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New TB drugs – Drug trials, Pretomanid (PA-824), AZD-5847

Why are new TB drugs needed?

New TB drugs are needed because of the complexity and toxicity of the current TB drug regimes and the major problem of TB drug resistance. This together with the problem of the interactions of the current TB drugs with the antiretroviral drugs taken by HIV positive people, means that there is an urgent need for new TB drugs. However, what is required of these new TB drugs is considerable as:

New TB drugs need to provide:1Ginsberg, A. “Drugs in Development for Tuberculosis”, Drugs, 70(17), 3 December 2010, 2201-2214 adisonline.com/drugs/Fulltext/2010/70170/Drugs_in_Development_for_Tuberculosis

  • Shorter and simpler, but still affordable, multi drug regimes for drug sensitive TB
  • Shorter, more effective , less toxic, and less expensive regimes for drug resistant TB
  • Short, simple, easily tolerable and safe regimes for latent TB
  • Drugs with few drug drug interactions, so they can be safely provided for people with HIV.

TB drug trials

Before a new TB drug is made available for general use it needs to go through a series of clinical trials, to check that among other things, it is effective and doesn’t have too many side effects. The main trials for any drug are referred to as phases 1, 2 and 3. In addition there are now trials referred to as phase 2a and phase 2b.2“Phases of clinical research”, Wikipedia https://en.wikipedia.org/wiki/Phases_of_clinical_research Those drugs going through a phase 3 trial are the closest to being made available for general use, provided of course that the phase 3 trial is successful.3“Understanding Clinical Trials”, U . S. National Institutes of Health clinicaltrials.gov/

Phase three trials for TB drugs take a long time. Such a trial requires a lengthy TB drug treatment period, followed by a one to two year period of patient follow up to determine treatment failure and relapse, in order to then know the effectiveness of the drug.

A drugs “pipeline” in drug development terms, refers to all the drugs at different stages of development, and how the drugs are progressing down the “pipeline” through the various clinical trial stages etc.. At the point at which they exit the “pipeline” they are available for general use.

The American NIAID is looking at the efficiency of the various stages of TB drug trials, and is trying to improving their design, as well as improving collaboration among researchers and companies.4Hafner, R. “NIAID TB Therapeutic Clinical Research Priorities”, Working Group on New TB Drugs 2011 Annual Meeting, 25-26 October 2011 www.newtbdrugs.org/meetings/annual-meeting-2011 However, organisations such as the American Thoracic Society have been calling for innovative collaborative relationships to aid new TB drug development since at least 1998, and there are still no new TB drugs.5O’Brien, R. “New Tuberculosis Drug Development How Can We Do Better?”, Am. J. Respir. Crit. Care Med., 157(6), 1 June 1998, 1705-1707 ajrccm.atsjournals.org/

New TB drugs under clinical development

The pipeline below of new drugs for TB under clinical development is not considered to be a very extensive drugs “pipeline” for such a major disease as TB.6Zhenkun, Ma. “Global tuberculosis drug development pipeline: the need and the reality”, The Lancet, Vol 375(9731), 12 June 2010, 2011-2109 www.thelancet.com/journals/lancet

TB drug clinical development pipeline
Phase 1 Phase 2 Phase 3
Q203-Novel anti-TB agent
Imidazopyridine
Sutezolid (PNU-100480)
Oxazolidinone
Bedaquiline (TMC207)
with OBR for MDR-TB
Diarylquinoline OBR = Optimized Background Regimen
SQ109
Ethylenediamine
Delamanid (OPC-67683)
with OBR for MDR-TB
Nitro-dihydro-imidazooxazole
Rifapentine for DS-TB
Rifamycin
Pretomanid – Moxifloxacin – Pyrazinamide
New chemical entity
Bedaquiline – Pretomanid – Pyrazinamide
Levofloxacin
Fluoroquinolone

The projects shown in the table below have been put on hold, or paused or completed.

