Phase 3 Randomized Double‑Blind Placebo‑Controlled Study of Efimosfermin Alfa in Adults with Biopsy‑Confirmed F2–F3 Metabolic Dysfunction‑Associated Steatohepatitis

The primary objective is to evaluate the effect of subcutaneous efimosfermin alfa compared with placebo on Metabolic Dysfunction-Associated Steatohepatitis by assessing histologic resolution of disease activity and improvement in fibrosis after 52 weeks of treatment, and by determining the time to a composite clinical outcome during up to 48 months of therapy.

Secondary objectives include:

• Assessment of safety and tolerability.
• Evaluation of histologic resolution and fibrosis improvement at both 52 weeks and 48 months.
• Measurement of liver stiffness (VCTE‑LSM) and controlled attenuation parameter (CAP) scores.
• Assessment of magnetic resonance elastography (MRE) score.
• Evaluation of the Enhanced Liver Fibrosis (ELF) score.
• Determination of hepatic fat fraction (HFF) and alanine aminotransferase (ALT) normalization.
• Analysis of glycemic and metabolic biomarkers.
• Evaluation of lipid profile changes.
• Assessment of immunogenicity.
• Evaluation of patient‑reported outcomes.
• Characterization of steady‑state pharmacokinetics.

The trial enrolled 1,027 adult participants, both female and male, aged 18 to 75 years, who were diagnosed with Metabolic Dysfunction-Associated Steatohepatitis (MASH) and met criteria for metabolic syndrome. Enrollment required documented liver biopsy confirming stage F2 or F3 fibrosis with a NAFLD Activity Score of at least 4, as assessed by a central pathologist, and the presence of two or more components of metabolic syndrome according to the American Heart Association definition. All subjects provided written informed consent prior to any study procedures. General health status was characterized by the underlying liver disease and associated metabolic abnormalities; no specific dietary or physical‑activity restrictions were imposed beyond those inherent to the metabolic syndrome criteria. Selection was based on these histologic and clinical parameters to ensure a homogeneous population of patients with clinically significant MASH.

The study is a Phase 3, randomized, double‑blind, placebo‑controlled, three‑arm trial evaluating the safety and efficacy of subcutaneous efimosfermin alfa in adults with biopsy‑confirmed Metabolic Dysfunction‑Associated Steatohepatitis (MASH) stage F2 or F3. After obtaining written informed consent, a screening visit confirms eligibility criteria, including age 18‑75, metabolic‑syndrome components, and central pathology review of liver biopsy. Eligible participants are randomized in a 1:1:1 ratio to receive efimosfermin alfa, an alternative dose (if applicable), or matching placebo, administered subcutaneously for 52 weeks. Follow‑up visits are scheduled at weeks 4, 12, 24, 36, and 52 to collect safety data, laboratory tests, imaging, and histologic assessments; an additional extended visit occurs at month 48 for analysis of the composite liver‑related clinical outcome. The end‑of‑study visit at week 52 (or month 48 for extended follow‑up) includes a repeat biopsy, final safety evaluations, and study drug discontinuation. Participant involvement therefore extends approximately one year, with optional observation up to 48 months. Early termination may be triggered by serious adverse events, non‑adherence to dosing, withdrawal of consent, or major protocol violations. Recruitment is planned to begin in July 2026 and conclude in December 2031.

The investigational product, efimosfermin alfa, is supplied as a powder for solution for injection intended for subcutaneous administration. The protocol specifies a dose of 0 mg per injection; the exact dosing schedule and interval are defined by the study design.

The comparator arm receives a placebo formulated for efimosfermin alfa. The placebo is presented as a non‑active preparation with no pharmaceutical form, dose, or route applicable, matching the appearance of the active product to maintain blinding.

All study injections are administered by qualified personnel in a clinical setting. Dosing adherence is monitored through site‑generated administration records and participant‑completed dosing diaries. Compliance assessments are performed at each scheduled visit to ensure protocol‑defined administration intervals are maintained throughout the trial period.

Efficacy will be evaluated using predefined histologic, imaging, laboratory, and patient‑reported endpoints. The primary histologic endpoints at Week 52 are the proportion of participants achieving improvement in fibrosis by ≥1 stage without worsening of steatohepatitis, and the proportion achieving resolution of steatohepatitis without worsening of the MASH CRN fibrosis score. A time‑to‑event analysis will assess the interval from randomization to a centrally adjudicated composite liver‑related clinical outcome over up to 48 months of treatment.

Secondary efficacy assessments include histologic measures of steatohepatitis resolution and fibrosis improvement at Week 52 and Month 48, quantitative changes from baseline in imaging biomarkers such as VCTE‑LSM and CAP scores, magnetic resonance elastography (MRE) scores, ELF score, and hepatic fat fraction measured by MRI‑PDFF. Laboratory parameters (ALT, AST, ALT/AST ratio, fasting lipids, HbA1c, and body weight) will be measured at baseline, Week 52, and Month 48. Patient‑reported outcomes will be captured using the CLDQ‑NASH and SF‑36 instruments at the same time points. Serum concentrations of efimosfermin alfa will be quantified to support exposure‑response analyses.