771-P: Efficacy of CT-996, an Oral Small Molecule GLP-1 Receptor Agonist, in Human GLP-1 Receptor Knockin Mice and Obese Cynomolgus Monkeys

Since FDA approval of exenatide in 2005, injectable GLP-1 receptor agonists (RAs) have established their clinical utility in the management of type 2 diabetes and obesity. However, rising treatment utilization urgently necessitates cost-effective, simpler solutions. Here, we describe CT-996, a potent, oral small molecule GLP-1RA, and present preclinical efficacy studies to support its development for daily oral human use. In vitro, CT-996 was equally efficacious at stimulating cAMP accumulation in cells expressing human or cynomolgus monkey GLP-1R, and stimulated insulin secretion in a human β-cell line. In contrast to native GLP-1, CT-996 exhibited minimal β-arrestin recruitment and weaker GLP-1R internalization. In vivo, a single oral dose of CT-996 potently and effectively suppressed postprandial blood glucose following a mixed meal tolerance test (MMTT) in mice expressing the human GLP-1 receptor and, in obese monkeys, enhanced glucose stimulated insulin secretion (GSIS) during an intravenous glucose challenge. In a 4-week study in obese monkeys, daily CT-996 dosing markedly suppressed both plasma glucose and insulin excursion during MMTT. Compared to vehicle-treated animals, CT-996 significantly decreased food intake, body weight, and fat mass. All doses were well tolerated. In summary, CT-996 is a small molecule GLP-1RA that exhibits biased cAMP signaling and reduced receptor internalization. Oral dosing of CT-996 enhanced glucose homeostasis and reduced weight and fat mass after 4-week treatment in obese monkeys. These observations corroborate the continued development of CT-996 as a next-generation GLP-1RA. CT-996 is currently being evaluated in a Phase 1 clinical trial. Disclosure J. Luo: Employee; Carmot Therapeutics, Inc. R. Rodriguez: Employee; Carmot Therapeutics, Inc. A. Hergarden: Employee; Carmot Therapeutics, Inc. T. Tracy: Employee; Carmot Therapeutics, Inc. D. Lam: Employee; Carmot Therapeutics, Inc. S. Garai: None. D. Marshall: None. S.K. Hansen: Board Member; Carmot Therapeutics, Inc. M. Chakravarthy: Employee; Carmot Therapeutics, Inc.