For centuries, tuberculosis (TB) has targeted the most vulnerable populations during their most productive working years, threatening economic and social wellbeing as well as health. TB is overwhelmingly concentrated in developing countries and its resurgence has been driven, in large measure, by the HIV/AIDS pandemic. Global control efforts, while making important strides, have been hampered by the shortcomings of existing diagnostic, prophylactic and therapeutic tools.
Breaking the links between TB and poverty and winning the battle against this killer depends upon modernizing today’s cumbersome TB therapy that induces noncompliance, burdens healthcare systems and drains economies. A major goal and public health priority today has to be to make TB therapy as straightforward as curing other common infections by using the best, most modern and effective antibiotics possible. Although developing and delivering more effective medicines is the norm for diseases in industrialized countries, this does not hold true
for diseases that disproportionately affect the poor. Fulfilling the Millennium Development Goals (MDGs) requires the international community to make an equal commitment to providing better treatments for TB and other diseases of poverty.
For the first time in almost half a century, a TB treatment breakthrough is possible due to concerted international efforts by members of the Working Group on New TB Drugs of the Stop TB Partnership. With contributions from public-private partnerships (PPPs), industry, academic and public researchers, multiple compounds are in or are advancing toward clinical trials, providing the foundation for a revolutionary drug regimen that can help achieve the MDG target to halt and begin to reverse the incidence of TB. The task is not simple, and success will depend on the sustained commitment and drive of scientists, policy-makers, donors and the public health community worldwide.
The need for new TB therapies
Modernizing TB therapy is a medical and moral imperative with direct public health benefits and significant socioeconomic returns. Improved TB treatment will save millions of lives by increasing compliance, speeding time to cure, overcoming resistance and being compatible with HIV/AIDS anti-retroviral (ARV) therapy.
Despite several important recent regional successes with the current method of drug delivery that helps ensure patient compliance – directly observed treatment short-course (DOTS) – overall disease trends reflect the inadequacy of the TB drugs themselves. It is estimated that between 2000 and 2020 nearly 1 billion people will be newly infected with TB, 200 million will become sick and 35 million will die.1 TB’s financial consequences for patients and their families as well as for healthcare systems and national economies are well understood. TB costs the world US$16 billion annually – $4 billion for the costs of diagnosis and treatment and $12 billion from lost income.2
These ongoing costs as well as the epidemic’s trends mobilized donors, endemic countries, patients, as well as advocacy and treatment organizations to create the global movement known as the Stop TB Partnership in 2000, with the goal of eliminating TB as a public health problem. The Partnership’s operative arm is composed of seven distinct Working Groups, three which work collaboratively to ensure that patients today are protected, diagnosed and treated as soon as possible while working diligently to develop the next generation of interventions (drugs, diagnostics and vaccines) and new control strategies to finally defeat this centuries-old foe. (The seven Stop TB Working Groups are: DOTS Expansion, TB/HIV, DOTS-Plus for MDR-TB, New TB Drugs, New Diagnostics, TB Vaccine Development and Advocacy/Communications/Social Mobilization.)
When it comes to treatment, the current arsenal of drugs is no match for TB. Standard TB treatment now relies on a 6–9 month regimen of four drugs, each of which has significant disadvantages. While the current regimen successfully treats TB under appropriately implemented DOTS, the combination has failed to substantially reduce the overall levels of morbidity and mortality. Patient noncompliance has fuelled the emergence of multi-drug resistant strains (MDR-TB), and the symbiotic interaction between TB and HIV/AIDS and the incompatibility of their separate treatment requirements is increasing the incidence of both diseases.
The Working Group on New TB Drugs (Working Group) of the Stop TB Partnership coordinates international R&D efforts with the goal of developing new, affordable TB drugs that: 1) simplify or reduce the necessary duration of treatment to 2 months or less; 2) effectively treat MDR-TB; 3) enable the simultaneous treatment of TB and HIV/AIDS; and 4) provide treatment for patients with latent TB infection. Since its inception, the Working Group recognized that drug development in general was a slow process (8–12 years), and that TB drug development, in particular, could not rely on traditional market forces for sustainability.
With the Global Alliance for TB Drug Development as its lead agency, the Working Group is tapping and strategically advancing the scientific discoveries, capacity and know-how of all its members. It acknowledges the reality that no new therapies can be effective unless they reach those whose lives depend on them. Intelligent R&D partnerships, often between and among its members, and a pragmatic approach help ensure that resulting regimens are priced affordably, embraced by public health-care workers and accessible to patients through adequate infrastructure.
A remarkable transformation in the TB drug pipeline has occurred in the few short years since the creation of the Working Group. Today, we are able to envision an environment by 2015 that will allow for the sustained development of new TB drugs that can ultimately be combined into completely novel and revolutionary TB regimens. The global community recognizes that continued worldwide commitment, sustained cutting-edge research and expanding grassroots support are necessary to maintain and advance a consistent pipeline of new antimicrobials in order to eradicate TB within the 21st century.
A revolutionary concept for TB drug development
Due to the complex biology of the TB bacillus and the history of TB control, TB treatment requires drugs taken in combination. The current 6-month TB therapy relies upon four drugs that date back to the 1960s or earlier: isoniazid, rifampin, pyrazinamide and ethambutol. In the standard regimens, these drugs are given daily for the first 2 months, followed by an additional 4-month therapy using only rifampin and isoniazid.
