IMPACT: Pemvidutide for MASH Resolution and Weight Loss, With Mazen Noureddin, MD, MHSc

Once a disease with no approved pharmacologic treatment options, the therapeutic landscape for metabolic dysfunction-associated steatohepatitis (MASH) has undergone rapid, unprecedented progress in recent years.

Sparked by the US Food and Drug Administration approval of resmetirom (Rezdiffra) in 2024 and semaglutide (Wegovy)’s 2025 approval, the MASH treatment armamentarium has greatly expanded and is expecting even more additions as more and more agents continue to progress through clinical development and show promise in trials.

Among these is pemvidutide, a balanced (1:1) GLP-1/glucagon dual receptor agonist in development for the treatment of MASH, alcohol use disorder, and alcohol-associated liver disease. Its use in biopsy-confirmed MASH and fibrosis stage F2 or F3 was assessed in the phase 2, randomized, placebo-controlled, double-blind IMPACT trial. Results of the primary analyses of the study at 24 weeks of treatment were presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025 by Mazen Noureddin, MD, MHSc, a professor of medicine at Houston Methodist Hospital and co-chairman of Summit Clinical Research’s Board of Directors.

In the trial, 212 patients were randomly assigned in a 1:2:2 ratio to receive once-weekly subcutaneous pemvidutide 1.2 mg or 1.8 mg administered without dose titration, or placebo. The dual primary endpoints were MASH resolution without worsening of fibrosis or ≥1 stage liver fibrosis improvement without worsening of MASH at 24 weeks.

Among the cohort, the mean age was 53 years, the mean BMI was 39 kg/m2, 58% of patients were female, and 43% had type 2 diabetes. MASH resolution without fibrosis worsening was observed in 18 (20%) of 86 patients in the placebo group, 24 (58%) of 41 patients in the pemvidutide 1.2 mg group (95% CI, 21 to 56; P <.0001), and 45 (52%) of 85 patients in the pemvidutide 1.8 mg group (95% CI, 19 to 46; P <.0001).

Fibrosis improvement without worsening of MASH was observed in 24 (28%) of 86 patients in the placebo group, 13 (33%) of 41 patients in the pemvidutide 1.2 mg group (95% CI, -13 to 22; P = .59), and 30 (36%) of 85 patients in the pemvidutide 1.8 mg group (95% CI, -6 to 22; P = .27). Additional AI-based analyses of the liver biopsies and non-invasive tests for MASH and fibrosis were statistically significant at both pemvidutide doses, consistent with an ongoing anti-fibrotic effect.

Mean weight losses were 0.5% in the placebo group compared with 4.8% (P <.001) in the 1.2 mg group and 5.8% (P <.001) in the 1.8 mg group. Pemvidutide was well-tolerated despite the absence of dose titration, with discontinuations due to adverse events of 2%, 0%, and 1%, in the placebo, 1.2 mg, and 1.8 mg groups, respectively.

For additional insight into pemvidutide and the IMPACT data presented at AASLD, the editorial team of HCPLive Hepatology spoke with Noureddin for the following Q&A:

HCPLive: Can you explain a little bit about pemvidutide and why we think it may be promising not only for MASH, but also alcohol use disorder and alcohol-associated liver disease?

Noureddin: Pemvidutide is a glucagon GLP-1, and the ratio is very attractive because it's one to one. It also does have a special PK property that makes it safe and well tolerated. They modified it in a way that it has delayed Tmax and lower Cmax, which makes it completely tolerable, especially with the formula that they have. So in terms of MASH, the glucagon has a direct effect on the liver, so as for ALD. What that does is a strong anti-fibrotic effect, and in addition to reducing steatosis, inflammation, and fibrosis in this patient population because of the dual property, especially with the glucagon, in alcohol, it can also decrease the craving via central effect. So it's an attractive drug for all steatotic liver disease in that perspective.

HCPLive: What were some of the key findings from IMPACT you presented here at AASLD?

Noureddin: This is a 48 week study, but what we at AASLD presented is 24 weeks, which is the primary endpoint and the histology. We had histology before and after, and we randomized participants to placebo versus 1.2 milligrams versus 1.8 milligrams. There was no titration, which is very important for this drug because all other glucagon GLP-1s titrate.

Patients went on it and had multiple other NITs, PDFF, VCTE, and we also looked at weight loss. Primary inclusion criteria was MASH and F2 and F3, PDFF 8%, BMI of 27, and we did biopsy before and after.

The primary endpoint was met on the MASH resolution. It's actually on the higher side, it was up to 58% of the population at week 24. For fibrosis, we had a change of magnitude of 38%, but we had a high placebo rate, so no statistical significance. However, when we did better methodology for assessing fibrosis, which is AI, it was statistically significant all the way around and all the NITs were also positive, so that was good. Importantly, there was statistical significance on weight loss by week 24, so this is the first glucagon GLP-1 that leads to both histological improvement as well as weight loss at week 24.

HCPLive: Did any safety concerns emerge?

Noureddin: The safety signal actually is a big differentiator for this drug. As a reminder, there’s no titration. The discontinuation rate due to adverse events was almost nothing. We had 1 patient on the higher dose and there were 2 patients on placebo, so we had more people stop due to AEs in the placebo than the drug. It's a very clean drug in terms of side effects.

I think it looks like discontinuation and the weight loss and NITs at 24 weeks are heading in the right direction. The plan to do it is for a longer duration where we think we're going to get more fibrosis and more weight loss in this patient population.

Editors’ Note: Noureddin reports relevant disclosures with Gilead, GlaxoSmithKline, Madrigal, Novo Nordisk, Takeda, 89BIO, Altimmune, Boehringer Ingelheim, and others.

References

1. Brooks A. Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH. HCPLive. March 14, 2024. Accessed November 13, 2025. https://www.hcplive.com/view/resmetirom-rezdiffra-receives-historic-fda-approval-for-noncirrhotic-nash

2. Brooks A. FDA Approves Semaglutide (Wegovy) Injection 2.4 mg for Noncirrhotic MASH. HCPLive. August 15, 2025. Accessed November 13, 2025. https://www.hcplive.com/view/fda-approves-semaglutide-wegovy-injection-2-4-mg-for-noncirrhotic-mash

3. Noureddin M, Harrison S, Loomba R, et al. A Phase 2, Multicenter, Randomized, Placebo-Controlled Trial of Pemvidutide in Metabolic Dysfunction-Associated Steatohepatitis. Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.