Clinical Review Report: Obeticholic Acid (Ocaliva): (Intercept Pharmaceuticals Canada, Inc.): Indication: For the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA or as monotherapy in adults unable to tolerate UDCA

Primary biliary cholangitis (PBC) occurs as a result of immune-mediated damage to bile ducts, with an associated inflammatory response leading to progressive fibrosis and loss of patency. This loss of patency leads, in turn, to hepatic accumulation of bile acids, resulting in liver damage with progressive fibrosis and, potentially, cirrhosis. PBC is more common in women than in men and is the most common reason for liver transplant among women. Patients with PBC report fatigue and pruritus as key symptoms that negatively impact quality of life. Patients are also clearly affected by the potential progression to severe liver disease and associated complications such as decompensated liver disease, hepatocellular carcinoma, liver transplant, and death. Thirty per cent of persons can progress to advanced liver disease, decompensated disease, or death. PBC is a relatively uncommon disease and affects between 9,000 and 11,000 Canadians,3 mostly women between the ages of 50 and 70 years, although some patients are diagnosed at an earlier age according to the clinical expert consulted for this review. A 2009 study focusing on the Calgary Health Region found an incidence of 30 cases per million for PBC and a prevalence that had risen from 100 cases per million in 1996 to 227 cases per million in 2002. There is currently only one approved therapy for PBC in Canada – ursodeoxycholic acid (UDCA) – and more than 80% of patients with PBC receive UDCA. Those patients who respond to UDCA tend to have improved clinical outcomes (e.g., transplant-free survival); however, about 40% to 50% of patients treated with UDCA do not respond to therapy. There are also a small number of patients who are unable to tolerate UDCA, approximately 10% according to the clinical expert. In their input to the CADTH Common Drug Review (CDR), patient groups described gastrointestinal symptoms (diarrhea), weight gain, alopecia, dizziness, and flu-like adverse effects while on UDCA, in addition to PBC-related symptoms such as pruritus and fatigue. Obeticholic acid (OCA) is a farnesoid X receptor agonist. Farnesoid receptors are a novel pharmacological target, and stimulation of these receptors appears to have multiple effects; in PBC, the most notable is the reduction in hepatocellular concentration of bile acids. OCA is approved by Health Canada for the treatment of PBC in combination with UDCA in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA. In approving OCA, Health Canada issued a notice of compliance with conditions (NOC/c) pending results of trials to verify the clinical benefit of OCA. One of these trials, study 747-302, was designed to evaluate OCA, either in combination with UDCA or as monotherapy in patients with early, moderately advanced, and advanced PBC, with a primary composite of clinical end points (e.g., death, transplant). The other trial, study 747-401, was designed to enrol a population of PBC patients with moderate to severe hepatic impairment (Child–Pugh class B and C). The recommended starting dose in the Health Canada–approved product monograph is 5 mg by mouth daily; however, patients may uptitrate to 10 mg daily after six months to improve response if an adequate reduction in alkaline phosphatase (ALP) or total bilirubin has not been achieved. Continuation of OCA in a patient with no improvement in biochemical markers of PBC (ALP and bilirubin) after one year on the maximum effective dose (10 mg) should be assessed based on the clinical course of PBC and the potential risks and benefits of continued use.