297-OR: A Novel GLP-1/FGF21 Dual Agonist ZT003 Has Therapeutic Potential for Obesity, Diabetes, and Nonalcoholic Steatohepatitis

Introduction: Combining two mechanisms (GLP-1 and FGF21) can deliver synergistic and complementary functions. ZT003 is a novel long-acting GLP-1/FGF21 dual agonist, and in this study, its therapeutic potential has been explored in animal models. Methods: In vitro GLP-1 and FGF21 activities of the fusion protein were measured using a BHK cell line overexpressing human GLP-1 receptor and a HEK293 cell line overexpressing human beta-Klotho. In vivo tests were carried out in DIO mice, db/db mice and NASH mice to demonstrate the pharmacological efficacy of ZT003 on body weight, food intake, plasma glucose, circulating lipids, liver fat content, NAS score and other metabolic parameters as compared to the benchmark molecules. The pharmacokinetic parameters were measured in non-human primates. Results: ZT003 is an engineered dual agonist fusion protein comprising GLP-1, anti-HSA nanobody (for half-life extension) and FGF21 conjugated with a small molecule to prevent C-terminal degradation. In cell-based assays, ZT003 showed an optimal GLP-1/FGF21 activity ratio. When tested in DIO obese mice and db/db diabetic mice, ZT003 demonstrated synergistic, sustained, and superior body weight reduction and glucose-lowering effect versus semaglutide, tirzepatide and YH25724. When tested in DIO NASH mice, ZT003 significantly improved lipid metabolism, hepatic steatosis, and liver histology, all of these effects being greater than semaglutide. The pharmacokinetic study in cynomolgus monkeys demonstrated the half-life of ZT003 is comparable to that of semaglutide, indicative that ZT003 is likely to be amenable for once-weekly dosing in humans. Conclusion: In conclusion, this novel GLP-1/FGF21 fusion protein in animals reveals therapeutically efficacious to treat obesity, diabetes, NASH and related co-morbidities, thus demonstrating the promise of the poly-pharmaceutical approach in metabolic drug discovery and development. Disclosure Y. Zhang: Employee; QL Biopharmaceutical Co. Ltd. Y. Zhang: None. C. Zhao: Employee; Beijing QL Biopharmaceutical Co., Ltd. S. Lin: None. W. Guo: Employee; Beijing QL Biopharmaceutical Co., Ltd. B. Wu: Employee; Beijing QL Biopharmaceutical Co. Ltd.