amount of sodium starch glycolate in the pharmaceutical formulation is approximately 7.2% (w / w). In certain embodiments, the amount of sodium starch glycolate in the pharmaceutical formulation is approximately 7.3% (w / w).

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

[0170] In various embodiments, the information provided in this disclosure includes: (i) Bempedoic acid at approximately 45% (w / w) to approximately 55% (w / w), (ii) Colloidal silicon dioxide at approximately 1% (w / w) to approximately 2% (w / w), (iii) Hydroxypropyl cellulose at approximately 3% (w / w) to approximately 5% (w / w), (iv) Lactose monohydrate at approximately 8% (w / w) to approximately 20% (w / w), (v) Magnesium stearate at approximately 1% (w / w) to approximately 3% (w / w), (vi) Microcrystalline cellulose at approximately 15% (w / w) to approximately 20% (w / w), (vii) Sodium starch glycolate at approximately 6.5% (w / w) to approximately 7.5% (w / w), It is a pharmaceutical preparation containing [a specific ingredient / substance].

[0171] In various embodiments, the information provided in this disclosure includes: (i) 180 mg of bempedoic acid, (ii) Approximately 3 mg to 6 mg of colloidal silicon dioxide, (iii) Approximately 10 mg to 20 mg of hydroxypropyl cellulose, (iv) Lactose monohydrate in an amount of approximately 20 mg to 80 mg, (v) Magnesium stearate, approximately 2 mg to 10 mg, (vi) Microcrystalline cellulose, approximately 55 mg to approximately 65 mg, (vii) Sodium starch glycolate, approximately 20 mg to approximately 30 mg, It is a pharmaceutical preparation containing [a specific ingredient / substance].

[0172] In certain embodiments, the pharmaceutical formulation further comprises a coating agent. In certain embodiments, the coating agent comprises OpaDry White 85F18422. In certain embodiments, the coating agent comprises OpaDry AMBII Blue.

[0173] In certain embodiments, the pharmaceutical composition containing bempedoic acid described herein is formulated for oral delivery. In certain embodiments, the pharmaceutical composition containing bempedoic acid is formulated as a tablet.

[0174] (2) Bempedoic acid and semaglutide In another embodiment, the present disclosure provides a pharmaceutical composition generally comprising bempedoic acid, semaglutide, and one or more pharmaceutically acceptable excipients.

[0175] In certain embodiments, the pharmaceutical composition contains bempedoic acid in amounts of approximately 30 mg to 300 mg, approximately 60 mg to 300 mg, approximately 90 mg to 300 mg, approximately 120 mg to 300 mg, approximately 150 mg to 300 mg, approximately 180 mg to 300 mg, approximately 210 mg to 300 mg, approximately 240 mg to 300 mg, approximately 270 mg to 300 mg, and approximately 30 mg to 270 mg. mg, about 30mg to about 240mg, about 30mg to about 210mg, about 30mg to about 180mg, about 30mg to about 150mg, about 30mg to about 120mg, about 30mg to about 90mg , about 30mg to about 60mg, about 60mg to about 270mg, about 60mg to about 240mg, about 60mg to about 210mg, about 60mg to about 180mg, about 60mg to about 150mg, about 60mg to about 120mg, about 60mg to about 90mg, about 90mg to about 270mg, about 90mg to about 240mg, about 90mg to about 210mg, about 90mg to about 180mg, about 90 mg ~ about 150mg, about 90mg - about 120mg, about 120mg - about 270mg, about 120mg - about 240mg, about 120mg - about 210mg, about 120mg - about 180mg, It contains approximately 120 mg to 150 mg, approximately 150 mg to 270 mg, approximately 150 mg to 240 mg, approximately 150 mg to 210 mg, approximately 150 mg to 180 mg, approximately 180 mg to 270 mg, approximately 180 mg to 240 mg, approximately 180 mg to 210 mg, approximately 210 mg to 270 mg, approximately 210 mg to 240 mg, or approximately 240 mg to 270 mg. In certain embodiments, the pharmaceutical composition contains approximately 120 mg to 240 mg of bempedoic acid.

[0176] In certain embodiments, the pharmaceutical composition contains approximately 30 mg, approximately 40 mg, approximately 50 mg, approximately 60 mg, approximately 70 mg, approximately 80 mg, approximately 90 mg, approximately 100 mg, approximately 110 mg, approximately 120 mg, approximately 130 mg, approximately 140 mg, approximately 150 mg, approximately 160 mg, approximately 170 mg, approximately 180 mg, approximately 190 mg, approximately 200 mg, approximately 210 mg, approximately 220 mg, approximately 230 mg, approximately 240 mg, approximately 250 mg, approximately 260 mg, approximately 270 mg, approximately 280 mg, approximately 290 mg, or approximately 300 mg of bempedoic acid. In certain embodiments, the pharmaceutical composition contains approximately 180 mg of bempedoic acid.

[0177] In a particular embodiment, the pharmaceutical composition contains semaglutide in the following concentrations: approximately 1 mg to approximately 30 mg, approximately 2 mg to approximately 30 mg, approximately 3 mg to approximately 30 mg, approximately 4 mg to approximately 30 mg, approximately 6 mg to approximately 30 mg, approximately 8 mg to approximately 30 mg, approximately 10 mg to approximately 30 mg, approximately 12 mg to approximately 30 mg, approximately 14 mg to approximately 30 mg, approximately 16 mg to approximately 30 mg, approximately 20 mg to approximately 30 mg, approximately 25 mg to approximately 30 mg, approximately 1 mg to approximately 25 mg, approximately 1 mg to approximately 20 mg, approximately 1 mg to approximately 16 mg, approximately 1 mg to approximately 14 mg, approximately 1 mg to approximately 12 mg, and approximately 1 mg ~10mg, 1mg~8mg, 1mg~6mg, 1mg~4mg, 1mg~3mg, 1mg~2mg, 2mg~25mg, 2mg~20mg, 2mg~16mg, 2mg~14mg, 2mg~12mg, Approximately 2 mg to approximately 10 mg, approximately 2 mg to approximately 8 mg, approximately 2 mg to approximately 6 mg, approximately 2 mg to approximately 4 mg, approximately 2 mg to approximately 3 mg, approximately 3 mg to approximately 25 mg, approximately 3 mg to approximately 20 mg, approximately 3 mg to approximately 16 mg, approximately 3 mg to approximately 14 mg, approximately 3 mg to approximately 12 mg, approximately 3 mg to approximately 10mg, approximately 3mg-8mg, approximately 3mg-6mg, approximately 3mg-4mg, approximately 4mg-25mg, approximately 4mg-20mg, approximately 4mg-16mg, approximately 4mg-14mg, approximately 4mg-12mg, approximately 4mg-10mg, approximately 4mg-8mg, approximately 4mg-6mg, approximately 6mg-25mg, approximately 6mg-20mg, approximately 6mg-16mg, approximately 6mg-14mg, approximately 6mg-12mg, approximately 6mg-10mg, approximately 6mg-8mg, approximately 8mg-25mg, approximately 8mg-20mg, approximately 8mg Contains approximately 16 mg, 8 mg to 14 mg, 8 mg to 12 mg, 8 mg to 10 mg, 10 mg to 25 mg, 10 mg to 20 mg, 10 mg to 16 mg, 10 mg to 14 mg, 10 mg to 12 mg, 12 mg to 25 mg, 12 mg to 20 mg, 12 mg to 16 mg, 12 mg to 14 mg, 14 mg to 25 mg, 14 mg to 20 mg, 14 mg to 16 mg, 16 mg to 25 mg, 16 mg to 20 mg, or 20 mg to 25 mg. In certain embodiments, the fixed dose combination contains approximately 3 mg to 14 mg of semaglutide.

[0178] In certain embodiments, the pharmaceutical composition contains 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 of semaglutide. In certain embodiments, the pharmaceutical composition contains about 3 mg of semaglutide. In certain embodiments, the pharmaceutical composition contains about 7 mg of semaglutide. In certain embodiments, the pharmaceutical composition contains about 14 mg of semaglutide.

