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

Mary Chau; Yang Li; Manuel Roqueta-Rivera; Kelsey Garlick; Ruichao Shen; Guoqiang Wang; Yat Sun Or; Li-Juan Jiang

doi:doi:10.11648/j.ijg.20190301.12

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

Mary Chau, Yang Li, Manuel Roqueta-Rivera, Kelsey Garlick, Ruichao Shen, Guoqiang Wang, Yat Sun Or, Li-Juan Jiang

Published in International Journal of Gastroenterology (Volume 3, Issue 1)

Received: 31 January 2019 Accepted: 25 March 2019 Published: 10 May 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 STAM^TM 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.

Published in	International Journal of Gastroenterology (Volume 3, Issue 1)
DOI	10.11648/j.ijg.20190301.12
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), 2019. Published by Science Publishing Group

Keywords

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

References

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APA Style

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://article.sciencepublishinggroup.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

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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Plain Text BibTeX RIS

APA Style

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://article.sciencepublishinggroup.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}
}

Copy | Download

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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