Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies

TLDR: The developmental pipeline and landscape of new and repurposed tuberculosis drugs, treatment regimens, and host-directed therapies (HDTs) for drug-sensitive and drug-resistant tuberculosis are reviewed and a range of HDTs and immune-based treatments are under investigation as adjunctive therapy.

Abstract: Summary Tuberculosis remains the world's leading cause of death from an infectious disease, responsible for an estimated 1 674 000 deaths annually. WHO estimated 600 000 cases of rifampicin-resistant tuberculosis in 2016—of which 490 000 were multidrug resistant (MDR), with less than 50% survival after receiving recommended treatment regimens. Concerted efforts of stakeholders, advocates, and researchers are advancing further development of shorter course, more effective, safer, and better tolerated treatment regimens. We review the developmental pipeline and landscape of new and repurposed tuberculosis drugs, treatment regimens, and host-directed therapies (HDTs) for drug-sensitive and drug-resistant tuberculosis. 14 candidate drugs for drug-susceptible, drug-resistant, and latent tuberculosis are in clinical stages of drug development; nine are novel in phase 1 and 2 trials, and three new drugs are in advanced stages of development for MDR tuberculosis. Specific updates are provided on clinical trials of bedaquiline, delamanid, pretomanid, and other licensed or repurposed drugs that are undergoing investigation, including trials aimed at shortening duration of tuberculosis treatment, improving treatment outcomes and patient adherence, and reducing toxic effects. Ongoing clinical trials for shortening tuberculosis treatment duration, improving treatment outcomes in MDR tuberculosis, and preventing disease in people with latent tuberculosis infection are reviewed. A range of HDTs and immune-based treatments are under investigation as adjunctive therapy for shortening duration of therapy, preventing permanent lung injury, and improving treatment outcomes of MDR tuberculosis. We discuss the HDT development pipeline, ongoing clinical trials, and translational research efforts for adjunct tuberculosis treatment.

Figures

Table 3: WHO categorisation of second-line anti-tuberculosis drugs recommended for the treatment of rifampicin-resistant and multidrug-resistant tuberculosis 37

Table 1: TB Drugs development pipeline -Class of drug, target, phase of trial and sponsor (Adapted from TAG Report http://www.pipelinereport.org/sites/default/files/2017%20Pipeline%20Report%20Final.pdf)

Table 4. Host-directed therapies in TB -Developmental pipeline: Ongoing clinical trials and translational research

Table 2 Planned, ongoing and recently completed clinical trials on drugs sensitive and drug resistant tuberculosis (as of November, 2017) (courtesy of CDC TB Trials Consortium)

Full text

Elsevier Editorial System(tm) for The Lancet
Infectious Diseases
Manuscript Draft
Manuscript Number:
Title: Tuberculosis: Progress and advances in development of new drugs,
treatment regimens and host-directed therapies.
Article Type: Invited Review
Corresponding Author: Professor Alimuddin Zumla, PhD.FRCP.FRCPath
Corresponding Author's Institution: University College London Medical
School,
First Author: Simon Tiberi, MD
Order of Authors: Simon Tiberi, MD; Nelita du Plessis, PhD; Gerhard
Walzl, PhD; Michael J Vjecha, MD; Martin Rao, PhD; Francine Ntoumi,
PhD.FRCP; Sayoki Mfinanga, PhD; Nathan Kapata, MPH; Peter Mwaba,
PhD.FRCP; Timothy D McHugh, PhD; Giuseppe Ippolito, FRCP; Giovanni B
Migliori, FRCP; Alimuddin Zumla, PhD.FRCP.FRCPath
Abstract: Tuberculosis (TB) remains the top killer from an infectious
globally causing an estimated 1.674.000 million deaths worldwide. In
2016, WHO estimates 600.000 cases of rifampicin-resistant TB of which
490.000 had multidrug-resistant (MDR) and less than half of them survive
after receiving currently recommended WHO treatment regimens,
illustrating weaknesses in current treatment approaches. We review
progress and advances in the development of new and repurposed TB drugs,
treatment trials and host-directed therapies. Updates are provided on
phase 3 trials of the new compounds bedaquiline, delamanid, pretomanid;
phase 2 trials of sutezolid, SQ-109, LCB01-0371, PBTZ-169; and five new
drugs in phase 1 development. Approved or repurposed drugs undergoing
further testing are rifampicin, rifapentine, clofazimine, and linezolid.
Update on ongoing clinical trials, which aim to shorten TB treatment and
improve treatment outcome is given. Several new or repurposed
antimicrobial drugs are in advanced trial stages for MDR-TB, and five
antimicrobial drug candidates are in phase 1 (Q203, TBI-166, OPC-167832,
GSK 070, TBA-7371) and 5 in pre-clinical studies. Specific issues of
safety and toxicity; drug-drug interactions; Therapeutic Drug Monitoring
are reviewed. A wide range of candidate host-directed therapies (HDTs)
and immune-based treatments are being investigated to accelerate the
eradication of M.tb infection and for use as adjunctive therapy in
shortening duration of treatment, preventing permanent lung injury and
improving treatment outcomes of MDR-TB. Ongoing clinical trials of HDTs
for TB treatment, the current HDT development pipeline and translational
research efforts for advancing further HDT options are presented.