[0179] In various embodiments, the present disclosure provides a pharmaceutical composition comprising about 120 mg to about 240 mg of bempedoic acid, about 3 mg to about 14 mg of semaglutide, and one or more pharmaceutically acceptable excipients.

[0180] In various embodiments, the present disclosure provides a pharmaceutical composition comprising about 180 mg of bempedoic acid, about 3 mg of semaglutide, and one or more pharmaceutically acceptable excipients.

[0181] In various embodiments, the present disclosure provides a pharmaceutical composition comprising about 180 mg of bempedoic acid, about 7 mg of semaglutide, and one or more pharmaceutically acceptable excipients.

[0182] In various embodiments, the present disclosure provides a pharmaceutical composition comprising about 180 mg of bempedoic acid, about 14 mg of semaglutide, and one or more pharmaceutically acceptable excipients.

[0183] The amounts of bempedoic acid and semaglutide compounds present in the pharmaceutical compositions described herein may vary depending on the target of treatment and / or the specific administration method.

[0184] In certain embodiments, the amounts of bempedoic acid and semaglutide that can be combined with pharmaceutically acceptable excipients to produce the pharmaceutical compositions described herein are generally such that the amounts of bempedoic acid and semaglutide produce a therapeutic effect.

[0185] pharmaceutically acceptable excipients intended to be useful in the preparation of pharmaceutical compositions containing bempedoic acid and semaglutide include, but are not limited to, fillers or bulking agents, sweeteners, binders, humectants, disintegrants, preservatives, odorants, flavoring agents, antioxidants, dissolution retarders, absorption enhancers, wetting agents, absorbents, lubricants, colorants, and release regulators. In some embodiments, the pharmaceutical composition may contain buffers. In some embodiments, the pharmaceutical composition may contain one or more excipients selected from lactose, lactose, high molecular weight polyethylene glycol, and combinations thereof.

[0186] In certain embodiments, the pharmaceutical composition comprising bempedoic acid and semaglutide described herein may further comprise one or more pharmaceutically acceptable excipients selected from the group consisting of cyclodextrins, cellulose, liposomes, micelle-forming agents, and polymer carriers. In some embodiments, the pharmaceutical composition may comprise antibacterial agents, antifungal agents, or combinations thereof. Examples of antibacterial and antifungal agents include, but are not limited to, parabens, chlorobutanol, phenol, and sorbic acid. In some embodiments, the pharmaceutical composition may comprise isotonic agents.

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

[0188] (3) Dosage form In another embodiment, the Disclosure provides solid dosage forms comprising the pharmaceutical formulations 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 oral dosage forms. Examples of oral dosage forms include, but are not limited to, drenches, tablets, capsules, softgel capsules, cachets, pills, emulsions, lozenges, solutions, suspensions, boluses, powders, elixirs or syrups, sachets, mouthwashes, granules, or pastes for application to the tongue. In some embodiments, the pharmaceutical formulations are formulated as tablets.

[0190] (4) Use In certain embodiments, the pharmaceutical compositions described herein may be used to treat fatty liver in subjects requiring treatment. In certain embodiments, the pharmaceutical compositions described herein may be used to treat hepatic fibrosis in subjects with fatty liver. In certain embodiments, the pharmaceutical compositions described herein may be used to regulate blood glucose control in subjects with fatty liver. In certain embodiments, the pharmaceutical compositions described herein may be used to lower HbA1c levels in the blood or serum of subjects with fatty liver. In certain embodiments, the pharmaceutical compositions described herein may be used to reduce the body weight of subjects with fatty liver. In certain embodiments, the pharmaceutical compositions described herein may be used to lower the systolic and / or diastolic blood pressure of subjects with fatty liver. In certain embodiments, the pharmaceutical compositions described herein may be used to reduce hepatic fat in subjects with fatty liver. In certain embodiments, the pharmaceutical compositions described herein may be used to reduce ballooning hepatocytes in subjects with fatty liver. In certain embodiments, the pharmaceutical compositions described herein may be used to reduce lobular inflammation in subjects with fatty liver.

[0191] Instructions for use and treatment methods Provided in this disclosure is a method for treating fatty liver in subjects requiring treatment. The method generally comprises administering to the subject an effective dose of a GLP-1 receptor agonist and an effective dose of bempedoic acid.

[0192] Furthermore, the present disclosure provides a method for treating a subject with fatty liver, generally comprising administering to the subject an effective dose of a GLP-1 receptor agonist and an effective dose of bempedoic acid, the treatment comprising, in the subject, one or more of the following: treating hepatic fibrosis, regulating blood glucose control, lowering blood or serum HbA1c levels, reducing body weight, lowering systolic and / or diastolic blood pressure, reducing hepatic fat, reducing ballooning hepatocytes, and reducing lobular inflammation.

[0193] Furthermore, this disclosure provides a method for treating fatty liver in a subject receiving GLP-1 receptor agonist therapy, which generally includes administering an effective amount of bempedoic acid to the subject.

[0194] Furthermore, the present disclosure provides a method for treating a subject with fatty liver who is being treated with a GLP-1 receptor agonist therapy, the method generally comprising administering an effective amount of bempedoic acid to the subject, the treatment comprising, in the subject, one or more of the following: treating hepatic fibrosis, regulating blood glucose control, lowering blood or serum HbA1c levels, reducing body weight, lowering systolic and / or diastolic blood pressure, reducing hepatic fat, reducing ballooning hepatocytes, and reducing lobular inflammation.

[0195] In various embodiments, the present disclosure provides a method for treating fatty liver in a subject requiring treatment, 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, the present disclosure provides a method for treating hepatic fibrosis in a subject with fatty liver, 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, the present disclosure provides a method for regulating blood glucose control in a subject with fatty liver, 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, the Disclosure provides a method for reducing HbA1c levels in the blood or serum of a subject with fatty liver, 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, the present disclosure provides a method for reducing the body weight of a subject with fatty liver, 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, the present disclosure provides a method for lowering the systolic and / or diastolic blood pressure of a subject with fatty liver, 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, the present disclosure provides a method for reducing hepatic fat in a subject with fatty liver, 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, the present disclosure provides a method for reducing ballooning hepatocytes in a subject with fatty liver, 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, the present disclosure provides a method for reducing lobular inflammation in a subject with fatty liver, 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 fatty liver is non-alcoholic steatohepatitis (NASH).

[0205] In certain embodiments, effective doses of the GLP-1 receptor agonist and bempedoic acid result in a lower hbA1c level in the subject's blood or serum than in subjects with fatty liver who have not received effective doses of the GLP-1 receptor agonist and bempedoic acid, or who have received (a) an effective dose of the GLP-1 receptor agonist or (b) an effective dose of bempedoic acid.

[0206] In certain embodiments, when the GLP-1 receptor agonist and bempedo acid are administered in effective doses, subjects with fatty liver disease show a greater weight loss compared to subjects who are not administered in effective doses of the GLP-1 receptor agonist and bempedo acid, or subjects who are administered in effective doses of either (a) the GLP-1 receptor agonist or (b) bempedo acid.

[0207] In certain embodiments, when the GLP-1 receptor agonist and bempedo acid are administered in effective doses, a significant reduction in liver fat is observed in subjects with fatty liver compared to subjects who are not administered in effective doses of the GLP-1 receptor agonist and bempedo acid, or subjects who are administered in effective doses of either (a) the GLP-1 receptor agonist or (b) bempedo acid.

[0208] In certain embodiments, when the GLP-1 receptor agonist and bempedo acid are administered in effective doses, a significant reduction in liver fibrosis is observed in subjects with fatty liver compared to subjects who are not administered in effective doses of the GLP-1 receptor agonist and bempedo acid, or subjects who are administered in effective doses of either (a) the GLP-1 receptor agonist or (b) bempedo acid.

[0209] In some embodiments, effective doses of the GLP-1 receptor agonist and bempedoic acid result in lower levels of apolipoprotein B (apoB) in the subject's blood or serum than in subjects who have not received effective doses of the GLP-1 receptor agonist and bempedoic acid, or who have received effective doses of either (a) the GLP-1 receptor agonist or (b) bempedoic acid.

