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

Abstract

BackgroundEDP‐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.MethodsEDP‐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.ResultsIn 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.ConclusionsEDP‐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.