The Global Alliance for TB Drug Development (TB Alliance) today released the results of a Phase lla study of PA-824, a member of a new drug class not previously used to treat tuberculosis (TB). PA-824, which belongs to the class of drugs known as nitroimidazoles, is the first TB drug candidate developed by a not-for-profit organization to reach clinical trials in patients.
The TB Alliance, a product development partnership accelerating the discovery and development of new drugs to fight TB, presented the results of the proof-of-concept study in TB patients on Sunday 26th October 2008 at the joint meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy and Infectious Diseases Society of America in Washington, D.C.
In this study, PA-824 demonstrated early therapeutic potency against Mycobacterium tuberculosis (M.tb), the bacterium that causes TB, suggesting its potential to help reduce the length of TB treatment. A previous preclinical study showed that PA-824, consistent with its novel mechanism of action, was effective against both drug-susceptible and multidrug-resistant M.tb.
The current study confirms that PA-824 could someday be incorporated into a regimen to treat drug-susceptible and drug-resistant TB more quickly and effectively.
The Phase IIa Early Bactericidal Activity (EBA) study evaluated PA-824's short-term potency when given as a single drug to TB patients. Patients received either PA-824 (200, 600, 1000 or 1200 mg once daily) or the standard, four-drug TB treatment for 14 days.
The randomized, partially double-blinded (i.e. double-blinded as to dose of PA-824 ) study was conducted at two sites in South Africa. There were 15 or 16 patients in each of the four PA-824 treatment groups. Study participants were immediately transferred to the full, standard TB treatment regimen at the completion of the trial.
Each of the four PA-824 study doses resulted in essentially equivalent EBA, with a steady decrease in the number of living M.tb in the sputum (~0.1 log drop in CFU per day for 14 days). Steady-state blood concentrations of PA-824 were achieved on approximately the fifth day of the study.
PA-824 was well-tolerated by study participants, confirming the positive safety data from two-week rat and monkey trials and the lack of dose-limiting adverse events in earlier Phase I studies of PA-824 in healthy volunteers.
In parallel with the EBA study, the TB Alliance conducted 3-month toxicity studies in the rat and monkey to support later stage clinical development. Data from these animal studies suggested that high doses of PA-824 may cause cataracts in rats and monkeys and have adverse effects on the male reproductive system in rats.
To further understand these findings, the TB Alliance is conducting ophthalmologic examinations in patients who participated in the Phase IIa study and those volunteers who received the highest exposures to PA-824 in Phase I. Further, the TB Alliance is conducting a three-month follow-up study in sexually mature monkeys and a six-month study in rats; both studies include extensive ocular and male reproductive systems monitoring.
Similar toxicities are not expected in human studies because the exposures at high doses achieved in the affected animals significantly exceeded the highest exposures achieved in humans. Importantly, in the EBA study, maximum efficacy was achieved at the lowest dose tested, so patients in future studies need receive only low doses of PA-824. If the results of the human ocular monitoring and the ongoing animal studies confirm that it is safe, the next clinical study is designed to explore the safety and efficacy of PA-824 doses equal to and lower than the lowest dose administered in the recently completed EBA study.
Tuberculosis is a growing global health threat that kills over 1.5 million people worldwide every year. New drugs that contribute to shorter treatments are essential to reducing the needless global burden of TB and eventually eliminating the disease. As the TB Alliance drives the development of the most comprehensive portfolio of TB drug candidates in history, we are encouraged by the PA-824 results and its potential benefit to patients.