[0210] In some embodiments, effective doses of the GLP-1 receptor agonist and bempedoic acid result in lower levels of non-high-density lipoprotein cholesterol in the subject's blood or serum than in subjects who have not received effective doses of the GLP-1 receptor agonist and bempedoic acid, or who have received (a) an effective dose of the GLP-1 receptor agonist or (b) an effective dose of bempedoic acid.

[0211] In some embodiments, effective doses of the GLP-1 receptor agonist and bempedoic acid result in triglyceride levels in the subject's blood or serum being lower than those in a subject who has not received effective doses of the GLP-1 receptor agonist and bempedoic acid, or who has received effective doses of either (a) the GLP-1 receptor agonist or (b) bempedoic acid.

[0212] In some embodiments, when the GLP-1 receptor agonist and bempedoic acid are administered in an effective dose, the number of LDL particles in the subject's blood or serum is less than the number of subjects who have not been administered an effective dose of the GLP-1 receptor agonist and bempedoic acid, or who have been administered an effective dose of either (a) the GLP-1 receptor agonist or (b) the bempedoic acid.

[0213] In some embodiments, when the GLP-1 receptor agonist and bempedoic acid are administered in an effective dose, the size of VLDL particles in the subject's blood or serum becomes smaller than that of a subject who has not been administered an effective dose of the GLP-1 receptor agonist and bempedoic acid, or who has been administered an effective dose of either (a) the GLP-1 receptor agonist or (b) an effective dose of bempedoic acid.

[0214] In some embodiments, when the GLP-1 receptor agonist and bempedoic acid are administered in an effective dose, the number of VLDL particles in the subject's blood or serum is less than the number of subjects who have not been administered an effective dose of the GLP-1 receptor agonist and bempedoic acid, or who have been administered an effective dose of either (a) the GLP-1 receptor agonist or (b) the bempedoic acid.

[0215] In some embodiments, effective doses of the GLP-1 receptor agonist and bempedoic acid result in higher levels of apolipoprotein A1 (apoA1) in the subject's blood or serum than in subjects who have not received effective doses of the GLP-1 receptor agonist and bempedoic acid, or who have received effective doses of either (a) the GLP-1 receptor agonist or (b) bempedoic acid.

[0216] In some embodiments, when the GLP-1 receptor agonist and bempedoic acid are administered in an effective dose, the level of apolipoprotein A1 (apoA1) in the subject's blood or serum does not change compared to the level in a subject who has not received an effective dose of the GLP-1 receptor agonist and bempedoic acid, or who has received an effective dose of either (a) the GLP-1 receptor agonist or (b) the bempedoic acid.

[0217] In some embodiments, effective doses of the GLP-1 receptor agonist and bempedoic acid result in lower levels of apolipoprotein A1 (apoA1) in the subject's blood or serum than in subjects who have not received effective doses of the GLP-1 receptor agonist and bempedoic acid, or who have received effective doses of either (a) the GLP-1 receptor agonist or (b) bempedoic acid.

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

[0219] In some embodiments, administration of an effective amount of GLP-1 receptor agonist and an effective amount of bempedoic acid to a subject reduces fatty liver content by approximately 20–70 percent, 20–65 percent, 20–60 percent, 20–55 percent, 20–45 percent, 20–40 percent, 20–35 percent, 20–30 percent, 20–25 percent, 10–60 percent, 10–55 percent, 10–50 percent, 10–45 percent, 10–40 percent, 10–35 percent, 10–30 percent, 10–25 percent, 10–20 percent, or 10–15 percent. In certain embodiments, effective doses of the GLP-1 receptor agonist and bempedoic acid reduce fatty liver content by more than 30%, 35%, 40%, 45%, 50%, 55%, 60%, or 65%. Fatty liver content may be measured in subjects by nuclear magnetic resonance spectroscopy or biopsy.

[0220] In some embodiments, administering to a subject an effective amount of a GLP-1 receptor agonist and an effective amount of bendroflumethiazide results in a decrease in the average 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, administering to the subject an effective amount of the GLP-1 receptor agonist and bendroflumethiazide results in a decrease in the average 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 above embodiments, the subject has diabetes (e.g., type 2 diabetes) and / or a baseline body mass index (BMI) is greater than 30 kg / m 2 superscript.

[0221] In some embodiments, administration of an effective dose of GLP-1 receptor agonist and an effective dose of pempedoic acid to a subject resulted in an increase in the subject's HbA1c level in the blood or serum by approximately 0.5–6 percent, 0.5–5.5 percent, 0.5–5 percent, 0.5–4.5 percent, 0.5–4 percent, 0.5–3.5 percent, 0.5–3 percent, 0.5–2.5 percent, and 0 percent. The levels decrease by approximately 0.5 to 2.0 percent, approximately 0.5 to 1.8 percent, approximately 0.8 to 6 percent, approximately 0.8 to 5.5 percent, approximately 0.8 to 5 percent, approximately 0.8 to 4.5 percent, approximately 0.8 to 4 percent, approximately 0.8 to 3.5 percent, approximately 0.8 to 3 percent, approximately 0.8 to 2.5 percent, approximately 0.8 to 2 percent, approximately 0.8 to 1.5 percent, or approximately 0.8 to 1.2 percent. In certain embodiments, administration of an effective dose of the GLP-1 receptor agonist and pempedoic acid to the subject results in a decrease in HbA1c levels of more than 1%, more than 1.5%, more than 2%, more than 2.5%, more than 3%, more than 3.5%, more than 4%, more than 4.5%, more than 5%, more than 5.5%, or more than 6%.

[0222] In some embodiments, administration of an effective dose of GLP-1 receptor agonist and an effective dose of bempedo acid resulted in the subject's systolic blood pressure being approximately 1-18 mmHg, 1-17 mmHg, 1-16 mmHg, 1-15 mmHg, 1-14 mmHg, 1-13 mmHg, 1-12 mmHg, 1-11 mmHg, 1-10 mmHg, 1-9 mmHg, 1-8 mmHg, 1-7 mmHg, 1-6 mmHg, 1-5 mmHg, 2-18 mmHg, 2-17 mmHg, 2-16 mmHg, 2-15 mmHg, and 2-1 It decreases by 4 mmHg, approximately 2 to 13 mmHg, approximately 2 to 12 mmHg, approximately 2 to 11 mmHg, approximately 2 to 10 mmHg, approximately 2 to 9 mmHg, approximately 2 to 8 mmHg, approximately 2 to 7 mmHg, approximately 2 to 6 mmHg, approximately 2 to 5 mmHg, approximately 3 to 18 mmHg, approximately 3 to 17 mmHg, approximately 3 to 16 mmHg, approximately 3 to 15 mmHg, approximately 3 to 14 mmHg, approximately 3 to 13 mmHg, approximately 3 to 12 mmHg, approximately 3 to 11 mmHg, approximately 3 to 10 mmHg, approximately 3 to 9 mmHg, approximately 3 to 8 mmHg, approximately 3 to 7 mmHg, approximately 3 to 6 mmHg, or approximately 3 to 5 mmHg. In certain embodiments, administration of an effective dose of the GLP-1 receptor agonist and bempedoic acid to a subject results in a decrease in the subject's systolic blood pressure 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 above embodiments, the subject has a baseline systolic blood pressure greater than 130 mg.

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

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

[0225] In certain embodiments, the GLP-1 receptor agonist is administered to the subject in an effective dose once, twice, three, four, or five times daily. In certain embodiments, the GLP-1 receptor agonist is administered to the subject in an effective dose once daily. In certain embodiments, the GLP-1 receptor agonist is administered to the subject in an effective dose twice daily.

[0226] In certain embodiments, the GLP-1 receptor agonist is administered to the subject in an effective dose once, twice, three, four, five, six, or seven times a week.

[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, administration of an effective dose of a GLP-1 receptor agonist includes administering to the subject about 0.25 mg to about 14 mg of semaglutide. In certain embodiments, administration of an effective dose of a GLP-1 receptor agonist includes parenterally administering to the subject about 0.25 mg to about 1 mg of semaglutide. In certain embodiments, administration of an effective dose of a GLP-1 receptor agonist includes parenterally administering to the subject about 0.25 mg to about 1 mg of semaglutide once a week. In certain embodiments, administration of an effective dose of a GLP-1 receptor agonist includes orally administering to the subject about 3 mg to about 14 mg of semaglutide. In certain embodiments, administration of an effective dose of a GLP-1 receptor agonist includes orally administering to the subject about 3 mg to about 14 mg of semaglutide once a day.

