1032-OR: ACCESS Trial: Dose-Ranging Evaluation of Aleniglipron, an Oral Small Molecule Nonpeptide GLP-1RA, Demonstrates Meaningful Weight Reductions in People Living with Obesity and Overweight

Introduction and Objective: Aleniglipron is a novel, oral, non-peptide small molecule GLP-1 RA, in development for obesity and type 2 diabetes management. This dose-ranging, Phase 2b ACCESS trial was designed to evaluate the efficacy, safety, and tolerability of aleniglipron in people with obesity, or overweight and ≥1 weight-related comorbidity, over 36 weeks. Methods: Adults (N = 230) were randomized 3:1 to aleniglipron arms (45, 90, or 120 mg) or placebo, starting at a 5 mg dose, escalated every 4 weeks to target dose. The primary endpoint was percentage change in body weight from baseline with aleniglipron vs. placebo. Secondary endpoints included percentage of participants with ≥5%, 10%, or 15% body weight loss at week 36. Results: Baseline characteristics were similar across arms, including a mean BMI of 39.5 kg/m2, and 54.3% were female. At week 36, the placebo-adjusted LS mean body weight from baseline was −8.2%, −9.8%, and −11.3% for the aleniglipron 45, 90, and 120 mg arms (p<0.0001, for all doses vs. placebo), respectively, with no signs of weight loss plateau as confirmed by up to -1.3% further weight loss by week-8 of the ongoing open-label extension. LSM body weight loss of ≥5% occurred in 86% of participants, ≥10% in 70%, and ≥15% in 38% of participants in the 120 mg dose arm. TEAEs and GI AEs were mostly mild or moderate, consistent with the expected profile for the GLP-1RA class. AE-related treatment discontinuation rate was 10.4% across aleniglipron arms, and 5.4% in placebo arm. There were no signals of liver toxicity. The placebo-adjusted LS mean change in HbA1c and systolic blood pressure from baseline were −0.37% and −7.5 mmHg in the aleniglipron 120 mg arm. Conclusion: ACCESS Phase 2b trial data support further development of aleniglipron, a novel, highly scalable, small-molecule GLP-1 RA and evaluation in Phase 3 registrational studies for people living with obesity. Disclosure J. Rosenstock: Advisory Panel; Ended; Amgen Inc. Research Support; Current; Amgen Inc., AstraZeneca. Advisory Panel; Ended; Biomea Fusion, Corcept Therapeutics, Eli Lilly and Company. Research Support; Ended; Eli Lilly and Company. Advisory Panel; Ended; Gan & Lee Pharmaceuticals, Hanmi Pharm. Co., Ltd., Boehringer Ingelheim International GmbH. Research Support; Ended; Boehringer Ingelheim International GmbH. Advisory Panel; Ended; Novo Nordisk. Research Support; Ended; Novo Nordisk, Pfizer Inc. Advisory Panel; Ended; Regeneron Pharmaceuticals Inc. Research Support; Ended; Regeneron Pharmaceuticals Inc. Advisory Panel; Ended; Regor. Research Support; Ended; Regor. Advisory Panel; Ended; Roche Pharmaceuticals. Advisory Panel; Current; Sanofi. Research Support; Current; Sanofi. Advisory Panel; Ended; Structure Therapeutics, Terns. D. Ryan: Advisory Panel; Current; Abbvie, Altimmune, Amgen, AstraZenica, Boehringer Ingelheim, Biohaven, Carmot/Roche/Genentech. Advisory Panel; Ended; eMed, Fractyl, Nestle. Consultant; Current; Pfizer, Source Bio, Protagonist, PPD, Regeneron, Regor. Advisory Panel; Current; Currax, Structure Therapeutics, Tenvie, Kailera. Speaker's Bureau; Current; LIlly, Novo Nordisk,. Other - I am a consultant to both and received stock options and consulting fees.; Current; Calibrate, Epitomee. Other - Data Monitoring Committee member; Current; CinRx, Rhythm, Lilly. Advisory Panel; Current; Viking, Weight Watchers, Wonder Health, Zealand. Other - ! received non-negotiable stock options from these companies years ago and have not worked for them in years.; Ended; Roman, Scientific Intake. A. Acosta: Other - Licensed Patent / Technology; Current; Phenomix Sciences, Gila Therapeutics. Advisory Panel; Current; Boehringer Ingelheim International GmbH, Structure Therapeutics. Research Support; Ended; Novo Nordisk. Research Support; Current; Rhythm Pharmaceuticals, Inc., Regeneron Pharmaceuticals Inc. T.C. Blevins: Research Support; Current; Abbott. Advisory Panel; Ended; Corcept Therapeutics. Research Support; Current; Dexcom, Inc., Lilly Diabetes, Novo Nordisk. Advisory Panel; Current; MannKind Corporation. Research Support; Current; Tandem Diabetes Care, Inc. Speaker's Bureau; Current; Tandem Diabetes Care, Inc. Research Support; Current; Medtronic. Speaker's Bureau; Current; Sanofi-Aventis U.S. Research Support; Current; Insulet Corporation. Advisory Panel; Ended; Lilly Diabetes. Research Support; Current; Amgen Inc., Viking Therapeutics, vTv Therapeutics, Abbott Diabetes. Speaker's Bureau; Current; Dexcom, Inc. M. Choi: None. F.L. Holmes: Consultant; Ended; Pfizer Inc. L. Connery: Advisory Panel; Current; Boehringer Ingelheim International GmbH. Research Support; Current; Boehringer Ingelheim International GmbH. Advisory Panel; Current; Eli Lilly and Company. Research Support; Current; Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Regeneron Pharmaceuticals Inc., Roche Pharmaceuticals, Viking Therapeutics, Vertex Pharmaceuticals Incorporated. T.R. Smith: Research Support; Ended; Alnylam Pharmaceuticals, Inc. Research Support; Current; Amgen Inc. Research Support; Ended; BioAge. Research Support; Current; Biohaven, Boehringer Ingelheim International GmbH, Graviton, Lilly, Merz, Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc. Research Support; Ended; Reata Pharmaceuticals, Inc. Research Support; Current; Structure Therapeutics. Research Support; Ended; Terns. Research Support; Current; Viking Therapeutics. M. Liu: Employee; Current; Structure Therapeutics. A. Barth: Employee; Current; Structure Therapeutics. J. Butcher: Employee; Current; Structure Therapeutics. A.E. Civitarese: None. H. Yue: None. B. Coll: Stock/Shareholder; Current; AbbVie Inc., Amgen Inc. Other - Employed by Structure Therapeutics and shareholder; Current; Structure Therapeutics.