Fibrosis due to nonalcoholic steatohepatitis (NASH) remains a major cause of liver-related mortality. Since complex biological pathways are involved in fibrosis progression, multi-disciplinary therapeutic approaches should be required to effectively deliver treatment effects on fibrosis. For this purpose, we developed a novel long-acting Glucagon/GIP/GLP-1 triple agonist, HM15211. Here, we evaluated the anti-fibrotic effect of HM15211 in various animal models of fibrosis, and investigated underlying mechanism in vitro. Mice fed with AMLN diet were concomitantly treated with thioacetamide (AMLN/TAA mice) for 16 weeks, and HM15211 was administered during last 8 weeks. HM15211 treatment significantly reduced hepatic (-53.9, -41.4 and -51.9 % vs. vehicle for α-SMA, TIMP-1 and collagen1a1 expression) and blood (-49.3, -48.0 and -49.1% vs. vehicle for TIMP-1, PIIINP and hyaluronic acid level) surrogate markers for fibrosis. HM15211 treatment was also associated with significant reduction in hepatic hydroxyproline (-53.1% vs. Veh) and sirius red positive area (-70.6% vs. Veh) in AMLN/TAA mice. Next, anti-fibrotic effect of HM15211 was further evaluated in choline-deficient and high fat diet (CD-HFD) mice. Strikingly, greater reduction in hepatic hydroxyproline and collagen contents (-4.2, -10.0, -31.2% vs. vehicle for acylated GLP-1, acylated GLP-1/GIP, HM15211) was observed compared to acylated GLP-1 or acylated GLP-1/GIP in CD-HFD mice. Additional in vitro studies in LX2 cell and rat primary hepatic stellate cell (HSC) unveiled that HM15211 could negatively affect multiple steps of TGF-β signaling in HSC. Based on these results, HM15211 may be a novel therapeutic option for liver fibrosis in addition to NASH itself. Hence, related mechanistic studies further highlight direct inhibitory effect of HM15211 on HSC activation. On-going human efficacy study will assess the clinical relevance of these findings.

Disclosure

J. Kim: Employee; Self; Hanmi Pharmaceutical. I. Choi: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. H. Kwon: Employee; Self; Hanmi Pharmaceutical. J. Choi: Employee; Self; Hanmi Pharmaceutical. E. Park: Employee; Self; Hanmi Pharmaceutical. S. Bae: Employee; Self; Hanmi Pharmaceutical. D. Kim: Employee; Self; Hanmi Pharmaceutical. Y. Kim: None.

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2021
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