1625-P: GS-4571, an Oral Small Molecule GLP-1R Agonist, Improves Glucose Tolerance and Suppresses Food Intake in Obese Diabetic Cynomolgus Monkeys

The Glucagon-like peptide 1 receptor (GLP-1R) is a class B1 G-protein-coupled receptor (GPCR) that is widely expressed and helps mediate insulin secretion, gastric emptying, and satiety. Currently, GLP-1R peptide agonists are used as standard of care for the treatment of T2DM and more recently for obesity. These GLP-1R peptide agonists require frequent subcutaneous injections or strict dosing guidelines thus increasing the need to develop an oral small-molecule GLP-1R agonist. Here we describe the identification of a novel small molecule GLP-1R agonist (GS-4571) which stimulated a potent cAMP response in pancreatic β-cells (EndoC-BH1) and selective agonism against human and monkey GLP-1R versus other class B GPCRs. In an intraperitoneal glucose tolerance test (IPGTT) it demonstrated improved glucose tolerance in humanized GLP-1R mice. Further studies, in obese cynomolgus monkeys, GS-4571 demonstrated similar improvements in glucose tolerance after a single dose treatment. Once-daily oral administration of GS-4571 in obese diabetic cynomolgus monkeys not only showed improved glycemic control but also showed a reduction in energy intake which led to an increase in weight loss over 36 days. Together these data support the continued development of GS-4571 into the clinic as a novel orally bioavailable GLP-1R small molecule agonist. Disclosure J. Vogel: None. M. Seung: None. B. Marchand: Employee; Gilead Sciences, Inc. Stock/Shareholder; Gilead Sciences, Inc., Pfizer Inc., Arrowhead Pharmaceuticals, Inc., Kronos Bio, Inc., Allogene Therapeutics, Inc., AbCellera Biologics Inc., Arbutus Biopharma Corporation. N. Bhangre: Employee; Gilead Sciences, Inc. Research Support; Gilead Sciences, Inc. Stock/Shareholder; Gilead Sciences, Inc. J. Mukherjee: None. S.E. Ammann: Employee; Gilead Sciences, Inc. M. Armstrong: Employee; Gilead Sciences, Inc. G. Brizgys: Employee; Gilead Sciences, Inc. E. Chin: Employee; Gilead Sciences, Inc. C. Chou: None. J. Cottell: Employee; Gilead Sciences, Inc. S.D. Schroeder: Employee; Gilead Sciences, Inc. R. Thomas-Tran: Employee; Gilead Sciences, Inc. Z. Yang: None. M. Peters: Employee; Gilead Sciences, Inc. G. Budas: Employee; Gilead Sciences, Inc. M.L. Mitchell: Employee; Gilead Sciences, Inc. M. Chojnacka: None. S. Jermain: None. J. Hung: Employee; Gilead Sciences, Inc. S. Kulkarni: None. Q. Yue: None. D.W. Lin: Employee; Gilead Sciences, Inc. D.A. Miranda: None.