R&D across health areas | Tuberculosis
R&D for Tuberculosis
How new tools can transform the fight
Tuberculosis (TB) has burdened humanity with symptoms including cough, fever, and emaciation for thousands of years. Today it is the world’s leading infectious disease killer: 10 million people fell ill from TB and 1.5 million died in 2018 alone. Yet only one low-efficacy TB vaccine exists, treatment takes months to years, and improved diagnostics designed specifically for low-resource settings are needed.
Meanwhile, growing resistance to available drugs is making the disease more deadly and difficult to treat. To end the epidemic, new technologies to prevent, treat, and diagnose TB are urgently needed.
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1.5 millionpeople die annually from TB
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$393,000treatment cost and productivity loss of MDR-TB patient in US
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45%treatment failure rate for MDR-TB
Research successes
Technologies have transformed the fight against TB:
- The first child-friendly TB medicines, developed with support from USAID, were introduced in 2015. Appropriately-dosed, dissolvable, and fruit-flavored for palatability, they have transformed treatment for children, with over 1 million courses ordered in 93 countries.
- Bedaquiline, a drug to combat multidrug-resistant TB (MDR-TB), was approved by the FDA in 2012. Developed with early support from NIH, at the time it was the first new drug approved to treat TB in over 40 years.
- Pretomanid, a new drug for highly drug-resistant TB, developed with USAID and NIH support, was approved by the FDA in 2019 as part of a combination regimen with bedaquiline and linezolid. The regimen reduces treatment time from up to two years to six months, while significantly improving treatment outcomes.
- Xpert MTB/RIF, a fully automated diagnostic test, developed with NIH and DOD support, was introduced in the early 2010s. It is simple to use and produces results in two hours, compared to prior methods which took up to six weeks.
- 3HP, a shorter preventative regimen that can be taken weekly, rather than daily, to prevent latent TB from becoming active, was first introduced in 2011. Developed with CDC and NIH support, it is improving treatment completion.
Continued progress is possible, not inevitable
Key missing tools
To end TB, we need new tools to detect, prevent, and treat infection including:
- Shorter, simplified treatment regimens for active TB to improve adherence and treatment outcomes and stem the rise of drug-resistant TB (DR-TB). Existing TB treatments can require thousands of pills and painful injections over the course of 6 to 20 months or longer, and certain drugs can cause severe side effects like liver damage and deafness.
- Improved treatments for drug-resistant strains to lower the mortality rate of MDR-TB and extensively drug-resistant TB, the deadliest and most difficult to treat forms of TB.
- New vaccines for prevention and treatment that are cost effective and address antimicrobial resistance (AMR). The TB vaccine currently is use was developed in 1921. Though effective at preventing some types of TB in infants, it offers inconsistent protection in adults against pulmonary TB, which affects the lungs.
- Rapid, non-sputum-based diagnostics, suitable for low-resource settings and primary healthcare facilities, as well as rapid DR-TB tests that enable treatment to be tailored to individuals and help safeguard against AMR.
Breakthroughs on the brink
- A new all-oral treatment regimen, BPaMZ, developed with NIH and USAID support, is in late-stage clinical trials, with the goal of reducing treatment time for drug-sensitive TB from 6 months to 4 months and for MDR-TB from 9 to 24 months to 6 months. Beyond BPaMZ, 13 new TB drug compounds are undergoing clinical trials.
- More than ten potential preventative and immunotherapeutic TB vaccines are in development, including a vaccine candidate, M72/AS01E, that prevented active pulmonary TB from developing in just over half the adults who received it in a phase 2 clinical trial.
- New approaches and strategies for TB vaccine research are invigorating the field, including research on new routes of administration, such as using inhaled aerosolized TB vaccines and new models for vaccine testing, such as the controlled human infection model, which exposes trial participants to a pathogen in a highly-controlled, safe environment.
- New innovative methods to administer treatment may lower the cost and burden of treatment by reducing the frequency and number of treatments that patients need. One example is a coiled wire device that slowly administers antibiotics into the stomach over several weeks, eliminating the need for daily oral pills.
- A new point-of-care urine test to detect TB in HIV-positive individuals is currently being evaluated, while subsequent iterations of the test for use in broader populations are in development. DNA-based tests, including next-generation sequencing, and digital tools, including computer-assisted X-rays, are also in development, which could more quickly detect and differentiate strains of TB and MDR-TB, leading to faster and more appropriate treatments for patients.
