bed aquiline

88 J Rational Pharmacother Res Vol. 1 No.2,April - June 2013

J Rational Pharmacother Res An Official Publication of ISRPT

R E V IE W A RT IC L E

From the Deptt. of Pharmacology, Govt Medical College Jammu, J&K -IndiaCorrespondence to : Dr Brij Mohan Gupta, Associate Prof. of Pharmacology, Department of Pharmacology.Govt.MedicalCollege, Jammu, J&K- IndiaE mail: [email protected]

Bedaquiline, First Drug Approved To Treat MDR-TBApeksha Gupta, Brij Mohan Gupta, Rohani Gupta

Infection with Mycobacterium tuberculosis causestuberculosis (TB), which is responsible for significantmorbidity and mortality worldwide. Transmission isairborne, and the infection primarily affects the lungs,but additional organs, such as the brain and kidneys, mayalso be involved. The US Centers for Disease Controland Prevention estimate that the incidence of TB in 2011was nearly 9 million globally.

Multidrug-resistant (MDR) tuberculosis (TB) is aserious form of TB and the term MDR implies resistanceto at least the essential first-line agents isoniazid (INH)and rifampin (RMP); because INH and RMP are nolonger effective, patients with MDR pulmonary TB mustbe treated for at least 20 months with potentially toxic,less efficacious drugs. [1] MDR Mycobacterium

tuberculosis isolates will frequently also be resistant tothe other first-line drugs pyrazinamide (PZA), ethambutol(EMB), or streptomycin (SM) and, at times, other drugssuch as ethionamide (Eth), a fluoroquinolone, or injectabledrugs such as kanamycin (KAN), amikacin, orcapreomycin (CAP). MDR TB with additional resistanceto the last two mentioned classes is termed extensivelydrug-resistant (XDR). The spread of MDR TB,particularly among communities with a high prevalenceof human immunodeficiency virus (HIV) infection, isthreatening the foundations of TB control programsworldwide.[2] TMC207, recently renamed bedaquiline, isa diarylquinoline with a novel mode of action specificallyinhibiting mycobacterial ATP synthase.[3]

Bedaquiline (trade name Sirturo, code names TMC207

AbstractMultidrug-resistant (MDR) tuberculosis (TB) is a serious form of TB and the term MDR implies resistanceto at least the essential first-line agents. TMC207, recently renamed bedaquiline, is a diarylquinoline with anovel mode of action specifically inhibiting mycobacterial ATP synthase. It is specifically approved to treatmulti-drug-resistant tuberculosis. The current review discus the potential efficacy and safety aspect of thisdrug in treatment of MDR TB.

Key WordsMultidrug-resistant (MDR) tuberculosis, Bedaquiline, Diarylquinoline

Received- 14.2.13 Revised -23.3.13 Accepted-15.4.13

Introduction

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and R207910) anti-tuberculosis drug was discovered bya team led by Koen Andries at Janssen Pharmaceutica.[4]

It is the first new medicine to fight TB in more than fortyyears and is specifically approved to treat multi-drug-resistant tuberculosis.[5] Bedaquiline affects the protonpump for ATP synthase. This mechanism is unlike that ofthe quinolones, whose target is DNA gyrase. [6]

Bedaquiline was described for the first time in 2004 atthe Interscience Conference on Antimicrobial Agents andChemotherapy (ICAAC) meeting, after the drug had beenin development for over seven years.[7] It is manufacturedby Johnson & Johnson (J&J), who sought acceleratedapproval of the drug, a type of temporary approval fordiseases lacking other viable treatment options.[8] It wasformally approved for use by the US Food and DrugAdministration (FDA) for use in tuberculosis (TB)treatment, as part of a fast-track approval for use only incases of multi-drug-resistant tuberculosis, and the moreresistant extensively drug resistant tuberculosis.

