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Tropifexor-Mediated Abrogation of Steatohepatitis and Fibrosis Is Associated With the Antioxidative Gene Expression Profile in Rodents

Hernandez, Eloy and Zheng, Lianxing and Kim, Young and Fang, Bin and Valdez, Reginald and Dietrich, Bill and Rucker, Paul and Chianelli, Donatella and Schmeits, James and Bao, Dingjiu and Zoll, Jocelyn and Dubois, Claire and Federe, Glenn and Chen, Lihao and Joseph, Sean and Klickstein, Lloyd and Walker, John and Molteni, Valentina and McNamara, Peter and Meeusen, Shelly and Tully, David and Badman, Michael and Xu, Jie and Laffitte, Bryan (2019) Tropifexor-Mediated Abrogation of Steatohepatitis and Fibrosis Is Associated With the Antioxidative Gene Expression Profile in Rodents. Hepatology Communications, 3 (8). pp. 1085-1097. ISSN 2471254X

Abstract

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.

Item Type: Article
Date Deposited: 01 Oct 2019 00:45
Last Modified: 01 Oct 2019 00:45
URI: https://oak.novartis.com/id/eprint/39058

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