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.