Dual GLP-1 and glucagon receptor agonist for the treatment of mash and cirrhosis

Abstract

Provided herein are methods for preventing or treating a metabolic liver disease, such as metabolic dysfunction-associated steatohepatitis (MASH), MASH-associated liver fibrosis and / or cirrhosis, MASH-associated liver cirrhosis, MASH-associated compensated liver cirrhosis, or MASH and compensated cirrhosis, by administering to a patient in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound comprising: H-H-Ac4c-QGTFTSDYSKYLDERAAKDFI-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-WLESA-NH 2 .

Description

[0001] Dual GLP-1 and Glucagon Receptor Agonist for the Treatment of MASH and Cirrhosis

[0002] BACKGROUND OF THE INVENTION

[0003] Fatty liver disease is a chronic condition characterized by excessive hepatic triglyceride deposition. It can be due to multiple causes, the major two forms being related to immoderate alcohol consumption or metabolic dysregulation in the absence of excessive alcohol intake. The latter has initially been termed nonalcoholic fatty liver disease (NAFLD) but is now commonly referred as metabolic dysfunction-associated steatotic liver disease (MASLD). It is commonly linked to the metabolic syndrome and its individual components (obesity, type 2 diabetes mellitus, dyslipidemia and hypertension). The spectrum of MASLD ranges from isolated hepatic steatosis also referred to as non-alcoholic fatty liver (NAFL) through metabolic dysfunction-associated steatohepatitis (MASH) characterized by hepatic triglyceride accumulation, hepatocellular injury and lobular inflammation, to liver fibrosis. Of note, fibrosis can be present to various degrees in patients with MASLD. The presence of MASLD with fibrosis is a strong risk factor for development of cirrhosis and potentially hepatocellular carcinoma.

[0004] MASLD has a prevalence of about 25% worldwide and is rapidly becoming the most common liver disease. While simple hepatic steatosis can have a benign non-progressive course, 46.9% of patients with MASLD are likely to progress to MASH. In the United States, MASH is believed to be the most common cause of liver cirrhosis. Chronic liver disease and cirrhosis are the 11th leading cause of death in the United States according to CDC. Patients with MASH are also at increased risk of hepatocellular carcinoma (HCC), even in the absence of cirrhosis. By 2030, the incidence of MASH is projected to increase by up to 56%. Furthermore, the incidence of MASLD-related HCC is projected to significantly increase by 2030, suggesting increases of 82%, 117% and 122% from 2016 in China, France and the USA, respectively.

[0005] WO 2015 / 055801 and WO 2015 / 055802 (incorporated herein by reference for all they teach and disclose) disclose glucagon analogue peptides having increased selectivity for the GLP-1 receptor as compared to human glucagon. Methods for the treatment of obesity, excess weight and diabetes on the basis of these peptides are also disclosed. Chronic liver disease and the consequences of end-stage liver disease are increasing globally despite improved prevention. This is due to the emerging epidemics of obesity and metabolic syndrome that are leading to an increased incidence of MASH. Compensated MASH cirrhosis is considered an advanced stage of MASH disease caused by ongoing metabolic dysfunction, where long-term liver inflammation has already caused significant hepatocyte damage with advanced progression of fibrosis to cirrhosis. The risk of transition to decompensated cirrhosis increases overtime, with manifestation of severe and life-threating complications like ascites, bleeding, and encephalopathy. To date, pharmacological therapy for MASH cirrhosis is very limited and usually non-liver-specific pharmacological management including weight loss, lifestyle changes, and pharmacotherapies associated with metabolic syndrome components is followed. Therefore, there is a need for treatment for MASH, specifically, MASH-associated liver cirrhosis, MASH-associated compensated liver cirrhosis (MASH cF4), MASH and compensated cirrhosis, or MASH-associated liver fibrosis and cirrhosis that comprises administration of a (long acting) medicament that preferably needs to be administered less frequently (e.g. weekly). At the same time, the treatment should still be effective, e.g. as determined by the improvement of a patient's cirrhosis and mild, moderate, and severe hepatic impairment or other relevant biomarkers (e.g. liver fat content reduction or change of liver enzymes).

[0006] SUMMARY OF THE INVENTION

[0007] Provided herein is the medical use of a long-acting dual GLP-1 / glucagon receptor agonist (Compound 1) (survodutide) in the prevention and / or slowing progression of and / or treatment of metabolic dysfunction-associated steatohepatitis (MASH), MASH-associated liver fibrosis and / or cirrhosis, MASH-associated liver cirrhosis (MASH cF4), MASH-associated compensated liver cirrhosis, or MASH and compensated cirrhosis.

[0008] The present invention, in one embodiment, is directed to Compound 1, i.e. H-H-Ac4c- QGTFTSDYSKYLDERAAKDFI-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-WLESA- / VH2 for use in a method for preventing or treating (e.g. slowing disease progression of metabolic dysfunction- associated steatohepatitis (MASH), MASH-associated liver fibrosis and / or cirrhosis, MASH- associated liver cirrhosis, MASH-associated compensated liver cirrhosis, or MASH and compensated cirrhosis.

[0009] The present invention includes a method for preventing or treating a metabolic liver disease, comprising administering to a patient in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound comprising: H-H-Ac4c-QGTFTSDYSKYLDERAAKDFI- K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-WLESA- / VH2(Compound 1). In embodiments, the method includes wherein the metabolic liver disease is MASH-associated liver cirrhosis, MASH- associated compensated liver cirrhosis (MASH cF4), MASH and compensated cirrhosis, or MASH- associated liver fibrosis and cirrhosis. In certain embodiments, the metabolic liver disease is MASH- associated liver cirrhosis which is mildly decompensated. In certain embodiments, the metabolic liver disease is MASH-associated compensated liver cirrhosis (MASH cF4).

[0010] In some embodiments of the present invention, the patient has MASH-associated compensated liver cirrhosis (MASH cF4) with a diagnosis of a Child-Turcotte-Pugh (CTP) cirrhosis class of A, B, or C; or a diagnosis of Child-Turcotte-Pugh (CTP) cirrhosis class of A or B; or a diagnosis of Child-Turcotte-Pugh (CTP) cirrhosis class of B or C; or a diagnosis of a Child-Turcotte-Pugh (CTP) cirrhosis class of A; or a diagnosis of a Child-Turcotte-Pugh (CTP) cirrhosis class of B.

[0011] In some embodiments, the methods of the invention reduce the absolute and / or percentage of the patient's liver fat. In embodiments, the percentage of the patient's liver fat is reduced by at least 30% from a baseline measurement, as measured by magnetic resonance imaging proton density fat fraction measurement.

[0012] In some embodiments, the methods of the invention reduce the patient's liver stiffness. In some embodiments, the patient's liver stiffness is reduced by at least 0.5kPa or more, or at least 0.8 kPa or more, from a baseline measurement, as measured by change in kPa via magnetic resonance elastography, and / or by transient elastography (FibroScan®).

[0013] In some embodiments, the methods of the invention reduce patient's Enhanced Liver Fibrosis (ELF) score. The patient's Enhanced Liver Fibrosis (ELF) score, in some embodiments, is reduced by at least 0.4 or more, or at least 0.5 or more.

[0014] In some embodiments, the methods of the invention reduce the patient's N-terminal type III collagen propeptide (Pro-C3). In some embodiments, the patient's Pro-C3 is reduced by a percentage change of about 10% or more, or a percentage change of about 20% or more, from a baseline measurement.

[0015] In some embodiments, the patient is diagnosed as being overweight or obese and / or is diagnosed as having a BMI as 27 kg / m2or greater. In some embodiments, the patient's dosage of Compound 1 for the methods of the invention is weekly for at least 28 weeks. In some embodiments, a dose escalation scheme is applied. In more specific embodiments, the dose is escalated over 20 weeks or longer to reach the maintenance dose. In some embodiments, the maintenance dose is 4.8 mg or 6.0 mg. In some embodiments, the patient's dose escalation for the methods of the invention is performed from 0.3 mg Compound 1 from Day 1 to 2.4, 4.8 or 6 mg at the start of Week 23. In some embodiments, the patient's dosage from the start of Week 24 to the start of Week 28 is 6 mg.

[0016] Further aspects and embodiments of the present invention will become apparent from the disclosure below.

[0017] BRI EF DESCRI PTION OF DRAWI NGS

[0018] Fig. 1 shows the trial design for (top) a single-dose pharmacokinetic evaluation of survodutide 0.3 mg subcutaneously in participants with compensated and decompensated cirrhosis (Child-Pugh class A, B, or C) and healthy participants with or without overweight / obesity matched for age, sex, and weight; and (bottom) open-label therapy delivered once-weekly subcutaneously with doses escalated to 6.0 mg over 24 weeks, then maintained for 4 weeks, in participants with overweight or obesity with or without cirrhosis and Child-Pugh class A or B . Abbreviations: MRE, magnetic resonance elastography; MRI, magnetic resonance imaging; PK, pharmacokinetics. (Example 1, Part B)

[0019] Fig. 2 shows changes in Liver Fat Content (Panel A), Liver Stiffness (Panel B), Enhanced Liver Fibrosis Score (Panel C), and Pro-C3 Levels (Panel D) with Open-Label Therapy (Treated Set). (Example 1, Part B)

[0020] Fig. 3 shows the percentage of participants who demonstrated greater than or equal to 30% reduction in liver fat as measured by MRI-PDFF after 28 weeks. (Example 1, Part B)

[0021] Fig. 4 shows the mean percent change from baseline for liver volume for participants after 28 weeks; descriptive statistics of % change in liver volume from baseline to week 28 by MRI T1 in the treated set (all participants who received >1 dose of survodutide) using on- and off-treatment data. (Example 1, Part B) DETAILED DESCRI PTION OF THE I NVENTION

[0022] Unless otherwise defined herein, scientific and technical terms used herein shall have the meanings that are commonly understood by those of ordinary skill in the art.

[0023] Throughout this specification, the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated integer or component, or of a stated group of integers or components, but not the exclusion of any other integer or component or group of integers or components.

[0024] The singular forms "a," "an," and "the" include the plurals unless the context clearly dictates otherwise.

[0025] The term "including" is used to mean "including but not limited to." "Including" and "including but not limited to" are used interchangeably.

[0026] The terms "patient", "subject," and "individual" may be used interchangeably and refers to a human.

[0027] Reference to Compound 1 comprises Compound 1 in neutral or charged states. Charged states are for example present in the form of salts, e.g. pharmaceutically acceptable salts, or in solutions, specifically in aqueous solutions.

[0028] The term "pharmaceutically acceptable salt" is intended to indicate a salt which is not harmful to a patient or subject to which the salt in question is administered. It may suitably be a salt chosen, e.g., among acid addition salts and basic salts. Examples of acid addition salts include chloride salts, citrate salts and acetate salts. Examples of basic salts include salts where the cation is selected among alkali metal cations, such as sodium or potassium ions, alkaline earth metal cations, such as calcium or magnesium ions, as well as substituted ammonium ions, such as ions of the type N(R1)(R2)(R3)(R4)+, where Rl, R2, R3 and R4 independently will typically designate hydrogen, optionally substituted Ci.6-al kyl or optionally substituted C2.6-alkenyl. Examples of relevant Ci.6-al kyl groups include methyl, ethyl, 1-propyl and 2-propyl groups. Examples of C2.6-alkenyl groups of possible relevance include ethenyl, 1-propenyl and 2-propenyl. Other examples of pharmaceutically acceptable salts are described in "Remington's Pharmaceutical Sciences", 17th edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985 (and more recent editions thereof). Throughout this specification, the conventional one letter and three letter codes for naturally occurring amino acids are used, as well the abbreviation for the non-proteinogenic amino acid Ac4c (1-amino-cyclobutanecarboxylic acid). The term "isoGlu" refers to a y-glutamic acid unit.

