Semaglutide Improves Steatohepatitis, Fibrosis in Phase 3 MASH Trial

New phase 3 data are shedding light on the safety and efficacy of semaglutide for the treatment of patients with metabolic dysfunction–associated steatohepatitis (MASH) and stage 2/3 fibrosis.1

Results from part 1 of the phase 3 Effect of Semaglutide in Subjects with Non-cirrhotic Non-alcoholic Steatohepatitis (ESSENCE) trial published in The New England Journal of Medicine show once-weekly semaglutide 2.4 mg outperformed placebo for resolution of steatohepatitis without worsening of fibrosis and reduction in liver fibrosis without worsening of steatohepatitis.1

“The ESSENCE data may represent key findings for patients in the treatment of MASH, which is estimated to affect about one in 20 adults in the US,” Arun Sanyal, MD, ESSENCE lead author and director of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University, said in a press release.2 “By treating both liver disease and its metabolic causes, semaglutide offers a promising new approach for millions of patients.”

Resmetirom (Rezdiffra), a thyroid hormone receptor-β selective agonist, is the only FDA-approved treatment for noncirrhotic MASH.3 However, semaglutide is one of several agents currently in clinical development for the progressive liver disease.

An ongoing phase 3, multicenter, randomized, double-blind, placebo-controlled trial, ESSENCE is being conducted at 253 clinical sites in 37 countries. It enrolled adult patients with biopsy-defined MASH and fibrosis stage 2 or 3 who were randomly assigned in a 2:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo for 240 weeks.1

In the semaglutide group, the starting dose was 0.25 mg once weekly, increased every 4 weeks to once-weekly doses of 0.5 mg, 1.0 mg, 1.7 mg, and 2.4 mg until the target dose of 2.4 mg was reached after the 16-week dose-escalation period.1

In part 1 of the trial, a planned interim analysis at week 72 involving the first 800 patients, the primary end points were a resolution of steatohepatitis, defined as a nonalcoholic fatty liver disease activity score of 0 for ballooning and 0 to 1 for inflammation, with no worsening of liver fibrosis and a reduction in liver fibrosis, defined as ≥ a 1-stage reduction on the Nonalcoholic Steatohepatitis Clinical Research Network fibrosis scale, with no worsening of steatohepatitis.1

From May 2021 to April 2023, a total of 1197 patients underwent randomization, 1195 of whom were included in the overall safety population. Part 1 of the trial included 534 patients in the semaglutide 2.4 mg group and 266 patients in the placebo group.1

The mean age of the total population was 56.0±11.6 years and most patients were White (67.5%) and female (57.1%).1

Part 1 results showed resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of the semaglutide group and in 34.3% of the placebo group, with an estimated difference of 28.7 percentage points (95% confidence interval [CI], 21.1 to 36.2; P <.001). Additionally, a reduction in liver fibrosis without worsening of steatohepatitis was reported in 36.8% of the semaglutide group and in 22.4% of the placebo group (estimated difference, 14.4 percentage points; 95% CI, 7.5 to 21.3; P <.001).1

Further analysis of secondary endpoints revealed combined resolution of steatohepatitis and reduction in liver fibrosis occurred in 32.7% of the semaglutide group and in 16.1% of the placebo group (estimated difference, 16.5 percentage points; 95% CI, 10.2 to 22.8; P <.001). The mean change in body weight was −10.5% with semaglutide and −2.0% with placebo (estimated difference, −8.5 percentage points; 95% CI, −9.6 to −7.4; P <.001).1

The mean change from baseline at week 72 for the bodily pain score on the SF-36 was 0.9 in the semaglutide group and −0.5 in the placebo group, indicating less pain with semaglutide (estimated difference, 1.3; 95% CI, 0.0 to 2.7; P = .05), but investigators noted this finding did not meet the prespecified criteria for statistical significance (P <.0045).1

Regarding safety, 86.3% of patients in the semaglutide group reported an adverse event compared with 79.7% in the placebo group, the most common of which were gastrointestinal disorders. Investigators noted nausea, diarrhea, constipation, and vomiting were more common in the semaglutide group. Serious adverse events were reported by 13.4% of patients in each group.1

“I’ve been working with GLP-1 treatments for sixteen years and these results are hugely exciting. MASLD is a growing problem worldwide and this trial will provide real hope for patients with MASH,” Philip Newsome, MBBS, PhD, director of the Roger Williams Institute of Liver Studies at King’s College London, said in a press release.4 “While these results must be treated with caution, the analysis shows semaglutide can be an effective tool to treat this advanced liver disease.”

References

1. Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 Trial of Semaglutide in Metabolic Dysfunction–Associated Steatohepatitis. N Engl J Med. doi:10.1056/NEJMoa2413258

2. Virginia Commonwealth University. VCU-led research highlights semaglutide’s potential for treating fatty liver disease. EurekAlert! April 30, 2025. Accessed April 30, 2025. https://www.eurekalert.org/news-releases/1082059

3. Brooks A. Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH. HCPLive. March 14, 2024. Accessed April 30, 2025. https://www.hcplive.com/view/resmetirom-rezdiffra-receives-historic-fda-approval-for-noncirrhotic-nash

4. King’s College London. Semaglutide treats liver disease in two thirds of patients. EurekAlert! April 30, 2025. Accessed April 30, 2025. https://www.eurekalert.org/news-releases/1081951