Aleniglipron Moves Toward Phase III as Structure Therapeutics Advances Oral GLP-1 Obesity Program

Structure Therapeutics said it plans to move its once-daily oral GLP-1 receptor agonist aleniglipron into Phase III clinical development after reporting positive topline results from its Phase II ACCESS program in adults with obesity or overweight and weight-related comorbidities.

The company, a clinical-stage biopharmaceutical firm focused on oral small molecule therapies for metabolic disease, expects to initiate the Phase III program by mid-2026 following discussions with the FDA.

The decision to advance aleniglipron is based on data from the randomized Phase IIb ACCESS study, the exploratory ACCESS II study and supportive findings from an ongoing open-label extension and body composition substudy.

Together, the studies evaluated multiple once-daily oral doses of aleniglipron over 36 weeks, with higher-dose cohorts followed longer in select arms. The results suggest dose-dependent weight loss with a safety profile consistent with the GLP-1 receptor agonist class, supporting further late-stage development.

With the long-term adherence challenges of injectable GLP-1s, oral small molecule GLP-1 agonists are being explored as a potential alternative approach. These oral pills could likely broaden treatment options, though long-term efficacy and safety must still be demonstrated in larger trials.

The core Phase IIb ACCESS trial was a randomized, double-blind, placebo-controlled study that enrolled 230 adults with obesity, defined as a body mass index of at least 30 kg/m², or overweight with at least one weight-related comorbidity.

Participants were randomized 3:1 to receive aleniglipron or placebo, meaning three participants received active treatment for every one receiving placebo, and were titrated over four weeks to target doses of 45 mg, 90 mg or 120 mg taken once daily.

The primary endpoint was percent change in body weight from baseline at 36 weeks, assessed under an estimand assuming participants remained on study treatment without initiating rescue weight-management interventions.

At 36 weeks, all three aleniglipron dose groups met the primary endpoint, showing statistically significant reductions in body weight compared with placebo.

The placebo-adjusted mean weight loss was 8.2% with the 45 mg dose, 9.8% with 90 mg and 11.3% with 120 mg. In the highest-dose group, 86% of participants achieved at least 5% weight loss and 70% achieved at least 10% weight loss.

Modest improvements in systolic blood pressure and HbA1c were also reported as secondary outcomes.

Additional efficacy data came from the exploratory ACCESS II study, which enrolled 85 adults and evaluated higher target doses up to 240 mg.

At a prespecified 36-week analysis, placebo-adjusted mean weight loss reached 14.1% at 120 mg, 14.4% at 180 mg and 15.3% at 240 mg, with all comparisons achieving statistical significance. The study remains ongoing, with longer-term data expected to further characterize durability of effect in this smaller, dose-exploratory population.

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Across studies, aleniglipron’s safety profile was generally consistent with that of the GLP-1 receptor agonist class.

Data from the open-label extension and a separate body composition substudy suggested that starting treatment at a lower 2.5 mg dose before titrating upward may improve tolerability. In these cohorts, weight loss appeared to continue beyond 36 weeks without evidence of an early plateau, according to interim analyses.

Based on the totality of the ACCESS program data, Structure Therapeutics plans to request a Type B end-of-Phase II meeting with the FDA in the first half of 2026 to finalize the Phase III trial design. The planned Phase III program is expected to evaluate multiple doses of aleniglipron, with a lower starting titration dose and target doses up to 240 mg.

While injectable GLP-1-based therapies such as semaglutide and tirzepatide remain widely, the development pipeline is expanding toward oral agents and multi-pathway approaches.

In 2025, Eli Lilly reported Phase III obesity data for the oral small molecule GLP-1 receptor agonist orforglipron, while Pfizer discontinued development of its oral GLP-1 candidate danuglipron following safety review. Separately, Novo Nordisk reported Phase Ib/ IIa clinical data for amycretin, a unimolecular therapy engaging both incretin and amylin biology.

Other companies also reported mid-stage progress in oral GLP-1 development, including Ascletis, which announced Phase II results for its oral GLP-1 receptor agonist ASC30.

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