MWN105—A Next-Generation GLP-1/GIP/FGF21 Agonist for the Treatment of NASH

Introduction and Objective: Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with limited treatment options. While the FDA-approved FGF21 agonist has shown efficacy, its response rate for NASH resolution and fibrosis improvement remains suboptimal. MWN105 is a novel unimolecular triple agonist designed to activate GLP-1, GIP, and FGF21 pathways synergistically, addressing both metabolic dysfunction and fibrosis in NASH. Methods: A highly stable and active FGF21 with combined point mutations was screened out and connected to a GLP-1 and GIP chimeric polypeptide through Fc fusion, resulting in MWN05. MWN105 was evaluated in preclinical models, including diet-induced obese (DIO) mice, B6-Alms1-del NASH mice, and NASH-diabetes nonhuman primates (NHPs). The study assessed liver histology, metabolic biomarkers, body weight, and enzyme activity compared to tirzepatide. Results: In the B6-Alms1-del NASH mouse model, MWN105 significantly reduced body weight, liver weight, and liver-to-body weight ratio. Plasma ALT, AST, CHOL, and LDL-C levels, as well as hepatic cholesterol and triglyceride content, were markedly reduced. Liver NAS scores (steatosis, ballooning) also improved significantly. In NHPs, MWN105 led to a 30-50% reduction in liver fat, a 2.5-point improvement in NAS score, and ≥1-stage fibrosis improvement after 10 weeks. MWN105-treated NHPs also showed 15% weight loss with better lean mass preservation than tirzepatide. In DIO mice, MWN105 resulted in ~30% sustained body weight reduction without rebound, while preserving lean mass better than tirzepatide. Conclusion: MWN105 demonstrates potent metabolic and antifibrotic effects, addressing key NASH pathologies. MWN105 has a potential best-in-class therapeutic profile for NASH. MWN105 has obtained IND clearance in both the U.S. and China and Further Phase I clinical study is on-going. Disclosure: W. Song: Employee; Shanghai minwei biotechnology Co,,LTD.