1804-P: HM15211, a Novel Long-Acting GLP-1/GIP/Glucagon Triple Agonist, Exhibits Anti-inflammatory and Fibrotic Effects in AMLN/TAA–Induced Liver Inflammation and Fibrosis Mice

Abstract

Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, is characterized by hepatic steatosis, inflammation, and fibrosis. Despite increased prevalence and related mortality, no approved medication is available, leading to a significant burden for public health. Although advances in targeting hepatic steatosis demonstrate meaningful benefits, their overall impact in inflammation and fibrosis remains elusive. Hence, recent approaches directly modulating inflammation and fibrosis still showed marginal efficacy. Thus, to provide novel option for NASH treatment, HM15211, a novel long-acting GLP-1/GIP/Glucagon triple agonist, is developed. Because of the benefits of GLP-1, GIP, and Glucagon in liver inflammation and fibrosis in addition to steatosis, HM15211 might confer more effective treatment in NASH. Previously, HM1521 treatment led to potent liver fat reduction along with weight loss in DIO mice. Here, we investigated the potential effect of HM15211 in animal model of liver inflammation and fibrosis. To induce liver inflammation and fibrosis, mice fed with AMLN diet were concomitantly treated with thioacetamide (AMLN/TAA mice) for 16 weeks, and HM15211 was administered during last 8 weeks. Of note, HM15211 treatment reduced the hepatic marker expression for inflammation (-92.8, -34.7 and -34.9% vs. vehicle (Veh) for F4/80, MCP-1 and IL-6) and fibrosis (-53.9, -41.4 and -51.9 % vs. Veh for α-SMA, TIMP-1 and collagen1a1). Similar reduction in blood level of TIMP-1, PIIINP and hyaluronic acid (-49.3, -48.0 and -49.1% vs. Veh) was observed. Strikingly, HM15211 significantly reduced both hepatic hydroxyproline (-53.1 % vs. Veh) and sirius red positive area (-70.6% vs. Veh). Therefore, in addition to steatosis improvement, HM15211 may provide anti-inflammatory and -fibrotic effect. Human studies are ongoing to assess the clinical relevance of these findings. Disclosure J. Kim: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. E. Park: 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.