Molecular magnetic resonance imaging accurately measures the antifibrotic effect of EDP‐305, a novel farnesoid X receptor agonist

Abstract

We examined a novel farnesoid X receptor agonist, EDP‐305, for its antifibrotic effect in bile duct ligation (BDL) and choline‐deficient, L‐amino acid‐defined, high‐fat diet (CDAHFD) models of hepatic injury. We used molecular magnetic resonance imaging with the type 1 collagen‐binding probe EP‐3533 and the oxidized collagen‐specific probe gadolinium hydrazide to noninvasively measure treatment response. BDL rats (n = 8 for each group) were treated with either low or high doses of EDP‐305 starting on day 4 after BDL and were imaged on day 18. CDAHFD mice (n = 8 for each group) were treated starting at 6 weeks after the diet and were imaged at 12 weeks. Liver tissue was subjected to pathologic and morphometric scoring of fibrosis, hydroxyproline quantitation, and determination of fibrogenic messenger RNA expression. High‐dose EDP‐305 (30 mg/kg) reduced liver fibrosis in both the BDL and CDAHFD models as measured by collagen proportional area, hydroxyproline analysis, and fibrogenic gene expression (all P < 0.05). Magnetic resonance signal intensity with both EP‐3533 in the BDL model and gadolinium hydrazide in the CDAHFD model was reduced with EDP‐305 30 mg/kg treatment (P < 0.01). Histologically, EDP‐305 30 mg/kg halted fibrosis progression in the CDAHFD model. Conclusion: EDP‐305 reduced fibrosis progression in rat BDL and mouse CDAHFD models. Molecular imaging of collagen and oxidized collagen is sensitive to changes in fibrosis and could be used to noninvasively measure treatment response in clinical trials. (Hepatology Communications 2018;2:821‐835)

Characterization of EDP-305, a Highly Potent and Selective Farnesoid X Receptor Agonist, for the Treatment of Non-alcoholic Steatohepatitis

“…Previously, EDP-305 was evaluated in an in vivo pharmacodynamics model for the regulation of FXR target genes after multiple days of dosing. In the liver, we observed dose dependent regulation by EDP-305 of hepatic Shp and Cyp7A1 mRNA [12]. Here we show that EDP-305 also regulates FXR target gene expression in the ileum.…”

Molecular imaging of fibrosis: recent advances and future directions

“…EP-3533 also quantified reduced fibrosis in BDL rats treated with the farnesoid X receptor agonist EDP-305 (104). In a mouse model of NASH, Gd-Hyd detected reduced fibrogenesis after treatment with EDP-305 (104). Reductions in Gd-Hydenhanced MR signal correlated with decreases in collagen proportionate area, hydroxyproline, and lysyl oxidase gene expression.…”

“…EP-3533 was used to monitor response to rapamycin therapy in a rat BDL model and accurately distinguished therapy responders from nonresponders (103). EP-3533 also quantified reduced fibrosis in BDL rats treated with the farnesoid X receptor agonist EDP-305 (104). In a mouse model of NASH, Gd-Hyd detected reduced fibrogenesis after treatment with EDP-305 (104).…”

Advances in functional and molecular MRI technologies in chronic liver diseases

“…EP-3533-enhanced MRI also detected decreased fibrosis in BDL rats in response to the farnesoid X receptor agonist EDP-305. 100 To improve the translational potential of EP-3533, a new version,…”