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

Introduction & Objective: Injectable peptidic GLP-1 receptor (GLP-1R) agonists are established treatments for Type 2 Diabetes Mellitus (T2DM) and obesity. An nonpeptide oral GLP-1R agonist without injection and cold chain storage offers many benefits for patients. Here we report the discovery of ASC30, a highly potent and orally available novel nonpeptide GLP-1R biased agonist as a potential once-daily oral therapy. Methods: ASC30 was tested for its activity against GLP-1 receptor by cAMP assay in Flp-In-293-GLP1R cells and for β-arrestin recruitment in cell-based assay. Further, ASC30 was tested in an intravenous glucose tolerance test (IVGTT) in nonhuman primates (NHPs). Orforglipron was used as a reference compound. Results: ASC30 strongly activated GLP-1R Gαs cAMP pathway with a mean EC50 of 0.011 nM (n=8), compared to a mean EC50 of 0.024 nM (n=8) for orforglipron. Both ASC30 and orforglipron did not induce measurable β-arrestin recruitment signaling (EC50 > 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 (p<0.01) and orforglipron (p<0.05). Further, ASC30 stimulated statistically and significantly more C-peptide secretion than vehicle control (p<0.001) and orforglipron (p<0.01). 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.