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Abstract
Bedaquiline is a much-needed novel drug which is highly effective against drug-resistant tuberculosis. While its clinical development has been laudably fast-tracked and the drug is now available for inclusion into treatment regimens when no suitable alternatives exist, clinical experience with bedaquiline is still limited. Phase III trial data and Phase IV studies are needed particularly to study different patient populations and to optimize treatment regimens. Drug resistance to bedaquiline needs to be monitored carefully, and full access to bedaquiline treatment where it is appropriate and needed must be promoted.
Financial & competing interests disclosure
MP Grobusch served as South African PI on the TMC207-C208 and C209 trials and is a member of the Bedaquiline Advisory Board to Janssen Pharmaceuticals. S Bélard is a participant in the Charité Clinical Scientist Program funded by the Charité – Universitätsmedizin Berlin and the Berlin Institute of Health. S Janssen is partially funded through a Marie Curie People grant. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Bedaquiline belongs to a new class of antituberculous drugs (diarylquinolines) and has received fast-track approval for the treatment of multidrug-resistant tuberculosis (MDR-TB) by the US FDA in 2012.
Bedaquiline inhibits the mycobacterial ATP synthase; its activity against drug-sensitive and drug-resistant TB has been demonstrated in pre-clinical studies.
Eleven Phase I trials provided understanding on pharmacokinetic characteristics, drug–drug interactions (with antiretrovirals, rifamycins and fluoroquinolones) and safety.
Four Phase II trials evaluating early bactericidal activity in drug-sensitive pulmonary TB patients showed significant bactericidal activity from day 4 onward and a significant linear trend for dose.
Bedaquiline added for 8 weeks to a background regimen for the treatment of pulmonary MDR-TB significantly reduced the time to sputum culture conversion, increased the proportion of patients with sputum culture conversion at 8 weeks (48 vs 9%) and reduced the risk for acquired resistance to companion drugs.
Bedaquiline added for 24 weeks to a background regimen for the treatment of pulmonary MDR-TB reduced the time to culture conversion from 125 to 83 days and increased the rate of culture conversion at 24 weeks (79 vs 58%) and 120 weeks (62 vs 44%).
In the Phase II Stage II trial, mortality was higher in the bedaquiline arm with none of the deaths having been related to bedaquiline.
Despite FDA approval, Phase III trials are needed to expand our knowledge on the efficacy and safety of bedaquiline with particular attention to mortality.
Following FDA approval, the WHO Interim Policy Guidance on Bedaquiline specifies that bedaquiline may be used as part of an MDR-TB treatment regimen when an effective MDR-TB regimen cannot otherwise be provided.
Bedaquiline has been made available through regulated compassionate use/early access programs, and the first reports confirm high efficacy of bedaquiline for drug-resistance TB.
