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Bedaquiline  – Dose, trials, side effects, cost

What is bedaquiline? How does it work?

Bedaquiline is the active substance in a TB drug which is also sometimes known by the trade name of Sirturo. Bedaquiline works by blocking an enzyme inside the Mycobacterium tuberculosis bacteria called ATP synthase. This enzyme is used by the bacteria to generate energy. Without the ability to generate energy, the TB bacteria die and the patient’s condition can start to improve.

When is bedaquiline used?

Bedaquiline is the active substance in the TB drug Sirturo

Bedaquiline is the active substance in the TB drug Sirturo

Bedaquiline is used in combination with other TB drugs to treat pulmonary TB in adults when they have multi drug resistant TB (MDR-TB). MDR-TB is when the TB bacteria that a person is infected with, are resistant to two of the main TB drugs isoniazid (INH) and rifampicin (RMP). This means that the drugs don’t work.

It should only be used when an effective TB treatment cannot otherwise be provided. It is also sometimes used when other drugs cannot be used because of their side effects.

It should be used in combination with at least 3 other TB drugs which drug susceptibility testing has shown that the patient is susceptible to. If drug susceptibility testing is not available then bedaquiline should be used with at least 4 other drugs to which the patient is likely to be susceptible.

Bedaquiline should not be used for the treatment of:

  • Latent TB infections due to Mycobacterium tuberculosis
  • Drug sensitive tuberculosis
  • Extrapulmonary tuberculosis
  • Infections caused by non tuberculosis mycobacteria.

The safety and efficacy of bedaquiline in the treatment of HIV positive patients with MDR-TB has not yet been established.

What is the recommended dose of bedaquiline?

Container of 100 mg bedaquiline tables

Container of 100 mg bedaquiline tablets

The recommended dose is 400 mg a day for two weeks and then 200 mg taken three times a week (with at least 48 hours between doses) for the next 22 weeks. Bedaquiline is available as 100 mg tablets, and the tablets should be swallowed whole with water and taken with food.

In the EU bedaquiline should only be obtainable with a prescription. Treatment should also be started and monitored by a doctor experienced in the treatment of MDR-TB. It is also recommended that patients are directly observed by a health care professional when taking the drug.1“Sirturo bedaquiline EPAR summary for the public”, European Medicines Agency 2014 www.ema.europa.eu/ema/

You should not drink alcohol when taking bedaquiline, and it is essential that the entire course of treatment is completed.

Missed doses

If a dose is missed during the first two weeks of treatment, the missed dose should not be made up but doses should continue to be taken as normal.

From week 3 onwards, if a dose is missed, patients should take the missed dose as soon as possible, and then resume the three times a week regimen.

What clinical trials of bedaquiline have taken place?

There have been only a limited number of clinical trials carried out with bedaquiline. Two early phase 2 studies of the drug took place and the results of these trials were presented at the Union World TB conferences in 2010 and 2011.2“Jansssen Research & Development Submits New Drug Application to FDA for Investigational Multi-Drug Resistant Tuberculosis Treatment Bedaquiline (TMC207)”, Fiercebiotech, www.fiercebiotech.com/press-releases/janssen-research-development-submits-new-drug-application-fda-investigation

In addition there has been one major placebo controlled double-blind randomized trial of adults with pulmonary multi drug resistant TB in which patients had the drug for 24 weeks. A placebo is a dummy treatment. Bedaquiline was compared with a placebo when added to combination treatment with other standard TB medicines. The other TB drugs were:

  • ethionamide
  • kanamycin
  • pyrazinamide
  • ofloxacin
  • cycloserine/terizidone or an available alternative.

The study showed that after 24 weeks 79% of the patients given bedaquiline were sputum smear negative, compared with 58% of patients given placebo. The average time it took to become smear negative was also shorter for patients in the bedaquiline  group than for those in the placebo group (83 days versus 125 days).

There is also data from a single arm study which included patients with XDR-TB.

A phase 3 trial TMC207-C210, was due to start in March 2013. It was going to be a double blind study of 600 patients with sputum smear positive MDR-TB, which would compare TB treatment with bedaquiline and a background regimen, with placebo and a background regimen. It was subsequently announced that the trial had been cancelled.

