A Phase 2a active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with nonalcoholic fatty liver disease

Background and aimsThis study assessed the effects of the GLP-1/glucagon receptor co-agonist efinopegdutide relative to the selective GLP-1 receptor agonist semaglutide on liver fat content (LFC) in patients with nonalcoholic fatty liver disease (NAFLD).MethodsThis was a Phase 2a, randomized, active-comparator-controlled, parallel-group, open-label study. A magnetic resonance imaging-estimated proton density fat fraction assessment was performed to determine LFC at screening and Week 24. Participants with an LFC of ≥10% at screening were randomized 1:1 to open-label efinopegdutide 10 mg subcutaneous (SC) once weekly or semaglutide 1 mg SC once weekly for 24 weeks, stratified according to concurrent diagnosis of type 2 diabetes. Both drugs were titrated to the target dose over an 8-week time period. The primary efficacy endpoint was relative reduction from baseline in LFC (%) after 24 weeks of treatment.ResultsAmong 145 randomized participants (efinopegdutide N=72, semaglutide N=73), 33.1% had T2DM. At baseline, mean body mass index was 34.3 kg/m2and mean LFC was 20.3%. The least squares (LS) mean relative reduction from baseline in LFC at Week 24 was significantly (p<0.001) greater with efinopegdutide (72.7% [90% CI: 66.8, 78.7]) than with semaglutide (42.3% [90% CI: 36.5, 48.1]). Both treatment groups had an LS mean percent reduction from baseline in body weight at Week 24 (efinopegdutide 8.5% vs semaglutide 7.1%; p=0.085). Slightly higher incidences of adverse events and drug-related adverse events were observed in the efinopegdutide group compared with the semaglutide group, primarily related to an imbalance in gastrointestinal adverse events.ConclusionsIn patients with NAFLD, treatment with efinopegdutide 10 mg weekly led to a significantly greater reduction in LFC than semaglutide 1 mg weekly. (EudraCT: 2020-005136-30; NCT: 04944992) IMPACT AND IMPLICATIONS: Currently, there are no approved therapies for nonalcoholic steatohepatitis (NASH). The weight loss associated with glucagon-like peptide-1 (GLP-1) receptor agonists has been shown to decrease hepatic inflammation in patients with NASH. In addition to reducing liver fat content (LFC) indirectly through weight loss, glucagon receptor agonism may also reduce LFC by acting on the liver directly to stimulate fatty acid oxidation and reduce lipogenesis. This study demonstrated that treatment of nonalcoholic fatty liver disease (NAFLD) patients with the GLP-1/glucagon receptor co-agonist efinopegdutide at 10 mg weekly led to a significantly greater reduction in LFC compared with the GLP-1 receptor agonist semaglutide at 1 mg weekly, suggesting that efinopegdutide may be an effective treatment for NASH.Clinical trial numberEudraCT: 2020-005136-30; NCT: 04944992.