1658-P: Characterization and Preclinical Efficacy of a Novel Unimolecular Amylin and GLP-1 Receptor Dual Agonist, VRB-104

Introduction and Objective: GLP-1 and amylin are peptide hormones that independently reduce appetite, slow gastric emptying, and decrease glucagon release. Combination of GLP-1 and amylin receptor agonists demonstrates greater weight loss and glycemic control than either agent alone. Here we assessed the in vitro potency, in vivo efficacy, and pharmacokinetics (PK) of VRB-104, a novel unimolecular amylin & GLP-1 receptor dual agonist. Methods: VRB-104 was tested in reporter cell lines overexpressing human GLP-1 receptor (hGLP-1R) or amylin receptor (hAMY3R); amycretin was used as a comparator. VRB-104 was administered via daily subcutaneous injection in a diet-induced obese (DIO) rat model for 14 days, with body weight and food intake recorded daily. Single dose subcutaneous PK studies with VRB-104 were performed in rats, mini-pigs, and cynomolgus monkeys. Results: In cell culture, VRB-104 showed 3-fold increased potency on the hAMY3R compared to amycretin, while showing 6-fold reduced potency on the GLP-1R compared to amycretin. In the DIO rat model, VRB-104 dosed daily for 14 days induced a -14% body weight loss from baseline compared to +1% weight gain for vehicle. Single subcutaneous dose PK studies showed a half-life of 12.3 h in rats, 67.9 h in minipigs, and 33.7 h in cynomolgus monkeys. Conclusion: VRB-104 is a novel unimolecular amylin & GLP-1 receptor dual agonist, with selectivity for hAMY3R over GLP-1R. These data support the continued development of VRB-104 for the treatment of obesity and type 2 diabetes. Disclosure M. Fenaux: None. J. Francis: Employee; Current; Verdiva Bio. C.L. Jones: Employee; Current; Verdiva Bio. S.J. Sharp: Research Support; Current; Verdiva Bio. H. Zou: Employee; Current; Sciwind Biosciences. Y. Li: Employee; Current; Sciwind Biosciences. X. Wu: Employee; Current; Sciwind Biosciences. R. Zhu: Employee; Current; Sciwind Biosciences. S. Hao: Employee; Current; Sciwind Biosciences. Z. Li: Employee; Current; Sciwind Biosciences. Y. Wang: Employee; Current; Sciwind Biosciences. J. Zhao: Employee; Current; Sciwind Biosciences. W. Zhong: None.