Phase 3 Randomized Double‑Blind Placebo‑Controlled Study of Efimosfermin Alfa Safety and Tolerability in Adults with F2‑F3 Metabolic Dysfunction‑Associated Steatohepatitis

The primary objective is to evaluate the safety and tolerability of EFIMOSFERMIN ALFA in participants with known or suspected F2‑ or F3‑stage Metabolic Dysfunction-Associated Steatohepatitis (MASH), providing essential data for risk‑benefit assessment in this population.

• Assess the effect of efimosfermin on the Enhanced Liver Fibrosis (ELF) score.
• Assess the effect of efimosfermin on vibration‑controlled transient elastography liver stiffness measurement (VCTE‑LSM) score.
• Assess the effect of efimosfermin on magnetic resonance elastography (MRE) score.
• Assess the effect of efimosfermin on hepatic fat fraction (HFF) and alanine aminotransferase (ALT) normalization.
• Assess the effect of efimosfermin on glycemic and metabolic biomarkers.
• Assess the effect of efimosfermin on lipid parameters.
• Assess the immunogenicity of efimosfermin.
• Assess the steady‑state pharmacokinetic profile of efimosfermin.

The trial enrolled 1,040 adult participants aged 18 to 75 years, inclusive of both female and male individuals. All subjects were required to have a documented history or current presence of at least two of the five criteria defining metabolic syndrome according to the American Heart Association, and a confirmed or suspected diagnosis of Metabolic Dysfunction-Associated Steatohepatitis (MASH). Eligibility required the ability to provide informed consent. The population comprised patients meeting these clinical characteristics; no specific dietary, physical activity, or habit restrictions were stipulated in the protocol. The selection process targeted individuals with the defined metabolic and hepatic profile, without further detail on exclusion criteria.

The study is a Phase 3, randomized, double‑blind, placebo‑controlled trial with three parallel arms evaluating subcutaneous efimosfermin alfa versus placebo in adults aged 18–75 years with known or suspected Metabolic Dysfunction-Associated Steatohepatitis (MASH); participants undergo a screening visit to confirm eligibility, followed by baseline randomization and subsequent visits at weeks 4, 12, 24, 36, and 52 for safety assessments, laboratory monitoring, and efficacy measurements, with the final end‑of‑study visit at week 52; total participant involvement spans approximately 52 weeks, and subjects may be withdrawn early for serious adverse events, discontinuation due to treatment‑emergent adverse events, or protocol non‑compliance; primary safety endpoints focus on the incidence and severity of treatment‑emergent adverse events and grade 3–4 laboratory abnormalities at week 52, while secondary endpoints assess changes in ELF score, VCTE‑LSM, MRI‑PDFF, liver enzymes, metabolic parameters, and immunogenicity.

The investigational product is Efimosfermin alfa, supplied as a powder for solution for injection and administered by the subcutaneous route. Each dose consists of 0 mg of the active substance, prepared according to the study‑specified reconstitution procedure and delivered as a single injection.

The comparator is a matching placebo for Efimosfermin alfa, provided in a formulation identical in appearance to the active product but containing no active pharmaceutical ingredient.

Both study interventions are given according to the dosing schedule defined in the protocol, with administration performed by qualified personnel at each study visit. Participant compliance is monitored through documented dosing records, inspection of used vials, and adherence checks conducted at each scheduled visit. The trial enrolls individuals with known or suspected Metabolic Dysfunction-Associated Steatohepatitis (MASH) at fibrosis stages F2 or F3, and safety and tolerability are the primary endpoints.

Efficacy will be assessed by quantifying the absolute and relative changes from baseline to Week 52 in a series of biomarkers and imaging parameters. These include the ELF score, the VCTE‑LSM score, magnetic resonance elastography (MRE) scores, hepatic fat fraction measured by MRI‑PDFF (HFF), serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and the ALT/AST ratio, the proportion of participants achieving normalization of ALT and HFF, the proportion attaining HFF ≤ 5 %, glycated haemoglobin (HbA1c) in participants with type‑2 diabetes mellitus, body weight, fasting total cholesterol, LDL‑C, HDL‑C and triglycerides, incidence of anti‑drug antibodies (ADAs), and efimosfermin serum concentrations in participants with pharmacokinetic data.

All efficacy parameters will be measured at baseline and at the Week 52 visit. Changes will be calculated as both absolute differences and percentage changes from baseline. Pre‑specified categorical outcomes, such as achieving an ELF score improvement of ≥ 0.5, a ≥ 30 % reduction in VCTE‑LSM, and normalization criteria for ALT and HFF, will be derived from these measurements. Statistical analyses will compare each treatment arm to placebo using appropriate summary statistics and inferential methods to evaluate the magnitude and significance of the observed effects.