NEW TOOLS to improve the treatment and control of tuberculosis (TB) are a critical component of any comprehensive strategy to eradicate the global TB epidemic. In particular, the development of new drugs is desperately needed. No truly novel TB drugs have been approved for more than 40 years, and the current treatment regimens are inadequate, taking six to nine months to treat drug-susceptible TB and as much as 30 months to treat drug-resistant TB. Patients must often take more than 10 pills a day, and the standard treatment of multidrug-resistant TB includes a daily parenteral injection in addition to multiple pills. Adherence to such regimens is extremely diffi cult, resulting in rising rates of drug-resistant TB.
As recently as a decade ago, there was little hope for a new regimen due to the lack of any new TB drug candidates in the pipeline. With little or no market incentive, coupled with the difficulties caused by an outdated and inadequate clinical trial infrastructure and the lack of regulatory guidance, the hurdles for TB drug and regimen development appeared extremely difficult to overcome. Among the neglected diseases, these issues made TB one of the most neglected.
However, in March 2010, an initiative that could dramatically speed the development of transformative, novel treatment regimens was launched—the Critical Path to New TB Regimens (CPTR). The Bill & Melinda Gates Foundation, the Global Alliance for TB Drug Development, and the Critical Path Institute founded the initiative, which works closely with the Food and Drug Administration and other regulators as well as the European and Developing Countries Clinical Trials Partnership to promote the development of new regulatory approaches that support innovative research into TB therapeutics and evaluate the safety and efficacy of new TB drug combinations.
The CPTR initiative also includes 11 TB drug sponsors—Anacor Pharmaceuticals, AstraZeneca, Bayer, GlaxoSmithKline, Johnson & Johnson, Novartis, Otsuka, Pfizer, sanofi -aventis, Sequella, and Vertex—as well as various civil society groups and other constituencies who will work together to reduce the time it takes to develop new TB treatment regimens from decades to years.
CPTR is based on the recognition that we can no longer allow the global epidemic to kill millions of people every year and that we must move even faster in our attempts to halt the devastation caused by this disease. For the first time ever, the group will build the regulatory science to enable TB drug developers to test regimens that include more than one experimental compound at a time, ostensibly shifting the unit of development from individual TB drugs to entire regimens. This new development paradigm eliminates the need to build new regimens through successive substitution of novel compounds into approved treatment regimens. Such an evolution means that it may be possible to make quantum leaps in the improvement of therapy, as opposed to incremental advances, and to do so at a markedly accelerated pace.
The goal is to create faster-acting novel regimens that could treat drug-susceptible and drug-resistant TB. What has made this initiative possible is the increased global commitment to TB drug research and development over the past decade. It is now feasible to develop markedly improved TB regimens from the nine TB drug candidates presently in clinical development along with the existing TB drugs. We have been very active in the pre-clinical testing of combinations and, along with our partners, have already identified nine or 10 TB drug regimens that look more promising than the current regimens.
The first CPTR clinical trial in humans will likely begin within a year. A working goal for the regimen that will be tested is to reduce the treatment time for TB to two to three months in both drug-susceptible and drug-resistant disease. With the continued maturation of the global TB drug pipeline, subsequent waves of innovation are likely to follow, meaning that the vision of treating TB in two weeks or less, just like many common bacterial infections, is more tangible than it has ever been.
CPTR’s success will largely be determined by the commitment of its partners and the execution of its efforts. Participants will encounter formidable scientific, logistical, and intellectual property challenges. However, we are confi dent that the necessary dedication and expertise to overcome such impediments exists among the partners.
The biggest challenge to CPTR’s long-term viability is, however, likely something far more elemental than any of these issues—funding. The Bill & Melinda Gates Foundation has provided seed money for this initiative, and a number of organizations and governments around the world have thankfully contributed to TB drug development. But if we, as a global community, are serious about defeating TB, we will need a wide-ranging, cross-sector mobilization of resources to support the substantial work still to be done. Success is costly, and with clinical development of new TB drugs becoming feasible as a result of successful discovery programs and CPTR, the primary challenge of TB eradication will shift from not having ample drugs to develop, to the need to secure the necessary resources to carry out such development. However, CPTR trials should also cost less than traditional development of TB drugs, as there are efficiencies to be gained when developing combination regimens at once, rather than stretching the development of a regimen out over decades.
The emergence of a global portfolio of drugs sparked hope in the millions living with TB’s dreaded diagnosis. It is not only our moral obligation to help these patients as quickly as possible, it is also in the interest of global prosperity that we allocate the necessary resources to fulfil this promise.
Mel Spigelman, MD
Global Alliance for TB Drug Development
New York, New York, USA
Raymond Woosley, MD, PhD
Critical Path Institute
Tucson, Arizona, USA
Jan Gheuens, MD, PhD
Bill & Melinda Gates Foundation
Seattle, Washington, USA