1 TB Drug Development: Year-in-ReviewBarbara Laughon, PhD Co-Chair Working Group on New TB Drugs 26 October 2016 Working Group on New TB Drugs Liverpool, U.K.

2 2015 Global TB Drug Pipeline 1Discovery Preclinical Development Clinical Development Lead Optimization Early Stage Development GLP Tox. Phase I Phase II Phase III Cyclopeptides Diarylquinolines DprE Inhibitors InhA Inhibitor, Indazoles LeuRS Inhibitors, Ureas Macrolides, Azaindoles Mycobacterial Gyrase Inhibitors Pyrazinamide Analogs Ruthenium(II) Complexes Spectinamides Translocase-1 Inhibitors TBI-166 CPZEN-45* SQ609* 1599* SEQ-9* PBTZ169* BTZ043* TBA-354 Q203* Sutezolid (PNU ) 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 Bedaquiline with OBR2 for MDR-TB Delamanid (OPC-67683) with OBR for MDR-TB Pretomanid- Moxifloxacin- Pyrazinamide Regimen Bedaquiline- Pretomanid-Linezolid NiX-TB Regimen Alphabetical within stage 2 Combination Regimens: NC-001-(J-M-Pa-Z), - novel TB drug regimen tested combinations of bedaquiline, moxifloxacin, PA-824, and pyrazinamide; Lancet NC-002-(M-Pa-Z)– PA-824, moxifloxacin, pyrazinamide in drug-sensitive and multidrug-resistant patients, begun March NC-003-(C-J-Pa-Z) evaluates clofazimine, TMC-207, PA-824, pyrazinamide in combinations, , begun October PanACEA-MAMS-TB-01-(H-R-Z-E-Q-M) evaluates four experimental 4-drug regimens for 3 months in adaptive design, begun May 2013. Chemical classes: fluoroquinolone, rifamycin, oxazolidinone, nitroimidazole, diarylquinoline, benzothiazinone, , imidazopyridine amide, New chemical class* 1 Details for projects listed can be found at and ongoing projects without a lead compound series identified can be viewed at 2OBR = Optimized Background Regimen Updated: December 2015

3 2015 Global TB Drug Pipeline 1Discovery Preclinical Development Clinical Development Lead Optimization Early Stage Development GLP Tox. Phase I Phase II Phase III Cyclopeptides Diarylquinolines DprE Inhibitors InhA Inhibitor Indazoles LeuRS Inhibitors, Ureas Macrolides, Azaindoles Mycobacterial Gyrase Inhibitors Pyrazinamide Analogs Ruthenium(II) Complexes Spectinamides Translocase-1 Inhibitors TBI-166 CPZEN-45* SQ609* 1599* SEQ-9* PBTZ169* BTZ043* TBA-354 Q203* Sutezolid (PNU ) 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 Bedaquiline with OBR2 for MDR-TB Delamanid (OPC-67683) with OBR for MDR-TB Pretomanid- Moxifloxacin- Pyrazinamide Regimen Bedaquiline- Pretomanid-Linezolid NiX-TB Regimen Alphabetical within stage 2 Combination Regimens: NC-001-(J-M-Pa-Z), - novel TB drug regimen tested combinations of bedaquiline, moxifloxacin, PA-824, and pyrazinamide; Lancet NC-002-(M-Pa-Z)– PA-824, moxifloxacin, pyrazinamide in drug-sensitive and multidrug-resistant patients, begun March NC-003-(C-J-Pa-Z) evaluates clofazimine, TMC-207, PA-824, pyrazinamide in combinations, , begun October PanACEA-MAMS-TB-01-(H-R-Z-E-Q-M) evaluates four experimental 4-drug regimens for 3 months in adaptive design, begun May 2013. Chemical classes: fluoroquinolone, rifamycin, oxazolidinone, nitroimidazole, diarylquinoline, benzothiazinone, , imidazopyridine amide, New chemical class* 1 Details for projects listed can be found at and ongoing projects without a lead compound series identified can be viewed at 2OBR = Optimized Background Regimen Updated: December 2015

