icon-folder.gif   Conference Reports for NATAP  
  The International Liver Congress™
EASL 2017 - European Association for the
Study of the Liver
Amsterdam, The Netherlands. 2017
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EDP-305, a novel and highly potent farnesoid X receptor agonist, improves liver steatosis, ballooning and non-alcoholic fatty liver disease (NAFLD) activity score (NAS) in a diet-induced murine model of non-alcoholic steatohepatitis
  Reported by Jules Levin
EASL 2017 April 19-23 Amsterdam Netherlands
Li-Juan Jiang1, Mary Chau1, Yang Li1, François Briand2, Thierry Sulpice2, Yat Sun Or1
       Enanta Pharmacueticals, Waterstown, Mass, Physiogenix, Laberge, France


Program Abstract
Background and aims

EDP-305 is a novel farnesoid X receptor (FXR) agonist with a single-digit nanomolar affinity for FXR in vitro. EDP-305 is highly selective for FXR and does not exhibit any cross-reactivity with other nuclear receptors, or the transmembrane G protein-coupled receptor TGR5. Herein, we compare and report the therapeutic efficacy of EDP-305 with the FXR agonist, obeticholic acid (OCA), in an experimental non-alcoholic steatohepatitis (NASH) mouse model.
NASH was induced in C57Bl/6 mice with a high fat/high cholesterol diet plus 10% fructose in drinking water (DIN). All treatments were administered between 6 wks (steatohepatitis with incipient ballooning) and 16 wks (advanced steatohepatitis with advanced ballooning) on DIN (n = 10/group). Treatments included: EDP-305 (10 or 30 mg/kg), OCA (30 mg/kg) or only DIN vehicle control (n = 10/group). Liver injury, progression of NASH, liver steatosis and ballooning were evaluated by serum chemistry and histology.
No apparent adverse effects of treatments were noted during the study. Mice receiving EDP-305 showed a distinct trend towards lower ALT/AST levels compared to vehicle control, whereas OCA had no effects. At both doses, EDP-305 significantly reduced liver lipids, such that there were significant reductions in hepatic cholesterol, triglycerides and fatty acids. OCA reduced liver lipids to a lesser extent than EDP-305. EDP-305 at 30 mg/kg significantly decreased liver cholesterol (48%↓: versus vehicle) compared to OCA at the same dose(31%↓: versus vehicle). Consistent with the observed reductions in liver lipids, liver steatosis was also significantly decreased in EDP-305-treated mice at both doses (p<0.01). Meanwhile, OCA did not exert a significant effect on liver steatosis. At both doses, EDP-305 significantly lowered hepatocyte ballooning scores, whereas treatment with OCA showed no improvement. Additionally, EDP-305 significantly reduced total NAS in both treatment groups, which is consistent with data showing that EDP-305 down-regulates expression of key genes involved in pathogenic inflammation (MCP-1, TGF-β) and fibrosis (TIMP-1, α-SMA).
In comparison to OCA, treatment with EDP-305 demonstrated significant therapeutic effect on NASH progression in the diet-induced NASH mouse model, such that it decreased liver steatosis, hepatocyte ballooning and total NAS score. These results warrant further investigation of EDP-305 as a potential therapy for NASH.