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

BACKGROUND: EDP-305 is a novel and potent 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 30mg/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 due to 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 favored 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 NASH.