4 Advances in Registration/Phase 3 landscape2016 Milestones in TB Drug Research Advances in Registration/Phase 3 landscape TB Alliance – Pretomanid/Moxifloxacin/PZA Phase 3 STAND trial suspended. Clinical hold lifted September 2016. TB Alliance – Nix TB (Pa BDQ LZD) study continues for XDR- TB patients. Sanofi/CDC TBTC Study 31/ACTG 5349 – Phase 3 rifapentine- containing regimes for treatment shortening began enrollment March 2016. BMRC – STREAM study of MDR TB regimens fully enrolled. Stage 2 began in March 2016 with inclusion of bedaquiline. University of Cape Town – NExT TB Open-label RCT for MDR (BDQ, LZD) began enrollment in early 2016.

5 Advances in Phase 2 landscape2016 Milestones in TB Drug Research Advances in Phase 2 landscape Task Foundation/GSK – Results of the meropenem /faropenem Phase 2 EBA published. Boston University/TBTC 32/NIAID – Levofloxacin for MDR-TB (Opti- Q) Phase 2 continues recruiting in Peru and South Africa TB Alliance – NC-005 (BDQ, Pa, MFX, PZA for 8 weeks) results presented at the Liverpool UNION meeting Thursday 17:30. NIAID – Phase 2 EBA trial of oxazolidinone AZD 5847 completed, but development halted by AZ. Results published November 2016. TRUNCATE – Adaptive alternative design with Phase 2c progressing. Two-month trials planned for 2017 (Singapore). Novartis – Clofazimine Phase 2/3 trial planned for 2016 suspended due to new guidelines. Company continuing active discussions with WHO.

6 Advances in Phase 1 landscape2016 Milestones in TB Drug Research Advances in Phase 1 landscape TB Alliance – Phase 1b trial of TBA-354 encounters toxicity issues and development discontinued (3/11/2016). Qurient – Phase 1a trial of Q203 imidazopyridine amide (FDA oversight) completed in the US (February 2016). Phase 1b began enrollment in August 2016.

7 Significant changes in development landscape2016 Milestones in TB Drug Research Significant changes in development landscape iM4TB Foundation (EPFL) – Formulation development in progress; spray-dried API under study; expecting to begin Phase 1 with PBTZ-169 in early 2017 in Switzerland. University of Munich – BTZ-043 completing PK/PD evaluations. GMP drug to be available in 2017. GSK – Announces selection of oxaborole candidate GSK-070 in April 2016. Microbiotix – Lead selection in spectinamides continues for protein synthesis inhibitors Lilly Initiative – Negotiating development agreements for inhalation delivery approach with CPZEN-45 Shortening Treatments by Advancing Novel Drugs = STAND Ecole Polytechnique Federale de Lausanne Michael Hoelscher, Prof., Ludwig-Maximilians - University of Munich ClinicalTrials.gov Identifier: NCT     Other Study ID Numbers: PanACEA-MAMS-TB-01 Study First Received: December 17, 2012 Last Updated: October 10, 2014 Health Authority: United States: Food and Drug Administration

8 Significant changes in discovery landscape2016 Milestones in TB Drug Research Significant changes in discovery landscape Sanofi – Continues discovery R&D for macrolides Gates TB Drug Accelerator – new members Eli Lilly, Abbvie, and TB Alliance Ongoing screening efforts to identify safer and more potent oxazolidinones SPRINT TB/University of Singapore – Multiple screening, target identification, candidate development projects reported at the EMBO Tuberculosis 2016 meeting in Paris GSK – New discovery project focusing on beta- lactams Shortening Treatments by Advancing Novel Drugs = STAND Ecole Polytechnique Federale de Lausanne Michael Hoelscher, Prof., Ludwig-Maximilians - University of Munich ClinicalTrials.gov Identifier: NCT     Other Study ID Numbers: PanACEA-MAMS-TB-01 Study First Received: December 17, 2012 Last Updated: October 10, 2014 Health Authority: United States: Food and Drug Administration