[0029] Unless otherwise indicated, reference is made to the L-isomeric forms of the amino acids in question.

[0030] Abbreviations:

[0031] NAFL: non-alcoholic fatty liver

[0032] MASLD: metabolic dysfunction-associated steatotic liver disease

[0033] NAFLD: non-alcoholic fatty liver disease

[0034] NAS: NAFLD activity score

[0035] MASH: metabolic dysfunction associated steatohepatitis

[0036] MRI-PDFF: magnetic resonance imaging proton density fat fraction

[0037] The term "therapeutically effective amount" as used herein in the context of the herein-described methods of treatment or other therapeutic interventions according to the invention refers to an amount that is sufficient to cure, ameliorate, alleviate, slow progression of, or partially arrest the clinical manifestations of the particular disease, disorder or condition that is the object of the treatment or other therapeutic intervention in question e.g. as measured by established clinical endpoints or other biomarkers (established or experimental), including liver biopsies. A therapeutically relevant amount may be determined empirically by one skilled in the art based on the indication being treated or prevented and the subject to whom the therapeutically relevant amount is being administered. For example, the skilled worker may measure one or more of the clinically relevant indicators of bioactivity described herein, e.g. enhanced liver fibrosis test (ELF) as a surrogate of histological changes in fibrosis, liver stiffness by MRE, or MAS (MAFLD activity score). The skilled worker may determine a clinically relevant amount through in vitro or in vivo measurements. Other exemplary measures include fibrosis markers (serum or plasma), weight loss, change in histological scores of MASH, cirrhosis or fibrosis, liver fat content reduction, liver stiffness, ELF score, Pro-C3 score, and / or change of liver enzymes. The ELF score is an accepted noninvasive biomarker blood test for prognostic risk assessment in advanced MASH. The ELF Score can help identify patients with advanced fibrosis (F3 or F4) at risk of progressing to cirrhosis and liver-related events (LREs), which is calculated according to known methods in the art, e.g., by measurement of an ECM marker set consisting of tissue inhibitor of metalloproteinases 1 (TIMP-1), amino-terminal propeptide of type III procollagen (PIIINP) and hyaluronic acid (HA).

[0038] An amount adequate to accomplish any or all of these effects is defined as a therapeutically effective amount. The administered amount and the method of administration can be tailored to achieve optimal efficacy. An amount effective for a given purpose will depend, inter alia, on the severity of the disease, disorder or condition that is the object of the particular treatment or other therapeutic intervention, on the body weight and general condition of the subject in question, on diet, on possible concurrent medication, and on other factors well known to those skilled in the medical arts.

[0039] The terms "treatment" and grammatical variants thereof (e.g. "treated", "treating", "treat") as employed in the present context refer to an approach for obtaining beneficial or desired clinical results. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilization (i.e. not worsening) of state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. Beneficial or desired results from the treatment can also mean prolonging survival relative to expected survival time if not receiving treatment or prolonging the time to required liver transplantation. A subject (a human) in need of treatment may thus be a subject already afflicted with the disease or disorder in question. The term "treatment" includes inhibition or reduction of an increase in severity of a pathological state or symptoms (e.g. progression to decompensated cirrhosis (e.g. ascites, hepatic encephalopathy, portal hypertension-related upper gastrointestinal bleeding and varices), progression to clinically significant portal hypertension, progression of fibrosis or worsening of MASH, e.g. increase of NAS, progression to liver failure and need for liver transplant, liver death) relative to the absence of treatment, and is not necessarily meant to imply complete cessation of the relevant disease, disorder or condition.

[0040] The terms "prevention" and grammatical variants thereof (e.g., "prevented", "preventing", "prevent") as employed in the present context refer to an approach for hindering or preventing the development of, or altering the pathology of, a condition, disease or disorder. Accordingly, "prevention" may refer to prophylactic or preventive measures. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, prevention or slowing of symptoms, progression or development of a disease, whether detectable or undetectable. A subject (e.g. a human) in need of "prevention" may thus be a subject not yet afflicted with the disease or disorder in question. The term "prevention" thus includes inhibiting or slowing the onset of disease relative to the absence of treatment and is not necessarily meant to imply permanent prevention of the relevant disease, disorder or condition. In a more specific aspect prevention refers to prevention of progression of MASH (e.g. progression to cirrhosis, progression of fibrosis or worsening of NASH, e.g. increase of NAS, progression to decompensated cirrhosis or progression to hepatocellular carcinoma (HCC).

[0041] All publications, patents and published patent applications referred to in this application are incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control.

[0042] Therapeutic uses

[0043] According to a first aspect of the invention, provided is a compound comprising or consisting of H-H- Ac4c-QGTFTSDYSKYLDERAAKDFI-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-WLESA- NH2(Compound 1, SEQ ID NO.: 1), and pharmaceutical compositions thereof for the treatment of a liver disease. Compound 1 is also referred to as survodutide (INN name). Peptidic compounds derived from glucagon that potently activate both the GLP-1 and the glucagon receptor are disclosed in WO 2015 / 055801, which is incorporated herein by reference for all it teaches and discloses.

[0044] In embodiments, the liver disease can be any one of, or a combination of, MASH-associated liver cirrhosis, MASH-associated compensated liver cirrhosis (MASH cF4), MASH and compensated cirrhosis, or MASH-associated liver fibrosis and cirrhosis. In embodiments, the MASH associated liver cirrhosis is decompensated, or mildly decompensated.

[0045] In a further related aspect the invention relates to the use of Compound 1 or a pharmaceutical composition comprising Compound 1 in a method of treating liver disease in a patient. In embodiments, the liver disease can be any one of, or a combination of, MASH-associated liver cirrhosis, MASH-associated compensated liver cirrhosis (MASH cF4), MASH and compensated cirrhosis, or MASH-associated liver fibrosis and cirrhosis comprising administering Compound 1 or a pharmaceutical composition comprising Compound 1. In embodiments, the MASH associated liver cirrhosis is decompensated, or mildly decompensated.

[0046] In a more specific aspect the invention relates to slowing down progression of the liver disease in a patient. The liver disease may or may not be associated with different stages of liver fibrosis. In a specific aspect, the patient is diagnosed as being overweight or obese. In another specific aspect, the patient has a BMI greater than or equal to 27 kg / m2.

[0047] The major pathways in MASH disease progression include those involved in metabolic dysfunction in the hepatocyte, activation of hepatic stellate cells, and activation and recruitment of macrophages leading to hepatic inflammation and fibrosis. Advanced fibrosis and cirrhosis are characterized by extensive collagen deposition and remodeling of the extracellular matrix. Additionally, there is evidence which suggests that lipotoxic intermediates of fatty acids likely contribute to the etiology of MASH.

[0048] Liver disease includes MASH-associated liver cirrhosis, MASH-associated compensated liver cirrhosis (MASH cF4), MASH and compensated cirrhosis, or MASH-associated liver fibrosis and cirrhosis. MASH-associated cirrhosis develops after a long period of inflammation that results in replacement of the healthy liver parenchyma with fibrotic tissue and regenerative nodules, leading to portal hypertension. Patients with FO MASH have no fibrosis whereas Fl MASH patients show perisinusoidal or periportal fibrosis; patients with F2 MASH show perisinusoidal and periportal fibrosis, F3 show bridging fibrosis and F4 MASH have cirrhosis. During compensated cirrhosis, severe scarring (fibrosis) restricts or blocks blood flow through the portal vein, leasing to portal hypertension. Elevated portal pressure may be mildly elevated, then as it increases, lead to development of varices (enlarged veins) or ascites (accumulation of fluid in the abdomen. Clinically significant portal hypertension (defined as a hepatic venous pressure gradient of greater than or equal to 10 mmHg) can cause formation of varices on the esophagus or other Gl organs and / or decreased liver function. Decompensated cirrhosis is defined by the presence of ascites, variceal bleeding, encephalopathy, and / or jaundice.

[0049] Cirrhosis in some aspects can be defined as liver stiffness >15 kPa measured by vibration-controlled transient elastography (VCTE) with FibroScan® (transient elastography (TE)).

[0050] The disease evolves from an asymptomatic phase (compensated cirrhosis) to a symptomatic phase (decompensated cirrhosis), the complications of which often result in hospitalization, impaired quality of life, and high mortality. Progressive portal hypertension, systemic inflammation, and liver failure drive disease outcomes. The natural history of cirrhosis is characterized by a silent course until decompensation, when the progressive deterioration of liver function causes a rapid decline of life expectancy.

[0051] The early stage of the disease is usually referred to as 'compensated cirrhosis', while the late one, defined by the appearance of ascites, bleeding, encephalopathy or jaundice, is termed 'decompensated cirrhosis'. Due to the strikingly different rates of survival, compensated and decompensated cirrhosis are considered two distinct clinical entities.

[0052] The rising prevalence of obesity-related disorders has contributed to a rapid increase in the prevalence of MASH. The proportion of MASH patients who progressed to fibrosis ranged from 22.5% to 50%. The proportion of patients who developed cirrhosis within 15 years of follow-up ranged from 7.1% (Denmark) to 10.8%, and who progressed to hepatocellular carcinoma (HCC) from 12.8% (US) to 30.9% (Japan). The frequency of MASH as the primary indication for liver transplantation increased over time from 0% in 2000 to 23.4% in 2012. Currently MASH is the leading cause of liver transplant in women and the fastest growing cause of liver transplant overall.

[0053] Patients with MASH have no specific symptoms for a long period of time but may progress to liver cirrhosis or hepatocellular carcinoma (HCC). The risk of progression from MASH to cirrhosis is particularly high in patients with advanced fibrosis. MASLD -related cirrhosis is an important risk factor in the further development of the disease into MASLD - related HCC. However, MASLD - related HCC may also develop in MASH patients without cirrhosis.

[0054] In specific aspects, efficacy for the methods of the present invention can be measured in any way known in the art, and in some aspects, include one or more of change from baseline (screening) to week 28 in liver fat content (by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) or FibroScan® Controlled Attenuation Parameter (CAP)), liver stiffness (by magnetic resonance elastography or measured by vibration-controlled transient elastography (VCTE) with FibroScan)), liver volume (MRI using Tl-weighted images), body weight, waist circumference, liver fibrosis markers (N-terminal type III collagen propeptide (Pro-C3) or Enhanced Liver Fibrosis (ELF) score). In specific aspects, the change from baseline for one or more aspects indicate improvement in the patient's liver disease. In specific aspects, the patient has MASH-associated compensated liver cirrhosis (MASH cF4) with a Child-Turcotte-Pugh (CTP) cirrhosis class of A, B, or C; or MASH-associated compensated liver cirrhosis (MASH cF4) with a Child-Turcotte-Pugh (CTP) cirrhosis class of B or B; or MASH-associated compensated liver cirrhosis (MASH cF4) with a Child-Turcotte-Pugh (CTP) cirrhosis class of B or C; or MASH-associated compensated liver cirrhosis (MASH cF4) with a Child-Turcotte-Pugh (CTP) cirrhosis class of A, or MASH-associated compensated liver cirrhosis (MASH cF4) with a Child-Turcotte-Pugh (CTP) cirrhosis class of B.

