NASH is a complex disease progressed by multiple mechanism. To date, no approved drug is available due to unsatisfied efficacy. Of note, recent studies demonstrate advantages of targeting multiple aspects of this disease. To aid multi-targeting and provide a novel treatment option with improved efficacy, HM15211, a long-acting Glucagon/GIP/GLP-1 triple agonist, has been developed. Previously, enhanced anti-steatosis effect of HM15211 and underlying mechanism were evidenced in DIO mice. Here, potential benefits of HM15211 was investigated by comparing its therapeutic effects with NASH drug candidates in high-fat diet induced mouse model of NASH. AMLN-diet induced NASH mice were administered either with HM15211 or obeticholic acid (OCA) for 12 weeks, followed by histological analysis. HM15211 treatment more efficiently normalized hepatic lipid contents (-48.9%, -93.0% vs. vehicle for OCA, HM15211) and steatosis score (2.9, 2.1, 0.1 for vehicle, OCA, HM15211) compared to OCA treatment. Consistently, HM15211 treatment significantly reduced histological score for lobular inflammation (1.6, 1.1, 0.9 for vehicle, OCA, HM15211) and ballooning (1.4, 0.7, 0.0 for vehicle, OCA, HM15211) along with blood ALT (546, 349, 138 U/L for vehicle, OCA, HM15211) even greater than OCA treatment. Notably, while all individuals (7/7) treated with HM15211 achieved NASH resolution criteria, only 14.3% (1/7) achieved it after OCA treatment. Additional study was performed to compare therapeutic effect of HM15211 with incretin analogs, and greater reduction in all sub-components of NAS was consistently observed when compared to acylated GLP-1 or GLP-1/GIP in AMLN mice, highlighting potential benefits of multi-target engagement of HM15211 over other incretin analog and FXR agonist for NASH treatment. Therefore, HM15211 may be a novel therapeutic option for NASH. Efficacy study in biopsy proven NASH patients is ongoing to assess the clinical relevance of these finding.
J. Kim: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. H. Kwon: Employee; Self; Hanmi Pharmaceutical. E. Park: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. S. Bae: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. I. Choi: Employee; Self; Hanmi Pharmaceutical.