[0229] In certain embodiments, administration of an effective dose of a GLP-1 receptor agonist includes parenterally administering about 0.6 mg to about 1.8 mg of liraglutide to the subject.

[0230] In certain embodiments, administration of an effective dose of a GLP-1 receptor agonist includes parenterally administering approximately 2 mg to approximately 10 mg of exenatide to the subject. In certain embodiments, administration of an effective dose of a GLP-1 receptor agonist includes parenterally administering approximately 2 mg to approximately 10 mg of exenatide twice daily to the subject.

[0231] In certain embodiments, administration of an effective dose of a GLP-1 receptor agonist includes parenterally administering approximately 0.75 mg to approximately 1.5 mg of dulaglutide to the subject.

[0232] In certain embodiments, administration of an effective dose of a GLP-1 receptor agonist includes parenterally administering about 30 mg to about 50 mg of albiglutide to the subject. In certain embodiments, administration of an effective dose of a GLP-1 receptor agonist includes parenterally administering about 30 mg to about 50 mg of albiglutide once a week to the subject.

[0233] In certain embodiments, administration of an effective dose of a GLP-1 receptor agonist includes parenterally administering about 10 mg to about 20 mg of lixisenatide to the subject.

[0234] In various embodiments, the present disclosure provides a method for treating fatty liver in a subject receiving a GLP-1 receptor agonist therapy, the method comprising administering an effective amount of bempedoic acid to the subject.

[0235] In various embodiments, the present disclosure provides a method for treating hepatic fibrosis in a subject receiving a GLP-1 receptor agonist therapy, the method comprising administering an effective amount of bempedoic acid to the subject.

[0236] In various embodiments, the present disclosure provides a method for regulating blood glucose control in a subject with fatty liver who is being treated with a GLP-1 receptor agonist, the method comprising administering an effective amount of bempedoic acid to the subject.

[0237] In various embodiments, the present disclosure provides a method for reducing the level of HbA1c in the blood or serum of a subject with fatty liver who is being treated with a GLP-1 receptor agonist therapy, the method comprising administering an effective amount of bempedoic acid to the subject.

[0238] In various embodiments, the present disclosure provides a method for reducing the body weight of a subject with fatty liver who is being treated with a GLP-1 receptor agonist therapy, the method comprising administering an effective amount of bempedoic acid to the subject.

[0239] In various embodiments, the present disclosure provides a method for lowering the systolic and / or diastolic blood pressure of a subject with fatty liver who is being treated with a GLP-1 receptor agonist therapy, the method comprising administering an effective amount of bempedoic acid to the subject.

[0240] In various embodiments, the present disclosure provides a method for reducing hepatic fat in a subject receiving a GLP-1 receptor agonist therapy, the method comprising administering an effective amount of bempedoic acid to the subject.

[0241] In various embodiments, the present disclosure provides a method for reducing ballooning hepatocytes in subjects receiving GLP-1 receptor agonist therapy, the method comprising administering an effective amount of bempedoic acid to the subjects.

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

[0243] In certain embodiments, the target is NASH.

[0244] In certain embodiments, administration of an effective dose of bempedoic acid results in a blood or serum hbA1c level in a subject receiving a GLP-1 receptor agonist therapy being lower than the levels in a subject with fatty liver who has not received an effective dose of bempedoic acid and a GLP-1 receptor agonist therapy, or in a subject who has received (a) a GLP-1 receptor agonist therapy or (b) an effective dose of bempedoic acid.

[0245] In certain embodiments, administration of an effective amount of bempedo acid results in a significant reduction in body weight in subjects receiving GLP-1 receptor agonist therapy, who have fatty liver, compared to subjects not receiving an effective amount of bempedo acid and GLP-1 receptor agonist therapy, or subjects receiving (a) GLP-1 receptor agonist therapy or (b) an effective amount of bempedo acid.

[0246] In certain embodiments, administration of an effective amount of bempedo acid results in a significant reduction in hepatic fat in subjects receiving GLP-1 receptor agonist therapy, compared to subjects with fatty liver who are not receiving an effective amount of bempedo acid and GLP-1 receptor agonist therapy, or subjects receiving (a) a GLP-1 receptor agonist therapy or (b) an effective amount of bempedo acid.

[0247] In certain embodiments, administration of an effective amount of bempedo acid significantly reduces hepatic fibrosis in subjects receiving GLP-1 receptor agonist therapy, where the condition is fatty liver, compared to subjects not receiving an effective amount of bempedo acid and GLP-1 receptor agonist therapy, or subjects receiving (a) GLP-1 receptor agonist therapy or (b) an effective amount of bempedo acid.

[0248] In some embodiments, administration of an effective dose of bempedoic acid results in lower levels of apolipoprotein B (apoB) in the blood or serum of subjects receiving a GLP-1 receptor agonist therapy than in subjects not receiving an effective dose of bempedoic acid and a GLP-1 receptor agonist therapy, or in subjects receiving (a) a GLP-1 receptor agonist therapy or (b) an effective dose of bempedoic acid.

[0249] In some embodiments, administration of an effective amount of bempedoic acid results in a lower level of non-high density lipoprotein cholesterol in the blood or serum of a subject receiving a GLP-1 receptor agonist therapeutic agent than in a subject not receiving an effective amount of bempedoic acid and a GLP-1 receptor agonist therapeutic agent, or in a subject receiving (a) a GLP-1 receptor agonist therapeutic agent or (b) an effective amount of bempedoic acid.

[0250] In some embodiments, administration of an effective amount of bempedoic acid results in a lower level of triglycerides in the blood or serum of a subject receiving a GLP-1 receptor agonist therapeutic agent than in a subject not receiving an effective amount of bempedoic acid and a GLP-1 receptor agonist therapeutic agent, or in a subject receiving (a) a GLP-1 receptor agonist therapeutic agent or (b) an effective amount of bempedoic acid.

[0251] In some embodiments, administration of an effective amount of bempedoic acid results in a lower number of LDL particles in the blood or serum of a subject receiving a GLP-1 receptor agonist therapeutic agent than in a subject not receiving an effective amount of bempedoic acid and a GLP-1 receptor agonist therapeutic agent, or in a subject receiving (a) a GLP-1 receptor agonist therapeutic agent or (b) an effective amount of bempedoic acid.

[0252] In some embodiments, administration of an effective amount of bempedoic acid results in a smaller size of VLDL particles in the blood or serum of a subject receiving a GLP-1 receptor agonist therapeutic agent than in a subject not receiving an effective amount of bempedoic acid and a GLP-1 receptor agonist therapeutic agent, or in a subject receiving (a) a GLP-1 receptor agonist therapeutic agent or (b) an effective amount of bempedoic acid.

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

[0254] In some embodiments, administration of an effective amount of bempedoic acid results in an increased level of apolipoprotein A1 (apoA1) in the blood or serum of a subject receiving a GLP-1 receptor agonist therapy compared to a subject not receiving an effective amount of bempedoic acid and a GLP-1 receptor agonist therapy, or in a subject receiving (a) a GLP-1 receptor agonist therapy or (b) an effective amount of bempedoic acid.

[0255] In some embodiments, administration of an effective amount of bempedoic acid results in no change in the level of apolipoprotein A1 (apoA1) in the blood or serum of a subject receiving a GLP-1 receptor agonist therapy compared to a subject not receiving an effective amount of bempedoic acid, or in a subject receiving (a) that GLP-1 receptor agonist therapy or (b) an effective amount of bempedoic acid.

[0256] In some embodiments, administration of an effective amount of bempedoic acid results in a lower level of apolipoprotein A�1 (apoA1) in the blood or serum of a subject receiving a GLP-1 receptor agonist therapy compared to a subject not receiving an effective amount of bempedoic acid and a GLP-1 receptor agonist therapy, or in a subject receiving (a) a GLP-1 receptor agonist therapy or (b) an effective amount of bempedoic acid.

