LISBON — Tuberculosis experts now generally agree that the main priority for improving TB therapy is to shorten and simplify the regimen for active disease, Dr. Ann Ginsberg said at the 12th International Congress on Infectious Diseases.
“This will have the greatest impact on the epidemic as compared to trying to improve MDR [multidrug-resistant] TB and TB/HIV-coinfected patients. Those are also extremely important problems, but epidemiologically speaking they don't involve the same number of patients as standard active disease,” noted Dr. Ginsberg, director of clinical development at the Global Alliance for TB Drug Development, New York.
A short-course treatment for latent infection—the norm today remains 9 months of isoniazid—would probably have the biggest impact of all on the epidemic. But it's not yet feasible. Not enough is understood about the biology underlying TB latency to permit rational drug development, she continued.
Treatment for active drug-responsive TB today typically involves a minimum of 6 months of daily therapy with complex combinations of four drugs: isoniazid, rifamycin, pyrazinamide, and ethambutol. The length and complexity of this regimen result in poor compliance, which promotes increased drug resistance. Treatment of TB patients coinfected with HIV—a large and growing population—is essentially the same, with the added complication that rifamycin and isoniazid interact adversely with key antiretroviral agents.
The near-term goal of the Global Alliance and other groups is to replace the current regimen, which entails taking 7–14 pills per day for 6 months, with 2–3 months of once-weekly therapy.
The longer-term goal is to shrink treatment to 2 weeks or less, much as other respiratory infections are treated. That must await better understanding of the mechanisms involved in TB persistence, Dr. Ginsberg explained at the congress, which was sponsored by the International Society for Infectious Diseases.
The last new class of TB drugs was introduced in the 1960s. Drug development then stagnated for more than 3 decades. That began to change a few years ago. Today the TB drug development pipeline is richer than at any point in the last half-century.
Some new compounds target the TB bacillus, others the host. Most are still in preclinical development. However, at least a half-dozen are in clinical trials, including moxifloxacin, now in phase III trials, and gatifloxacin, slated to begin phase III studies within several months. Both fluoroquinolones have pharmacokinetics amenable to weekly dosing, as does rifapentine, another drug well along in the pipeline.
Animal studies suggest a shorter, simpler 2- to 3-month regimen of weekly therapy is probably achievable with drugs now in development, perhaps used in combination with some current drugs. However, all of the current first-line drugs have suboptimal profiles, and none may wind up in the new optimized regimen, according to Dr. Ginsberg.
Developing a truly novel TB drug regimen in a timely fashion will require a philosophic shift on the part of the Food and Drug Administration and other regulatory agencies. The conventional development process evaluates one new drug at a time, substituting it in studies for one of the agents in the current regimen. With the conventional process, a regimen with multiple new drugs could take 30 years to gain approval.
“Given the urgency of the global TB epidemic, this is not acceptable,” she said.
The Global Alliance has urged the FDA to allow an alternative pathway to clinical development, in which whole new regimens would be tested against the standard combination. In this way, a more efficacious optimized regimen could be established in a 6-year clinical development period if all goes smoothly, Dr. Ginsberg said.