Efimosfermin alfa (BOS-580) once per month in people with metabolic dysfunction-associated steatohepatitis with F2 or F3 fibrosis: results from a 24-week, randomised, double-blind, placebo-controlled, phase 2 trial

Abstract

Background: The growing prevalence of metabolic dysfunction-associated steatohepatitis (MASH) underscores the unmet need for effective and safe liver-targeted therapies to prevent fibrosis and disease progression. The aim of this study was to evaluate the efficacy and safety of efimosfermin alfa (henceforth referred to as efimosfermin, formerly BOS-580), an FGF21 analogue taken once per month, in patients with MASH and moderate or advanced fibrosis.

Methods: This 24-week, randomised, double-blind, placebo-controlled, phase 2 trial evaluated the safety and efficacy of efimosfermin in participants aged 18-75 years with a BMI of at least 27 kg/m² and MASH and F2 or F3 fibrosis present on a diagnostic liver biopsy done either during screening or within 6 months before the first day of dosing, and total activity Nonalcoholic Fatty Liver Disease Activity Score (NAS) of at least 4 with a minimum score of 1 point for all three NAS components (steatosis, hepatocyte ballooning, and lobular inflammation). The trial was conducted at 34 clinical research study sites in the USA. Participants were randomly assigned 1:1 to efimosfermin 300 mg or placebo administered by subcutaneous injection every 4 weeks (Q4W) over 24 weeks, stratified by MASH fibrosis stage (F2 vs F3 stage). Participants, investigators, and those assessing outcomes were masked to group assignment. The primary endpoint was safety and tolerability (ie, treatment-emergent adverse events, changes from baseline to week 24 in blood pressure and heart rate, and the incidence of grade 3 and grade 4 laboratory abnormalities at week 24), analysed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov (NCT04880031) and was completed on Sept 18, 2024.

Findings: Between May 4, 2023, and March 22, 2024, of 1171 participants screened, 84 participants were randomly assigned to efimosfermin 300 mg Q4W (n=43) or placebo (n=41); 44 (52%) were female and 40 (48%) were male. 48 (57%) had F2 fibrosis and 36 (43%) had F3 fibrosis; 65 had evaluable week-24 biopsy results. All 43 in the efimosfermin group and 40 of 41 participants in the placebo group received at least one dose. Adverse events were reported in 29 (67%) of 43 participants receiving efimosfermin and 22 (55%) of 40 receiving placebo. The majority of treatment-emergent adverse events were mild (24 [56%] of 43 in the efimosfermin group vs 15 [38%] of 40 in the placebo group) or moderate (18 [42%] vs 14 [35%]) in severity. Most frequent adverse events were gastrointestinal events, which were transient and occurred within the first few weeks of treatment. There were no clinically meaningful changes in vital signs between treatment and placebo groups, and no clinically significant grade 3 or higher laboratory abnormalities observed for either group. No deaths or adverse events greater than grade 3 were observed during the study.

Interpretation: In this phase 2 trial, treatment with efimosfermin once per month was generally well tolerated in participants with biopsy-confirmed MASH and F2 or F3 fibrosis. These results support the further development of efimosfermin for treatment of MASH-related fibrosis.

Funding: Boston Pharmaceuticals and GSK.