1639-P: Tirzepatide and Efruxifermin Demonstrate Therapeutic Benefits for NASH in a Preclinical Metabolic Syndrome Animal Model, B6-Alms1-del Mice

The escalating prevalence of metabolic syndrome has led to NAFLD and its severe form, nonalcoholic steatohepatitis (NASH), becoming a major public health concern. While numerous anti-NAFLD/NASH agents have entered development pipelines, only Resmetirom has advanced to the NDA stage. There remains a high demand for novel therapies in the NAFLD/NASH field.We tested two promising anti-NASH agents, Tirzepatide and Efruxifermin in the B6-Alms1-del mice, which develop NASH spontaneously. B6-Alms1-del mice at 16 weeks of age received twice a week treatment of vehicle, 30 nmol/kg Tirzepatide or 30 nmol/kg Efruxifermin subcutaneously for 6 weeks. Our finding revealed that, compared with vehicle treatment, both Tirzepatide and Efruxifermin treatment significantly decreased body weight, plasma ALT and AST, fasting blood glucose and blood lipid. However, Efruxifermin demonstrated a significantly greater inhibitory effect on body weight than Tirzepatide treatment. Additionally, Tirzepatide significantly reduced the food intake of mice, while the effect of Efruxifermin on food intake was not significant. The results of metabolic parameters suggested that Efruxifermin's metabolic benefits on B6-Alms1-del mice did not mainly rely on reduced energy intake. Morphology analysis indicated that liver hypertrophy observed in B6-Alms1-del mice was marked reduced upon treatment with both Tirzepatide and Efruxifermin. Particularly, treatment with Efruxifermin nearly restored the liver weight of B6-Alms1-del mice to that of B6J mice. Consistently, Efruxifermin treatment exhibited more significant NASH resolution than Tirzepatide treatment.In summary, we demonstrated the therapeutic effects of Tirzepatide and Efruxifermin in B6-Alms1-del mice, which aligned with recent clinical observations. Consequently, B6-Alms1-del mice could serve as a valuable model for preclinical studies of anti-NASH agents targeting GLP-1R/GIPR and FGF21. Disclosure Z. Chen: None. Y. Shen: None. H. Wang: None. H. Wang: None. J. Liang: None. J. Zhao: None. X. Gao: None. M. Gao: None.