Efinopegdutide Improves MASH Resolution, Fibrosis in Phase 2b Trial

Efinopegdutide, an investigational once-weekly glucagon-like peptide-1 (GLP-1)/glucagon receptor co-agonist, significantly increased resolution of metabolic dysfunction-associated steatohepatitis (MASH) without worsening of fibrosis compared with placebo in adults with F2-F3 fibrosis, according to phase 2b results presented at AASLD The Liver Meeting 2026.¹

The 7 mg dose improved fibrosis by at least 1 stage in approximately half of participants at 1 year.¹

Jörn Schattenberg, MD, of Saarland University Medical Center in Homburg, Germany, presented the results and discussed them in an interview with HCPLive. He described a shift in MASH drug development toward mechanisms targeting the liver directly, rather than relying on weight loss alone, noting glucagon receptors are expressed on hepatocytes and hepatic immune cells.

“By adding the glucagon, you get more efficacy on the liver endpoints,” Schattenberg said.

How Did Efinopegdutide Perform in the Phase 2b Trial?

The trial randomly assigned 381 adults with biopsy-proven MASH and F2 (63%) or F3 (37%) fibrosis in a 1:1:1:1:1 ratio to once-weekly subcutaneous efinopegdutide 4, 7, or 10 mg; placebo; or open-label semaglutide 2.4 mg.¹ Schattenberg noted including an active standard-of-care comparator is uncommon in current MASH trials.

At Week 52, MASH resolution without worsening of fibrosis occurred in 56%, 63%, and 61% of participants receiving efinopegdutide 4, 7, and 10 mg, respectively, vs 13% receiving placebo (P < .001 for all doses).¹ The difference vs placebo was 49.5 percentage points (95% CI, 31.4-64.2) for the 7 mg dose. Among participants receiving semaglutide 2.4 mg, 53% achieved this endpoint.¹

Fibrosis improvement of at least 1 stage without worsening of steatohepatitis occurred in 43%, 52%, and 34% of participants receiving efinopegdutide 4, 7, and 10 mg, respectively, compared with 21% receiving placebo.¹ Differences were significant for 4 mg (21.7 percentage points; P = .004) and 7 mg (30.4 percentage points; 95% CI, 15.4-44.3; P < .001), but not for 10 mg (P = .072). Among participants receiving semaglutide, 25% achieved fibrosis improvement.¹

Where Could Efinopegdutide Fit in MASH Treatment?

Gastrointestinal adverse events were most common, with the highest rates at 10 mg. Adverse events led to discontinuation in 11% of participants receiving efinopegdutide 10 mg, compared with 3% to 4% in the other efinopegdutide groups, 1% with placebo, and 1% with semaglutide. Investigators concluded the 7 mg dose demonstrated the most favorable benefit-risk profile.¹

Schattenberg said he sees patients receiving GLP-1 receptor agonists with residual liver disease and suggested switching these patients to a GLP-1/glucagon co-agonist may be a future strategy. He also highlighted exploratory findings in the 7 mg group showing 2-stage fibrosis reductions and, in some patients, fibrosis regression to F0.

“It’s rather a switch than an add on because you want to use the benefits you get from GLP-1 metabolic, but also improve liver disease through glucagon,” he said.

Schattenberg cautioned the semaglutide arm was not a direct comparison for the primary endpoint. Key open questions include efficacy in compensated cirrhosis, which Merck is evaluating in a separate phase 2 trial, and dose selection and titration to support long-term adherence.²

Semaglutide 2.4 mg received accelerated approval for noncirrhotic MASH with F2-F3 fibrosis based on the phase 3 ESSENCE trial.³

Editors’ note: Schattenberg reports relevat disclosures with 89bio, Boehringer Ingelheim, Madrigal, Akero Therapeutics, Altimmune, Takeda, Merck, and others.

References:

1. Schattenberg J, Lawitz E, Shankar RR, et al. A phase 2b randomized placebo-controlled study to evaluate the efficacy and safety of efinopegdutide in adults with metabolic dysfunction-associated steatohepatitis and stage 2-3 fibrosis. Presented at: The Liver Meeting 2026; November 5-9, 2026; Denver, CO.

2. A clinical study of efinopegdutide in people with compensated cirrhosis due to steatohepatitis (MK-6024-017). ClinicalTrials.gov identifier: NCT06465186. Accessed November 9, 2026. https://clinicaltrials.gov/study/NCT06465186

3. Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis. N Engl J Med. 2025;392(21):2089-2099. doi:10.1056/NEJMoa2413258