Non-alcoholic fatty liver disease is considered as a hepatic manifestation of the metabolic syndrome and as the most prevalent chronic liver disease in the world, with up to 30% of adults being affected. This reversible pathology can progress to non-alcoholic steatohepatitis (NASH) which additionally involves hepatic inflammation and liver cell damage.
The resulting permanent hepatic stress often leads to liver fibrosis as a first step towards liver cirrhosis. Moreover, NASH is accompanied by markedly increased risk for hepatocellular carcinoma, but despite its high prevalence and severe consequences, no pharmacotherapy is available for NASH to date. An experimental drug in stage 3 of clinical trials has validated the nuclear farnesoid X receptor (FXR) as a suitable target for NASH treatment, but its considerable adverse effects might limit the use of this drug. In addition, FXR activation fails to counter all aspects of NASH. In this therapeutic gap, we have developed an innovative agent that activates FXR and inhibits the enzyme soluble epoxide hydrolase (sEH).
By potently modulating two complementary anti-NASH targets, this FXRA/sEHi achieves a triad of anti-NASH effects and exhibits anti-steatotic, anti-fibrotic and anti-inflammatory activity. Proof-of-concept in vivo experiments have already demonstrated therapeutic efficacy of the FXRA/sEHi in diet- and toxin-induced NASH in mice. To promote preclinical development of this innovative agent and enable early clinical trials of the FXRA/sEHi, the experimental drug shall undergo further characterization with a focus on demonstrating synergistic efficacy and superior safety.