‘A Watershed Moment’: GLP-1 Drug Succeeds in Late-Stage MASH Trial

Semaglutide (Wegovy) improved liver fibrosis in patients with metabolic dysfunction-associated steatohepatitis (MASH) and led to greater rates of MASH resolution, an interim analysis of a phase III trial showed.

In part 1 of the so-called ESSENCE trial, treatment with the GLP-1 receptor agonist resulted in higher week-72 rates of steatohepatitis resolution without worsening of liver fibrosis (63% vs 34% with placebo) and improvement in liver fibrosis without worsening of steatohepatitis (37% vs 23%; P

Furthermore, twice as many patients assigned to semaglutide achieved the dual secondary endpoint of both MASH resolution and liver fibrosis improvement (33% vs 16%, P

Newsome’s presentation at the annual meeting of the American Association for the Study of Liver Diseases in San Diego was met with sustained applause, with one audience member calling the results “the highlight of our meeting.” Another said it was “a watershed moment for the MASH field.”

“It is great to be able to report the first GLP-1 receptor agonist to demonstrate efficacy in a phase III trial of MASH, with superiority confirmed for semaglutide against placebo for both the primary endpoints,” the dual secondary endpoint, and for a host of non-invasive markers of liver fibrosis, Newsome said during a late-breaking abstract session. “Reassuringly, the safety profile is in keeping with a previous phase II clinical trial and also the larger body of data for semaglutide.”

The primary endpoint for part 2 of the trial will evaluate semaglutide’s effect on cirrhosis-free survival, but maker Novo Nordisk has already announced it will file for regulatory approval in MASH next year based on the current results.

Only one drug is currently indicated for MASH, a severe form of metabolic dysfunction-associated steatotic liver disease (MASLD). The FDA granted accelerated approval to resmetirom (Rezdiffra) earlier this year based on results of the MAESTRO-NASH study.

ESSENCE is an ongoing, double-blind, multicenter phase III trial involving 1,200 adult participants with biopsy-defined MASH and stage 2/3 liver fibrosis. The study randomized participants 2:1 to once-weekly subcutaneous semaglutide at a dose of 2.4 mg (after a 16-week dose escalation) or matching placebo for 240 weeks.

Eligibility criteria included a non-alcoholic fatty liver disease (NAFLD) activity score ≥4. Patients were excluded if they had chronic liver diseases other than MASLD; had known or suspected excessive alcohol use; were already on a GLP-1 receptor agonist; or had unstable use of other glucose-lowering, lipid-lowering, or weight-loss medications within 90 days of screening.

Newsome reported interim safety and efficacy results for the first 800 people who completed 72 weeks of treatment. These patients had a mean age of about 55 years, and the majority were women. About 55% had type 2 diabetes, the mean body mass index was 34-35, and more than two-thirds had stage 3 liver fibrosis.

The primary endpoints for part 1 of the study included steatohepatitis resolution without worsening of liver fibrosis and improvement in liver fibrosis without worsening of steatohepatitis at week 72.

In addition to the efficacy results described above, Newsome reported that patients treated with semaglutide achieved an 11% reduction in body weight compared with 2% with placebo.

Other secondary endpoints showed improvements with semaglutide in liver enzymes (alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyltransferase); in liver stiffness on vibration-controlled transient elastography; on the Enhanced Liver Fibrosis test; and in cardiometabolic risk parameters (blood pressure, glycemic control, dyslipidemia, and highly sensitive C-reactive protein).

Adverse events (AEs) were reported in 86% of the semaglutide group and 80% of the placebo group, with AEs leading to trial discontinuation in 2.6% and 3.3%, respectively. The most common AEs with semaglutide included nausea (36%), diarrhea (27%), constipation (22%), vomiting (19%), and decreased appetite (14%).

“Reassuringly, there was no increase in serious or fatal adverse events in patients receiving semaglutide,” said Newsome. Fatal AEs occurred in 0.4% of those on semaglutide and 1.5% of those on placebo, with serious AEs occurring in 13% of each group.