International Journal of Gastroenterology

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

Received: Jan. 31, 2019    Accepted: Mar. 25, 2019    Published: May 10, 2019
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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.

DOI 10.11648/j.ijg.20190301.12
Published in International Journal of Gastroenterology ( Volume 3, Issue 1, June 2019 )
Page(s) 4-16
Creative Commons

This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.

Copyright

Copyright © The Author(s), 2024. Published by Science Publishing Group

Keywords

Anti-fibrotic, Anti-inflammatory, Low Density Lipoprotein Receptor, Bile Acid, Anti-steatosis

References
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    Mary Chau, Yang Li, Manuel Roqueta-Rivera, Kelsey Garlick, Ruichao Shen, et al. (2019). Characterization of EDP-305, a Highly Potent and Selective Farnesoid X Receptor Agonist, for the Treatment of Non-alcoholic Steatohepatitis. International Journal of Gastroenterology, 3(1), 4-16. https://doi.org/10.11648/j.ijg.20190301.12

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    ACS Style

    Mary Chau; Yang Li; Manuel Roqueta-Rivera; Kelsey Garlick; Ruichao Shen, et al. Characterization of EDP-305, a Highly Potent and Selective Farnesoid X Receptor Agonist, for the Treatment of Non-alcoholic Steatohepatitis. Int. J. Gastroenterol. 2019, 3(1), 4-16. doi: 10.11648/j.ijg.20190301.12

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    AMA Style

    Mary Chau, Yang Li, Manuel Roqueta-Rivera, Kelsey Garlick, Ruichao Shen, et al. Characterization of EDP-305, a Highly Potent and Selective Farnesoid X Receptor Agonist, for the Treatment of Non-alcoholic Steatohepatitis. Int J Gastroenterol. 2019;3(1):4-16. doi: 10.11648/j.ijg.20190301.12

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  • @article{10.11648/j.ijg.20190301.12,
      author = {Mary Chau and Yang Li and Manuel Roqueta-Rivera and Kelsey Garlick and Ruichao Shen and Guoqiang Wang and Yat Sun Or and Li-Juan Jiang},
      title = {Characterization of EDP-305, a Highly Potent and Selective Farnesoid X Receptor Agonist, for the Treatment of Non-alcoholic Steatohepatitis},
      journal = {International Journal of Gastroenterology},
      volume = {3},
      number = {1},
      pages = {4-16},
      doi = {10.11648/j.ijg.20190301.12},
      url = {https://doi.org/10.11648/j.ijg.20190301.12},
      eprint = {https://download.sciencepg.com/pdf/10.11648.j.ijg.20190301.12},
      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.},
     year = {2019}
    }
    

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  • TY  - JOUR
    T1  - Characterization of EDP-305, a Highly Potent and Selective Farnesoid X Receptor Agonist, for the Treatment of Non-alcoholic Steatohepatitis
    AU  - Mary Chau
    AU  - Yang Li
    AU  - Manuel Roqueta-Rivera
    AU  - Kelsey Garlick
    AU  - Ruichao Shen
    AU  - Guoqiang Wang
    AU  - Yat Sun Or
    AU  - Li-Juan Jiang
    Y1  - 2019/05/10
    PY  - 2019
    N1  - https://doi.org/10.11648/j.ijg.20190301.12
    DO  - 10.11648/j.ijg.20190301.12
    T2  - International Journal of Gastroenterology
    JF  - International Journal of Gastroenterology
    JO  - International Journal of Gastroenterology
    SP  - 4
    EP  - 16
    PB  - Science Publishing Group
    SN  - 2640-169X
    UR  - https://doi.org/10.11648/j.ijg.20190301.12
    AB  - 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.
    VL  - 3
    IS  - 1
    ER  - 

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Author Information
  • Enanta Pharmaceuticals, Inc., Watertown, USA

  • Enanta Pharmaceuticals, Inc., Watertown, USA

  • Enanta Pharmaceuticals, Inc., Watertown, USA

  • Enanta Pharmaceuticals, Inc., Watertown, USA

  • Enanta Pharmaceuticals, Inc., Watertown, USA

  • Enanta Pharmaceuticals, Inc., Watertown, USA

  • Enanta Pharmaceuticals, Inc., Watertown, USA

  • Enanta Pharmaceuticals, Inc., Watertown, USA

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