Merck's GLP-1/glucagon co-agonist raised MASH resolution versus placebo at 52 weeks, but fibrosis and dose-response questions remain.
Once-weekly efinopegdutide, an investigational glucagon-like peptide-1 (GLP-1) and glucagon receptor co-agonist, met its primary endpoint in a phase 2b trial in adults with metabolic dysfunction–associated steatohepatitis (MASH) and stage F2 or F3 liver fibrosis.¹ Merck presented 52-week results at The Liver Meeting in Denver, with simultaneous publication in The Lancet.¹˒²
Merck is developing the molecule under an exclusive license from Hanmi Pharmaceutical,¹ and the results arrive in a field that has only recently gained approved therapies.
“MASH poses a substantial risk of progression to cirrhosis and ultimately liver failure, underscoring the urgent need for new treatment options,” said Dr. Eliav Barr, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories. “We are highly encouraged by these results which add to the evidence that efinopegdutide, a distinct GLP-1/glucagon receptor co-agonist, has the potential to provide clinically meaningful responses for MASH resolution and fibrosis regression.”¹
The trial, MK-6024-013, was a multicenter, randomized, double-blind, placebo-controlled study that enrolled 386 adults with biopsy-confirmed MASH and fibrosis stage F2 or F3.¹ A total of 381 participants received at least one dose: efinopegdutide 4 mg (77 participants), 7 mg (77) or 10 mg (79); placebo (79); or open-label semaglutide 2.4 mg (69) as an active reference arm.¹
Treatment lasted 52 weeks, and 92% of participants completed the study.¹ The primary endpoint was MASH resolution without worsening of fibrosis, evaluated by blinded independent central review.¹
MASH resolution at 52 weeks occurred in 56%, 63%, and 61% of participants receiving the 4 mg, 7 mg, and 10 mg doses, respectively, compared with 13% for placebo (p<0.0001 for each dose).¹ Fibrosis improvement of at least one stage without worsening of steatohepatitis, a key secondary endpoint, occurred in 43%, 52%, and 34%, compared with 21% for placebo.¹
The release did not report statistical testing for that endpoint or explain why the response at 10 mg was lower than at 7 mg. Merck described the safety profile as generally consistent with semaglutide.¹
Nausea occurred in 29%, 39%, and 44% of efinopegdutide participants by ascending dose, versus 39% with semaglutide and 11% with placebo.¹ Vomiting rates were 20%, 8%, and 28%, versus 15% and 3%.¹ Discontinuations because of adverse events were 3%, 4%, and 11%, compared with 1% for both semaglutide and placebo.¹
MASH, formerly called nonalcoholic steatohepatitis, is a progressive form of metabolic dysfunction–associated steatotic liver disease marked by hepatic fat accumulation, inflammation, hepatocyte injury, and varying stages of fibrosis.¹ Left untreated, it can advance to cirrhosis and liver failure, and estimates suggest about 5% of the global population may be living with the disease.¹
“MASH is a chronic inflammatory liver disease, with limited treatment options. Achieving disease resolution establishes an important treatment goal,” said Professor Jӧrn M. Schattenberg, M.D., Department of Internal Medicine II, Saarland University Medical Center, Homburg, Germany. “The improvements observed in fibrosis grading following efinopegdutide treatment in this study are notable and underscore its potential as a therapeutic option in patients with MASH and fibrosis.”¹
Efinopegdutide co-activates GLP-1 and glucagon receptors. Merck says the design aims to pair the metabolic and appetite-regulating actions of GLP-1 with glucagon-mediated increases in energy expenditure, lipid metabolism and direct anti-steatotic effects in the liver.¹
The FDA has granted the drug Fast Track designation for MASH.¹ The FDA granted resmetirom, an oral thyroid hormone receptor-beta agonist, accelerated approval in March 2024 as the first MASH treatment.³
Semaglutide 2.4 mg followed in August 2025 for noncirrhotic MASH with moderate to advanced fibrosis.⁴ Both approvals are conditional on confirmatory evidence of clinical benefit.³˒⁴
In the phase 3 ESSENCE trial that supported the semaglutide decision, 63% of participants had MASH resolution without worsening of fibrosis at 72 weeks versus 34% with placebo, and 37% had fibrosis improvement versus 22%.⁴
Cross-trial comparisons carry limits. ESSENCE was a larger phase 3 study with a 72-week treatment period, whereas the efinopegdutide study was a phase 2b trial with 52-week histologic endpoints that do not establish effects on liver-related clinical outcomes.
The semaglutide arm was open-label, and the release did not report a direct comparison with efinopegdutide. Higher rates of nausea and vomiting at 10 mg, along with an 11% discontinuation rate, leave open which dose Merck would advance.
The release did not specify that choice or outline phase 3 plans or regulatory timelines.¹
