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

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Hernandez ED, Zheng L, Kim Y, Fang B, Liu B, Valdez RA, Dietrich WF, Rucker PV, Chianelli D, Schmeits J, Bao D, Zoll J, Dubois C, Federe GC, Chen L, Joseph SB, Klickstein LB, Walker J, Molteni V, McNamara P, Meeusen S, Tully DC, Badman MK, Xu J, Laffitte B

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

Hepatol Commun. 2019 May 17;3(8):1085-1097. doi: 10.1002/hep4.1368. eCollection 2019 Aug.

PubMed ID

31388629 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Obeticholic acid	Bile acid receptor	Protein	Humans	Yes	Agonist	Details
Tropifexor	Bile acid receptor	Protein	Humans	Unknown	Agonist Binder	Details