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

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.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Non–Bile Acid FXR Agonist Tropifexor (LJN452) in Healthy Volunteers

“…Its potency has been attributed to the inclusion of a bicyclic nortropine‐substituted benzothiazole carboxylic acid . Recently, preclinical validation of tropifexor was performed in various animal models of cholestasis and NASH, demonstrating effective reduction in various disease parameters including fibrosis . Here, we present results from a phase 1 study of the safety, tolerability, PK, and pharmacodynamics (PD) of tropifexor.…”

“…18 Recently, preclinical validation of tropifexor was performed in various animal models of cholestasis and NASH, demonstrating effective reduction in various disease parameters including fibrosis. 19,20 Here, we present results from a phase 1 study of the safety, tolerability, PK, and pharmacodynamics (PD) of tropifexor. In addition to lean, healthy volunteers, a cohort of obese volunteers was also included to investigate PK and PD in individuals resembling those with nonalcoholic fatty liver disease/NASH.…”

Bile Acids and FXR: Novel Targets for Liver Diseases

“…Tropifexor is a representative of non-steroidal FXR agonists. In mouse models of NASH, tropifexor significantly reduced oxidative stress, steatosis, inflammation, and fibrosis (124). It will be very interesting to see whether, as a non-steroidal FXR agonist, tropifexor will present similar adverse effect to the steroidal FXR agonists.…”

Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities

“…Tropifexor is another non-steroidal FXR agonist with promising results in preclinical studies in non-alcoholic [103,104]. Along considerations above, tropifexor may hold therapeutic prospects in PSC, but currently no trials in PSC are listed for tropifexor at clinicaltrials.gov.…”