BETHESDA, MD 13 April 2012—FDA approved rifampin for the treatment of tuberculosis (TB) in 1971, the same year Intel Corporation invented the first microprocessor.
Since then, advances in computer technology have revolutionized the way people live and work. But no additional medications have been approved by FDA for the treatment of Mycobacterium tuberculosis infection—a problem that federal officials and others want to fix.
"It can't take 40 years for us to get our next drug candidates for tuberculosis developed," said Janet Woodcock, chief of FDA's Center for Drug Evaluation and Research, during a March 19 briefing in Washington, D.C., sponsored by the Critical Path to TB Drug Regimens partnership.
Launched in 2010, the partnership was founded by the Bill and Melinda Gates Foundation, the Critical Path Institute, and the Global Alliance for TB Drug Development, also known as the TB Alliance. The partnership promotes innovative ways to speed the development of new TB drugs.
Complacency. The mortality rate for TB infection in the United States declined from nearly 200 deaths per 100,000 population in 1900 to less than 1 per 100,000 population by 1980, said Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases.
Fauci said the near-disappearance of TB deaths in the United States and the developed world "led to widespread complacency and the perception that we had an adequate tuberculosis armamentarium."
But by failing to look beyond their borders, he said, countries in the developed world essentially forgot about the burden of TB elsewhere.
The 2011 global report on TB control from the World Health Organization (WHO) estimates that there were nearly 9 million new cases of TB and nearly 1.5 million deaths from the disease in 2010. About one third of the world's population have a latent Mycobacterium tuberculosis infection, putting them at increased risk for the development of active TB, according to WHO.
WHO declared TB a global public health emergency in 1993. Nearly 20 years later, Fauci said, the current state of TB science is "embarrassing": too little is known about how the bacterium causes disease, diagnostics are inadequate, treatment regimens are cumbersome to administer, and the only vaccine against TB is antiquated and fails to prevent the most transmissible form of TB, pulmonary tuberculosis, in adults.
Drug regimens. Currently accepted treatment regimens for TB consist of multiple drugs that must be taken for several months. Patients infected with multiple-drug-resistant (MDR) Mycobacterium tuberculosis strains may require more than two years of treatment.
The complexity and length of these regimens can make adherence difficult for patients and encourage the development of drug-resistant strains of Mycobacterium tuberculosis.
"A six-month treatment requirement is really a setup for failure and development of resistance, and that's what we're seeing," Woodcock said.
A WHO-supported working group on TB drug development has identified about a dozen drugs and combination regimens in clinical testing and seven others in preclinical development.
"For the first time in a very long time, the TB drug pipeline is finally showing promise, and we're seeing a significant number of new entities that might be tested," Woodcock said.
Mel Spigelman, president of the TB Alliance, said an ideal treatment regimen for TB would clear the infection after 7–10 days of oral therapy.
"Right now, I don't know of any clear path to take us to 7–10 days because the biology [of TB] is not well enough understood," he said.
But he said a drug combination used in a new Phase II study, dubbed NC-002, shows promise of reducing treatment duration from current standards, regardless of whether the patient is infected with drug-resistant or drug-susceptible bacteria. He said preliminary research indicates that a four-month regimen could be possible.
"This would be a once-a-day, completely oral regimen, that would reduce the treatment time by about 80%" in patients with MDR TB, Spigelman said. "Equally important, it would reduce the cost of treating MDR patients by about 90%" compared with current treatment regimens, he said.
Adults with pulmonary tuberculosis who enroll in NC-002 will be treated with a combination of moxifloxacin, pyrazinamide, and PA-824, an investigational nitroimidazole drug under development by the TB Alliance. The trial seeks to enroll 230 participants in Brazil, South Africa, and Tanzania and is expected to continue through next June.
The primary outcome being measured in the trial is the rate of change in the amount of bacteria present in sputum samples collected over eight weeks of treatment.
Spigelman said this is the first time a TB regimen has been simultaneously tested against drug-susceptible and drug-resistant infections in patients.
FDA's efforts. Woodcock said FDA is adjusting its requirements for clinical trials in which multiple drug regimens are the standard of care for treating a disease, as is the case for TB. The agency in December 2010 issued a guidance document to help manufacturers understand FDA's expectations for this type of study.
The agency that year also awarded $3 million in grants to the TB Alliance and others to investigate clinical trial design, biomarkers, and diagnostic tools and to establish a repository of TB specimens from clinical trial participants.
FDA on March 16 proposed to reclassify nucleic acid-based tests for TB as moderate-risk medical devices instead of high-risk ones. The agency took this step to encourage manufacturers to develop new, rapid diagnostic tests for TB infection.
FDA said nucleic acid-based tests hold the promise of shortening the time of TB diagnosis to hours from the days or weeks required with current diagnostic methods.