US government investment in tuberculosis R&D (in 2018) US$ millions
US Government R&D efforts
The US government is leading efforts to advance research and development (R&D) to end the TB epidemic through a whole-of-government approach:
- National Institutes of Health conducts basic, translational, and clinical research to accelerate the development of new tools to diagnose, prevent, and treat TB.
- US Agency for International Development supports R&D for new TB diagnostics and drugs. The agency also works with CDC and NIH to support basic and applied R&D for MDR-TB as part of the National Action Plan for Combating Multidrug-Resistant Tuberculosis.
- Centers for Disease Control and Prevention supports clinical and epidemiological research for TB through national and international partnerships such as the TB Trials Consortium, which has supported the development and implementation of new TB technologies and significantly improved global TB treatment and prevention guidelines.
- Department of Defense has funded research on TB vaccines, drugs, and diagnostics through the Congressionally Directed Medical Research Programs.
- Food and Drug Administration administers the Tropical Disease Priority Review Voucher Program to incentivize investment in products for neglected diseases, including TB, and implements an expedited approval pathway for antibiotics that can apply to DR-TB products.
Introduction
It is today the world’s leading infectious disease killer: 10 million people fell ill from TB and 1.5 million died: World Health Organization. Global Tuberculosis Report 2019. Geneva: World Health Organization; 2019. https://www.who.int/tb/publications/global_report/en/.
Only one low-efficacy vaccine exists, treatment takes months to years, and improved diagnostics designed specifically for low-resource settings are needed:
World Health Organization. Global investments in tuberculosis research and development: past, present, and future. A policy paper prepared for the first WHO global ministerial conference on ending tuberculosis in the sustainable development era: a multisectoral response. Geneva: World Health Organization; 2017. https://apps.who.int/iris/bitstream/handle/10665/259412/9789241513326-eng.pdf;jsessionid=BC5E45D3DD06E1CD7934C3B2172C6557?sequence=1.
Suleiman K, Lessem E. An Activist’s Guide to Tuberculosis Diagnostic Tools. New York: Treatment Action Group; 2017. http://www.treatmentactiongroup.org/sites/default/files/TB%20Diagnostics%20Guide.pdf.
$393 thousand treatment cost and productivity loss of MDR-TB patient in US: Centers for Disease Control and Prevention. The Costly Burden of Drug-Resistant TB in the U.S. Atlanta: Centers for Disease Control and Prevention; 2018. https://www.cdc.gov/nchhstp/newsroom/docs/factsheets/costly-burden-dr-tb-508.pdf.
45% treatment failure rate for MDR-TB: World Health Organization. Global Tuberculosis Report 2019. Geneva: World Health Organization; 2019. https://www.who.int/tb/publications/global_report/en/.
Research successes
First child-friendly TB medicines: TB Alliance website. Child-friendly medicines page. https://www.tballiance.org/child-friendly-medicines. Accessed August 27, 2019.
Bedaquiline, a drug to combat multi-drug resistant TB:
Mirsaeidi M. After 40 years, new medicine for combating TB. International Journal of Mycobacteriology. 2013;2(1):1–2. http://www.ijmyco.org/article.asp?issn=2212-5531;year=2013;volume=2;issue=1;spage=1;epage=2;aulast=Mirsaeidi.
NIH statement on World Tuberculosis Day [press release]. Bethesda, Maryland: National Institutes of Health; March 24, 2017. https://www.niaid.nih.gov/news-events/nih-statement-world-tuberculosis-day-0.
Pretomanid, a new drug for highly-drug resistant TB: FDA approves new treatment for highly drug-resistant forms of tuberculosis [press release]. TB Alliance; August 14, 2019. https://www.tballiance.org/news/fda-approves-new-treatment-highly-drug-resistant-forms-tuberculosis.
Xpert MTB/RIF, a fully automated diagnostic test: Lawn SD, Nicol MP. Xpert® MTB/RIF assay: development, evaluation and implementation of a new rapid molecular diagnostic for tuberculosis and rifampicin resistance. Future Microbiology. 2011 Sep;6(9): 1067–1082. https://www.futuremedicine.com/doi/10.2217/fmb.11.84?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dwww.ncbi.nlm.nih.gov.
3HP, a shorter preventative regimen: Centers for Disease Control and Prevention website. 3HP FAQs for providers page. https://www.cdc.gov/tb/education/FAQforProviders.htm. Accessed October 15, 2019.
Continued progress is possible, not inevitable
Bill & Melinda Gates Foundation and Institute for Health Metrics and Evaluation. The Goalkeepers Report 2019: How Geography and Gender Stack the Deck For (or Against) You. Seattle: Bill & Melinda Gates Foundation; 2019. https://www.gatesfoundation.org/goalkeepers/report/2019-report/#ExaminingInequality.
