2184-LB: Novel Oral Small Molecule ACCG-2671—A Dual Amylin and Calcitonin Receptor Agonist Development Candidate for Obesity Therapy

Introduction and Objective: Amylin, a peptide hormone co-secreted with insulin by pancreatic beta cells in response to food intake, suppresses appetite and delays gastric emptying, making it an attractive target for obesity therapy. Cagrilintide, a long-acting dual amylin and calcitonin receptor agonist (DACRA) peptide, has demonstrated promising efficacy and safety profile in clinical trials, but an oral small molecule DACRA with good bioavailability and stability could provide a more convenient and accessible alternative for obesity treatment. This study evaluates the in vitro and in vivo pharmacological properties of ACCG-2671 for obesity treatment. Methods: The in vitro binding affinity and functional potency of ACCG-2671 were assessed for the calcitonin receptor (CTR) and amylin receptor (AMY3R). Chronic weight-loss effects were evaluated in diet-induced obese (DIO) rats by oral daily dosing of ACCG-2671 as single treatments or in combination treatments with semaglutide using two treatment regimens: add-on and concurrent combination. Results: ACCG-2671 demonstrated high binding affinity and balanced potency in human CTR and AMY3R functional assays. In DIO rats, oral administration of ACCG-2671 resulted in significant, dose-dependent body weight reductions. Combination treatments (add-on and concurrent) resulted in superior weight loss compared to single treatments. Conclusion: ACCG-2671 is a novel oral small molecule DACRA that significantly reduces body weight in obese rats. Its pharmacological profile and preclinical efficacy support its advancement as a development candidate, alone and in combination for obesity treatment, potentially offering a novel, convenient, and accessible therapeutic option. Disclosure X. Fang: Employee; Structure Therapeutics, Inc. Z. Zhang: Employee; Structure Therapeutics, Inc. H. Zhang: Employee; Structure Therapeutics, Inc. C. Lu: None. D. Xue: Employee; Structure Therapeutics, Inc. Z. Wang: Employee; Structure Therapeutics, Inc. S. Zhan: Employee; Structure Therapeutics, Inc. X. Wang: Employee; Structure Therapeutics, Inc. W. Liang: Employee; Structure Therapeutics, Inc. T. Ma: Employee; Structure Therapeutics, Inc. N. Hu: Employee; Structure Therapeutics, Inc. J.J. Zhang: None. L. Chen: None. X. Lai: None. D. He: None. C. Li: Employee; Structure Therapeutics, Inc. Z. Gao: Employee; Structure Therapeutics, Inc. X. Lin: None. X. Jiang: Employee; Structure Therapeutics, Inc. H. Lei: Employee; Structure Therapeutics, Inc. F. Zhang: Stock/Shareholder; Eli Lilly and Company, Novo Nordisk A/S. Employee; Structure Therapeutics, Inc.