PreDiCT-TB

Model-based preclinical development of anti-tuberculosis drug combinations
Model-based preclinical development of anti-tuberculosis drug combinations

FACTS & FIGURES

Start Date
End Date
Call
IMI1 - Call 3
Grant agreement number
115337

Contributions
IMI Funding
14 778 855
EFPIA in kind
9 296 106
Other
4 484 175
Total Cost28 559 136

Summary

Tuberculosis (TB) infects over 9 million people worldwide every year and kills 1.7 million. Treatment takes several months, and many patients struggle to take their antibiotics properly, fuelling the rise of drug-resistant strains of the disease. However, putting together a new, shorter treatment regimen could take a quarter of a century using today’s methods. The IMI-funded PreDiCT-TB project aims to speed up the search for new, more effective combinations of treatments to tackle the deadly disease. PreDiCT-TB is one of the world’s only initiatives focused on tackling pre-clinical research barriers to the discovery and development of new TB drug combinations.

TB is an airborne, infectious disease caused by the bacterium Mycobacterium tuberculosis. It usually affects the lungs, and symptoms include coughing, weight loss, night sweats, fever, and fatigue. Although it is both preventable and curable, it remains a leading cause of disease and death by infection, particularly in developing countries. TB treatment is tough; patients must take four antibiotics for at least six months. The length and complexity of this regimen mean that many patients do not take their treatment properly, or stop taking the drugs before the bacteria have been completely eradicated from the body. Thus poor compliance may well be driving a rise in multidrug-resistant (MDR) strains of TB that simply do not respond to the main first-line antibiotics. If the treatment regimen for standard TB is tough, the regimen for MDR TB is even tougher, taking upwards of two years and involving drugs that often cause severe side effects such as liver, skin and hearing problems. In addition, recent years have seen growing reports of extensively drug resistant (XDR) TB, which does not respond to a number of the core first and second line antibiotics.

There is therefore an urgent need to develop a more potent, yet patient-friendly, combination of drugs to tackle TB. However, very few new TB drugs have been developed in recent decades. Furthermore, to prevent TB from developing resistance, it must be treated with a combination of multiple drugs. Until now, new drug candidates were developed and added to the existing regimen one by one. As it takes at least six years to change one drug in the regimen by either substitution or addition, approving a new four-drug regimen through successive trials would take a quarter of a century.  Shortening this period is a top priority for the fight against TB, but current clinical trial methodologies make it very difficult to evaluate the optimal doses and combinations of drugs.

PreDiCTing the best treatment regimens
We need a way to facilitate the complex decisions around which doses and combinations of new drugs should enter clinical trials, and that’s where the PreDiCT-TB project will focus its combined resources.  PreDiCT-TB aims to develop an integrated set of laboratory-based models that will provide much-needed data to indicate the most appropriate doses and combinations of drugs for patients. In addition, the project will generate a comprehensive database of patient data from previous and on-going clinical trials for use as a reference for evaluating the performance of combination anti-TB drug regimens in these newly developed laboratory models.  Ultimately, they aim to enable researchers to be able to use the information generated by the novel models to design better clinical trials involving TB patients.  Therefore PreDiCT-TB brings together internationally-respected TB scientists and physicians with expertise in the biology, immunology and imaging of the disease, as well as those specialising in the behaviour of drugs in the body (pharmacokinetics), their interactions with one another (pharmacodynamics), and clinical trials.

A boost for TB patients
Today’s long, complex TB treatment regimen is simply not patient-friendly enough and potentially raises the risk of patients developing (and passing on to others) drug-resistant forms of the disease. By speeding up the development of better and shorter treatment regimens, PreDiCT-TB should dramatically increase the likelihood of patients completing the course of treatment successfully in future years.

New leads for the industry
By assessing combinations of new candidate drugs and optimising clinical trial design, PreDiCT-TB is set to revolutionise the speed and effectiveness of drug discovery and development in the field of TB.

Making good on a promise
Tackling TB is a high priority for governments worldwide; the international Stop TB Partnership has set the goal of eliminating TB as a global public health problem by 2050. The results of PreDiCT-TB are set to give a new impetus to efforts to deliver novel treatments against this deadly disease.

Achievements & News

New PreDiCT-TB test to speed up tuberculosis drug development
Current methods of diagnosing tuberculosis (TB) and measuring the effect of potential new treatments in clinical and pre-clinical trials depend on either culturing TB bacteria from a patient-derived specimen, or DNA-based diagnostic tests. ### Growing a culture is very slow, taking up to three months before a result is available. DNA tests on the other hand are fast, but they remain positive even after the bacteria is dead, making them unsuitable for tracking the effectiveness of potential new treatments. A new method fine-tuned by the PreDiCT-TB project offers a much faster way to diagnose tuberculosis and has the potential to improve both the speed and effectiveness of preclinical and clinical TB trials. The method is based on measuring ribosomal RNA, which is part of the structure of the organisms’ protein synthesis machinery. The RNA is easy to detect even when there are very few organisms present, and unlike the DNA, it does not survive long after the bug is killed by antibiotics. The method gives an answer in as little as four hours, and might also be able to identify a population of more persistent, antibiotic-resistant bacteria. Although the test was initially developed prior to PreDiCT-TB, the work done within the consortium enabled the creation of a test that is easier to use and is more reliable. 'PreDiCT-TB has increased the speed with which we have been able to apply this test to defined regimens and the consortium has allowed us to draw on the expertise from across the community,' said Justin Green, PreDiCT-TB project coordinator. ‘We believe this test may contribute to the speeding up of the evaluation of new drugs. It also has the potential to improve clinical management of hard to treat patients.’ PreDiCT-TB aims to speed up the search for new, more effective combinations of treatments to tackle TB, and is one of the world’s only initiatives focused on tackling pre-clinical research barriers to the discovery and development of new drug combinations for this deadly disease.
(December 2016)

