Dec 31, 2012 (CIDRAP News) – The US Food and Drug Administration (FDA) today announced its approval of Sirturo (bedaquiline), the first drug developed specifically to treat multidrug-resistant tuberculosis (MDR-TB), saying it must be used in combination with other TB medications.
The drug, developed by Jannsen Therapeutics, Titusville, N.J., inhibits an enzyme that Mycobacterium tuberculosis uses to replicate and spread, the FDA said in a news release. Janssen officials said it is the first TB drug in 40 years that has a new mechanism of action.
MDR-TB strains are those that resist isoniazid and rifampin, the two drugs most commonly used to treat TB patients, the FDA noted.
"Multi-drug resistant tuberculosis poses a serious health threat throughout the world, and Sirturo provides much-needed treatment for patients who don't have other therapeutic options available," said Edward Cox, MD, MPH, in the FDA release. He is director of the Office of Antimicrobial Products in the FDA's Center for Drug Evaluation and Research.
But he warned that the drug carries significant risks, including heart arrhythmias, and therefore must be used carefully and limited to patients who lack other treatment options.
About 310,000 cases of MDR-TB were identified among reported pulmonary TB patients in 2011, according to the World Health Organization. In the United States, MDR-TB is considered an orphan disease, with 98 patients reported in 2011, according to a Janssen press release.
The FDA said it endorsed Sirturo under its accelerated approval program, which allows the agency to approve a drug on the basis of a demonstrated effect on a surrogate end point that is reasonably likely to predict a clinical benefit to patients. The program speeds the availability of new drugs while requiring companies to conduct more studies of their benefits and safety.
The FDA also granted Sirturo fast-track status, priority review, and orphan-product designation. The drug showed the potential to fill an unmet medical need, has the potential to provide safe and effective treatment where no other satisfactory therapy exists, and is intended to treat a rare disease, the agency said.
Sirturo's safety and effectiveness were established in two phase 2 clinical trials involving 440 patients, the FDA reported. The surrogate end point used in the studies was the time it took for patients' sputum to be clear of M tuberculosis (sputum culture conversion).
Patients in the first trial were randomly assigned to be treated either with Sirturo plus other TB drugs or with a placebo and other TB drugs. Patients in the Sirturo group had a median sputum conversion time of 83 days, versus 125 days for the placebo group.
In the second trial, which is ongoing, all patients received Sirturo plus other TB drugs. Results so far have shown a median time to sputum conversion of 57 days, supporting the efficacy findings of the first trial, the FDA said.
Common side effects identified in the clinical trials include nausea, joint pain, and headache, the agency noted.
The FDA and Janssen said Sirturo carries a boxed warning that the drug can affect the heart's electrical activity by prolonging the QT interval, which could lead to an abnormal and potentially fatal heart rhythm.
The warning also says that in the placebo-controlled trial, 9 of 79 patients (11.4%) in the treatment group died, compared with 2 of 81 (2.5%) in the placebo group.
"Five of the deaths in the Sirturo 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 Sirturo-treated patients could be identified," the FDA said.
The Janssen statement said Sirturo inhibits mycobacterial adenosine 5'-triphosphate, an essential enzyme for generating energy in M tuberculosis. The drug was discovered more than a decade ago, said Paul Stoffels, MD, chief scientific officer and worldwide pharmaceuticals chairman at Johnson & Johnson, Janssen's parent company.
Dec 31 FDA press release
Dec 31 Janssen press release
WHO TB information