Summary:
In patients with biopsy-confirmed MASH and fibrosis stage F2-F3 (n=212), once-weekly pemvidutide (1.2 or 1.8 mg), a GLP-1/glucagon dual agonist, for 24 weeks significantly achieved MASH resolution without fibrosis worsening in 52-58% vs 20% with placebo (p<0.0001) compared to placebo, though it was associated with no significant fibrosis improvement at this timepoint and excellent tolerability (0-1% discontinuation).
| PICO | Description |
|---|---|
| Population | Patients with biopsy-confirmed MASH and liver fibrosis stage F2 or F3 (n=212) from 83 sites in USA and Australia (IMPACT trial). |
| Intervention | Once-weekly subcutaneous pemvidutide (1.2 mg or 1.8 mg), a GLP-1-glucagon dual receptor agonist, administered without dose titration for 24 weeks. |
| Comparison | Placebo injection once weekly for 24 weeks (1:2:2 randomization ratio). |
| Outcome | MASH resolution without fibrosis worsening: 58% (1.2 mg) and 52% (1.8 mg) vs 20% placebo (p<0.0001). Fibrosis improvement without MASH worsening: 33-36% vs 28% (NS). Discontinuation due to AEs: 0-1% vs 2%. Most AEs mild-moderate. |
Clinical Context
Metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH) represents a growing global health burden, with an estimated 5% of adults worldwide affected. MASH is characterized by hepatic steatosis, inflammation, and hepatocyte injury, often progressing to fibrosis, cirrhosis, and hepatocellular carcinoma. Currently, resmetirom (Rezdiffra) is the only FDA-approved treatment specifically for MASH, highlighting the urgent need for additional therapeutic options.
GLP-1 receptor agonists have shown promise in MASH treatment through their effects on weight loss, insulin sensitivity, and direct hepatic effects. The addition of glucagon receptor agonism creates a dual mechanism that may enhance hepatic lipid oxidation and energy expenditure beyond GLP-1 alone. Pemvidutide is a novel GLP-1/glucagon dual receptor agonist designed to leverage both pathways.
The IMPACT trial specifically enrolled patients with moderate-to-advanced fibrosis (F2-F3), the population at highest risk for progression to cirrhosis and most in need of effective treatment. The 24-week interim analysis provides early efficacy signals while the full 48-week data will address longer-term histological outcomes.
Clinical Pearls
1. Impressive MASH Resolution Rates: The 52-58% MASH resolution rate without fibrosis worsening represents a 32-38 percentage point improvement over placebo. These rates compare favorably to other agents in development and exceed the typical 10-15% spontaneous resolution seen with lifestyle intervention alone.
2. Fibrosis Improvement Requires Longer Treatment: The lack of significant fibrosis improvement at 24 weeks is not unexpected—fibrosis regression typically requires 48-72 weeks of treatment. The full 48-week IMPACT data will be critical for assessing this endpoint. MASH resolution often precedes fibrosis improvement.
3. No Dose Titration Required: Unlike many GLP-1 agonists requiring weeks of dose escalation, pemvidutide was administered at full dose from initiation. This simplifies clinical use and may accelerate therapeutic benefit, though may explain higher initial GI side effects.
4. Excellent Tolerability Profile: The 0-1% discontinuation rate due to adverse events is remarkably low for this drug class. This suggests pemvidutide may have advantages in tolerability despite the dual receptor mechanism, potentially improving real-world adherence.
Practical Application
While pemvidutide is not yet FDA-approved, these results position it as a promising candidate for MASH treatment. For clinicians managing MASH patients, this trial reinforces that incretin-based therapies represent a major therapeutic direction. Patients with F2-F3 fibrosis should be counseled about emerging treatment options and considered for clinical trial enrollment where available.
The dual GLP-1/glucagon mechanism suggests pemvidutide may offer metabolic benefits beyond pure GLP-1 agonism. For patients who have not achieved adequate response with semaglutide or tirzepatide for metabolic liver disease, dual agonists may represent a future alternative pending regulatory approval.
The 48-week full trial results and subsequent phase 3 studies will determine pemvidutide’s ultimate role in MASH management. Monitor ongoing regulatory developments for this therapeutic class.
Broader Evidence Context
Pemvidutide joins a competitive landscape of MASH therapeutics including resmetirom (approved), survodutide (phase 3), tirzepatide (phase 3 for MASH), and semaglutide (positive phase 2 data). The GLP-1/glucagon dual agonist class is emerging as particularly promising, with survodutide showing similar histological benefits in its phase 2 program.
Regulatory pathways for MASH drugs now accept histological endpoints (MASH resolution, fibrosis improvement) as primary outcomes, with cardiovascular and liver-related clinical outcomes as confirmatory endpoints in post-marketing studies.
Study Limitations
The 24-week timepoint may be too early to assess fibrosis regression. Phase 2b sample size (n=212) limits subgroup analyses. The 1:2:2 randomization resulted in smaller placebo group. Long-term safety and durability of response require the full 48-week data and phase 3 trials. Sites limited to USA and Australia may affect generalizability.
Bottom Line
Weekly pemvidutide achieves MASH resolution without fibrosis worsening in over half of patients with F2-F3 fibrosis at 24 weeks, significantly outperforming placebo with excellent tolerability, though fibrosis improvement was not demonstrated at this early timepoint.
Source: Noureddin M, et al. “Safety and efficacy of weekly pemvidutide versus placebo for metabolic dysfunction-associated steatohepatitis (IMPACT): 24-week results from a multicentre, randomised, double-blind, phase 2b study.” Lancet. 2025;406(10520):2644-2655. Read article