9 Significant changes on the horizon2016 Milestones in TB Drug Research 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); inhibition of non-replicating cells. Repurposed drugs under evaluation – Linezolid, colistin, carbapenems, efflux inhibitors, thioridazine, dry powder inhalation administration Ecole Polytechnique Federale de Lausanne Michael Hoelscher, Prof., Ludwig-Maximilians - University of Munich ClinicalTrials.gov Identifier: NCT     Other Study ID Numbers: PanACEA-MAMS-TB-01 Study First Received: December 17, 2012 Last Updated: October 10, 2014 Health Authority: United States: Food and Drug Administration

10 Benzothiazinone BTZ 043 Advanced preclinical development of BTZ043 continues by the University of Munich and others Inhibits essential enzyme for cell wall structure (DprE1) J = bedaquiline (TMC-207) Pa = PA-824 Z = pyrazinamide C = clofazimine

11 Benzothiazinone PBTZ 169 Inhibits essential enzyme for cell wall structure (DprE1) Clinical results from Phase 1a conducted by NearMedic in Russia presented at EMBO Tuberculosis 2016 conference Formulation development of PBTZ 169 continues by EPFL and iM4TB; Phase 1 to start in 2017 Synergistic with bedaquiline J = bedaquiline (TMC-207) Pa = PA-824 Z = pyrazinamide C = clofazimine

12 Imidazopyridines Q203 (Qurient)Targets the cytochrome b subunit (QcrB) of the cytochrome bc1 complex - an essential component of the respiratory electron transport chain. Q203 causes depletion of intracellular ATP. Q203 has been licensed to Infectex, LLC for the Russia and the CIS Qurient began Phase 1b safety studies in the US in 4Q2016 J = bedaquiline (TMC-207) Pa = PA-824 Z = pyrazinamide C = clofazimine

13 Bactericidal efficacy in mice1,4-Azaindole TBA 7371 (TB Alliance) Targets DprE1 Bactericidal efficacy in mice Good safety margin in rats Human clinical trial to begin in 2017 J = bedaquiline (TMC-207) Pa = PA-824 Z = pyrazinamide C = clofazimine

14 Griselimycin cyclopeptideSATB 082 (Sanofi, TB Alliance) Targets DnaN (sliding clamp of DNA polymerase) Candidate to replace CGM analog announced at EMBO Tuberculosis conference in Paris Good efficacy in mice; LORA assay Improved safety profile. Some human data from the 1970s. J = bedaquiline (TMC-207) Pa = PA-824 Z = pyrazinamide C = clofazimine

15 Targets WecA (decaprenyl phosphate GlcNAc-1-phosphate transferase) Caprazamycin CPZEN-45 (IMC, Lilly TB Drug Initiative) Targets WecA (decaprenyl phosphate GlcNAc-1-phosphate transferase) Natural product from Streptomyces strain Efficacy in mice against DS and DR Mtb Production and formulation development progressing J = bedaquiline (TMC-207) Pa = PA-824 Z = pyrazinamide C = clofazimine

16 With Participation From:The TB Drug Accelerator The TBDA is a groundbreaking partnership between eight pharmaceutical companies, eight research institutions, and a product development partnership that seeks to develop a new TB drug regimen through collaboration in early-stage drug discovery research. With Participation From:

