Laird Harrison

November 15, 2015

SAN FRANCISCO — Obeticholic acid maintains reduced levels of key biomarkers for primary biliary cholangitis (previously known as primary biliary cirrhosis) for up to 5 years, according to the results of a new study.

"As a long-term therapy, both as monotherapy and in combination with ursodeoxycholic acid, you can get a good response," Kris Kowdley, MD, from the Swedish Medical Center in Seattle, Washington, told Medscape Medical News.

The treatment also was safe and generally well tolerated, with the exception of some pruritus, he added.

Dr Kowdley presented the finding here at the Liver Meeting 2015: American Association for the Study of Liver Diseases (AASLD).

Obeticholic acid is a selective farnesoid X receptor agonist that works by stimulating the release of bile acid, Dr Kowdley explained. It was originally developed for primary biliary cholangitis because the only treatment currently available for this disorder, ursodeoxycholic acid, does not work in many patients.

This is the latest in a series of positive reports for the drug, which is also being explored as a treatment for nonalcoholic steatohepatitis and primary sclerosing cholangitis.

After successful phase 3 trials of obeticholic acid in primary biliary cholangitis, an application for this indication was submitted to the US Food and Drug Administration.

Initial Phase 2 Trial

Researchers initially conducted a 12-week, phase 2, double-blind, placebo-controlled study to evaluate obeticholic acid as monotherapy. Patients were randomly assigned to receive a placebo or either 10 or 50 mg obeticholic acid daily.

After the 12 weeks, the drug reduced mean alkaline phosphatase levels between 38% and 45%.

"We feel very comfortable using alkaline phosphatase as a surrogate marker in predicting clinical outcomes in primary biliary cholangitis," said Dr Kowdley, as previous studies have shown that patients with high alkaline phosphatase levels often develop clinical liver problems.

Long-term Study

Twenty-eight patients from the phase 2 trial enrolled in the long-term study, either maintaining the dose of obeticholic acid they had been taking or starting at 10 mg with the option to titrate up to a maximum dose of 50 mg.

In the double-blind phase, patients took obeticholic acid as monotherapy. In the long-term safety trial, they could add ursodeoxycholic acid; seven patients chose that option.

Participants had a mean age of 60 years, 84% percent were women, and 43% are currently taking 10 mg obeticholic acid or less. A total of 18 patients completed 5 years of treatment, with a median of 5.2 years of exposure to the drug.

At baseline, the 18 patients had mean alkaline phosphatase levels of 453.3 U/L.

Long-term treatment with obeticholic acid alone or in combination with ursodeoxycholic acid was associated with sustained reductions not only in alkaline phosphatase levels but also in gamma-glutamyl transpeptidase, alanine aminotransferase, aspartate aminotransferase, and total bilirubin.

Table. Changes in Biomarkers Over 5 Years

Treatment Group Baseline (U/L) 5-Year Change (U/L) P Value
Obeticholic acid plus ursodeoxycholic acid (n = 18)      
   Alkaline phosphatase 453.3 −269.0 .0025
   Gamma-glutamyl transpeptidase 469.7 −350.0 .0012
   Alanine aminotransferase 70.4 −41.0 .0003
   Aspartate aminotransferase 61.9 −23.0 .0033
   Total bilirubin 12.5 −2.0 .1708
Obeticholic acid only (n = 11)      
   Alkaline phosphatase 378.7 −182.0 .0090
   Gamma-glutamyl transpeptidase 438.3 −260.0 .0104
   Alanine aminotransferase 67.2 −33.0 .0021
   Aspartate aminotransferase 57.8 −16.0 .0127
   Total bilirubin 11.6 1.0 .6397

Adverse Events

The most common adverse event was pruritus, which affected 25 of the 28 patients originally enrolled in the long-term study.

"It's difficult to assess pruritus in primary biliary cholangitis, because it's also a common symptom of the disease," said Dr Kowdley. However, he noted that in the phase 3 trials of the drug, patients are taking 5 mg titrated up to 10 mg, and the incidence and severity of pruritus are much lower.

Ten patients dropped out of the study: one withdrew consent, five stopped because of an adverse event other than pruritus, and two stopped because of pruritus. The investigators did not document the reasons for the other two withdrawals.

Among the other adverse events were arthralgia, nausea, headache, fatigue, constipation, diarrhea, myalgia, upper abdominal pain, back pain, peripheral edema, upper respiratory tract infection, and insomnia.

Eight patients experienced serious adverse events, including choledocholithiasis and jaundice, but the researchers judged these not to be related to the obeticholic acid.

Obeticholic acid looks promising. Dr Keith Lindor

"Obeticholic acid looks promising," said Keith Lindor, MD, from Arizona State University in Phoenix.

When people with primary biliary cholangitis can keep their alkaline phosphatase levels below 200 U/L, they usually avoid clinical problems, he explained.

If approved as a treatment in this disorder, obeticholic acid could become a valuable add-on treatment for those patients who do not get good results with ursodeoxycholic acid alone, said Dr Lindor.

This study was funded by Intercept Pharmaceuticals. Dr Kowdley serves on the advisory board to Intercept. Dr Lindor has disclosed no relevant financial relationships.

The Liver Meeting 2015: American Association for the Study of Liver Diseases (AASLD): Abstract 628. Presented November 14, 2015.



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