Tropifexor‐Mediated Abrogation of Steatohepatitis and Fibrosis Is Associated With the Antioxidative Gene Expression Profile in Rodents
Farnesoid X receptor (FXR) agonism is emerging as an important potential therapeutic mechanism of action for multiple chronic liver diseases. The bile acid‐derived FXR agonist obeticholic acid (OCA) has shown promise in a phase 2 study in patients with nonalcoholic steatohepatitis (NASH). Here, we r...
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Published in | Hepatology communications Vol. 3; no. 8; pp. 1085 - 1097 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Wolters Kluwer Health Medical Research, Lippincott Williams & Wilkins
01.08.2019
John Wiley and Sons Inc Wolters Kluwer Health/LWW |
Subjects | |
Online Access | Get full text |
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Summary: | Farnesoid X receptor (FXR) agonism is emerging as an important potential therapeutic mechanism of action for multiple chronic liver diseases. The bile acid‐derived FXR agonist obeticholic acid (OCA) has shown promise in a phase 2 study in patients with nonalcoholic steatohepatitis (NASH). Here, we report efficacy of the novel nonbile acid FXR agonist tropifexor (LJN452) in two distinct preclinical models of NASH. The efficacy of tropifexor at <1 mg/kg doses was superior to that of OCA at 25 mg/kg in the liver in both NASH models. In a chemical and dietary model of NASH (Stelic animal model [STAM]), tropifexor reversed established fibrosis and reduced the nonalcoholic fatty liver disease activity score and hepatic triglycerides. In an insulin‐resistant obese NASH model (amylin liver NASH model [AMLN]), tropifexor markedly reduced steatohepatitis, fibrosis, and profibrogenic gene expression. Transcriptome analysis of livers from AMLN mice revealed 461 differentially expressed genes following tropifexor treatment that included a combination of signatures associated with reduction of oxidative stress, fibrogenesis, and inflammation. Conclusion: Based on preclinical validation in animal models, tropifexor is a promising investigational therapy that is currently under phase 2 development for NASH. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Potential conflict of interest: Dr. Zheng, Dr. Fang, Dr. Dietrich, Dr. Bao, Dr. Klickstein, Dr. Molteni, Dr. McNamara, Dr. Tully, Dr. Badman, and Dr. Xu own stock in and are employed by Novartis; Dr. Hernandez, Dr. Kim, Dr. Rucker, Dr. Chianelli, Dr. Schmeits, Dr. Zoll, Dr. Federe, Dr. Chen, Dr. Walker and Dr. Meeusen are employed by Novartis; Dr. Liu and Dr. Laffitte owns stock in Novartis; the other authors have nothing to report. |
ISSN: | 2471-254X 2471-254X |
DOI: | 10.1002/hep4.1368 |