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Positive Results Reported for Bile Acid Analog in Pivotal Phase III Study

Treatment reduces alkaline phosphatase in patients with biliary cirrhosis

An international phase III trial of obeticholic acid (OCA, Intercept Pharmaceuticals) for the treatment of primary biliary cirrhosis (PBC) has demonstrated that OCA, at both a 10-mg dose and a 5-mg dose titrated to 10 mg, met the study’s primary endpoint of achieving a reduction in serum alkaline phosphatase (ALP) to less than 1.67 times the upper limit of normal, with a reduction of 15% or more from baseline, and a normal bilirubin level after 12 months of therapy.

OCA is a bile-acid analog and a first-in-class agonist of the farnesoid X receptor (FXR) in development for the treatment of PBC, nonalcoholic steatohepatitis (NASH), and other liver and intestinal diseases.

The phase III POISE trial studied the safety and efficacy of once-daily treatment with OCA in patients with PBC who had shown an inadequate therapeutic response to, or who were unable to tolerate, ursodiol (ursodeoxycholic acid). A total of 217 patients were randomly assigned to one of three treatment groups: placebo, OCA 10 mg, or OCA 5 mg for 6 months titrated to OCA 10 mg based on the patient’s clinical response. Of the 217 enrolled patients, 216 were dosed.

The proportions of patients meeting the trial’s primary endpoint were 10% in the placebo group, 47% in the 10-mg OCA group, and 46% in the 5- to 10-mg OCA group (P < 0.0001 vs. placebo for both dose groups) in an intention-to-treat analysis. The placebo group experienced a mean decrease in ALP from baseline of 5%, compared with a significant mean decrease of 39% in the 10-mg OCA dose group and 33% in the 5- to 10-mg OCA titration group (P < 0.0001 vs. placebo in both dose groups).

In addition, both OCA-treated groups met pre-specified secondary endpoints of improvements in other liver-function parameters, including GGT, ALT, AST and total bilirubin (P < 0.0005 vs. placebo for both dose groups).

Pruritus (generally mild to moderate in severity) was the most frequently reported adverse event associated with OCA treatment (placebo: 38%, OCA 10 mg: 68%, OCA 5- to 10-mg titration: 56%). Eight patients discontinued therapy because of pruritus: none in the placebo group, seven patients (10%) in the 10-mg OCA group, and one patient (1%) in the OCA 5- to 10-mg titration group.

To evaluate the clinical relevance of the POISE trial’s primary endpoint, an independent study was conducted by the Global PBC Study Group. This analysis involved 15 PBC centers in eight countries, resulting in a clinical outcomes database of more than 6,000 PBC patients. In this study, patients who did not achieve the POISE endpoint after 1 year were shown to have a greatly increased risk of liver transplant or death compared with those who achieved the endpoint (hazard ratio, 2.83).

Results from the POISE trial will be presented at the upcoming International Liver Congress of the European Association for the Study of the Liver (EASL), to be held April 9–13 in London.

PBC is an autoimmune liver disease that may progress to cirrhosis and liver failure. It is currently the fifth leading indication for liver transplant in the U.S. PBC is primarily a disease of women, afflicting approximately one in 1,000 women over the age of 40. Clinically, the progress of the disease is assessed by measuring the blood levels of ALP and bilirubin, which have been shown to correlate with the risk of adverse outcomes.

Ursodiol is the only approved drug treatment for PBC, but studies have shown that up to 50% of PBC patients fail to respond adequately, thereby remaining at risk of adverse outcomes.

Source: Intercept Pharmaceuticals; March 16, 2014.

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