Projects put on hold, paused or completed
Phase 1 Phase 2 Phase 3
TBA-354

Nitroimidazole

AZD5847

Oxazolidinone

Gatifloxacin

Fluoroquinolone

Moxifloxacin for

Drug-Sensitive TB

©2016 Working Group on New TB Drugs7www.newtbdrugs.org/pipeline.php 8www.newtbdrugs.org/pipeline-hold.php

TB drug bedaquiline

Bedaquiline is the active substance in the new TB drug Sirturo. Sirturo is available for the treatment of drug resistant TB, when there are an insufficient numbers of other TB drugs available. There is much more about bedaquiline.

The Nitroimidazoles

The Nitroimidazoles are an existing class of drugs known to have antimicrobial activity. Two “next generation” or derivatives of this class of drugs, OPC-67683 (now also known as delamanid) and PA-824 are under development as potential TB drugs.9“OPC-67683”, www.tbonline.info/ There is much more about delamanid.

TB drug Pretomanid (PA-824)

PA-824 is another nitroimidazo-oxazole currently being developed by the TB Alliance. It also can potentially be used for the treatment of both drug sensitive and drug resistant TB, and it has also shown activity against both latent and active TB. A phase two study of PA-824 is currently being carried out, but there have been some setbacks with the development of this drug and the clinical trials are taking a very long time.10“PA-824”, www.tballiance.org/news/pa-824-has-new-generic-name-pretomanid

TB drug TBA-354

Working on the possible new TB drug TBA-354

Working on the possible new TB drug TBA-354

TBA-354 is a drug in the same class as PA-824 but it has been more potent in preclinical studies. It is also said to be longer lasting and has greater activity against resistant strains of the disease. TBA-354 was selected by the TB Alliance for further development.11“Promising New Zealand compound selected as drug candidate for tuberculosis”, University of Auckland, 21 September 2012 https://www.fmhs.auckland.ac.nz/en/faculty/about/news-and-events/news/2012/09/21/promising-new-zealand.html The first human trial of TBA-354 started in February 2015.12www.tballiance.org/news/tb-alliance-advances-next-generation-tb-drug-candidate-clinical-testing The phase 1 trial was started in January 2016 and in March 2016 it was announced that the TB Alliance had voluntarily halted the clinical development program for TBA-354.13“Phase 1 Clinical Trial of TB Drug Candidate TBA-354 Discontinued”, www.tballiance.org/news/phase-1-clinical-trial-tb-drug-candidate-tba-354-discontinued

AZD5847

AZD5847 is a potential new TB drug being developed by AstraZeneca. In December 2012 it was announced that the first patient had been enrolled in a Phase 2a trial of the drug in South Africa, to assess the effectiveness of the drug for patients with TB, including patients with HIV and TB coinfection.14“AstraZeneca, Case Western Reserve initiate AZD5847 Phase 2a trial in TB”, 12 December 2012, www.news-medical.net/news/20121212/AstraZeneca-Case-Western-Reserve-initiate-AZD5847-Phase-2a-trial-in-TB The study is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), which is part of the U.S. National Institutes of Health.

The Fluoroquinolones

Several members of the fluoroquinoles class of drugs are currently already used as second line TB drugs for the treatment of multi drug resistant TB. However, the older drugs such as ofloxacin and levofloxacin are often used rather than the newer fluoroquinolones moxifloxacin and gatifloxacin. Moxifloxacin and gatifloxacin are currently being developed for the treatment of drug sensitive TB. Each of these potential TB drugs is currently undergoing evaluation in a phase 3 trial, to see how effective it is when substituted for either ethambutol or isoniazid, to shorten the treatment of drug sensitive TB from the standard six months to four months. The gatifloxacin trial is being conducted by the Oflotub Consortium and moxifloxacin is being developed by Bayer and the TB Alliance.15Ginsberg, A. “Drugs in Development for Tuberculosis”, Drugs, 70(17), 3 December 2010, 2201-2214 adisonline.com/drugs/Fulltext/2010/70170/Drugs_in_Development_for_Tuberculosis

