The US Food and Drug Administration (FDA) approved bedaquiline today as part of the treatment regimen for multidrug-resistant tuberculosis (MDR-TB) when other agents are unavailable.
Bedaquiline, to be sold under the brand name Sirturo by Janssen Therapeutics, a division of Janssen Products LP, was approved under the FDA's accelerated approval program on the basis of phase 2 efficacy and safety data that used the surrogate study endpoint of sputum culture conversion rather than clinical cure. The FDA had allowed the company to move forward with the phase 2 data to support its new drug application for accelerated approval because of the unmet need. However, as a condition of submission under accelerated approval, the company is obligated to conduct a confirmatory phase 3 trial.
Bedaquiline is the first new TB drug since the introduction of rifampin in 1970.
"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," Edward Cox, MD, MPH, director of the Office of Antimicrobial Products in the FDA's Center for Drug Evaluation and Research, said in an FDA news release. "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."
Bedaquiline works via a novel mechanism of action — inhibition of a mycobacterial enzyme that is essential to the bacteria's action — and will be indicated as part of combination therapy for the treatment of pulmonary TB caused by MDR Mycobacterium tuberculosis in adults, to be administered under directly observed therapy.
The approval comes after an FDA advisory panel endorsed the efficacy of the drug at a hearing on November 28, 2012, although many panel members had expressed safety concerns. The vote was unanimous (18 to 0) in supporting bedaquiline's efficacy, but the panel had split 11 to 7 on safety in support of accelerated approval.
Janssen had presented data from 2 studies involving a total of 440 patients with MDR-TB, defined as TB that is resistant to at least rifampin and isoniazid. In a study that was placebo-controlled, bedaquiline resulted in a significant 33% faster culture conversion within 24 weeks, with approximately 79% of those taking bedaquiline converting at 24 weeks in both the placebo-controlled and an open-label trial.
Safety concerns reported by both Janssen and the FDA included signals for increased risks for QT interval prolongation, hepatotoxicity, and a greater number of deaths in the bedaquiline group compared with in the placebo group. The number of deaths was small, and at least half were deemed to be related to the TB itself, but the difference between bedaquiline and placebo (12.7% vs 2.5%) was statistically significant.
The drug will carry a boxed warning alerting patients and healthcare professionals that it can affect QT prolongation. The warning also notes deaths in patients treated with bedaquiline.
At the advisory committee hearing, Fred Gordin, MD, chief of infectious diseases at the Veterans Affairs Medical Center, Washington, DC, who voted yes on the efficacy but no on the safety of bedaquiline, had said he still supported the drug's approval "with the caveat that we need much more safety data.... There's clearly a role for this drug, but in many patients who have other options, I think it has to be very clear to providers that there are long-term safety issues."
Janssen's phase 3 trial is planned for 2013. It is designed as a double-blind study comparing 9 months of treatment with bedaquiline with treatment with placebo, both with a background regimen.