735-P: Direct Anti-Inflammatory and Antifibrotic Effects of a Novel Long-Acting Glucagon/GIP/GLP-1 Triple Agonist, HM15211, in Thioacetamide-Induced Mouse Model of Liver Injury and Fibrosis

HM152 is a novel long-acting triple agonist consisting of Glucagon/GIP/GLP-1 triple agonist conjugated to human IgG FC fragment via short PEG linker. Previously, therapeutic benefits of HM152 were demonstrated in diet-induced animal models of NASH and fibrosis. Here, direct anti-inflammatory and -fibrotic effects of HM152 were further evaluated in TAA (thioacetamide) -induced liver injury and fibrosis mouse, and investigate underlying mechanism. To induce liver injury and fibrosis, gradually increased dose of TAA was injected to mouse for 12 weeks, and HM152 was administered during last weeks. Interestingly, HM152 treatment significantly reduced hepatic hydroxyproline (-51% vs. Veh, p<0.01) , Sirius red positive area (-65% vs. Veh, p<0.001) , and fibrosis score (0.7 for HM152 vs. 3.0 for Veh, p<0.001) . Considering baseline fibrosis score at week 2 (1.0) , HM152 could confer both potential reversal effect on pre-existing fibrosis and prevention effect on fibrogenesis. Consistently, expression of hepatic marker genes for fibrosis (i.e. collagen-1α1) and inflammation (i.e. F4/80, TNF-α) were significantly reduced in HM152 group. Furthermore, multiplex cytokine analysis revealed that HM152 treatment was associated with robust reduction across pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6. Significant reduction in blood level of liver enzymes was also confirmed. Mechanistically, PMA/LPS-induced pro-inflammatory cytokine secretion of THP-1 cell was significantly attenuated by HM15211. TGF-β-induced collagen production was also reduced in LX2 cell.

In conclusion, HM152 markedly improved liver inflammation and fibrosis in TAA mice, and related mechanism was elaborated by in vitro studies. Thus, HM152 could be a novel therapeutic option for fibrosis due to NASH. Human study is ongoing to assess the clinical relevance of these findings.