[0055] In more detail, The Child-Pugh scoring system (also known as the Child-Pugh-Turcotte or the Child- Turcotte-Pugh (CTP) score) was designed to predict mortality in cirrhosis patients. Originally conceptualized by Child and Turcotte in 1964 to guide the selection of patients who would benefit from elective surgery for portal decompression, it broke down patients into three categories (herein also referred to as "cirrhosis class"): A - good hepatic function, B - moderately impaired hepatic function, and C - advanced hepatic dysfunction. Their original scoring system used five clinical and laboratory criteria to categorize patients: serum bilirubin, serum albumin, ascites, neurological disorder, and clinical nutrition status. The scoring system was modified later by Pugh et al., substituting prothrombin time for clinical nutrition status. Additionally, they introduced variable points for each criterion based on increasing severity:

[0056] Encephalopathy: None = 1 point, Grade 1 and 2 = 2 points, Grade 3 and 4 = 3 points

[0057] Ascites: None = 1 point, slight = 2 points, moderate = 3 points

[0058] Bilirubin: under 2 mg / ml = 1 point, 2 to 3 mg / ml = 2 points, over 3 mg / ml = 3 points

[0059] Albumin: greater than 3.5mg / ml = 1 point, 2.8 to 3.5mg / ml = 2 points, less than 2.8mg / ml = 3 points

[0060] Prothrombin Time (PT) (sec prolonged): less than 4 sec = 1 point, 4 to 6 sec = 2 points, over 6 sec = 3 points. Frequently international normalized ratio (INR) will be used as a substitute for PT, with INR under 1.7 = 1 point, INR 1.7 to 2.2 = 2 points, INR above 2.2 = 3 points.

[0061] The severity of cirrhosis:

[0062] Child-Pugh A: 5 to 6 points

[0063] Child-Pugh B: 7 to 9 points

[0064] Child-Pugh C: 10 to 15 points The severity of hepatic encephalopathy is graded based on the level of impairment of autonomy, changes in consciousness, intellectual function, behavior, and dependence on therapy.

[0065] Grade 0 - No obvious changes other than a potentially mild decrease in intellectual ability and coordination

[0066] Grade 1 - Trivial lack of awareness; euphoria or anxiety; shortened attention span; impaired performance of addition or subtraction

[0067] Grade 2 - Lethargy or apathy; minimal disorientation for time or place; subtle personality change; inappropriate behavior

[0068] Grade 3 - Somnolence to semistupor, but responsive to verbal stimuli; confusion; gross disorientation

[0069] Grade 4 - Coma

[0070] In embodiments, the dosage of the compounds of the present invention for the methods of the invention is weekly for at least 2 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, at least 20 weeks, at least 21 weeks, at least 22 weeks, at least 23 weeks, at least 24 weeks, at least 25 weeks, at least 26 weeks, at least 27 weeks, at least 28 weeks, at least 29 weeks, at least 30 weeks, at least 31 weeks, at least 32 weeks, at least 33 weeks, at least 34 weeks, at least 35 weeks, at least 36 weeks, at least 37 weeks, at least 38 weeks, at least 39 weeks, at least 40 weeks, at least 41 weeks, at least 42 weeks, at least 43 weeks, at least 44 weeks, at least 45 weeks, at least 46 weeks, at least 47 weeks, at least 48 weeks, at least 49 weeks, at least 50 weeks, at least 51 weeks, at least 52 weeks, at least 53 weeks, at least 54 weeks, at least 55 weeks, at least 56 weeks, at least 57 weeks, at least 58 weeks, at least 59 weeks, at least 60 weeks, at least 61 weeks, at least 62 weeks, at least 63 weeks, at least 64 weeks, at least 65 weeks, at least 66 weeks, at least 67 weeks, at least 68 weeks, at least 69 weeks, at least 70 weeks, at least 71 weeks, at least 72 weeks, at least 73 weeks, at least 74 weeks, at least 75 weeks, at least 76 weeks, at least 77 weeks, at least 78 weeks, at least 79 weeks, at least 80 weeks, at least 81 weeks, at least 82 weeks, at least 83 weeks, at least 84 weeks, at least 85 weeks, at least 86 weeks, at least 87 weeks, at least 88 weeks, at least 89 weeks, at least 90 weeks, at least 91 weeks, at least 92 weeks, at least 93 weeks, or more. In embodiments, the dosage is weekly for at least 23 weeks, at least 28 weeks, or at least 76 weeks or chronically. In one specific aspect, by the methods of the present invention, the absolute and / or percentage of liver fat is reduced. In embodiments, the percentage liver fat is reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, as measured by magnetic resonance imaging proton density fat fraction measurement from baseline. In embodiments, the patient has a CTP score of A and has a reduction of liver fat percentage of at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% as measured by magnetic resonance imaging proton density fat fraction measurement from baseline. In embodiments, the patient has a CTP score of A and has a reduction in liver fat percentage of at least 30% from baseline.

[0071] In one specific aspect, by the methods of the present invention, the patient's liver stiffness is reduced. In embodiments, the amount of liver stiffness can be measured by absolute change from baseline in kPa using magnetic resonance elastography, and / or by transient elastography (FibroScan®). In some embodiments, the reduction is about 0.2 kPa or more, about 0.4 kPa or more, about 0.5 kPa or more, about 0.6 kPa or more, about 0.7 kPa or more, about 0.8 kPa or more, about 0.9 kPa or more, about 1.0 kPa or more, about 1.1 kPa or more, or about 1.2 kPa or more as measured by magnetic resonance elastography.

[0072] In one specific aspect, by the methods of the present invention, the patient's Enhanced Liver Fibrosis (ELF) score is reduced. ELF scores can be determined as known in the art, e.g. are calculated via measurement of an ECM marker set consisting of tissue inhibitor of metalloproteinases 1 (TIMP- 1), amino-terminal propeptide of type III procollagen (PIIINP) and hyaluronic acid (HA). In embodiments, the patient's Enhanced Liver Fibrosis (ELF) score is reduced by at least 0.1, at least 0.2, at least 0.3, at least 0.4, at least 0.4, at least 0.5, or at least 0.6 as compared to a baseline measurement.

[0073] In one specific aspect, by the methods of the present invention, the patient's N-terminal type III collagen propeptide (Pro-C3) is reduced. The amount of Pro-C3 can be determined as known by those of skill in the art. In embodiments, the patient's Pro-C3 is reduced by a percentage change of about 1% or more, about 2% or more, about 3% or more, about 4% or more, about 5% or more, about 6% or more, about 7% or more, about 8% or more, about 9% or more, about 10% or more, about 11% or more, about 12% or more, about 13% or more, about 14% or more, about 15% or more, about 16% or more, about 17% or more, about 18% or more, about 19% or more, about 20% or more, about 21% or more, about 22% or more, or about 23% or more from a baseline measurement. In embodiments, the percentage change in the patient's Pro-C3 is greater than about 10% or greater than about 20%.

[0074] Pharmaceutical compositions

[0075] The invention also extends to compositions, such as pharmaceutical compositions, comprising Compound 1 for use in method of preventing or treating metabolic liver disease, particularly for treating MASH-associated liver cirrhosis, MASH-associated compensated liver cirrhosis (MASH cF4), MASH and compensated cirrhosis, or MASH-associated liver fibrosis and cirrhosis. As with all aspects of the invention, it is to be understood that reference to Compound 1 encompasses reference to compounds in the form of a pharmaceutically acceptable salt.

[0076] Compound 1 may be formulated as pharmaceutical compositions which are suited for administration, and which typically comprise a therapeutically effective amount of Compound 1, together with a pharmaceutically acceptable carrier, excipient or vehicle.

[0077] The term "pharmaceutically acceptable carrier" includes any of the standard pharmaceutical carriers. Pharmaceutically acceptable carriers for therapeutic use are well known in the pharmaceutical art and are described, for example, in "Remington's Pharmaceutical Sciences", 17th edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985. For example, sterile saline and phosphate-buffered saline at slightly acidic or physiological pH may be used. Suitable pH-buffering agents may, e.g., be phosphate, citrate, acetate, tris(hydroxymethyl)aminomethane (TRIS), N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS), ammonium bicarbonate, diethanolamine, histidine, arginine, lysine or acetate (e.g. as sodium acetate), or mixtures thereof. The term further encompasses any carrier agents listed in the US Pharmacopeia for use in humans.

[0078] A pharmaceutical composition of the invention may be in unit dosage form. In such form, the composition is divided into unit doses containing appropriate quantities of the active component or components. The unit dosage form may be presented as a packaged preparation, the package containing discrete quantities of the preparation, for example, packaged tablets, capsules or powders in vials or ampoules. The unit dosage form may also be, e.g., a capsule, cachet or tablet in itself, or it may be an appropriate number of any of these packaged forms. A unit dosage form may also be provided in injectable form in a device for application, for example in the form of a pen device or an auto-injector containing a liquid-phase (typically aqueous) composition. Subcutaneous administration is the most common route of application of therapeutic peptides generally, in some embodiments suitable for Compound 1. For this case a single-use (provides the quantity of the compound for a single dosage unit) or a multiple use (provides the quantity of the compound for more than one dosage unit) device can be used. Suitable devices comprise autoinjector (e.g. for single-use) or pens (e.g. for multiple use) containing a cartridge with a liquid (e.g. aqueous) formulation of the compound.

[0079] Dosages

[0080] A typical dosage of Compound 1 may be in the range from about 0.0005 to about 5 mg / kg body weight per week, e.g. from about 0.001 to about 0.5 mg / kg body weight per week. The exact dosage employed may depend, inter alia, on: the nature and severity of the disease or disorder to be treated, on the sex, age, body weight and general condition of the subject to be treated, on possible other, concomitant, disease or disorder that is undergoing or is to undergo treatment, as well as on other factors that will be known to a medical practitioner of skill in the art.

[0081] In one specific aspect, dose escalation of Compound 1 is performed from 0.3 mg Compound 1 from the start of treatment to until a maintenance dose (e.g. 2.4, 4.8 or 6 mg per week) is reached.

[0082] In some embodiments, the invention relates to a device comprising Compound 1 or a combination as defined above or pharmaceutical composition of the invention, for delivery of the compound to a subject.

[0083] PARTICULAR EMBODIMENTS

[0084] Further embodiments of the invention are described:

[0085] Compound 1: H-H-Ac4c-QGTFTSDYSKYLDERAAKDFI-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)- WLESA- / VH2for use in a method of treatment and / or prevention of MASH -associated liver cirrhosis, MASH-associated compensated liver cirrhosis (MASH cF4), MASH and compensated cirrhosis, or MASH-associated liver fibrosis and cirrhosis.

[0086] A method of preventing or treating MASH-associated liver cirrhosis, MASH-associated compensated liver cirrhosis (MASH cF4), MASH and compensated cirrhosis, or MASH-associated liver fibrosis and cirrhosis comprising administering a therapeutically effective amount of Compound 1 or a pharmaceutical composition comprising Compound 1. Use of Compound 1 or a pharmaceutical composition comprising Compound 1 in a method of treating MASH-associated liver cirrhosis, MASH-associated compensated liver cirrhosis (MASH cF4), MASH and compensated cirrhosis, or MASH-associated liver fibrosis and cirrhosis.

[0087] Use of Compound 1 or a pharmaceutical composition comprising Compound 1 in a method for slowing progression of MASH-associated liver cirrhosis, MASH-associated compensated liver cirrhosis (MASH cF4), MASH and compensated cirrhosis, or MASH-associated liver fibrosis and cirrhosis.

[0088] Use of Compound 1 or a pharmaceutical composition comprising Compound 1 in a method of preventing progression of MASH-associated liver cirrhosis, MASH-associated compensated liver cirrhosis (MASH cF4), MASH and compensated cirrhosis, or MASH-associated liver fibrosis and cirrhosis.

