Use of long-acting oxin-modulin derivatives for the treatment of fatty liver disease

Abstract

The use of long-acting oxin-modulin derivatives for the treatment of fatty liver disease is disclosed. In particular, the use of efinopegdutide and its pharmaceutically acceptable salts for the treatment of non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) is disclosed.

Description

[Technical Field]

[0001] Cross-reference with related applications This application claims the interests of U.S. Provisional Patent Application No. 63 / 509,894, filed on 23 June 2023, the entire contents of which are incorporated herein by reference.

[0002] Reference to electronically submitted sequence list The contents of the electronic sequence list (25679-WO-PCT_SL.xml; size: 7,539 bytes; creation date: July 17, 2023) are incorporated herein by reference in their entirety.

[0003] This invention relates to the use of long-acting oxintmodulin derivatives for the treatment of fatty liver disease. In particular, this invention relates to the use of long-acting oxintmodulin derivatives (e.g., efinopegdutide) for the treatment of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. [Background technology]

[0004] Non-alcoholic fatty liver disease (NAFLD) is a condition associated with increased accumulation of triglycerides in the liver, and it is estimated that approximately 25% of the world's adult population is affected.

[0253] NAFLD encompasses a wide range of fatty liver diseases, from simple steatosis to non-alcoholic steatohepatitis (NASH). Non-alcoholic steatohepatitis (NASH) is a type of fatty liver disease with chronic inflammation, and histologically it is described as steatohepatitis regardless of the presence or absence of fibrosis.

[0254] Approximately 20% of individuals with NASH progress to cirrhosis, which is associated with an increased rate of hepatocellular carcinoma and an increased overall mortality rate and liver-related mortality rate.

[0255] NAFLD is increasingly recognized as a hepatic manifestation of underlying metabolic dysregulation and is considered a consequence of obesity-related insulin resistance. This leads to increased transport of fatty acids from adipose tissue to the liver, resulting in de novo lipid biosynthesis in the liver.

[0256] 、

[0257] Overweight and obesity are considered to be major pathological factors for metabolic diseases, NAFLD, and ultimately NASH.

[0257] 。

[0005] Currently, there is no approved treatment for NASH. The management of NAFLD / NASH mainly focuses on improving lifestyle habits such as diet and exercise targeted at weight loss. As drug therapies for NASH confirmed by biopsy, pioglitazone and high-dose vitamin E (800 IU / day) are recommended. Here, pioglitazone is recommended for patients with type 2 diabetes (T2DM), and vitamin E is recommended for patients without diabetes.

[0258] 。

[0006] Glucagon-like peptide-1 (GLP-1) agonists are associated with a decrease in serum glucose levels and weight loss. GLP-1 receptor agonists promote glucose-stimulated insulin secretion and have become a useful treatment for type 2 diabetes (T2DM). At the dosages developed for diabetes indications (for example, the maximum dosage of liraglutide is 1.8 mg per day, and the maximum dosage of semaglutide is 2 mg once a week), GLP-1 receptor agonists are associated with a weight loss of approximately 3% - 5%, which is generally due to a reduction in food intake. In recent years, for the weight loss indication, high-dose administration of GLP-1 receptor agonists has been pursued. At the dosages approved for weight loss, when liraglutide was subcutaneously administered daily (SC) at a dosage of 3 mg over 56 weeks, a weight loss of approximately 7.4% was achieved.

[0259] On the other hand, when semaglutide was administered SC once a week at a dosage of 2.4 mg over 68 weeks, a weight loss of approximately 15% was achieved.

[0260] The weight loss associated with GLP-1 agonists has been shown to be related to the reduction of liver inflammation in patients with NASH. In the "Effectiveness and Action of Liraglutide" in the NASH (LEAN) Phase 2 trial, NASH resolved in 39% (9 / 23) of the participants who were administered liraglutide at a dosage of 1.8 mg per day SC and underwent a liver biopsy at the end of the treatment after 48 weeks, compared with 9% (2 / 22) in the placebo group.

[0261] In a Phase 2b trial in which semaglutide was administered once daily at doses of 0.1 mg, 0.2 mg, or 0.4 mg (total weekly dose of 0.7 mg to 2.8 mg), after 72 weeks of administration, histological improvement in NASH was observed in 40.4% to 58.9% of participants compared to the placebo group (17.2%), without worsening of fibrosis, but no significant improvement in fibrosis was observed.

[0262] .

[0007] Glucagon receptor activation has several mechanisms that can complement the beneficial effects of GLP-1 receptor agonists in the treatment of NASH.

[0263] Glucagon has been shown to induce weight loss by reducing food intake and increasing energy expenditure. In addition to indirectly reducing liver fat content (LFC) through weight loss, glucagon agonists can reduce LFC by directly acting on the liver to promote fatty acid oxidation and suppress fat synthesis.

[0264] .

[0008] Oxintomodulin, a 37-amino acid peptide product derived from the proglucagon gene released from L cells in the small intestine in response to food intake, has been shown to reduce appetite and body weight in overweight and obese individuals.

[0265] 、

[0266] Efinopegdutide is a long-acting GLP-1 receptor / glucagon receptor dual agonist containing an oxintomodulin derivative conjugated to the Fc region of human IgG4, with a relative potency of approximately 2:1 between the GLP-1 receptor and the glucagon receptor. The effect of efinopegdutide on weight loss was investigated in two phase 2 dose-range studies in obese patients with and without T2DM.

[0267] 、

[0268] In all trials, treatment with efinopegdutide resulted in a dose-dependent and significant reduction in body weight.

[0267] 、

[0268] . [Overview of the Initiative] [Means for solving the problem]

[0009] This invention provides a treatment for fatty liver diseases, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), using efinopegdutide, a long-acting GLP-1 receptor / glucagon receptor dual agonist. This invention is based on findings from a clinical trial involving patients with elevated liver fat concentration (LFC) (mean LFC: 20.3%), in which administration of efinopegdutide at a dose of 10 mg once weekly for approximately 24 weeks reduced the LFC in these patients. At 24 weeks, the mean LFC in the patient group was approximately 4.6%, which falls within the "normal" range of less than 5%.

[0010] In one embodiment of the present invention, a method for reducing LFC in an individual suffering from fatty liver disease comprises administering to the individual suffering from fatty liver disease approximately 2 mg to approximately 10 mg (in a particular embodiment, approximately 2 mg, 4 mg, 7 mg, or approximately 10 mg) of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for a period sufficient to reduce the LFC of the individual suffering from fatty liver disease to less than 5%. The LFC can be evaluated by proton density lipid fraction (MRI-PDFF) estimated by magnetic resonance imaging. Efinopegdutide or a pharmaceutically acceptable salt thereof can be administered subcutaneously.

[0011] In further embodiments of the method described above, the time sufficient to reduce the LFC to less than 5% may be about 24 weeks or more. In a particular embodiment, the time sufficient to reduce the LFC to less than 5% may be [value missing]. However, depending on the individual's LFC, the time sufficient to reduce the individual's LFC may be greater than 24 weeks or less than 24 weeks. In a particular embodiment, the time sufficient to reduce the individual's LFC may be greater than 24 weeks but less than 52 weeks. It is understood that the time sufficient to reduce the LFC to less than 5% in any particular individual depends on the nature of the individual's disease and the individual's response to treatment.

[0012] In a further embodiment of the method, the fatty liver disease is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). In a further embodiment of the method, the NASH is pre-cirrhotic NASH or cirrhotic NASH. Depending on the individual's LFC and the severity of the fatty liver disease, the time sufficient to reduce the individual's LFC to less than 5% can be more than 24 weeks or less than 24 weeks.

[0013] In a further embodiment of the method, an individual suffering from fatty liver disease has an LFC of 5% or more before administration of 10 mg of efinepegdutide or a pharmaceutically acceptable salt thereof. In a further embodiment of the method, an individual suffering from fatty liver disease has an LFC of 10% or more before administration of 10 mg of efinepegdutide or a pharmaceutically acceptable salt thereof. In a further embodiment of the method, an individual suffering from fatty liver disease has an LFC of 15% or more before administration of 10 mg of efinepegdutide or a pharmaceutically acceptable salt thereof. In a further embodiment of the method, an individual suffering from fatty liver disease has an LFC of 20% or more before administration of 10 mg of efinepegdutide or a pharmaceutically acceptable salt thereof.

[0014] In a further embodiment of the method, the individual has type 1 diabetes (T1DM) or type 2 diabetes (T2M). In a further embodiment of the method, the individual has type 2 diabetes (T2M) and is overweight or obese. In a further embodiment of the method, the individual is overweight or obese.

[0015] The present invention further provides a method for reducing liver fat content (LFC) to less than 5% in an individual with elevated LFC, wherein the method comprises the following steps in the following order: (a) administering to the individual a dose of about 2.0 mg or about 2.4 mg of efinepegdutide or a pharmaceutically acceptable salt thereof once a week for 4 weeks; (b) administering to the individual a dose of about 4.0 mg or about 5.0 mg of efinepegdutide or a pharmaceutically acceptable salt thereof once a week for 4 weeks; and (c) administering to the individual a dose of about 10 mg of efinepegdutide or a pharmaceutically acceptable salt thereof once a week for a period sufficient to reduce the LFC to less than 5%. The LFC can be evaluated by MRI-PDFF. The efinepegdutide or a pharmaceutically acceptable salt thereof can be administered subcutaneously.

[0016] In a further embodiment of the method, the period sufficient to reduce liver fat to less than 5% is about 24 weeks. However, depending on the LFC of the individual, the period sufficient to reduce the individual's LFC to less than 5% can be more than 24 weeks or less than 24 weeks. In a further embodiment of the method, the individual with elevated LFC has fatty liver disease. In a particular embodiment, the fatty liver disease is non-alcoholic fatty liver disease (NAFLD). In a further embodiment, the fatty liver disease is non-alcoholic steatohepatitis (NASH). In a further embodiment of the method, the NASH is pre-cirrhotic NASH or cirrhotic NASH. Depending on the LFC of the individual and the severity of the fatty liver disease, the time sufficient to reduce the individual's LFC to less than 5% can be more than 24 weeks or less than 24 weeks.

[0017] In a further embodiment of the method, individuals suffering from fatty liver disease have 5% or more LFC before the start of the method. In a further embodiment of the method, individuals suffering from fatty liver disease have 10% or more LFC before the start of the method. In a further embodiment of the method, individuals suffering from fatty liver disease have 15% or more LFC before the start of the method. In a further embodiment of the method, individuals suffering from fatty liver disease have 20% or more LFC before the start of the method.

[0018] In a further embodiment of the method, the individual has type 1 diabetes (T1DM) or type 2 diabetes (T2M). In a further embodiment of the method, the individual has type 2 diabetes (T2M) and is overweight or obese. In a further embodiment of the method, the individual is overweight or obese.

