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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 - PowerPoint PPT Presentation
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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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3
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5
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0 4 8
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 2 4 6 8 10 12 14-3
-2.5
-2
-1.5
-1
-0.5
0
0.5Bi-linear Regression: LogCFU changes from baseline
Rifafour e275
Day
LogC
FU c
hang
e fro
m b
asel
ine
0 2 4 6 8 10 12 14-3
-2.5
-2
-1.5
-1
-0.5
0
0.5Bi-linear Regression: LogCFU changes from baseline
Rifafour e275 TMC207
Day
LogC
FU c
hang
e fro
m b
asel
ine
0 2 4 6 8 10 12 14-3
-2.5
-2
-1.5
-1
-0.5
0
0.5Bi-linear Regression: LogCFU changes from baseline
Rifafour e275 TMC207 TMC207 & PZA
Day
LogC
FU c
hang
e fro
m b
asel
ine
0 2 4 6 8 10 12 14-3
-2.5
-2
-1.5
-1
-0.5
0
0.5Bi-linear Regression: LogCFU changes from baseline
Rifafour e275 TMC207 TMC207 & PZAPA-824 & TMC207
Day
LogC
FU c
hang
e fro
m b
asel
ine
0 2 4 6 8 10 12 14-3
-2.5
-2
-1.5
-1
-0.5
0
0.5Bi-linear Regression: LogCFU changes from baseline
Rifafour e275 TMC207 TMC207 & PZAPA-824 & PZA PA-824 & TMC207
Day
LogC
FU c
hang
e fro
m b
asel
ine
0 2 4 6 8 10 12 14-3
-2.5
-2
-1.5
-1
-0.5
0
0.5Bi-linear Regression: LogCFU changes from baseline
Rifafour e275 TMC207TMC207 & PZA PA-824 & PZAPA-824 & TMC207 PA-824 & PZA & Moxifloxacin
Day
LogC
FU c
hang
e fro
m b
asel
ine
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All Treatment Groups: Bi-linear Regression Mean of TTP Over Day; Change from Baseline (Day X – Day 0)
050
100
150
200
TTP
cha
nge
from
bas
elin
e
0 2 4 6 8 10 12 14Day
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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