In a newly published phase III clinical trial, once-weekly semaglutide demonstrated efficacy in treating metabolic dysfunction–associated steatohepatitis with liver fibrosis. The ESSENCE trial results showed that the glucagon-like peptide-1 receptor agonist achieved both primary histologic endpoints with statistical significance.
In the trial, researchers assigned 1,197 patients with biopsy-confirmed metabolic dysfunction–associated steatohepatitis (MASH) and stage II or III fibrosis in a 2:1 ratio to receive either subcutaneous semaglutide (2.4 mg weekly) or placebo for 240 weeks. The current publication reported results from a planned interim analysis of the first 800 patients at week 72 (part 1 of the trial).
After 72 weeks of treatment, resolution of steatohepatitis—defined as a nonalcoholic fatty liver disease activity score (NAS) of 0 for hepatocyte ballooning and 0 to 1 for inflammation—without worsening of liver fibrosis occurred in 62.9% of the patients in the semaglutide group compared with 34.3% of those in the placebo group (estimated difference = 28.7 percentage points;, 95% confidence interval [CI] = 21.1–36.2, P < .001). Similarly, reduction in liver fibrosis by at least one stage without worsening of steatohepatitis was observed in 36.8% of the semaglutide-treated patients vs 22.4% of the placebo recipients (estimated difference = 14.4 percentage points, 95% CI = 7.5–21.3, P < .001).
Lead study author Arun J. Sanyal, MD, of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, and colleagues noted that combined resolution of steatohepatitis and reduction in liver fibrosis was achieved in 32.7% of the patients receiving semaglutide vs 16.1% of those receiving placebo (P < .001).
"In patients with MASH and moderate or advanced liver fibrosis, once-weekly semaglutide at a dose of 2.4 mg improved liver histologic results," stated the study authors.
The semaglutide group also experienced significantly greater weight loss (−10.5% vs −2.0% with placebo, P < .001). Positive treatment effects were observed in glycemia, insulin resistance, and multiple noninvasive markers of liver health, including enhanced liver fibrosis score and liver stiffness.
Regarding safety, 88.0% of patients in the semaglutide group maintained the target dose until week 72. Gastrointestinal adverse events were more common with semaglutide, with nausea (36.2% vs 13.2%), diarrhea (26.9% vs 12.2%), constipation (22.2% vs 8.4%), and vomiting (18.6% vs 5.6%) occurring most frequently. However, the incidence of serious adverse events was similar between the groups (13.4% in both arms).
The findings may be particularly significant given the limited treatment options for MASH. Currently, only resmetirom has received accelerated approval from the U.S. Food and Drug Administration for MASH with stage II or III liver fibrosis. This part 1 analysis focused on histologic endpoints, while the ongoing trial (continuing to 240 weeks) will assess effects on clinical outcomes, including cirrhosis-free survival.
