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

Abstract

NASH, a severe form of NAFLD, can lead to end stage liver disease such as cirrhosis. Despite increasing prevalence and as a burden for public health, advances in the development of therapeutics are slow with yet no approved drug for NASH treatment. Since liver fat accumulation and inflammation are associated with NASH progression, targeting both aspects may contribute to NASH resolution and fibrosis improvement. Thus, to directly aid those aspects, we developed a novel long-acting, GLP-1/GIP/Glucagon triple agonist, HM15211. With a unique activity profile, HM15211 showed a liver preferential distribution, and exerted potent hepatic triglyceride (TG) reduction in addition to efficient weight loss in DIO mice, suggesting HM15211 as a novel therapeutic option for NASH treatment. Here, we evaluated the therapeutic potential of HM15211 in NASH and fibrosis animal models including monkeys. In MCD-diet mice (6 weeks induction), HM15211 led to significant decrease in hepatic TG content (-82.6% vs. vehicle), which coincided with reduction of elevated ALT and bilirubin. Time course MRI confirmed the progressive resolution of steatosis. Histological analysis also indicated a significant reduction both in 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 were used for an extended period (up to 12 weeks induction) for overt liver fibrosis induction. In line with NASH improvement, HM15211 reduced hepatic hydroxyproline and the fibrosis score markedly. Finally, obese and NASH monkeys were administered with HM15211, and efficient weight loss, improvement of lipotoxicity and improvement of histological NASH/fibrosis markers were confirmed in primates too. Based on these results, HM15211 may provide efficacy for the treatment of NASH and fibrosis. Further studies are needed to assess the clinical relevance of these findings. Disclosure J. Kim: None. J. Lee: None. D. Kim: None. E. Park: None. Y. Kim: None. I. Choi: Employee; Self; Hanmi Pharm. Co., Ltd.