Phase 3 trial results of semaglutide in MASH with liver fibrosis

In an interim analysis of ESSENCE among patients with metabolic dysfunction–associated steatohepatitis (MASH) and liver fibrosis, subcutaneous semaglutide 2.4 mg once weekly resulted in histological reductions in steatohepatitis and fibrosis compared with placebo, with no new safety concerns.

This summary is based on the publication of Sanyal AJ, Newsome PN, Kliers I, et al. - Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. N Engl J Med. 2025 Jun 5;392(21):2089-2099. doi: 10.1056/NEJMoa2413258.

Introduction and methods

Background

Metabolic dysfunction–associated steatohepatitis (MASH; previously called nonalcoholic steatohepatitis) is characterized by steatosis, hepatocellular damage, and inflammation [1-3], which can lead to liver fibrosis, liver cirrhosis, and hepatocellular carcinoma [4,5]. Patients with MASH are also at increased risk of CVD [6]. In a previous phase 2 RCT among MASH patients with liver fibrosis, once-daily administration of subcutaneous semaglutide (0.1–0.4 mg) for 72 weeks resulted in a higher proportion of patients showing resolution of steatohepatitis with no worsening of fibrosis compared with placebo [7].

Aim of the study

The authors investigated the efficacy and safety of once-weekly subcutaneous semaglutide 2.4 mg in patients with MASH and liver fibrosis.

Methods

The ESSENCE (Effect of Semaglutide in Subjects with Non‐cirrhotic Non‐alcoholic Steatohepatitis) trial is an ongoing, international, multicenter, double-blind, placebo-controlled, phase 3 RCT in which 1197 patients with biopsy-defined MASH and fibrosis stage 2 or 3 according to the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) classification were randomized in a 2:1 ratio to subcutaneous semaglutide 2.4 mg once weekly or placebo for 240 weeks, in addition to standard care. The trial consists of 2 parts: Part 1 focuses on histological events, whereas the objective of part 2 are clinical outcomes.

The current analysis was a planned interim analysis conducted at 72 weeks and involving the first 800 randomized patients.

Outcomes

The primary efficacy endpoints of part 1 were: (1) resolution of steatohepatitis (i.e., nonalcoholic fatty liver disease activity score (NAS) for hepatocellular ballooning: 0 points, and NAS for inflammation: 0–1 points) with no worsening of liver fibrosis and (2) reduction in liver fibrosis (i.e., NASH CRN fibrosis scale reduction ≥1 stages) with no worsening of steatohepatitis, both assessed at 72 weeks. Confirmatory secondary efficacy endpoints, controlled for multiplicity, were tested hierarchically in the following order: change in body weight from baseline to 72 weeks, proportion of patients with both resolution of steatohepatitis and reduction in liver fibrosis at 72 weeks, and change in the bodily pain score on the 36-Item Short Form Health Survey (SF-36) from baseline to 72 weeks.

Key safety endpoints were adverse events and laboratory parameters.

Main results

Efficacy

• At 72 weeks, resolution of steatohepatitis with no worsening of liver fibrosis (first primary endpoint) was observed in 62.9% of the 534 patients treated with semaglutide and 34.3% of the 266 patients receiving placebo (estimated difference: 28.7 percentage points; 95%CI: 21.1–36.2; P<0.001).
• A reduction in liver fibrosis with no worsening of steatohepatitis at 72 weeks (second primary endpoint) occurred in 36.8% of the patients in the semaglutide group and 22.4% of those in the placebo group (estimated difference: 14.4 percentage points; 95%CI: 7.5–21.3; P<0.001).
• The mean percentage change in body weight from baseline to 72 weeks was −10.5% in the semaglutide group and −2.0% in the placebo group (estimated difference: −8.5 percentage points; 95%CI: −9.6 to −7.4; P<0.001).
• A higher proportion of patients in the semaglutide group demonstrated combined resolution of steatohepatitis and reduction in liver fibrosis compared with the placebo group (32.7% vs. 16.1%; estimated difference: 16.5 percentage points; 95%CI: 10.2–22.8; P<0.001).
• There was no statistically significant difference in the mean change in bodily pain score on the SF-36 from baseline to 72 weeks between semaglutide-treated patients and placebo-treated patients (0.9 vs. –0.5 points; estimated difference: 1.3; 95%CI: 0.0–2.7; P=0.05).

Safety

• In the safety analysis population (n=1195), the frequency of adverse events was 86.3% in the semaglutide group (n=800) and 79.7% in the placebo group (n=395). Most adverse events in both treatment groups were gastrointestinal disorders, including nausea, diarrhea, constipation, and vomiting.
• The rate of adverse events leading to study drug discontinuation was 2.6% in the semaglutide group and 3.3% in the placebo group, whereas the rate of serious adverse events was 13.4% in both groups.
• In total, 9 patients died (3 in semaglutide group and 6 in placebo group).

Conclusion

In this planned interim analysis of the ESSENCE trial among patients with MASH and moderate or advanced liver fibrosis, once-weekly administration of subcutaneous semaglutide 2.4 mg for 72 weeks resulted in more patients with histological reductions in steatohepatitis and liver fibrosis compared with placebo. The safety profile of semaglutide was consistent with that observed in previous trials. The authors believe semaglutide provides “a holistic therapeutic approach to both liver disease and associated cardiometabolic illnesses.”

Find this article online at N Engl J Med.

References

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