A Phase III, randomized, double-blind, placebo-controlled, three-arm study to investigate the safety and tolerability of efimosfermin alfa in participants with known or suspected F2- or F3-Stage metabolic dysfunction-associated steatohepatitis (MASH) (ZENITH-2)
Metabolic dysfunction-associated steatohepatitis (MASH)
Participants will be randomized in a 2:2:1 ratio to receive 225 mg efimosfermin, 300 mg efimosfermin, or placebo. The study drug will be administered and dispensed at study visits Q4W for a period of up to 52 weeks. The total time of participation in the study, inclusive of screening and safety follow-up, is approximately 64 weeks. Since injection volumes for the 225-mg and 300-mg efimosfermin arms are 1.5 ml and 2.0 ml, respectively, additional measures will be implemented to preserve the study blind. Instructions are provided in the pharmacy manual. Criteria are established in this protocol for dose interruption, modification, discontinuation, and resumption based on investigator discretion and following consultation with the study medical monitor (the sponsor or designee) in specific circumstances.
1. Able and willing to understand and sign a written informed consent form (ICF) that must be obtained prior to the initiation of study procedures 2. Age >=18 through <=75 years at enrolment 3. History or presence of 2 or more of the 5 components of metabolic syndrome per American Heart Association definition 4. History or presence of known or suspected MASH
1. ALT or AST >=5 × upper limit of normal (ULN). 2. Total bilirubin (BILI) >=1.3 mg/dl. Individuals with documented Gilbert's syndrome may be enrolled if they experienced an isolated increase in total BILI of >=1.3 mg/dL and direct BILI is <=20% of total BILI; otherwise, the individual will be excluded. 3. Serum albumin <=3.5 g/dl 4. International normalized ratio (INR) >=1.3 not due to therapeutic anticoagulation. Individuals receiving chronic anticoagulant treatment with higher INR values may be enrolled at the discretion of the Investigator and Study Medical Monitor. 5. Alkaline phosphatase (ALP) >=2 × ULN 6. Platelet (PLT) count <140,000/mm³; individuals with a PLT count between 110,000/mm³ and 140,000/mm³ may be enrolled after discussion with the Study Medical Monitor 7. Serum creatinine >=1.5 mg/dL or creatinine clearance <=60 ml/min/1.73 m² by the Chronic Kidney Disease Epidemiology Collaboration equation. 8. HbA1c >=9.0% 9. International normalized ratio (INR) >=1.3 not due to therapeutic anticoagulation. Individuals receiving chronic anticoagulant treatment with Model for End-Stage Liver Disease (MELD) 3.0 score >=12 unless the score is elevated in the absence of liver dysfunction (eg, Gilbert's syndrome). 10. Phosphatidylethanol (PEth) >=80 ng/ml at screening. 11. Known co-infection with any of the following: 11.1. Human immunodeficiency virus 11.2. Hepatitis B virus 11.3. Hepatitis C virus (HCV) 11.4. Hepatitis D virus 11.5. Hepatitis E virus 12. Chronic liver disease from any other cause including, but not limited to, alcoholic liver disease; evidence of portal hypertension; viral hepatitis, or any history or evidence of cirrhosis; or decompensated liver disease such as clinical ascites, bleeding gastroesophageal varices, hepatorenal syndrome, or hepatic encephalopathy prior to Screening or Day 1. 13. Current or history of excessive alcohol intake for >=3 months within the 12-month period prior to Screening