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

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

[0259] In certain embodiments, the GLP-1 receptor agonist therapy agent is administered to the subject once, twice, three, four, five, six, or seven times per week. In certain embodiments, the GLP-1 receptor agonist therapy agent is administered to the subject once per week.

[0260] In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 0.25 mg to approximately 14 mg of semaglutide. In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 0.25 mg to approximately 1 mg of semaglutide. In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 0.25 mg to approximately 1 mg of semaglutide parenterally. In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 0.25 mg to approximately 1 mg of semaglutide parenterally once a week. In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 3 mg to approximately 14 mg of semaglutide. In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are orally administered approximately 3 mg to approximately 14 mg of semaglutide. In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are orally administered approximately 3 mg to approximately 14 mg of semaglutide once daily.

[0261] In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 0.6 mg to approximately 1.8 mg of liraglutide. In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 0.6 mg to approximately 1.8 mg of liraglutide parenterally. In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 0.6 mg to approximately 1.8 mg of liraglutide parenterally once daily.

[0262] In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 2 mg to approximately 10 mg of exenatide. In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 2 mg to approximately 10 mg of exenatide parenterally. In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 2 mg to approximately 10 mg of exenatide parenterally twice a day.

[0263] In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 0.75 mg to approximately 1.5 mg of dulaglutide. In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 0.75 mg to approximately 1.5 mg of dulaglutide parenterally. In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 0.75 mg to approximately 1.5 mg of dulaglutide parenterally once a week.

[0264] In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 30 mg to approximately 50 mg of albiglutide. In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 30 mg to approximately 50 mg of albiglutide parenterally. In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 30 mg to approximately 50 mg of albiglutide parenterally once a week.

[0265] In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 10 mg to approximately 20 mg of lixisenatide. In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 10 mg to approximately 20 mg of lixisenatide parenterally. In certain embodiments, subjects receiving GLP-1 receptor agonist therapy are administered approximately 10 mg to approximately 20 mg of lixisenatide parenterally once daily.

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

[0267] In certain embodiments, an effective amount of bempedo acid is administered to the subject once, twice, three times, four times, or five times a day. In certain embodiments, an effective amount of bempedo acid is administered to the subject once a day.

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

[0269] In some embodiments, the method described herein reduces LDL-C in the subject's blood or serum. In some embodiments, the method described herein reduces systolic and / or diastolic blood pressure in the subject. In some embodiments, the method described herein reduces uric acid in the subject's blood or serum. In some embodiments, the method described herein reduces hsCRP in the subject's blood or serum. In some embodiments, the method described herein reduces the subject's body weight. In some embodiments, the method described herein reduces the risk of atherosclerotic cardiovascular disease in the subject. In some embodiments, the method described herein reduces the level of hbA1c in the subject's blood or serum.

[0270] In some embodiments, the method described herein results in a lower level of apolipoprotein B (apoB) in the blood or serum of the subject than the level of the subject not administered with the GLP-1 receptor agonist and bempedoic acid combination. In some embodiments, the method described herein results in a lower level of non-high-density lipoprotein cholesterol in the blood or serum of the subject than the level of the subject not administered with the GLP-1 receptor agonist and bempedoic acid combination. In some embodiments, the method described herein results in a lower level of triglycerides in the blood or serum of the subject than the level of the subject not administered with the GLP-1 receptor agonist and bempedoic acid combination. In some embodiments, the method described herein results in a lower number of LDL particles in the blood or serum of the subject than the number of LDL particles in the subject not administered with the GLP-1 receptor agonist and bempedoic acid combination. In some embodiments, the method described herein results in a smaller size of VLDL particles in the blood or serum of the subject than the size of VLDL particles in the subject not administered with the GLP-1 receptor agonist and bempedoic acid combination. In some embodiments, the method described herein results in a lower number of VLDL particles in the subject's blood or serum compared to the number of subjects not administered the GLP-1 receptor agonist and bempedoic acid combination. In some embodiments, the method described herein results in an increased level of apolipoprotein A1 (apoA1) in the subject's blood or serum compared to the level of subjects not administered the GLP-1 receptor agonist and bempedoic acid combination. In some embodiments, the method described herein results in no change in the level of apolipoprotein A1 (apoA1) in the subject's blood or serum compared to the level of subjects not administered the GLP-1 receptor agonist and bempedoic acid combination. In some embodiments, the method described herein results in a lower level of apolipoprotein A1 (apoA1) in the subject's blood or serum compared to the level of subjects not administered the GLP-1 receptor agonist and bempedoic acid combination.

Example

[0271] The following are examples of specific embodiments for implementing the present disclosure. The examples are provided 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 in this specification should be understood to have the meanings commonly associated with those terms as understood within the technical field of the present disclosure. In this specification, certain terms are discussed to provide additional guidance to the practitioner when describing the compositions, devices, methods, etc. of aspects of the present disclosure and the methods of making or using them. It will be apparent that the same thing may be referred to in more than one way. Thus, alternative languages and synonyms may be used for any one or more of the terms discussed in this specification. Whether a term is detailed or discussed in this specification is not important. Several synonyms or alternative ways, materials, etc. are provided. The description of one or a few synonyms or equivalents does not exclude the use of other synonyms or equivalents unless explicitly stated. The 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 present disclosure in this specification.

[0273] Example 1 - A study to evaluate the effects of the combination of bempedoic acid and liraglutide in a mouse model of metabolism-related steatohepatitis and hepatic fibrosis. (1) Method animal All in vivo experiments were approved by the McMaster University Animal Ethics Committee and conducted in accordance with Canadian guidelines for animal research. Male mice with a background of C57BL / 6J were purchased from Jackson Laboratories at 6-7 weeks of age. Mice were housed in cages of 3-5 individuals in a controlled environment with a 12-hour light-dark cycle, and were given free-range feed and water, as well as enrichment. At 8 weeks of age, mice were moved to specific pathogen-free (SPF) microisolators in a room maintained at approximately 29°C and fed a high-fat, high-fructose diet (NASH diet, ND, 40% fat, 20% fructose, 0.02% cholesterol, mainly palm-derived). Since fructose was added to the diet, the diet was changed every few weeks. After 16 weeks, mice were grouped by randomly matching body weight and hyperlipidemia and placing them in their respective intervention arms. Hyperlipidemia was assessed based on time-domain NMR using a Bruker Minispec LF90II. Control mice were given only diet. Vehicle-treated mice (vehicle) were given saline subcutaneously every other day, 1-2 hours before the dark cycle. Bempedoic acid-treated mice (BemA) were given the drug added to their diet at a dose of 10 mg / kg. Liraglutide-treated mice (Lira) were given Victoza® diluted in saline subcutaneously at a dose of 70 μg / kg every other day, 1-2 hours before the dark cycle. Combination-treated mice (Lira + BemA) were given Victoza® diluted in saline subcutaneously at a dose of 70 μg / kg every other day, along with bempedoic acid added to their diet at a dose of 10 mg / kg, 1-2 hours before the dark cycle. After 9 weeks of treatment, all mice were euthanized between 09:00 and 11:00 while feeding using a sedative ketamine / xylazine mixture, and blood was collected by cardiac puncture. It was assumed that the mice died from blood loss, and cervical dislocation was performed as a secondary measure.

[0274] Metabolic test Metabolic tests were performed in the following order during weeks 4–9 of the intervention: 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 7:00 and baseline values ​​assessed at 13:00. Intraperitoneal pyruvate tolerance tests (ipPTT, 1.5 g / kg) were performed in 15-hour fasted mice, with fasting continuing overnight and baseline values ​​assessed at 9:00. Fasting blood glucose and serum were collected in 6-hour fasted mice to mimic the ipGTT and ipITT times. Blood collection for these tests was performed by making a wound in the tail.

[0275] Analysis of liver lipids The percentage of liver fat was assessed based on time-domain NMR using a Bruker Minispec LF90II. Briefly, approximately 30–50 mg of tissue chips were obtained on dry ice, left on ice for 10 minutes to thaw, and left at room temperature for 10 minutes to equilibrate before being placed in biopsy tubes purchased from Bruker. Liver triglycerides were assessed using the Cayman Chemicals Triglyceride Colorimetric Assay kit (item number 10010303). Briefly, 10–20 mg of frozen liver was immediately homogenized in 400 μL of diluted NP40 alternative assay reagent. All other aspects of the assay were followed according to the manufacturer's instructions.

