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Clinical Study NC-001 Stephen Murray, MD, PhD Global Alliance for TB Drug Development

Clinical Study NC-001 Stephen Murray, MD, PhD Global Alliance for TB Drug Development. 14-day bactericidal activity of PA-824, bedaquiline , pyrazinamide , and moxifloxacin combinations: a randomised trial

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Clinical Study NC-001 Stephen Murray, MD, PhD Global Alliance for TB Drug Development

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  1. Clinical Study NC-001Stephen Murray, MD, PhDGlobal Alliance for TB Drug Development 14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacincombinations: a randomised trial Andreas H Diacon, Rodney Dawson, Florian von Groote-Bidlingmaier, Gregory Symons, Amour Venter, Peter R Donald, Christo van Niekerk, Daniel Everitt, Helen Winter, Piet Becker, Carl M Mendel, Melvin K Spigelman The Lancet, On-line publication July 23, 2012

  2. Bactericidal Activity of Different Treatment Regimens in the Mouse Log10 CFU in Lungs R = rifampin H = isoniazid Z = pyrazinamide Pa = PA-824 M = moxifloxacin Weeks 2

  3. Bactericidal Activity of NC-001 Regimens Over 4 Weeks in Mice Andries et al, Science (2005); 307:223 Ibrahim et al, AAC (2007); 51:1011 Lounis et al, AAC (2008); 52:3568 Nuermberger et al, AAC (2008); 52:1522 Tasneen et al, AAC (2011); in press Unpublished data 3

  4. First Novel Combo EBA: NC-001 J J-Z J-Pa 14 daily doses Pa-Z Pa-M-Z Rifafour 15 per group Serial 16 hour pooled sputum samples for CFU Count Randomize Z=pyrazinamide, C=clofazimine , Pa = PA-824 , J = TMC207 4 Participants with newly diagnosed smear positive DS TB

  5. Subjects Enrolled in NC-001 • Subjects with newly diagnosed pulmonary smear and culture positive drug sensitive TB 6 subjects were HIV+ 5

  6. All Treatment Groups: Bi-linear Regression Mean of logCFU Over Day; Change from Baseline (Day X – Day 0) 6

  7. All Treatment Groups: Bi-linear Regression Mean of TTP Over Day; Change from Baseline (Day X – Day 0) 7

  8. NC-001 Conclusions Pa = PA-824; M = moxifloxacin; Z = pyrazinamide; J = TMC207 8 • Validation of mouse data: • J-Z synergy, Pa-Z additivity, Pa-J lack of additivity • Pa-M-Z is an enhanced novel regimen in 2-wk study • All three compounds contribute to observed effect • Z enhances the EBA of both Pa and J • EBA can distinguish between treatments • Just as it has previously distinguished between doses • CFU and TTP give similar results

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