B-881b. Interim Analysis of a Double-Blind, Placebo-Controlled Study with TMC207 in Patients with Multi-Drug Resistant (MDR) Tuberculosis
Session: Slide Session: Mycobacteria: New Therapies, Mechanisms and Models
Sunday, October 26, 2008: 12:00 AM
Room: Independence I (Grand Hyatt)
Background: TMC207 is a first-in-class investigational anti-TB agent with a novel mechanism of action and potent preclinical activity against susceptible and resistant TB isolates. We report on the first stage of a phase IIB trial in patients with newly diagnosed MDR TB. Methods: Forty-seven patients were randomized to receive a 5-drug MDR regimen (KAN+OFX+ETA+TER+PZA) plus either placebo (n=24) or TMC207 (n=23) for 8 weeks and then continued with the MDR regimen. Safety was monitored throughout. Triplicate spot sputa were cultured weekly in MGIT tubes, and serial sputum colony counting (SSCC) was performed on 16-hour pooled sputa specimens in a subgroup of patients (n=22). Patients were considered culture negative following 2 consecutive negative readings. Results: Groups did not differ in biometrics, adherence, or resistance to second line agents. There were no serious adverse events attributable to study drug. When assessed by MGIT, 47.5% of TMC207 treated patients became culture negative versus 8.7% treated with placebo (p=0.003) within 8 weeks. For those assessed by SSCC, none of the 9 TMC207 treated patients were reported with a positive SSCC culture at Week 4 or later, compared to 9 out of 13 patients in the control group. Conclusions: Our data clinically validate ATP synthase as an exciting new target for TB treatment and confirm results obtained with TMC207 in the mouse model. TMC207 administered for 8 weeks with a standardized 5-drug MDR regimen was generally well tolerated and significantly increased the proportion of subjects that became culture negative compared to placebo.
R Krause, MD1, R van Heeswijk2, T de Marez, PhD2, Alexander Pym, MD3, Andreas Diacon, MD4, C Pistorius, MD1, David McNeeley, MD2, K de Beule2, K Andries, PhD5, M Bogoshi, MD6, Martin Grobusch, MD7, N Lounis2, P Meyvisch2 and  A. H. Diacon, None., (1)QdotPharma, (2)Tibotec, (3)Medical Research Council, (4)Univ of Stellenbosch, (5)Tibotec Pharmaceuticals Ltd., BVBA, (6)Aurum Health, (7)Univ of Witersrand and NHLS



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