medwireNews: Treatment with semaglutide can lead to resolution of nonalcoholic steatohepatitis (NASH) in people with or without type 2 diabetes, show phase 2 trial findings, although a question mark remains over its effect on fibrosis.
The trial, which is published in The New England Journal of Medicine, was conducted at 143 sites in 16 countries and involved 320 patients with histologically confirmed NASH.
Study participants, 62% of whom had type 2 diabetes, were randomly assigned to receive once-daily subcutaneous semaglutide at doses of 0.1, 0.2, or 0.4 mg, or matching placebo, with three people assigned to active treatment for every one given placebo.
“At the time of designing the trial the once-daily administration form was thought to have fewer side effects, although it is now evident that the once weekly administration is well-tolerated,” lead researcher Philip Newsome (University of Birmingham, UK) explained to medwireNews.
“I suspect any future phase 3 trial for semaglutide in NASH will use a once-weekly administration.”
The primary endpoint of NASH resolution without worsening of fibrosis was assessed at 72 weeks in the 72% of patients who had stage F2 or F3 fibrosis at baseline, revealing rates of 40%, 36%, and 59% in the semaglutide 0.1, 0.2, and 0.4 mg groups, respectively, compared with 17% in the placebo group. The differences between all three treatment groups and placebo were statistically significant, at odds ratios of 3.36, 2.71, and 6.87, respectively.
However, there were no significant between-group differences for the confirmatory secondary endpoint of improvement in liver fibrosis without worsening of NASH, with rates of 49%, 32%, and 43% in the semaglutide 0.1, 0.2, and 0.4 mg groups, respectively, and 33% in the placebo group.
This “was unexpected, given that previous studies have suggested that resolution of NASH and improvements in activity scores for the components of nonalcoholic fatty liver disease are associated with regression of fibrosis,” write the researchers.
But Newsome stressed that despite the lack of effect on fibrosis overall, “there were significant improvements in surrogate markers of liver fibrosis – the [enhanced liver fibrosis] score and liver stiffness as measured by FibroScan.”
In addition, he noted that among all study participants (including those with stage F1 fibrosis) there was a dose-dependent reduction in the proportion of patients with worsening of fibrosis. This occurred in 10%, 8%, and 5% of those taking semaglutide 0.1, 0.2, and 0.4 mg, respectively, versus 19% of those given placebo. Progression to stage F4 fibrosis occurred in a corresponding 3%, 3%, 0%, and 4%.
He concluded: “I believe these data support potential improvements in fibrosis and a larger phase 3 trial may allow these improvements to reach statistical significance.”
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