Bedaquiline Approved for Multidrug-resistant Tuberculosis after Long Wait


The U.S. Food and Drug Administration last week approved bedaquiline (brand name Sirturo, formerly TMC207) as part of a combination regimen for adults with multidrug-resistant pulmonary tuberculosis (TB) -- the first approval of a new TB drug in more than 40 years.

According to the Centers for Disease Control and Prevention (CDC), nearly 9 million people worldwide and more than 10,500 people in the U.S. became ill with TB in 2011. Globally, TB is the leading killer of people with HIV, and MDR-TB -- resistant to both isoniazid and rifampin -- is a growing problem. Bedaquiline is the first drug ever approved specifically for MDR-TB.

"Multi-drug resistant tuberculosis poses a serious health threat throughout the world, and Sirturo provides much-needed treatment for patients who have don’t have other therapeutic options available," said Edward Cox, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research. "However, because the drug also carries some significant risks, doctors should make sure they use it appropriately and only in patients who don’t have other treatment options."

In late November the FDA's Anti-Infective Drugs Advisory Committee unanimously voted in favor of the drug's efficacy in treating MDR-TB, but opinions about its safety were mixed. Last week's decision was made under the accelerated approval process, which allows the FDA to approve drugs to treat serious diseases based on surrogate endpoints that are reasonably likely to predict a clinical benefit -- like CD4 T-cell count for people with HIV. Because it meets an unmet medical need and treats an uncommon type of TB, it also received fast-track designation, priority review, and orphan drug status.

Bedaquiline is a diarylquinolineclass drug that works by a novel mechanism -- interfering with a Mycobacterium tuberculosis enzyme that generates energy -- enabling it to remain active against bacteria that have developed resistance to existing TB drugs.

In a pair of Phase 2 clinical trials that together enrolled more than 400 patients, bedaquiline used as part of a combination regimen with existing drugs cleared TB bacteria from sputum cultures (known as conversion) faster than placebo plus existing drugs. In the larger trial 78% of patients in the bedaquiline arm experienced sputum conversion by week 24, which occurred in a median of 83 days, compared with 58% and 125 days for the placebo group.

The most common adverse side effects associated with bedaquiline were nausea, joint pain, and headache. Adverse events occurred more often among participants receiving bedaquiline compared with placebo in these studies; of note, 9 patients who received bedaquiline died, compared with 2 people taking placebo (11% vs 3%, respectively).

While many adverse events and deaths were due to TB itself, it is unclear whether the study drug might also have been a contributing factor. Reviewersasked for more data about whether bedaquiline causes liver or heart toxicity. A Phase 3 trial scheduled to start this year will gather further safety data. More information is also needed about how well bedaquiline works for people with HIV.

The drug's label will carry a "Boxed Warning" alerting patients and clinicians that bedaquiline can affect cardiac electrical activity, causing an abnormal ECG pattern known as QT prolongation, and was associated with increased risk of death in clinical trials.

Developer Janssen Therapeuticswill distribute bedaquiline from a single source through public health agencies in order to limit its use to appropriate patients, and will provide educational materials to help ensure the drug is used correctly.

The consumer advocacy group Public Citizen had asked the FDA to decline approval due to the increased risk of death among people taking bedaquiline.

But the Treatment Action Group (TAG) -- which started as an HIV/AIDS treatment advocacy group -- praised the quick approval.

"By granting accelerated approval of bedaquiline, the FDA has sent a clear signal that there is hope for people with MDR-TB, and that fighting TB is a priority," said TAG executive director Mark Harrington. "Over one million people need new TB drugs this year, and the FDA’s approval shows that there is a clear regulatory pathway for approving new TB treatments and regimens. In order for bedaquiline to continue to be effective, and lives to be saved, we will need new, safer, better companion drugs. This historic occasion must mark a new beginning for TB drug development."



U.S. Food and Drug Administration. FDA Approves First Drug to Treat Multi-Drug Resistant Tuberculosis. Press release. December 28, 2012.

Janssen Therapeutics. FDA Grants Accelerated Approval for SIRTURO (bedaquiline) as Part of Combination Therapy to Treat Adults with Pulmonary Multi-Drug Resistant Tuberculosis. Press release. December 31, 2012.

Treatment Action Group. Treatment Action Group Lauds FDA Approval of First New Tuberculosis Drug in Half a Century. Press release. December 31, 2012.

Public Citizen. Public Citizen Urges FDA to Reject Accelerated Approval for Possibly Dangerous Anti-TB Drug Bedaquiline. Press release. December 21, 2012.