A study to test whether survodutide helps people living with obesity or overweight and with a confirmed or presumed liver disease called non-alcoholic steatohepatitis (NASH) to reduce liver fat and to lose weight

Prior treatment

• Previous or planned (during the trial period) treatment for obesity with surgery or a weight loss device, or prior surgery of the GI tract that could interfere with body weight. The following are allowed: (1) liposuction and/or abdominoplasty, if performed >1 year before screening, (2) lap banding, if the band has been removed >1 year before screening, (3) intragastric balloon, if the balloon has been removed >1 year before screening, (4) duodenal-jejunal bypass sleeve, if the sleeve has been removed >1 year before screening (5) appendectomy, (6) simple hernia repair, or (7) cholecystectomy.
• Intake of medications associated with liver injury, hepatic steatosis or steatohepatitis
• History of other chronic liver diseases (e.g. viral hepatitis, autoimmune liver disease, primary biliary cholangitis , primary sclerosing cholangitis, Wilson’s disease, hemochromatosis, A1At deficiency, history of liver transplantation). Hepatitis B and C testing will be done at Visit 1. Participants with positive HBsAg should be excluded. Participants 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. Trial patients with positive HCV antibody and no history of HCV treatment require a negative HCV RNA test at screening to be eligible for the trial.
• Current decompensated liver disease or previous hepatic decompensation (ascites, spontaneous bacterial peritonitis, portal hypertension bleeding, hepatic encephalopathy, hepatorenal syndrome).
• Previous or current evidence of portal hypertension (e.g. splenomegaly, oesophageal varices, or other portosystemic collateral pathways).
• Body weight variation (self-reported) >5% within 3 months before screening
• Medications for obesity within 3 months before screening

Other illness

• Current or history of significant alcohol consumption (defined as intake of >210 g/week in men and >140 g/week in women on average over a consecutive period of more than 3 months) or inability to reliably quantify alcohol consumption based on the investigator’s judgement within the last 5 years.
• Obesity induced by other endocrinologic disorders (i.e. Cushing Syndrome) or diagnosed monogenetic or syndromic forms of obesity (i.e. melanocortin 4 receptor deficiency, leptin deficiency, or Prader Willi Syndrome)
• Cirrhosis based on clinical assessment, abdominal imaging, liver histology or noninvasive tests assessed at screening (ELF ≥11.3, FIB4 ≥3.48, FibroScan® VCTE™ ≥20 kPa, or MRE ≥4.68 kPa), or history of cirrhosis.

Lab values

• Any of the following liver laboratory test abnormalities at screening: • Serum AST and/or ALT elevation ≥5x ULN • Total serum bilirubin concentration ≥1.2x ULN (except for cases of known Gilbert’s Syndrome) • Alkaline phosphatase >2x ULN • INR ≥1.3 (unless patient is on anticoagulants)

• Age ≥18 years at the time of signing informed consent, and at least the legal age of consent in countries where it is >18 years
• BMI ≥30 kg/m², OR BMI ≥27 kg/m² and at least one weight-related comorbidity at screening: • Hypertension (defined as repeated, i.e. at least 3 measurements in resting condition, SBP values of ≥140 mmHg and/or DBP values of ≥90 mmHg in the absence of antihypertensive treatment, or intake of at least 1 anti-hypertensive drug to maintain a normotensive blood pressure) • Dyslipidaemia (defined as at least 1 lipid-lowering treatment required to maintain normal blood lipid levels, or low-density lipoprotein [LDL] ≥160 mg/dL [≥4.1 mmol/L] or triglycerides ≥150 mg/dL [≥1.7 mmol/L], or high-density lipoprotein (HDL] <40 mg/dL (<1.0 mmol/L] for men or HDL<50 mg/dL (<1.3 mmol/L) for women • Obstructive sleep apnoea • Cardiovascular disease (e.g. heart failure with New York Heart Association [NYHA] functional class II-III, history of ischaemic or haemorrhagic stroke or cerebrovascular revascularisation procedure [e.g. carotid endarterectomy and/or stent], MI, coronary artery disease, or peripheral vascular disease) • T2DM (diagnosed at least 180 days prior to screening, with glycated haemoglobin [HbA1c] ≥6.5% [48 mmol/mol] and <10% [86 mmol/mol] as measured by the central laboratory at screening)
• Presumed/confirmed NASH: Evidence of hepatic steatosis (defined by an MRIPDFF ≥8% at screening) with the exclusion of secondary causes of hepatic fat accumulation such as significant alcohol consumption, other chronic liver diseases and/or steatogenic medications, AND at least one of the following: • MRE ≥2.61 and <4.68 kPa at screening, OR • MAST score ≥0.242 at screening, when MAST score = exp(MAST)/(1+exp[MAST]), where MAST = -12.17 + 7.07 logMRE + 0.037 PDFF + 3.55 log AST OR • FAST score ≥0.5 at screening, OR • FibroScan® VCTE™ ≥8 kPa and <20 kPa at screening, OR • FIB-4 score ≥2.67 and <3.48 at screening, OR • ELF score >7.7 and <11.3 at screening, OR • cT1 ≥875 ms at screening, OR • Recent liver biopsy (within 3 years of screening) consistent with NASH (defined as the presence of steatosis, inflammation, and ballooning) with stage ≤3 fibrosis according to the NASH Clinical Research Network classification.
• History of at least one self-reported unsuccessful dietary effort to lose body weight