[0089] Any of the previous embodiments, wherein the disease is MASH-associated liver cirrhosis.

[0090] Any of the previous embodiments, wherein the disease is MASH-associated compensated liver cirrhosis (MASH cF4).

[0091] Any of the previous embodiments, wherein the disease is MASH and compensated cirrhosis.

[0092] Any of the previous embodiments, wherein the disease is MASH-associated liver fibrosis and cirrhosis.

[0093] Any of the previous embodiments, wherein the disease is associated with different stages of liver fibrosis.

[0094] Any of the previous embodiments, wherein the disease is associated with liver fibrosis.

[0095] Any of the previous embodiments, wherein the disease is associated with advanced liver fibrosis (e.g. moderate fibrosis stage (F2) and / or severe fibrosis stage (F3)).

[0096] Any of the previous embodiments, wherein the patient is diagnosed as being overweight or obese.

[0097] Any of the previous embodiments, wherein the patient has a BMI >27 kg / m2.

[0098] Any of the previous embodiments, wherein the patient has MASH-associated compensated liver cirrhosis (MASH cF4) with a diagnosis of a Child-Turcotte-Pugh (CTP) cirrhosis class of A, B, or C. Any of the previous embodiments, wherein the patient has MASH-associated compensated liver cirrhosis (MASH cF4) with a diagnosis of Child-Turcotte-Pugh (CTP) cirrhosis class of A or B.

[0099] Any of the previous embodiments, wherein the patient has MASH-associated compensated liver cirrhosis (MASH cF4) with a diagnosis of Child-Turcotte-Pugh (CTP) cirrhosis class of B or C.

[0100] Any of the previous embodiments, wherein the patient has MASH-associated compensated liver cirrhosis (MASH cF4) with a diagnosis of a Child-Turcotte-Pugh (CTP) cirrhosis class of A.

[0101] Any of the previous embodiments, wherein the patient has MASH-associated compensated liver cirrhosis (MASH cF4) with a diagnosis of a Child-Turcotte-Pugh (CTP) cirrhosis class of B.

[0102] Any of the previous embodiments, wherein the patient has MASH-associated compensated liver cirrhosis (MASH cF4) and treatment is associated with a reduction of the absolute and / or percentage of the patient's liver fat.

[0103] Any of the previous embodiments, wherein the patient has MASH-associated compensated liver cirrhosis (MASH cF4) and treatment is associated with a reduction of at least 30% of liver fat from a baseline measurement, as measured by magnetic resonance imaging proton density fat fraction measurement.

[0104] Any of the previous embodiments, wherein the patient has MASH-associated compensated liver cirrhosis (MASH cF4) and treatment is associated with a reduction of the patient's liver stiffness.

[0105] Any of the previous embodiments, wherein the patient has MASH-associated compensated liver cirrhosis (MASH cF4) and treatment is associated with a reduction of liver stiffness by at least 0.5kPa or more from a baseline measurement, as measured by change in kPa via magnetic resonance elastography, and / or by transient elastography (e.g., FibroScan®).

[0106] Any of the previous embodiments, wherein the patient has MASH-associated compensated liver cirrhosis (MASH cF4) and treatment is associated with a reduction of liver stiffness by at least 0.8 kPa or more, from a baseline measurement, as measured by change in kPa via magnetic resonance elastography, and / or by transient elastography (e.g., FibroScan®).

[0107] Any of the previous embodiments, wherein the patient has MASH-associated compensated liver cirrhosis (MASH cF4) and treatment is associated with a reduction of the patient's Enhanced Liver Fibrosis (ELF) score. Any of the previous embodiments, wherein the patient has MASH-associated compensated liver cirrhosis (MASH cF4) and treatment is associated with a reduction of the patient's Enhanced Liver Fibrosis (ELF) score reduced by at least 0.4 or more, e.g. after 28 weeks of treatment.

[0108] Any of the previous embodiments, wherein the patient has MASH-associated compensated liver cirrhosis (MASH cF4) and treatment is associated with a reduction of the patient's Enhanced Liver Fibrosis (ELF) score reduced by at least 0.5 or more, e.g. after 28 weeks of treatment.

[0109] Any of the previous embodiments, wherein the patient has MASH-associated compensated liver cirrhosis (MASH cF4) and treatment is associated with a reduction of the patient's N-terminal type III collagen propeptide (Pro-C3), e.g. after 28 weeks of treatment.

[0110] Any of the previous embodiments, wherein the patient has MASH-associated compensated liver cirrhosis (MASH cF4) and treatment is associated with a reduction of the patient's N-terminal type III collagen propeptide (Pro-C3) by a percentage change of about 10% or more from a baseline measurement, e.g. after 28 weeks of treatment.

[0111] Any of the previous embodiments, wherein the patient has MASH-associated compensated liver cirrhosis (MASH cF4) and treatment is associated with a reduction of the patient's N-terminal type III collagen propeptide (Pro-C3) by a percentage change of about 20% or more, from a baseline measurement, e.g. after 28 weeks of treatment.

[0112] Any of the previous embodiments, wherein the patient's dosage of Compound 1 for the methods of the invention is weekly for at least 28 weeks.

[0113] Any of the previous embodiments, wherein the patient's dose escalation for the methods of the invention is performed from 0.3 mg Compound 1 from Day 1 to 2.4, 4.8 or 6 mg at the start of Week 23.

[0114] Any of the previous embodiments, wherein the patient's dosage from the start of Week 24 is 6 mg.

[0115] Any of the previous embodiments, wherein Compound 1 is in the form of a salt, more specifically in the form of a pharmaceutically acceptable salt. EXAMPLES

[0116] Example 1

[0117] A multicenter, non-randomized open-label combined phase 1 / phase 2 trial (NCT05296733) of survodutide consisting of two parts (A and B). The main objective of Part A was to assess the pharmacokinetics, safety, and tolerability of a single subcutaneous dose of survodutide in patients with cirrhosis and varying degrees of hepatic impairment, relative to healthy participants, with and without overweight or obesity. Part B assessed the safety, tolerability, and efficacy of multiple subcutaneous doses of survodutide in patients living with overweight or obesity and cirrhosis in Child-Pugh class A and Child-Pugh class B relative to patients living with overweight or obesity without cirrhosis.

[0118] Impact and implications

[0119] Survodutide is a glucagon receptor / glucagon-like peptide-1 receptor dual agonist in development for treatment of metabolic dysfunction-associated steatohepatitis (MASH), which causes cirrhosis in ~20% of cases. This trial delineates the pharmacokinetic and safety profile of survodutide in people with compensated or decompensated cirrhosis, and revealed associated reductions in liver fat content, markers of liver fibrosis and body weight. These findings have potential relevance for people with MASH— including those with decompensated cirrhosis, who are usually excluded from clinical trials of investigational drugs. Based on this study, further investigation of survodutide for MASH-related cirrhosis is warranted.

[0120] Background & Aims: Survodutide is a glucagon / glucagon-like peptide-1 receptor dual agonist in development for treatment of metabolic dysfunction-associated steatohepatitis (MASH). We investigated survodutide in people with cirrhosis.

[0121] Methods: This multinational, non-randomized, open-label, phase 1 clinical trial initially evaluated a single subcutaneous (s.c.) dose of survodutide 0.3 mg in people with Child-Pugh class A, B or C cirrhosis and healthy individuals with or without overweight / obesity matched for age, sex, and weight; the primary endpoints were the area under the plasma concentration-time curve from 0 to infinity (AUCO-00) and maximal plasma concentration (Cmax). Subsequently, people with overweight / obesity with or without cirrhosis and Child-Pugh class A or B received once-weekly s.c. doses escalated from 0.3 mg to 6.0 mg over 24 weeks then maintained for 4 weeks; the primary endpoint was drug-related treatment-emergent adverse events, with MASH / cirrhosis-related endpoints explored.

[0122] Results: In the single-dose cohorts (n = 41), mean AUCO-00and Cmax were similar in those with cirrhosis compared with healthy individuals (90% confidence intervals for adjusted geometric mean ratios spanned 1). Drug-related adverse events occurred in 25.0% of healthy individuals and <25.0% of those with cirrhosis after single doses, and 82.4% and 87.5%, respectively, of the multiple-dose cohorts (n = 41) over 28 weeks. Liver fat content, liver stiffness, liver volume, body weight, and other hepatic and metabolic disease markers were generally reduced after 28 weeks of survodutide treatment.

[0123] Conclusions: Survodutide is generally tolerable in people with compensated or decompensated cirrhosis, does not require pharmacokinetic-related dose adjustment, and may improve outcomes of liver-related non-invasive tests, supporting its investigation for MASH-related cirrhosis.

[0124] Introduction

[0125] Metabolic dysfunction-associated steatohepatitis (MASH), formerly termed non-alcoholic steatohepatitis, is an advanced stage of metabolic dysfunction-associated steatotic liver disease (MASLD) associated with obesity, type 2 diabetes, and other cardio-kidney-metabolic diseases. MASH is defined as >5% hepatic steatosis with inflammation and hepatocyte injury (ballooning) with or without fibrosis, and leads to cirrhosis in ~20% of cases, with complications of hepatocellular cancer, end-stage liver disease, liver transplant, and death. In the United States (US) and globally, MASLD and MASH are estimated to affect >30% and >5% of the population, respectively, and are increasingly prevalent.

[0126] There are no approved pharmacotherapies for MASH cirrhosis. Clinical guidelines for MASH recommend weight loss and consideration of vitamin E and off-label use of medications for obesity (glucagon-like peptide-1 [GLP-1] receptor agonists) or type 2 diabetes (GLP-1 receptor agonists or pioglitazone). The poor prognosis for decompensated MASH cirrhosis represents a high unmet therapeutic need.

[0127] Survodutide (Bl 456906) is a unimolecular dual agonist of the glucagon and GLP-1 receptors. In addition to anorexigenic effects of GLP-1 receptor stimulation, glucagon receptor agonism may directly elicit hepatic fat loss by increasing energy expenditure, decrease hepatic inflammation by improving mitochondrial function, and impact hepatic fibrosis by reducing stellate cell activation. In phase 1 trials in healthy volunteers and people with overweight or obesity, subcutaneous survodutide exhibited linear pharmacokinetics. The plasma half-life of survodutide is ~6 days, enabling once-weekly dosing, and it has high binding to human serum albumin (>99%) synthesized exclusively by the liver, which is also responsible for ~10% of albumin degradation.

[0128] We investigated potential effects of cirrhosis on the pharmacokinetics, tolerability, and safety of survodutide, then its efficacy in compensated and decompensated cirrhosis.

[0129] Patients and methods

[0130] Trial design and oversight

[0131] We conducted this phase 1, non-randomized, open-label, 2-part trial at 15 sites in six countries to investigate the pharmacokinetics, safety, tolerability, and efficacy of subcutaneous doses of survodutide in people with compensated and decompensated cirrhosis relative to those without cirrhosis. The trial began with a single-dose pharmacokinetic evaluation of survodutide 0.3 mg subcutaneously in participants with compensated and decompensated cirrhosis (Child-Pugh class A, B, or C) and healthy participants with or without overweight / obesity matched for age, sex, and weight (Fig. 1, top). Subsequently, open-label therapy was delivered once-weekly subcutaneously with doses escalated to 6.0 mg over 24 weeks, then maintained for 4 weeks, in participants with overweight or obesity with or without cirrhosis and Child-Pugh class A or B (Fig. 1, bottom). The protocol was approved by institutional review boards / ethics committees for each site (supplementary data), and the trial was conducted according to the Declaration of Helsinki principles and the International Council for Harmonisation Guideline for Good Clinical Practice. All participants provided written informed consent before enrollment.

