2543-P: IBI3042: A Novel Oral Once-Weekly Small-Molecule GLP-1 Receptor Agonist for Type 2 Diabetes and Obesity

Introduction and Objective: Peptide-based GLP-1 receptor agonists, such as Semaglutide, are highly effective for managing type 2 diabetes (T2D) and obesity but are limited by high costs and the need for injections. Orforglipron, an oral small-molecule GLP-1 receptor agonist requiring daily dosing, has demonstrated promising efficacy in phase 3 trials for both indications. A once-weekly oral small-molecule GLP-1 receptor agonist would address a significant unmet need by enhancing patient convenience and potentially improving affordability. IBI3042 is a novel small-molecule GLP-1 receptor agonist evaluated in preclinical models, including DIO humanized GLP-1 receptor knock-in mice and obese cynomolgus monkeys. Methods: In DIO humanized GLP-1 receptor knock-in mice, IBI3042 was administered orally at doses of 0.3, 1, and 3 mg/kg twice weekly and compared with Orforglipron at 1.5 mg/kg once daily (QD) or 3 mg/kg twice weekly. In a separate study in obese cynomolgus monkeys, IBI3042 was given orally at 7 mg/kg once weekly, with Orforglipron 1 mg/kg QD as the comparator. Primary outcomes included body weight reduction and tolerability. Results: In DIO humanized GLP-1 receptor knock-in mice, twice-weekly IBI3042 at 1 mg/kg achieved body weight reduction comparable to daily orforglipron 1.5 mg/kg, while the 3 mg/kg dose showed superior efficacy. Orforglipron at 3 mg/kg twice weekly exhibited no notable efficacy. In obese cynomolgus monkeys, once-weekly IBI3042 at 7 mg/kg produced body weight reduction that matched or exceeded that of daily orforglipron 1 mg/kg. Conclusion: IBI3042 demonstrated robust, dose-dependent body weight reduction with twice-weekly oral dosing in DIO humanized GLP-1 receptor knock-in mice and confirmed once-weekly oral efficacy in obese cynomolgus monkeys. These preclinical data position IBI3042 as a promising once-weekly oral small-molecule GLP-1 receptor agonist for the treatment of type 2 diabetes and obesity. Disclosure Y. Jiang: None. J. Ding: None. Y. Xiong: None. S. Liu: None. D. Ren: None.