Sir, The Food and Drug Administration (FDA), on 28 December 2012, granted accelerated approval to SIRTURO™ (bedaquiline) Tablets as a part of combination therapy in adults with multi-drug-resistant TB (MDR-TB).[1] It is the first new anti-TB drug to be approved after 1998 (rifapentine was approved in 1998) and the first anti-TB drug with a novel mechanism of action to be approved after 40 years (rifampicin was approved in 1974).[2] It is also the first to be introduced specifically for the treatment of MDR-TB in combination with other drugs.[1] MDR-TB is an infection with a strain of Mycobacterium tuberculosis that is resistant to isoniazid and rifampin, the two most potent first-line anti-TB drugs. MDR-TB has emerged as a serious health threat globally. It affected nearly 630,000 people in 2011, and incidence is increasing in many parts of the world. Unlike Drug-sensitive TB (DS-TB), the treatment of MDR-TB is more complex, requires intense chemotherapy, extensive monitoring and is considerably costly. Use of existing less efficacious second-line drugs is associated with greater side-effects.[3] Bedaquiline, a diarylquinoline, binds to subunit c of mycobacterial ATP synthase (an enzyme essential for the energy production in M. tuberculosis) and inhibits its activity.[4] It is highly selective for mycobacterial ATP synthase enzyme compared to homologous eukaryotic enzyme (Selectivity Index >20 000). Thus, it is less likely to produce target-based toxicity in the host cells.[5] Due to an entirely new mechanism of action, bedaquiline belongs to a novel class of anti-TB compounds. The distinct target and unique mode of action of bedaquiline reduces the potential for cross-resistance with the existing anti-TB drugs. It is active against DS, MDR, Pre-XDR, and XDR strains of M. tuberculosis in vitro.[6] Bedaquiline is available as 100 mg tablet for oral administration. Its bioavailability is enhanced in presence of food. It is highly plasma protein bound (>99%) and shows tri-exponential decline in plasma concentration with effective half-life of approximately 24-30 hours and terminal half-life (t1/2, term) of approximately 4-5 months. It is metabolized by CYP3A4 to N-monodesmethyl metabolite, which is 4-6 times less potent than the parent drug. Enzyme inducers can reduce the efficacy of bedaquiline, whereas enzyme inhibitors can predispose to its adverse reactions. It is eliminated mainly in feces.[7] Bedaquiline should be administered as directly observed therapy (DOT) along with standard MDR-TB regimen. Recommended dose is 400 mg once daily for 2 weeks followed by 200 mg thrice weekly for 22 weeks. After 24 weeks of bedaquiline therapy, MDR-TB regimen should be continued as per national TB treatment guidelines.[7] The most common side-effects reported with bedaquiline therapy are nausea (30%), arthralgia (26%), headache (22%), hemoptysis (14%), chest pain (9%), anorexia (7%), and rash (6%). Important cardiovascular adverse effect is QT prolongation. Concurrent use of other QT-prolonging drugs causes additive QT prolongation. Other important adverse effect is elevation of hepatic transaminases, which is moderate and reversible on discontinuation of therapy.[7] There are no clinical data in pediatric patients, adolescents (<18 yrs), and pregnant and lactating women. The safety and efficacy of bedaquiline for treatment of drug-sensitive TB, extra-pulmonary TB, and HIV-infected patients is not established. Therefore, use of bedaquiline is not recommended in these settings.[7] What Is an Accelerated Approval? The accelerated approval program allows FDA to approve a drug for treatment of a serious or life-threatening disease on the basis of clinical data establishing the effect of drug on surrogate endpoints that reasonably predict clinical benefit. Thus, patients get earlier access to promising new drugs. However, the company has to conduct further clinical studies to verify efficacy and safety of the drug to get traditional approval from FDA.[8] The accelerated approval to bedaquiline is based on its effect on surrogate endpoint of time to sputum culture conversion in two phase II clinical trials (C208 and C209). C208 was a randomized, double-blind, placebo-controlled trial with two consecutive but separate stages (stage 1 and 2). In this trial, subjects with sputum smear-positive MDR-TB were assigned to either bedaquiline or placebo along with background regimen of other anti-TB drugs. The primary endpoint of this study was time to sputum culture conversion (SCC) defined as time required for two consecutive negative sputum cultures after start of therapy. The secondary endpoint was culture conversion rate at 24 weeks. Results of C208 demonstrated a median time of 83 days for SCC with bedaquiline combination therapy compared to 125 days in placebo combination therapy. Culture conversion rate at the end of 24 weeks was 79 percent in bedaquiline treatment group compared to 58 percent in the placebo treatment group. In an open label C 209 study, which is still ongoing, sputum smear-positive subjects with MDR-TB received bedaquiline with background regimen of anti-TB drugs (no placebo group). Primary and secondary endpoints were same as previous study. In C209 trial, the median time to SCC was 57 days and a culture conversion rate was 80 percent further supporting the efficacy findings.[9] Phase III trial of bedaquiline is planned to confirm the efficacy findings from previous phase II clinical trials and to obtain additional safety data. Bedaquiline will get traditional FDA approval if results of phase III trial confirm that the drug actually provides clinical benefit.[9] FDA speculates that bedaquiline has the potential to fulfill an unmet medical need for the treatment of MDR-TB and will reduce the risk of development of resistance to other anti-TB drugs in the standard regimen.