Key missing tools
Existing TB treatments take 6 to 20 months or longer, and certain drugs can cause severe side effects like liver damage and deafness: World Health Organization. WHO consolidated guidelines on drug-resistant tuberculosis treatment. Geneva: World Health Organization; 2019. https://apps.who.int/iris/bitstream/handle/10665/311389/9789241550529-eng.pdf?ua=1.
New vaccines: Schrager L, Harris R, Vekemans J. Research and development of new tuberculosis vaccines: a review. F1000 Research. 2019 Feb;7(1732). https://doi.org/10.12688/f1000research.16521.2.
Breakthroughs on the brink
A new all-oral treatment regimen, BPaMZ: TB Alliance. SimpliciTB and the BPaMZ Regimen. TB Alliance; 2019. https://www.dropbox.com/s/c1u2yj8zpz1pmha/tba_SimpliciTB_Factsheet.pdf?dl=0.
13 new compounds are undergoing clinical trials: World Health Organization. Global tuberculosis report 2019. Geneva: World Health Organization; 2019. https://www.who.int/tb/publications/global_report/en/.
More than ten potential preventative and immunotherapeutic TB vaccines are in development:
Tuberculosis Vaccine Initiative. Pipeline of Vaccines. Netherlands; 2015. https://www.tbvi.eu/what-we-do/pipeline-of-vaccines/. Accessed August 29, 2019.
Schrager L, Harris R, Vekemans J. Research and development of new tuberculosis vaccines: a review. F1000 Research. 2019 Feb;7(1732). https://doi.org/10.12688/f1000research.16521.2.
M72/AS01E vaccine candidate: GSK candidate vaccine helps prevent active pulmonary tuberculosis in HIV negative adults in phase II study [press release]. London: Aeras; September 25, 2018. https://www.aeras.org/pressreleases/gsk-candidate-vaccine-helps-prevent-active-pulmonary-tuberculosis-in-hiv-ne#.XaYRKkZKiUk.
New approaches and strategies for TB vaccine research: Schrager L, Harris R, Vekemans J. Research and development of new tuberculosis vaccines: a review. F1000 Research. 2019 Feb;7(1732). https://doi.org/10.12688/f1000research.16521.2.
New innovative methods to administer treatment:
Verma M, Vishwanath K, Eweje F, et al. A gastric resident drug delivery system for prolonged gram-level dosing of tuberculosis treatment. Science Translational Medicine. 2019;11(483):eaau6267. https://doi.org/10.1126/scitranslmed.aau6267
Omwoyo WN, Ogutu B, Oloo F, et al. Preparation, characterization, and optimization of primaquine-loaded solid lipid nanoparticles. International Journal of Nanomedicine. 2014;9(1):3865–3874. https://doi.org/10.2147/IJN.S62630.
A new point-of-care urine test: Mahon C. New rapid test significantly more effective for TB-diagnosis in people with HIV. Avert. June 11, 2019. https://www.avert.org/news/new-rapid-test-significantly-more-effective-tb-diagnosis-people-hiv.
DNA-based tests and digital tools: World Health Organization. Global tuberculosis report 2018. Geneva: World Health Organization; 2018. https://www.who.int/tb/publications/global_report/en/.
US government investment in tuberculosis R&D
Policy Cures Research. G-FINDER Public Search Tool. Sydney, Australia: Policy Cures Research; 2019. https://gfinder.policycuresresearch.org/PublicSearchTool/. [Early access to 2018 data was provided by Policy Cures Research in December 2019. Data is now available online as of January 30, 2019.]
US government R&D efforts
Department of Defense Congressionally Directed Medical Research Programs. Search Awards. Fort Detrick, Maryland: Congressionally Directed Medical Research Programs. https://cdmrp.army.mil/search.aspx. Accessed August 26, 2019.
Kaiser Family Foundation. The U.S. Government and Global Tuberculosis Efforts. Washington, DC: Kaiser Family Foundation; 2019. https://www.kff.org/global-health-policy/fact-sheet/the-u-s-government-and-global-tuberculosis-efforts/.
US Food & Drug Administration website. Tropical Disease Priority Review Voucher Program page. https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/tropical-disease-priority-review-voucher-program. Accessed October 23, 2019.
US Food & Drug Administration website. Limited Population Pathway for Antibacterial and Antifungal Drugs – the LPAD Pathway. https://www.fda.gov/drugs/development-resources/limited-population-pathway-antibacterial-and-antifungal-drugs-lpad-pathway. Accessed October 23, 2019.