Characterization of EDP-305, a Highly Potent and Selective Farnesoid X Receptor Agonist, for the Treatment of Non-alcoholic Steatohepatitis
International Journal of Gastroenterology
Volume 3, Issue 1, June 2019, Pages: 4-16
Received: Jan. 31, 2019;
Accepted: Mar. 25, 2019;
Published: May 10, 2019
Views 601 Downloads 193
Mary Chau, Enanta Pharmaceuticals, Inc., Watertown, USA
Yang Li, Enanta Pharmaceuticals, Inc., Watertown, USA
Manuel Roqueta-Rivera, Enanta Pharmaceuticals, Inc., Watertown, USA
Kelsey Garlick, Enanta Pharmaceuticals, Inc., Watertown, USA
Ruichao Shen, Enanta Pharmaceuticals, Inc., Watertown, USA
Guoqiang Wang, Enanta Pharmaceuticals, Inc., Watertown, USA
Yat Sun Or, Enanta Pharmaceuticals, Inc., Watertown, USA
Li-Juan Jiang, Enanta Pharmaceuticals, Inc., Watertown, USA
Non-alcoholic steatohepatitis (NASH), characterized by hepatocyte injury, inflammation, and fibrosis, is the main cause of chronic liver disease in the Western world. There are currently no approved pharmacological therapies for NASH, underscoring the urgent need for effective treatments. The farnesoid X receptor (FXR) has emerged as an attractive target for the treatment of metabolic and chronic liver diseases. EDP-305 is an FXR agonist currently in phase 2 clinical trials for Primary Biliary Cholangitis (PBC) and NASH. Here, we demonstrate that EDP-305 is a selective and potent FXR agonist that regulates multiple pathways relevant to NASH progression. EDP-305 exhibits anti-fibrotic and anti-inflammatory gene signatures in human macrophage and stellate cell lines, as well as favorable effects on lipid metabolism in hepatocytes, including enhanced low density lipoprotein (LDL)-cholesterol uptake and decreased triglyceride accumulation. The therapeutic potential of EDP-305 was further evaluated in two murine models of NASH: a streptozotocin-high fat diet STAMTM model and a dietary induced NASH (DIN) model driven by high fat, cholesterol, and fructose feeding. In both NASH models, EDP-305 significantly decreased hepatocyte ballooning and lowered the non-alcoholic fatty liver disease (NAFLD) activity score. EDP-305 also significantly attenuated hepatic steatosis and dyslipidemia observed in the DIN mouse model. Conclusion: EDP-305 is a potent FXR agonist with a favorable gene expression profile for NASH treatment as evidenced by the hepato-protective and anti-steatotic effects observed in vivo. The preclinical characterization of EDP-305 presented here suggests that it holds promise for the treatment of NASH.
Yat Sun Or,
Characterization of EDP-305, a Highly Potent and Selective Farnesoid X Receptor Agonist, for the Treatment of Non-alcoholic Steatohepatitis, International Journal of Gastroenterology.
Vol. 3, No. 1,
2019, pp. 4-16.
Schaap, F. G., M. Trauner, and P. L. Jansen, Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol, 2014. 11(1): p. 55-67.
Lefebvre, P., et al., Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev, 2009. 89(1): p. 147-91.
Adorini, L., M. Pruzanski, and D. Shapiro, Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis. Drug Discov Today, 2012. 17(17-18): p. 988-97.
Neuschwander-Tetri, B. A., et al., Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet, 2015. 385(9972): p. 956-65.
Mudaliar, S., et al., Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology, 2013. 145(3): p. 574-82 e1.
Hirschfield, G. M., et al., Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology, 2015. 148(4): p. 751-61 e8.
Nevens, F., et al., A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis. N Engl J Med, 2016. 375(7): p. 631-43.
Attili, A. F., et al., Bile acid-induced liver toxicity: relation to the hydrophobic-hydrophilic balance of bile acids. Med Hypotheses, 1986. 19(1): p. 57-69.
Tully, D. C., et al., Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH). J Med Chem, 2017. 60(24): p. 9960-9973.
Alemi, F., et al., The TGR5 receptor mediates bile acid-induced itch and analgesia. J Clin Invest, 2013. 123(4): p. 1513-30.
Lieu, T., et al., The bile acid receptor TGR5 activates the TRPA1 channel to induce itch in mice. Gastroenterology, 2014. 147(6): p. 1417-28.
Erstad, D. J., et al., Molecular magnetic resonance imaging accurately measures the antifibrotic effect of EDP-305, a novel farnesoid X receptor agonist. Hepatol Commun, 2018. 2(7): p. 821-835.
Diffenderfer, M. R. and E. J. Schaefer, The composition and metabolism of large and small LDL. Curr Opin Lipidol, 2014. 25(3): p. 221-6.
Schuppan, D. and Y. O. Kim, Evolving therapies for liver fibrosis. J Clin Invest, 2013. 123(5): p. 1887-901.
Moreira, R. K., Hepatic stellate cells and liver fibrosis. Arch Pathol Lab Med, 2007. 131(11): p. 1728-34.
Schuppan, D., Liver fibrosis: Common mechanisms and antifibrotic therapies. Clin Res Hepatol Gastroenterol, 2015. 39 Suppl 1: p. S51-9.
Gressner, A. M. and R. Weiskirchen, Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets. J Cell Mol Med, 2006. 10(1): p. 76-99.
Fujii, M., et al., A murine model for non-alcoholic steatohepatitis showing evidence of association between diabetes and hepatocellular carcinoma. Med Mol Morphol, 2013. 46(3): p. 141-52.
Saito, K., et al., Characterization of hepatic lipid profiles in a mouse model with nonalcoholic steatohepatitis and subsequent fibrosis. Sci Rep, 2015. 5: p. 12466.
Dash, A., et al., Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro, 2017. 39: p. 93-103.
Briand, F., Farnesoid X Receptor Agonist Obeticholic Acid Raises LDL-cholesterol and reduces HDL-cholesterol in the Diet-induced NASH (DIN) Hamster, a Novel Preclinical Model for Evaluating Efficacy and Side effects of Drugs targeting Non-Alcoholic Liver Diseases. Hepatology, 2016. 64(Supplement S1).
Pellicoro, A., et al., Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat Rev Immunol, 2014. 14(3): p. 181-94.
Caldwell, S., et al., Hepatocellular ballooning in NASH. J Hepatol, 2010. 53(4): p. 719-23.
Erstad, D., et al., The Novel FXR Agonist, EDP-305, Reduces Fibrosis Progression in Rodent Models of Primary Biliary Cholangitis and Non-alcoholic Steatohepatitis. Hepatology, 2016. 64(Supplement S1): p. 323A.