Oral Aleniglipron Achieves Up to 11.3% Weight Loss in Overweight/Obese Adults in Phase 2b Trial

The global prevalence of obesity continues to rise, posing significant public health challenges. While injectable glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have revolutionized weight management, their administration route can be a barrier for some patients, impacting adherence and accessibility. There is a critical need for effective, well-tolerated oral alternatives that can activate the GLP-1R pathway, offering a more convenient option for long-term weight loss and metabolic health improvement. Oral small-molecule GLP-1 RAs aim to fill this gap by providing comparable efficacy with enhanced patient convenience.

The ACCESS phase 2b, randomized, double-blind, placebo-controlled study enrolled 230 adults (mean BMI 39.5 kg m-2, 54% female) with obesity or overweight. Participants were randomized to receive once-daily aleniglipron escalated every 4 weeks to target doses of 45, 90, or 120 mg, or placebo. The primary endpoint was the change in body weight from baseline at week 36. Safety and tolerability, including gastrointestinal events and discontinuations, were also assessed throughout the trial.

The trial successfully met its primary endpoint, demonstrating significant placebo-adjusted body-weight reductions across all aleniglipron dose arms at week 36.

The highest dose of aleniglipron (120 mg) achieved a placebo-adjusted body-weight change of -11.3% (95% CI: -13.9 to -8.6%) from baseline at week 36 (P < 0.0001). The 90 mg arm showed a -9.8% weight change (95% CI: -12.5 to -7.2%), and the 45 mg arm achieved -8.2% (95% CI: -11.1 to -5.3%), with all doses significantly different from placebo (P < 0.0001). No apparent weight-loss plateau was observed by the end of the double-blind period, and continued weight loss was noted in the ongoing open-label extension. Gastrointestinal adverse events were generally mild to moderate, decreasing in frequency over time, with minimal recurrence of vomiting after dose interruptions. Treatment-related discontinuations were 10.4% across all aleniglipron arms, and no cases of drug-induced liver injury were reported, indicating a tolerability profile consistent with the GLP-1RA class.