[0276] Tissue diagnosis The tissue was fixed in 10% neutral buffered formalin for 48 hours and then stored in 70% ethanol. The middle lobe of the liver was processed, paraffin-embedded, and serial sections were prepared, which were stained with hematoxylin and eosin (H&E), Masson's trichrome, and picrosilius red (PSR) by the center of the tissue diagnostic facility at McMaster Immunology Research Centre. Images were acquired using an upright microscope, Nikon 90i Eclipse. Liver tissue diagnostic scores were obtained by blinded pathologists using a description based on the one documented by Kleiner et al. (Kleiner et al. 2005). The NAFLD activity score was calculated as the sum of the scores for fatty liver, lobular inflammation, and ballooning hepatocytes, when evaluated using H&E-stained slides. The fibrosis score was obtained by evaluating slides stained with both Masson's trichrome and PSR.

[0277] RNA isolation and analysis Liver tissue (approximately 15 mg) was dissolved in 1 mL of TRIzol reagent (Invitrogen) using ceramic beads and a Precellys24 homogenizer (Bertin Technologies). The sample was spun down for 10 minutes at 12000 g and 4°C. 200 μL of chloroform was added, and the mixture was shaken vigorously before spinning the sample again at the same settings. The supernatant was placed in a new tube, an equal volume of 70% ethanol was added, and the mixture was vortexed. The solution was delivered to an RNeasy column according to the manufacturer's instructions (Qiagen).

[0278] Gene expression analysis using NanoString For analysis using NanoString, 4-5 RNA samples per group were examined using BioAnalyzer's quality control testing. McMaster Genomics Facility ran the nCounter Fibrosis v2 Panel (NanoString Technologies), which contains 760 target genes, and the CustomSet Panel, consisting of 22 orthologous mus musculus genes corresponding to the NASH severity signatures of 25 genes described by 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). Before differential gene expression analysis and calculation of pathway signature scores, gene expression data was normalized and logarithmically transformed using NanoString Technologies' nSolver 4.0 software (version 4.0.70) and the embedded PLAGE algorithm.

[0279] Intrinsically regulated genes were defined as genes differentially expressed (FDR < 0.05) between the control and combination therapy (but not monotherapy). Additively regulated genes were defined as genes differentially expressed (FDR < 0.05) that showed the largest multiplier change between the control and combination therapy (compared to monotherapy). Based on the overlap between intrinsically and additively regulated genes and differential expression between combination therapy and monotherapy (p-value < 0.05), combination-specific signatures were derived. Using an elastic net normalized model with 10-fold cross-validation, a subset of genes associated with fibrosis stages greater than 2 was further identified in a cohort of 216 human NAFLD / NASH patients using methods performed with caret v6.0.93 and glmnet v4.1.6. Pathway overpopulation was determined by summarizing the gene and associated pathway annotations in a table for the sets of intrinsic and additive genes. Statistical significance was calculated using the chi-squared test.

[0280] RNA-Seq analysis Patient-derived RNA-Seq data were obtained from the GEO repository GSE135251 and processed for quality control, alignment, and counting as previously described (Govaere et al. 2020). Relative mRNA abundances were calculated using DESeq2 v1.36.0 with the application of dispersion stabilization transformations.

[0281] Integrated analysis of human and mouse gene expression Gene expression data derived from NanoString and DESeq2 analyses were transformed using logarithmic scales and Z-scores before being integrated with human data. Hierarchical clustering using PCA and Pearson correlations, as performed in stats v4.2.2, was applied to the integrated gene expression data to assess sample similarity between the treatment cohort and human NASH / NAFLD disease stages.

[0282] We predicted the progression stage of fibrosis in patients using multivariate logistic regression with combination therapy-specific gene signatures and 25 gene signatures reported by Govaere et al., as performed in caret v6.0.93. We evaluated the predictive performance of each gene signature by calculating the AUROC score using the method performed in pROC v1.18.0.

[0283] Using Nearest Template Prediction, patient classification was calculated based on similarity to combination-specific gene signatures, as performed in GenePattern (Hoshida Y.; Nearest template prediction: A single-sample-based flexible class prediction with confidence assessment.; PLoS One.; 2010; 5(11): 1-8). Gene sets associated with similar classes were defined as upregulated genes within the combination-specific gene signature. Gene sets associated with different classes were defined as downregulated genes within the combination-specific gene signature. Only patients with statistically significant classifications (p < 0.05) were included in the downstream analysis.

[0284] ssGSEA was performed as performed in GenePattern. Along with log-transformed gene expression, the Hallmark gene set and the Aizarani hepatocyte type gene set derived from MSIgDB were used as inputs for ssGSEA. Following a t-test, differential ssGSEA scores were calculated using FDR correction, and significance was defined as FDR < 0.05.

[0285] Serum measurement Serum insulin was evaluated in 6-hour fasted samples using the manufacturer's instructions for the Ultra-Sensitive Mouse Insulin ELISA Kit (Crystal Chem, catalog #90080). Saturated serum samples were evaluated using the manufacturer's instructions for Cholesterol E (Fujifilm, No. 999-02601), Triglycerides (Cayman Chemicals, item no. 10010303), Unesterified 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). Using ThermoFisher's ProCartaPlex mouse kit, CRP and CXCL10 levels were measured with Bio-Rad's BioPlex Reader.

[0286] Statistics information All other statistical analyses not previously specified were performed using the R package or the GenePattern software, and GraphPad Prism 9. Throughout the figure, values ​​are shown on the graph as mean ± SEM, along with recorded p-values. Colored bars indicate a comparison between the groups (each colored) and the control groups (both ND and ND+Veh). Significance was allowed at p<0.05 and determined by independent t-tests, one-way ANOVA, or repeated measures two-way ANOVA, along with Tukey or Sidak post-hoc tests (where appropriate). For histological score analysis, the Kruskal-Wallis test or Mann-Whitney test was used; these are nonparametric tests, the Kruskal-Wallis test compares the rank of each column to all other columns, and Dunn's post-hoc test was used to correct for multiple comparisons. White circles represent individual mice per group (n=8-9 mice / group).

[0287] (2) Results The combination of liraglutide and bempedoic acid reduces body weight, excess fat, glucose intolerance, insulin resistance, and serum cholesterol. When C57BL6J mice were housed in a warm environment and fed a diet high in fat and fructose, they exhibited 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 the intervention arm by matching body weight and hyperlipidemia to ensure no difference at the start of the treatment period, which lasted for 9 weeks.

[0288] Bempedoic acid (BemA) did not reduce body weight, hyperlipidemia, glucose tolerance, insulin sensitivity, pyruvate tolerance (a measure of hepatic gluconeogenesis), or fasting serum insulin or triglyceride levels, but it did reduce serum cholesterol (Figures 5A-5H). With BemA, hepatic fat percentage, pathological scoring of fatty liver disease, ballooning hepatocytes, and a composite of NAFLD activity were reduced, regardless of the degree of hyperlipidemia and glucose homeostasis (Figures 6A-6G). Importantly, with BemA, the percentage of fibrosis area, as assessed using picrosilius red (PSR), was also reduced (Figure 6H). These data, consistent with previous studies that used warm-temperature rearing but had shorter pre-treatment dietary intervention periods (10 weeks compared to 16 weeks in the study disclosed here), demonstrate that BemA reduces fatty liver disease, ballooning hepatocytes, and fibrosis, independently of changes in obesity or hyperlipidemia.