[0132] Participants

[0133] In the single-dose pharmacokinetic part, key inclusion criteria were age >18 years, body mass index (BMI) 18.5-40.0 kg / m2, and either no cirrhosis (cohort 1) or cirrhosis (cohorts 2, 3, 4). Cohort 1 participants had to have normal levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, prothrombin time, and albumin. Participants in cohorts 2-4 had cirrhosis, defined as liver stiffness >15 kPa measured by vibration-controlled transient elastography (VCTE) with FibroScan®, and hepatic impairment meeting criteria for Child-Pugh class A, B, or C, respectively.

[0134] Individuals were excluded from all cohorts if they had hepatocellular carcinoma or any other malignancy within the previous 5 years, excluded from cohort 1 if they had chronic liver disease (including viral hepatitis), and excluded from cohorts 2-4 if they had any of the following: hepatorenal syndrome or limited life expectancy; diagnosis of hepatic dysfunction secondary to any acute hepatocellular process or cholestatic etiology; gastrointestinal hemorrhage in the previous 3 months; hepatic encephalopathy impairing informed consent; severe ascites (except those in cohort 4, if medically stable); ALT or AST >5xupper limit of normal (ULN).

[0135] Open-label therapy participants were eligible if they had BMI >27 kg / m2, body weight >70 kg in females / >80 kg in males, and no cirrhosis and normal ALT / AST / bilirubin / prothrombin time / albumin (cohort 1), or Child-Pugh A cirrhosis (cohort 2), or Child-Pugh B cirrhosis (cohort 3). Exclusion criteria mirrored the single-dose pharmacokinetic exclusions.

[0136] Procedures: A single subcutaneous 0.3 mg dose of survodutide was delivered following overnight fast, after which participants stayed at the trial site for 3 days then returned daily from days 4-16. Blood was sampled regularly for serial pharmacokinetic analyses and participants were monitored for adverse events. To demographically match healthy participants in cohort 1 with the hepatically impaired in cohorts 2-4 (for age, body weight, sex), median weight and age were calculated after dosing of >5 participants each in >2 of the latter cohorts; dosing of healthy participants then began, ~50% of whom were required to have weight and age above and below the median values for cohorts 2-4.

[0137] Open-label therapy was initiated after comparing pharmacokinetic parameters between the above participants with cirrhosis and healthy participants. Participants received once-weekly subcutaneous doses of survodutide up-titrated from 0.3 mg to 6.0 mg maximum over 24 weeks if tolerated, according to a pre-defined dose-escalation scheme permitting dose reduction for tolerability (Table 1). The maximal dose was then administered for a further 4 weeks. Participants were monitored weekly either remotely (weeks 5, 7, 9, 11, 13-15) or on-site (all other weeks). Table 1. Dose escalation scheme for open-label therapy

[0138] Dose adjustment was allowed once during the dose escalation period from week 14 onwards. Dose adjustment was only allowed if a subject did not tolerate a dose due to adverse events in the previous two weeks and wished to reduce the dose; in such cases, the dose was to be decreased to the next lower allowed and tolerated dose. Allowed doses for dose modifications are 2.4 mg and 4.8 mg (i.e. no doses in between). For example:

[0139] If a subject did not tolerate a dose of 3.0 mg over two weeks during the dose escalation period and wished to reduce the dose, the dose could be changed to 2.4 mg; the subject was treated with 2.4 mg survodutide until the end of the study, i.e. no further dose increases were to be planned.

[0140] If a subject did not tolerate a dose of 3.6 mg over two weeks during the dose escalation period and wished to reduce the dose, the dose could be changed to 2.4 mg; the subject was treated with 2.4 mg survodutide until the end of the study, i.e. no further dose increases were to be planned.

[0141] If a subject did not tolerate a dose of 5.4 mg over two weeks during the dose escalation period and wished to reduce the dose, the dose could be changed to 4.8 mg; the subject was treated with 4.8 mg survodutide until the end of the study, i.e. no further dose increases were to be planned.

[0142] If a subject did not tolerate a dose of 6.0 mg over two weeks during the dose escalation period, and wished to reduce the dose, the dose could be changed to 4.8 mg; the subject was treated with 4.8 mg survodutide until the end of the study.

[0143] Assessments at screening (the 2 weeks before first dose) and during treatment included blood sampling for pharmacokinetic analyses and laboratory tests (including biomarkers of liver fibrosis such as N-terminal type III collagen propeptide [Pro-C3] and Enhanced Liver Fibrosis [ELF] score), vital signs, weight (all during on-site visits only), and monitoring of adverse events, as well as liver fat content by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) and FibroScan® Controlled Attenuation Parameter (CAP), liver volume by MRI T1 weighted, and liver stiffness by magnetic resonance elastography and FibroScan® VCTE (all at week 28 on-site).

[0144] Endpoints

[0145] There were two primary endpoints for the single-dose pharmacokinetic portion: the area under the plasma concentration-time curve from 0 to infinity (AUCO-00) for survodutide, and its maximal plasma concentration (Cmax). The primary endpoint of open-label therapy was drug-related adverse events. Further pre-defined endpoints included, but were not limited to, change from baseline (screening) to week 28 in liver fat content (by MRI-PDFF and FibroScan® CAP), liver stiffness (by magnetic resonance elastography and FibroScan® VCTE), liver volume (MRI using Tl-weighted images), body weight, and waist circumference. Statistical analysis

[0146] We did not formally plan sample sizes based on power calculations for this exploratory trial. For single-dose pharmacokinetics, we planned to include ~40 participants (16 in cohort 1, 8 each in cohorts 2-4), which was considered sufficient to detect pharmacokinetic differences between cohorts 1 and 2-4, and consistent with regulatory guidance that 6 individuals per cohort is sufficient for hepatic-impairment trials.14 For open-label therapy, we also planned to include ~40 participants (16, 16, 8 in cohorts 1, 2, 3, respectively), based on a sample size of 16 in cohorts 1 and 2 providing 81.5% probability to detect a common adverse event if the common adverse event rate was >10%.

[0147] For single-dose pharmacokinetics, the effect of hepatic impairment on the pharmacokinetic primary endpoints was estimated by the ratio of geometric means between cohorts 2-4 and cohort 1 with two-sided 90% confidence intervals (Cis), using an analysis of variance model on the logarithmic scale including the degree of hepatic impairment as a fixed effect. Furthermore, descriptive statistics were calculated for these and all other endpoints in both the single-dose and open-label parts of the trial.

[0148] Data for adverse events, body weight, waist circumference, and liver fat content, stiffness and fibrosis biomarkers were analyzed for all participants treated with >1 dose of survodutide (the treated set), while pharmacokinetic parameters were analyzed for all participants in the treated set with data for >1 pharmacokinetic endpoint (the pharmacokinetic parameter analysis set).

[0149] RESULTS

[0150] Participants

[0151] 169 individuals were screened for eligibility and 82 were assigned to receive survodutide (41 each in the single-dose and open-label parts). At baseline, the single-dose pharmacokinetic group had mean age of 56.7 years and BMI of 31.40 kg / m2, with 85.4% male and 92.7% White (Table 2). The openlabel group had mean age of 53.7 years and BMI of 35.78 kg / m2, with 51.2% male and 95.4% White. Overall, 28.4% of participants were Hispanic / Latino. The etiology for 87.5% of the Child-Pugh A and B participants in the open-label group was MASH. Participants with cirrhosis had lower liver fat content than those without cirrhosis, while liver stiffness and liver fibrosis biomarkers (Pro-C3, ELF score) were higher. Comparative trial demographics are described in Table 2. Table 2. Demographic and clinical characteristics of participants at baseline (treated set).

[0152] Inclusion and exclusion criteria: Inclusion criteria

[0153] Part A

[0154] 1. Male or female subjects with age >18 years (or the minimum country specific age of consent if >18 years) and 75 years, inclusive at the screening visit.

[0155] 2. BMI of 18.5-40.0 kg / m2(inclusive).

[0156] 3. Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial. 4. Women of childbearing potential must be willing and able to use two forms of effective contraception where at least one form is highly effective method of birth control that results in a low failure rate (i.e. <1% per year when used consistently and correctly). A list of contraception methods meeting these criteria is provided in the subject information. Please note that oral contraceptives are not allowed during the treatment period.

[0157] A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Tubal ligation is NOT a method of permanent sterilization. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.

[0158] 5. Subjects in Cohort 1 (i.e. healthy subject with or without overweight / obesity, with no cirrhosis / hepatic impairment) must additionally: a. Have no known or suspected hepatic impairment, and meet the following criteria at the screening visit: alanine aminotransferase (ALT) <ULN, aspartate aminotransferase (AST) <ULN, total bilirubin <ULN, albumin >LLN, prothrombin time <ULN.

[0159] Note: subjects with a history of Gilbert syndrome (and hence elevated total bilirubin) are eligible provided that direct bilirubin level <ULN, ALT <ULN, AST <ULN, alkaline phosphatase <ULN, hemoglobin <ULN, and reticulocyte count <ULN. b. Be matched to patients included in Cohorts 2, 3, and 4 based on age, body weight, and sex. In order to do this, median body weight and age will be calculated after >5 patients each (i.e. at least 10 subjects overall dosed) in at least two hepatic impairment cohorts (i.e. Cohorts 2, 3, or 4) have been dosed. Healthy subjects with or without overweight / obesity (Cohort 1) will then be included in the trial; approximately 50% of participants from Cohort 1 (i.e. 8 subjects) should be on each side of the median calculated across the hepatic impairment cohorts as described above.

[0160] 6. Patients in Cohorts 2, 3, and 4 (i.e. with cirrhosis and mild, moderate, and severe hepatic impairment, respectively) must additionally have: a. liver cirrhosis (i.e. liver stiffness >15 kPa measured by FibroScan® at the screening visit), and b. hepatic impairment that meets the criteria for Child-Turcotte-Pugh classes A, B, or C.

[0161] Part B

[0162] Numbering of inclusion criteria for Part B starts with 51 for technical reasons. 51. Male or female subjects between the ages of >18 (or the minimum country specific age of consent if >18 years) and 75 years, inclusive, at the screening visit.

[0163] 52. Subjects with overweight or obesity, defined as BMI >27 kg / m2at the screening visit.

[0164] 53. A minimum absolute body weight of 70 kg for females and 80 kg for males at the screening visit.

[0165] 54. Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial.

[0166] 55. Women of childbearing potential must be willing and able to use two forms of effective contraception where at least one form is highly effective methods of birth control that result in a low failure rate (<1% per year when used consistently and correctly). A list of contraception methods meeting these criteria is provided in the subject information. Please note that oral contraceptives are not allowed during the treatment period.

[0167] A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.

[0168] Tubal ligation is NOT a method of permanent sterilization. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.

[0169] 56. Patients in Cohort 1 (i.e. overweight / obese with no cirrhosis / hepatic impairment) must additionally have no known or suspected hepatic impairment, and meet the following criteria at the screening visit: alanine aminotransferase (ALT) <ULN, aspartate aminotransferase (AST) <ULN, total bilirubin <ULN, albumin >LLN, prothrombin time <ULN

[0170] Note: Patients with a history of Gilbert syndrome (and hence elevated total bilirubin) are eligible provided that direct bilirubin level <ULN, ALT <ULN, AST <ULN, alkaline phosphatase <ULN, hemoglobin <ULN, and reticulocyte count <ULN.

