Semaglutide cleared liver inflammation and improved scarring in phase 3 MASH trial

Weekly injections of semaglutide 2.4 mg helped clear liver inflammation in people with metabolic dysfunction-associated steatohepatitis, or MASH, who also had moderate or advanced liver scarring, according to a phase 3 trial published in the New England Journal of Medicine ^[1].

ESSENCE is an ongoing multicenter, randomized, double-blind, placebo-controlled study ^[1]. It enrolled 1,197 adults whose MASH and fibrosis stage 2 or 3 had been confirmed by biopsy ^[1]. Participants were assigned in a 2-to-1 ratio, so twice as many received semaglutide as received placebo, and treatment was planned to last 240 weeks ^[1]. The published data come from a preplanned interim analysis at week 72 covering the first 800 people enrolled, a group the paper calls part 1 ^[1].

In that interim group, 534 people were taking semaglutide and 266 were taking placebo ^[1]. Two main outcomes were assessed with repeat liver biopsies. Steatohepatitis — the inflamed form of the disease — resolved without fibrosis getting worse in 62.9% of the semaglutide arm and 34.3% of the placebo arm, an estimated difference of 28.7 percentage points (95% confidence interval, 21.1 to 36.2; P<0.001) ^[1].

Scarring itself improved without steatohepatitis worsening in 36.8% of those on semaglutide and 22.4% of those on placebo, 14.4 percentage points apart (95% CI, 7.5 to 21.3; P<0.001) ^[1]. Meeting both goals at once happened in 32.7% versus 16.1%, a difference of 16.5 percentage points (95% CI, 10.2 to 22.8; P<0.001) ^[1].

Body weight was not one of the listed primary endpoints, but it fell by an average of 10.5% in the semaglutide group and 2.0% in the placebo group, a gap of 8.5 percentage points (95% CI, -9.6 to -7.4; P<0.001) ^[1]. Average bodily pain scores did not differ significantly between the arms ^[1]. Stomach and intestinal side effects were more common among people taking semaglutide, though the abstract does not give rates or specify which events occurred ^[1]. Novo Nordisk funded the study, which is registered as NCT04822181 ^[1].

Why it matters for patients

MASH involves fat buildup in the liver along with inflammation and liver-cell injury, and it can progress to cirrhosis. Everyone enrolled here already had stage 2 or 3 fibrosis, meaning scarring had started but had not reached the most advanced stage ^[1].

The trial measured success with liver biopsies rather than blood tests or imaging ^[1]. Biopsy is the standard used to judge whether a therapy is actually changing the liver, so results measured this way carry weight in the field. They also show the limits of the treatment: about a third of people on semaglutide did not meet the inflammation goal, and roughly two-thirds did not show improved scarring within the interim period ^[1].

The report does not establish how much of the liver effect came from weight loss rather than a separate action of the drug, and it does not report how the arms compared on progression to cirrhosis, liver transplants, or death ^[1]. Because enrollment required biopsy-proven MASH with stage 2 or 3 fibrosis, these figures do not describe people with earlier-stage disease or with cirrhosis ^[1].

Semaglutide is a glucagon-like peptide-1 receptor agonist ^[1]. The dose and schedule used here were 2.4 mg once weekly by subcutaneous injection, given for a liver condition rather than for diabetes or weight management ^[1].

What happens next

Treatment in the trial is scheduled to run 240 weeks, and results from that full follow-up have not been reported ^[1]. The part 1 findings cover only the first 800 of 1,197 participants and only the first 72 weeks ^[1].

Whether semaglutide will be submitted for regulatory review for MASH, or when a decision might come, is not addressed in the trial report ^[1].