[0019] The present invention further provides the use of efinopegdutide or a pharmaceutically acceptable salt thereof for producing a pharmacopoeci for reducing liver fat content (LFC) to less than 5% in individuals with elevated LFC. In further embodiments, the treatment comprises about 2 mg to about 10 mg (in specific embodiments, about 2 mg, 2.4 mg, 4 mg, 7 mg, or about 10 mg) of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0020] The present invention further provides the use of efinopegdutide or a pharmaceutically acceptable salt thereof to reduce liver fat content (LFC) to less than 5% in individuals with elevated LFC. In further embodiments, the efinopegdutide or a pharmaceutically acceptable salt thereof is provided in doses of about 2 mg to about 10 mg (in specific embodiments, about 2 mg, 2.4 mg, 4 mg, 7 mg, or about 10 mg). [Brief explanation of the drawing]

[0021] [Figure 1] Figure 1 shows the test design. [Figure 2]Figure 2 shows the arrangement of the participants. [Figure 3A] Figure 3A shows the least squares (LS) mean relative reduction in liver fat content (LFC) from baseline at 24 weeks. [Figure 3B] Figure 3B shows the percentage of participants who, at week 24, showed a relative reduction of ≥30%, ≥50%, and ≥70% from baseline in LFC. [Figure 3C] Figure 3C shows the mean relative percentage decrease in LFC from baseline at 24 weeks, based on weight loss categories (weight loss from baseline of ≤5%, >5% to ≤10%, and >10%). [Figure 4A] Figure 4A shows the mean (SE) change in heart rate over time from baseline. [Figure 4B] Figure 4B shows the mean (SE) change in systolic blood pressure over time from baseline. [Figure 4C] Figure 4C shows the mean (SE) change in diastolic blood pressure over time from baseline. [Figure 5A] Figure 5A shows the mean (SE) change in alanine aminotransferase (ALT) over time from baseline. [Figure 5B] Figure 5B shows the mean (SE) change in aspartate aminotransferase (AST) over time from baseline. [Figure 6A] Figures 6A and 6B together show the structure of effinopegdutide. Effinopegdutide comprises an oxynmodulin derivative having the amino acid sequence described in SEQ ID NO: 2, conjugated to the N-terminus of one Fc of a nonglycosylated IgG4 Fc homodimer, where the nonglycosylated IgG4 Fc has the amino acid sequence described in SEQ ID NO: 3. The molecular weight of effinopegdutide is approximately 64 kDa. [Figure 6B]Figures 6A and 6B together show the structure of effinopegdutide. Effinopegdutide comprises an oxynmodulin derivative having the amino acid sequence described in SEQ ID NO: 2, conjugated to the N-terminus of one Fc of a nonglycosylated IgG4 Fc homodimer, where the nonglycosylated IgG4 Fc has the amino acid sequence described in SEQ ID NO: 3. The molecular weight of effinopegdutide is approximately 64 kDa. [Modes for carrying out the invention]

[0022] definition Where used herein, the term “about” indicates a range of ±10% of the value it modifies (rounded up to the nearest integer if the value is indivisible, such as the number of molecules or nucleotides). When the term “about” modifies the amount of a substance or composition (e.g., mg), a parameter of a substance or composition, or a parameter used to characterize a step in a method, it may take into account the variation in the numerical quantity that may occur. For example, such variation may occur through typical measurement, handling, and sampling procedures associated with the preparation, characterization, and / or use of a substance or composition, through careless errors in these procedures, or through differences in the manufacture, source, or purity of components used in the production or use of a composition or in the implementation of a procedure.

[0023] As used herein, the term "oxyntmodulin" refers to a peptide produced from preglucagon, a precursor of glucagon. In the present invention, oxyntmodulin is intended to encompass native oxyntmodulin and its precursors, analogs (derivatives), fragments, and variants. Oxintmodulin has the amino acid sequence described in SEQ ID NO: 1.

[0024] As used herein, the term “oxyntmodulin variant” refers to a peptide that differs from the amino acid sequence of native oxyntmodulin by one or more amino acid residues and has the function of activating both the GLP-1 receptor and the glucagon receptor. Oxintmodulin variants can be prepared by one or a combination thereof of substitution, addition, deletion, or modification of some amino acids of native oxyntmodulin.

[0025] As used herein, the term “oxyntmodulin derivative” refers to a peptide, peptide derivative, or peptide mimetic prepared by adding, deleting, or substituting some amino acids of the native oxyntmodulin, and capable of activating both the GLP-1 receptor and the glucagon receptor at a higher level than that activated by the native oxyntmodulin. Efinopegdutide is a long-acting oxyntmodulin derivative.

[0026] As used herein, the term “effinopegdutide” refers to a biological compound represented by the formula shown in Figure 6A / Figure 6B, comprising an oxintmodulin derivative having the amino acid sequence described in SEQ ID NO: 2, wherein the oxintmodulin derivative is conjugated to the N-terminus of a non-glycosylated IgG4 Fc analog (SEQ ID NO: 3) lacking amino acids 1-8 in the hinge region at its C-terminal cysteine ​​residue by a non-peptidic 10 kD polyethylene linker. Effinopegdutide has a molecular weight of approximately 64 kDa; a 10 mg dose of effinopegdutide is approximately 150 nanomoles. In certain embodiments, the non-glycosylated IgG4 Fc analog of effinopegdutide may lack C-terminal lysine (see SEQ ID NO: 4).

[0027] As used herein, the term “semaglutide” refers to a compound comprising a GLP-1 derivative having the amino acid sequence described in SEQ ID NO: 4, wherein the GLP-1 derivative is conjugated at the 20th position of lysine to a polyethylene linker linked to a C18 fatty diacitic acid. The molecular weight of semaglutide is 4113.58 Da; the dose of 1 mg of semaglutide is approximately 2.4 nanomoles.

[0028] As used herein, the terms “fatty liver disease” or “hepatic steatohepatitis” refer to a condition in which the proportion of fat to the weight of the liver is 5% or more. In the present invention, fatty liver disease includes non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), nutritional fatty liver disease (NFLD), starvation fatty liver disease (SFLD), obesity fatty liver disease, diabetic fatty liver disease, or steatohepatitis. The NAFLD includes not only primary NAFLD and secondary NAFLD, but also NAFLD resulting from primary hyperlipidemia, diabetes, or obesity.

[0029] As used herein, the term “non-alcoholic fatty liver disease” or “NAFLD” refers to cases of fatty liver disease in individuals with no history of alcohol consumption or in whom alcohol consumption is not associated with the onset of the disease. “Fatty liver” refers to a phenomenon in which triglycerides accumulate abnormally within liver cells compared to normal levels. Approximately 5% of a normal liver is composed of adipose tissue, the main components of which are triglycerides, fatty acids, phospholipids, cholesterol, and cholesterol esters. However, when fatty liver develops, most of these components are replaced by triglycerides. Fatty liver is diagnosed when the amount of triglycerides exceeds 5% of the liver weight. Fatty liver is caused by lipid metabolism disorders, or impaired processes of excessive fat transport into liver cells, and is primarily due to abnormalities in lipid metabolism in the liver. The majority of the fat accumulated in fatty liver can be triglycerides. NAFLD includes non-alcoholic fatty liver disease (NAFL), non-alcoholic steatohepatitis (NASH), cirrhosis, and liver cancer, but these are not limited to the fatty liver diseases that can be prevented or treated with the compositions of the present invention. Furthermore, in the present invention, NAFLD is intended to include simple steatosis, NASH, hepatic fibrosis, and / or cirrhosis resulting from the progression of such diseases.

[0030] Individuals with NAFLD have elevated LFC levels, and their body mass index (BMI) is 25 kg / m². 2 The above and 50 kg / m 2 The following may be true: The individual may either have no history of T2DM, or may have a history of T2DM with an A1C of 8.5% or less.

[0031] As used herein, the terms fatty liver, “steatosis,” and “fatty changes” refer to a condition in which an abnormal amount of lipids accumulates in 5% or more of the liver cells.

[0032] As used herein, the terms “elevated liver fat content” or “elevated LFC” refer to 10% or more of LFC in an individual, which can be assessed by the proton-density lipid fraction (MRI-PDFF) estimated by magnetic resonance imaging. Histologically, the liver is considered steatotic if, in tissue sections stained with hematoxylin and eosin, 5% or more of the hepatocytes contain megalocular steatosis.

[0033] As used herein, the term “hyperlipidemia” refers to a condition associated with abnormally elevated levels of lipids in the blood (e.g., free cholesterol, cholesterol esters, phospholipids, and triglycerides). While hyperlipidemia itself may not present with specific symptoms, excess lipids in the blood can adhere to the blood vessel walls, reducing their diameter and leading to arteriosclerosis through inflammatory responses. For these reasons, coronary heart disease, cerebrovascular disease, and peripheral vascular occlusion may occur.

[0034] As used herein, the term “obesity” means 30 kg / m². 2 The above shows the Body Mass Index (BMI). Obesity generally results from a long-term energy imbalance in which energy intake exceeds energy expenditure. Obesity is a metabolic disorder that affects the entire body and is likely to cause diabetes and hyperlipidemia. Furthermore, obesity is associated with sexual dysfunction, arthritis, and an increased risk of developing cardiovascular disease, and in some cases, fatty liver disease and cancer.

[0035] As used herein, the term “overweight” means 25 kg / m² in relation to an individual. 2 The above is 30 kg / m 2 This refers to individuals with a BMI below a certain level.

[0036] As used herein, the terms “diabetes” or “diabetes mellitus” refer to a type of metabolic disorder characterized by insufficient insulin secretion or impaired insulin function. Diabetes is characterized by hyperglycemia (high blood glucose levels), which leads to a variety of symptoms and, as a result, glucose is excreted in the urine. Type 1 diabetes mellitus (T1DM), formerly known as juvenile diabetes mellitus or insulin-dependent diabetes mellitus, is a chronic condition. In this condition, the pancreas produces little to no insulin. In type 2 diabetes mellitus (T2DM), formerly known as adult-onset diabetes mellitus, but which can also occur in children, the pancreas produces less insulin than before, and the body becomes resistant to insulin. The main difference between T1DM and T2DM is that T1DM is a genetic disorder that often develops in youth, while T2DM is primarily related to lifestyle and develops over time.

[0037] As used herein, the term “prevention” refers to any effect that suppresses or delays the onset of a target disease. As used herein, the term “prevention” means administering a therapeutically effective dose of efinopegdutide to an individual for a period sufficient to suppress or delay the onset of a fatty liver disease such as NAFLD or NASH, or for a period sufficient to suppress or delay the progression of a fatty liver disease from an early stage to a more advanced stage. For example, to suppress or delay the progression from an early stage of NAFLD to a more advanced form, non-alcoholic steatohepatitis (NASH), and ultimately to cirrhosis or liver cancer.

[0038] As used herein, the terms “treatment,” “treat,” or “treating” refer to administering the therapeutic agent to a subject or patient suffering from a disease or disorder in which the therapeutic agent exhibits therapeutic or prophylactic activity, or to a subject or patient suspected of suffering from such a disease or disorder. For example, administering a therapeutically effective dose of efinopegdutide to an individual for a period sufficient to alleviate, improve, or reduce fatty liver disease (e.g., NAFLD or NASH), or for a period sufficient to delay the progression of fatty liver disease from an existing stage to a more advanced stage. The use of efinopegdutide may provide both therapeutic and prophylactic effects. When used therapeutically in an individual suffering from fatty liver disease, a therapeutically effective dose of efinopegdutide will alleviate, improve, or reduce the symptoms of fatty liver disease over time. When used prophylactically in individuals with fatty liver disease, therapeutically effective doses of efinopegdutide suppress or delay the progression of fatty liver disease to more advanced stages over time (e.g., progression from NAFLD to NASH, cirrhosis, or liver cancer).

[0039] As used herein, the term “therapeutically effective amount” refers to the amount, concentration, or dose of efinopegdutide or a pharmaceutically acceptable salt thereof that, when administered to an individual in need, produces the desired effect in the individual during diagnosis or treatment (i.e., may result in a clinically measurable difference in the individual’s condition, e.g., a reduction in LFC). The effective amount can be readily determined by a person skilled in the art by observing results obtained under similar circumstances using known techniques. Many factors are considered when determining the effective amount for an individual, but are not limited to, the mammalian species, its size, age, and general health status; the specific disease or disorder involved; the degree, involvement, or severity of the disease or disorder; the individual’s response; the specific incretin analog administered; the method of administration; the bioavailability characteristics of the administered preparation; the chosen dosing regimen; the use of concomitant medications; and other relevant circumstances. For example, the therapeutic effective amount of efinopegdutide may be 10 mg. As described herein, when 10 mg of efinopegdutide was administered once weekly for 24 weeks to individuals with elevated liver fat content (LFC), efinopegdutide reduced the LFC of said individuals to less than 5%.

[0040] Where used herein, “pharmaceutically acceptable salt” is well known to those skilled in the art. The pharmaceutically acceptable salts and the general techniques for preparing them are well known to those skilled in the art (see, for example, Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use, 2nd Revised Edition (Wiley-VCH, 2011)). Pharmaceutically acceptable salts for use herein include, but are not limited to, sodium salts, trifluoroacetates, hydrochlorides, citrates, and / or acetates.

[0041] Introduction Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological disease entity that is increasingly recognized as a major health problem in developed countries. It encompasses a wide range of liver damage, from simple steatosis to non-alcoholic steatohepatitis (NASH), progressive fibrosis, and, rarely, progression to cirrhosis. NAFLD is strongly associated with the features of a metabolic syndrome that includes non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma. The development of NAFLD appears to correlate with the rise in obesity and diabetes. In the United States, 80 to 100 million people have NAFLD, and about 25% of them progress to NASH. NASH is one of the most common reasons for liver transplantation. The current annual medical and social costs of NAFLD in the United States are estimated at $292 billion. Obesity is a common sign of the presence of NAFLD, which can progress to NASH, a more progressive form of the disease. Currently, there are no approved treatments for NASH.

