Aleniglipron, an oral small-molecule glucagon-like peptide-1 receptor agonist (GLP-1 RA) in development for obesity, met its primary endpoint across all 3 dose arms in the phase 2b ACCESS trial, with placebo-adjusted body weight reductions ranging from 8.2% to 11.3% at 36 weeks.
The trial results were simultaneously published in Nature Medicine and presented at the 2026 American Diabetes Association (ADA) Scientific Sessions in New Orleans, Louisiana, by Julio Rosenstock, MD, director of the Dallas Diabetes Research Center at Medical City and Clinical Professor of Medicine at the University of Texas Southwestern Medical Center.
The growing availability of oral small-molecule GLP-1 RAs represents a shift toward more scalable obesity pharmacotherapy. Unlike injectable peptide-based agents, small molecules can be manufactured at lower cost and without refrigeration requirements, factors with direct implications for access. Aleniglipron, developed by Structure Therapeutics, was designed using structure-based drug discovery specifically to optimize chemical stability and manufacturing scalability.
The ACCESS trial was a randomized, double-blind, placebo-controlled, dose-ranging study enrolling 230 adults across 38 US sites. Eligible participants had obesity (BMI ≥30 kg/m²) or overweight with ≥ 1 weight-related comorbidity, including hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease, or metabolic-dysfunction-associated steatohepatitis.
Mean baseline BMI was 39.5 kg/m² and 54% of participants were female. Participants were randomly assigned in a 3:1 ratio to aleniglipron or placebo within each of 3 dose cohorts (45, 90, or 120 mg). All active arms began at a starting dose of 5 mg, with titration every 4 weeks to the assigned maintenance dose. The primary endpoint was placebo-adjusted percentage change in body weight from baseline to week 36.
The primary endpoint was met at all 3 dose levels (P <.0001 for each versus placebo).¹ Placebo-adjusted LS mean body weight reductions were −8.2% (95% CI, −11.1 to −5.3%) in the 45-mg arm, −9.8% (95% CI, −12.5 to −7.2%) in the 90-mg arm, and −11.3% (95% CI, −13.9 to −8.6%) in the 120-mg arm.¹ No weight loss plateau was apparent at the close of the double-blind period.
An interim analysis of the ongoing open-label extension (OLE), after a median follow-up of 20 additional weeks, showed continued weight reduction, reaching mean total losses from randomization of 13.3%, 16.2%, and 15.3% in the 45-, 90-, and 120-mg arms, respectively, at week 56.
At 36 weeks in the 120-mg arm, 86% of participants achieved ≥5% body weight loss, 70% achieved ≥10%, and 38% achieved ≥15%, compared with 23%, 7%, and 1% in the placebo group, respectively.¹ Exploratory analyses showed clinically relevant reductions in systolic blood pressure (placebo-adjusted −7.5 mmHg in the 120-mg arm) and HbA1c (placebo-adjusted −0.37% in the 120-mg arm).¹ High-sensitivity C-reactive protein declined by 28.8% to 46.4% across aleniglipron arms versus 6.9% in placebo.¹ No clinically meaningful changes in lipid profiles were observed.
Treatment-emergent adverse events (TEAEs) were predominantly gastrointestinal, including nausea, diarrhea, vomiting, and constipation, consistent with the GLP-1 RA class profile.¹ Most GI events were mild to moderate and attenuated with continued treatment.
Discontinuation due to TEAEs occurred in 10.4% of participants across aleniglipron arms, with no dose-response relationship across dose levels; most discontinuations occurred during early titration steps.
A notable tolerability signal emerged in the OLE, where former placebo participants initiating aleniglipron at a lower 2.5-mg starting dose (versus 5 mg in the double-blind phase) reported no vomiting events and no TEAE-related discontinuations over 20 weeks of median follow-up.¹ Participants who required dose interruptions during the double-blind phase rarely experienced vomiting recurrence upon reinitiation.¹ No drug-induced liver injury or persistent liver enzyme elevations were observed, and no deaths occurred during the trial.
References
Rosenstock J, Lingvay I, Ryan D, et al. Oral small molecule GLP-1 receptor agonist aleniglipron in people with overweight or obesity: a randomized, double-blind, placebo-controlled phase 2b trial. Nat Med. 2026. doi:10.1038/s41591-026-04476-6