The Rifamycins

The Rifamycins are potent inhibitors of mycobacterial activity. Three semi synthetic rifamycins – rifampicin, rifapentine, and rifabutin – have been used for the treatment of various microbial infections. Rifampicin is a key component of first line drug treatment for TB. Rifapentine is attractive as a possible TB drug for shortening treatment, and for intermittent TB drug treatment, and clinical trials are under way to further assess this.16Zhenkun, Ma. “Global tuberculosis drug development pipeline: the need and the reality”, The Lancet, Vol 375(9731), 12 June 2010, 2011-2109 www.thelancet.com/journals/lancet

TB drug combinations

What is ideally needed is not just one new TB drug but several which can be used together. In July 2012 it was announced that a phase 2A study had been carried out investigating a number of drug combinations including PA-824 over a 14 day period to assess their suitability for further development. The combination of PA-824 moxifloxacin and pyrazinamide had the greatest early bactericidal activity (EBA).

One advantage of this drug combination is that it does not involve either isoniazid or rifampicin. It is therefore suitable for use with patients who are resistant to these drugs. A regimen without rifampicin would greatly simplify the provision of TB treatment alongside HIV antiretroviral therapy.

This three drug combination now needs to be further investigated over a longer period of time, taking into account that PA-824 and moxifloxacin all have at least some potential to cause cardiac side effects.17Diacon, A. “14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial”, The Lancet, 23 July 2012, www.thelancet.com/journals/lancet/article/

References

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1. Ginsberg, A. “Drugs in Development for Tuberculosis”, Drugs, 70(17), 3 December 2010, 2201-2214 adisonline.com/drugs/Fulltext/2010/70170/Drugs_in_Development_for_Tuberculosis
2. “Phases of clinical research”, Wikipedia https://en.wikipedia.org/wiki/Phases_of_clinical_research
3. “Understanding Clinical Trials”, U . S. National Institutes of Health clinicaltrials.gov/
4. Hafner, R. “NIAID TB Therapeutic Clinical Research Priorities”, Working Group on New TB Drugs 2011 Annual Meeting, 25-26 October 2011 www.newtbdrugs.org/meetings/annual-meeting-2011
5. O’Brien, R. “New Tuberculosis Drug Development How Can We Do Better?”, Am. J. Respir. Crit. Care Med., 157(6), 1 June 1998, 1705-1707 ajrccm.atsjournals.org/
6. Zhenkun, Ma. “Global tuberculosis drug development pipeline: the need and the reality”, The Lancet, Vol 375(9731), 12 June 2010, 2011-2109 www.thelancet.com/journals/lancet
7. www.newtbdrugs.org/pipeline.php
8. www.newtbdrugs.org/pipeline-hold.php
9. “OPC-67683”, www.tbonline.info/
10. “PA-824”, www.tballiance.org/news/pa-824-has-new-generic-name-pretomanid
11. “Promising New Zealand compound selected as drug candidate for tuberculosis”, University of Auckland, 21 September 2012 https://www.fmhs.auckland.ac.nz/en/faculty/about/news-and-events/news/2012/09/21/promising-new-zealand.html
12. www.tballiance.org/news/tb-alliance-advances-next-generation-tb-drug-candidate-clinical-testing
13. “Phase 1 Clinical Trial of TB Drug Candidate TBA-354 Discontinued”, www.tballiance.org/news/phase-1-clinical-trial-tb-drug-candidate-tba-354-discontinued
14. “AstraZeneca, Case Western Reserve initiate AZD5847 Phase 2a trial in TB”, 12 December 2012, www.news-medical.net/news/20121212/AstraZeneca-Case-Western-Reserve-initiate-AZD5847-Phase-2a-trial-in-TB
15. Ginsberg, A. “Drugs in Development for Tuberculosis”, Drugs, 70(17), 3 December 2010, 2201-2214 adisonline.com/drugs/Fulltext/2010/70170/Drugs_in_Development_for_Tuberculosis
16. Zhenkun, Ma. “Global tuberculosis drug development pipeline: the need and the reality”, The Lancet, Vol 375(9731), 12 June 2010, 2011-2109 www.thelancet.com/journals/lancet
17. Diacon, A. “14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial”, The Lancet, 23 July 2012, www.thelancet.com/journals/lancet/article/