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

Area of Science:

• Hepatology and pharmacology
• Molecular mechanisms of liver disease

Background:

• Farnesoid X receptor (FXR) agonism is a potential therapeutic strategy for chronic liver diseases.
• Obeticholic acid (OCA), a bile acid-derived FXR agonist, has shown promise in nonalcoholic steatohepatitis (NASH) patients.
• Novel FXR agonists are being developed to improve upon existing therapies.

Purpose of the Study:

• To evaluate the efficacy of the novel nonbile acid FXR agonist tropifexor (LJN452) in preclinical models of NASH.
• To compare tropifexor's efficacy against OCA in established NASH models.
• To investigate the molecular mechanisms underlying tropifexor's therapeutic effects.

Main Methods:

• Two distinct preclinical models of NASH were utilized: the Stelic animal model (STAM) and the amylin liver NASH model (AMLN).
• Tropifexor and OCA were administered at specific doses, and efficacy was assessed by measuring fibrosis, steatohepatitis, hepatic triglycerides, and gene expression.
• Transcriptome analysis was performed on liver samples from AMLN mice treated with tropifexor.

Main Results:

• Tropifexor (<1 mg/kg) showed superior efficacy to OCA (25 mg/kg) in both NASH models.
• In the STAM model, tropifexor reversed established fibrosis and reduced NASH activity score and hepatic triglycerides.
• In the AMLN model, tropifexor reduced steatohepatitis, fibrosis, and profibrogenic gene expression, with transcriptome analysis revealing signatures of reduced oxidative stress, fibrogenesis, and inflammation.

Conclusions:

• Tropifexor demonstrates significant preclinical efficacy in reversing fibrosis and improving key NASH parameters.
• The novel nonbile acid FXR agonist tropifexor is a promising therapeutic candidate for NASH.
• Further clinical development, including Phase 2 trials, is warranted for tropifexor in NASH treatment.