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 trialAndreas 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 SpigelmanThe Lancet, On-line publication July 23, 2012

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

Bactericidal Activity of Different Treatment Regimens in the Mouse

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Untreated

RHZ

PaMZ

PaM

PaZ

MZ

Log10 CFU in Lungs

Weeks

R = rifampin

H = isoniazid

Z = pyrazinamide

Pa = PA-824

M = moxifloxacin

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Bactericidal Activity of NC-001 Regimens Over 4 Weeks in Mice

Andries et al, Science (2005); 307:223Ibrahim et al, AAC (2007); 51:1011Lounis et al, AAC (2008); 52:3568

Nuermberger et al, AAC (2008); 52:1522Tasneen et al, AAC (2011); in pressUnpublished data

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Participants with newly diagnosed smear positive DS TBFirst Novel Combo EBA: NC-001

J-Z

J-Pa

Pa-Z

Rifafour

J

Z=pyrazinamide, C=clofazimine , Pa = PA-824 , J = TMC207

14 daily doses

Randomize

15 per group

Serial 16 hour pooled sputum samples for CFU Count

Pa-M-Z

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Subjects Enrolled in NC-001

•Subjects with newly diagnosed pulmonary smear and culture positive drug sensitive TB

Number of Subjects

Randomized

Gender Average Age(Range)

85 26% women74% men

31 years(19 – 53)

6 subjects were HIV+

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

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0.5Bi-linear Regression: LogCFU changes from baseline

Rifafour e275

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0.5Bi-linear Regression: LogCFU changes from baseline

Rifafour e275 TMC207

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0.5Bi-linear Regression: LogCFU changes from baseline

Rifafour e275 TMC207 TMC207 & PZA

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0.5Bi-linear Regression: LogCFU changes from baseline

Rifafour e275 TMC207 TMC207 & PZAPA-824 & TMC207

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0.5Bi-linear Regression: LogCFU changes from baseline

Rifafour e275 TMC207 TMC207 & PZAPA-824 & PZA PA-824 & TMC207

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LogC

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0.5Bi-linear Regression: LogCFU changes from baseline

Rifafour e275 TMC207TMC207 & PZA PA-824 & PZAPA-824 & TMC207 PA-824 & PZA & Moxifloxacin

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

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TTP

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TMC207 TMC207 & PyrazinamideTMC207 & PA-824 PA-824 & Pyrazynamide PA-824 & Pyr & Moxifloxacin Rifafour e275

Bi-linear regression: TTP change from baseline

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NC-001 Conclusions

• 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

Pa = PA-824; M = moxifloxacin; Z = pyrazinamide; J = TMC207

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