Obeticholic acid for the treatment of primary biliary cirrhosis

Abstract

Primary biliary cirrhosis (PBC) is characterized by progressive nonsuppurative destruction of small bile ducts, resulting in intrahepatic cholestasis, fibrosis and ultimately end-stage liver disease. Timely intervention with ursodeoxycholic acid is associated with excellent survival, although approximately one-third of all patients fail to achieve biochemical response, signifying a critical need for additional therapeutic strategies. Obeticholic acid (OCA) is a potent ligand of the nuclear hormone receptor farnesoid X receptor (FXR). Activation of FXR inhibits bile acid synthesis and protects against toxic accumulation in models of cholestasis and facilitates hepatic regeneration in preclinical studies. Data from recent Phase II and III controlled trials suggest a therapeutic impact of OCA in PBC biochemical nonresponders, as evidenced by change in proven laboratory surrogates of long-term outcome. Dose-dependent pruritus is a common adverse effect, but may be overcome through dose-titration. Longer term studies are needed with focus on safety and long-term clinical efficacy.

Keywords:

• autoimmune disease
• cholangitis
• obeticholic acid
• primary biliary cirrhosis
• ursodeoxycholic acid

Acknowledgements

The authors wish to thank Intercept Pharmaceuticals for provision of data necessary for figure construction (Figures 3,4 and 5b).

Financial & competing interests disclosure

The authors were supported by Intercept Pharmaceuticals for provision of data necessary for figure construction. G Hirschfield is an investigator and consultant to Intercept Pharmaceuticals. GMH is a coinvestigator for UK-PBC (www.uk-pbc.com) supported by a Stratified Medicine Award from the UK Medical Research Council and principal investigator for UK-PSC, a NIHR Rare Disease Translational Collaboration. GMH and PJT have received funding from the NIHR Biomedical Research Unit. PJT is recipient of a Wellcome Trust Clinical Research Fellowship. The views expressed are those of the authors(s) and not necessarily those of the National Health System, the National Institute for Health Research, or the Department of Health. 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.

Key issues

• Primary biliary cirrhosis (PBC) is a chronic autoimmune liver disease in which clinical course is characterized by cholestasis, and outcome dictated by the development of cirrhosis and portal hypertension.

• Presently, ursodeoxycholic acid (UDCA) is the only licensed medical treatment; and for those who meet specific biochemical response criteria (60–70% of all patients), clinical outcome is excellent.

• However, therapeutic shortfall of UDCA is evident in approximately one-third of the PBC population, particularly those failing to attain biochemical response, who experience progressive liver disease despite adequate UDCA provision.

• Obeticholic acid (OCA) is a semisynthetic analog of chenodeoxycholic acid that demonstrates potent anticholestatic, anti-inflammatory, antifibrotic and cell-proliferative effects in preclinical models of hepatobiliary injury, mediated through activation of the nuclear farnesoid X receptor.

• In Phase II and III PBC clinical trials, OCA (monotherapy, or in addition to UDCA) resulted in significantly greater improvement to proven biochemical surrogates of clinical outcome, relative to placebo (± UDCA).

• Pruritus is the most significant side effect of OCA treatment, although this can be overcome through appropriate dosage titration and provision of bile acid sequestrants.

• Longer-term studies are needed to explore safety concerns and validate clinical efficacy.