Table 1 shows the global TB drug development pipeline, from discovery through clinical trials. It is noteworthy that this is the first pipeline for new potential TB drugs in decades. Just as in any drug development endeavour, several of these candidates will likely fail to meet all of their developmental hurdles. Nevertheless, the pipeline is deep enough that other candidates can succeed and become new TB drugs or serve as the basis for the successful development of analogues or derivatives. Three key factors provide optimism that the pipeline could yield a significantly shorter and better regimen that would also overcome MDR-TB and be used in conjunction with ARV treatment: 1) preclinical results that many of these drugs, when used strategically in the existing regimen, may help reduce treatment time by as much as 50%; 2) the chemical diversity of the pipeline candidates; and 3) the fact that all of these candidates are screened for cytochrome P450 enzyme interactions to ensure compatibility with ARV treatment.
In recent years, the operating strategy for new TB drug development has been to improve therapy by substituting new drugs, one at a time, into the current combination. This strategy is demonstrated and being successfully implemented in ongoing clinical trials in which quinolones such as moxifloxacin and gatifloxacin are substituted for ethambutol or isoniazid.
However, given the depth, scope and quality of the current drug pipeline, it is possible to envision a revolutionary new paradigm that allows the design of novel treatments by rationally combining totally new drugs into completely new therapeutic regimens. These new regimens will remove some of the most pressing public health hurdles for TB treatment today, such as the length of therapy, the severity of multi-drug resistance and the difficulty of simultaneous TB-HIV therapy. They will also expand the scope of current TB control by redefining public health targets – for example, by allowing the treatment of a larger pool of TB patients before they become contagious. When combined with other new interventions in development, such as improved diagnostics, new drugs will have an even greater impact.
Leveraging the drug pipeline’s potential, it is possible to apply classic principles of drug development and testing in a novel and rapidly progressive way. Each drug candidate will advance in the traditional way through Phase I, establishing its preclinical efficacy, safety and pharmacokinetic profile. Successful candidates could then be tested in combination. By examining individual drug profiles and looking for complementary targets, optimal combinations can be created and moved through preclinical and clinical evaluation, even as new molecular entities continue to be tested individually for inclusion in the pipeline. Early bactericidal activity (EBA) studies, used to predict drug potency, will be conducted on combinations that successfully pass Phase I human safety studies to solve a major problem in TB drug development. Combination therapy minimizes the threat of developing drug resistance, so EBA studies using combinations could safely be extended from the current 3–5 days to as long as 2 weeks, providing truly predictive data that assures that only the most effective and safe combinations will move into the larger and more costly Phase II and Phase III studies.
To implement this revolutionary paradigm, we must enlist the guidance and help of regulatory agencies worldwide, fortify and expand clinical trial capacity to provide good clinical practice (GCP) facilities in which to conduct the highest quality ethical clinical trials. In addition, it is imperative to establish valid surrogate and biomarkers to help shorten the duration of clinical trials substantially.
The successful introduction of new tools, such as new drugs and new regimens for TB, depends on acceptance by broad constituencies, including governments, international health organizations, health care providers and patients and their advocates. For this reason, new and harmonized guidelines are necessary to accelerate the approval and adoption of new TB therapies. Furthermore, any drug development partnership must result in affordable pricing and leverage the contributions of developing countries’ expanding scientific and medical capacities.
On the agenda: lessons learned and the job ahead
Today we have a unique opportunity to successfully and rapidly develop new TB drugs and design breakthrough regimens. Success will depend on strong collaboration between and among all participants of this enterprise – from public-private partnerships to pharmaceutical and academic scientists to regulatory officials – as well as the public sector, particularly donor and endemic country governments. By sharing the responsibility and moving forward in a concerted way, we set a course to ensure resources are efficiently and effectively leveraged. Specifically, there are four areas where this broad collaboration can further advance the efforts made to date in modernizing TB treatment:
Identifying new candidates – the TB pipeline needs to be nurtured and strengthened with additional promising compounds. Identifying and validating new targets, particularly those associated with the persistent state of
Mycobacterium tuberculosis, is critical to screen and select new compounds for development. Such compounds may already exist in libraries or may come from basic research discovery.
Expanding clinical trial capacity – there is an urgent need to expand and improve TB drug clinical trial capacity to evaluate new multi-drug regimens. The recent commitment by the European Union to fund clinical trial networks for AIDS, TB and malaria is an example of how donor countries can contribute, and endemic countries can work side-by-side with investigators to prepare and sustain the infrastructure necessary for ongoing clinical trials.
Advancing new technologies – the successful use of surrogate markers in the evaluation of HIV/AIDS therapeutics has demonstrated that valid surrogate and biomarkers can significantly reduce the length of clinical drug trials. Such markers must be developed for TB.
Ensuring regulatory harmonization – to avoid delays in the approval of new therapies and to accelerate the adoption of new TB drug regimens, TB-specific regulatory guidelines and their global harmonization are essential.
Without new medicines, TB will only grow as a global threat, driven by its deadly synergy with HIV/AIDS, complicated by multi-drug resistant strains, and amplified by the consequences of poverty. New, more effective and shorter treatment regimens will speed cure rates and save lives – they will increase productivity, enhance current TB control efforts, and alleviate much of the current burden on health care systems. When introduced alongside other advancements, such as diagnostics and vaccines, new drugs will expand the scope of current TB control and redefine public health targets. All of this requires adequate funding and a continuing commitment from public, private and governmental sources throughout the world every step of the way. We are in this effort together.
1. World Health Organization estimates, ‘Basic Facts on Tuberculosis.’ Available from: www.who.int
2. WHO estimates in Dr Barry Bloom 2001 presentation to US State Department. Available from: www.hsph.harvard.edu