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
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Authors
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
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Abstract
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.
Keywords
Anti-fibrotic, Anti-inflammatory, Low Density Lipoprotein Receptor, Bile Acid, Anti-steatosis
To cite this article
Mary Chau, Yang Li, Manuel Roqueta-Rivera, Kelsey Garlick, Ruichao Shen, Guoqiang Wang, Yat Sun Or, Li-Juan Jiang, 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. doi: 10.11648/j.ijg.20190301.12
Copyright
Copyright © 2019 Authors retain the copyright of this article.
This article is an open access article distributed under the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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