[0042] Non-alcoholic fatty liver disease (NAFLD) is known to be caused by a variety of etiologies, including insulin resistance, lipotoxicity, and inflammatory responses. Of these, insulin resistance is considered a major causative factor in both NAFLD and metabolic syndromes. Significant efforts have been made to improve insulin resistance in order to prevent and treat NAFLD. For example, clinical trials of thiazolidinediones (TZD) or metformin (a type of insulin sensitivity enhancer) have been actively conducted (see "Hepatology (2003) 38: 1008-17, J Clin Invest (2001) 108: 1167-74").

[0043] However, treatment with TZD-type drugs has the disadvantage of causing significant weight gain and slowing fluid flow, and therefore, such treatments may not be suitable for patients with heart disease. In addition to TZD-type drugs, clinical trials using GLP-1 receptor agonists such as Victoza® or Byetta® have also been conducted for non-alcoholic fatty liver disease. However, these GLP-1 receptor agonists have an extremely short in vivo half-life, and therefore, patients must receive repeated doses at least once a day, and in some cases twice a day, which is inconvenient for patients and unsuitable for long-term treatment. Furthermore, using common medications designed for treating diabetes simply to treat NAFLD through mechanisms that improve insulin resistance has disadvantages, such as inducing various side effects. Therefore, it remains debatable whether drugs known to be effective in treating diabetes (e.g., drugs to improve insulin resistance) can be reliably used as treatments for NAFLD. Therefore, there is a need to develop drugs that can treat NAFLD with minimal or no side effects, while ensuring patient convenience.

[0044] Efinopegdutide is disclosed in U.S. Patent No. 9,731,031, and the oxytomodulin derivative constituting effinopegdutide is disclosed in U.S. Patent No. 9,527,898. The use of effinopegdutide for the treatment of diabetes or obesity is disclosed in U.S. Patent No. 1,055,0168, its use in combination with long-acting insulin for the treatment of diabetes is disclosed in U.S. Patent No. 1,018,8703, its use for the treatment of severe diabetes is disclosed in International PCT Publication WO2019,171,352, and its use for the treatment of severe non-diabetic obesity is disclosed in International PCT Publication WO2020,289,67. The use of effinopegdutide for the treatment of liver diseases such as NAFLD or NASH is described in U.S. Patents No. 9,901,621 and No. 1,023,3230.

[0045] Efinopegdutide is being studied in nine clinical trials to evaluate its safety and efficacy in non-diabetic severely obese patients (NCT03486392), severely obese T2DM patients (NCT03586830), T2DM patients (NCT03235219), healthy overweight / obese patients (NCT03586843), and patients with varying degrees of renal failure (NCT03546205). Two clinical trials related to safety, tolerability, pharmacokinetics, and pharmacodynamics have been completed (NCT02862431 and NCT03618160). The other two trials include the effect of efinopegdutide on cardiac repolarization (NCT003606057) and its use compared to semaglutide in patients with NAFLD (NCT04944992).

[0046] Use of efinopegdutide to treat fatty liver disease The present invention provides the use of efinopegdutide or a pharmaceutically acceptable salt thereof at a dose of 10 mg once a week for a period sufficient to reduce the liver fat content (LFC) to less than 5% in individuals with elevated liver fat content (LFC).

[0047] The present invention provides a dosage regimen for reducing LFC to less than 5% in an individual with elevated LFC, wherein the dosage regimen comprises the following steps in the following order: (a) administering the individual a dose of 2.4 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 4 weeks; (b) administering the individual a dose of 5.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 4 weeks; and (c) administering the individual a dose of 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for a period sufficient to reduce the LFC to less than 5%. Depending on the individual's LFC, the period sufficient to reduce the individual's LFC to less than 5% may be more than 24 weeks or less than 24 weeks. In certain embodiments, efinopegdutide or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg once weekly for at least 10 weeks, at least 20 weeks, or at least 24 weeks to reduce the LFC in an individual to less than 5%.

[0048] The present invention further provides a maintenance therapy for maintaining liver fat at less than 5% in individuals who have undergone LFC reduction, wherein the method comprises administering to the individual a dose of 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof on a once-weekly basis.

[0049] In certain embodiments, the present invention also provides a method for treating fatty liver disease in an individual, wherein the method involves administering efinopegdutide or a pharmaceutically acceptable salt thereof to the individual at a dose of 10 mg once weekly for a period sufficient to reduce the individual's LFC to less than 5%. The present invention further provides a dosage regimen for treating an individual suffering from fatty liver disease, wherein the dosage regimen comprises the following steps in the following order: (a) administering the individual a dose of 2.4 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 4 weeks; (b) administering the individual a dose of 5.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 4 weeks; and administering the individual a dose of 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for a period sufficient to reduce the LFC to less than 5%, thereby treating the individual's fatty liver disease.

[0050] Depending on the individual's LFC and the severity of fatty liver disease, the period sufficient to reduce the individual's LFC to less than 5% may be more than 24 weeks or less than 24 weeks. In certain embodiments, 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof is administered once a week for at least 10 weeks, at least 20 weeks, or at least 24 weeks to reduce the individual's LFC to less than 5%.

[0051] The present invention further provides maintenance therapy for individuals who have received therapeutic therapy for fatty liver disease containing efinopegdutide or a pharmaceutically acceptable salt thereof in an amount and for a period of time that reduces the individual's LFC to less than 5%, wherein the maintenance therapy comprises administering 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof to the individual on a once-weekly basis.

[0052] In certain embodiments, the present invention also provides a method for treating NAFLD in an individual, wherein the method involves administering to the individual a dose of 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for a period sufficient to reduce the individual's LFC to less than 5%, thereby treating the individual's NAFLD. The present invention further provides a dosage regimen for treating an individual suffering from NAFLD, wherein the dosage regimen comprises the following steps in the following order: (a) administering the individual a dose of 2.4 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 4 weeks; (b) administering the individual a dose of 5.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 4 weeks; and administering the individual a dose of 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for a period sufficient to reduce the LFC to less than 5%, thereby treating the individual's NAFLD.

[0053] Depending on the severity of an individual's LFC and NAFLD, the period sufficient to reduce the individual's LFC to less than 5% may be more than 24 weeks or less than 24 weeks. In certain embodiments, 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof is administered once a week for at least 10 weeks, at least 20 weeks, or at least 24 weeks to reduce the individual's LFC to less than 5%.

[0054] The present invention further provides maintenance therapy for individuals who have received NAFLD treatment therapy with efinopegdutide or a pharmaceutically acceptable salt thereof in an amount and for a period of time that reduces the individual's LFC to less than 5%, wherein the maintenance therapy comprises administering 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof to the individual on a once-weekly basis.

[0055] In certain embodiments, the present invention also provides a method for treating NASH in an individual, wherein the method involves administering to the individual a dose of 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for a period sufficient to reduce the individual's LFC to less than 5%, thereby treating the individual's NASH. The present invention further provides a dosage regimen for treating an individual suffering from NASH, wherein the dosage regimen comprises the following steps in the following order: (a) administering the individual a dose of 2.4 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 4 weeks; (b) administering the individual a dose of 5.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 4 weeks; and administering the individual a dose of 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for a period sufficient to reduce the LFC to less than 5%, thereby treating the individual's NASH.

[0056] Depending on the severity of the individual's LFC and NASH, the period sufficient to reduce the individual's LFC to less than 5% may be more than 24 weeks or less than 24 weeks. In certain embodiments, 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof is administered once a week for at least 10 weeks, at least 20 weeks, or at least 24 weeks to reduce the individual's LFC to less than 5%.

[0057] The present invention further provides maintenance therapy for individuals who have received treatment for NASH with efinopegdutide or a pharmaceutically acceptable salt thereof in an amount and for a period of time that reduces the individual's LFC to less than 5%, wherein the maintenance therapy comprises administering to the individual a dose of 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof on a once-weekly basis.

[0058] In certain embodiments, the present invention also provides a method for treating pre-cirrhotic NASH in an individual, wherein the method involves administering to the individual a dose of 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for a period sufficient to reduce the individual's LFC to less than 5%, thereby treating the individual's pre-cirrhotic NASH. The present invention further provides a dosage regimen for treating an individual suffering from pre-cirrhotic NASH, wherein the dosage regimen comprises the following steps in the following order: (a) administering the individual a dose of 2.4 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 4 weeks; (b) administering the individual a dose of 5.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 4 weeks; and administering the individual a dose of 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for a period sufficient to reduce the LFC to less than 5%, thereby treating the individual's pre-cirrhotic NASH.

[0059] Depending on the individual's LFC and the severity of pre-cirrhotic NASH, the period sufficient to reduce the individual's LFC to less than 5% may be more than 24 weeks or less than 24 weeks. In certain embodiments, 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof is administered once a week for at least 10 weeks, at least 20 weeks, or at least 24 weeks to reduce the individual's LFC to less than 5%.

[0060] The present invention further provides maintenance therapy for individuals who have received pre-cirrhotic NASH treatment therapy with efinopegdutide or a pharmaceutically acceptable salt thereof in an amount and duration that reduces the individual's LFC to less than 5%, wherein the maintenance therapy comprises administering to the individual a dose of 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof on a once-weekly basis.

[0061] In certain embodiments, the present invention also provides a method for treating cirrhotic NASH in an individual, wherein the method involves administering to the individual a dose of 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for a period sufficient to reduce the individual's LFC to less than 5%, thereby treating the cirrhotic NASH in the individual. The present invention further provides a dosage regimen for treating an individual suffering from cirrhotic NASH, wherein the dosage regimen comprises the following steps in the following order: (a) administering the individual a dose of 2.4 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 4 weeks; (b) administering the individual a dose of 5.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 4 weeks; and administering the individual a dose of 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for a period sufficient to reduce the LFC to less than 5%, thereby treating the individual's cirrhotic NASH.

[0062] Depending on the individual's LFC and the severity of cirrhotic NASH, the period sufficient to reduce the individual's LFC to less than 5% may be more than 24 weeks or less than 24 weeks. In certain embodiments, 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof is administered once a week for at least 10 weeks, at least 20 weeks, or at least 24 weeks to reduce the individual's LFC to less than 5%.

[0063] The present invention further provides maintenance therapy for individuals who have received treatment for cirrhotic NASH with efinopegdutide or a pharmaceutically acceptable salt thereof in an amount and for a period of time that reduces the individual's LFC to less than 5%, wherein the maintenance therapy comprises administering to the individual a dose of 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof on a once-weekly basis.

[0064] In certain embodiments, the present invention also provides a method for treating or suppressing steatosis in an individual, wherein the method involves administering to the individual a dose of 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for a period sufficient to reduce the individual's LFC to less than 5%, thereby treating or suppressing steatosis in the individual. The present invention further provides a dosage regimen for treating or suppressing steatosis in an individual, wherein the dosage regimen comprises the following steps in the following order: (a) administering the individual a dose of 2.4 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 4 weeks; (b) administering the individual a dose of 5.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 4 weeks; and administering the individual a dose of 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for a period sufficient to reduce the LFC to less than 5%, thereby treating or suppressing the steatosis.

[0065] Depending on the individual's LFC and the severity of steatosis, the period sufficient to reduce the individual's LFC to less than 5% may be more than 24 weeks or less than 24 weeks. In certain embodiments, 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof is administered once a week for at least 10 weeks, at least 20 weeks, or at least 24 weeks to reduce the individual's LFC to less than 5%.

[0066] The present invention further provides maintenance therapy for individuals who have received treatment for steatosis containing efinopegdutide or a pharmaceutically acceptable salt thereof in an amount and for a period of time that reduces the individual's LFC to less than 5%, wherein the maintenance therapy comprises administering to the individual a dose of 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof on a once-weekly basis.

[0067] The efficacy of a once-weekly 10 mg dose for reducing an individual's LFC to less than 5% was discovered by the inventors during a Phase 2b trial comparing the efficacy and safety of the GLP-1-glucagon receptor synagonism induced by a 10 mg dose of efinopegdutide with the efficacy and safety of the GLP-1 monoagonal action induced by a 1 mg dose of semaglutide in patients with NAFLD (see Examples). In the aforementioned trial, both active agents resulted in a clinically significant reduction in LFC from baseline. However, efinopegdutide reduced LFC significantly more than semaglutide. With efinopegdutide treatment, two-thirds of participants achieved normal LFC levels (less than 5%), compared to less than one-fifth of participants with semaglutide. A 10 mg dose of efinopegdutide (molecular weight 64 kDa) is approximately 1.5 nanomoles, while a 1 mg dose of semaglutide (molecular weight 6113.58 Da) is approximately 2.4 nanomoles.

