1. PanACEA Studies: Phase I Phase IIa Phase IIb Phase III Q203 BTZ043
Pre-clinical
Phase I
Phase IIa
Phase IIb
Phase III
BTZ043
in cooperation with DZIF
Q203
in cooperation with PanACEA
HIGHRIF-01 (68 patients)
SQ (90 patients)
HIGHRIF-02 (150 patients)
MAMS-TB-01 (372 patients)
ReMox (1931 patients)
Q203
BTZ043
Mission:
To identify novel regimen that have a high potential to shorten and simplify the treatment of tuberculosis

2. Drug targets DprE1 Cell wall DNA mRNA respiratory chain Peptide
Multiple targets – Nitroimidazoles
Inhibit cell wall synthesis and cell respiration
Delamanid / Deltyba
PA-824, TBA-354
Multiple targets – Pyrazinamide
Including intracellular acidification,
disprupts plasma membran
Pyrazinamide (PZA)
Multiple targets – Riminophenazines
Clofazimine
TBI 166
arabinosyl transferase – ethambutol
Inhibit cell wall synthesis
Ethambutol
LEGEND:
Licenced drug
Licenced drug but repurposed for TB
Drug in phase IIb/III studies
Drug in Phase IIa studies
Late preclinical development
DNA gyrase – Quinolones
Inhibit DNA synthesis
Moxifloxacin
Gatifloxacin
InhA – isoniazid
Inhibit cell wall synthesis
Isoniazid
DprE1
DNA
RNA polymerase – Rifamycins
Inhibit transcription
Rifampicin
Rifapentin
Rifabutin
DprE1 – benzothiazinone
Inhibit cell wall synthesis
BTZ043
PBTZ169
Ribosome – Oxazolidinones
inhibit protein synthesis
Linezolid
Sutezolid
Other Oxalinezolids
GSK’143 aminoacyl-tRNA synthetase LeuRS inhibitor
Cell wall
mRNA
Transpeptidase + b-lactamase – Carbapenems + Clavulanic acid
Inhibit cell wall synthesis
Faropenem
respiratory chain
Peptide H+
GSK 147
Inhibits the protein synthesis
½ O2
H2O
ADP
ATP
Cell wall synthesis – Dimethlydiamine
Inhibit cell wall synthesis
(transport and processing)
SQ109
ATP–synthase – Diarylquinolines
Inhibit ATP synthesis
Bedaquiine / Sirturo
Cytochrome bc complex - Imidazopyridines
Essential for proton gradient and ATP synthesis
Q203
2 H+

3. Q203 Mechanism of action study
Q203 inhibits ATP synthesis in tuberculosis more potently than bedaquiline both in aerobic and hypoxic conditions
Aerobic
Hypoxic
0.5 4 12
Q203
Bedaquiline
333 50
100
150
200
250
RLU (x100)
-11
-10 -9 -8 -7 -6 -5 50
100
150
Concentration (M)
RLU (x100)
Bedaquiline
Q203
ATP IC50
(nM)
Q203
1.12
Bedaquiline
27.7
ATP IC50
(nM)
Q203
7.57
Bedaquiline 82

4. Q203 against resistant mutant strains
Q203 has a distinct target from Bedaquiline
Q-203
I-Series resistant mutant 1
I-Series resistant mutant 2
I-Series resistant mutant 3
TMC207 resistant mutant 1
Hill Slope
0.4625
-1.118
-1.342
MIC50 (uM)
16.7
5.295
6.935
qcrB (Rv2196): ubiquinol cytochrome C reductase
Essential key sub-unit of the cytochrome bc1 complex
Required for maintenance of proton gradient and ATP synthesis
Substitution of codon Thr313 to Ile313 / Ala313 confers resistance in M. tuberculosis (24/24 resistant mutants)

5. Q203 MOA

7. Efficacy in BALB/c mice
PK data for this experiment is underway

8. Time line
Q203: complete Phase I SAD and MAD in 2016
PK/PD modelling in Balb/c mice
IL13tg mouse model to assess penetration in lesions (2016)
combination testing in chronic mouse model (2016)
BTZ043: submit IMPD in 2016 and start phase I in 2017
PK/PD modelling in Balb/c completed in 2015
IL13tg mouse model to assess penetration in lesions (2016)
combination testing in chronic mouse model (2016)