[0171] 57. Patients in Cohorts 2 and 3 (i.e. with mild and moderate hepatic impairment, respectively) must additionally have: a. liver cirrhosis (i.e. liver stiffness >15 kPa measured by FibroScan® at the screening visit if not done at pre-screening visit), and b. hepatic impairment that meets the criteria for Child-Turcotte-Pugh classes A or B. Exclusion criteria

[0172] Part A

[0173] 1. Estimated Glomerular Filtration Rate (eGFR) <60 mL / min / 1.73 m2(Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula).

[0174] 2. Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, manifest hypo- or hyperthyroidism at screening.

[0175] 3. Calcitonin >20 pg / mL (5.84 pmol / L) at the screening visit.

[0176] 4. History of chronic or acute pancreatitis or elevation of serum lipase / amylase >2xULN, or fasting serum triglyceride levels of >500 mg / dL (>5.65 mmol / L) at screening.

[0177] 5. Resting Heart Rate >100 beat per minutes (bpm) and / or systolic blood pressure >160 mmHg and / or diastolic blood pressure >95 mmHg at screening.

[0178] Additional exclusion criteria apply.

[0179] 26. Subjects in Cohort 1 (i.e. healthy subjects with or without overweight / obesity, with no cirrhosis / hepatic impairment) will be excluded if they have evidence of chronic liver disease (e.g. autoimmune liver disease, primary biliary sclerosis, primary sclerosing cholangitis, Wilson's disease) including ongoing active or chronic viral hepatitis. Subjects with the following laboratory findings are excluded: a. HAV: subjects with positive HAV IgM and / or HAV RNA b. HBV: subjects with positive HBsAg c. HCV: subjects with positive HCV RNA (subjects treated for hepatitis C must have a negative RNA test at screening and also be HCV RNA negative for at least 3 years prior to screening in order to be eligible for the trial

[0180] 27. Patients in Cohorts 2, 3, and 4 (i.e. with cirrhosis and mild, moderate, or severe hepatic impairment) will be excluded if they have: a. hepatorenal syndrome or limited predicted life expectancy (defined as <1 year in Cohorts 2 &

[0181] 3 and <6 months for Cohort 4). b. a diagnosis of hepatic dysfunction secondary to any acute ongoing hepatocellular process c. primary sclerosing cholangitis or primary biliary cholangitis. d. a history of gastrointestinal hemorrhage within 3 months prior to screening. e. Hepatic encephalopathy compromising subject's ability to express an informed consent. f. severe ascites that requires less than every 4-week paracentesis and / or pleural effusion, except for those categorized in Cohort 4 who may be enrolled provided the subject is medically stable per the investigator's medical judgement. g. ALT or AST >5xULN at the screening visit.

[0182] Part B

[0183] Numbering of exclusion criteria for Part B starts with 51 for technical reasons.

[0184] 51. Prior surgery of the gastrointestinal tract that could interfere with body weight (including minimally invasive / endoscopic bariatric devices, bariatric surgery including metabolic operation that involves resection and / or reconstruction of any portion of the gastrointestinal tract) except appendectomy and simple hernia repair before randomization. However, a subject previously treated with reversible weight loss devices such as gastric banding, or intragastric balloon and removed longer than 12 months before screening should not be excluded.

[0185] 52. HbAlc >11% at screening or diagnosed with type 1 diabetes mellitus.

[0186] 53. Exposure to GLP-1 receptor agonist-based therapies (within 3 months prior to screening or within 5 half-lives of the drug, whichever is longer).

[0187] 54. Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, manifest hypo- or hyperthyroidism at screening.

[0188] 55. Calcitonin >20 pg / mL (5.84 pmol / L) at the screening visit.

[0189] 56. History of chronic or acute pancreatitis or elevation of serum lipase / amylase >2xULN, or fasting serum triglyceride levels of >500 mg / dl (>5.65 mmol / L) at screening.

[0190] 57. Resting Heart Rate >100 beat per minutes (bpm) and / or systolic blood pressure >160 mmHg and / or diastolic blood pressure >95 mmHg at screening.

[0191] Additional exclusion criteria apply.

[0192] Definition of hepatic injury

[0193] Hepatic injury was considered an adverse event of special interest for the study, defined by the following alterations of hepatic laboratory parameters:

[0194] Bilirubin, alanine aminotransferase (ALT), and / or aspartate aminotransferase (AST) is normal at baseline: If ALT and / or AST is more than 8xULN (upper limit of normal)

[0195] If ALT and / or AST is 5-8xULN for more than 2 weeks (only Part B)

[0196] If ALT and / or AST is 3x-8xULN AND total bilirubin is >2 mg / dL

[0197] Bilirubin, ALT, and / or AST is >ULN at baseline and:

[0198] If ALT and / or AST is <2xULN at baseline, AND ALT and / or AST is >5xbaseline value

[0199] If ALT and / or AST is 2-5xULN at baseline, AND ALT and / or AST is >3xbaseline value

[0200] Pharmacokinetics, Tolerability, and Safety of Single Doses in Cirrhosis

[0201] AUC0-°° and Cmax of survodutide were similar in participants with cirrhosis and Child-Pugh class A, B, or C compared with participants without cirrhosis, with 90% Cis for the adjusted geometric mean ratios spanning 1 (Table 3). Values for other pharmacokinetic parameters were also similar. See Table 4. Drug-related adverse events occurred in 25.0% of healthy participants and 0%, 25.0%, and 0% of Child-Pugh A, B, or C participants, respectively. No adverse events were serious, fatal, or led to trial discontinuation, and no cases of hepatic injury occurred.

[0202] Table 3. Pharmacokinetics of Single 0.3 mg Doses of Survodutide (Pharmacokinetic Parameter Analysis Set)

[0203] AUCo ~ denotes area under the plasma concentration time curve from 0 to infinity, Cl confidence interval, Cmax maximal plasma concentration, gMean geometric mean, and gSE standard error of the geometric mean.

[0204] * Based on analysis of variance model adjusted for age, sex, and log(body weight).

[0205] + n=7 as for 1 participant the drug concentration at the last time point was higher than previous time points, precluding calculation of AUC0-°°. Table 4. Pharmacokinetic Parameters After Single Doses (Pharmacokinetic Parameter Analysis Set).

[0206] Values are descriptive gMean ±gCV (%). AUCo-«= denotes area under the plasma concentration time curve from 0 to infinity, CL / F apparent plasma clearance, Cmaxmaximal plasma concentration, gCV geometric coefficient of variation, gMean geometric mean, tmaxtime to maximal plasma concentration, ti / 2plasma terminal half-life, and Vz / F apparent volume of distribution.

[0207] * n=7 as for 1 participant the drug concentration at the last time point was higher than previous time points, precluding calculation of AUCo-«=, ti / 2, CL / F, and VzF.

[0208] Tolerability, Safety, and Efficacy of Open-Label Therapy in Cirrhosis

[0209] During the 28 weeks of survodutide treatment (24 weeks of up-titration from 0.3 mg to 6.0 mg then 4 weeks at maximal doses) dose reductions occurred in 3 of the 8 participants without cirrhosis who did not prematurely discontinue trial drug, 2 of 11 with Child-Pugh A, and none of 6 with Child-Pugh B.

[0210] Mean change in heart rate at 28 weeks was +4.1, +8.5, and +7.6 beats per minute in healthy, Child- Pugh A, and B participants, respectively. No participants had onset of QTcF >500 milliseconds or change from baseline of >60 milliseconds, and no safety signals suggestive of increased risk of arrhythmias or QTcF prolongation were identified.

[0211] All three cohorts exhibited reductions at week 28 in liver fat content by MRI-PDFF (-43.29%, - 51.59%, -0.48% in those without cirrhosis, Child-Pugh A, Child-Pugh B, respectively), liver stiffness by magnetic resonance elastography (-0.13 kPa, -1.12 kPa, -1.02 kPa), ELF scores (-0.149, -0.369, - 0.522), and plasma Pro-C3 levels (-35.79%, -22.59%, -22.67%) (Fig. 2). Similarly, there were generally reductions at week 28 in FibroScan-measured liver fat content (-17.9%, -18.9%, 9.9% in those without cirrhosis, Child-Pugh A, Child-Pugh B, respectively) and stiffness (3.85%, -11.62%, - 2.63%), liver volume by MRI (-15.24%, -17.36%, -22.00%), and body weight (-14.80%, -10.40%, - 8.69%) (Table 5, Figure 4. Liver enzymes and platelets were generally reduced across cohorts, with minor, less consistent changes in bilirubin and international normalized ratio.

[0212] See also Figure 2 and Figure 3. Figure 2 shows changes in Liver Fat Content (Panel A), Liver Stiffness (Panel B), Enhanced Liver Fibrosis Score (Panel C), and Pro-C3 Levels (Panel D) with Open-Label Therapy (Treated Set). Figure 3 shows participants that had >30% reduction in liver fat by MRI-PDFF after 28 weeks (% participants), in the treated set (all participants who received >1 dose of survodutide) using on- and off-treatment data, including measurements from the end of treatment for participants who prematurely discontinued. Mean values are for the entire cohort, not just those with >30% reduction in liver fat content.

[0213] Fig. 4 shows the mean percent change from baseline for liver volume for participants after 28 weeks; descriptive statistics of % change in liver volume from baseline to week 28 by MRI T1 in the treated set (all participants who received >1 dose of survodutide) using on- and off-treatment data.

[0214] Table 5. Mean change from baseline to week 28 in other hepatic and metabolic parameters with open-label therapy (treated set).

[0215] Data are meaniSD. CAP, controlled attenuation parameter; LDL, low-density lipoprotein; MRI, magnetic resonance imaging. * Data are for 13, 13, and 8 of the healthy participants and those with Child-Pugh class A or B, respectively.

[0216] + Data are for 15, 13, and 6 of the healthy participants and those with Child-Pugh class A or B, respectively. t Data are for 8, 10, and 5 of the healthy participants and those with Child-Pugh class A or B, respectively.

[0217] § Data are for 8, 12, and 6 of the healthy participants and those with Child-Pugh class A or B, respectively.

[0218] ** Data are for 6, 9, and 6 of the healthy participants and those with Child-Pugh class A or B, respectively.

[0219] Discussion

[0220] Figure 2 shows changes in Liver Fat Content (Panel A), Liver Stiffness (Panel B), Enhanced Liver Fibrosis Score (Panel C), and Pro-C3 Levels (Panel D) with Open-Label Therapy (Treated Set). Predefined further end points for open-label therapy included changes from baseline to week 28 in liver fat content by magnetic resonance imaging-proton density fat fraction, liver stiffness by magnetic resonance elastography, Enhanced Liver Fibrosis score, and N-terminal type III collagen propeptide (Pro-C3) levels. Baseline mean values are for 17, 16, and 8 of the healthy, Child-Pugh A, and Child- Pugh B participants, respectively, in panels A, C, and D, and 17, 13, and 7 participants, respectively in panel B.

[0221] This two-stage trial evaluated both the pharmacokinetics of a single dose of survodutide, a glucagon / GLP-1 receptor dual agonist, and adaptive open-label therapy in people with compensated or decompensated cirrhosis compared to healthy individuals and those with excess body fat. These are the first safety and efficacy data for a dual agonist in people with decompensated cirrhosis, who are typically excluded from clinical trials of investigational drugs. Apart from various severities of liver disease, the demographic and clinical characteristics of participants were similar across cohorts. Overall, survodutide exhibited a similar pharmacokinetic profile in participants with or without cirrhosis, was generally tolerable, and was associated with clinically meaningful reductions in liver fat, liver stiffness and biomarkers of liver fibrosis, liver volume, and body weight.