[0068] The significantly greater reduction in LFC with efinopegdutide compared to semaglutide occurred despite both treatments resulting in similar weight loss. The study was initiated before high-dose semaglutide (2.4 mg per week) became available (it is currently approved for the treatment of obesity and is being evaluated in a Phase 3 trial as a potential treatment option for patients with NASH). While the greater weight loss observed with high-dose semaglutide may result in an additional anti-steatotic effect compared to the dose used in the study, previous studies have shown that high-dose semaglutide relatively reduced liver fat by 36–46% at 6 months.

[0270] -

[0272] .

[0069] Dietary therapy for weight loss

[0273] , pharmacological therapy

[0274] and surgical treatment

[0275] 、

[0276] Consistent with our experience, participants in both treatment groups with greater weight loss also experienced greater reductions in LFC. Relative reductions from baseline in LFC at 24 weeks across specific weight loss categories (weight loss from baseline: ≤5%, >5% to ≤10%, and >10%) were all higher in the efinopegdutide group than in the semaglutide group. Particularly noteworthy was the magnitude of LFC reduction in participants in the lowest weight loss category. Among participants with a weight loss of 5% or less from baseline, the LFC reduction with efinopegdutide was 52.4%, compared to 13.4% in the semaglutide group. These findings suggest that, beyond the weight loss-related mechanisms, there are other mechanisms that contribute to the greater LFC reduction effect of efinopegdutide compared to semaglutide. This difference may be due to efinopegdutide's glucagon receptor agonist action directly promoting fatty acid oxidation in the liver and suppressing lipogenesis.

[0264] .

[0070] The aforementioned study demonstrated that treatment with efinopegdutide was generally well tolerated. The incidence of adverse events and drug-related adverse events was slightly higher in the efinopegdutide group, mainly due to an imbalance in gastrointestinal adverse events. Otherwise, there were no significant differences between the two treatment groups in the incidence of overall adverse events, serious adverse events, or drug-related adverse events, including those leading to discontinuation. Dose-dependent gastrointestinal adverse events (mainly nausea and vomiting) have already been reported in two phase 2 dose-range trials of efinopegdutide in obese patients with T2DM and obese patients without T2DM.

[0267] 、

[0268] Furthermore, GLP-1R agonists and other GLP-1R / GCGR co-agonists are also well described.

[0277] Notably, the two Phase II dose-range studies using efinopegdutide did not employ a titration regimen.

[0267] 、

[0268] Since escalation regimens to reduce the incidence of gastrointestinal adverse events have been successfully implemented with commercially available GLP-1 agonists, a titration strategy was also adopted in this study. In this study, the incidence of nausea and vomiting reported in the efinopegdutide group (27.8% and 16.7%, respectively) was similar to that reported in the semaglutide group (31.5% and 15.1%, respectively), and was significantly lower than the incidence reported in the previous Phase 2 dose-range study using 10 mg of efinopegdutide (42.9-66.9% and 34.7-55.1%, respectively).

[0267] 、

[0268] This indicates that the dose escalation strategy was effective in mitigating these adverse events. The effects of efinopegdutide on heart rate and blood pressure in this study were slightly greater than those observed with semaglutide and were consistent with observations in previous studies using efinopegdutide. These hemodynamic changes did not appear to be mitigated by the use of the dose escalation strategy and may reflect a combined effect of GLP-1 and glucagon activity.

[0071] Results observed with efinopegdutide in the previous Phase 2 trial

[0267] 、

[0268] Similarly, in this study, no significant mean change from baseline was observed in A1C levels or fasting plasma glucose levels at 24 weeks in the efinopegdutide group. This is thought to be because the effects of GLP-1 and glucagon receptor synergy on glucose metabolism were balanced, resulting in no change in blood glucose activity. The reduction in serum lipids observed with efinopegdutide was also similar to that reported in the previous Phase 2 trial.

[0267] 、

[0268] The decrease in hemoglobin has not been reported with GLP-1 receptor agonists and is considered to be a pharmacological effect of glucagon agonism. Glucagon has been shown to suppress erythrocyte formation and has been shown to reduce heme production in rodent models.

[0279] Furthermore, normochromic normocytic anemia frequently occurs in patients with glucagonoma syndrome (approximately 35%).

[0280] .

[0072] In summary, the aforementioned studies demonstrate that the present invention provides treatment with efinopegdutide, which can result in a significant improvement in LFC compared to semaglutide, particularly in patients with NAFLD. Treatment with efinopegdutide is also generally well-tolerated, and its tolerability profile is similar to that of semaglutide. The substantial benefit of treatment with efinopegdutide in reducing hepatic fat may be due to a complementary dual mechanism of action involving GLP-1 receptor agonism and glucagon receptor agonism. Together, these lead to improvement in the core pathophysiological defects associated with NAFLD.

[0073] Composition of effinopegdutide Effinopegdutide can be provided in a composition containing 93 nmol / mL to 565 nmol / mL of effinopegdutide, 5 mM to 25 mM of a buffer (wherein the buffer is selected from citric acid and its salts, acetic acid and its salts, histidine and its salts, phosphoric acid and its salts, and combinations thereof) so that the pH of the liquid formulation is 4.8 to 5.5, 4% (w / v) to 10% (w / v) of a sugar alcohol, 0.001% (w / v) to 0.1% (w / v) of a nonionic surfactant (wherein the nonionic surfactant is selected from poloxamer, polysorbate, or combinations thereof), and 0.01 to 1 mg / mL of L-methionine. In a further embodiment, the composition contains 274 nmol / mL to 474 nmol / mL of effinopegdutide.

[0074] In further embodiments, the composition comprises 93 nmol / mL to 565 nmol / mL of efinopegdutide in 5-50 mM histidine; 2-15% (w / v) of mannitol; 0.01-1 mg / mL of methionine; and 0.001-0.1% (w / v) of polysorbate 20.

[0075] In further embodiments, the composition comprises 374 nmol / mL efinopegdutide, 20 mM citrate-sodium citrate (pH 5.4), 6% mannitol, 0.02% polysorbate 20, and 0.1 mg / mL L-methionine.

[0076] In another embodiment, the effinopegdutide may be provided in a composition comprising 93 nmol / mL to 565 nmol / mL of effinopegdutide, 5 mM to 25 mM of a buffer (wherein the buffer is selected from citric acid and its salts, acetic acid and its salts, histidine and its salts, phosphoric acid and its salts, and combinations thereof) so that the pH of the liquid formulation is 4.8 to 5.5, 4% (w / v) to 10% (w / v) of sugars, and 0.01% (w / v) to 0.1% (w / v) of a nonionic surfactant (wherein the nonionic surfactant is selected from poloxamer, polysorbate, or combinations thereof). In a further embodiment, the composition comprises 274 nmol / mL to 474 nmol / mL of effinopegdutide.

[0077] In further embodiments, the composition comprises 374 nmol / mL efinopegdutide, 10 mM sodium acetate (pH 5.1), 8.5% sucrose, and 0.02% polysorbate 20.

[0078] The effinopegdutide may be provided in a vial as a liquid for use in a syringe, or as a lyophilized powder (which can be reconstituted in water for use in a syringe). The effinopegdutide may be provided as a liquid in an injection device designed to provide one or more doses of the composition (where each dose contains up to 10 mg of effinopegdutide). The effinopegdutide may be provided as a liquid in an adjustable injection device designed to allow the user of the device to select one or more doses of the composition (where each dose contains 2.0 mg, 2.4 mg, 2.5 mg, 5 mg, 7 mg, or 10 mg of effinopegdutide).

[0079] Specific embodiments of the present invention include the following: Embodiment 1. A method for reducing liver fat content (LFC) in individuals suffering from fatty liver disease, The method comprising administering to the individual a dose of efinopegdutide or a pharmaceutically acceptable salt thereof in an amount of about 2 mg to about 10 mg once a week for a period sufficient to reduce the LFC in the individual.

[0080] Embodiment 2. The method according to Embodiment 1, wherein the dose is approximately 2 mg (2.4 mg in an alternative embodiment) of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0081] Embodiment 3. The method according to Embodiment 1, wherein the dose is 2 mg (2.4 mg in an alternative embodiment) of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0082] Embodiment 4. The method according to Embodiment 1, wherein the dose is approximately 4 mg (5 mg in an alternative embodiment) of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0083] Embodiment 5. The method according to Embodiment 1, wherein the dose is 4 mg (5 mg in an alternative embodiment) of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0084] Embodiment 6. The method according to Embodiment 1, wherein the dose is approximately 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0085] Embodiment 7. The method according to Embodiment 1, wherein the dose is 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0086] Embodiment 8. The method according to Embodiment 1, wherein the dose is approximately 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0087] Embodiment 9. The method according to Embodiment 1, wherein the dose is 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0088] Embodiment 10. The method according to any one of Embodiments 1-9, wherein the fatty liver disease is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

[0089] Embodiment 11. The method according to Embodiment 10, wherein the NASH is pre-cirrhotic NASH.

[0090] Embodiment 12. The method according to Embodiment 10, wherein the NASH is cirrhotic NASH.

[0091] Embodiment 13. The method according to any one of Embodiments 1-12, wherein the period sufficient to reduce the LFC is approximately 24 weeks.

[0092] Embodiment 14. The method according to any one of Embodiments 1-13, wherein the individual suffering from fatty liver disease has 5% or more LFC before administration of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0093] Embodiment 15. The method according to any one of Embodiments 1-13, wherein the individual suffering from fatty liver disease has 10% or more LFC before administration of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0094] Embodiment 16. The method according to any one of Embodiments 1-13, wherein the individual suffering from fatty liver disease has 15% or more LFC before administration of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0095] Embodiment 17. The method according to any one of Embodiments 1-13, wherein the individual suffering from fatty liver disease has 20% or more LFC before administration of 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0096] Embodiment 18. The method according to any one of Embodiments 1-17, wherein the LFC in the individual is reduced to less than 5%.

[0097] Embodiment 19. The method according to any one of Embodiments 1-18, wherein the individual has type 1 diabetes (T1DM) or type 2 diabetes (T2M).

[0098] Embodiment 20. The method according to Embodiment 19, wherein the individual has type 2 diabetes (T2M) and is overweight or obese.

[0099] Embodiment 21. The method according to any one of Embodiments 1-19, wherein the individual is overweight or obese.

[0100] Embodiment 22. A method for treating fatty liver disease in individuals who require treatment for fatty liver disease, The method comprising administering to the individual a dose of efinopegdutide or a pharmaceutically acceptable salt thereof in an amount of about 2 mg to about 10 mg once a week for a period sufficient to treat fatty liver disease in the individual.

[0101] Embodiment 23. The method according to Embodiment 22, wherein the dose is approximately 2 mg (2.4 mg in an alternative embodiment) of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0102] Embodiment 24. The method according to Embodiment 22, wherein the dose is 2 mg (2.4 mg in an alternative embodiment) of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0103] Embodiment 25. The method according to Embodiment 22, wherein the dose is approximately 4 mg (5 mg in an alternative embodiment) of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0104] Embodiment 26. The method according to Embodiment 22, wherein the dose is 4 mg (5 mg in an alternative embodiment) of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0105] Embodiment 27. The method according to Embodiment 22, wherein the dose is approximately 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0106] Embodiment 28. The method according to Embodiment 22, wherein the dose is 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0107] Embodiment 29. The method according to Embodiment 22, wherein the dose is approximately 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0108] Embodiment 30. The method according to Embodiment 22, wherein the dose is 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0109] Embodiment 31. The method according to any one of Embodiments 22-30, wherein the fatty liver disease is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

[0110] Embodiment 32. The method according to Embodiment 31, wherein the NASH is pre-cirrhotic NASH.

[0111] Embodiment 33. The method according to Embodiment 31, wherein the NASH is cirrhotic NASH.

[0112] Embodiment 34. The method according to any one of embodiments 22-33, wherein the period sufficient to treat the aforementioned fatty liver disease is approximately 24 weeks.

