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
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
Bactericidal Activity of Different Treatment
Regimens in the Mouse
9
8
Log10 CFU in Lungs
Untreated
7
RHZ
6
PaMZ
5
PaM
PaZ
4
MZ
3
R = rifampin
2
H = isoniazid
1
Z = pyrazinamide
0
0
4
Weeks
8
Pa = PA-824
M = moxifloxacin
2
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Unpublished data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
First Novel Combo EBA: NC-001
Participants with newly diagnosed smear positive DS TB
J
J-Z
J-Pa
14 daily doses
Pa-Z
Pa-M-Z
Rifafour
15 per group
Randomize
Serial 16 hour pooled sputum samples for CFU Count
Z=pyrazinamide, C=clofazimine , Pa = PA-824 , J = TMC207
4
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% women
74% men
31 years
(19 – 53)
6 subjects were HIV+
5
All Treatment Groups: Bi-linear Regression Mean of logCFU Over
Day; Change from Baseline (Day X – Day 0)
6
Bi-linear Regression: LogCFU changes from baseline
LogCFU change from baseline
0.5
0.5
00
-0.5
-0.5
-1-1
-1.5
-1.5
-2-2
-2.5
-2.5
-3-3
00
22
44
66
88
1010
1212
1414
Day
Rifafoure275
e275
TMC207 TMC207 & PZA
Rifafour
TMC207
Rifafour
TMC207
Rifafour
e275
& PZA
Rifafour
e275TMC207
e275Rifafour
TMC207
TMC207
e275
PA-824
& PZA&
TMC207
PZA
TMC207
PA-824&&PZA
TMC207
PA-824
&
PZA
PA-824
&
TMC207
PA-824 & TMC207
PA-824 & PZA & Moxifloxacin
6
All Treatment Groups: Bi-linear Regression Mean of TTP Over
Day; Change from Baseline
(Day X – Day 0)
0
50
100
150
200
Bi-linear regression: TTP change from baseline
0
2
4
6
8
10
12
14
Day
TMC207
TMC207 & PA-824
PA-824 & Pyr & Moxifloxacin
TMC207 & Pyrazinamide
PA-824 & Pyrazynamide
Rifafour e275
7
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
8