However in April 2016 it was announced that in Mongolia, the first patients had been recruited to the STREAM stage 2 clinical study. This trial aims to test the effectiveness of an MDR-TB treatment shortened from 24 months to 6 or 9 months. It also is the first phase III trial to test the effectiveness of bedaquiline within a shortened regimen.3“STREAM  stage 2 clinical study enrols patients in first trial to include bedaquiline to test shortened MDR-TB treatment regimens”, International Union Against Tuberculosis and Lung Disease 2016 www.theunion.org

What are the side effects of bedaquiline?

The most common side effects are headache, dizziness, feeling sick, being sick, joint pain and increases in liver enzymes. Side effects can be experienced by more than one in ten people.

Another potentially significant side effect is that QTc prolongation was noticed during treatment. A prolonged QT interval means some alterations in the heart’s electrical activity. There were also a higher number of reported deaths in the bedaquiline group, although these were not necessarily caused by bedaquiline.4“Sirturo bedaquiline Summary of opinion (initial authorisation)”, European Medicines Agency 2013 www.ema.europa.eu

First FDA approved TB drug for 40 years

Model of the chemical formula of bedaquiline

Model of the chemical formula of bedaquiline

The US Food and Drug Administration (FDA) on 28th December 2012 granted approval for bedaquiline to be used to treat drug resistant TB.5FDA News Release, 31st December 2012 www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ This was the first new medicine for TB in more than forty years.

In October 2013 the CDC issued new federal guidelines on the use of the drug, for the treatment of multi drug resistant TB.6“Provisional CDC Guidelines for the Use and Safety Monitoring of Bedaquiline Fumarate (Sirturo) for the Treatment of Multidrug-Resistant Tuberculosis”, CDC October 2013 www.cdc.gov/mmwr/preview/mmwrhtml The new guidelines offered advice on the use of the drug for the treatment of TB in children, pregnant women and individuals with other health complications.

World Health Organisation (WHO) guidance on the use of bedaquiline

In June 2013 the WHO issued interim guidance on the inclusion of bedaquiline in combination drug therapy for people with MDR TB.7“Janssen-Cilag files for EU approval of bedaquiline in MDR-TB”, The Pharma Letter,  www.thepharmaletter.com/file/116136/janssen-cilag-files-for-eu-approval-of-bedaquiline-in-mdr-tb

The cost of bedaquiline

The bedaquiline donation program involves the company Janssen providing free bedaquiline to be used in low and middle income countries. The program was set up in March 2015 when USAID and the company Janssen Therapeutics signed an agreement to provide bedaquiline free to eligible MDR-TB patients.  Under the agreement Janssen will donate $30 million worth (30,000 treatment courses) of the drug over a four year period to be used for the treatment of drug resistant TB. It was said at the time that this would enable over 100 low and middle income countries to have the drug available for free withing their existing national MDR-TB programs.8“The Bedaquiline Donation Program”, Stop TB Partnership, 2015, www.stoptb.org/gdf/drugsupply/bedaquilineDonation.asp

Bedaquiline cost in high income countries

For high income countries the situation is very different, with bedaquiline costing US$30,000 in the United States. This is equivalent to £18,800 in the UK.9Wolfson, L “Cost-effectiveness of Adding Bedaquiline to Drug Regimens for the Treatment of Multidrug-Resistant Tuberculosis in the UK”, PLoS One 2015, www.ncbi.nlm.nih.gov/pubmed/25794045

Worldwide approval

By 2015 bedaquiline had received approval for use in the United States, the EU, South Korea, South Africa, India, the Russian Federation and Peru.10“First time in decades: New antibiotic to treat Multidrug-Resistant Tuberculosis (MDR-TB) receives approval in Peru”, Stop TB Partnership, 2015, www.stoptb.org/news/frompartners/2015/fp15_012.asp However, by October 2016 only 5,700 patients had been able to receive the drug.11“Access: MSF reports on use of the new tuberculosis drugs bedaquiline and delamanid”, MSF, http://www.msf.org/en/article/access-msf-reports-use-new-tuberculosis-drugs-bedaquiline-and-delamanid

Bedaquiline use in South Africa

In December 2012 the South African Medicine Control Council (MCC) approved a national program to treat selected drug resistant TB patients with bedaquiline. This program began in March 2013. The program operated at five South African sites and was subsequently extended to twelve sites. In October 2014 the MCC approved the use of bedaquiline within the national TB programme.12“Good outcomes within the National Bedaquiline Clinical Access programme in South Africa”, HIV treatment bulletin, January 2015, http://i-base.info/htb/27735

Bedaquiline to become available in India

In February 2016 it was announced that bedaquiline is to be made available in India.13“India set to roll out bedaquiline to combat extensively drug-resistant TB”, The Pharma Letter,  www.thepharmaletter.com/article/india-set-to-roll-out-bedaquiline-to-combat-extensively-drug-resistant-tb The drug will be available as part of second line treatment for patients suffering from MDR-TB and XDR-TB. The drug recently underwent clinical trials at the national level in certain hospitals for safety and efficacy. There is more about the treatment of drug resistant TB in India.

Bedaquiline is a promising new TB drug but it must be carefully introduced and monitored. I have already seen media reports from India which call bedaquiline a ‘miracle drug’. This worries me – terms like ‘miracle drug’ should not be used lightly as it can raise expectations and also encourage abuse. More evidence is needed on how bedaquiline fits in with existing and other new drug regimens. It is not intended to be used alone”

Dr Madhukar Pai, Director of McGill Global Health Programme Canada14Mascarenhes, Anuradha,”The roll out of a TB curing miracle drug Bedaquiline”, The Indian Express, March 2016, http://indianexpress.com/article/explained/tuberculosis-bedaquiline-new-medicine-for-tb-cure/

There is also an issue about the private sector in India. More than half the TB patients in India seek care in the private sector. There is concern about whether the Indian government is engaging sufficiently with private health care providers about the use of the drug.

You can read more about:

Delamanid

or TB drugs

References

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1. “Sirturo bedaquiline EPAR summary for the public”, European Medicines Agency 2014 www.ema.europa.eu/ema/
2. “Jansssen Research & Development Submits New Drug Application to FDA for Investigational Multi-Drug Resistant Tuberculosis Treatment Bedaquiline (TMC207)”, Fiercebiotech, www.fiercebiotech.com/press-releases/janssen-research-development-submits-new-drug-application-fda-investigation
3. “STREAM  stage 2 clinical study enrols patients in first trial to include bedaquiline to test shortened MDR-TB treatment regimens”, International Union Against Tuberculosis and Lung Disease 2016 www.theunion.org
4. “Sirturo bedaquiline Summary of opinion (initial authorisation)”, European Medicines Agency 2013 www.ema.europa.eu
5. FDA News Release, 31st December 2012 www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/
6. “Provisional CDC Guidelines for the Use and Safety Monitoring of Bedaquiline Fumarate (Sirturo) for the Treatment of Multidrug-Resistant Tuberculosis”, CDC October 2013 www.cdc.gov/mmwr/preview/mmwrhtml
7. “Janssen-Cilag files for EU approval of bedaquiline in MDR-TB”, The Pharma Letter,  www.thepharmaletter.com/file/116136/janssen-cilag-files-for-eu-approval-of-bedaquiline-in-mdr-tb
8. “The Bedaquiline Donation Program”, Stop TB Partnership, 2015, www.stoptb.org/gdf/drugsupply/bedaquilineDonation.asp
9. Wolfson, L “Cost-effectiveness of Adding Bedaquiline to Drug Regimens for the Treatment of Multidrug-Resistant Tuberculosis in the UK”, PLoS One 2015, www.ncbi.nlm.nih.gov/pubmed/25794045
10. “First time in decades: New antibiotic to treat Multidrug-Resistant Tuberculosis (MDR-TB) receives approval in Peru”, Stop TB Partnership, 2015, www.stoptb.org/news/frompartners/2015/fp15_012.asp
11. “Access: MSF reports on use of the new tuberculosis drugs bedaquiline and delamanid”, MSF, http://www.msf.org/en/article/access-msf-reports-use-new-tuberculosis-drugs-bedaquiline-and-delamanid
12. “Good outcomes within the National Bedaquiline Clinical Access programme in South Africa”, HIV treatment bulletin, January 2015, http://i-base.info/htb/27735
13. “India set to roll out bedaquiline to combat extensively drug-resistant TB”, The Pharma Letter,  www.thepharmaletter.com/article/india-set-to-roll-out-bedaquiline-to-combat-extensively-drug-resistant-tb
14. Mascarenhes, Anuradha,”The roll out of a TB curing miracle drug Bedaquiline”, The Indian Express, March 2016, http://indianexpress.com/article/explained/tuberculosis-bedaquiline-new-medicine-for-tb-cure/