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) SQ109-01 (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

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+

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

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 -0.4786 -0.3214 -1.118 -1.342 MIC50 (uM) 16.7 5.295 6.935 0.00165 0.00328 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)

Q203 MOA

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

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)