Targets and investigative treatments for primary biliary cholangitis

ABSTRACT

Introduction: Primary biliary cholangitis (PBC) is an autoimmune disease of the liver that can slowly progress to cirrhosis, end-stage liver disease and its consequent complications.

Areas covered: Ursodeoxycholic acid (UDCA) is approved for the treatment of PBC at a daily dose of 13 to 15 mg/kg/day, and should be continued indefinitely unless intolerance to UDCA occurs. Nearly 40% of patients have inadequate response to UDCA; therefore, there is a compelling need for newer and more effective therapies. Research has led to the discovery of several novel pathways that are thought to be implicated in the pathogenesis of PBC. Phase II and III clinical trials of obeticholic acid (OCA), the leading farnesoid X receptor agonist compound, in PBC patients with inadequate response to UDCA have shown that the use of OCA results in significant improvement in liver biochemistries. OCA has been recently recommended by the FDA’s Advisory Board for approval for treatment of PBC.

Expert opinion: PBC remains a medical and socioeconomic problem. UDCA is currently the only medication approved for treatment of PBC. The discovery of novel therapeutic targets in PBC will hopefully lead to better outcomes in PBC.

KEYWORDS:

• Primary biliary cholangitis
• ursodeoxycholic acid
• farnesoid X receptor
• obeticholic acid
• liver transplantation
• antimitochondrial antibody
• cirrhosis
• end-stage liver disease

Article highlights

• Primary biliary cholangitis (PBC) is an autoimmune disease of the liver that can slowly progress to cirrhosis and end-stage liver disease.

• PBC, despite its rarity, is an important cause of morbidity and mortality in Western Society.

• Ursodeoxycholic acid (UDCA), a naturally occurring bile acid, improves liver biochemistry abnormalities and liver transplant-free survival in PBC, and is currently the only agent approved by the US FDA for the treatment of PBC.

• Up to 40% of PBC have inadequate response to UDCA, and these patients usually progress to detrimental sequelae of PBC (i.e., cirrhosis and end-stage liver disease requiring liver transplantation).

• Several agents, with different mechanisms of actions, have either been or currently being tested as therapeutic options for those who have inadequate response to UDCA. Some of these agents hold promise as potential add-on or alternative therapy for PBC.

• Obeticholic acid (OCA), a first-in-class farnesoid X receptor agonist, has been evaluated in PBC patients with inadequate response to UDCA. Its use resulted in significant improvement in liver biochemistries. It is expected that it will be approved by the US FDA as an alternative option for treatment of PBC.

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Declaration of interest

K Lindor is an unpaid advisor for Intercept pharmaceuticals and Shire pharmaceuticals. E Carey serves as a consultant to NGM Biopharmaceuticals. 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.

Additional information

Funding

E Carey receives research funding from Intercept, CymaBay, and EuroPharma. However, no funding was received for the preparation of this manuscript.