Efficacy and safety of danuglipron (PF-06882961) in adults with obesity: A randomized, placebo-controlled, dose-ranging phase 2b study.

AIMS: This randomized, double-blind, placebo-controlled Phase 2b study aimed to assess the efficacy, safety, and tolerability of danuglipron (PF-06882961), an oral small-molecule glucagon-like peptide-1 (GLP-1) receptor agonist, in adults with obesity. MATERIALS AND METHODS: Eligible participants (aged 18-75 years; with obesity, without diabetes) were randomized to receive danuglipron or placebo twice daily (BID) for 26 or 32 weeks. Danuglipron was escalated to doses of 40-200 mg BID in 1-, 2-, or 4-week intervals. Assessments included body weight, waist circumference, and safety evaluations. RESULTS: Overall, 628 participants were randomized; of 626 receiving study treatment (placebo, n = 90; danuglipron, n = 536), 39.3% completed treatment. Approximately 38% of participants discontinued treatment because of adverse events (AEs) and 22% discontinued for other reasons. The primary endpoint was the change in weight from baseline to the end of treatment; all danuglipron groups demonstrated statistically significant reductions with least squares mean percentage decreases from baseline ranging from -5.0% (90% confidence interval [CI] -6.8%, -3.2%) to -12.9% (90% CI -16.1%, -9.5%) relative to placebo. Danuglipron was considered safe. Consistent with the mechanism, the most frequently reported events were nausea and vomiting, and increased rates of gastrointestinal AEs were generally observed at higher doses. Most events were reported as mild, and no other dose-related trends were observed in safety endpoints. CONCLUSIONS: In participants with obesity, danuglipron resulted in statistically significant and clinically meaningful reductions in body weight versus placebo over 26 or 32 weeks. The overall safety profile observed in this study was consistent with expectations for the mechanism, although discontinuation rates due to AEs were higher than anticipated across all treatment groups, including placebo. CLINICALTRIALS: gov identifier: NCT04707313.