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Efimosfermin showed promise in reducing liver fat and maintaining safety across multiple doses in adults with phenotypic MASH.  

A study published in the June 2025 issue of Lancet Gastroenterology and Hepatology described Metabolic dysfunction-associated steatohepatitis (MASH) as a progressive liver disease marked by steatosis, inflammation, and fibrosis, and explored efimosfermin alfa as a long-acting FGF21 analogue with extended biological activity.  

Researchers assessed the safety and tolerability of multiple efimosfermin dosing regimens compared with placebo and examined exploratory efficacy biomarkers in individuals with phenotypic MASH.  

They carried out a phase 2a trial at 12 centers in the USA. Adults aged 18–75 years with phenotypic MASH and BMI between 30–45 kg/m² were enrolled. Participants were randomly assigned to 1 of 5 dosing cohorts: efimosfermin 75 mg every 4 weeks, 75 mg every 2 weeks, 150 mg every 4 weeks, 150 mg every 2 weeks, or 300 mg every 4 weeks for 12 weeks. All cohorts except the 150 mg every 4 weeks group followed a 1:1:1:1 ratio; this cohort was added after the others were filled. Within each cohort, participants were randomized 4:1 to receive efimosfermin or placebo via subcutaneous injection, using fixed blocks of 5. Randomization was performed centrally without stratification. Investigators and participants remained blinded to allocation. Safety and tolerability were the primary endpoints, assessed throughout the 12-week period and at a 4-week post-treatment follow-up. The full analysis set included all enrolled participants who received at least 1 dose of the study drug.  

The results showed that between Aug 27, 2021, and July 22, 2022, 360 individuals were screened, and 102 were eligible and randomly assigned to receive either placebo (n=37) or efimosfermin at 75 mg every 4 weeks (n=8), 75 mg every 2 weeks (n=14), 150 mg every 4 weeks (n=15), 150 mg every 2 weeks (n=15), or 300 mg every 4 weeks (n=13) over 12 weeks. Of the 102 participants, 45 (44%) were female and 57 (56%) were male, with a mean age of 53 years (SD 11) and a mean BMI of 36.5 kg/m² (SD 4.1). Among 65 individuals receiving efimosfermin, 43 (66%) reported treatment-emergent adverse events (TEAEs), compared to 18 (49%) of 37 in the placebo group. The TEAEs occurred in 4 (50%) of 8 receiving 75 mg every 4 weeks, 10 (71%) of 14 receiving 75 mg every 2 weeks, 6 (40%) of 15 receiving 150 mg every 4 weeks, 12 (80%) of 15 receiving 150 mg every 2 weeks, and 11 (85%) of 13 receiving 300 mg every 4 weeks. Most TEAEs were mild to moderate and self-limiting. Gastrointestinal symptoms were the most common, reported in 9 (24%) of 37 placebo recipients and 26 (40%) of 65 efimosfermin-treated participants. No treatment-related deaths occurred. At week 12, at least a 30% reduction in hepatic fat fraction was observed in 47 (89%) of 53 efimosfermin-treated individuals with available data: 5 (63%) of 8 receiving 75 mg every 4 weeks, 11 (92%) of 12 receiving 75 mg every 2 weeks, 9 (90%) of 10 receiving 150 mg every 4 weeks, 11 (92%) of 12 receiving 150 mg every 2 weeks, and all 11 (100%) receiving 300 mg every 4 weeks, compared to 2 (7%) of 30 placebo recipients.  

Investigators concluded that efimosfermin was well tolerated and led to meaningful reductions in hepatic steatosis among individuals with phenotypic MASH. 

Source: thelancet.com/journals/langas/article/PIIS2468-1253(25)00067-6/abstract