Safety and efficacy of weekly pemvidutide versus placebo for metabolic dysfunction-associated steatohepatitis (IMPACT): 48-week results from a multicentre, randomised, double-blind, phase 2b study

Glucagon-GLP-1 dual receptor agonists have shown promise in treating metabolic dysfunction-associated steatohepatitis (MASH).

The aim of the IMPACT trial was to assess the effects of one such agent, pemvidutide, in patients with MASH and stage F2 or F3 fibrosis. We previously reported the 24-week primary endpoints of MASH resolution and fibrosis improvement.

Here we report the secondary endpoints following 48 weeks of treatment. IMPACT was a 48-week, randomised, placebo-controlled, double-blind, phase 2b trial in patients with biopsy-confirmed MASH and fibrosis stage F2 or F3.

Patients from 83 sites, including academic and community hospitals and private clinical research clinics, in the USA and Australia were randomly assigned (1:2:2) using an interactive web response system to receive once-weekly subcutaneous pemvidutide (1·2 mg or 1·8 mg), administered without dose titration, or placebo. Patients, investigators, the funder, and all other staff, were masked to treatment assignments throughout the study.

The dual primary endpoints of MASH resolution without worsening of fibrosis or at least one stage liver fibrosis improvement without worsening of MASH were assessed at week 24. Liver biopsies were not collected at week 48, and only secondary endpoints were assessed at this timepoint.

All analyses were conducted in the intention-to-treat population consisting of all randomly assigned patients. The trial was registered with ClinicalTrials.gov (NCT05989711) and is complete.

From July 27, 2023, to Nov 21, 2025, 1557 patients were screened and 212 patients were randomly assigned to pemvidutide 1·2 mg (n=41), pemvidutide 1·8 mg (n=85), or placebo (n=86). Mean age was 53·4 years (SD 12·4), mean BMI was 38·7 kg/m 2 (7·8), 123 (58%) patients were female, 89 (42%) were male, and 90 (42%) had type 2 diabetes.

At week 48, least-squares mean relative changes in liver fat content were -45·2% (95% CI -56·0 to -34·5; difference from placebo -37·1 percentage points [95% CI -50·6 to -23·5]; p<0·0001) in the pemvidutide 1·2 mg group, -54·7% (-62·3 to -47·1; difference from placebo -46·5 percentage points [-57·7 to -35·3]; p<0·0001) in the pemvidutide 1·8 mg group, and -8·2% (-16·5 to 0·2) in the placebo group. The least-squares mean absolute change in corrected T1 relaxation time was -124·2 ms (95% CI -157·1 to -91·4; difference from placebo -103·8 [95% CI -143·9 to -63·6]; p<0·0001) in the pemvidutide 1·2 mg group, -139·5 ms (-161·7 to -117·3; difference from placebo -119·0 [-151·2 to -86·9]; p<0·0001) in the pemvidutide 1·8 mg group, and -20·5 ms (-44·5 to 3·6) in the placebo group.

Least-squares mean changes in alanine aminotransferase were -37·8 IU/L (95% CI -44·5 to -31·1; difference from placebo -27·5 [95% CI -35·8 to -19·2]; p<0·0001) in the pemvidutide 1·2 mg group and -37·4 IU/L (-42·1 to -32·7; difference from placebo -27·1 [-33·9 to -20·3]; p<0·0001) in the pemvidutide 1·8 mg group versus -10·3 IU/L (-15·2 to -5·4) for the placebo group. Least-squares mean changes in enhanced liver fibrosis score were -0·49 (95% CI -0·71 to -0·28; difference from placebo -0·65 [95 % CI -0·92 to -0·38]; p<0·0001) in the pemvidutide 1·2 mg group, -0·58 (-0·74 to -0·43; difference from placebo -0·74 [-0·97 to -0·52]; p<0·0001) in the pemvidutide 1·8 mg group, and 0·16 (-0·01 to 0·32) for the placebo group.

The most frequent pemvidutide-related adverse events were nausea (occurring in nine [a clinically meaningful level] of 41 patients in the pemvidutide 1·2 mg group, 35 [41%] of 85 patients in the pemvidutide 1·8 mg group, and 15 [17%] of 86 patients in the placebo group), diarrhoea (five [12%] in the pemvidutide 1·2 mg group, 19 [a clinically meaningful level] in the pemvidutide 1·8 mg group, and seven [8%] in the placebo group), and constipation (five [12%] in the pemvidutide 1·2 mg group, 15 [18%] in the pemvidutide 1·8 mg group, and ten [12%] in the placebo group). No severe or serious adverse events were defined as study medication related.

Discontinuations due to adverse events occurred in no patients in the pemvidutide 1·2 mg group, one (1%) in the pemvidutide 1·8 mg group, and three (3%) in the placebo group.

In patients with MASH, 48 weeks of pemvidutide treatment led to significant reductions in non-invasive tests of MASH inflammation and fibrosis, suggesting continued improvement in liver health.

These data warrant the continued investigation of pemvidutide in a Phase 3 trial.