Introduction and Objective: DA-1241, a novel G protein-coupled receptor 119 agonist, recently completed a Phase 2a clinical trial in presumed metabolic dysfunction-associated steatohepatitis (MASH) patients. This study extended previous findings on its hepatoprotective synergy with glucagon-like peptide-1-based drugs and evaluated its anti-MASH effects in combination with a fibroblast growth factor 21 analogue.Methods: Male C57BL/6JRj mice were fed a GAN diet for 36 weeks before receiving vehicle, DA-1241 (100 mg/kg, QD, oral), Efruxifermin (EFX; 1 mg/kg, QW, subcutaneous), or their combination for 12 weeks.Results: DA-1241 was weight-neutral, while EFX induced 17% weight loss (p<0.05 vs. vehicle), with no further reduction in combination. Each treatment ameliorated plasma transaminases and liver cholesterol levels, with combination therapy providing greater improvement compared to monotherapies. In combination, 94% of mice had a ≥2-point improvement in non-alcoholic fatty liver disease activity score from baseline, indicating an additive effect. Liver lipid area and steatotic hepatocytes also decreased more with the combination. Liver immunohistochemistry revealed significantly reduced inflammatory (galectin-3) and fibrotic (type 1 collagen and α-SMA) markers, suggesting enhanced effects over monotherapy. mRNA analysis showed marked decreases in inflammatory (Tnfα -58%, Cxcl10 -56%) and fibrotic (Col1a1 -72%) genes, confirming synergy. Notably, hedgehog-interacting protein, a suppressor of hepatic stellate cell activation, was upregulated more (+321%) in the combination than in each alone. These findings suggest that combination therapy benefits liver pathology in MASH.Conclusion: For the first time, we suggest a beneficial combination effect of DA-1241 and EFX in MASH treatment, highlighting the therapeutic potential of combining GPR119 agonists and FGF21 analogues, likely by further inhibiting steatosis, fibrosis, and inflammation.
Y. Chae: None. T. Kim: None. S. Lee: None. I. Jung: None. M. Kim: None. H. Kim: Employee; Dong-A ST Co., Ltd., MetaVia Inc.
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