Introduction and Objective: Non-peptide oral GLP-1 receptor agonists represent an important advance for metabolic disease treatment. This study aimed to characterize the in vitro potency, pharmacokinetics across species, and anti-obesity efficacy in preclinical models of IBI3032, a novel, orally available agonist, to support its ongoing clinical development. Methods: Potency and selectivity were assessed using cAMP accumulation in cells expressing human GLP-1R. Pharmacokinetic parameters were evaluated following single intravenous and oral administration in mice, rats, dogs, and cynomolgus monkeys. In vivo efficacy was tested in humanized GLP-1R knock-in mice with diet-induced obesity (DIO) following once-daily oral dosing over 28 days. A 28-day efficacy study was conducted in cynomolgus monkeys. Results: IBI3032 exhibited potent activation of the human GLP-1R (EC50 = 0.53 nM) with high selectivity and minimal β-arrestin recruitment. Pharmacokinetic studies revealed high oral exposure in cynomolgus monkeys, with a bioavailability of 35% and a half-life of 7.1 hours, addressing a key challenge for oral non-peptide GLP-1R agonists and supporting once-daily dosing. In a 28-day study in hGLP-1R knock-in DIO mice, oral IBI3032 produced dose-dependent body weight loss relative to vehicle (1 mg/kg: -6.5%; 6 mg/kg: -12.4%; 12 mg/kg: -14.9%; all P0.01 vs. vehicle). In a 28-day cynomolgus monkey study, once-daily oral administration of IBI3032 (1 mg/kg) produced 11.2% body weight loss versus vehicle. Conclusion: IBI3032 is a potent, selective oral GLP-1R agonist with favorable pharmacokinetics, robust and dose-dependent weight loss in preclinical models, and is currently being evaluated in Phase 1 clinical trials as a once-daily oral therapy for type 2 diabetes and obesity. Disclosure Y. Jiang: None. J. Ding: None. Y. Xiong: None. N. Yu: None. D. Ren: None.
Jiang et al. (Fri,) studied this question.