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.

BACKGROUND: GLP-1-glucagon dual receptor agonists such as pemvidutide have shown promise in treating metabolic dysfunction-associated steatohepatitis (MASH). The aim of this trial was to assess the effects of pemvidutide on MASH resolution and fibrosis improvement in patients with liver fibrosis stage F2 or F3 MASH at 24 weeks of treatment. METHODS: IMPACT is an ongoing 48-week international, randomised, double-blind, placebo-controlled, phase 2b trial in patients with biopsy-confirmed MASH and fibrosis stage F2 or F3. Patients from 83 sites in the USA and Australia were randomly assigned 1:2:2 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 at least one stage liver fibrosis improvement without worsening of MASH at 24 weeks in the intention-to-treat population. This trial was registered with ClinicalTrials.gov, NCT05989711. FINDINGS: From July 27, 2023, to April 29, 2025, 1557 patients were screened and 212 patients were randomly assigned. MASH resolution without fibrosis worsening was observed in 18 (20%) of 86 patients in the placebo group, 24 (58%) of 41 patients in the 1·2 mg pemvidutide group (difference of 38% [95% CI 21-56]; p<0·0001), and 45 (52%) of 85 patients in the 1·8 mg pemvidutide group (difference of 32% [95% CI 19-46]; p<0·0001). 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 1·2 mg pemvidutide group (difference of 5% [95% CI -13 to 22]; p=0·59), and 30 (36%) of 85 patients in the 1·8 mg pemvidutide group (difference of 8% [95% CI -6 to 22]; p=0·27). Adverse events were reported in 32 (78%) of 41 patients receiving 1·2 mg pemvidutide, 69 (81%) of 85 patients receiving 1·8 mg pemvidutide, and 58 (67%) of 86 patients receiving placebo, the majority of which were mild or moderate in severity. Pemvidutide was well tolerated, with discontinuations due to adverse events in none of 41 patients in the 1·2 mg pemvidutide group, one (1%) of 85 patients in the 1·8 mg pemvidutide group, and two (2%) of 86 patients in the placebo group. INTERPRETATION: Pemvidutide treatment met the primary endpoint of MASH resolution without worsening of fibrosis at 24 weeks but did not meet the other primary endpoint of fibrosis improvement without worsening of MASH at this timepoint. Additional trials of longer duration are planned. FUNDING: Altimmune.