764-P: Discovery of ASC30, a Highly Potent and Orally Available Novel Nonpetide GLP-1 Receptor Biased Agonist

Introduction 30,000 nM), which indicated both were GLP-1R biased agonists. In IVGTT NHP model, efficacy of ASC30 on insulin secretion, C-peptide secretion and glucose control was compared to orforglipron. With a single i.v. bonus injection of 1.5 mg/kg ASC30 and 6 mg/kg orforglipron, ASC30 stimulated statistically and significantly more insulin secretion than vehicle control (p0.01) and orforglipron (p0.05). Further, ASC30 stimulated statistically and significantly more C-peptide secretion than vehicle control (p0.001) and orforglipron (p0.01). After a single oral dosing in rats, ASC30’s exposure over 48 hours (AUC0-48h) is 14-fold of that of orforglipron. Overall, ASC30 demonstrated more potent in vitro cAMP activation and more in vivo efficacy in stimulating insulin and C-peptide secretion than orforglipron. Conclusion: ASC30 is a highly potent and orally available GLP-1R biased agonist. Human clinical trials are warranted to further evaluate ASC30 as a potential oral therapy for T2DM and obesity. Disclosure J. Wu: None.