[0113] Embodiment 35. The method according to any one of Embodiments 22-34, wherein the individual suffering from fatty liver disease has a liver fat content (LFC) of 5% or more before administration of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0114] Embodiment 36. The method according to any one of Embodiments 22-34, wherein the individual suffering from fatty liver disease has 10% or more LFC before administration of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0115] Embodiment 37. The method according to any one of Embodiments 22-34, wherein the individual suffering from fatty liver disease has 15% or more LFC before administration of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0116] Embodiment 38. The method according to any one of Embodiments 22-34, wherein the individual suffering from fatty liver disease has 20% or more LFC before administration of 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0117] Embodiment 39. The method according to any one of embodiments 22-38, wherein the LFC in the individual is reduced to less than 5%.

[0118] Embodiment 40. The method according to any one of Embodiments 22-39, wherein the individual has type 1 diabetes (T1DM) or type 2 diabetes (T2M).

[0119] Embodiment 41. The method according to Embodiment 40, wherein the individual has type 2 diabetes (T2M) and is overweight or obese.

[0120] Embodiment 42. The method according to any one of embodiments 22-40, wherein the individual is overweight or obese.

[0121] Embodiment 43. A method for reducing liver fat content (LFC) to less than 5% in individuals with elevated LFC, comprising the following steps in the following order: (a) The individual is administered approximately 2.0 mg (2.4 mg in an alternative embodiment) of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (b) The individual is administered approximately 5.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (c) The individual is administered approximately 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for a period sufficient to reduce the LFC to less than 5%; The method, including the method described above.

[0122] Embodiment 44. The following steps are in the following order: (a) The individual is administered 2.0 mg (2.4 mg in an alternative embodiment) of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (b) The individual is administered 5.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (c) The individual is administered 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for a period sufficient to reduce the LFC to less than 5%; The method according to Embodiment 43, including the method described in Embodiment 43.

[0123] Embodiment 45. A method for reducing liver fat content (LFC) to less than 5% in individuals with elevated LFC, comprising the following steps in the following order: (a) The individual is administered approximately 2.0 mg (2.4 mg in an alternative embodiment) of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (b) The individual is administered approximately 4.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 48 weeks; The method, including the method described above.

[0124] Embodiment 46. The following steps are in the following order: (a) The individual is administered 2.0 mg (2.4 mg in an alternative embodiment) of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (b) The individual is administered 4.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 48 weeks; The method according to embodiment 45, including the method described in embodiment 45.

[0125] Embodiment 47. A method for reducing liver fat content (LFC) to less than 5% in individuals with elevated LFC, comprising the following steps in the following order: (a) The individual is administered approximately 2.0 mg (2.4 mg in an alternative embodiment) of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (b) The individual is administered approximately 4.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (c) The individual is administered approximately 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 44 weeks; The method, including the method described above.

[0126] Embodiment 48. The following steps are in the following order: (a) The individual is administered 2.0 mg (2.4 mg in an alternative embodiment) of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (b) The individual is administered 4.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (c) The individual is administered 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 44 weeks; The method according to Embodiment 47, including the method described in Embodiment 47.

[0127] Embodiment 49. A method for reducing liver fat content (LFC) to less than 5% in individuals with elevated LFC, comprising the following steps in the following order: (a) The individual is administered approximately 2.0 mg (2.4 mg in an alternative embodiment) of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (b) The individual is administered approximately 4.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (c) The individual is administered approximately 7.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (d) The individual is administered approximately 10.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 40 weeks; The method, including the method described above.

[0128] Embodiment 50. The following steps are in the following order: (a) The individual is administered 2.0 mg (2.4 mg in an alternative embodiment) of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (b) The individual is administered 4.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (c) The individual is administered 7.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (d) The individual is administered 10.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 40 weeks; The method according to Embodiment 49, including the method described in Embodiment 49.

[0129] Embodiment 51. The method according to any one of embodiments 43-50, wherein the individual whose LFC is elevated is suffering from fatty liver disease.

[0130] Embodiment 52. The method according to Embodiment 51, wherein the fatty liver disease is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

[0131] Embodiment 53. The method according to Embodiment 52, wherein the NASH is pre-cirrhotic NASH.

[0132] Embodiment 54. The method according to Embodiment 52, wherein the NASH is cirrhotic NASH.

[0133] Embodiment 55. The method according to Embodiment 43 or Embodiment 44, wherein the period sufficient to reduce the liver fat to less than 5% is approximately 24 weeks.

[0134] Embodiment 56. The method according to any one of Embodiments 43-55, wherein the individual suffering from fatty liver disease has 5% or more LFC before commencing the method.

[0135] Embodiment 57. The method according to any one of Embodiments 43-55, wherein the individual suffering from fatty liver disease has 10% or more LFC before commencing the method.

[0136] Embodiment 58. The method according to any one of Embodiments 43-55, wherein the individual suffering from fatty liver disease has 15% or more LFC before commencing the method.

[0137] Embodiment 59. The method according to any one of Embodiments 43-55, wherein the individual suffering from fatty liver disease has 20% or more LFC before commencing the method.

[0138] Embodiment 60. The method according to any one of embodiments 43-59, wherein the individual has type 1 diabetes (T1DM) or type 2 diabetes (T2M).

[0139] Embodiment 61. The method according to Embodiment 60, wherein the individual has type 2 diabetes (T2M) and is overweight or obese.

[0140] Embodiment 62. The method according to any one of embodiments 43-60, wherein the individual is overweight or obese.

[0141] Embodiment 63. A method for treating fatty liver disease in individuals requiring treatment, comprising the following steps in the following order: (a) The individual is administered approximately 2.0 mg (2.4 mg in an alternative embodiment) of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (b) The individual is administered approximately 5.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (c) The individual is administered approximately 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for a period sufficient to treat fatty liver disease in the individual; The method, including the method described above.

[0142] Embodiment 64. The following steps are in the following order: (a) The individual is administered 2.0 mg (2.4 mg in an alternative embodiment) of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (b) The individual is administered 5.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (c) The individual is administered 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for a period sufficient to reduce the LFC to less than 5%; The method according to embodiment 63, including the method described in embodiment 63.

[0143] Embodiment 65. A method for treating fatty liver disease in individuals requiring treatment, comprising the following steps in the following order: (a) The individual is administered approximately 2.0 mg (2.4 mg in an alternative embodiment) of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (b) The individual is administered approximately 4.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 48 weeks; The method, including the method described above.

[0144] Embodiment 66. The following steps are in the following order: (a) The individual is administered 2.0 mg (2.4 mg in an alternative embodiment) of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (b) The individual is administered 4.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 48 weeks; The method according to embodiment 65, including the method described in embodiment 65.

[0145] Embodiment 67. A method for treating fatty liver disease in individuals requiring treatment, comprising the following steps in the following order: (a) The individual is administered approximately 2.0 mg (2.4 mg in an alternative embodiment) of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (b) The individual is administered approximately 4.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (c) The individual is administered approximately 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 44 weeks; The method, including the method described above.

[0146] Embodiment 68. The following steps are in the following order: (a) The individual is administered 2.0 mg (2.4 mg in an alternative embodiment) of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (b) The individual is administered 4.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (c) The individual is administered 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 44 weeks; The method according to embodiment 67, including the method described in embodiment 67.

[0147] Embodiment 69. A method for treating fatty liver disease in individuals requiring treatment, comprising the following steps in the following order: (a) The individual is administered approximately 2.0 mg (2.4 mg in an alternative embodiment) of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (b) The individual is administered approximately 4.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (c) The individual is administered approximately 7.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (d) The individual is administered approximately 10.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 40 weeks; The method, including the method described above.

[0148] Embodiment 70. The following steps are in the following order: (a) The individual is administered 2.0 mg (2.4 mg in an alternative embodiment) of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (b) The individual is administered 4.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (c) The individual is administered 7.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (d) The individual is administered 10.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 40 weeks; The method according to embodiment 69, including the method described in embodiment 69.

[0149] Embodiment 71. The method according to any one of embodiments 63 to 70, wherein the individual suffering from fatty liver disease has an elevated liver fat content (LFC).

[0150] Embodiment 72. The method according to Embodiment 71, wherein the fatty liver disease is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

[0151] Embodiment 73. The method according to Embodiment 72, wherein the NASH is pre-cirrhotic NASH.

[0152] Embodiment 74. The method according to Embodiment 72, wherein the NASH is cirrhotic NASH.

[0153] Embodiment 75. The method according to Embodiment 63 or Embodiment 64, wherein the period sufficient to treat fatty liver disease in the individual is approximately 24 weeks.

[0154] Embodiment 76. The method according to any one of embodiments 63-75, wherein the individual suffering from fatty liver disease has 5% or more LFC before commencing the method.

[0155] Embodiment 77. The method according to any one of embodiments 63-75, wherein the individual suffering from fatty liver disease has 10% or more LFC before commencing the method.

[0156] Embodiment 78. The method according to any one of embodiments 63-75, wherein the individual suffering from fatty liver disease has 15% or more LFC before commencing the method.

[0157] Embodiment 79. The method according to any one of embodiments 63-75, wherein the individual suffering from fatty liver disease has 20% or more LFC before commencing the method.

[0158] Embodiment 80. The method according to any one of embodiments 63-79, wherein the individual has type 1 diabetes (T1DM) or type 2 diabetes (T2M).

[0159] Embodiment 81. The method according to Embodiment 80, wherein the individual has type 2 diabetes (T2M) and is overweight or obese.

[0160] Embodiment 82. The method according to any one of embodiments 63-80, wherein the individual is overweight or obese.

[0161] Embodiment 83. The use of efinopegdutide or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical product for reducing liver fat content (LFC) to less than 5% in individuals with elevated LFC.

[0162] Embodiment 84. The use according to Embodiment 83, wherein the pharmaceutical product comprises about 2 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0163] Embodiment 85. The use according to Embodiment 83, wherein the pharmaceutical product comprises 2 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0164] Embodiment 86. The use according to Embodiment 83, wherein the pharmaceutical product comprises approximately 4 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0165] Embodiment 87. The use according to Embodiment 83, wherein the pharmaceutical product comprises 4 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0166] Embodiment 88. The use according to Embodiment 83, wherein the pharmaceutical product comprises approximately 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0167] Embodiment 89. The use according to Embodiment 83, wherein the pharmaceutical product comprises 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0168] Embodiment 90. The use according to Embodiment 83, wherein the pharmaceutical product comprises about 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0169] Embodiment 91. The use according to Embodiment 83, wherein the pharmaceutical product comprises 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0170] Embodiment 92. The use of efinopegdutide or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical for the treatment of fatty liver disease in an individual who requires treatment for fatty liver disease.

[0171] Embodiment 93. The use according to Embodiment 92, wherein the fatty liver disease is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

[0172] Embodiment 94. The use according to Embodiment 93, wherein the NASH is pre-cirrhotic NASH.

[0173] Embodiment 95. The use according to Embodiment 93, wherein the NASH is cirrhotic NASH.

[0174] Embodiment 96. The use according to Embodiment 93, wherein the individual suffering from fatty liver disease has a liver fat content (LFC) of 5% or more before administration of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0175] Embodiment 97. The use according to any one of Embodiments 92-96, wherein the pharmaceutical product comprises about 2 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0176] Embodiment 98. The use according to any one of Embodiments 92-96, wherein the pharmaceutical product comprises 2 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0177] Embodiment 99. The use according to any one of Embodiments 92-96, wherein the pharmaceutical product comprises about 4 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0178] Embodiment 100. The use according to any one of Embodiments 92-96, wherein the pharmaceutical product comprises 4 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0179] Embodiment 101. The use according to any one of Embodiments 92-96, wherein the pharmaceutical product comprises about 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0180] Embodiment 102. The use according to any one of Embodiments 92-96, wherein the pharmaceutical product comprises 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0181] Embodiment 103. The use according to any one of Embodiments 92-96, wherein the pharmaceutical product comprises about 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0182] Embodiment 104. The use according to any one of Embodiments 92-96, wherein the pharmaceutical product comprises 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

[0183] Embodiment 105. Efinopegdutide or a pharmaceutically acceptable salt thereof for reducing liver fat content (LFC) to less than 5% in individuals with elevated LFC.