[0289] A significant reduction in obesity can resolve NASH in rodents. GLP-1R agonists, such as liraglutide (Lira), suppress appetite and obesity in a dose-dependent manner, and at high doses, obesity can be reduced by more than 50% over a 10-week treatment period. Therefore, to increase the potential for the application of Lira to the treatment of NASH in humans, we used doses and frequencies that similarly reduced obesity / excessive fatness observed in participants of a clinical trial (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) in which a 5-10% weight loss was observed. When mice were treated with liraglutide (Lira), their obesity level decreased by 6% after 9 weeks of treatment, and this effect remained unchanged even with the addition of BemA (Lira + BemA) (Figures 1A and 1B). Compared to vehicle control mice, Lira and Lira + BemA improved glucose tolerance (Figure 1C) and insulin sensitivity (Figure 1D), but did not alter pyruvate tolerance (Figure 1E). Lira lowered fasting insulin levels (Figure 1F), and this effect was maintained even with the addition of BemA. Lira lowered serum cholesterol levels (Figure 1G), and this effect tended to be enhanced with the addition of BemA. Serum triglycerides (Figure 1H) remained unchanged in either the Lira group or the Lira + BemA combination group.

[0290] The combination of liraglutide and bempedoic acid provides additive benefits in treating fatty liver disease, ballooning ulcers, and fibrosis. Compared to the vehicle group, the percentage of hepatic fat decreased by 36% in the Lira group and 47% in the Lira+BemA group (Figure 2A), and triglycerides decreased by 69% in the Lira group and 81% in the Lira+BemA group (Figure 2B). Consistent with these observations, the fatty liver score obtained from H&E sections decreased to 63% in the Lira group and 74% in the Lira+BemA group (Figures 2C and 2D). The ballooning hepatocyte enlargement score also decreased to 56% in the Lira group and 94% in the Lira+BemA group (Figures 2C and 2E). In both the Lira and Lira+BemA groups, the lobular inflammation score decreased to a similar extent (approximately 50%) (Figures 2C and 2F). In summary, the NAFLD activity score (NAS) decreased by 56% in the Lira group and 75% in the Lira+BemA group (NAS: Figure 2G). Importantly, the Lira-treated group and the Lira+BemA-treated group showed a reduction in fibrosis area as assessed using PSR (40% and 44%, respectively) (Figures 2C and 2H), and moderate zone 3 and perisinusoidal fibrosis (1C) was less frequent (1 out of 9 in Lira) or absent (0 out of 9 in Lira+BemA) compared to vehicle-treated mice (4 out of 8) (Figures 2C and 2I). Finally, serum markers of hepatic inflammation / damage (including alanine transaminase (ALT), aspartate aminotransferase (AST), serum amyloid A (SAA), CXC-motif chemokine ligand 10 (CXCL10), C-reactive protein (CRP), and secretory phospholipase A2 (sPLA2)) were measured. BemA reduced ALT, AST, and CXCL10, but these effects were blunted in Lira. BemA also reduced the effects of SAA, CRP, and sPLA2, and these effects were maintained (SAA, CRP) or increased (sPLA2) with treatment with Lira + BemA (Table 1). TIFF2026522971000008.tif228164

[0291] Considering these factors, the combination of Lira and BemA resulted in a significant reduction in the percentages of fatty liver, ballooning liver enlargement, NAS, PSR, and sPLA2 compared to Lira monotherapy, while also lowering the p-value, suggesting a possible additive effect on improving liver pathology.

[0292] By profiling the expression of target genes, additive downregulations of fibrosis-related molecular pathways that predict resolution of NASH can be identified. To determine transcriptional differences between treatment cohorts, the nCounter Fibrosis v2 Panel was used to examine the expression of 760 genes involved in 49 fibrosis-related pathways. Differential expression analysis comparing liraglutide, bempedoic acid, and combination therapy with diseased controls revealed 249 genes with liraglutide, 132 with bempedoic acid, and 263 genes with combination therapy (Figures 7A and 10). Combination therapy increased the number of downregulated genes, with a significant decrease in the expression of 172 genes compared to 97 genes with Lira alone and 86 genes with BemA alone. Of these, 56 genes were uniquely altered by combination therapy, and 113 genes and 3 genes that overlapped with the overall treatment cohort were upregulated by Lira but downregulated in the combination cohort (Figures 7B and 11). Conversely, 8 genes were uniquely upregulated by combination therapy (Figure 7C). Over-exposure analysis of uniquely downregulated and duplicated genes (defined as additive when the effect size is largest in the cohort of combination therapy) identified seven target disease processes related to inflammation, fibrosis, and wound healing (Figures 7D and 12). Subsequently, PLAGE was used to identify pathway-level changes induced by combination therapy using a more comprehensive parallel approach and to assess the predictiveness of phenotypic observations (Figure 8A) (Tomfohr et al.; Pathway level analysis of gene expression using singular value decomposition; BMC Bioinformatics; 2005; 6:1-11). Combination therapy identified reductions in 17 pathways via hierarchical clustering, encompassing comprehensive disease processes related to fibrosis (e.g., collagen biosynthesis and modification, myofibroblast regulation), inflammation (e.g., chemokine signaling, cytokine signaling), and wound healing (e.g., phagocytic function, angiogenesis), a phenomenon consistent with pathway annotation analysis (Figure 3A).

[0293] To evaluate the gene sets associated with phenotypic observations, disease outcome measures were regressed on the first principal component (PC1) of 17 gene sets most influenced by combination therapy compared to monotherapy (Figure 3B). This showed a significant predictive relationship between PC1 escalation and resolution of fatty liver, inflammation, fibrosis, hyperlipidemia, and NAS (Figure 3C). Hierarchical clustering of given gene sets into disease processes related to fibrosis, inflammation, and wound healing was consistent with overpopulation analysis using differentially expressed genes.

[0294] Since hepatic stellate cells are essential for promoting hepatic fibrosis, we investigated the expression of key markers involved in NASH progression (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 (Col1a1, Col1a2, Col3a1, Lox, Timp1) were significantly reduced in the Lira + BemA treatment group to a greater extent than in Lira or BemA monotherapy (Figure 3D). Interestingly, BemA appeared to counteract Lira-induced upregulation of TGFβ effectors (including Smad3, a transcription factor essential for upregulating the fibrotic pathway in NASH) (Figure 8B). Furthermore, the combination therapy generally reduced the expression of several chemokines involved in NASH progression more significantly than Lira or BemA monotherapy (Figure 3E). Considering these factors, these data suggest that the Lira+BemA combination therapy induces anti-fibrotic and anti-inflammatory gene expression profiles that predict the reduction of liver pathologies (fatty liver, ballooning vasoconstriction, and fibrosis).

[0295] Combination therapy induces a gene expression profile that is prognostically favorable and most closely resembles the profile obtained from healthy human liver biopsy specimens. In humans, 25 gene signatures have been established as predictors of NASH severity (Govaere et al. 2020). Therefore, to contextualize the clinical significance of experimental therapies, an integrated analysis was performed combining expression data of 22 orthologous genes derived from a treatment cohort with expression data derived from 216 NAFLD / NASH patients. In this prognostic signature, the combination therapy significantly downregulated the expression of 13 genes. Hierarchical clustering using Pearson correlation revealed four clusters with differential compositions of healthy individuals, patients with pre-fibrotic disease (NAFLD, F0-F1) or fibrotic disease (F2-F4), and the experimental cohort (Figure 4A). Cluster II showed the most clinically benign phenotype. This cluster represents a dataset derived from 80% of healthy individuals in the patient population, compared to 7.55% (stage F2 of the disease), 1.85% (stage F3 of the disease), and 0% (stage F4 of the disease) (Figure 4B). Four out of six combination therapy samples co-localized in this cluster, while most monotherapy samples were grouped into clusters I and II, representing more advanced disease. Using PCA, incremental resolution of NASH in human patients in PC1 is demonstrated (Figure 4C). Mapping the control, monotherapy, and combination therapy cohorts by human NASH disease stage further supports the fact that the transcriptional similarity between healthy individuals and combination therapy samples is higher than the similarity obtained using Lira and BemA alone.

[0296] Classifying patients into disease subtypes based on the expression of specific gene signatures provides information for risk stratification and reveals molecular characteristics across disease subtypes. Recent studies have similarly used treatment-specific gene signatures to classify patients with similar or different 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 provides preliminary evidence for clinical application and may reveal molecular differences that promote treatment response in patients. Therefore, gene signatures specific to combination therapy were derived by filtering for genes differentially regulated by combination therapy compared to both control and monotherapy (Figure 9A).

