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Background The diarylquinoline TMC207 offers a new mechanism of antituberculosis action by inhibiting mycobacterial ATP synthase. TMC207 potently inhibits drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro and shows bactericidal activity in patients who have drug-susceptible pulmonary tuberculosis.
Methods In the first stage of a two-stage, phase 2, randomized, controlled trial, we randomly assigned 47 patients who had newly diagnosed multidrug-resistant pulmonary tuberculosis to receive either TMC207 (400 mg daily for 2 weeks, followed by 200 mg three times a week for 6 weeks) (23 patients) or placebo (24 patients) in combination with a standard five-drug, second-line antituberculosis regimen. The primary efficacy end point was the conversion of sputum cultures, in liquid broth, from positive to negative.
Results The addition of TMC207 to standard therapy for multidrug-resistant tuberculosis reduced the time to conversion to a negative sputum culture, as compared with placebo (hazard ratio, 11.8; 95% confidence interval, 2.3 to 61.3; P=0.003 by Cox regression analysis) and increased the proportion of patients with conversion of sputum culture (48% vs. 9%). The mean log10 count of colony-forming units in the sputum declined more rapidly in the TMC207 group than in the placebo group. No significant differences in average plasma TMC207 concentrations were noted between patients with and those without culture conversion. Most adverse events were mild to moderate, and only nausea occurred significantly more frequently among patients in the TMC207 group than among patients in the placebo group (26% vs. 4%, P=0.04).
Conclusions The clinical activity of TMC207 validates ATP synthase as a viable target for the treatment of tuberculosis. (ClinicalTrials.gov number, NCT00449644
[ClinicalTrials.gov]
.)
Source Information
From the Centre for Clinical Tuberculosis Research, the Department of Science and Technology and National Research Foundation Centre of Excellence for Biomedical Tuberculosis Research, Faculty of Health Sciences, University of Stellenbosch, Tygerberg (A.H.D., R.P., A.V.); Medical Research Council, Durban (A.P., R.R., J.A.); Division of Clinical Microbiology and Infectious Diseases, National Health Laboratory Service and Faculty of Health Sciences, University of the Witwatersrand, Johannesburg (M.G.); Right to Care, Johannesburg (L.P.-S.); Jose Pearson Hospital, Port Elizabeth (C.P.); Harry Comay Hospital, George (R.K.); and Aurum Health Institute, Johannesburg (M.B., G.C.) — all in South Africa; Prince Leopold Institute of Tropical Medicine, Antwerp, Belgium (J.C.P.); Tibotec, Yardley, PA (T.D.M., D.F.M.); and Tibotec BVBA, Mechelen, Belgium (R.P.G.H., N.L., P.M., J.V., W.P., K.B., K.A.).
Address reprint requests to Dr. Mc Neeley at Tibotec, 1020 Stoney Hill Rd., Suite 300, Yardley, PA 19067, or at dmcneele{at}its.jnj.com.
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