Concise Review: Efficacy and Safety of Bedaquiline
Is bedaquiline needed for the treatment of MDR-TB?
The current MDR-TB regimens include very toxic drugs. Injectable drugs like kanamycin can cause
irreversible deafness. Moreover, for patients with MDR-TB that is also resistant to one or both of
two additional classes of drugs, fluoroquinolones and injectables (i.e. patients with (pre-)XDR-TB),
the standard MDR-TB regimens are largely ineffective. Thus, for patients with (pre-)XDR-TB and for
patients suffering from hearing loss, new medicines are urgently needed. Bedaquiline (BDQ) is the
first new drug to be approved for treating drug-resistant TB in more than 40 years. The drug has a
mechanism of action that does not exist in any other known (MDR-) TB drug: it works by blocking
the energy pump of the mycobacterial cell so that the bacteria cannot continue its normal functions.
The drug is in a family called the diarylquinolines.
Has bedaquiline been approved by official bodies?
The drug has been conditionally approved for the treatment of MDR-TB by stringent regulatory
agencies in the United States (FDA), Europe (EMA), and South Africa (CDA). In 2013, the World
Health Organization recommended the use of BDQ in the treatment of patients with MDR-TB,
provided it is used in programs that meet the following 5 criteria: 1) careful selection of patients; 2)
use in a combination regimen that is constructed according to WHO recommendations; 3) close
patient monitoring; 4) informed consent is signed by the patient; and 5) active pharmacovigilance
exists for monitoringi.
Should bedaquiline treatment be given under clinical trial or operational research
conditions?
There are multiple ongoing clinical trials to test the optimal way to use BDQ. BDQ was approved
based on phase IIb clinical trial data1, because options for the treatment of MDR-TB (which is
potentially lethal) are limited. Of note, most of the other drugs routinely used in the treatment of
MDR-TB have not even been tested in phase IIb clinical trials but their use is instead based on
expert opinion. BDQ has been approved by stringent medical authorities and has been
recommended by the World Health Organization for the treatment of MDR-TBii. Given these
approvals and recommendations, BDQ use can begin in earnest as part of routine programmatic
treatment of MDR-TB outside of clinical trials. Under program implementation, BDQ is
recommended to be given as part of routine patient care in selected populations. National TB
Programs will follow WHO guidance to determine which patients will be treated with BDQ, and
there is no control or placebo group in this setting. Countries may plan to start using BDQ in a
small group of patients, gain experience, and then plan to scale-up to a larger group. The WHO is
not carrying out a research study on BDQ, and based on data presented to them, feels that it is
reasonable to give BDQ to selected groups of patients as part of routine patient care. Clinical trials
of BDQ are not required in multiple settings and may be both difficult and expensive to carry out
while at the same time delaying access to therapy for those in need.
Does use of bedaquiline result in better treatment outcomes than the current MDR-TB
regimens?
The data on the efficacy of BDQ comes from clinical trials and some so-called compassionate use
programs, which provide the drug to patients who really need it under strict conditions. Data are
available from South Africa (160 newly diagnosed pulmonary MDR-TB patients in a phase IIb trialv,
151 patients in a compassionate use programiii), and France (35 patients in a compassionate use
programiv). In summary, especially among (pre-)XDR TB patients, culture conversion was achieved
sooner and more patients were cured (see Table below).
Phase I trials tend to focus on short-term studies to identify doses and safety, usually in health individuals.
Phase II trials assess the drug in the population of interest in both smaller (phase IIa) and moderate size
(phase IIb) studies. Phase III trials are usually done to refine dosing and safety issues in hundreds of
individuals.
1
Is the use of bedaquiline safe for the patients?
In the majority of patients receiving bedaqiline in both phase I and phase II trials, the drug has
been reasonably well tolerated. The most common adverse events seen were headache, dizziness
and nausea. From the two compassionate use programs listed below, no clinical cardiac events
were noted, and the majority of patients tolerated BDQ well.
Table. Summary of efficacy and safety data available from phase IIb clinical trial and
compassionate use programs.
Description
Phase IIb trialv
Compassionate use
Compassionate
programiii
use programiv
Study?
