Obeticholic Acid Effective in Primary Biliary Cholangitis

By Will Boggs MD

August 24, 2016

NEW YORK (Reuters Health) - Obeticholic acid reduces alkaline phosphatase and total bilirubin levels in patients with primary biliary cholangitis, according to results from the POISE study.

"Treatment with obeticholic acid should be considered in all patients with alkaline phosphatase >1.67 times the upper limit of normal and/or elevated bilirubin," Dr. Frederik Nevens from University Hospital KU Leuven, Belgium told Reuters Health by email.

Primary biliary cholangitis (PBC), formerly called primary biliary cirrhosis, affects 20 to 40 individuals per 100,000 population and can progress to cirrhosis, end-stage liver disease, and death. Higher alkaline phosphatase and bilirubin levels correlate with disease progression, whereas lower levels are predictive of survival without the need for liver transplantation.

Earlier studies showed significantly greater reductions in alkaline phosphatase and bilirubin levels with obeticholic acid versus placebo.

Dr. Nevens and colleagues in the POISE study assessed the longer-term efficacy, safety, and adverse event profile of obeticholic acid in 217 patients with PBC.

The primary composite endpoint was an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% from baseline, and a total bilirubin level at or below the upper limit of the normal range at 12 months.

Nearly half of patients treated with 5-10 mg (46%) or 10 mg (47%) obeticholic acid experienced this endpoint, versus only 10% of patients receiving placebo.

Response to obeticholic acid was rapid: the advantage over placebo emerged by week 2 and remained at each time point thereafter in the 12-month trial, according to the August 18th report in The New England Journal of Medicine.

In secondary analyses, patients treated with obeticholic acid fared better than those treated with placebo in each of the individual components of the primary composite endpoint.

These improvements, however, did not translate into significant improvements in symptoms or in noninvasive measures of liver fibrosis.

Pruritus was the most common adverse event, affecting 56% of patients in the 5-10 mg group and 68% of patients in the 10 mg group, compared with 38% of patients in the placebo group.

Although the incidence of serious adverse events was greater with obeticholic acid, all serious adverse events resolved without sequelae.

"Ursodiol was the only approved treatment and is successful in >60% of the patients," Dr. Nevens said. "It is well tolerated and cheap. Therefore, the place of obeticholic acid is currently in second line."

"Doses more than 10 mg once daily are not more effective," Dr. Nevens added. "Recommended dose is 5 mg once daily and if no significant decline in alkaline phosphatase after 3-6 months, increase to 10 mg (necessary in 50% of the patients). In case of pruritus, decrease the dose."

In an editorial, Dr. Daniel S. Pratt writes, "A new therapy is available for immediate use in a group of patients who desperately need a second-line treatment. It is now contingent on clinicians who care for patients with primary biliary cholangitis to determine whether their patients do not have a response to ursodiol, and if they do not, to consider them for treatment with obeticholic acid."

"What about the patients who do not have a biochemical response to obeticholic acid at 12 months - which will include approximately 50% of the patients, according to the POISE results?" he wondered. "Should patients without a response continue taking obeticholic acid indefinitely, without data supporting its long-term use and at a cost of approximately $70,000 per year?"

"These are exciting times for primary biliary cholangitis, with a new name and a new therapy," Dr. Pratt concluded. "However, although the results presented here are encouraging, questions remain. Obeticholic acid is a well-received addition to the treatment of primary biliary cholangitis, but it is not the end of our search for effective therapies for this challenging and poorly understood disease."

Dr. Keith Lindor from the Mayo Clinic and Arizona State University in Phoenix, who recently reviewed the use of obeticholic acid for the treatment of PBC, told Reuters Health, "I was pleased to see how effective obeticholic acid (OCA) was for so many of these patients. I was also pleased and surprised how well the dose escalation approach worked, both for patient improvement but also as part of the study design."

"I think OCA will be used primarily in those patients who have inadequate biochemical responses to ursodiol (UDCA), especially if these patients do not have a history of itching," he said. "OCA will need to be used cautiously in those patients with itching. OCA also provides an alternative for those few patients who cannot take UDCA."

"Physicians should now know that there is an alternative to UDCA," Dr. Lindor said. "The new drug is expensive, and this may influence access to the drug."

Obeticholic acid received accelerated FDA approval on May 27 for the treatment of adults with PBC who have an inadequate response to ursodiol or who are unable to take ursodiol because of side effects.

Intercept Pharmaceuticals funded the study.

SOURCE: http://bit.ly/2bex5SO and http://bit.ly/2bcz6oi

N Engl J Med 2016.