The emergence of drug-resistance is a major threat toglobal tuberculosis (TB) care and control. WHO estimatesthat around 310,000 multidrug-resistant tuberculosis(MDR-TB) cases (i.e. resistant to at least rifampicin andisoniazid) occurred among notified TB patients in 2011.Of these, only 19% were reported to WHO, largely as aresult of critical gaps in diagnostic and treatment capacityin most countries. Furthermore, 85 countries have nowreported at least one case of extensively drug-resistanttuberculosis (XDR-TB), a form of TB which is resistantto at least four of the core anti-TB drugs, (rifampicin,isoniazid, fluoroquinolones and second-line injectableagents), and associated with high mortality, particularlyamong HIV-infected persons.[9]

One of the first published trials of bedaquiline was aPhase II trial of 47 patients, which showed that the drugwas effective in reducing the time to TB-free sputumcultures.[10]

WHO Expert Group Meeting Report (2013)[11] atGeneva elucidated the following studies and trialsconducted by the drug developer:

A total of 265 subjects participated in II Phase I trialswith bedaquiline (208 subjects were enrolled in 8 single-dose trials evaluating bedaquiline doses up to 800 mg;and 57 subjects were enrolled in 3 multiple-dose trialsevaluating bedaquiline doses up to 400 mg daily with amaximum treatment duration of 15 days). The Phase Itrials provided a basic understanding of bedaquiline'spharmacokinetic characteristics, drug-drug interaction(DDI) potential, and short term safety/tolerability inhealthy subjects and in a special population (moderatelyhepatic-impaired subjects, trial C112). A double-blind,single-dose trial (TBC1003) was conducted to evaluatethe effect of a single supra-therapeutic (800 mg) dose ofbedaquiline on the corrected QT interval (QTc).

A Phase IIa 7-day extended early bactericidal activitytrial (C202) in 75 patients with drug susceptible TB(evaluating doses up to 400 mg bedaquiline daily) wasconducted to evaluate the antimycobacterial activity ofbedaquiline.

Main findings on efficacy and safety originated fromtwo Phase IIb trials: C208, a two-stage trial of whichStage 1 was an exploratory study, and Stage 2 was amulti-centre, stratified, randomised, double-blind placebo-controlled trial serving as a pivotal proof-of-efficacy study,and C209, a single-arm, open label trial are summarisedas follows:Evidence for the efficacy of bedaquiline in thetreatment of MDR-TB

Subjects aged 18 to 65 years with newly diagnosedMDR-TB were enrolled in the C208 Stage 2 efficacytrial from 15 sites in India, Russia, Latvia, Peru, Brazil,Thailand, the Philippines and South Africa; 160 subjectswere randomized to receive bedaquiline or placebo ontop of a standardised 5-drug MDR-TB backgroundregimen (BR), that consisted of various combinations offluoroquinolones, aminoglycosides, pyrazinamide,ethionamide, ethambutol, and/or cycloserine/terizidone.Bedaquiline was given at 400 mg daily for the first 2weeks, followed by 200 mg three times per week for theremaining 22 weeks. After 24 weeks, subjects continued

90 J Rational Pharmacother Res Vol. 1 No.2,April - June 2013


the BR of MDR-TB therapy until a total treatmentduration of 96 weeks was achieved. The total studyduration was 120 weeks (24+96).

The primary efficacy endpoint was time to sputumculture conversion in commercial liquid culture (MGIT™960 Mycobacterial Detection System, Becton Dickinson(BD) Diagnostic systems, USA) during the 24-weekinvestigational treatment period (subjects whodiscontinued before week 24 were considered as nothaving culture converted). The analysis was conductedon a "modified" intention to treat population (mITT) of132 subjects (66 in each of the bedaquiline and placebogroups. Subjects who had drug-sensitive TB, XDR- orunconfirmed MDR-TB (based on susceptibility tests takenprior to randomization), or had missing or negative baselinecultures, or who were positive at baseline, but had nopost-baseline culture results, were excluded from the ITT

