The purpose of this study is to assess the safety and efficacy of efimosfermin alfa in the resolution of steatohepatitis and improvement of liver-related clinical outcome compared to placebo in individuals with MASH and biopsy-confirmed F2- or F3-stage fibrosis.
Able and willing to understand and sign a written informed consent form that must be obtained prior to the initiation of study procedures
Age >=18 and <=75 years at enrollment
History or presence of 2 or more of the 5 components of metabolic syndrome per American Heart Association definition
Liver biopsy confirmation of MASH consistent with stage F2 or F3 fibrosis and a NAS score >=4 confirmed by a central pathologist
Contraindication or ineligibility for percutaneous liver biopsy
ALT or AST >=5 x upper limit of normal (ULN)
Total bilirubin >=1.3 milligram per deciliter (mg/dL). Individuals with documented Gilbert's syndrome may be enrolled if they experienced an isolated increase in total bilirubin of >=1.3 mg/dL and direct bilirubin is <=20% of total bilirubin; otherwise, the individual will be excluded.
Serum albumin <=3.5 grams per deciliter (g/dL)
Parallel
Efimosfermin alfa
DrugEfimosfermin alfa will be administered
Efimosfermin alfa
DrugEfimosfermin alfa will be administered
Placebo
DrugPlacebo will be administered
Proportion of participants experiencing improvement in fibrosis by >=1 stage and no worsening of steatohepatitis at Week 52
Proportion of participants experiencing improvement in fibrosis of greater than or equal to (\>=) 1 stage by MASH clinical research network (CRN) fibrosis scores and no worsening of steatohepatitis (defined as no increase in nonalcoholic fatty liver disease activity score \[NAS\] for ballooning, inflammation, or steatosis) at 52 weeks will be assessed. MASH CRN fibrosis score ranges from 0 to 4, higher score indicates greater severity. NAS score ranges from 0 to 8, higher score indicates worse disease activity.
Proportion of participants experiencing resolution of steatohepatitis reading and no worsening of MASH CRN fibrosis score at Week 52
Resolution of steatohepatitis is defined as absence of fatty liver disease or isolated or simple steatosis without steatohepatitis and a NAS of 0 or 1 for inflammation, 0 for ballooning, and any value for steatosis. NAS score ranges from 0 to 8, higher score indicates worse disease activity. MASH CRN fibrosis score ranges from 0 to 4, higher score indicates greater severity.
Time from randomization to an adjudicated composite liver-related clinical outcome
Liver-related outcome will comprised of all-cause mortality; transplantation; occurrence of significant hepatic events.
Number of participants with treatment-emergent adverse events (TEAEs) and TEAEs by severity
Number of participants with TEAEs leading to discontinuation and TEAEs leading to discontinuation by severity
Number of participants with Grade 3 and Grade 4 laboratory abnormalities
Proportion of participants experiencing resolution of steatohepatitis on overall histopathological reading and improvement in liver fibrosis of >=1 stage at Week 52
Resolution of steatohepatitis is defined as absence of fatty liver disease or isolated or simple steatosis without steatohepatitis on overall histopathological reading on liver biopsies. Proportion of participants experiencing improvement in fibrosis of \>=1 stage by MASH CRN fibrosis scores and resolution of steatohepatitis on overall histopathological reading at 52 weeks will be assessed. MASH CRN fibrosis score ranges from 0 to 4, higher score indicates greater severity
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