1
Invited Review for Lancet ID World TB Day Series, 2018
Title:
Tuberculosis: Progress and advances in development of new drugs, treatment regimens
and host-directed therapies.
Authors:
Simon Tiberi MD, Nelita du Plessis PhD, Gerhard Walzl PhD, Michael J. Vjecha MD,
Martin Rao PhD, Francine Ntoumi FRCP, Sayoki Mfinanga PhD, Nathan Kapata MPH, Peter
Mwaba FRCP, Timothy D McHugh PhD, Giuseppe Ippolito FRCP, Giovanni Batista
Migliori FRCP, Markus J Maeurer FRCP, Alimuddin Zumla FRCP*
Institutional affiliations:
Division of Infection, Royal London Hospital, Barts Health NHS Trust, London, United
Kingdom (Dr Simon Tiberi MD Email: Simon.Tiberi@bartshealth.nhs.uk)
South African Medical Research Council, Centre for Tuberculosis Research, Division of
Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences,
Stellenbosch University, Cape Town, South Africa. (Professor Gerhard Walzl PhD. FRCP
Email: gwalzl@sun.ac.za and Dr Nelita du Plessis PhD. Email: nelita@sun.ac.za)
CDC TB Trials Consortium (TBTC) Core Science Group, Veterans Affairs Medical Center,
Washington, DC, USA. (Dr Michael J. Vjecha MD. Email: mvjecha@sent.com)
Division of Therapeutic Immunology (TIM), Karolinska Institute, Stockholm, Sweden.
(Professor Markus Maeurer PhD.FRCP. Email:markus.maeurer@gmail.com and Dr Martin
Rao PhD. Email: martin.rao@gmail.com)
Fondation Congolaise pour la Recherche Medicale (FCRM), and Faculte des Sciences et
Techniques, Universite M. Ngouabi, Brazzaville, Rep du Congo. (Professor Francine Ntoumi
FRCP.PhD. Email: ffntoumi@hotmail.com fntoumi@fcrm-congo.com)
National Institute for Medical Research, Muhimbili Medical Research Centre, Dar es Salaam,
Tanzania (Professor Sayoki Mfinanga PhD. Email: gsmfinanga@yahoo.com)
UNZA-UCLMS Research and Training Programme and Apex University, Lusaka, Zambia.
(Professor Peter Mwaba PhD.FRCP Email: pbmwaba2000@gmail.com)
Institute of Public Health, Ministry of Health, Lusaka, Zambia (Dr Nathan Kapata MPH.
Email: nkapata@gmail.com)
Manuscript

2
National Institute for Infectious Disease, L. Spallanzani, Rome, Italy. (Professor Giuseppe
Ippolito MD. FRCP. Email: giuseppe.ippolito@inmi.it)
World Health Organization Collaborating Centre for Tuberculosis and Lung Diseases,
Fondazione S. Maugeri, Istituto di Ricovero e Cura a Carattere Sceintifico, Tradate Italy.
(Professor Giovanni-Battista Migliori MD. FRCP. Email: giovannibattista.migliori@fsm.it)
Centre for Clinical Microbiology, Division of Infection and Immunity, University College
London, UK (Professor Timothy McHugh PhD Email: t.mchugh@ucl.ac.uk and Professor
Alimuddin Zumla PhD. FRCP. Email: a.i.zumla@gmail.com)
NIHR Biomedical Research Centre, UCL Hospitals NHS Foundation Trust, London, UK
(Professor Alimuddin Zumla. Email. a.i.zumla@gmail.com)
Keywords: Tuberculosis, drugs, treatment regimens, host-directed therapies, treatment, drug
discovery, pipeline
Abstract: 243 words
Text: Word count: 4,735 words
Displays: Tables 4: Figures: 1
Appendix: 1
References: 155 (main body of text) and 27 (online Appendix Table 4 references)
Correspondence:
Professor Sir Alimuddin Zumla PhD.FRCP
Division of Infection and Immunity, University College London and NIHR Biomedical
Research Centre, UCL Hospitals NHS Foundation Trust, London, United Kingdom
Email: a.i.zumla@gmail.com

