Investigational farnesoid X receptor agonists for the treatment of primary biliary cholangitis

ABSTRACT

Introduction

Up to 40% of Primary biliary cholangitis (PBC) patients have a suboptimal response to Ursodeoxycholic acid (UDCA). Close to half of such patients show a remarkable improvement when additionally treated with Obeticholic acid (OCA) but have a dose-dependent increase of pruritus. This relative success of OCA, a first-in-class Farnesoid receptor (FXR) agonist, has positioned FXR as an attractive target for drug development. Novel candidates have since emerged, providing hope for this subgroup of patients who lack effective and safe treatments.

Areas covered

We discussed the role of bile acids in PBC pathogenesis and how the FXR agonists provide therapeutic value by affecting bile acid synthesis and transport. Novel FXR agonists undergoing pre-clinical and clinical trials for PBC were enlisted via literature search by including the terms ‘FXR agonists,’ ‘FXR PBC,’ ‘PBC clinical trials’ on PubMed, MEDLINE via Ovid, and Clinicaltrials.gov.

Expert opinion

Novel FXR agonists currently under investigation for PBC improve the disease surrogate markers in early trials. However, as with OCA, pruritus remains a concern with the newer drugs despite targeted chemical modifications to increase FXR specificity. Directing future resources toward studying the molecular mechanisms behind pruritus may lead to better drug design and efficacious yet safer drugs.

KEYWORDS:

• FXR agonist
• primary biliary cholangitis
• obeticholic acid
• new drugs for PBC
• itching
• TGR5
• tropifexor
• cilofexor

Article highlights

• Obeticholic acid (OCA), a Farnesoid X receptor (FXR) agonist, is a critical therapeutic option in Primary biliary cholangitis (PBC) patients nonresponsive to UDCA. However, dose-dependent increase in pruritus is a concern with OCA, and limitations exist regarding its utility in some patients.

• To circumvent these issues, a new generation of FXR agonists are being investigated in various phases of clinical trials. Some of these agents showed favorable results in Phase 2 clinical trials.

• In this review, we discuss the possible mechanisms underlying the effectiveness of FXR agonists for PBC, summarize the therapeutic evidence gathered on OCA, and delve into molecular structures, efficacy, and adverse effect profiles of novel FXR agonists in the investigational pipeline for PBC.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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

Additional information

Funding

This manuscript was not funded.