Miriam E. Tucker

April 15, 2014

LONDON, United Kingdom — Obeticholic acid could become the first new treatment for primary biliary cirrhosis in more than 2 decades, according to a new phase 3 study.

Ursodeoxycholic acid (UDCA) is the only drug currently approved to treat primary biliary cirrhosis, but up to 50% of patients don't respond to it adequately. Obeticholic acid is a selective farnesoid X receptor agonist, and has a different mechanism of action.

When obeticholic acid was given to patients who could not tolerate or had an inadequate response to UDCA, it "produced clinically and statistically meaningful biochemical improvements, which have been shown to be strongly correlated with clinical benefit," said Frederik Nevens, MD, chair of the Department of Hepatology at the University of Leuven in Belgium.

Dr. Nevens presented data from the pivotal multinational POISE trial during a latebreaker session here at the European Association for the Study of the Liver (EASL) International Liver Congress 2014. The study was funded by Intercept Pharmaceuticals, which developed obeticholic acid.

Significant Changes in Surrogate Markers

The study involved 216 patients with primary biliary cirrhosis who could not tolerate or had not responded adequately to UDCA. All had alkaline phosphatase (ALP) levels at least 1.67 times the upper limit of normal (ULN) and/or total bilirubin levels from the ULN to less than 2 times the ULN.

The primary end point was the proportion of patients achieving an ALP level below 1.67 times the ULN, a decrease in ALP of at least 15% from baseline, and a normal total bilirubin level after 12 months of treatment.

At baseline, the mean age of the patients was 56 years, and the mean age at diagnosis of primary biliary cirrhosis was 47 years. Of the cohort, 91% was female and 93% was taking UDCA. Of the 216 patients in the intent-to-treat population, 198 completed the study.

Patients were randomized to receive obeticholic acid 5 mg daily, obeticholic acid 10 mg daily, or placebo for 12 months.

At 6 months, about half the patients in the 5 mg group who tolerated the drug but still had an ALP level at least 1.67 times the ULN or a bilirubin level below the ULN were titrated to the 10 mg dose.

There was no statistical difference between the titration group, the 5 mg group, and the 10 mg group in the proportion achieving the primary end point.

In the intention-to-treat analysis, the primary end point was met by more patients in the 10 mg group than in the placebo group (47% vs 10%; P < .0001), and by more patients in the titration group (46% vs 10%; P < .0001).

The mean decrease in ALP level from baseline was better in the 10 mg group than in the placebo group (39% vs 5%; P < .0001), and was better in the titration group (33% vs 5%; P < .0001).

There was a significant reduction in total bilirubin in the 10 mg and titration groups (P < .05), whereas there was a tendency toward an increase in the placebo group. In addition, there was a significant decrease in other liver function parameters, including gamma-glutamyl transpeptidase, alanine transaminase, and aspartate aminotransferase (P < .001 for all).

Univariate and multivariate analyses are currently underway to determine whether any predictors of response can be identified, Dr. Nevens reported.

Pruritus a Problem?

Of all the adverse effects reported by at least 5% of the study population, pruritus was the only one that differed significantly between obeticholic acid and placebo. It was reported by 68% of the 10 mg group, 56% of the titration group, and 38% of the placebo group.

The study protocol allowed for patients with severe pruritus to be treated with cholestyramine. It was used by 26% of the 10 mg group, 19% of the titration group, and 11% of the placebo group.

At 6 months, there were no differences in visual analog scale scores for pruritus among the 3 groups.

Discontinuation of the study drug occurred in 12% of the 10 mg group, 9% of the titration group, and 4% of the placebo group. Pruritus led to discontinuation for 7 patients in the 10 mg group and 1 patient in the titration group. An 82-year-old man in the titration group who had pre-existing congestive heart failure died, but his death was deemed to be unrelated to obeticholic acid.

Most of the patients in this study (95%) voluntarily chose to continue in an open-label 5-year extension study to evaluate the long-term safety and efficacy of obeticholic acid. That proportion is "quite high," Dr. Nevens told Medscape Medical News.

Surrogate End Points Are Not Outcomes

POISE is a "good" multicenter, prospective, double-blind study, and is "reliable," said Mauro Bernardi, MD, professor of internal medicine at the University of Bologna in Italy, and a member of the EASL governing board.

However, he pointed out, the study evaluated surrogate end points rather than hard clinical outcomes. Because primary biliary cirrhosis and other chronic liver diseases develop over many years or decades, surrogate markers must be relied on.

 
Primary biliary cirrhosis is a story you have to look at over 10, 20 years.
 

"We take for granted that with an improvement in biochemical criteria, we will be able to influence the natural history of the disease," he explained. "We know there is a relation between the extent of biochemical damage and prognosis, but it's not exactly the same. When I am giving the drug, I cannot say that I'm reducing the mortality or the need for transplantation in these patients. We have no data to say that," said Dr. Bernardi, who was not involved in the study.

Dr. Nevens pointed to data from a previous study — presented at the 2013 EASL meeting and also supported by Intercept — confirming that surrogate markers, including ALP below a certain threshold and normalization of bilirubin, are clearly linked to long-term outcome.

"We don't take statins to lower cholesterol and expect that within 24 hours you will have less strokes and less heart attack. Primary biliary cirrhosis is a story you have to look at over 10, 20 years," Dr. Nevens told Medscape Medical News.

Dr. Bernardi said he agrees. "For treatments that must be taken for years, tolerability is a major point. And obeticholic acid is quite well tolerated."

Despite his caveat about the use of surrogate end points, Dr. Bernardi noted that "here you have an answer for people who are not tolerating UDCA, and possibly an answer for those who don't have a positive response to UDCA alone."

Intercept Pharmaceuticals is evaluating obeticholic acid for other chronic liver diseases, including nonalcoholic steatohepatitis, cirrhosis, portal hypertension, alcoholic hepatitis, primary sclerosing cholangitis, and bile acid diarrhea.

According to a company statement, "Intercept plans to submit data from the phase 3 POISE trial and the 2 phase 2 trials of obeticholic acid for the treatment of primary biliary cirrhosis as part of a New Drug Application to the US Food and Drug Administration and a Marketing Authorization Application to the European Medicines Agency. These regulatory filings are currently anticipated at the end of 2014."

The study was funded by Intercept Pharmaceuticals. Dr. Nevens and Dr. Bernardi have disclosed no relevant financial relationships.

European Association for the Study of the Liver (EASL) International Liver Congress 2014: Abstract 0168. Presented April 12, 2014.

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