3
Search strategy and selection criteria
We searched reports published in English between November 1
st
2014 and November 1
st
2017 on Google, Google Scholar, PubMed, and ClinicalTrials.gov using the search keywords
 -drug-resistant (MDR)-TB, -drug-resistant (XDR) TB,
    -directed the   
immune- tuberculosis plus clinical trials, biomarkers, and
drug development. Individual searches were also performed for the following new and
repurposed TB drugs: Q203, SQ109, PBTZ169, bedaquiline, delamanid, clofazimine,
levofloxacin, moxifloxacin, pretomanid, pyrazinamide, rifapentine, rifampicin, linezolid,
delpazolid and sutezolid. Information on new drugs and compounds was reviewed from the
WHO Annual TB Report 2017, websites of the Global Alliance for TB Drug Development
(TB Alliance), Unitaid, Treatment Action Group (TAG), and the Stop TB Partnership
Working Group for New TB Drugs. Search results which were found to be relevant to this
review were selected. We also collated and synthesised information on the development of
new TB drugs, treatment regimens and host-directed therapies through communications with
various stakeholders including review of presentations and abstracts at the October 2017
conference of the International Union Against Tuberculosis and Lung Disease held in
Guadalajara, Mexico.

4
ABSTRACT
Tuberculosis (TB) remains the top killer from an infectious globally causing an estimated
1.674.000 million deaths worldwide. In 2016, WHO estimates 600.000 cases of rifampicin-
resistant TB of which 490.000 had multidrug-resistant (MDR) and less than half of them
survive after receiving currently recommended WHO treatment regimens, illustrating
weaknesses in current treatment approaches. We review progress and advances in the
development of new and repurposed TB drugs, treatment trials and host-directed therapies.
Updates are provided on phase 3 trials of the new compounds bedaquiline, delamanid,
pretomanid; phase 2 trials of sutezolid, SQ-109, LCB01-0371, PBTZ-169; and five new
drugs in phase 1 development. Approved or repurposed drugs undergoing further testing are
rifampicin, rifapentine, clofazimine, and linezolid. Update on ongoing clinical trials, which
aim to shorten TB treatment and improve treatment outcome is given. Several new or
repurposed antimicrobial drugs are in advanced trial stages for MDR-TB, and five
antimicrobial drug candidates are in phase 1 (Q203, TBI-166, OPC-167832, GSK 070, TBA-
7371) and 5 in pre-clinical studies. Specific issues of safety and toxicity; drug-drug
interactions; Therapeutic Drug Monitoring are reviewed. A wide range of candidate host-
directed therapies (HDTs) and immune-based treatments are being investigated to accelerate
the eradication of M.tb infection and for use as adjunctive therapy in shortening duration of
treatment, preventing permanent lung injury and improving treatment outcomes of MDR-TB.
Ongoing clinical trials of HDTs for TB treatment, the current HDT development pipeline and
translational research efforts for advancing further HDT options are presented.

Frequently asked questions

Q1. What are the contributions mentioned in the paper "Tuberculosis: progress and advances in development of new drugs, treatment regimens" ?

The authors review progress and advances in the development of new and repurposed TB drugs, treatment trials and host-directed therapies. Approved or repurposed drugs undergoing further testing are rifampicin, rifapentine, clofazimine, and linezolid. Ongoing clinical trials of HDTs for TB treatment, the current HDT development pipeline and translational research efforts for advancing further HDT options are presented. 

Q2. What is the effect of statins on TB?

105In addition to lipid-lowering properties, statins possess potent anti-inflammatory activities 106 with beneficial effects in TB. 

Q3. What is the role of Efflux pump inhibitors in TB?

Efflux pump inhibitors like verapamil may have a role in lowering resistance and boosting antimicrobial activity of drugs like bedaquiline. 

Q4. What is the purpose of the RIFASHORT and STAND trials?

The RIFASHORT, and STAND trials are focused on shortening the current pan- sensitive TB regimen, evaluating the utility of rifapentine, high dose of rifampicin and a completely new regimen. 

Q5. What is the use of bedaquiline in the NIX-TB trial?

