Fibrosis due to nonalcoholic steatohepatitis (NASH) remains a major cause of liver-related mortality. However, no medication has been approved despite accelerated drug development. Since multiple biological pathways are involved, strategy simultaneously targeting multiple pathways might be required to effectively treat fibrosis. To address this, we developed a novel long-acting GLP-1/GIP/Glucagon triple agonist, HM15211. Previously, HM15211 significantly improved fibrosis as well as steatosis and inflammation in MCD-diet mice. In addition to the diet-induced models, bile duct ligation (BDL) has also been extensively used as an animal model of fibrosis. Here, we further investigated the anti-fibrotic effects of HM15211 in BDL-induced fibrosis mice. Two days post BDL (single ligation), the mice were administered either with HM152111 or obeticholic acid (OCA) for 2 weeks, followed by histological analysis. HM15211 treatment showed greater reduction in hepatic hydroxyproline (HP) (450.5, 351.7 and 253.6 nmol/g liver for vehicle, OCA and HM15211) and fibrosis score (1.7, 1.8 and 1.0 for vehicle, OCA and HM15211) compared to OCA. Consistently, HM15211, but not OCA, treatment was associated with the reduction of serum surrogate markers of fibrosis including TGF-β (-61.4, 9.1% vs. vehicle for HM15211, OCA), TIMP-1 (-71.6, -13.9% vs. vehicle), and hyaluronic acid (-68.9, 25.0% vs. vehicle). To further clarify its benefits in fibrosis, BDL (double ligation) mice with an extended induction period (up to 2 weeks) was used. Notably, despite the progression to advanced liver fibrosis, HM15211 treatment still attenuated HP (571.5 and 334.3 nmol/g liver for vehicle and HM15211) and fibrosis score markedly. Considering the pathologic features of BDL mice (liver fibrosis without liver fat accumulation), these results demonstrate the direct anti-fibrotic effect of HM15211. Further studies are needed to assess the clinical relevance of these findings.
J. Kim: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. H. Kwon: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. D. Kim: Board Member; Self; Hanmi Pharmaceutical. S. Bae: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. I. Choi: Board Member; Self; Hanmi Pharmaceutical.