Effect of a Novel Long-Acting GLP-1/GIP/Glucagon Triple Agonist (HM15211) in a NASH and Fibrosis Animal Model

Abstract

Nonalcoholic steatohepatitis (NASH), a potential consequence of NAFLD, may lead to end stage liver disease including cirrhosis and hepatocellular carcinoma. Despite its severity and prevalence, NASH currently lacks effective treatment. In this respect, we developed a novel long-acting, GLP-1/GIP/Glucagon triple agonist, HM15211. With a unique activity profile, HM15211 could provide synergistic benefits on body weight loss and lipid profile improvement while avoiding hyperglycemic risk. Previously, we showed that HM15211 exerts potent reductions in body weight and hepatic TG (triglycerides) in DIO mice, and showed a liver preferential distribution, suggesting HM15211 as a potential treatment for NASH. Here, we evaluated the effect of HM15211 in NASH and fibrosis using MCD-diet mice with various disease induction periods. In MCD-diet mice (6 weeks induction), HM15211 treatment led to significant decrease in hepatic TG (-82.6% vs. vehicle) and TBARS (oxidative stress marker, -60.7% vs. vehicle), which coincided with significant reduction in ALT and bilirubin. Time course MRI/MRS imaging further confirmed the progressive steatosis resolution by HM15211. Furthermore, histopathological analysis indicated that HM15211 significantly reduced hepatic inflammatory gene expression and NAFLD activity score (1.3 for HM15211, 3.4 for liraglutide, and 2.7 for vehicle). To further evaluate the therapeutic potential in fibrosis, MCD-diet mice was used for an extended period (10 weeks induction) to achieve overt liver fibrosis. In line with NASH improvement, HM15211 successfully resolved liver fibrosis as demonstrated in histological evaluation. Histological improvements were accompanied by a remarkable decrease in disease biomarkers including hepatic hydroxyproline. Based on these observations, HM15211 may offer a therapeutic potential for NASH and fibrosis as well as obesity. Disclosure I. Choi: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. J. Kim: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. E. Park: Employee; Self; Hanmi Pharmaceutical. Y. Kim: Employee; Self; Hanmi Pharmaceutical. S. Jung: None. S. Kim: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical.