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Advances in the development of new tuberculosis drugs and treatment regimens

Key Points

  • Despite the introduction 40 years ago of the inexpensive and effective four-drug (isoniazid, rifampicin, pyrazinamide and ethambutol) treatment regimen, tuberculosis (TB) continues to cause significant morbidity and mortality worldwide.

  • After five decades of near inactivity in TB drug development, the past 5 years has seen the development of a promising TB drug pipeline. For the first time since the 1960s, new and novel drugs and regimens for all forms of TB are emerging.

  • Several new TB drug candidates are in Phase II and Phase III clinical trials in addition to high activity in the hit-to-lead and lead optimization stages.

  • New TB drug development has led to the submission of two new TB drugs for regulatory approval: delamanid (also known as OPC67683) and bedaquiline (also known as TMC207 or R207910).

  • The US Food and Drug Administration recently approved bedaquiline as part of a combination therapy in the treatment of adults with multidrug-resistant TB.

  • New TB treatment regimens aimed at reducing the duration of chemotherapy or for use against drug-resistant TB using new chemical entities are now progressing through clinical trials.

  • Many of the candidates in clinical trials are drugs that were developed to treat other infectious diseases and have since been repurposed for TB (for example, fluoroquinolones, rifamycins, oxazolidinones and clofazimine).

  • Several newer approaches are currently being pursued with the aim of reducing the time required for evaluating new TB drugs through the various phases of clinical trials. These include the use of 14-day early bactericidal activity (EBA) studies to rapidly determine bactericidal activity, the use of innovative trial designs that include multi-arm, multi-stage determinations of efficacy of new drug combinations, and the exploration and qualification of new surrogate markers of treatment effect.

  • To facilitate this more rapid evaluation of new TB drugs, current clinical trials are initially testing new combinations of TB drugs in patients with drug-susceptible pulmonary TB.

  • This article covers current concepts and recent advances in TB drug discovery and development, including an update of ongoing TB treatment trials, newer clinical trial designs, TB biomarkers and adjunct host-directed therapies.

Abstract

Despite the introduction 40 years ago of the inexpensive and effective four-drug (isoniazid, rifampicin, pyrazinamide and ethambutol) treatment regimen, tuberculosis (TB) continues to cause considerable morbidity and mortality worldwide. For the first time since the 1960s, new and novel drugs and regimens for all forms of TB are emerging. Such regimens are likely to utilize both repurposed drugs and new chemical entities, and several of these regimens are now progressing through clinical trials. This article covers current concepts and recent advances in TB drug discovery and development, including an update of ongoing TB treatment trials, newer clinical trial designs, TB biomarkers and adjunct host-directed therapies.

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Figure 1: Repurposed drugs for tuberculosis treatment.
Figure 2: Current global pipeline of new tuberculosis drugs.
Figure 3: Schematic showing the site of action of various tuberculosis drug candidates.
Figure 4: New clinical trials 'MAMS' design.

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Acknowledgements

The work of S.T.C. is supported by the European Community's Seventh Framework Programme (FP7/2007–2013) under the grant agreement number 260872. The work of A.Z. is supported by the Medical Research Council, UK, the European Union FP7, the European Developing Countries Clinical Trials Partnership, the National Institutes for Health Research (NIHR) University College London (UCL) Hospitals NHS Trust Biomedical Research Centre and the UBS Optimus Foundation, Switzerland. The work of P.N. is supported by the National Institutes of Health through National Institute of Allergy and Infectious Diseases funding (1R01AI104589), the Centers for Disease Control and Prevention TB Trials Consortium, and the Bill and Melinda Gates Foundation. Adam Zumla, UCL School of Pharmacy, UK, provided technical and administrative assistance.

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Glossary

Multidrug-resistant TB

(MDR-TB). Tuberculosis (TB) caused by Mycobacterium tuberculosis bacilli that are resistant to at least isoniazid and rifampicin.

Extensively drug-resistant TB

(XDR-TB). Tuberculosis (TB) caused by Mycobacterium tuberculosis bacilli that are resistant to rifampicin, isoniazid, plus any fluoroquinolone and at least one of the three injectable second-line drugs: amikacin, kanamycin and capreomycin.

Directly observed therapy

(DOT). An approach to patient management that involves carers directly observing patients taking their tuberculosis drugs.

Drug-susceptible TB

Tuberculosis (TB) caused by Mycobacterium tuberculosis bacilli that is susceptible to first-line TB drugs.

Early bactericidal activity

(EBA). A commonly used assay in which the Mycobacterium tuberculosis bacilli load in sputum from the lungs of infected patients is periodically monitored for loss of viability, or culture conversion, using microbiological techniques. The duration of the assay has been extended from 7 days to 14 days since its conception.

Antiretroviral therapy

(ART). A combination of antiviral drugs used for treatment of diseases due to HIV.

Randomized, controlled clinical trial

The random allocation of patients to therapeutic regimens after enrolment. Assurances on strict adherence to interventions and minimizing losses from the trial population throughout treatment and follow-up are also key elements of randomized clinical trials.

Repurposed drugs

In this article, these are drugs that were developed to treat other diseases and have since been repurposed for treating tuberculosis.

Immune reconstitution inflammatory syndrome

Describes a collection of inflammatory disorders that are associated with the paradoxical worsening of pre-existing infectious conditions following the initiation of antiretroviral therapy in HIV-infected individuals.

Biomarker

A host or pathogen (for example, Mycobacterium tuberculosis) characteristic that is objectively measured and evaluated as an indicator of normal biological processes or pathogenic processes, or as an indicator of pharmacological responses to a therapeutic intervention.

Paucibacillary disease

Pulmonary tuberculosis with low Mycobacterium tuberculosis load in sputum.

Biobanks

Repositories that store biospecimens and data obtained from well-characterized patient cohorts who have had adequate follow-up for therapeutic failure and relapse. Biobanks will constitute a significant resource for the biomarker discovery field.

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Zumla, A., Nahid, P. & Cole, S. Advances in the development of new tuberculosis drugs and treatment regimens. Nat Rev Drug Discov 12, 388–404 (2013). https://doi.org/10.1038/nrd4001

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