Obeticholic acid, a drug approved as a second-line treatment for a rare liver disease called primary biliary cholangitis, appears to substantially increase the risk of liver decompensation in patients with cirrhosis.
The same drug is in front of the FDA for approval to treat much more common fatty liver disease, and researchers are concerned that widespread approval of the drug could do more harm than good, according to a study published in Hepatology Communications led by Binu V. John, M.D., M.P.H., affiliate associate professor in the Division of Digestive Health and Liver Diseases at the University of Miami Miller School of Medicine.
“Obeticholic acid is supposed to help patients with primary biliary cholangitis. But we found patients on the drug were at about a four-fold higher risk than patients not on the drug to progress from compensated cirrhosis, where the liver has scarring but still works well, to decompensated cirrhosis, where patients’ liver function worsens,” Dr. John said.
Primary biliary cholangitis is an autoimmune disease, in which the body’s immune system attacks its own liver and bile ducts and causes liver damage. The first-line treatment is the medication ursodeoxycholic acid, but about 40% of patients don’t respond to that medication, according to Dr. John.
When the FDA approved obeticholic acid in 2016 as the second-line treatment for primary biliary cholangitis, it was approved based on studies mostly in patients without cirrhosis. Cirrhosis is scar tissue in the liver that can result from hepatitis C, alcohol use, fatty liver disease or primary biliary cholangitis.
In recent years, patients taking obeticholic acid started becoming very sick. The FDA issued a warning in 2017 that providers should be cautious about using this drug in decompensated cirrhosis, but the warning did not say anything about compensated cirrhosis, according to Dr. John.
“We wanted to look at this medication to see what happens if you give it to patients with primary biliary cholangitis who have compensated cirrhosis, or functioning livers,” he said.
In the paper, Dr. John and colleagues looked retrospectively at 509 patients with primary biliary cholangitis and cirrhosis from a national database of U.S. veterans. While they found that obeticholic acid resulted in nearly four times the risk of decompensation in compensated cirrhosis patients, the drug was not associated with liver-related death or transplantation.
Another concern is that obeticholic acid is in late-stage trials to get FDA approval for treatment of nonalcoholic steatohepatitis (NASH), the most common type of fatty liver disease. Fatty liver disease is estimated to affect 25% of the U.S. population, according to the American Liver Foundation.
“There is concern that if this drug is associated with decompensation in patients with cirrhosis, and gets approved for fatty liver, this may affect much larger numbers of patients, since fatty liver disease is much more common compared to primary biliary cholangitis,” Dr. John said.
Miller School researchers joined Virginia Commonwealth University, Yale School of Medicine, University of Pennsylvania, and VA researchers to conduct what Dr. John believes is one of the first studies to test the safety of obeticholic acid, which according to Drugs.com costs about $96,000 a year for cirrhosis patients.
The study adds to the body of data urging caution in the use of this drug, which has prompted the FDA to ask for more data and larger prospective studies specifically in patients with cirrhosis, according to Dr. John.
“For now, we are telling doctors all over the world that they should be cautious when using this medication until there are more and larger studies that can show that it is safe. They should be cautious until then, even in patients with compensated cirrhosis,” he said.
Other Miller School researchers who contributed this research are Cynthia Levy, M.D., professor of medicine, the Arthur H. Hertz Endowed Chair in Liver Diseases, and associate director of the Schiff Center for Liver Diseases, and Paul Martin, M.D., professor and chief of the Division of Digestive Health and Liver Diseases.