[0222] Until the US Food and Drug Administration (FDA) March 2024 approval of resmetirom, a hepatic thyroid hormone receptor-0 agonist, for treatment of non-cirrhotic MASH and stages F2-F3 fibrosis, there were no pharmacotherapies licensed for MASH. Unlike resmetirom and many investigational compounds, GLP-l-based compounds elicit substantial weight loss, a key consideration given the role of obesity as both a cause and comorbidity of MASH. Furthermore, glucagon receptor agonism may enhance liver fat reduction and increase energy expenditure. Unlike GLP-1 receptor agonism, glucagon receptor agonism has direct hepatic effects on inflammation and fibrosis; the antiinflammatory effects may be mediated by reducing oxidative stress and improving mitochondrial function, while anti-fibrotic effects may be mediated by reducing stellate cell activity. These direct effects on inflammation and fibrosis could be beneficial in patients with advanced fibrosis and cirrhosis. Here, we demonstrated with multiple noninvasive markers benefits in liver stiffness and markers of fibrosis associated with survodutide treatment. The magnetic resonance elastography- measured reduction in liver stiffness of ~1 kPa in participants with Child-Pugh A or B cirrhosis is encouraging, given that an increase of this magnitude is associated with '“3-fold increase in odds for decompensation. In terms of the metabolic effects of survodutide, a synthetic acylated peptide that exhibits simultaneous agonism of the glucagon and GLP-1 receptors at a ratio of ~1 :8, this compound elicits substantial weight loss while improving glycemic control— a dual effect not necessarily shared by other glucagon / GLP-1 receptor dual agonists with a different balance of agonist activity. By targeting liver fat directly and increasing energy expenditure, glucagon / GLP-1 receptor dual agonists may offer advantages over GLP-1 receptor mono-agonists for treating MASH, which seem to reduce liver fat via general body weight reduction without ameliorating liver stiffness or fibrosis. The reductions in liver fat content and liver fibrosis markers during survodutide treatment are consistent with this theory, albeit without a control arm for comparison. Furthermore, the average glycated hemoglobin reductions suggest clinically meaningful improvements in glycemic control— particularly in the Child-Pugh B cohort (-0.73%), which had the highest mean baseline level (6.51%) and proportion of participants with T2D (75.0%).

[0223] Survodutide has demonstrated efficacy for MASH with earlier stages of fibrosis, and this trial provides safety and efficacy insights into its use in individuals with the most advanced disease stage, including decompensated cirrhosis. These patients have the highest rates of hepatic morbidity and mortality, creating an urgent unmet need for treatments for MASH cirrhosis.

[0224] The pharmacokinetics of survodutide in individuals with cirrhosis in this trial were consistent with phase 1 trials in healthy volunteers and those with overweight or obesity. These pharmacokinetic properties support once-weekly dosing with no need for dose adjustment in people with hepatic impairment. Furthermore, previous phase 1 trials were conducted exclusively in Germany and Japan, so this multinational study extends the pharmacokinetic data for survodutide to a more diverse population, including individuals in the US. The safety profile of survodutide in people with hepatic impairment in this trial was also generally consistent with previous studies, with gastrointestinal disorders being the predominant type of adverse event. The mean increase in heart rate after 28 weeks in participants with cirrhosis was slightly higher than in previous trials. In addition to the GLP-1 class effect on heart rate, this finding could reflect underlying portal hypertension and hyperdynamic state due to sympathetic activation in those participants.

[0225] A study limitation was the mostly White population, which may restrict its generalizability, although over one quarter were Hispanic / Latino. Furthermore, males were overrepresented in the singledose cohorts (85.4%); however, the sex ratio was balanced in the open-label, multiple-dose cohorts (51.2% male, 48.8% female). In addition, individuals with primary biliary cholangitis or primary sclerosing cholangitis were excluded, as were individuals with Child-Pugh C cirrhosis in open-label treatment. Although steady-state pharmacokinetic parameters were not calculated for open-label therapy, this is consistent with FDA guidance for hepatic impairment studies with compounds that exhibit linear pharmacokinetics, which enables accurate prediction of multiple-dose pharmacokinetics from single doses. Nevertheless, the different etiologies of cirrhosis in the singledose and open-label cohorts (predominantly alcohol-associated liver disease and MASH, respectively) could potentially influence pharmacokinetics. Additionally, the small sample size, open-label design, lack of therapeutic comparator, and relatively short treatment duration should be considered when drawing conclusions on the efficacy and safety of survodutide in cirrhosis. Conversely, this is the first trial to assess GLP-l-based therapy in people with decompensated cirrhosis.

[0226] Example 2

[0227] Clinical Trial Protocol:

[0228] A Phase III double-blind, randomised, placebo-controlled trial to evaluate liver-related clinical outcomes and safety of once weekly injected survodutide in participants with compensated nonalcoholic steatohepatitis / metabolic dysfunction associated steatohepatitis (NASH / MASH) cirrhosis.

[0229] Trial rationale

[0230] Chronic liver disease and the consequences of end-stage liver disease are increasing globally despite improved prevention. This is due to the emerging epidemics of obesity and metabolic syndrome that are leading to an increased incidence of MASH. MASH cirrhosis is a widely prevalent worldwide liver disease and is considered an advanced stage of MASH caused by metabolic- related dysfunction, where ongoing liver inflammation has caused hepatocyte damage with significant progression to fibrosis. To date, pharmacological therapy for MASH cirrhosis is very limited and usually non-liver-specific pharmacological management including weight loss, lifestyle changes, and pharmacotherapies associated with metabolic syndrome components is followed.

[0231] This Phase III trial aims to investigate the efficacy and safety of survodutide administered once weekly vs. placebo on liver-related outcome events and all-cause mortality in participants with compensated MASH cirrhosis.

[0232] Benefit-risk assessment and ethical considerations

[0233] For trial participants with compensated MASH cirrhosis, the expected benefit of participating in this trial is to stop or slow progression of fibrosis, prevent clinical decompensation and improve survival. Body weight and metabolic status are also anticipated to be improved in this population and, therefore, improving the overall health of the trial participants. The risks for participants caused by participation in the trial, including the trial procedures and exposure to the trial drug, are reasonably low and do not outweigh the potential benefits. The inclusion of the placebo comparator helps to better identify the difference between treated active arm with lifestyle modification versus lifestyle modification only in the placebo arm. Overall, the potential benefits, coupled with an acceptable safety profile and a well- controlled clinical trial environment support the initiation of the trial.

[0234] Trial objective(s)

[0235] The primary objective of this trial is to demonstrate superiority of survodutide compared with placebo by means of the hazard ratio (survodutide vs. placebo) ofttimes to composite endpoint that includes liver-related clinical outcome events, and all-cause mortality in participants with compensated MASH cirrhosis.

[0236] The secondary objectives are to demonstrate superiority of survodutide from baseline to Week 76 / EoS compared with placebo on

[0237] - The difference of means for absolute change in enhanced liver fibrosis (ELF) score (at Week 76) -The difference of means for percentage change in body weight (at Week 76)

[0238] -The difference of means for absolute change in glycosylated hemoglobin Ale (HbAlc) in participants with type 2 diabetes mellitus (T2DM) at baseline (at Week 76) - The difference of means for absolute change in liver stiffness in FibroScan®vibration-controlled transient elastography (VCTE) (at Week 76)

[0239] - The difference of means for percentage change in liver stiffness in Fi broScan® CTE (at Week 76)

[0240] - The hazard ratio for time to first occurrence of progression to clinically significant portal hypertension (CSPH) defined as new 'high-risk' gastroesophageal varices (GOV) formation confirmed in upper gastrointestinal endoscopy ( UG E) (at EoS)

[0241] - The hazard ratio for time to first occurrence of any of the hepatic decompensation events (ascites, hepatic encephalopathy [HE] or portal hypertension-related upper gastrointestinal [Gl] bleeding), or worsening of Model of End-Stage Liver Disease (MELD) score to 15 (at EoS)

[0242] - Occurrence of total all-cause hospitalization (first and recurrent) (at EoS)

[0243] - The hazard ratio for time to first occurrence of any of the adjudicated components of the composite endpoint consisting of cardiovascular (CV) death, non-fatal strake, non-fatal myocardial infarction (Ml), ischemia related coronary revascularization, or heart failure (HF) events (this includes hospitalization for HF [HHF], emergency room visit, urgent care visit, or urgent outpatient HF visit) (5P-MACE) (at EoS).

[0244] Trial endpoints. Primary endpoint:

[0245] Time to first occurrence of any component of the composite clinical endpoint (at EoS) consisting of:

[0246] All-cause mortality

[0247] Liver transplant

[0248] Hepatic decompensation events including: Ascites requiring treatment; HE requiring treatment; Portal hypertension-related upper Gl bleeding, including events of bleeding from esophageal varices, gastric varices, and portal hypertensive gastropathy (PHG).

[0249] Worsening of MELD score to >15

[0250] Progression to CSPH, defined as 'high-risk' GOVs confirmed in UGE (the 'high-risk' GOVs are defined as large varices)

[0251] Key secondary endpoints:

[0252] At Week 76:

[0253] Absolute change from baseline in ELF score Percentage change from baseline in body weight

[0254] Absolute change from baseline in HbAlc (%) in participants with T2DM at baseline

[0255] Absolute change from baseline in liver stiffness (kPA) in FibroScan®VCTE

[0256] Percentage change from baseline in liver stiffness in FibroScan® VCTE

[0257] At EoS:

[0258] Time to first occurrence of progression to CSPH (defined as 'high-risk' GOVs confirmed in UGE)

[0259] Time to first occurrence of any of the hepatic decompensation events (ascites, HE, or portal hypertension-related upper Gl bleeding), or worsening of MELD score to >15

[0260] Occurrence of all-cause hospitalization (first and recurrent)

[0261] Time to first occurrence of any of the adjudicated components of the composite endpoint consisting of: CV death, non-fatal stroke, non-fatal Ml, ischemia related coronary revascularization, or HF events (this includes HHF, emergency room visit, urgent care visit, or urgent outpatient HF visit) (5P- MACE)

[0262] Additional secondary endpoints:

[0263] At Week 76

[0264] Absolute changes from baseline in lipids (mg / dL) (including but not limited to: total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, free fatty acids)

[0265] Absolute change from baseline in AST (U / L)

[0266] Absolute change from baseline in ALT (U / L)

[0267] Absolute change from baseline in liver stiffness (kPA) assessed by magnetic resonance elastography (MRE) (sub-population of approximately 200 trial participants joining the magnetic resonance imaging [MRI] sub-study)

[0268] Trial design

[0269] Placebo-controlled, randomized, double-blind, parallel-group design comparison of 2 arms over approximately 4.5 years. Total number of trial participants randomized: Approximately 1590

[0270] Diagnosis, main inclusion and exclusion criteria

[0271] Main diagnosis

[0272] Compensated MASH cirrhosis with no current or history of hepatic decompensation events

[0273] Main inclusion criteria

[0274] • Male or female adults >18 years of age at the time of screening, and at least the legal age of consent in countries where it is >18 years

[0275] • BMI >27 kg / m2 (>25 kg / m2 for Asian trial participants)

[0276] • Compensated MASH cirrhosis diagnosed by 1 of the following:

[0277] A) The most recent liver biopsy (<5 years prior to randomization) showing cirrhosis with steatohepatitis. There is no evidence for a competing etiology (see NOTE 1 below).

[0278] B) Historical biopsy (<5 years prior to randomization) showed steatohepatitis with F1-F3 fibrosis, but now with cirrhosis either by non-invasive tests (NITs), or biopsy. There is no evidence of competing etiology. If there is a current biopsy (<6 months prior to randomization), and it does not show evidence of steatosis or steatohepatitis, there is at least 1 coexisting or history of metabolic comorbidity.