[0297] To determine the prognostic significance of this gene signature, its predictive performance using multivariate logistic regression was compared to a reference gene signature derived from the literature by Govaere et al. in a human NAFLD / NASH cohort. For predicting fibrosis stage 2 or higher, the receiver operating characteristic area (AUROC) score was 0.899 for the complete signature and 0.893 for the subset derived using elastic net regularization, compared to an estimated 0.922 for the reference signature (Figure 4D). Among these signature genes, AXL, SLC2A2, CYBB, DOCK2, C3AR1, CYFIP1, and LEPR were significantly associated with advanced fibrosis in their multivariate models. Subsequently, patients were classified based on their expression similarity to their treatment signatures using Nearest Template Prediction. (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 were mainly in the pre-fibrotic disease stage (NAFLD and F0-F1), while patients classified as different were mostly in the fibrotic stage (F2-F4) (Figure 9C). Single-sample GSEA (ssGSEA) of the Hallmark gene set and hepatocyte type reveals transcriptional profiles favorable to NASH resolution. In patients of the similar class, significant downregulation of gene sets associated with fibrosis, inflammation, and cytotoxicity was observed, while pathways related to fatty acid metabolism, oxidative phosphorylation, and DNA repair were significantly upregulated (Figure 9D).Accordingly, analysis of hepatocyte types based on markers derived from a human liver cell atlas (Aizarani et al.; A human liver cell atlas reveals heterogeneity and epithelial progenitors.; Nature.; 2019; 572(7768): 199-204) revealed that all non-parenchymal hepatocyte types (including hepatic stellate cells and hepatic sinusoidal endothelial cells) were significantly downregulated, while hepatocytes were upregulated (Figures 9B and 4E). Overall, the gene expression patterns identified in patients showing similar gene signature profiles to those treated with the combination therapy support the resolution of fibrosis, fatty liver, and inflammation among NAFLD / NASH patients.

[0298] (3) Conclusion In a diet-induced NASH mouse model raised in a warm environment, the addition of bempedoic acid to the GLP-1R agonist liraglutide as a combination therapy yielded additional benefits compared to liraglutide alone in treating NASH and hepatic fibrosis. These two therapies were selected because they have different targets, favorable safety profiles, and the potential to simultaneously treat separate comorbidities associated with NAFLD. In this study, liraglutide resulted in reductions in body weight, hyperlipidemia, glucose tolerance, and insulin resistance, while treatment with bempedoic acid lowered total cholesterol. These data suggest that these interventions were effective in treating obesity and insulin resistance-related comorbidities, as well as hypercholesterolemia, respectively.

[0299] Since hepatic liposuction (DNL) plays a major role in the accumulation of hepatic 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 of acetyl-CoA carboxylase (ACC)) with the inhibitor bempedoic acid provides an opportunity to reduce fatty acid and cholesterol synthesis in 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 study described herein, liver fat percentage, triglycerides, and fatty liver score were significantly reduced with treatment with both bempedoic acid and liraglutide alone. These combinations resulted in even greater reductions in liver fat percentage and triglycerides. Importantly, serum triglycerides did not increase with these changes.

[0300] As the term suggests, a distinguishing feature that differentiates steatohepatitis from simple steatohepatitis is the manifestation of inflammation. Transcriptome analysis revealed that the combination of both bempedoic acid and liraglutide showed a distinct cluster of inflammatory markers characterized by significant reductions in cytokine and chemokine signaling, adenosine pathways, TLR and NF-κB signaling, phagocytic function, neutrophil degranulation, and interferon signaling. Furthermore, the reduction in inflammatory markers within the liver was even more extensive, as evidenced by significant decreases in CRP and SAA in serum systemic inflammatory marker measurements.

[0301] Perhaps most importantly, this study found that combining bempedoic acid with liraglutide reduced fibrosis. These pathological findings were supported by transcriptome data, which showed that the combination therapy reduced extracellular matrix synthesis, epithelial-to-mesenchymal transition, myofibroblast regulation, focal adhesion kinases, and collagen biosynthesis and modification. This is highly significant because, to date, neither liraglutide nor semaglutide has been shown to be effective in reducing fibrosis stages in NASH patients. Furthermore, analysis revealed that the effect of bempedoic acid on the Lira-induced increase of the TGF-β-activated transcription factor Smad3 (a major driving force of fibrosis), contrary to the above, may be due to a potentially unique effect of bempedoic acid (Schwabe et al.; Mechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis.; Gastroenterology[Internet].2020;158(7):1913-28). Since 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): 1-19), and treatment with bempedoic acid attenuates TGF-β-mediated activation in vitro in both mouse and human stellate cells (Morrow et al.; 2022), this direct effect on hepatic stellate cells may be important in alleviating fibrosis.

[0302] In summary, this study suggests that combining treatment with bempedoic acid and liraglutide in mouse models of metabolism-related NASH and fibrosis provides additive benefits.

[0303] Reference Each of the patent documents and scientific papers referenced herein is incorporated by reference in its entirety for any purpose.

[0304] Equivalents This disclosure can be embodied in other specific forms without departing from its spirit or essential features. Therefore, the embodiments described herein should be considered illustrative in all respects and not limiting the disclosure as described herein. That is, the scope of this disclosure is indicated not by the foregoing description but by the appended claims, and all modifications within the meaning and equivalents of the claims are intended to be included in this disclosure.

Claims

1. A method for treating fatty liver in a subject requiring treatment, comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.

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

3. A method for regulating blood glucose control in a subject with fatty liver, comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.

4. A method for reducing the level of hemoglobin A1C (HbA1c) in the blood or serum of a subject with fatty liver, comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.

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

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

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

8. A method for reducing balloon-like enlargement of hepatocytes in a subject with fatty liver, comprising administering to the subject an effective amount of a GLP-1 receptor agonist and an effective amount of bempedoic acid.

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

10. The method according to any one of claims 1 to 9, wherein the fatty liver is non-alcoholic steatohepatitis (NASH).

11. The method according to any one of claims 1 to 10, wherein when an effective amount of the GLP-1 receptor agonist and bempedoic acid is administered, the level of hbA1c in the subject's blood or serum becomes lower than that of a subject with fatty liver who has not been administered an effective amount of the GLP-1 receptor agonist and bempedoic acid, or who has been administered (a) an effective amount of the GLP-1 receptor agonist or (b) an effective amount of bempedoic acid.

12. The method according to any one of claims 1 to 11, wherein administration of an effective amount of the GLP-1 receptor agonist and bempedoic acid results in a greater weight loss in the subject compared to a subject who has fatty liver and has not been administered an effective amount of the GLP-1 receptor agonist and bempedoic acid, or a subject who has been administered (a) an effective amount of the GLP-1 receptor agonist or (b) an effective amount of bempedoic acid.

13. The method according to any one of claims 1 to 12, wherein when an effective amount of the GLP-1 receptor agonist and bempedo acid is administered, a significant reduction in liver fat is observed in the subject, in the subject having fatty liver, compared to a subject who has not been administered an effective amount of the GLP-1 receptor agonist and bempedo acid, or a subject who has been administered (a) an effective amount of the GLP-1 receptor agonist or (b) an effective amount of bempedo acid.

14. The method according to any one of claims 1 to 13, wherein when an effective amount of the GLP-1 receptor agonist and bempedo acid is administered, a significant reduction in liver fibrosis is observed in the subject, compared to a subject who has fatty liver and has not been administered an effective amount of the GLP-1 receptor agonist and bempedo acid, or a subject who has been administered (a) an effective amount of the GLP-1 receptor agonist or (b) an effective amount of bempedo acid.

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

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

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

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

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

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

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

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

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

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

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

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

27. A method for reducing balloon-like swelling of hepatocytes in a subject receiving GLP-1 receptor agonist therapy, comprising administering an effective amount of bempedoic acid to the subject.

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

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

30. The method according to any one of claims 24 to 29, wherein the subject receiving GLP-1 receptor agonist therapy is administered semaglutide in an amount of approximately 0.25 mg to approximately 14 mg.

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

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

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

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

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

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

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

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

39. The method according to any one of claims 1 to 38, wherein the effective amount of bempedo acid is approximately 180 mg.

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