[0184] Embodiment 106. The efinopegdutide or pharmaceutically acceptable salt thereof according to Embodiment 105, wherein the efinopegdutide or a pharmaceutically acceptable salt thereof is provided in a dose of about 2 mg (2.4 mg in an alternative embodiment).

[0185] Embodiment 107. The efinopegdutide or pharmaceutically acceptable salt thereof according to Embodiment 105, wherein the efinopegdutide or a pharmaceutically acceptable salt thereof is provided in a dose of 2 mg (2.4 mg in an alternative embodiment).

[0186] Embodiment 108. The efinopegdutide or pharmaceutically acceptable salt thereof according to Embodiment 105, wherein the efinopegdutide or a pharmaceutically acceptable salt thereof is provided in a dose of about 4 mg.

[0187] Embodiment 109. The efinopegdutide or pharmaceutically acceptable salt thereof according to Embodiment 105, wherein the efinopegdutide or pharmaceutically acceptable salt thereof is provided in a dose of 4 mg.

[0188] Embodiment 110. The efinopegdutide or pharmaceutically acceptable salt thereof according to Embodiment 105, wherein the efinopegdutide or a pharmaceutically acceptable salt thereof is provided in a dose of about 7 mg.

[0189] Embodiment 111. The efinopegdutide or pharmaceutically acceptable salt thereof according to Embodiment 105, wherein the efinopegdutide or a pharmaceutically acceptable salt thereof is provided in a dose of 7 mg.

[0190] Embodiment 112. The efinopegdutide or pharmaceutically acceptable salt thereof according to Embodiment 105, wherein the efinopegdutide or a pharmaceutically acceptable salt thereof is provided in a dose of about 10 mg.

[0191] Embodiment 113. The efinopegdutide or pharmaceutically acceptable salt thereof according to Embodiment 105, wherein the efinopegdutide or pharmaceutically acceptable salt thereof is provided in a dose of 10 mg.

[0192] Embodiment 114. A pharmaceutical composition comprising approximately 2 mg (2.4 mg in an alternative embodiment) of efinopegdutide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0193] Embodiment 115. A pharmaceutical composition comprising 2 mg (2.4 mg in an alternative embodiment) of efinopegdutide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0194] Embodiment 116. A pharmaceutical composition comprising approximately 4 mg of efinopegdutide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0195] Embodiment 117. A pharmaceutical composition comprising 4 mg of efinopegdutide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0196] Embodiment 118. A pharmaceutical composition comprising approximately 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0197] Embodiment 119. A pharmaceutical composition comprising 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0198] Embodiment 120. A pharmaceutical composition comprising approximately 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0199] Embodiment 121. A pharmaceutical composition comprising 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0200] Embodiment 121A. A pharmaceutical composition according to any one of Embodiments 112-121, comprising: effinopegdutide in an amount of approximately 93 nmol / mL to approximately 565 nmol / mL (in a particular embodiment, 93 nmol / mL to 565 nmol / mL); and a buffer in an amount of approximately 5 mM to approximately 25 mM (in a particular embodiment, 5 mM to 25 mM) (wherein the buffer is selected from the group consisting of citric acid or a pharmaceutically acceptable salt thereof, acetic acid or a pharmaceutically acceptable salt thereof, histidine or a pharmaceutically acceptable salt thereof, phosphoric acid or a pharmaceutically acceptable salt thereof, and combinations thereof).

[0201] Embodiment 121B. The pharmaceutical composition according to Embodiment 121A, wherein the pH of the liquid formulation is about 4.8 to about 5.5 (4.8 to 5.5 in a particular embodiment); and comprises about 4% (w / v) to about 10% (w / v) (4% (w / v) to 10% (w / v) in a particular embodiment) of sugar alcohol, about 0.001% (w / v) to about 0.1% (w / v) (0.001% (w / v) to 0.1% (w / v) in a particular embodiment) of a nonionic surfactant (where the nonionic surfactant is selected from the group consisting of poloxamer, polysorbate, or a combination thereof), and about 0.01 to about 1 mg / mL (0.01 to 1 mg / mL in a particular embodiment) of L-methionine.

[0202] Embodiment 121C. A pharmaceutical composition according to Embodiment 121A or Embodiment 121B, comprising efinopegdutide or a pharmaceutically acceptable salt thereof in a concentration of approximately 274 nmol / mL to approximately 474 nmol / mL (274 nmol / mL to 474 nmol / mL in certain embodiments).

[0203] Embodiment 121D. The pharmaceutical composition according to Embodiment 121, comprising approximately 93 nmol / mL to approximately 565 nmol / mL (in a specific embodiment, 93 nmol / mL to 565 nmol / mL) of efinopegdutide or a pharmaceutically acceptable salt thereof, approximately 5 to 50 mM (in a specific embodiment, 5 to 50 mM) of histidine, approximately 2 to approximately 15% (w / v) (in a specific embodiment, 2 to 15% (w / v)) of mannitol, approximately 0.01 to approximately 1 mg / mL (in a specific embodiment, 0.01 to 1 mg / mL) of methionine, and approximately 0.001 to approximately 0.1% (w / v) (in a specific embodiment, 0.001 to 0.1% (w / v)) of polysorbate 20.

[0204] Embodiment 121E. The pharmaceutical composition according to Embodiment 121, comprising approximately 374 nmol / mL (374 nmol / mL in a particular embodiment) efinopegdutide or a pharmaceutically acceptable salt thereof, approximately 20 mM (20 mM in a particular embodiment) citrate-sodium citrate, approximately 6% (w / v) (6% (w / v) in a particular embodiment) mannitol, approximately 0.1 mg / mL (0.1 mg / mL in a particular embodiment) methionine, and approximately 0.02% (w / v) (0.02% (w / v) in a particular embodiment) polysorbate 20, wherein the pH is approximately 5.4 (5.4 in a particular embodiment).

[0205] Embodiment 121F. An efinopegdutide or a pharmaceutically acceptable salt thereof at about 93 nmol / mL to about 565 nmol / mL (in certain embodiments, 93 nmol / mL to 565 nmol / mL), a buffer at about 5 mM to about 25 mM (in certain embodiments, 5 mM to 25 mM), wherein the buffer is selected from the group consisting of citric acid or a pharmaceutically acceptable salt thereof, acetic acid or a pharmaceutically acceptable salt thereof, histidine or a pharmaceutically acceptable salt thereof, phosphoric acid or a pharmaceutically acceptable salt thereof, or a combination thereof, a saccharide at about 4% (w / v) to about 10% (w / v) (in certain embodiments, 4% (w / v) to 10% (w / v)), and a nonionic surfactant at about 0.01% (w / v) to about 0.1% (w / v) (in certain embodiments, 0.01% (w / v) to 0.1% (w / v)), wherein the nonionic surfactant is selected from the group consisting of poloxamer, polysorbate, or a combination thereof, and having a pH of about 4.8 to about 5.5 (in certain embodiments, 4.8 to 5.5), the pharmaceutical composition according to Embodiment 121.

[0206] Embodiment 121G. The pharmaceutical composition according to Embodiment 121G, comprising efinopegdutide or a pharmaceutically acceptable salt thereof at about 274 nmol / mL to about 474 nmol / mL (in certain embodiments, 274 to 474 nmol / mL).

[0207] Embodiment 121H. The pharmaceutical composition according to Embodiment 121, comprising efinopegdutide or a pharmaceutically acceptable salt thereof at about 374 nmol / mL (in certain embodiments, 374 nmol / mL), sodium acetate at about 10 mM (in certain embodiments, 10 mM), sucrose at about 8.5% (in certain embodiments, 8.5%), and polysorbate 20 at about 0.02% (w / v) (in certain embodiments, 0.02% (w / v)), and having a pH of about 5.1 (in certain embodiments, 5.1).

[0208] Embodiments 121 to 121H are separate embodiments of Embodiment 121 and are individually referred to in the following embodiments.

[0209] Embodiment 122. The method according to any one of Embodiments 1-82, wherein the efinopegdutide or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0210] Embodiment 123. Use according to any one of Embodiments 83-104, wherein the medicament is for subcutaneous administration.

[0211] Embodiment 124. Efinopegdutide or a pharmaceutically acceptable salt thereof according to any one of Embodiments 105-113 for subcutaneous administration.

[0212] Embodiment 125. Pharmaceutical composition according to any one of Embodiments 114-121 for subcutaneous administration.

[0213] Embodiment 126. The method, use, efinopegdutide or a pharmaceutically acceptable salt thereof or pharmaceutical composition according to any one of Embodiments 1-125, wherein at the 24th week of treatment, the LFC in the individual (or individuals) is reduced by ≧ about 30%, about ≧ 50% or ≧ about 70% (in certain embodiments, ≧ 30%, ≧ 50% or ≧ 70%) from baseline.

[0214] Embodiment 127. The method, use, efinopegdutide or a pharmaceutically acceptable salt thereof or pharmaceutical composition according to any one of Embodiments 1-125, wherein at the 24th week of treatment, the body weight in the individual (or individuals) is reduced by ≧ about 5%, > about 5% to ≦ about 10% or > about 1 (or, in certain embodiments, ≧ 5%, > 5% to ≦ or > 10%) from baseline.

[0215] The following examples are intended to facilitate further understanding of the present invention.

Example

[0216] Example 1 The Phase 2a trial in this embodiment was conducted to evaluate the efficacy and safety of efinopegdutide, a GLP-1 and glucagon receptor co-agonist, compared to semaglutide-based GLP-1 agonist alone, in NAFLD patients with and without T2DM, and to provide information on the potential of efinopegdutide as a novel treatment for NASH. The results showed that treatment with efinopegdutide significantly reduced liver fat content in NAFLD patients compared to semaglutide, suggesting that efinopegdutide may be an effective treatment for NASH.

[0217] Participant Selection This study included men and women aged 18 to 70. Inclusion criteria included a lean fat percentage (LFC) of 10% or higher, as assessed by estimated proton density fraction (MRI-PDFF), and a body mass index (BMI) of 25 kg / m². 2 The criteria included being 50 kg / m2 or less, having a stable weight (based on self-reporting) defined as a weight change of 5% or less for at least 3 months prior to screening, and having no history of T2DM or, if there is a history of T2DM, having an A1C of 8.5% or less at the time of screening and being managed with diet and / or a stable dose of metformin for 3 months prior to screening. Other antihyperglycemic agents were not permitted.

[0218] The main exclusion criteria included: a history or findings of chronic liver disease other than NAFLD or NASH; a known history of cirrhosis (fibrosis stage greater than 3 based on past liver biopsy, or a liver stiffness score greater than 14 kPa based on past FibroScan® assessments (FibroScan® is a non-invasive diagnostic ultrasound device used to measure scarring or fibrosis of the liver resulting from various liver diseases)); and decompensated liver disease (this includes, but is not limited to, a history of ascites, esophageal or gastric variceal bleeding, hepatocellular carcinoma, hepatic encephalopathy, splenomegaly, or spontaneous bacterial peritonitis). This includes; treatment with a GLP-1 receptor agonist or an investigational GLP-1 / glucagon receptor co-agonist within 6 months prior to screening; treatment with thiazolidinediones (i.e., pioglitazone, rosiglitazone) within 6 months prior to screening; a history (past or present) of using prescription weight management medications or commercially available weight loss medications or therapies within 3 months prior to screening; treatment with non-stable doses of antihyperlipidemia therapy for at least 1 month prior to screening; and treatment with non-stable doses of vitamin E exceeding 100 international units (IU) / day for at least 3 months prior to screening.

[0219] Test design This was a Phase 2a, randomized, active comparator-controlled, parallel-group, multi-site, open-label trial of efinopegdutide in patients with NAFLD (Protocol 001; EudraCT:2020-005136-30; NCT: 04944992; ClinicalTrials.gov, June 30, 2021). The trial protocol was approved by the institutional review board or independent ethics committee at each trial site and was conducted in accordance with the ethical principles and applicable regulations for the implementation of appropriate clinical trial practices as defined by the International Conference on Harmonisation (ICH) and the Declaration of Helsinki. Written informed consent was obtained from all participants.

[0220] The study design is shown in Figure 1. The study duration was approximately 32 weeks, including a phased screening period of approximately 4 weeks, an activity-comparative control treatment period of 24 weeks, and approximately 5 weeks of post-treatment follow-up visits after the final dose of the study intervention.

