Treatment with the investigational GLP-1/glucagon dual receptor agonist pemvidutide led to resolution of metabolic dysfunction-associated steatohepatitis (MASH) without worsening of fibrosis, but did not improve fibrosis without worsening of MASH, the phase IIb IMPACT trial showed.
At 24 weeks, MASH resolution without worsening of fibrosis occurred in 20% of those receiving placebo compared with 58% and 52% of those receiving once-weekly subcutaneous pemvidutide 1.2 mg or 1.8 mg, respectively (P<0.0001 for both), reported Mazen Noureddin, MD, of Houston Methodist Hospital, at the American Association for the Study of Liver Diseases annual meeting.
"Pemvidutide provides multiple [mechanisms of action] addressing important areas of MASH management in a single therapy," Noureddin said.
On the other hand, fibrosis improvement without worsening of MASH was observed in 28% of patients in the placebo group compared with 33% of those in the 1.2-mg pemvidutide group and 36% of those in the 1.8-mg pemvidutide group (P=0.59 and P=0.27, respectively).
In The Lancet, where the findings were also published, Noureddin and colleagues noted that this pattern aligns with other GLP-1-based therapies, which typically show delayed antifibrotic effects.
"A 24-week readout could give an incomplete interpretation of pemvidutide's effect on hepatic fibrosis, which might have been seen at a later timepoint typical of other trials with GLP-1-based agents," they wrote.
When asked if the time window was too short to expect a full-stage fibrosis reduction, Noureddin referred to the "magnitude of fibrosis improvement in the intention-to-treat analysis -- that was equivalent to other 6-month studies."
"The placebo -- the story of our life -- was on the higher side," he said, adding that future research will have a longer duration, "and we'll see more weight loss, as well as more fibrosis improvement."
For this randomized double-blind trial, the researchers enrolled 212 participants with biopsy-confirmed MASH and fibrosis stage F2 or F3 from 83 sites in the U.S. and Australia between July 2023 and April 2025, and randomly assigned them 1:2:2 to 1.2-mg pemvidutide, 1.8-mg pemvidutide, or placebo via once-weekly subcutaneous injection for 48 weeks. Mean age was 53.4 years, 58% were women, 90% were white, and mean BMI was 38.7.
Significant metabolic and imaging-based improvements were also observed with pemvidutide. Mean liver fat content measured by MRI proton density fat fraction was relatively reduced by 52% and 58% in the 1.2-mg and 1.8-mg arms, respectively, compared with an 11% relative reduction in the placebo group (P<0.001 for both). Normalization of liver fat content to less than 5% occurred in 31% and 44% of the two treatment groups versus 4% of placebo patients (P<0.0001 for both). The percentage change in body weight was -4.8% and -5.8% with the 1.2-mg and 1.8-mg doses compared with -0.05% with placebo (P<0.001 for both).
Meena Bansal, MD, of the Icahn School of Medicine at Mount Sinai in New York City, described the MASH resolution observed in the study as encouraging and told MedPage Today that dual GLP-1/glucagon receptor agonists are expected to be part of the treatment landscape in the future.
"In addition to weight loss and other benefits of GLP-1 receptor agonism, the glucagon receptor agonism brings in additional liver-targeted effects," said Bansal, who was not involved in the research. "Fibrosis takes time to resolve. MASH resolution is encouraging, and we need to look at longer time points to see if there is improvement in fibrosis. It is also a good sign that they saw reductions in many non-invasive tests for liver fibrosis."
Adverse events occurred in 78% of patients in the 1.2-mg group, 81% of the 1.8-mg group, and 67% of the placebo group, but were mostly mild, including nausea, diarrhea, and constipation. Only one patient taking pemvidutide discontinued the treatment due to adverse events, compared with two in the placebo arm. No severe gastrointestinal or treatment-related serious adverse events were reported.
The absence of a dose-titration phase distinguishes pemvidutide from other incretin-based therapies. The investigators attributed its tolerability to the drug's prolonged time to peak concentration and reduced peak concentration compared with other peptide incretins.
Limitations included the moderate sample size typical of a phase II trial and a smaller cohort in the 1.2-mg arm, which may have limited the ability to assess dose response.
Disclosures
The study was funded by Altimmune.
Noureddin reported relationships with Allergan, Aligos Therapeutics, Altimmune, Akero, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Boston Pharma, Conatus, Corcept, Curve Bioscience, CytoDyn, Enanta, Eli Lilly, Gilead, Galectin, Genfit, GSK, HistoIndex, Kowa, Kriya Therapeutics, Madrigal, Merck, Novartis, Novo Nordisk, OPKO, Rivus, Sagimet, Shire, Takeda, Terns, Viking, Zydus, Clinical Gastroenterology and Hepatology, and the American Association for the Study of Liver Diseases.
Co-authors reported multiple relationships with industry.
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