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.