2552-P: Preclinical Proof of Concept of ZT009, a Novel Unimolecular Long-Acting GLP-1 and Amylin Receptor Agonist

Introduction and Objective: Combination of GLP 1 and amylin analogs has emerged as next generation therapeutics for the treatment of obesity. We developed ZT009, a novel, long-acting unimolecular GLP-1 and Amylin receptor agonist, aiming to provide better efficacious and convenient treatment for obesity. Here, we report preclinical data supporting its therapeutic potential. Methods: In vitro activities of ZT009 on GLP-1 and amylin were assessed using a BHK cell line that overexpresses the human GLP-1 receptor, and a CHO cell line co-overexpressing the human amylin receptor-3 (AMY3R), respectively. In vivo tests were carried out in both lean rats and diet-induced obese (DIO) rats to demonstrate the pharmacological efficacy of ZT009 as compared to amycretin. The pharmacokinetic (PK) parameters were measured in rats, minipigs and monkeys. Results: ZT009 is an engineered peptide conjugate comprising GLP-1 and amylin analogs linked via a peptide linker and acylated with a fatty acid for time-action extension. It demonstrated high solubility and stability at neutral pH. In cell-based assays, ZT009 was designed to enhance AMY3R activity by 5.1-fold compared to amycretin, maximizing beneficial metabolic effects. Additionally, it was designed to moderately reduce GLP-1 activity to 0.6-fold that of amycretin, thereby minimizing GI side effects, while maintaining a wide safety margin. In lean rats and DIO rats, ZT009 dose-dependently reduced body weight and food intake with effects exceeding those of amycretin at same dose. Importantly, ZT009 exhibited a significantly prolonged half-life and delayed Tmax across all species tested compared to amycretin, suggesting reduced peak-to-trough variability and enhanced GI tolerability in clinical translation. Conclusion: These preclinical data demonstrate that ZT009 is a potent, long-acting dual GLP-1 and amylin receptor agonist with superior pharmacology and pharmacokinetic properties. ZT009 represents a promising next-generation candidate for obesity therapy, supporting further clinical development. Disclosure Y. Zhang: None. B. Wu: None. B. Zhang: None. X. Zhao: None. X. Chen: None. M. Wang: None. H. Jiang: None. P. Gao: None. S. Lin: None. X. Zhang: None. Y. Zhang: None.