767-P: TERN-601, a Novel Oral GLP-1R Agonist, Suppresses Food Intake and Improves Glucose Tolerance in Transgenic Mice Expressing Human GLP-1 Receptor

Synthetic peptide agonists of the GLP-1 receptor (GLP-1R) are approved for the treatment of diabetes and obesity based on their ability to lower blood glucose and induce weight loss. TERN-601 is a novel, oral small molecule GLP-1R agonist in preclinical development. In vitro, TERN-601 potently stimulated (EC50 = 2.9 ± 0.8 nM) intracellular cAMP generation, a downstream consequence of GLP-1R activation, in CHO-K1 cells stably expressing human GLP-1R. In vivo, single oral doses of TERN-601 (10, 30, or 60 mg/kg) led to significant dose-dependent suppression of food intake (2- to 24-hours post dose) in transgenic C57BL/6J mice (n = 10 per group) expressing human GLP-1R (hGLP-1R). In an intraperitoneal glucose tolerance test (IPGTT) on overnight fasted hGLP-1R mice (n = 7 per group), single oral doses of TERN-601 (0.3, 1, and 3 mg/kg) administered 30 minutes prior to IP glucose injection significantly lowered blood glucose area under the curve (AUC0-120min) with comparable efficacy to liraglutide (0.3 mg/kg). TERN-601 is a potent, orally bioavailable small molecule agonist of human GLP-1R in preclinical development for the treatment of chronic obesity. In transgenic mice expressing human GLP-1R, single oral doses of TERN-601 significantly suppressed food intake and improved glucose tolerance. Together these data support the continued development of TERN-601. Disclosure C.Jones: Employee; Terns Pharmaceuticals. K.P.Quinn: None. C.H.Nelson: Employee; Terns Pharmaceuticals, Gilead Sciences, Inc., Stock/Shareholder; Terns Pharmaceuticals, Gilead Sciences, Inc. O.Osborn: Employee; Terns, Stock/Shareholder; ClicBio. G.Luehr: None. J.R.Jasper: Advisory Panel; Rubedo Life Sciences, Employee; Terns Pharmaceuticals, Rubedo Life Sciences.