3070-LB: ABK-GIPR-1, an Oral Small-Molecule GIPR Antagonist, Enhanced GLP-1RA’s Efficacy in Reducing Body Weight and Improving Metabolic Profile in Preclinical Obesity Models

Introduction and Objective: Incretin-based therapies have emerged as effective interventions for weight management. While small-molecule glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as Orforglipron, demonstrate meaningful clinical efficacy, evidence from MariTide indicates that simultaneously agonizing GLP-1R and antagonizing glucose-dependent insulinotropic polypeptide receptor (GIPR) pathways can provide more robust outcomes than targeting GLP-1R alone. Here we report the in vitro and in vivo pharmacology profiles of ABK-GIPR-1, a highly potent, orally available, novel small molecule GIPR antagonist Methods: The in vitro potencies of small molecules on human and mouse GIPR as well as GLP-1R and glucagon receptors were determined using cAMP functional assays in cells overexpressing corresponding receptors. Mice with human-GIPR knocked-in were used to evaluate the in vivo effects on glucose homeostasis. Chronic effects on body weight and metabolic profile was evaluated using high-fat-diet-induced obesity (DIO) mouse model Results: ABK-GIPR-1 was discovered as a GIPR antagonist with high potency, good selectivity, and excellent PK property. In a DIO mouse model, combined administration of ABK-GIPR-1 and Semaglutide lowered body weight over 40% from baseline (vehicle corrected), significantly more than that of Semaglutide alone and comparable with Tirzepatide. Fat mass loss was the major contributor to body weight loss. Combination treatment also decreased hepatic lipid accumulation and improved blood lipid profile and glucose metabolism. Furthermore, combination with ABK-GIPR-1 was able to potentiate GLP1-R small molecule Orforglipron’s weight-reducing effect. Conclusion: In summary, ABK-GIPR-1 is a promising selective orally bioavailable GIPR antagonist to enhance weight loss and improve metabolic profile when combining with GLP1-RA.Its superior profile supports fast-track preclinical development. Disclosure S. Liu: Employee; Current; Abbisko Therapeutics Co., Ltd. Stock/Shareholder; Current; Abbisko Therapeutics Co., Ltd. W. Lu: Employee; Current; Abbisko Therapeutics Co., Ltd. Stock/Shareholder; Current; Abbisko Therapeutics Co., Ltd. Y. Li: None. F. Yang: Employee; Current; Abbisko Therapeutics Co., Ltd. J. Song: Employee; Current; Abbisko Therapeutics Co., Ltd. Stock/Shareholder; Current; Abbisko Therapeutics Co., Ltd. Y. Ning: Employee; Current; Abbisko Therapeutics Co., Ltd. Stock/Shareholder; Ended; WuXi AppTec Co., Ltd. Stock/Shareholder; Current; Jiangsu Hengrui Pharmaceuticals Co., Ltd. J. Wang: Employee; Current; Abbisko Therapeutics Co., Ltd. Stock/Shareholder; Current; Abbisko Therapeutics Co., Ltd. H. Deng: Employee; Ended; Abbisko Therapeutics Co., Ltd. Stock/Shareholder; Ended; Ascletis pharma, Hengrui. H. Yu: Employee; Current; Abbisko therapeutics Co. Ltd. H. Ying: Employee; Current; Abbisko Therapeutics. Stock/Shareholder; Current; Abbisko Therapeutics.