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No. 4, 2013

Bedaquiline, a New Drug for MDR TB

On October 24, 2013, Dr. Sundari Mase, Medical Officer with DTBE’s Field Services and Evaluation Branch, gave a Brown Bag presentation on the new TB drug, bedaquiline (BDQ). The following is a summary of her talk.

What is BDQ? It’s a diarylquinoline, i.e., it’s in the fluoroquinolone class of drugs. It’s intended to be used as part of combination therapy in adults (≥ 18 years) with pulmonary multidrug-resistant (MDR) TB. This is the first new type of drug in 40 years to obtain approval from the Food and Drug Administration (FDA) for treating TB. It works through an unusual mechanism: it inhibits a process (the ATP synthase proton pump) that creates energy for the bacterium. BDQ is manufactured by Janssen, a subsidiary of Johnson & Johnson, and sold under the trade name Sirturo. BDQ is available from one distributor, Metro Medical Supply, which is in Tennessee. During the initial roll-out, Janssen will oversee the process of BDQ distribution to the 68 CDC-funded jurisdictions.

BDQ was approved under the FDA’s accelerated approval program, which allows FDA to approve a drug that treats a serious disease, based on clinical data showing that

  • The drug has an effect on a surrogate endpoint, time to sputum culture conversion from positive results for M. tuberculosis to negative results, that is reasonably likely to predict a clinical benefit to patients with a serious or life-threatening illness
  • It provides meaningful therapeutic benefit to patients over existing treatments.

Effectiveness: When tested in the laboratory, at recommended levels, BDQ is potent against both active and inactive M. tuberculosis. And when tested in mice, BDQ has significant bactericidal and sterilizing activity. However, at lower levels (0.3 mcg/ml), bedaquiline has a bacteriostatic effect and acquired resistance is more likely. (A bacteriostatic agent is an agent that stops bacteria from reproducing, while not necessarily harming them otherwise. Upon its removal, the bacteria usually start to grow again. This is in contrast to bactericidal agents, which kill bacteria.)

Dosage: The recommended dose of BDQ for the treatment of pulmonary MDR TB in adults is 400 mg given orally once daily for 2 weeks, followed by 200 mg orally three times weekly, for a total treatment duration of 24 weeks. It is to be taken with food and in combination with other anti-TB drugs. The drug is available in 100 mg tablets.

Cost: This is a major consideration. A 24-week regimen costs

  • $30,000 for privately insured individual patients
  • $23,070 through the VA 340B plan for public health departments and other governmental entities

Procurement process:  So far, most jurisdictions do not have a contract for Medicaid patients to get coverage for BDQ. Private insurance payment decisions will be made on a case-by-case basis. The good news is that patient assistance will be available for uninsured patients through the J&J foundation. Insured patients will have the option of a co-pay adjustment program.

Limitations: The FDA label states that neither the safety nor efficacy of BDQ has been established for the treatment of extrapulmonary TB, latent TB infection (LTBI), or drug-susceptible TB. However, the CDC guidelines give recommendations for off-label use of BDQ for extrapulmonary TB. The CDC guidelines do not mention its use for LTBI or drug-susceptible TB.

Warnings: For safety, you should reserve BDQ for when you cannot otherwise provide an effective treatment regimen for a patient with MDR TB. BDQ’s safety risks require careful patient selection and active monitoring. It should be administered by directly observed therapy (DOT). Specific concerns are as follows:

Increased risk of death. In one placebo-controlled trial, there were increased deaths in the BDQ treatment group (9/79, 11.4%) compared to the placebo treatment group (2/81, 2.5%).

There was a significant imbalance in deaths, with more in the BDQ group. TB was the cause of death in 2/2 placebo deaths and in 5/10 BDQ deaths, which were all after BDQ treatment had ended. Of the 10 deaths in the BDQ group, 8 patients had a conversion of sputum culture results from positive for M. tuberdculosis to negative (i.e., had culture conversion). No pattern was observed between death and culture conversion, relapse, microbiologic response, susceptibility to background regimen (i.e., standard four- or five-drug therapy, to which BDQ is added), HIV infection, and severity of disease. The reason for imbalance in deaths is unknown.

Cardiac events: The drug can cause an irregular heart rhythm owing to QT interval prolongation. In cardiology, the QT interval is a measure of the time between the start of one wave (the Q wave) and the end of the following wave (the T wave) in the heart's electrical cycle. A lengthened QT interval is a biomarker for ventricular heart rhythm disorders and a risk factor for sudden death. And using BDQ with other drugs that prolong the QT interval (such as some drugs for HIV infection) may cause additive QT prolongation. This could be life-threatening.

Liver damage: BDQ can be toxic to the liver. Concurrent conditions and medications associated with liver toxicity could pose additive hazards. Make the following adjustments in patients with kidney or liver impairment:

  • Mild or moderate kidney or liver impairment — no dosage adjustment needed
  • Severe kidney impairment — use with caution
  • Severe liver impairment -- do not use

Lingering effects: BDQ has a long half-life. It remains in the body for months after the drug is stopped. Consider discontinuing BDQ 4–5 months before stopping the other drugs in the regimen, to reduce or avoid an extended period of exposure to low levels of BDQ in the absence of other medications which are likely to be active against the infecting M. tuberculosis isolate. In addition, the QT interval (see above) takes a few months to revert to baseline.

Concerning but indefinite conclusions: A greater number of deaths among patients who took BDQ in the treatment trials.  The reason for the imbalance could not be determined from the current safety data. Half the deaths were attributed to worsening of the underlying condition.

The role of BDQ in deaths where liver toxicity and heart failure are contributors could not be excluded. An association between BDQ and these deaths is difficult to determine because of the underlying condition, other co-existent medical conditions, and other drugs being given concurrently (background regimen).

What else do TB programs and clinicians need to know?  You will need to monitor patient’s progress as follows:

  • Symptoms. Monitor patient weekly for nausea, headache, hemoptysis, chest pain, arthralgia (joint pain), and rash. 
  • Drug side effects. Monitor patient for other side effects related to other drugs in regimen.

Note: Do not use BDQ with rifamycins, or other drugs that induce or suppress CYP3A4.

  • Culture. Send one sputum specimen monthly to a TB laboratory for culture.

CDC also asks that you participate in monitoring for resistance. With the help of your public health laboratory, send one pre-treatment isolate and one additional isolate per month to CDC for surveillance of BDQ resistance.

Distribution. Janssen is providing oversight of BDQ distribution. A point of contact (POC) has been selected for each of the 68 CDC-funded jurisdictions. These persons will (1) ensure that the patient meets criteria for BDQ, (2) facilitate procurement of BDQ, (3) work with the clinician, nurse, and case manager, and (4) ensure that expert consultation is sought. So far, the process has been smooth.

In summary, how could BDQ help? It could provide

  • A stronger regimen for cases with extensive resistance or drug intolerance.
  • A shorter regimen.
  • A regimen less toxic than current MDR TB regimens.

Importantly, how could it hurt?

  • Could cause liver toxicity and death.
  • Prevents use of other drugs, i.e., moxifloxacin (MFX), clofazimine; most pre-XDR or XDR cases are treated with MFX.
  • Could be misused, or used in a weak regimen leading to drug resistance.
  • Can be costly and complex to procure.

TB program directors can call their DTBE Program Consultant for further information, such as the name of the POC for their jurisdiction.

 

—Reported by Sundari Mase, MD,
and Ann Lanner
Div of TB Elimination

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