[0221] During the screening period, all participants who met other screening eligibility requirements underwent magnetic resonance imaging-proton density lipid fractionation (MRI-PDFF). Participants who had an LFC of 10% or greater as assessed by MRI-PDFF, as determined by a blinded independent central review (BICR), and who met all other eligibility criteria, proceeded to randomization.

[0222] At baseline (Day 1), eligible participants were stratified according to their diagnosis of comorbid T2DM at the time of randomization and randomly assigned in a 1:1 ratio to receive either 10 mg of efinopegdutide subcutaneously once weekly (open-label) or 1 mg of semaglutide subcutaneously once weekly.

[0223] Participants were randomized to receive either 10 mg of efinopegdutide once weekly or 1 mg of semaglutide once weekly, and subsequently followed a three-step dose-escalation regimen to reach the planned study dose. Participants randomized to the 10 mg of efinopegdutide once weekly group started with a dose of 2.4 mg once weekly from week 1 to week 4; this dose was increased to 5 mg Q1W from week 4 to week 8, and then to 10 mg once weekly from week 8 to week 24. Participants who could not tolerate the 10 mg dose of efinopegdutide once weekly were able to continue the study with a dose of 5 mg of efinopegdutide once weekly. With regard to efinopegdutide, dose reductions below 5 mg once weekly were not permitted, and participants who could not tolerate at least 5 mg of efinopegdutide once weekly were discontinued from the study. Participants randomized to the 1 mg semaglutide once weekly treatment group started with a 0.25 mg once weekly dose from week 1 to week 4; this dose was increased to 0.5 mg once weekly from week 4 to week 8, and then increased to 1 mg once weekly from week 8 to week 24. Participants who could not tolerate 1 mg of semaglutide once weekly were able to continue the study with a 0.5 mg dose of semaglutide once weekly. With regard to semaglutide, dose reductions below 0.5 mg once weekly were not permitted, and participants who could not tolerate at least 0.5 mg of semaglutide once weekly were discontinued from the study treatment.

[0224] Effectiveness evaluation items The primary efficacy evaluation item was the relative reduction rate from the baseline of LFC measured by the MRI-PDFF method after 24 weeks of treatment (evaluated by BICR). The second efficacy evaluation item included the change rates from the baseline of body weight and fasting lipid levels (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides) after 24 weeks of treatment. The following exploratory evaluation items supported the primary efficacy evaluation item: the proportions of participants with a relative reduction from the baseline of LFC of 30% or more, 0% or more, and 70% or more; the proportion of participants who achieved a normal LFC (< 5%); and the mean relative reduction rate from the baseline of LFC based on the weight loss category (weight loss rate from the baseline: ≤ 5%, or more than 5% to 10% or less, and more than 10%).

[0225] Safety evaluation The safety and tolerability of efinopegdutide were monitored throughout the trial by clinical evaluation of adverse events and examination of other research parameters (which included physical examination, 12-lead electrocardiogram (ECG), vital signs, and laboratory safety tests).

[0226] statistical analysis The efficacy analysis population included all randomized participants who received at least one dose of the study intervention and had at least one evaluation.

[0227] In the primary efficacy analysis, the efficacy of efinopegdutide and semaglutide was compared for the relative reduction amount from the baseline of LFC at the 24-week time point. The difference in means (efinopegdutide minus semaglutide) and the associated 90% confidence interval (CI) and p-value were provided based on a longitudinal data analysis (LDA) model.

[0269] . When the one-sided p-value was < 0.05, efinopegdutide was considered superior to semaglutide. The model-based least squares (LS) mean change amount from the baseline for each treatment group and the difference (with CI) between treatment groups at the 24-week time point from the baseline were summarized.

[0228] Percentage changes in body weight and fasting lipid levels were analyzed using the same LDA model described for the primary endpoint.

[0229] The safety analysis population consisted of all randomized participants who received at least one dose of the study intervention.

[0230] The sample size of 65 participants per group provided approximately 99% power to establish that efinopegdutide is superior to semaglutide (one-sided α=0.05), assuming a true treatment difference of approximately 19.4%, a common standard deviation (SD) of 20%, and an interruption rate of 10%.

[0231] result This study was conducted from August 4, 2021 to October 19, 2022, at 79 sites in 16 countries (Argentina, Australia, Canada, France, Israel, Italy, South Korea, Mexico, New Zealand, Poland, Russia, Spain, Taiwan, Turkey, Ukraine, and the United States). Participant allocation is shown in Figure 2. A total of 145 participants were randomly assigned to treatment, and 135 of them completed the study.

[0232] Demographic characteristics and baseline characteristics The two treatment groups had similar demographic and baseline characteristics (Table 1). [Table 1]

[0233] Of the 145 randomized subjects (efinopegdutide: N=72, semaglutide: N=73), the majority of participants (55.2%) were male, with a mean age of 49.5 years and a mean body mass index (BMI) of 34.3 kg / m². 2 The average weight was 97.3 kg, 33.1% of participants had T2DM, and the average LFC was 20.3%.

[0234] Effectiveness At 24 weeks, treatment with efinopegdutide resulted in a significantly greater relative reduction in LFC from baseline (p<0.001) compared with semaglutide; the mean relative reduction in LFC from baseline was 72.7% (90% CI: 66.8, 78.7) with efinopegdutide, compared to 42.3% (36.5, 48.1) with semaglutide (Figure 3A, Table 2). [Table 2] TIFF2026521823000004.tif233166 TIFF2026521823000005.tif26166

[0235] At 24 weeks, the median relative reduction in LFC from baseline was 83.8% for efinopegdutide and 44.4% for semaglutide. At 24 weeks, the proportion of participants achieving normal LFC levels (<5%) was higher with efinopegdutide (66.7%) compared with semaglutide (17.8%). At 24 weeks, the proportion of participants with a relative reduction of 30%, 50%, and 70% or more from baseline was higher with efinopegdutide (81.9%, 77.8%, and 70.8%, respectively) compared with semaglutide (67.1%, 43.8%, and 12.3%, respectively) (Figure 3B).

[0236] In both treatment groups, the mean percentage reduction in LS from baseline at 24 weeks was efinopegdutide (8.5%) versus semaglutide (7.1%) (p=0.085) (Table 2).

[0237] Based on weight loss categories (percentage of weight loss from baseline: ≤5%, >5% to ≤10%, and >10%), the relative percentage of LFC loss from baseline at 24 weeks was greater in the efinopegdutide group (52.4%, 76.6%, and 86.2%, respectively) compared to the semaglutide group (13.4%, 39.6%, and 64.2%, respectively) (Figure 3C).

[0238] In the efinopegdutide group, at 24 weeks, mean LS reductions from baseline were observed for total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides of 15.2%, 8.1%, 13.0%, and 30.9%, respectively (Table 2). In the semaglutide group, at 24 weeks, mean LS reductions from baseline were observed for total cholesterol, low-density lipoprotein cholesterol, and triglycerides of 8.0%, 6.9%, and 23.3%, respectively, while a mean LS reduction from baseline of 3.6% was observed for high-density lipoprotein cholesterol (Table 2).

[0239] safety In the efinopegdutide group, a slightly higher incidence of adverse events and drug-related adverse events was observed, mainly due to an imbalance in gastrointestinal adverse events (Table 3). [Table 3] TIFF2026521823000007.tif120165

[0240] There were no significant differences between the two treatment groups in the incidence of overall adverse events, serious adverse events, or drug-related adverse events (including adverse events leading to discontinuation) (Table 3). The overall profile of adverse events reported by at least four participants was similar between the two treatment groups (Table 3). The incidence of nausea and vomiting was similar between the two treatment groups (Table 3). Three specific adverse events in the broad category of gastrointestinal organs were reported at a higher incidence with efinopegdutide compared with semaglutide: abdominal pain (12.5% ​​vs. 2.7%), epigastric pain (9.7% vs. 1.4%), and constipation (16.7% vs. 5.5%) (Table 3). Compared to semaglutide, efinopegdutide showed a slight increase in mean heart rate from baseline, as well as a slightly larger decrease from baseline in both mean systolic and mean diastolic blood pressure (Figures 4A-4C). No significant imbalance was observed in adverse events thought to be related to changes in heart rate or blood pressure.

[0241] Although there was a slight imbalance in the increase in the number of subjects experiencing alanine aminotransferase (ALT) adverse events, similar reductions from baseline were observed in mean ALT and mean aspartate aminotransferase (AST) levels in both treatment groups, which began by week 4 and persisted throughout the 24-week treatment period (Figure 5A-5B). Treatment with efinopegdutide resulted in a mean increase of 0.2 mg / dL from baseline in fasting plasma glucose levels and a mean change of 0.0% in A1C levels at week 24, while semaglutide resulted in a mean decrease of 11.6 mg / dL in fasting plasma glucose levels and a mean decrease of 0.5% in A1C levels. Treatment with efinopegdutide and semaglutide resulted in mean decreases of 1.0 g / dL and 0.2 g / dL from baseline in hemoglobin levels at week 24. No adverse events associated with hemoglobin reduction were observed in either treatment group. No significant differences were observed in other experimental quality assessments. [Table 4]

[0242] References [Table 5] TIFF2026521823000010.tif248166 TIFF2026521823000011.tif110165

[0243] While the present invention is described herein with reference to the exemplary embodiments, it should be understood that the invention is not limited thereto. Those skilled in the art will be able to use the teachings herein to recognize further modifications and embodiments within that scope. Accordingly, the present invention is limited only by the claims appended herein.

Claims

1. A method for reducing liver fat content (LFC) in individuals suffering from fatty liver disease, The method comprising administering to the individual a dose of efinopegdutide or a pharmaceutically acceptable salt thereof in an amount of about 2 mg to about 10 mg once a week for a period sufficient to reduce the LFC in the individual.

2. The method according to claim 1, wherein the dose is approximately 2 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

3. The method according to claim 1, wherein the dose is 2 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

4. The method according to claim 1, wherein the dose is approximately 4 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

5. The method according to claim 1, wherein the dose is 4 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

6. The method according to claim 1, wherein the dose is approximately 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

7. The method according to claim 1, wherein the dose is 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

8. The method according to claim 1, wherein the dose is approximately 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

9. The method according to claim 1, wherein the dose is 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

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

11. The method according to claim 10, wherein the NASH is pre-cirrhotic NASH.

12. The method according to claim 10, wherein the NASH is cirrhotic NASH.

13. The method according to any one of claims 1 to 12, wherein the period sufficient to reduce the LFC is about 24 weeks.

14. The method according to any one of claims 1 to 13, wherein the individual suffering from fatty liver disease has 5% or more LFC before administration of efinopegdutide or a pharmaceutically acceptable salt thereof.

15. The method according to any one of claims 1 to 13, wherein the individual suffering from fatty liver disease has 10% or more LFC before administration of efinopegdutide or a pharmaceutically acceptable salt thereof.

16. The method according to any one of claims 1 to 13, wherein the individual suffering from fatty liver disease has 15% or more LFC before administration of efinopegdutide or a pharmaceutically acceptable salt thereof.

17. The method according to any one of claims 1 to 13, wherein the individual suffering from fatty liver disease has 20% or more LFC before administration of 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

18. The method according to any one of claims 1 to 17, wherein the LFC in the individual is reduced to less than 5%.

19. The method according to any one of claims 1 to 18, wherein the individual suffers from type 1 diabetes (T1DM) or type 2 diabetes (T2M).

20. The method according to claim 19, wherein the individual has type 2 diabetes (T2M) and is overweight or obese.

21. The method according to any one of claims 1 to 19, wherein the individual is overweight or obese.

22. A method for treating fatty liver disease in individuals who require treatment for fatty liver disease, The method comprising administering to the individual a dose of efinopegdutide or a pharmaceutically acceptable salt thereof in an amount of about 2 mg to about 10 mg once a week for a period sufficient to treat fatty liver disease in the individual.

23. The method according to claim 22, wherein the dose is about 2 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

24. The method according to claim 22, wherein the dose is 2 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

25. The method according to claim 22, wherein the dose is approximately 4 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

26. The method according to claim 22, wherein the dose is 4 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

27. The method according to claim 22, wherein the dose is approximately 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

28. The method according to claim 22, wherein the dose is 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

29. The method according to claim 22, wherein the dose is about 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

30. The method according to claim 22, wherein the dose is 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

31. The method according to any one of claims 22-30, wherein the fatty liver disease is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

32. The method according to claim 31, wherein the NASH is pre-cirrhotic NASH.

33. The method according to claim 31, wherein the NASH is cirrhotic NASH.

34. The method according to any one of claims 22-33, wherein the period sufficient to treat the fatty liver disease is about 24 weeks.

