3101-LB: Exploring a Lower Starting Dose of Aleniglipron, an Oral Small Molecule GLP-1RA, to Improve GI Tolerability in Obesity: Beyond the ACCESS Trials

Introduction and Objective: Aleniglipron is a novel oral non-peptide small-molecule GLP-1 RA in development for obesity and T2D management. Two ongoing trials of aleniglipron in adults with obesity, the ACCESS open-label extension (OLE) and the body composition (BC) trials, explored GI tolerability at a lower 2.5 mg starting dose vs. 5 mg starting dose that was used in the phase 2 ACCESS and ACCESS II trials. Methods: At an interim analysis, 36 participants in the OLE and 59 participants in the BC trial had received the aleniglipron 2.5 mg starting dose. The dose was increased to 5 mg at 4 weeks. We compared the incidence of nausea and vomiting during the first 8 weeks after initiating aleniglipron at 2.5 mg daily vs. 5 mg daily in the original ACCESS (N=173) and ACCESS II studies (N=71). Results: The prevalence of nausea and vomiting in the first 4 weeks of treatment was lower when starting with the 2.5 mg rather than the 5 mg dose (Figure 1). No increase in nausea occurred during weeks 5-8 when the dose was titrated to 5 mg. No participants in the 2.5 mg starting dose groups discontinued treatment due to AEs vs. 4.6% (ACCESS) and 9.9% (ACCESS II) in the 5 mg starting dose groups over 8 weeks. Conclusion: Starting aleniglipron at a lower dose (2.5 mg vs. 5 mg daily) is associated with a lower frequency of nausea and vomiting, suggesting better GI tolerability. Disclosure 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. 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. K. Cannon: None. M. Choi: None. F.L. Holmes: Consultant; Ended; Pfizer Inc. R. Kushner: Advisory Panel; Current; AbbVie Inc. Consultant; Ended; Altimmune. Advisory Panel; Current; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Consultant; Current; Eli Lilly and Company, Regeneron Pharmaceuticals Inc., Viking Therapeutics. Advisory Panel; Current; Antag, Weight Watchers, Structure. I. Lingvay: Consultant; Current; Aadvarak Therapeutics, Abbvie, Alveus Therapeutics, Amgen, Antag Therapeutics, Arrowhead Pharmaceuticals, Astra Zeneca, Baim Institute, Bain Capital, Bayer, Betagenon AB, Bioio Inc., Biomea, Boehringe. Research Support; Current; Novo Nordisk A/S, Dexcom, Inc., Boehringer Ingelheim International GmbH. Consultant; Current; Eli Lilly, Genentech, Janssen/J 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 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.H. 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. J. Butcher: Employee; Current; Structure Therapeutics. A.E. Civitarese: None. H. Yue: None. Y. Li: Employee; Current; Structure Therapeutics. A. Barth: Employee; Current; Structure Therapeutics. M. Liu: Employee; Current; Structure Therapeutics. B. Coll: Stock/Shareholder; Current; AbbVie Inc., Amgen Inc. Other - Employed by Structure Therapeutics and shareholder; Current; Structure Therapeutics.