Predict-TB marks world TB day
On 24 March, World TB Day, IMI’s tuberculosis (TB) project PreDiCT-TB highlighted how it is contributing to efforts to ‘unite to end TB’ – the motto of this year’s events. ### According to the World Health Organization (WHO), in 2014, 9.6 million people fell ill with TB and 1.5 million died; most of these cases were in low and middle income countries. Treatment still requires six months or more of combinations of antibiotics to ensure a complete cure and more effective drugs are urgently needed to shorten treatment. The goal of the PreDiCT-TB consortium is to find the most rapid and reliable ways of identifying the most potent combinations of new drugs and hasten their arrival in the clinic. On World TB Day, PreDiCT-TB published new materials, including articles, videos and images explaining the project’s activities and progress.

PreDiCT-TB marks World TB Day
Tuberculosis (TB) project PreDiCT-TB marked World TB Day on 24 March with a series of articles, videos and tweets on its activities. TB is an infectious bacterial disease. Although it is both preventable and treatable, in 2013, 9 million people fell ill with TB and 1.5 million died. The goal of PreDiCT-TB is to find the most rapid and reliable ways of identifying the most potent combinations of new drugs and hasten their arrival in the clinic. ###Material released on World TB Day included:
- An article on the University of St Andrews’s work in the project. The team looks at ways of detecting TB bacteria that are naturally resistant to current treatment and using this information to understand and predict the effect of current and future treatment regimens.
- Videos from the team at the University of Liverpool, including an overview of the project and a discussion on historical clinical trial data.
- A day in the life of Sanofi’s Lucie Eckenberg-Friedlander, who heads up the project’s work package on data management.
- An article on the team at École Polytechnique Fédérale de Lausanne (EPFL), which is developing tools to assess the efficacy of TB drugs.
- An interview with the project’s academic coordinator, Dr Gerry Davies of the University of Liverpool.
(March 2015)

IMI and C-Path tuberculosis projects sign Memorandum of Understanding
IMI’s PreDiCT-TB and C-Path’s CPTR projects have signed a Memorandum of Understanding to coordinate their work in developing new and effective treatment regimens for tuberculosis (TB). ###TB is a leading cause of death worldwide, with nearly 9 million new cases and 1.4 million deaths reported every year. A major challenge for those tackling the disease is the length of TB treatment – even standard cases require at least six months of treatment with a multi-drug regimen, while drug-resistant strains of the disease can take two years to treat. Both PreDiCT-TB and CPTR are working to speed up the development of shorter, more patient-friendly treatment regimens. By working together, the teams will be able to combine their forces to take on the challenges in this area more effectively.
(March 2013)

Participants Show participants on map

EFPIA companies
  • Glaxosmithkline Investigacion Y Desarrollo SL, Tres Cantos, Spain
  • Janssen Pharmaceutica NV, Beerse, Belgium
  • Sanofi-Aventis Research and Development, Chilly Mazarin, France
Universities, research organisations, public bodies, non-profit groups
  • (UK) Department of Health, Leeds, United Kingdom
  • Ecole Polytechnique Federale De Lausanne, Lausanne, Switzerland
  • Erasmus Universitair Medisch Centrum Rotterdam, Rotterdam, Netherlands
  • Institute Pasteur , Paris, France
  • Liverpool School of Tropical Medicine, Liverpool, United Kingdom
  • Max-Planck-Gesellschaft zur Foerderung der Wissenschaften e.V., Munich, Germany
  • STICHTING VUmc, Amsterdam, Netherlands
  • St George’s Hospital Medical School (trading as St George's University of London), London, United Kingdom
  • The University Court of the University of St Andrews, St Andrews, Fife, United Kingdom
  • Universidad Carlos III de Madrid, Getafe (Madrid), Spain
  • University College London, London, United Kingdom
  • University of Leicester, Leicester, United Kingdom
  • University of Liverpool, Liverpool, United Kingdom
  • University of Sussex, Brighton, United Kingdom
  • Uppsala universitet, Uppsala, Sweden
Small and medium-sized enterprises (SMEs)
  • Microsens Medtech Ltd, London, United Kingdom
  • Zf-Screens BV, Leiden, Netherlands

CONTACT

Project coordinator
Justin A Green
GLAXOSMITHKLINE INVESTIGACION Y DESARROLLO SL
Spain
+44 20 8990 2092
justin.a.green[at]gsk.com
Managing entity
Gerry Davies
University of Liverpool
United Kingdom
+44 151 4280422
gerrydavies[at]doctors.org.uk