The FDA has granted accelerated approval to bedaquiline (Sirturo, Janssen Therapeutics), despite safety concerns, to be used as part of combination therapy to treat adults with multidrug resistant pulmonary tuberculosis (MDR-TB) when other alternatives are not available.

Earlier this week, the consumer watch group Public Citizen urged the FDA not to approve the bedaquiline for this indication due to concerns about higher mortality associated with the drug.

In a letter to Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research the group pointed out that results from a phase II, randomized trial of bedaquiline showed a mortality rate five times higher in patients taking the drug plus a standard regimen compared with those taking the standard regimen with a placebo.

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The accelerated approval is based on data from TMC207-C208 Study 1 and Study 2. The primary endpoint was time to sputum culture conversion, defined as the interval in days between the first dose of study drug and the date of the first of two consecutive negative sputum cultures collected at least 25 days apart during treatment.

In the first stage of the 8-week C208 trial, more than 47% of 21 patients receiving bedaquiline met the study’s endpoint of acceptable sputum culture conversion compared with just over 8% on placebo (P=0.004). That significance remained for nearly 2 years, the FDA said.

In the ongoing second stage of the C208 trial, 81% of bedaquiline patients had acceptable cultures compared with 65% of patients on placebo (P=0.293) after 24 weeks.

Bedaquiline is an immediate-release tablet taken orally. The drug is taken at 400 mg once a day for 3 weeks followed by 22 weeks of 200 mg three times a week.

Common side effects identified in the clinical trials include nausea, joint pain and headache. The drug will carry a Boxed Warning about the potential risk for QT prolongation, which could lead to an abnormal and potentially fatal heart rhythm and also notes deaths in patients treated with bedaquiline.

Nine patients treated with bedaquiline died compared with two patients who received placebo. Five of the deaths in the dedaquiline group and all of the deaths in the placebo arm seemed to be related to tuberculosis, but no consistent reason for the deaths in the remaining bedaquiline-treated patients could be identified.

Bedaquiline is a diarylquinolone antimycobacterial drug that inhibits mycobacterial ATP synthase, an enzyme essential for the generation of energy in Mycobacterium tuberculosis.

TB has grown resistant to first-line therapies including isoniazid and rifampin, and the second-line drug classes aminoglycoside and fluoroquinolone. Bedaquiline is the first TB drug approved with a new mechanism in 40 years.