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A NOVEL FARNESOID X RECEPTOR (FXR) AGONIST, EDP-305, REDUCES FIBROSIS PROGRESSION IN ANIMAL MODELS OF HEPATOBILIARY INJURY
Derek J. Erstad*1, Christian T. Farrar2, Ricard Masia3, Diego Dos Santos Ferreira2, Ji-Kyung Choi2, Sarani Ghoshal1, Nicholas Rotile2, Yang Li4, Mary Chau4, Kenneth K. Tanabe1, Yat Sun Or4, Peter Caravan2, Li-Juan Jiang4, Bryan C. Fuchs1
1Surgery, Massachusetts General Hospital, Cambridge, MA; 2Martinos Center, Massachusetts General Hospital, Charlestown, MA; 3Pathology, Massachusetts General Hospital, Boston, MA; 4Enanta Pharmaceuticals, Watertown, MA
Background and Aims:
The aim of this study was to examine a novel FXR agonist, EDP-305, for its ability to reduce fibrosis progression in two models: (i) a mouse model of NASH induced with a choline-deficient, L-amino acid-defined, high-fat diet consisting of 60 kcal% fat and 0.1% methionine by weight (CDAHFD); and (ii) a rat model of PBC induced by bile duct ligation (BDL). The FXR agonist obeticholic acid (OCA) was also tested as a control. We used a novel gadolinium (Gd)-based magnetic resonance (MR) probe, termed Gd-Hyd, that detects lysyl oxidase-mediated collagen crosslinking, and the Type I collagen-targeted, Gd-based MR contrast agent, EP-3533, to monitor response in the CDAHFD model and BDL model, respectively.
Methods:
Male C57BL/6 were fed either CDAHFD or normal chow. CDAHFD mice (n=8 for each group) were treated with either vehicle control, OCA 30mpk, EDP-305 10mpk, or EDP-305 30mpk by oral gavage daily starting at week 6 post diet. All mice were imaged with Gd-Hyd at week 12 post diet on a 4.7T MR scanner. Male CD rats underwent BDL or sham laparotomy. BDL rats (n=8 for each group) were treated with either vehicle control, OCA 10mpk, OCA 30mpk, EDP-305 10mpk, or EDP-305 30mpk by oral gavage daily starting on day 4 post BDL. Rats were imaged with EP-3533 on day 18 post BDL on a clinical 1.5T scanner. Following imaging, liver tissue was subjected to (i) morphometric scoring of fibrosis, (ii) analysis of hydroxyproline (Hyp) content, and (iii) determination of COL1A1 mRNA expression.
Results:
A significant decrease in fibrosis was seen at the higher EDP-305 dose when assessed by morphometric quantification, Hyp, and COL1A1 expression. Consistently, a significant decrease in molecular imaging of collagen crosslinking was observed in CDAHFD mice that received EDP-305 30 mpk (SNR=0.06±0.02 vs 0.10±0.03, p<0.01). Similarly, a significant decrease in fibrosis was seen in the BDL model with the higher EDP-305 dose when assessed by morphometric quantification, Hyp, and COL1A1 expression. In addition, a significant decrease in molecular imaging of Type I collagen was observed in BDL rats that received EDP-305 30 mpk (ΔR1=0.75±0.19s-1 vs 0.99±0.28s-1, p<0.01). By comparison, OCA increased fibrosis in both models by all measurements.
Conclusions:
EDP-305 reduced fibrosis progression in the mouse CDAHFD and rat BDL models. Quantitative molecular imaging of collagen crosslinking and Type I collagen are sensitive to changes in fibrosis and could be used to non-invasively monitor response in clinical trials.
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