3043-LB: Synergistic Hepatoprotective and Weight-Loss Effects of Vanoglipel and Resmetirom Combination Therapy in a Diet-Induced Obese, Biopsy-Confirmed Mouse Model of MASH

Introduction and Objective: Vanoglipel (DA-1241), a novel G protein-coupled receptor 119 (GPR119) agonist, completed a Phase 2a trial in patients with presumed metabolic dysfunction-associated steatohepatitis (MASH). To determine whether combining vanoglipel with a thyroid hormone receptor beta (THRβ) agonist enhances efficacy for MASH, this study evaluated their combined effects in a diet-induced obese MASH mouse model. Methods: Male C57BL/6JRj mice were fed a GAN diet for 39 weeks. Biopsy-proven mice (NAFLD activity score (NAS) ≥5, F2-F3) were randomized to 16 weeks of control diet or diet containing vanoglipel (100 mg/kg/day), resmetirom (3 mg/kg/day), or both. Data were analyzed by one-way ANOVA with multiple-comparison tests. Results: Monotherapies had no significant effect on body weight, whereas the combination induced marked weight loss (23.6% vs. control, p<0.05), with endpoint fat mass and epididymal fat weight 43.5% and 42.1% lower than control, respectively (p<0.05). All treatments decreased ALT, with the lowest level in the combination group (83.5% reduction, p<0.05). Histopathologically, vanoglipel improved NAS by ≥1 point in 88.9% of mice (p<0.05), while 81.3% of combination-treated mice achieved a ≥2-point NAS improvement with synergistic reductions in hepatic lipid % area (84.6%, p<0.05). Vanoglipel also showed a trend toward fibrosis improvement. Consistently, α-SMA % area was reduced in the vanoglipel and combination groups (52-54%, p<0.05), suggesting suppression of stellate cell activation. Galectin-3, type I collagen, and hepatic hydroxyproline were also reduced by 43.7%, 33.5%, and 69.6%, respectively (all p<0.05), supporting greater benefit than either monotherapy. Conclusion: When combined with resmetirom, vanoglipel unlocks synergistic benefits, highlighting its potential as a combination strategy for MASH. This study is the first to demonstrate the therapeutic potential of combined targeting of GPR119 and THRβ for MASH. Disclosure Y. Chae: None. T. Kim: None. S. Lee: None. I. Jeong: None. H. Kim: None. M. Kim: None. H.H. Hansen: Employee; Current; Gubra.