1663-P: Discovery and Development of CH3127, a Prodrug of Semaglutide for Once Weekly Oral Tablet Dosing

Introduction and Objective: CH3127 is a prodrug of semaglutide intended for once weekly oral tablet dosing in clinical trials with a flat drug concentration time curve of semaglutide released to enhance efficacy and to reduce side effects. Methods: Prodrugs of semaglutide that does not have intrinsic activity against GLP-1 receptor but act as a reservoir, in vivo, that can release semaglutide at desired rates with PK profiles of reduced Cmax, increased Ctrough, prolonged Tmax, T1/2 and Tlast were designed and evaluated. Results: CH3127 tablets demonstrated oral bio-availability up to 3.04% vs. IV or 6% vs SC dosing. It showed enhanced efficacy in DIO mice study comparing with directly SC dosed semaglutide due to enhanced PK profile (Graph below). FDA has cleared the IND of CH3127 tablets for once weekly dosing. Conclusion: CH3127 demonstrated high oral bioavailability in cyno monkeys with PK profile of reduced Cmax, increased Ctrough, prolonged Tmax, T1/2 and Tlast, such PK profile will enable once weekly oral dosing in the clinical without causing the side effects resulting from high Cmax of directly dosed semaglutide. Disclosure S. Zhao: None. X. Jin: None. G. Chen: None. T. Qian: None. K. Xu: None. W. Chen: None. K. Hu: None. X. Li: None. R. Xiong: None.