The identification of farnesoid X receptor modulators as treatment options for nonalcoholic fatty liver disease

ABSTRACT

Introduction

The farnesoid-x-receptor (FXR) is a ubiquitously expressed nuclear receptor selectively activated by primary bile acids.

Area covered

FXR is a validated pharmacological target. Herein, the authors review preclinical and clinical data supporting the development of FXR agonists in the treatment of nonalcoholic fatty liver disease.

Expert opinion

Development of systemic FXR agonists to treat the metabolic liver disease has been proven challenging because the side effects associated with these agents including increased levels of cholesterol and LDL-c and reduced HDL-c raising concerns over their long-term cardiovascular safety. Additionally, pruritus has emerged as a common, although poorly explained, dose-related side effect with all FXR ligands, but is especially common with OCA. FXR agonists that are currently undergoing phase 2/3 trials are cilofexor, tropifexor, nidufexor and MET409. Some of these agents are currently being developed as combination therapies with other agents including cenicriviroc, a CCR2/CCR5 inhibitor, or firsocostat an acetyl CoA carboxylase inhibitor. Additional investigations are needed to evaluate the beneficial effects of combination of these agents with statins. It is expected that in the coming years, FXR agonists will be developed as a combination therapy to minimize side effects and increase likelihood of success by targeting different metabolic pathways.

KEYWORDS:

• Bile acids
• farnesoid -X-receptor
• nonalcoholic steatohepatitis
• obeticholic acid
• cilofexor
• tropifexor
• nidufexor

Article highlights

• The farnesoid-x-receptor (FXR) and the G Protein Coupled Bile Acid Receptor (GPBAR)1 (also known as TGR5) are two bile acids activated receptors expressed in the liver and intestine.

• FXR is a validated target in the treatment of liver disorders and several FXR agonists are undergoing clinical trials for the treatment of non-alcoholic steatohepatitis (NASH) including obeticholic acid, cilofexor, nidufexor, tropifexor and MET409.

• Results from clinical trials in NASH have shown that obeticholic acid and other FXR agonists, cause class-related side effects including pruritus, increased cholesterol plasma levels and reduced levels of high-density lipoprotein (HDL). While effects on liver steatosis and fibrosis have been variable.

• Development of packages combining FXR agonists with currently available or novel agents acting on different molecular targets might reduce side effects and improve efficacy.

• Development of intestine restricted FXR agonists or dual FXR/GPBAR1 ligands might have clinical utility.

Declaration of interest

S Fiorucci and A Zampella have received grants from BAR Pharmaceuticals SrL (Italy). Furthermore, S Fiorucci and A Zampella are the inventors of BAR501 and BAR502, while S Fiorucci is also the inventor of INT767. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers in this manuscript have no relevant financial or other relationships to disclose.