54Bedaquiline is used in the TB Alliance NIX-TB trial and appears useful in the treatment of XDR-TB, pre-XDR-TB, and treatment-intolerant or treatment-non-responsive MDR-TB. 

Q6. What is the role of vitamin A in TB?

Vitamin A (vitA) possesses host immunomodulatory potential and in vitro anti-mycobacterial capabilities, 125 deficiency strongly predicts the risk of incident TB amongst TB household contacts (HHC) and supplementation (with zinc) improves TB treatment outcomes. 

Q7. How many patients had completed the six-month regimen?

55 As of October 2017, 103 participants are enrolled in the study, 70 had completed the six-month treatment course, and 31 had finished six months of follow-up. 

Q8. What is the role of IFN- in TB?

153 IFN-γ is important to protective anti-TB immunity and administration has nominal benefit in drug-sensitive, 154 and drug-resistant TB. 

Q9. How many anti-TB drugs are in clinical development?

20 There are twelve anti-TB drugs in clinical development for the treatment of drug-susceptible, MDR-TB or latent TB infection (LTBI), of which nine are new, and three are already approved or repurposed. 

Q10. How many participants have been recruited in the NEXT-TB trial?

is being tested as a flat, not weight-based, dose of 1200 mg daily in a phase 3 study TBTC S31/ACTG A5349 as part of two four-month regimens for shortened treatment of DS-TB enrolling to date more than 1,400 of a target of 2,500 participants. 

Q11. What is the purpose of the TB-PRACTECAL trial?

The TB-PRACTECAL trial is a Phase II/III adaptive trial to evaluate the safety and efficacy of 6-month regimens that contain bedaquiline, pretomanid and linezolid, with or without moxifloxacin or clofazimine, for the treatment of adults with MDR-TB or XDR-TB. 

Q12. What are the main approaches being developed for adjunct therapy for TB?

93,94 Translational studies are being developed will incorporate novel technologies, such as tissue-embedded microchips and ex vivo 3D culture models for evaluating HDTs in conjunction with anti-TB drugs. 

Q13. How many cases of delamanid were used in Latvia?

The Otsuka delamanid studies provided consistent results with high proportion of favourable outcomes: phase 2 trial 204 (192 cases), 74.5%; 65 phase 2 trial 213 (339 cases), 81.4%, 66 and programmatic use in Latvia (19 cases), 84.2%. 

Q14. What is the average number of patients who discontinued bedaquiline?

In 44/1,293 (3,4%) cases bedaquiline was discontinued due to adverse events, while only 8/857 (0.9%) discontinued the drug specifically for QT prolongation (2 of these 8 cases being able to re-start it after temporary interruption). 

Q15. What are the results of the VQUIN and TB-CHAMP studies?

The V-QUIN and TB-CHAMP studies, which both opened in 2016, are double-blind cluster-randomized phase 3 trials evaluating the safety and efficacy of six months of daily levofloxacin versus placebo for preventing TB among household contacts of MDR-TB. 

Q16. What are the main approaches being taken forward for HDT?

Three main approaches are being taken forward for HDTs as adjunct therapy for TB treatment: (i) amplification of host immunity, (ii) modulation of inflammation to reduce lung tissue destruction and (iii) killing of Mtb.Table 4 lists the HDT development pipeline for adjunct TB treatment. 

Q17. What is the recommended regimen for RR-TB?

38,39 A 9–12-month standardised regimen is recommended by WHO for all patients with pulmonary MDR/rifampicin-resistant (RR)-TB(excluding pregnant women and extrapulmonary cases) not previously treated with second line agents and susceptible to fluoroquinolones and aminoglycosides. 

Q18. What are the main reasons for the decline in the development of PBTZ-169?

with these advances there have also been some setbacks: sutezolid (undergoing phase 2 trials) has to re-perform some phase 1 studies; the development of AZD5847 was officially ended (due to lack of demonstrated anti-TBactivity); the development of TBA-354 was discontinued (due to signs of neurotoxicity in the Phase The authortrial), 19 and SQ109 has not demonstrated anti-mycobacterial activity, (however it may still retain usefulness as a companion drug and therefore function to protect the action of core drugs by raising the resistance threshold). 

Q19. What is the current classification of anti-TB drugs by WHO?

36The updated classification of new anti-TB drugs by WHO is given in table 3, 37 The taxonomy of anti-TB drugs, and their combinations are undergoing a rapid transformation as a result of clinical trials and meta-analyses.