Worldwide, tuberculosis (TB) claims an estimated 1.6 million lives each year, 4400 each day, more than any other infectious disease. The majority of TB-related deaths occur in developing countries in Africa and Southeast Asia. In 2005, 80% of new TB cases occurred in just 22 countries.

TB is caused by infection with a bacillus, Mycobacterium tuberculosis (M. tuberculosis; Mtb). TB is spread from person to person through the air, and primarily affects the lungs. Infection with M. tuberculosis is relatively common, but most people who test positive for TB infection will never get sick. An estimated 10% of infected individuals will develop active TB over the course of their lifetime. At any given point in time, 14 million people are battling TB somewhere in the world.

TB is treatable. For patients who complete treatment, which involves at least 6 months of a combination of drugs, 85% can achieve a complete cure. However, the long duration of the combination regimen, and potentially significant side effects, can lead to poor compliance with treatment. This is true even in the developed world where therapy and supportive care can be optimized. Currently only about a quarter of patients who get treatment receive a complete course.

Suboptimal drug combinations and compliance have fueled the emergence of drug-resistant TB strains. An estimated 400,000 or more new cases of multidrug resistant TB (MDR-TB) arise every year. So-called extensively drug resistant TB (XDR-TB) is potentially an even more serious problem, as all first line TB drugs, as well as other classes of agents, are ineffective against XDR-TB infected patients. XDR-TB afflicts 25-30,000 patients each year, and is associated with mortality rates of more than 50%. XDR-TB has been described by World Health Organization (WHO) officials as a threat to the security and stability of global health. The problem of drug-resistant TB is further exacerbated by the severe medical and social complications associated with common debilitating co-infections, such as HIV/AIDS, which is prevalent in places where TB is endemic.

Further global spread of TB, especially drug-resistant strains, appears imminent and new therapeutic options are desperately needed. Without new treatments and better disease control, an estimated 1 billion people will become newly infected by 2020, of which 150 million will become sick and 36 million will die.

Limited progress has been made in recent years to develop new and more effective therapies. The last new TB drug was introduced into routine clinical practice 30 years ago.

Suggested Reading: Tuberculosis

Research into new and more effective strategies to control TB are advancing on multiple fronts. There is general consensus that new therapies should target shorter treatment durations and simpler combinations, both of which could lead to better compliance. To address these needs, researchers are renewing investigation of existing antibiotic classes. These new classes target new mechanisms that underpin the proliferation, virulence and persistence of Mtb, as well as the host response to infection.

The 1998 publication of the complete sequence of M. tuberculosis has allowed researchers to better understand specific targets involved in TB and to develop new compounds for these targets. In the near-term, the biggest impact to TB treatment may be made by conventional drug development. Researchers are hard at work in this area trying to determine if broad spectrum antibiotics already on the market, such as the fluoroquinolones moxifloxacin and gatifloxacin, may help to increase the effectiveness of TB therapy.

In this field, four leading organizations have emerged to advance novel approaches to addressing key treatment needs in TB, with the hope of reversing the TB epidemic on a global scale.

In February 2000, the Global Alliance for TB Drug Development was launched to accelerate the discovery and development of new TB drugs. The goal of the TB Alliance is to develop new drugs that will shorten TB treatment, be effective against susceptible and resistant strains, be compatible with antiretroviral therapies, and improve treatment of latent infection. The TB Alliance collaborates with public and private laboratories worldwide, to engage top minds of both science and business in advancing a robust portfolio of new TB drug candidates.

In June 2003, Eli Lilly established the Lilly Multi-Drug Resistant TB Partnership, a private-public partnership focused on the treatment and prevention of multi-drug resistant TB. In addition to Lilly, the partnership includes other private and public health care professionals, academic institutions, patients, community advocates, international organizations, and producers of medicines in developing regions. They have aligned their efforts to address this public health threat. The partnership seeks to control the spread of MDR-TB through a variety of educational, advocacy and support programs, and through the transfer of technology for the production of two Lilly MDR-TB drugs (cycloserine and capreomycin) to countries where the burden of MDR-TB is greatest.

The Novartis Institute for Tropical Diseases (NITD) is seeking to develop novel therapies for multi-drug resistant TB through the application of genomics and bioinformatics technologies. Broadly, the institute is focused on applying drug discovery expertise and technology to discover novel treatments and prevention methods for major tropical diseases including dengue fever and malaria.

The Gates Foundation has granted more than $250 million to various organizations involved in the treatment, prevention and discovery of new medicines for TB. The foundation’s support is largely focused on those organizations discovering and developing new tools to prevent and treat TB, working to better manage the disease with existing health strategies, working to ensure access to new TB products, and on organizations that work to build commitment and financial support to combat TB.

Like these entities, Vertex believes that there is an urgent need for novel therapeutic strategies and regimens to fight TB. Vertex is engaging a global network of scientific and clinical TB experts, and is exploring ways to apply expertise in cellular signaling to TB drug discovery and development. Specifically, Vertex research is focused on modulating cell signaling pathways to either restore defective host defense mechanisms in infected cells or interfere with critical Mtb mechanisms. The goal of this research is to discover novel compounds that could potentially undermine the ability of M. tuberculosis to survive within infected host cells and offer new treatment options for TB, including multidrug resistant TB.