Tuberculosis Roars Back: A global alliance forms to speed development of new drugs

October 9, 2000

In early October, an unusual alliance of 25 government and international health agencies, drug companies, and philanthropic foundations will meet in Bangkok to lay out their strategy for a new world war. The mutual enemy is tuberculosis , one of mankind's oldest scourges, and rapidly becoming one of its deadliest once again. The Global Alliance for TB Drug Development, the first international disease effort of its kind, plans to issue a blueprint on Oct. 10 for the development of the first new drugs to fight TB in more than 30 years--and, ultimately, of a vaccine that may one day eradicate the disease.

All of a sudden, TB is hot. In the past two years a confluence of rapidly spreading disease, scientific breakthroughs, and, most critically, increased funding, has given renewed urgency to the study of a disease that only 20 years ago scientists thought had been beaten. The National Institutes of Health (NIH) and the Centers for Disease Control and Prevention (CDC) have both started intensive TB research efforts, and several biotech companies have recently reported promising new drug and vaccine candidates. Researchers have also benefited from funding grants from Glaxo Wellcome's seven-year-old Action TB program and the Bill & Melinda Gates Foundation, which has donated $845 million to TB projects since 1998.

The need couldn't be more urgent. The World Health Organization (WHO) estimates that Mycobacterium tuberculosis , the bug that causes TB, has now infected some 2 billion people around the world--one in every three. Only about 10% of these carriers are expected to develop the disease, and thus become infectious. Those who do will each go on to infect an average of 10 to 15 others.

Once activated, TB attacks and destroys the lungs and is easily spread by coughing and sneezing. So prevalent is the disease that scientists do not even call its resurgence over the past decade an epidemic--it is endemic, permanently lodged in the world's populations. Each year, almost 3 million people die of TB, most of them young adults. It's the fifth-largest cause of death globally and the No. 1 killer of women, according to WHO, which also predicts there will be 1 billion new cases of TB by 2020 and 70 million deaths. SUPERBUG. Finding new drugs is critical, due to the rapid rise of a new strain of the bacteria that is resistant to all existing treatments. And scientists are beginning to realize that the search will be never-ending, because the TB bug seems to be frighteningly good at developing resistance to each new drug that comes along. The current treatment calls for four antibiotics to be taken over six months, but recent studies have found that in 80% of patients, at least one of these antibiotics is no longer effective. "We are running out of medications that will work against TB,'' warns Dr. Kenneth G. Castro, director of the CDC's TB Elimination Div. "This scenario threatens to return us to the pre-antibiotic era.''

Harsh economics share the responsibility for this scenario. Because the bulk of tuberculosis infections are in developing nations, drug companies have shown little interest in developing new treatments, having concluded that there would be no money to pay for them. ``There's lots of interest in the nonprofit community, and some interest in the biotech community, but there is still a lot of skepticism from the large pharmaceutical companies,'' laments Carol A. Nacy, founder of Sequella Global TB Foundation in Rockville, Md.

But with TB gaining victims in the industrialized nations--15 million are already infected in the U.S. alone--there are suddenly plenty of patients who can pay. TB treatment costs more than $16,000 per patient in the U.S., according to the Institute of Medicine, and the cost of treating drug-resistant strains runs much higher. There would likely be huge demand for anything that reduces the bill. FAST TRACK. The Global Alliance is also determined to make TB research far less costly than the $300 million to $500 million typically spent to develop a new drug. The alliance, whose members include the CDC, NIH, the World Bank, and the International Federation of Pharmaceutical Manufacturers, is attempting to coordinate an international research effort that would share resources and place drug discovery on a fast track. It is also drawing up an economic analysis of the potential market. "I think we can prove that there is a very significant market opportunity,'' says Ariel Pablos-Mendes, associate director for health equity at the Rockefeller Foundation and a key organizer of the global alliance. He figures a TB drug could bring in at least $500 million a year, far more than many cancer drugs.

TB research is getting a scientific boost as well a financial one. The field moved to the cutting edge of medical research two years ago after scientists funded by the Wellcome Trust sequenced the M. tuberculosis genome. Researchers suddenly had 4,000 genes to screen, raising the possibility of targeted therapies that could be far more effective than general antibiotics.

There is still much to learn, however, about M. tuberculosis' ability to reside harmlessly in an infected person for decades. ``TB is very, very persistent,'' says John D. McKinney, director of Rockefeller University's Laboratory of Infection Biology. ``A person infected 60 years ago could still harbor the bug.'' The bacteria usually becomes active after the patient's immune system weakens for some other reason, such as infection by the HIV virus. In fact, TB is the leading cause of death for AIDS victims.

Researchers still have only a dim idea of what prompts the bacterium to turn deadly. It lurks in immune system cells located in the lungs called macrophages, which ingest foreign microorganisms. M. tuberculosis can apparently survive inside the macrophages, where it grows and divides into protective structures called granulomas. The bacteria lie dormant in these structures until activated, when they break out and attack the lungs.

One of the most promising drug candidates so far, reported in June by PathoGenesis Corp. of Seattle, attacks the bacteria in the macrophage. In lab tests, PA-824 inhibited the synthesis of a fatty acid on the bug's cell wall, which seems to both slow the microbe down and prevent it from producing needed proteins--a potential death blow. Most significantly, the compound worked against the bug in its dormant phase.

In contrast, existing drugs are generally effective only after the bacteria activates.

A second significant breakthrough was announced by a research consortium in August. The team, which included Rockefeller's McKinney, discovered an enzyme that is critical to the survival of the bacteria in the granulomas. When the gene for that enzyme is knocked out, the bug can no longer resist the body's immune response. The team is now working with Glaxo-Wellcome to develop drugs that would target this enzyme.

Any commercial drug is still at least seven years away from approval, researchers caution. Even further out is a possible vaccine. The greatest roadblock is the 2 billion people already infected--to be truly effective, a vaccine would have to be able to clear their bodies of the dormant bugs. Because the TB bacterium can hide from the immune system, a typical antibody-based vaccine would not work in most people. And the efficacy of the one TB vaccine in existence, commonly called BCG, is so erratic that it is rarely used in the U.S. FUSED INTO ONE. The NIH is conducting a major effort to develop a TB vaccine, and expects a few candidates to enter early human trials next year. One of these was developed by Corixa Corp. in Seattle. The company identified a group of U.S. doctors who were exposed to TB while working in South America but were able to purge the infection. Corixa isolated the specific proteins in the TB bug that the doctors' immune systems were able to act against, and fused them together into one big immune-stimulating molecule. It has already been tested in monkeys. Next year, with funding from SmithKline Beecham PLC, Corixa hopes to start testing in health-care workers.

The main challenge now is to make sure that interest remains high. ``We've got a very good start, but we need to sustain it,'' warns the CDC's Castro. ``We can't have funding for two years and then have it disappear.'' With a steadily rising death toll, the world can ill afford to turn complacent again.