1. TB Drug Development: Year-in-Review Barbara Laughon, PhD Co-Chair Working Group on New TB Drugs 4 December 2015 Working Group on New TB Drugs Cape Town, South Africa

2. Lead Optimization Early Stage Development GLP Tox. Phase IPhase IIPhase III DC-159a SQ609 SQ641 CPZEN-45 TBI-166 Spectinamide 1599 Preclinical Development Discovery Clinical Development Cyclopeptides Diarylquinoline DprE Inhibitors GyrB inhibitors InhA Inhibitors LeuRS Inhibitors MGyrX1 inhibitors Mycobacterial Gyrase Inhibitors Pyrazinamide Analogs Riminophenazines Ruthenium (II) complexes Translocase-1 Inhibitors Chemical classes: fluoroquinolone, rifamycin, oxazolidinone, nitroimidazole, diarylquinoline, benzothiazinone * Trial completed ** Trial results reported Global TB Drug Pipeline Updated: October 2014 PBTZ169 Q203 TBA-354 www.newtbdrugs.org Gatifloxacin** Moxifloxacin** Rifapentine** Delamanid AZD5847* Linezolid* Sutezolid ** Rifapentine** Rifampin (High)* PA-824** Bedaquiline* SQ-109*

3. Advances in Registration/Phase 3 landscape  Sanofi – FDA approves rifapentine/INH for latent TB infection (12/2/2014)  British National Health Service – Commissions bedaquiline and delamanid for MDR TB (8/23/2015)  TB Alliance – Pretomanid/Moxifloxacin/PZA begins Phase 3 STAND trial (3/18/2015). Enrollment paused October 2015.  TB Alliance – Nix TB (Pa BDQ LZD) study begins (5/18/2015)  CDC TBTC Study 31/ACTG 5349 – Phase 3 rifapentine-containing regimes for treatment shortening to begin January 2016.  BMRC – STREAM 1 study of MDR TB regimens fully enrolled. Stage 2 to begin in 2016 and to include the Janssen – Phase 3 for bedaquiline. 2015 Milestones in TB Drug Research

4. Advances in pre-approval landscape  South Africa NTP – MCC approves bedaquiline registration and begins clinical access program.  Otsuka – Publication of Trial 204 results on delamanid for XDR TB NEJM (7/16/2015)  Sequella – Development plans for SQ109 and sutezolid finalized.  Infectex Study (Russian Federation) – SQ 109-containing 6- month therapy showing no serious adverse effects and completing last patient visit in February 2016.  MSF – TB-Practecal Phase 2/3 of 6-month DR regimens planned to begin in February 2016. 2015 Milestones in TB Drug Research

5. Advances in Phase 2 landscape  Task Foundation – Meropenem /faropenem Phase 2 EBA completed (January 2015)  Boston University – Levofloxacin for MDR-TB (Opti-Q) begins Phase 2 (January 2015)  PanACEA/EDCTP – MAMS-TB-001 results presented at CROI that higher doses of rifampicin shortens time to culture conversion. PK/PD in analysis  TB Alliance – Pretomanid/Moxifloxacin/ PZA Phase 2b published (3/18/2015)  NIAID – Phase 2 EBA trial of oxazolidinone AZD 5847 completed, but development halted by AZ.  TRUNCATE – Study design alternatives; Phase 2c design discussions  Novartis – Clofazimine Phase 2/3 trial planned to begin March 2016. OBR +\- clofazimine at 200 mg/day for 18 weeks then 100 mg/day 2015 Milestones in TB Drug Research

6. Advances in Phase 1 landscape  TB Alliance – Phase 1 trial of TBA-354 begins (2/18/2015)  Qurient – Phase 1 trial of Q203 imidazopyridine amide (FDA oversight) begins in US (8/23/2015) 2015 Milestones in TB Drug Research

7. Significant changes in development landscape  Dartois, Prideux – Lung lesion distribution of TB drugs; imaging MALDI/MS (Nature Medicine 2015)  iM4TB Foundation (EPFL) – Manufacturing and formulation development; ADME in process; expect to begin Phase 1 with PBTZ169 2Q 2016 in Switzerland.  University of Munich – BTZ043 in Animal model and PK/PD evaluations  GSK – reports progression of several discovery projects  Microbiotix – Spectinamides in development to overcome efflux and inhibit protein synthesis  Lilly Initiative – examining inhalation delivery approach with CPZEN-45 2015 Milestones in TB Drug Research

8. Significant changes in discovery landscape  Sanofi – Continues discovery R&D for macrolides (SEQ-9) and cyclopeptides  Gates TB Drug Accelerator – new members Eli Lilly, Abbvie, and TB Alliance  Merck – ongoing screening efforts reported at 2015 Gordon Conference  SPRINT TB/University of Singapore – Screening, target identification, candidate development 2015 Milestones in TB Drug Research

9. Significant changes on the horizon  Renewed interest in host-directed therapies – NIAID and others (ex. imatinib (Gleevec), statins, eicosanoid synthesis pathway inhibitors)  Fundamental research – new findings in genetic and metabolic controls for multiple targets; promiscuous targets (MmpL3)  Repurposed drugs under evaluation – Linezolid, colistin, carbapenems, efflux inhibitors, Thioridazine, aerosol administration 2014 Milestones in TB Drug Research

