Clinical Context

Infection with Mycobacterium tuberculosis causes tuberculosis (TB), which is responsible for significant morbidity and mortality worldwide. Transmission is airborne, and the infection primarily affects the lungs, but additional organs, such as the brain and kidneys, may also be involved. The US Centers for Disease Control and Prevention estimate that the incidence of TB in 2011 was 10,528 in the United States and nearly 9 million globally.

Multidrug-resistant TB (MDR-TB) refers to infection with M tuberculosis resistant to isoniazid and rifampin. Bedaquiline is the first new TB drug since rifampin was introduced in 1970 and the first drug approved to treat MDR-TB. Its mechanism of action is to inhibit an enzyme needed by M tuberculosis to replicate and spread throughout the body.

Study Synopsis and Perspective

As of late last year, bedaquiline (Sirturo) became the first drug approved by the US Food and Drug Administration (FDA) for use as part of a combination treatment regimen for MDR-TB when other agents are not available. By definition, MDR-TB is resistant to isoniazid and rifampin. A boxed warning notes the risks for QT prolongation and death.

The FDA's accelerated approval was based on phase 2 efficacy and safety data, because there are currently few therapeutic options in MDR-TB, and there is still an unmet need for new drugs. In addition to accelerated approval, the FDA also granted bedaquiline fast-track designation, priority review, and orphan-product designation. Accelerated approval allows patients earlier access to promising new drugs while additional safety and efficacy studies are underway.

Although the FDA advisory panel deciding on approval voted unanimously (18 to 0) regarding the efficacy of bedaquiline, the vote was split 11 to 7 regarding safety. The FDA is therefore requiring drug maker to perform a confirmatory phase 3 trial as a condition of submission under accelerated approval.

Two phase 2 studies, enrolling a total of 440 patients, were the basis for accelerated FDA approval. The outcome measure for efficacy was sputum culture conversion (SCC) rather than clinical cure rate. There was a significant, 33% faster SCC within 24 weeks with bedaquiline vs placebo in one of these studies, with median time to SCC of 83 days vs 125 days. In the ongoing, open-label trial, median time to SCC was 57 days. More than three quarters (79%) of patients receiving bedaquiline in both trials had SCC by 24 weeks.

Dosage and Administration

Bedaquiline is supplied as 100-mg tablets, to be swallowed whole with water and ingested with food. Initial dosage is 400 mg once daily for 2 weeks, followed by 200 mg 3 times per week for 22 weeks.

Boxed Warning

The FDA has required a boxed warning on the bedaquiline label regarding increased risks for QT interval prolongation and deaths occurring in patients treated with the drug. The percentage of patients who died was statistically significantly higher in the bedaquiline group (12.7%) vs the placebo group (2.5%). However, at least half of the deaths were thought to be caused by the underlying TB.

Warnings and Precautions

Because QT prolongation may occur, patients taking bedaquiline should undergo frequent electrocardiographic monitoring, particularly if they are taking other drugs linked to QT prolongation. The drug should be discontinued in patients in whom a significant ventricular arrhythmia or a QTcF interval of more than 500 milliseconds develops.

Another safety concern with bedaquiline is hepatotoxicity, so liver function tests should be monitored.

Patients who do not adhere to the treatment regimen may have treatment failure or development of drug resistance.

Adverse effects commonly reported in the clinical trials were nausea, joint pain, and headache.

More information about the bedaquiline approval is available in the FDA announcement, and the prescribing information is posted on the FDA Web site.

Clinical Implications

• The FDA has approved bedaquiline as part of a combination treatment regimen for MDR-TB when other agents are unavailable. Because of the unmet need for drugs to treat MDR-TB, the FDA approved bedaquiline under its accelerated approval program. This was based on phase 2 efficacy and safety data using a surrogate study endpoint of SCC rather than clinical cure, and the FDA is now requiring the drug maker to perform a confirmatory phase 3 trial.
• In a placebo-controlled phase 2 study, bedaquiline was associated with a significant, 33% faster SCC within 24 weeks. In this placebo-controlled study and in an open-label phase 2 trial, approximately 79% of patients with MDR-TB receiving bedaquiline had a SCC by 24 weeks. An FDA advisory panel voted unanimously in support of the efficacy of bedaquiline.
• A boxed warning for bedaquiline notes that deaths have occurred in patients taking the drug and that it can cause QT interval prolongation. Hepatotoxicity is another safety concern. In the placebo-controlled phase 2 study, the number of deaths was statistically significantly greater with bedaquiline vs placebo.

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