1664-P: Discovery of Selective, Long-Acting Amylin Receptor Agonist for Obesity

Introduction and Objective: CH-AM-1 to 3 are potent, long-acting amylin receptor agonists under research for obesity. Unlike some amylin agonist molecules (e.g. Cagrilintide), they are designed to have minimal calcitonin activity. Methods: Peptides were designed and tested in cAMP assay for activity against AMY1R, AMY3R and selectivity over calcitonin (CTR) receptors, evaluated for body weight reduction in SD or DIO rats and studied for pharmacokinetic (PK) profiles in cynomolgus monkeys. Eloralintide (Lilly), a selective AMY1R agonist in clinical studies, was used as a comparator. Results: cAMP assay EC50 (nM) against AMY1R, selectivity ratios over AMY3R and CTR for CH-AM-1 to 3 vs. eloralintide and Cyno monkey PK result for CH-AM-1 are listed below; CH-AM-1 to 3 generally have higher selectivity than eloralintide against AMY3R and CTR. They also have long T1/2s in monkeys, potentially enabling once monthly dosing in human. Pre-clinical profiling studies of the agonists are on-going. Conclusion: CH-AM-1 to 3 demonstrated potency against AMY1R, efficacy in rats and PK in cyno monkeys comparable to eloralintide but with enhanced receptors selectivity over AMY3R and CTR. The AMY3R and CTR selectivity is proposed to enable eloralintide having enhanced efficacy and tolerability profiles in clinical trials. Disclosure S. Zhao: None. X. Jin: None. G. Chen: None. T. Qian: None. K. Xu: None. W. Chen: None. K. Hu: None.