10. Lead Optimization Early Stage Development GLP Tox. Phase IPhase IIPhase III Bedaquiline with OBR 2 for MDR-TB Delamanid (OPC-67683) with OBR for MDR-TB Pretomanid-oxifloxacin- Pyrazinamide Regimen Bedaquiline- Pretomanid-Linezolid NiX-TB Regimen Sutezolid (PNU-100480) Linezolid EBA SQ109* Rifapentine for DS-TB High Dose Rifampicin for DS-TB Bedaquiline (TMC207)- Pretomanid (PA-824) - Pyrazinamide Regimen Levofloxacin with OBR for MDR-TB TBI-166 CPZEN-45* SQ609* 1599* SEQ-9* Preclinical Development Discovery Clinical Development Chemical classes: fluoroquinolone, rifamycin, oxazolidinone, nitroimidazole, diarylquinoline, benzothiazinone,, imidazopyridine amide, New chemical class* 1 Details for projects listed can be found at http://www.newtbdrugs.org/pipeline.php and ongoing projects without a lead compound series identified can be viewed at http://www.newtbdrugs.org/pipeline-discovery.phphttp://www.newtbdrugs.org/pipeline.php http://www.newtbdrugs.org/pipeline-discovery.php 2 OBR = Optimized Background Regimen Global TB Drug Pipeline 1 Updated: December 2015 PBTZ169* BTZ043* www.newtbdrugs.org TBA-354 Q203* Cyclopeptides Diarylquinolines DprE Inhibitors InhA Inhibitor, Indazoles LeuRS Inhibitors, Ureas Macrolides, Azaindoles Mycobacterial Gyrase Inhibitors Pyrazinamide Analogs Ruthenium(II) Complexes Spectinamides Translocase-1 Inhibitors

11. Early Stage Development GLP Tox.Phase IPhase IIPhase III Bedaquiline (TMC-207) with OBR 2 for MDR-TB Delamanid (OPC-67683) with OBR for MDR-TB Pretomanid- Moxifloxacin- Pyrazinamide Regimen Bedaquiline- Pretomanid-Linezolid NiX-TB Regimen Sutezolid (PNU-100480) Linezolid EBA SQ109* Rifapentine for DS-TB High Dose Rifampicin for DS-TB Bedaquiline-Pretomanid- Pyrazinamide Regimen Levofloxacin with OBR for MDR-TB Riminophenazine TBI-166 Caprazene nucleoside CPZEN-45* Capuramycin SQ609* Spectinamide 1599* Macrolide SEQ-9* Preclinical DevelopmentClinical Development Chemical classes: fluoroquinolone, rifamycin, oxazolidinone, nitroimidazole, diarylquinoline, benzothiazinone, imidazopyridine amide, New chemical class* 1 Details for projects listed can be found at http://www.newtbdrugs.org/pipeline.php and ongoing projects without a lead compound series identified can be viewed at http://www.newtbdrugs.org/pipeline-discovery.php.http://www.newtbdrugs.org/pipeline.php http://www.newtbdrugs.org/pipeline-discovery.php 2 OBR = Optimized Background Regimen Global TB Drug Pipeline 1 Updated: December 2015 PBTZ169* BTZ-043* www.newtbdrugs.org TBA-354 Q203*

12. Hit-to-LeadLead Optimization Actinomycete Metabolites (U ILL Chicago, Myongii U) Novel Hit-to-Lead Programs (Lilly DDi) GATB Adamantanids (U ILL Chicago) Whole-Cell Hit-to-Lead (GSK, GATB) Malate Synthase Inhibitors (GSK, TAMU, GATB) Menaquinone Synthase Inhibitors (CSU) M. tb Energy Metabolism Inhibitors (UPenn, GATB) Isoprenoid Biosynthesis Inhibitors (Lilly DDi) Whole-Cell Hit-to-Lead (GATB, Sanofi) RNA Polymerase Inhibitors (GATB, Rutgers U) ATP Synthesis Inhibitors (GATB, Calibr) Diarylquinolines (GATB, U Auckland, Janssen) InhA Inhibitors (GSK) LeuRS Inhibitors (Anacor Pharmaceuticals, GSK) Pyrazinamide Analogs (GATB, Yonsei U) Translocase-1 Inhibitors (Sequella) DprE Inhibitors Azaindoles (GATB, Calibr) Ureas (Sanofi, GATB) Ruthenium(II)phosphine/picolinate Complexes (FAPESP/Brazil) Spectinamides (St. Jude, U Tenn, CSU, UZ, Microbiotix) Indazoles (GATB, GSK) Macrolides (GATB, Sanofi) Cyclopeptides (GATB, Sanofi) DrpE Inhibitros (GATB) SPR-113 (Gates Foundation) 1 Details for projects listed can be found at http://www.newtbdrugs.org/pipeline-discovery.php and clinical development projects can be viewed at http://www.newtbdrugs.org/pipeline.php.http://www.newtbdrugs.org/pipeline-discovery.phphttp://www.newtbdrugs.org/pipeline.php Abbreviations of Developers: CSU-Colorado State University; FAPESP-São Paulo Research Foundation; GATB-Global Alliance for TB Drug Development (TB Alliance); GSK-GlaxoSmithKline; Lilly DDi-Lilly TB Drug Discovery Initiative; RI-Research Institute; St. Jude-St. Jude Children’s Research Hospital; TAMU- Texas A&M University; U-University; U ILL-University of Illinois; UPenn-University of Pennsylvania; U Tenn-University of Tennessee; UZ-University of Zurich Global TB Drug Discovery Pipeline 1 Updated:December 2015 www.newtbdrugs.org