On Friday, May 27, the U.S. Food and Drug Administration granted accelerated approval for Ocaliva (obeticholic acid) for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as a single therapy in adults unable to tolerate UDCA.
PBC is a chronic, or long lasting, disease that causes the small bile ducts in the liver to become inflamed, damaged and ultimately destroyed. This causes bile to remain in the liver, which damages the liver cells over time, and results in cirrhosis, or scarring of the liver. As cirrhosis progresses, and the amount of scar tissue in the liver increases, the liver loses its ability to function.
"Patients left untreated, or who have not responded to UDCA, are at risk for liver failure and death," said Amy Egan, M.D., M.P.H., deputy director of the Office of Drug Evaluation III in the FDA's Center for Drug Evaluation and Research. "Today's approval of Ocaliva provides an important treatment option for patients living with PBC who have not responded to the only other approved therapy, UDCA. "
Ocaliva, given orally, binds to the farnesoid X receptor (FXR), a receptor found in the nucleus of cells in the liver and intestine. FXR is a key regulator of bile acid metabolic pathways. Ocaliva increases bile flow from the liver and suppresses bile acid production in the liver, thus reducing the exposure of the liver to toxic levels of bile acids.
The FDA's approval is based on a reduction in the level of the biomarker alkaline phosphatase (ALP), as a surrogate endpoint which, based on multiple levels of evidence (mechanistic, clinical trial, epidemiologic), could be relied upon to be reasonably likely to predict clinical benefit, including an improvement in transplant free-survival. The safety and efficacy of Ocaliva were demonstrated in a controlled clinical trial with 216 participants. After twelve months, the proportion of participants achieving reductions in ALP levels was higher among Ocaliva-treated participants compared to placebo-treated participants.
The most common side effects of Ocaliva are severe itching of the skin (pruritus), fatigue, abdominal pain and discomfort, joint pain (arthralgia), pain in the middle part of the throat (oropharyngeal), dizziness and constipation. Ocaliva should not be used in patients with complete biliary obstruction.
There is one other approved treatment for PBC, UDCA, which was approved by the FDA in 1997. UDCA is effective in more than 50 percent of patients, but up to 40 percent of patients do not achieve an adequate reduction in blood chemistries (e.g., ALP and/or total bilirubin) with UDCA, while 5-10 percent are unable to tolerate UDCA.
The FDA granted Ocaliva fast track designation, a process designed to facilitate the development, and expedite the review of drugs that are intended to treat serious conditions and that demonstrate the potential to address an unmet medical need. The FDA also granted Ocaliva an orphan drug designation.Orphan drug designationprovides incentives such as tax credits, user fee waivers and eligibility for orphan drug exclusivity to assist and encourage the development of drugs for rare diseases.
Ocaliva was approved under the agency's accelerated approval program, which allows the approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients. This program provides earlier patient access to promising new drugs while the company conducts confirmatory clinical trials.
An improvement in survival, progression to cirrhosis, or other disease-related symptoms in patients being treated with Ocaliva has not yet been established, although a confirmatory trial is currently ongoing.