Nonalcoholic steatohepatitis (NASH) is a progressive liver disease characterized by steatosis and inflammation, which results in fibrosis. In particular, advanced fibrosis due to NASH is associated with a high risk of liver-related mortality, becoming one main cause for liver transplant. To date, there are, however, no pharmacological therapy approved. One major hurdle for the drug development is limited pathologic features of current animal models, in terms of clinical relevance. The choline-deficient and high fat diet (CDHFD) mice have known to develop multiple aspects of NASH and fibrosis similarly with those in human, being increasingly recognized as a feasible disease model. HM15211 is a novel long-acting GLP-1/GIP/Glucagon triple agonist. Previously, HM15211 treatment improved liver fat and fibrosis in various animal models of NASH and fibrosis. Here, we further explored its efficacy in CDHFD mice. In CDHFD mice (8 wks induction), HM15211 significantly reduced hepatic TG and TBARS (oxidative stress marker). Histological analysis indicated a significant reduction both in hepatic inflammatory marker expression and NAFLD activity score. Of note, when compared to FXR agonist or ACC (acetyl CoA carboxylase) inhibitor, HM15211 treatment was associated with greater efficacy improvement. To further confirm, CDHFD mice with an extended induction period (up to 16 wks) was used. Despite the severe disease progression featured by advanced liver fibrosis, HM15211 reduced hepatic hydroxyproline (-42% vs. vehicle) and sirius red positive area (11.9% vs. 4.1% for vehicle and HM15211) markedly in addition to significant liver TG reduction (66.2% vs. vehicle). Therefore, consistent efficacy in various animal models including CDHFD mice suggests the beneficial effect of HM15211 on NASH and fibrosis. Efficacy studies in biopsy proven NASH patients are ongoing to assess the clinical relevance of these findings.
J. Choi: Employee; Self; Hanmi Pharmaceutical. J. Kim: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. H. Kwon: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. S. Bae: Employee; Self; Hanmi Pharmaceutical. D. Kim: Board Member; Self; Hanmi Pharmaceutical. I. Choi: Board Member; Self; Hanmi Pharmaceutical.