1673-P: ASC37 Oral Tablets, GLP-1R/GIPR/GCGR Triple Agonist Peptide, Achieved Average Absolute Oral Bioavailability of 4.2% in Nonhuman Primate Studies

Introduction and Objective: ASC37 is an oral GLP-1R/GIPR/GCGR triple agonist peptide, discovered and developed in-house at Ascletis. Peptide Oral Transport ENhancement Technology (POTENT) is a proprietary technology of Ascletis for oral peptides. POTENT technology impedes enzymatic degradation of peptides and increases gastrointestinal permeability of peptides. Methods: ASC37 oral tablets were developed utilizing Ascletis’ POTENT technology. The absolute oral bioavailability and drug exposure of ASC37 tablets were evaluated in non-human primate (NHP) models. ASC37 in vitro activity was also evaluated. Results: ASC37, a GLP-1R, GIPR, and GCGR triple agonist peptide, was discovered and optimized in-house utilizing Ascletis’ Artificial Intelligence-assisted Structure-Based Drug Discovery (AISBDD). ASC37 oral tablets achieved an average absolute oral bioavailability of 4.2%, approximately 9-, 30-, and 60-fold higher than semaglutide, tirzepatide, and retatrutide in the oral SNAC formulation, respectively, in head-to-head non-human primate (NHP) studies. ASC37 oral tablets’ drug exposure, as measured by the area under curve (AUC), was approximately 57-fold of retatrutide’s drug exposure in head-to-head NHP studies. Average observed half-life (as measured by time to 50% Cmax) of ASC37 oral tablets was approximately 56 hours in NHP studies, supporting once daily and less frequent oral dosing. ASC37 in vitro activity was approximately 5-, 4- and 4-fold more potent than retatrutide for GLP-1R, GIPR and GCGR, respectively. Conclusion: ASC37 is a promising oral GLP-1R/GIPR/GCGR triple agonist peptide for clinical development Disclosure J.