17 Global TB Drug Pipeline 1Discovery Preclinical Development Clinical Development Lead Optimization Early Stage Development GLP Tox. Phase 1 Phase 2 Phase 3 Diarylquinolines DprE Inhibitors InhA Inhibitor, Ureas Macrolides, Azaindoles Mycobacterial Gyrase Inhibitors Pyrazinamide Analogs Ruthenium(II)Complexes Spectinamides Translocase-1 Inhibitors, Clp, MmpL3, Oxazolidinones, Pyrimidines DprE1, Aryl Sulfonamides, PKS13, Squaramides TBI-166 CPZEN-45* 1599* SATB-082* OPC BTZ-043* PBTZ-169* TBA-7371* GSK-070* Q203* PBTZ-169* Sutezolid (PNU ) Linezolid EBA High Dose Rifampicin for DS-TB Bedaquiline (TMC207)- Pretomanid (PA-824) - Pyrazinamide Regimen Levofloxacin with OBR for MDR-TB Rifapentine - Moxifloxacin for Drug Sensitive TB Delamanid (OPC-67683) with OBR for MDR-TB Pretomanid-Moxifloxacin- Pyrazinamide Regimen (STAND) Bedaquiline-Pretomanid- Linezolid NiX-TB Regimen Bedaquiline-STREAM MDR-TB Trial Stage 2 with oral OBR (9 mo) or OBR with injectables (6 mo) Bedaquiline-Linezolid with OBR for MDR-TB (NExT Trial) Alphabetical within stage 2 Combination Regimens: NC-001-(J-M-Pa-Z), - novel TB drug regimen tested combinations of bedaquiline, moxifloxacin, PA-824, and pyrazinamide; Lancet NC-002-(M-Pa-Z)– PA-824, moxifloxacin, pyrazinamide in drug-sensitive and multidrug-resistant patients, begun March NC-003-(C-J-Pa-Z) evaluates clofazimine, TMC-207, PA-824, pyrazinamide in combinations, , begun October PanACEA-MAMS-TB-01-(H-R-Z-E-Q-M) evaluates four experimental 4-drug regimens for 3 months in adaptive design, begun May 2013. Chemical classes: fluoroquinolone, rifamycin, oxazolidinone, nitroimidazole, diarylquinoline, benzothiazinone, , imidazopyridine amide. New chemical class* 1 Details for projects listed can be found at and ongoing projects without a lead compound series identified can be viewed at 2OBR = Optimized Background Regimen Updated: October 2016

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19 Global TB Drug Pipeline 1Preclinical Development Clinical Development Early Stage GLP Tox. Phase 1 Phase 2 Phase 3 Riminophenazine TBI-166 Caprazene nucleoside CPZEN-45* Spectinamide 1599* Cyclopeptide SATB082* BTZ-043* PBTZ169* TBA-7371* GSK-070* Q203* PBTZ169* Sutezolid (PNU ) Linezolid EBA High Dose Rifampicin for DS-TB Bedaquiline (TMC207)- Pretomanid (PA-824) - Pyrazinamide Regimen Levofloxacin with OBR for MDR-TB Rifapentine - Moxifloxacin for Drug Sensitive TB Delamanid (OPC-67683) with OBR for MDR-TB Pretomanid-Moxifloxacin- Pyrazinamide Regimen (STAND) Bedaquiline-Pretomanid- Linezolid (NiX-TB Regimen) Bedaquiline-STREAM MDR-TB Trial Stage 2 with oral OBR (9 mo) or OBR with injectables (6 mo) Bedaquiline-Linezolid with OBR for MDR-TB (NExT Trial) Chemical classes: fluoroquinolone, rifamycin, oxazolidinone, nitroimidazole, diarylquinoline, benzothiazinone , imidazopyridine amide. New chemical class* 1 Details for projects listed can be found at and ongoing projects without a lead compound series identified can be viewed at 2 OBR = Optimized Background Regimen Updated: October 2016

20 Global TB Drug Discovery Pipeline 1Hit-to-Lead Lead 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) 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) ClpC/P1P2 (GATB) POA Prodrugs (GATB, Yonsei) PEPCK (GATB, Roche, TAMU) Diarylquinolines (GATB, U Auckland, Janssen) InhA Inhibitors (GSK) DprE Inhibitors Azaindoles (GATB, Calibr) Ureas (Sanofi, GATB) Ruthenium(II)phosphine/picolinate Complexes (FAPESP/Brazil) Spectinamides (St. Jude, U Tenn, CSU, UZ, Microbiotix) Macrolides (GATB, Sanofi) DrpE Inhibitors (GATB) Clp (SPRINT TB / A* Star) MmpL3 (GATB, TBDA) Oxazolidinones (GATB, IMM, TBDA) Pyrimidines DprE1 (GATB, GSK, TBDA) Aryl Sulfonamides (GATB, GSK, TBDA) PKS13 (GATB, DDU, TAMU, GSK, TBDA) Squaramides (GATB, TBDA) 1 Details for projects listed can be found at and clinical development projects can be viewed at Abbreviations of Developers: A*Star- Agency for Scienct Technology and Research 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; SPRINT TB-Singapore Programme of Research Investigating New Approaches to Treatment of TB 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 Updated: October 2016