35. The method according to any one of claims 22-34, wherein the individual suffering from fatty liver disease has a liver fat content (LFC) of 5% or more before administration of efinopegdutide or a pharmaceutically acceptable salt thereof.

36. The method according to any one of claims 22-34, wherein the individual suffering from fatty liver disease has 10% or more LFC before administration of efinopegdutide or a pharmaceutically acceptable salt thereof.

37. The method according to any one of claims 22-34, wherein the individual suffering from fatty liver disease has 15% or more LFC before administration of efinopegdutide or a pharmaceutically acceptable salt thereof.

38. The method according to any one of claims 22-34, wherein the individual suffering from fatty liver disease has 20% or more LFC before administration of 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

39. The method according to any one of claims 22-38, wherein the LFC in the individual is reduced to less than 5%.

40. The method according to any one of claims 22-39, wherein the individual suffers from type 1 diabetes (T1DM) or type 2 diabetes (T2M).

41. The method according to claim 40, wherein the individual has type 2 diabetes (T2M) and is overweight or obese.

42. The method according to any one of claims 22-40, wherein the individual is overweight or obese.

43. A method for reducing liver fat content (LFC) to less than 5% in individuals with elevated LFC, comprising the following steps in the following order: (a) The individual is administered approximately 2.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (b) The individual is administered approximately 5.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (c) The individual is administered approximately 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for a period sufficient to reduce the LFC to less than 5%; The method, including the method described above.

44. The following steps are in the following order: (a) The individual is administered 2.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (b) The individual is administered 5.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (c) The individual is administered 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for a period sufficient to reduce the LFC to less than 5%; The method according to claim 43, including the method described in claim 43.

45. A method for reducing liver fat content (LFC) to less than 5% in individuals with elevated LFC, comprising the following steps in the following order: (a) The individual is administered approximately 2.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (b) The individual is administered approximately 4.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 48 weeks; The method, including the method described above.

46. The following steps are in the following order: (a) The individual is administered 2.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (b) The individual is administered 4.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 48 weeks; The method according to claim 45, including the method described in claim 45.

47. A method for reducing liver fat content (LFC) to less than 5% in individuals with elevated LFC, comprising the following steps in the following order: (a) The individual is administered approximately 2.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (b) The individual is administered approximately 4.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (c) The individual is administered approximately 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 44 weeks; The method, including the method described above.

48. The following steps are in the following order: (a) The individual is administered 2.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (b) The individual is administered 4.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (c) The individual is administered 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 44 weeks; The method according to claim 47, including the method described in claim 47.

49. A method for reducing liver fat content (LFC) to less than 5% in individuals with elevated LFC, comprising the following steps in the following order: (a) The individual is administered approximately 2.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (b) The individual is administered approximately 4.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (c) The individual is administered approximately 7.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (d) The individual is administered approximately 10.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 40 weeks; The method, including the method described above.

50. The following steps are in the following order: (a) The individual is administered 2.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (b) The individual is administered 4.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (c) The individual is administered 7.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (d) The individual is administered 10.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 40 weeks; The method according to claim 49, including the method described in claim 49.

51. The method according to any one of claims 43-50, wherein the individual whose LFC is elevated is suffering from fatty liver disease.

52. The method according to claim 51, wherein the fatty liver disease is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

53. The method according to claim 52, wherein the NASH is pre-cirrhotic NASH.

54. The method according to claim 52, wherein the NASH is cirrhotic NASH.

55. The method according to claim 43 or claim 44, wherein the period sufficient to reduce the liver fat to less than 5% is approximately 24 weeks.

56. The method according to any one of claims 43-55, wherein the individual suffering from fatty liver disease has 5% or more LFC before commencing the method.

57. The method according to any one of claims 43-55, wherein the individual suffering from fatty liver disease has 10% or more LFC before commencing the method.

58. The method according to any one of claims 43-55, wherein the individual suffering from fatty liver disease has 15% or more LFC before commencing the method.

59. The method according to any one of claims 43-55, wherein the individual suffering from fatty liver disease has 20% or more LFC before commencing the method.

60. The method according to any one of claims 43 to 59, wherein the individual has type 1 diabetes (T1DM) or type 2 diabetes (T2M).

61. The method according to claim 60, wherein the individual has type 2 diabetes (T2M) and is overweight or obese.

62. The method according to any one of claims 43-60, wherein the individual is overweight or obese.

63. A method for treating fatty liver disease in individuals requiring treatment, comprising the following steps in the following order: (a) The individual is administered approximately 2.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (b) The individual is administered approximately 5.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (c) The individual is administered approximately 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for a period sufficient to treat fatty liver disease in the individual; The method, including the method described above.

64. The following steps are in the following order: (a) The individual is administered 2.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (b) The individual is administered 5.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (c) The individual is administered 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for a period sufficient to reduce the LFC to less than 5%; The method according to claim 63, including the method described in claim 63.

65. A method for treating fatty liver disease in individuals requiring treatment, comprising the following steps in the following order: (a) The individual is administered approximately 2.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (b) The individual is administered approximately 4.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 48 weeks; The method, including the method described above.

66. The following steps are in the following order: (a) The individual is administered 2.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (b) The individual is administered 4.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 48 weeks; The method according to claim 65, including the method described in claim 65.

67. A method for treating fatty liver disease in individuals requiring treatment, comprising the following steps in the following order: (a) The individual is administered approximately 2.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (b) The individual is administered approximately 4.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (c) The individual is administered approximately 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 44 weeks; The method, including the method described above.

68. The following steps are in the following order: (a) The individual is administered 2.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (b) The individual is administered 4.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (c) The individual is administered 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 44 weeks; The method according to claim 67, including the method described in claim 67.

69. A method for treating fatty liver disease in individuals requiring treatment, comprising the following steps in the following order: (a) The individual is administered approximately 2.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (b) The individual is administered approximately 4.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (c) The individual is administered approximately 7.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (d) The individual is administered approximately 10.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 40 weeks; The method, including the method described above.

70. The following steps are in the following order: (a) The individual is administered 2.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (b) The individual is administered 4.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; (c) The individual is administered 7.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for four weeks; and, (d) The individual is administered 10.0 mg of efinopegdutide or a pharmaceutically acceptable salt thereof once a week for 40 weeks; The method according to claim 69, including the method described in claim 69.

71. The method according to any one of claims 63-70, wherein the individual suffering from fatty liver disease has an elevated liver fat content (LFC).

72. The method according to claim 71, wherein the fatty liver disease is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

73. The method according to claim 72, wherein the NASH is pre-cirrhotic NASH.

74. The method according to claim 72, wherein the NASH is cirrhotic NASH.

75. The method according to claim 63 or claim 64, wherein the period sufficient to treat fatty liver disease in the individual is approximately 24 weeks.

76. The method according to any one of claims 63-75, wherein the individual suffering from fatty liver disease has 5% or more LFC before commencing the method.

77. The method according to any one of claims 63-75, wherein the individual suffering from fatty liver disease has 10% or more LFC before commencing the method.

78. The method according to any one of claims 63-75, wherein the individual suffering from fatty liver disease has 15% or more LFC before commencing the method.

79. The method according to any one of claims 63-75, wherein the individual suffering from fatty liver disease has 20% or more LFC before commencing the method.

80. The method according to any one of claims 63 to 79, wherein the individual suffers from type 1 diabetes (T1DM) or type 2 diabetes (T2M).

81. The method according to claim 80, wherein the individual has type 2 diabetes (T2M) and is overweight or obese.

82. The method according to any one of claims 63-80, wherein the individual is overweight or obese.

83. The use of efinopegdutide or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical product for reducing liver fat content (LFC) to less than 5% in individuals with elevated LFC.

84. The use according to claim 83, wherein the pharmaceutical product comprises about 2 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

85. The use according to claim 83, wherein the pharmaceutical product comprises 2 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

86. The use according to claim 83, wherein the pharmaceutical product comprises about 4 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

87. The use according to claim 83, wherein the pharmaceutical product comprises 4 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

88. The use according to claim 83, wherein the pharmaceutical product comprises about 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

89. The use according to claim 83, wherein the pharmaceutical product comprises 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

90. The use according to claim 83, wherein the pharmaceutical product comprises about 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

91. The use according to claim 83, wherein the pharmaceutical product comprises 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

92. The use of efinopegdutide or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical for the treatment of fatty liver disease in an individual who requires treatment for fatty liver disease.

93. The use according to claim 92, wherein the fatty liver disease is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

94. The use according to claim 93, wherein the NASH is pre-cirrhotic NASH.

95. The use according to claim 93, wherein the NASH is liver cirrhosis-related NASH.

96. The use according to claim 93, wherein the individual suffering from fatty liver disease has a liver fat content (LFC) of 5% or more before administration of efinopegdutide or a pharmaceutically acceptable salt thereof.

97. The use according to any one of claims 92-96, wherein the pharmaceutical product comprises about 2 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

98. The use according to any one of claims 92-96, wherein the pharmaceutical product comprises 2 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

99. The use according to any one of claims 92-96, wherein the pharmaceutical product comprises about 4 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

100. The use according to any one of claims 92-96, wherein the pharmaceutical product comprises 4 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

101. The use according to any one of claims 92-96, wherein the pharmaceutical product comprises about 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

102. The use according to any one of claims 92-96, wherein the pharmaceutical product comprises 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

103. The use according to any one of claims 92-96, wherein the pharmaceutical product comprises about 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

104. The use according to any one of claims 92-96, wherein the pharmaceutical product comprises 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof.

105. Efinopegdutide or a pharmaceutically acceptable salt thereof for reducing liver fat content (LFC) to less than 5% in individuals with elevated LFC.

106. The efinopegdutide or pharmaceutically acceptable salt thereof according to claim 105, wherein the efinopegdutide or a pharmaceutically acceptable salt thereof is provided in a dose of about 2 mg.

107. The efinopegdutide or pharmaceutically acceptable salt thereof according to claim 105, wherein the efinopegdutide or a pharmaceutically acceptable salt thereof is provided in a dose of 2 mg.

108. The efinopegdutide or pharmaceutically acceptable salt thereof according to claim 105, wherein the efinopegdutide or a pharmaceutically acceptable salt thereof is provided in a dose of about 4 mg.

109. The efinopegdutide or pharmaceutically acceptable salt thereof according to claim 105, wherein the efinopegdutide or a pharmaceutically acceptable salt thereof is provided in a dose of 4 mg.

110. The efinopegdutide or pharmaceutically acceptable salt thereof according to claim 105, wherein the efinopegdutide or a pharmaceutically acceptable salt thereof is provided in a dose of about 7 mg.

111. The efinopegdutide or pharmaceutically acceptable salt thereof according to claim 105, wherein the efinopegdutide or a pharmaceutically acceptable salt thereof is provided in a dose of 7 mg.

112. The efinopegdutide or pharmaceutically acceptable salt thereof according to claim 105, wherein the efinopegdutide or a pharmaceutically acceptable salt thereof is provided in a dose of about 10 mg.

113. The efinopegdutide or pharmaceutically acceptable salt thereof according to claim 105, wherein the efinopegdutide or a pharmaceutically acceptable salt thereof is provided in a dose of 10 mg.

114. A pharmaceutical composition comprising approximately 2 mg of efinopegdutide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

115. A pharmaceutical composition comprising 2 mg of efinopegdutide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

116. A pharmaceutical composition comprising approximately 4 mg of efinopegdutide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

117. A pharmaceutical composition comprising 4 mg of efinopegdutide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

118. A pharmaceutical composition comprising approximately 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

119. A pharmaceutical composition comprising 7 mg of efinopegdutide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

120. A pharmaceutical composition comprising approximately 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

121. A pharmaceutical composition comprising 10 mg of efinopegdutide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

122. The method according to any one of claims 1 to 82, wherein the efinopegdutide or a pharmaceutically acceptable salt thereof is administered subcutaneously.

123. The use according to any one of claims 83-104, wherein the pharmaceutical product is for subcutaneous administration.

124. Efinopegdutide or a pharmaceutically acceptable salt thereof according to any one of claims 105-113, for subcutaneous administration.

125. A pharmaceutical composition according to any one of claims 114-121 for subcutaneous administration.

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