DD01, Pemvidutide Data Suggest Dual Agonists Target MASH Directly: Mazen Nourredin, MD

Dual agonists targeting both glucagon-like peptide 1 (GLP-1) and glucagon receptors are showing promise in metabolic dysfunction-associated steatohepatitis (MASH), with new phase 2 data suggesting the drugs can reduce liver fat and stiffness through mechanisms that go beyond weight loss alone and with a tolerability profile that may outpace existing options, explained Mazen Noureddin, MD, MHSc, professor of medicine and transplant hepatologist at Houston Methodist Hospital.

Two abstracts at the European Association for the Study of the Liver (EASL) Congress offered encouraging phase 2 data for a pair of investigational dual agonists targeting MASH. The first examined DD01, a GLP-1/glucagon dual receptor agonist, which produced rapid, significant reductions in liver fat content and stiffness—including in patients who lost little weight—suggesting a direct hepatic effect from glucagon.¹ The second presented 48-week results from the IMPACT trial of pemvidutide, another dual agonist, showing sustained, dose-dependent improvements in noninvasive markers of MASH inflammation and fibrosis alongside meaningful weight loss and a strong tolerability profile.²

This interview has been lightly edited for clarity and readability.

AJMC: The DD01 late-breaker data suggest that glucagon's direct hepatic effects—independent of weight loss—can produce meaningful reductions in steatosis and liver stiffness. How was that weight-independent effect established in the study design—was weight loss absent, minimal, or statistically controlled for—and what does the distinction mean for patients who don't achieve significant weight loss on dual agonists?

Noureddin: This is a 48-week trial, but we looked at data initially at week 12 and then continued until week 48. We presented the week 12 data, where we showed significant reductions in MRI-PDFF [MRI proton density fat fraction, a measure of liver fat content]—30%, 50%, 70% reduction thresholds—and almost half of the patients normalized their liver fat in that trial. One of the things we focused on was that early time point in the trial and how that early reduction in liver fat was occurring at a moment when you don't have much weight loss yet—weight loss is in the 5% range or so. We saw that independent effect from DD01 regardless of whether patients lost weight or not.

Overall, at week 12—and again, this is the early read of an ongoing trial—we observed a really remarkable MRI-PDFF reduction: 76% of patients achieved a 30% relative MRI-PDFF reduction, compared to only 12% in the placebo group, which was statistically significant. If you raise the bar to 50% reduction and then 70% liver fat reduction, we also saw statistically significant results with DD01 compared to placebo. As I mentioned, half of the patients had normalization of liver fat at week 12, which is a really early time point. We also saw changes as early as week 12, supporting the idea that if you address the fat, fibrosis improves as well. We saw that reduction despite minimal weight loss, and when weight loss was greater, we saw even more MRI-PDFF reduction.

AJMC: The 24-week histologic results for pemvidutide were already statistically significant, and the 48-week noninvasive test data show sustained, dose-dependent reductions in fibrosis and inflammation markers. What does the trajectory of those markers tell you about the durability of pemvidutide's effect, and how does that inform expectations for the phase 3 trial?

Noureddin: We met the primary end point at week 24, as you said, which was MASH resolution. Fibrosis improvement was not statistically significant, but there was a high placebo response, and when we applied machine learning, we did see statistically significant fibrosis improvement at week 24. The continuation to week 48 showed us that patients had weight loss that did not plateau on the 1.8-mg dose at week 48, and we also saw sustained improvement in MRI-PDFF reduction at that point, along with other biomarkers such as ALT [alanine aminotransferase] and AST [aspartate aminotransferase].

What's important about this is that, since we have histology data at week 24, it gives us assurance that we're going to meet the primary end point in phase 3. And in phase 3, we're going to go beyond week 24. The FDA requires at least 1 year, and there will be a biopsy at that point. Seeing those sustained effects at week 48 gives us assurance there is no plateauing of effects, there is ongoing weight loss, and that MRI-PDFF reduction continues. MRI-PDFF reduction does correlate with histological response with both MASH resolution and fibrosis improvement. It's really strong data.

AJMC: Pemvidutide was administered without dose titration and showed discontinuation rates due to adverse events at the higher dose that were lower than the placebo. What explains that tolerability profile, and does it meaningfully differentiate pemvidutide from other pharmacotherapy being developed or used for MASH in terms of how you'd approach patient selection?

Noureddin: It does, it does. We're borrowing ideas from the obesity field. The obesity field right now is focused not just on how much weight is lost but on the quality of weight loss—how often you need to titrate, how difficult titration is, and how many people discontinue. The molecular design of pemvidutide is constructed in a unique way that we believe increases tolerability of the drug. As you mentioned, more patients in the placebo group discontinued the drug compared to those on pemvidutide, and that will be a significant differentiator from other GLP-1 receptor agonists where people discontinue them.³ I do think that's going to make a meaningful difference. I expect we're going to achieve a strong histological response in phase 3, but adding things like tolerability will really help us.

References

1. Noureddin M. Patil R, Desai D, et al. Weight loss–independent Glucagon effect led to rapid, clinically significant reductions in MASH severity, including steatosis and liver stiffness, during a 48-week randomized controlled trial of dual agonist DD01. Presented at: EASL Congress; May 27-30, 2026; Barcelona, Spain. Poster LBP-029.

2. Noureddin M, Alkhouri N, Harrison SA, et al. Week 48 top-line results from the phase 2b, multicenter, randomized, placebo-controlled IMPACT trial of pemvidutide in metabolic dysfunction-associated steatohepatitis controlled IMPACT trial of pemvidutide in metabolic dysfunction-associated steatohepatitis. Presented at: EASL Congress; May 27-30, 2026; Barcelona, Spain. Abstract 3470.

3. Do D, Lee T, Peasah SK, Good CB, Inneh A, Patel U. GLP-1 receptor agonist discontinuation among patients with obesity and/or type 2 diabetes. JAMA Netw Open. 2024;7(5):e2413172. doi:10.1001/jamanetworkopen.2024.13172