Patients
Clinical trial –patients
received bedaquiline or
placebo (both with
optimized background
regimen)
160 newly diagnosed
pulmonary MDR-TB
patients
No; programmatic use
No; programmatic
use
151 patients; 58 patients
with treatment outcome
data; 91 patients with
safety data
South Africa
35 patients;
interim analysis at
6 months of
treatment
France
Country
South Africa
% of patients
with (pre-)XDR
TB
28% with pre-XDR TB
36% with XDR-TB; 63%
pre-XDR-TB
54% XDR-TB; 40%
pre-XDR-TB
% of patients
with HIV coinfection
8% vs. 21% in placebo
arm
60%
0%
% of patients on
relevant
companion drugs
None (all received
optimized background
regimen)
75% clofazimine
70% linezolid
84% levofloxacin
94% linezolid
74% PAS
14% clofazimine
Median time to
culture
conversion
Median 83 days vs. 125
days (p<0.001)
Not reported
Median 85 days
Treatment
outcome
Cured: 58% of patients on
BDQ vs. 32% of patients
on placebo (p=0.003)
9/79 (11%) in BDQ group
vs. 2/81 (3%) in placebo
groupv; all but 1 death
(during BDQ treatment
probably unrelated to BDQ
QTc: 5-10 msec increase
compared to control group
Cured (culture negative at
end of treatment): 83%
not available
n=3 (1 during BDQ
treatment; all not related
to BDQ)
N= 1 death,
unrelated to BDQ
or TB treatment
QTc: median 8ms
increase; 14
patients >40ms increase;
2 patients >500 ms (1
had BDQ temporarily
stopped and 1 had
spontaneous resolution in
24 hrs)
1 patient developed atrial
fibrillation on BDQ: BDQ
withdrawn
3 reports of
psychosis/mood
disorder/delusion; not
related to BDQ
QTc: median 2ms
increase; 7
patients (20%)
≥60-ms increase:
BDQ
discontinuation in
2 (6%) cases
Death
Cardiac events
Other adverse
events of
relevance
Pancreatitis (1 patient on
BDQ), spontaneous
abortion (1 patient on
placebo); other AEs similar
between the two groups.
2 patients with
severe liver
enzyme elevation
occurred in 2
patients (6%)
Conclusion
The WHO has recommended that BDQ be used in the management of patients with MDR-TB as part
of programmatic management of MDR-TB with special selection and monitoring conditions.
Although clinical trials of the drug are ongoing, there are sufficient data on safety and efficacy of
the drug to warrant its immediate use in patient care. Data from two cohorts of patients using
BDQ under field conditions show that programs can use the drug in a way that improves patient
outcomes with minimal risks. Ongoing work is needed to understand the optimal conditions for
BDQ use in a variety of settings, but it should be used to treat high-risk patients as part of
programmatic management of MDR-TB.
World Health Organization. The use of bedaquiline in the treatment of multidrug-resistant
tuberculosis, Interim policy guidance, Geneva, World Health Organization. 2013; Available from:
http://apps.who.int/iris/bitstream/10665/84879/1/9789241505482_eng.pdf.
i
World Health Organization. The use of bedaquiline in the treatment of multidrug-resistant
tuberculosis, Interim policy guidance, Geneva, World Health Organization. 2013; Available from:
http://apps.who.int/iris/bitstream/10665/84879/1/9789241505482_eng.pdf
ii
Ndjeka, N., et al. Access to bedaquiline and interim outcomes for patients within the DR-TB
Expanded Access Program in South Africa. 45th Union World Conference on Lung Health, October
31, 2014.
iii
Guglielmetti, L. et al. Compassionate use of bedaquiline for the treatment of multidrug-resistant
and extensively drug-resistant tuberculosis: interim analysis of a French cohort. Clin Inf Dis,
published ahead of print November 8, 2014
iv
Diacon, A. et al. 2012. Randomized Pilot Trial of Eight Weeks of Bedaquiline (TMC207) Treatment
for Multidrug-Resistant Tuberculosis: Long-Term Outcome, Tolerability, and Effect on Emergence of
Drug Resistance. Antimicrob. Agents Chemother. 56:3271-3276. doi: 10.1128/AAC.06126-11.
v