[0279] C) The most recent liver biopsy (<5 years prior to randomization) showing cirrhosis with steatosis. There are at least 2 coexisting metabolic comorbidities or history of metabolic comorbidities, including obesity and / or T2DM. There is no evidence for a competing etiology (see NOTE 1 below).

[0280] D) Historical biopsy (<5 years prior to randomization) showed steatosis, but now with cirrhosis, either by NITs, or biopsy. If there is a current biopsy (<6 months prior to randomization), and it does not show evidence of steatosis or steatohepatitis, there are at least 2 coexisting or history of metabolic comorbidities including obesity and / or T2DM. There is no evidence of competing etiology.

[0281] E) Trial participant with cirrhosis with current or previous imaging showing evidence of steatosis (by liver ultrasound or computed tomography [CT] scan or FibroScan® with Controlled Attenuation Parameter [CAP] >288 dB / m or magnetic resonance imaging proton density fat fraction [MRI-PDFF] >5%). There is no liver histology available. There are at least 2 coexisting or history of metabolic comorbidities, including obesity and / or T2DM. There is no evidence of competing etiology.

[0282] F) 'Cryptogenic cirrhosis' (either by clinical history or current features, imaging, NITs, or biopsy) without current or previous evidence of steatosis by imaging or steatosis / steatohepatitis by histology (not to exceed 5% of trial participants). There are at least 2 coexisting or history of metabolic comorbidities, including obesity and / or T2DM. There is no evidence of competing etiology.

[0283] NOTE 1: No weight loss of >10% should have occurred in the time period between biopsy and randomization (based on medical history).

[0284] NOTE 2: In the absence of a biopsy, cirrhosis is defined based on NITs at screening:

[0285] VCTE >20 kPa (if MRE not available) or MRE >5 kPa

[0286] VCTE >15 kPa and <20 kPa and 1 of the following:

[0287] ELF score >10.25, 2) MRE >4.2, or 3) Platelets

[0288] <150,000 / pL (<150 Gl / L)

[0289] VCTE >10 kPa and <15 kPa and 2 of the following:

[0290] ELF score >10.25, 2) MRE >4.2, or 3) Platelets

[0291] <110,000 / pL (<110 Gl / L)

[0292] NOTE 3: Metabolic comorbidities include hypertension, dyslipidemia, T2DM, or obesity.

[0293] MRI-PDFF fat fraction >5% or FibroScan® with CAP >288 dB / m, obtained during the screening period or a historic MRI-PDFF <12 weeks prior to randomization (except for patients with 'cryptogenic cirrhosis' where MRI-PDFF <5% or FibroScan®with CAP <288 dB / m is allowed). This inclusion criterion does not apply for participants with a recent (<12 months prior to randomization) liver biopsy showing steatosis / steatohepatitis. Main exclusion criteria

[0294] Liver related

[0295] • Current or history (<5 years) of significant alcohol consumption, defined as an average of >140 g / week in female patients and >210 g / week in male patients, for a period of >3 consecutive months, or an inability to reliably quantify alcohol consumption based upon judgment of the investigator.

[0296] • MELD score >12 due to liver disease

[0297] • History or current (i.e. at screening) hepatic decompensation event of any of the following but not limited to:

[0298] • History of portal hypertension-related upper Gl bleeding

[0299] • Ascites

[0300] • HE >Grade 1 according to the West Haven criteria

[0301] • Any of the following lab test result at screening

[0302] • Albumin below <3.5 g / dL (<35.0 g / L)

[0303] • INR >1.3 unless due to therapeutic anticoagulants

[0304] • NOTE: INR may be repeated once to reassess eligibility.

[0305] • Total bilirubin (TBL) >1 .2x ULN

[0306] • NOTE: Trial participants with Gilbert Syndrome are eligible with a TBL >1.2x upper limit of normal (ULN) if reticulocyte count is within normal limits, hemoglobin is within normal limits unless due to chronic anemia and unrelated to hemolysis, and direct bilirubin is <20% of TBL.

[0307] • Alkaline phosphatase >l.5x ULN

[0308] • Platelet count (PLT) <90,000 / pL (<90 Gl / L)

[0309] • History or evidence of other chronic liver diseases, such as primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis or overlap syndrome, Wilson's disease, alpha-1- antitrypsin deficiency, or genetic hemochromatosis

[0310] • Hepatitis B positive (defined as positive HBsAg) or history of chronic hepatits B virus (HBV) infection

[0311] • Hepatitis C positive (defined as positive hepatitis C virus [HCV] antibody and a positive HCV RNA), or history of chronic HCV infection

[0312] • Serum aspartate aminotransferase (AST) and / or alanine aminotransferase (ALT) >5x ULN

[0313] • History of liver transplantation or listed for liver transplantation History of transjugular intrahepatic portosystemic shunt (TIPS) or other radiological / surgical procedure for portal hypertension treatment

[0314] Glycemia:

[0315] HbAlc >10% (>86 mmol / mol) as measured by the central laboratory at screening History of T1DM or any other type than type 2 (e.g. endocrinopathy, genetic syndromes)

[0316] Uncontrolled and potentially unstable diabetic retinopathy or maculopathy, verified by an eye examination within 3 months before screening or in the period between screening and randomization

[0317] Other medical:

[0318] • Use of restricted medication

[0319] • Impaired renal function, defined as estimated glomerular filtration rate (eGFR) <30 mL / min / 1.73 m2 (Chronic Kidney Disease Epidemiology Collaboration creatinine equation [CKD-EPicr] ) at screening or trial participants requiring dialysis

[0320] • Known clinically significant gastric emptying abnormality (e.g. severe diabetic gastroparesis or gastric outlet obstruction)

[0321] • History of either chronic or acute pancreatitis or elevation of serum lipase or amylase >2x ULN as measured by the central laboratory at screening

[0322] • Trial participants who demonstrate recent evidence (within 6 months prior to screening) of acute or unstable CV events, e.g. hospitalization for HF, acute coronary syndrome, unstable angina, Ml, ischemic or hemorrhagic stroke, transient ischemic attack, and / or acute peripheral vascular event HF with New York Heart Association (NYHA) functional class IV or known left ventricular ejection fraction <20%

[0323] • QTc (Fridericia) mean interval that is greater than 500 ms at screening (triplicate electrocardiogram [ECG]) or personal or family history of long QT syndrome

[0324] • Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN 2) Trial intervention and test product: Survodutide

[0325] Dose and mode of administration: S.c. maintenance dose of 6.0 mg once weekly

[0326] Comparator product: Placebo

[0327] Dose and mode of administration: Matching s.c. injection

[0328] Duration of treatment

[0329] Trial participants will be treated with either survodutide or placebo in addition to their background medication, until the required number of clinical events for the primary endpoint is reached (estimated trial duration is approximately 4.5 years with a recruitment period of approximately 36 months). The trial duration may be prolonged or shortened depending on when the required number of 318 clinical events or the primary endpoint has been reached.

Claims

ClaimsWhat is claimed is:

1. Use of Compound 1 for the prevention or treatment of a metabolic liver disease, wherein Compound 1 is H-H-Ac4c-QGTFTSDYSKYLDERAAKDFI-K([17-carboxy-heptadecanoyl]-isoGlu-GSGSGG)-WLESA- NH2(SEQ ID NO:1), and wherein the metabolic liver disease is selected from the group consisting of MASH-associated liver cirrhosis, MASH-associated compensated liver cirrhosis (MASH cF4), MASH and compensated cirrhosis, or MASH-associated liver fibrosis and cirrhosis.

2. The use according to claim 1, wherein the metabolic liver disease is MASH-associated liver cirrhosis which is mildly decompensated.

3. The use according to claim 1, wherein the metabolic liver disease is MASH-associated compensated liver cirrhosis (MASH cF4).

4. The use according to any one of the previous claims, wherein the Compound 1 is administered once weekly.

5. The use according to the previous claim, wherein the Compound 1 is administered for at least 28 weeks.

6. The use according to claim 5, wherein dose escalation is performed from 0.3 mg Compound 1 at the beginning of treatment to a maintenance dose of 2.4, 4.8 or 6 mg, respectively.

7. The use according to claim 6, wherein the maintenance dose is 6 mg.

8. The use according to any one of the previous claims, wherein the patient has MASH-associated compensated liver cirrhosis (MASH cF4) with a Child-Turcotte-Pugh (CTP) cirrhosis class of A, B, or C.

9. The use according to any one of claims 1 to 7, wherein the patient has MASH-associated compensated liver cirrhosis (MASH cF4) with a Child-Turcotte-Pugh (CTP) cirrhosis class of B or C.

10. The use according to any one of claims 1 to 7, wherein the patient has MASH-associated compensated liver cirrhosis (MASH cF4) with a Child-Turcotte-Pugh (CTP) cirrhosis class of A.

11. The use according to any one of claims 1 to 7, wherein the patient has MASH-associated compensated liver cirrhosis (MASH cF4) with a Child-Turcotte-Pugh (CTP) cirrhosis class of B.

12. The use according to any one of the previous claims, wherein the absolute and / or percentage of the patient's liver fat is reduced.

13. The use according to any one of claims 1 to 11, wherein the percentage of the patient's liver fat is reduced by at least 30% from a baseline measurement, as measured by magnetic resonance imaging proton density fat fraction measurement.

14. The use according to any one of the previous claims, wherein after treatment for Week 24, the patient's liver stiffness is reduced.

15. The use according to claim 14, wherein the patient's liver stiffness is reduced by at least 0.5kPa or more from a baseline measurement, as measured by change in kPa via magnetic resonance elastography, and / or by transient elastography (FibroScan®).

16. The use according to claim 14, wherein the patient's liver stiffness is reduced by at least 0.8kPa or more from a baseline measurement, as measured by change in kPa via magnetic resonance elastography, and / or by transient elastography (FibroScan®).

17. The use according to any one of the previous claims, wherein the patient's Enhanced Liver Fibrosis (ELF) score is reduced.

18. The use according to claim 17, wherein the patient's Enhanced Liver Fibrosis (ELF) score is reduced by at least 0.4 or more.

19. The use according to claim 17, wherein the patient's Enhanced Liver Fibrosis (ELF) score is reduced by at least 0.5 or more.

20. The use according to any one of the previous claims, wherein the patient's N-terminal type III collagen propeptide (Pro-C3) is reduced.

21. The use according to claim 20, wherein the patient's Pro-C3 is reduced by a percentage change of about 10% or more from a baseline measurement.

22. The use according to claim 20, wherein the patient's Pro-C3 is reduced by a percentage change of about 20% or more from a baseline measurement.

23. The use according to any one of the previous claims, wherein the patient is diagnosed as being overweight or obese.

24. The use according to any one of claims 1 to 22, wherein the patient's BMI is greater than or equal to 27 kg / m2.

25. Compound 1 for use in a method of treating a metabolic liver disease, whereinCompound 1 is H-H-Ac4c-QGTFTSDYSKYLDERAAKDFI-K([17-carboxy-heptadecanoyl]-isoGlu- GSGSGG)-WLESA- / VH2(SEQ ID NO:1), and wherein the metabolic liver disease is selected from the group consisting of MASH -associated liver cirrhosis, MASH-associated compensated liver cirrhosis (MASH cF4), MASH and compensated cirrhosis, or MASH-associated liver fibrosis and cirrhosis.

26. Compound 1 for use in a method of treating a metabolic liver disease, wherein the method is defined in claim 25 and any one of claims 2 to 24.

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