The median time to culture conversion was 83 days

(95%CI: 56, 97) in the bedaquiline group vs. 125 days

(95% CI: 98, 168) in the placebo group. Using Cox

proportional hazards model (adjusted for lung cavitation

and pooled centre) there was a higher chance of faster

culture conversion in the bedaquiline vs. placebo arm

(HR=2.44 [1.57, 3.80], p<0.0001). The proportion of

subjects with culture conversion at Week 24 (secondary

efficacy endpoint) was 78.8% in the bedaquiline group

vs. 57.6% in the placebo group (p=0.008). The percentage

of responders at Week 72 (i.e. the time point attained by

all Stage 2 subjects at the interim analysis) was 71.2% in

the bedaquiline group vs. 56.1% in the placebo group

(p=0.069). Utilizing all available efficacy data up to end

of study (Week 120), the percentage was 62.1% in the

bedaquiline group vs. 43.9% in the placebo group

(p=0.035). Efficacy was further evaluated using WHO-

recommended treatment outcome definitions applied to

Week 120 final data. The proportion of subjects defined

as cured at 120 weeks was 57.6 % in the bedaquiline

arm vs. 31.8 in the placebo arm (p=0.003).

Evidence for the safety of bedaquiline in the treatmentof MDR-TB

Information was available from pooled data from C208Stage 1 and Stage 2 trials, with 102 subjects in the "Anybedaquiline" group and 105 subjects in the "Any placebo"group: 96.1% of subjects in the Any bedaquiline groupand 95.2% subjects in the Any placebo group experiencedat least one adverse event (AE). The most frequentlyreported AEs in the Any bedaquiline group (> 20.0% ofsubjects) were nausea (35.3%), arthralgia (29.4%),headache (23.5%), hyperuricemia (22.5%), and vomiting(20.6%). The incidence of these AEs was generallysimilar in the Any bedaquiline and the Any placebo groups,except for headache (in 23.5% and 11.4% of subjects,respectively), nausea (35.3% and 25.7%, respectively),and arthralgia (29.4% and 20.0%, respectively).Additional AEs were, in order of frequency: dizziness,increased transaminases, myalgia, diarrhoea and QTcprolongation on the ECG. There was a higher incidenceof events related to hepatic disorders (mostly increasesin transaminases) in the Any bedaquiline group comparedto the Any placebo group. QTc prolongations wereobserved in both the bedaquiline and placebo groups, butwere more pronounced in the bedaquiline group. The useof bedaquiline with other QT prolonging medications (e.g.clofazimine) was found to increase the risk of prolongedQT interval.

Twelve deaths were reported from the C208 Stage 2trial. Of these, 10/79 (12.7%) came from the bedaquilinegroup and 2/81 (2.5%) from the placebo group (p=0.017)(Intention to treat analysis). In the bedaquiline group, 8of the 10 deaths occurred in culture converters. TB wasthe cause of death in the two placebo-arm deaths and in5 of the 10 bedaquiline-arm deaths (all occurred offbedaquiline treatment). There was no discernible patternbetween death and culture conversion, relapse,microbiologic response, sensitivity to BR, HIV status, orseverity of disease. Despite detailed descriptive line listingsof all deaths the reason (s) for the imbalance werenot clear.

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Source of Support : Nil Conflict of Interest: Declared

1. World Health Organization. Global tuberculosis control

2011. World Health Organization, Geneva, Switzerland,2011a. http://www.who.int/tb/ publications/ 2011/en/index.html.

2. World Health Organization. Guidelines for the programmaticmanagement of drug-resistant tuberculosis. World HealthOrganization, Geneva, Switzerland, 2011b. http://

www.who.int/tb/publications/2011/en/index .html.

3. Andries K. A diarylquinoline drug active on the ATPsynthase of Mycobacterium tuberculosis. Science 2005;

307: 223-27.

4. de Jonge MR, Koymans LH, Guillemont JE, Koul A, AndriesK. "A computational model of the inhibition of

Mycobacterium tuberculosis ATPase by a new drugcandidate R207910". Proteins 2007; 67 (4): 971-80.

5. "FDA Approves 1st New Tuberculosis Drug in 40 Years".

ABC News. Retrieved 31 December 2012.

6. Kotz J. "Targeting tuberculosis". Nature Chemical Biology2005 (June).

How to Cite This Article : Gupta A, Gupta BM, Gupta R. Bedaquiline, First Drug Approved To Treat MDR-TB. JRational Pharmacother Res 2013; 1(2): 88-91

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bed aquiline

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