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28-06-2024 | Non-Alcoholic Fatty Liver Disease | Editor's Choice | News

Survodutide shows promise for treating metabolic dysfunction–associated steatohepatitis

Author: Dr. Jonathan Smith

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medwireNews: Survodutide reduces symptoms of metabolic dysfunction–associated steatohepatitis (MASH) without worsening fibrosis, a phase 2 trial has found.

“The results of this phase 2 trial support the potential for survodutide as a treatment for patients with MASH and liver fibrosis. These results warrant further investigation of this compound in phase 3 trials,” write Arun Sanyal (Virginia Commonwealth University, Richmond, USA) and colleagues in The New England Journal of Medicine.

Survodutide is a dual agonist of the glucagon and glucagon-like peptide (GLP)-1 receptors. Dual agonism could be more effective than a single agonist because “the extrahepatic benefits of GLP-1 receptor agonism (glucose control, reduced appetite, and weight loss) are combined with direct hepatic effects (increased energy expenditure, lipolysis, and mobilization of hepatic fat) associated with glucagon receptor agonism,” the authors say.

The investigators recruited 293 adults with biopsy-confirmed MASH and fibrosis stages F1 through F3. MASH was diagnosed based on at least 4 points on the nonalcoholic fatty liver disease (NAFLD) activity score, which ranges from 0 to 8 points, with a higher score indicating more severe disease. It was also based on patients scoring at least 1 point each on scores related to lobular inflammation (ranging from 0–3 points) and hepatocellular ballooning (0–2 points).

The patients were randomly assigned to receive weekly injections of survodutide at doses of 2.4 mg (n=73), 4.8 mg (n=72), 6.0 mg (n=74), or placebo (n=74). The trial first involved a 24-week rapid-dose-escalation phase, where the dose was increased every 2 weeks to reach the target dose, followed by a 24-week maintenance phase.

The mean age of the patients was 50.8 years and 53.0% were women. The average BMI was 35.8 kg/m2 and 39.0% of the participants had type 2 diabetes. According to biopsies at baseline, 70% of the participants had an NAFLD activity score of 5 points or more, and 16%, 41%, and 35% of the patients had F1B, F2, and F3 fibrosis, respectively.

Sanyal and colleagues found that significantly more patients taking survodutide met the primary efficacy endpoint of the trial – a composite of a decrease of at least 2 points on the NAFLD activity score, a decrease of at least 1 point in either lobular inflammation or hepatocellular ballooning, and no worsening of fibrosis – after 48 weeks of treatment than did those taking placebo. The rates were a respective 47%, 62%, and 43% for participants receiving 2.4 mg, 4.8 mg, and 6.0 mg of survodutide versus 14% for the placebo group.

The results also suggested  improvement in fibrosis, whereby a respective 34%, 36%, and 34% of participants taking survodutide 2.4 mg, 4.8 mg, and 6.0 mg experienced an improvement of at least one liver fibrosis stage, as assessed by biopsy, compared with 22% of those in the placebo group.

Using magnetic resonance imaging proton density fat fraction, the researchers also found that liver fat content decreased by at least 30% in 63%, 67%, and 57% of patients in the 2.4 mg, 4.8 mg, and 6.0 mg survodutide treatment groups, respectively, which was significantly greater than the 14% of patients in the placebo group.

Survodutide treatment also beat placebo in other measures including improvement in fibrosis with no worsening of MASH, resolution of MASH, and MASH resolution with a decrease of at least 2 points on the NAFLD activity score and with no worsening of fibrosis.

Sanyal et al observe that survodutide treatment resulted in significantly greater decreases in liver enzyme levels by 48 weeks of treatment, with reductions of 38.5 U/L in alanine aminotransferase and 32.2 U/L in aspartate aminotransferase, compared with corresponding decreases in the placebo group of 5.7 U/L and 2.4 U/L.

Adverse events (AEs) were reported by slightly more patients receiving survodutide 95% than those receiving placebo, at 95% versus 92%, with the most common including nausea (66 vs 23%), diarrhea (49 vs 23%), and vomiting (41 vs 4%). Serious AEs occurred in 8% of the survodutide groups and 7% of the placebo group, with 6% and 3% of participants, respectively, requiring hospital stays.

Sanyal and colleagues note that some trials of other dual agonists of the glucagon receptor and GLP-1 receptor were stopped early due to AEs and that the latest findings “suggest that an appropriate ratio of glucagon receptor to GLP-1 receptor activation may achieve a beneficial effect of glucagon receptor–GLP-1 receptor dual agonism in patients with MASH, with a potentially acceptable adverse-event profile.”

As a limitation of the trial, the researchers acknowledge that the majority of the participants in the trial were White, which “may restrict the generalizability of the findings.”

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group

N Engl J Med 2024; doi:10.1056/NEJMoa2401755

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