Main Inclusion Criteria

• 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.
• BMI ≥ 27 kg/m2 (≥ 25 kg/m2 for Asian trial participants)
• Compensated MASH cirrhosis diagnosed by 1 of the following:
  • The most recent liver biopsy (≤ 5 years prior to randomisation) showing cirrhosis with steatohepatitis. There is no evidence for a competing aetiology.
  • Historical biopsy (≤ 5 years prior to randomisation) showed steatohepatitis with F1– F3 fibrosis, but now with cirrhosis either by clinical history or current features, imaging, non-invasive tests (NITs), or biopsy. There is no evidence of competing aetiology. If there is a current biopsy (≤ 6 months prior to randomisation), and it does not show evidence of steatosis or steatohepatitis, there is at least 1 coexisting or history of metabolic comorbidity.
  • The most recent liver biopsy (≤ 5 years prior to randomisation) 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 aetiology.
  • Historical biopsy (≤ 5 years prior to randomisation) showed steatosis, but now with cirrhosis, either by clinical history or current features, imaging, NITs, or biopsy. If there is a current biopsy (≤ 6 months prior to randomisation), 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 aetiology.
  • 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 aetiology.
  • ‘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 aetiology. NOTE 1: No weight loss of ≥ 10% should have occurred in the time period between biopsy and randomisation (based on medical history). NOTE 2: In the absence of a biopsy, cirrhosis is defined based on NITs at screening:  VCTE ≥ 20 kPa (if MRE not available) or MRE ≥ 5 kPa  VCTE ≥ 15 kPa and < 20 kPa and 1 of the following: 1) ELF score ≥ 10.25, 2) MRE ≥ 4.2, or 3) Platelets ≤ 150,000/µL (≤ 150 GI/L)  VCTE ≥ 10 kPa and < 15 kPa and 2 of the following: 1) ELF score ≥ 10.25, 2) MRE ≥ 4.2, or 3) Platelets ≤ 110,000/µL (≤ 110 GI/L) NOTE 3: Metabolic comorbidities include hypertension, dyslipidaemia, T2DM, or obesity.
• MRI-PDFF fat fraction ≥ 5% or FibroScan® with CAP ≥ 288 dB/m, obtained during the screening period or a historic MRI-PDFF or FibroScan® with CAP ≤ 12 weeks prior to randomisation (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 randomisation) liver biopsy showing steatosis/steatohepatitis.

Main Exclusion Criteria Liver related

• Current or history (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.
• MELD score >12 due to liver disease.
• History or current (i.e. at screening) hepatic decompensation event of any of the following but not limited to:
  • History of portal hypertension-related upper GI bleeding
  • Ascites
  • HE ≥ Grade 1 according to the West Haven criteria
• Any of the following lab test result at screening
  • Albumin below < 3 .5 g/dL (< 35.0 g/L)
  • INR > 1.3 unless due to therapeutic anticoagulants NOTE: INR may be repeated once to reassess eligibility.
  • Total bilirubin (TBL) > 1.2x ULN 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, haemoglobin is within normal limits unless due to chronic anaemia and unrelated to haemolysis, and direct bilirubin is < 20% of TBL.
  • Alkaline phosphatase > 1.5x ULN
  • Platelet count < 100,000/µL (< 100 GI/L)
• 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 haemochromatosis.
• Hepatitis B positive (defined as positive HBsAg)
• Hepatitis C positive (defined as positive HCV antibody and a positive HCV RNA)
• Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 5x ULN
• 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.

Glycaemia:

• HbA1c > 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)
• 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 randomisation

Other medical:

• Use of restricted medication.
• Impaired renal function, defined as estimated glomerular filtration rate (eGFR) 2x ULN as measured by the central laboratory at screening.
• Trial participants who demonstrate recent evidence (within 6 months prior to screening) of acute or unstable CV events, e.g. hospitalisation for HF, acute coronary syndrome, unstable angina, MI, ischaemic or haemorrhagic stroke, transient ischaemic attack, and/or acute peripheral vascular event.
• HF with New York Heart Association (NYHA) functional class IV or known left ventricular ejection fraction <20%.
• QTc (Fridericia) mean interval that is greater than 500 ms at screening (triplicate electrocardiogram [ECG]) or personal or family history of long QT syndrome.
• Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN 2).

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 8/09/2024. Questions regarding updates should be directed to the study team contact.