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

Hernandez, Eloy , Zheng, Lianxing, Kim, Young, Fang, Bin, Valdez, Reginald, Dietrich, Bill, Rucker, Paul, Chianelli, Donatella, Schmeits, James, Bao, Dingjiu, Zoll, Jocelyn, Dubois, Claire, Federe, Glenn, Chen, Lihao, Joseph, Sean, Klickstein, Lloyd, Walker, John, Molteni, Valentina, McNamara, Peter, Meeusen, Shelly, Tully, David, Badman, Michael, Xu, Jie and Laffitte, Bryan (2019) Tropifexor-Mediated Abrogation of Steatohepatitis and Fibrosis Is Associated With Antioxidative Gene Expression Profile in Rodents. Hepatology Communications, 3 (8). pp. 1085-1097. ISSN 2471-254X2471-254X

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; 6-ethyl chenodeoxycholic acid) has shown promise in a phase 2 study in patients with nonalcoholic steatohepatitis (NASH). Here, we report efficacy of a novel, non–bile 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 (STAM model), tropifexor reversed established fibrosis and reduced nonalcoholic fatty liver disease activity score and hepatic triglycerides. In an insulin-resistant, obese 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, which included a combination of signatures associated with reduction of oxidative stress, fibrogenesis, and inflammation. Conclusion: Based on the 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: 24 Mar 2020 00:45
Last Modified: 24 Mar 2020 00:45
URI: https://oak.novartis.com/id/eprint/39963

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