Bedaquiline is a diarylquinoline that inhibits mycobacterial ATP synthase, and was recently licensed in the UK for use as part of an appropriate combination regimen for pulmonary multidrug-resistant tuberculosis (MDR-TB) in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability.
The unexpected finding of a mortality imbalance in the study (10 vs. 2 deaths) is an important concern; however, the length of time between the last receipt of bedaquiline and death makes it difficult to discern a mechanism by which bedaquiline could be directly related to the deaths, even taking into account its long half-life. Nonetheless, the product label does convey the seriousness of the mortality finding and the licence restricts its use to patients with MDR-TB for whom an effective treatment regimen cannot be constructed without including bedaquiline. Regulatory approvals were based on the judgement that the benefits of bedaquiline outweigh the risks, as previously cited historical data show that outcomes are very poor in patients who do not receive adequate treatment. It is hoped that the confirmatory trial required as part of the accelerated approval of bedaquiline will bring further clarity to the observed mortality finding. Non-surrogate end points such as patient survival, clinical resolution of TB, and rate of relapse will be included in the confirmatory trial.