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&J, Juvena, Keros Therapeutic, Inc, Mediflix, Metsera, Neurocrine, Novo Nordisk, Penguin Bio, Pfizer, Regeneron, Response Pharmaceutical, Roche, Sanofi, Shionogi, Skye B, Tenvie, TERNS Pharma, Verdiva Bio, Viking Therapeutics, and Zealand Pharma. 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.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.