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.