Semaglutide 2.4 mg gets US FDA approval for MASH

Subcutaneous (SC) semaglutide 2.4 mg QW is recently granted accelerated approval by the US FDA for treatment of metabolic dysfunction–associated steatohepatitis (MASH) in adults with moderate-to-advanced fibrosis.

The approval is based on week 72 interim analysis results of the ongoing, phase III, multicentre, randomized, double-blind, placebo-controlled ESSENCE trial, which showed significant improvements in liver histologic results with SC semaglutide 2.4 mg QW vs placebo. [N Engl J Med 2025;392:2089-2099]

In the trial, 1,197 adults with biopsy-defined MASH and fibrosis of stage 2 or 3 were randomized 2:1 to receive SC semaglutide 2.4 mg QW or placebo, in addition to standard care for MASH and related comorbidities, for 240 weeks.

The planned interim analysis at week 72 involved the first 800 patients enrolled (semaglutide 2.4 mg group: n=534; mean age, 56.3 years; female, 58.6 percent; Asian, 26.6 percent) (placebo group: n=266; mean age, 55.4 years; female, 54.1 percent; Asian, 27.8 percent).

Histologic reductions in steatohepatitis and fibrosis

At 72 weeks, significantly more patients in the semaglutide 2.4 mg vs placebo group achieved the first primary endpoint of resolution of steatohepatitis without worsening of liver fibrosis (62.9 vs 34.3 percent; estimated difference, 28.7 percentage points; 95 percent confidence interval [CI], 21.1–36.2; p<0.001).

Reduction in liver fibrosis without worsening of steatohepatitis, the second primary endpoint, was also achieved by significantly more patients in the semaglutide 2.4 mg vs placebo group at week 72 (36.8 vs 22.4 percent; estimated difference, 14.4 percentage points; 95 percent CI, 7.5–21.3; p<0.001).

In subgroup analyses according to age, sex, BMI, diabetes diagnosis, and fibrosis stage, these responses were consistent with those in the overall trial population.

Secondary endpoint and safety results

Combined resolution of steatohepatitis and reduction in liver fibrosis was achieved in 32.7 vs 16.1 percent of patients in the semaglutide 2.4 mg vs placebo group (estimated difference, 16.5 percentage points; 95 percent CI, 10.2–22.8; p<0.001).

Noninvasive testing, including enhanced liver fibrosis (ELF) score, liver stiffness, and FibroScan-AST (FAST) score, showed better results with semaglutide 2.4 mg vs placebo after 72 weeks, while reductions in aminotransferase levels were apparent as early as week 12.

Decrease in ELF score of ≥0.5 was achieved in more patients in the semaglutide 2.4 mg vs placebo group (55.8 vs 25.5 percent), as was decrease in liver stiffness of ≥30 percent (52.0 vs 30.3 percent).

Mean change in body weight was -10.5 vs -2.0 percent with semaglutide 2.4 mg vs placebo (estimated difference, -8.5 percentage points; 95 percent CI, -9.6 to -7.4; p<0.001). Mean changes in bodily pain scores, however, did not differ significantly between the two groups.

Positive effects on glycaemia, insulin resistance, systemic low-grade inflammation, lipids, steatosis, ballooning, and total nonalcoholic fatty liver disease activity score (NAS) were also observed with semaglutide 2.4 mg.

The safety profile of semaglutide 2.4 mg was consistent with the body of evidence for semaglutide, with no new safety signals identified and gastrointestinal adverse events being the most common.