A novel non-bile acid FXR agonist EDP-305 potently suppresses liver injury and fibrosis without worsening of ductular reaction.

Abstract

BACKGROUND:

EDP-305 is a novel and potent farnesoid X receptor (FXR) agonist, with no/minimal cross-reactivity to TGR5 or other nuclear receptors. Herein we report therapeutic efficacy of EDP-305, in direct comparison with the first-in-class FXR agonist obeticholic acid (OCA), in mouse models of liver disease.

METHODS:

EDP-305 (10 and 30 mg/kg/day) or OCA (30mg/kg/day) was tested in mouse models of pre-established biliary fibrosis (BALBc.Mdr2-/-, n = 9-12/group) and steatohepatitis induced by methionine/choline-deficient diet (MCD, n = 7-12/group). Effects on biliary epithelium were evaluated in vivo and in primary EpCAM + hepatic progenitor cell (HPC) cultures.

RESULTS:

In a BALBc.Mdr2-/- model, EDP-305 reduced serum transaminases by up to 53% and decreased portal pressure, compared to untreated controls. Periportal bridging fibrosis was suppressed by EDP-305 at both doses, with up to a 39% decrease in collagen deposition in high-dose EDP-305. In MCD-fed mice, EDP-305 treatment reduced serum ALT by 62% compared to controls, and profoundly inhibited perisinusoidal 'chicken wire' fibrosis, with over 80% reduction in collagen deposition. In both models, treatment with 30mg/kg OCA reduced serum transaminases up to 30%, but did not improve fibrosis. The limited impact on fibrosis was mediated by cholestasis-independent worsening of ductular reaction by OCA in both disease models; OCA but not EDP-305 at therapeutic doses promoted ductular proliferation in healthy mice and favoured differentiation of primary HPC towards cholangiocyte lineage in vitro.

CONCLUSIONS:

EDP-305 potently improved pre-established liver injury and hepatic fibrosis in murine biliary and metabolic models of liver disease, supporting the clinical evaluation of EDP-305 in fibrotic liver diseases including cholangiopathies and non-alcoholic steatohepatitis.

• Authors: Ping An, Guangyan Wei, Pinzhu Huang, Wenda Li, Xiaolong Qi, Yi Lin, Kahini A Vaid, Jun Wang, Shucha Zhang, Yang Li, Yat Sun Or, Li-Juan Jiang, Yury V Popov
• Journal: Liver international : official journal of the International Association for the Study of the Liver (Liver Int) Vol. 40 Issue 7 Pg. 1655-1669 (07 2020) ISSN: 1478-3231 [Electronic] United States
• PMID: 32329946 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Liver International published by John Wiley & Sons Ltd.

Chemical References

• EDP-305
• Steroids
• Chenodeoxycholic Acid

Topics

• Animals
• Chenodeoxycholic Acid (pharmacology)
• Fibrosis
• Liver (pathology)
• Liver Cirrhosis (drug therapy, pathology)
• Mice
• Mice, Inbred C57BL
• Steroids