TB Drug Development: 2018 Year-in-Review

Transcription

1 TB Drug Development: 2018 Year-in-Review Barbara Laughon, PhD Co-Chair Working Group on New TB Drugs 24 October 2018 Working Group on New TB Drugs The Hague, Netherlands

2 2018 Global New TB Drug Pipeline 1 Discovery Preclinical Development Clinical Development Lead Optimization Early Stage Development GMP/ GLP Tox. Phase 1 Phase 2 Phase 3 Diarylthiazoles DprE1 Inhibitors InhA Inhibitor Mtb energy metabolism Macrolides Mycobacterial Gyrase Inhibitors Arylsulfonamides Inhibitors of MmpL3, Translocase-1, Clp, PKS13 Oxazolidinones Squaramides CPZEN-45* Spectinamide * SPR720* TB-47* TBAJ-587 TBAJ-876 GSK-286* TBI-223 Sanfetrinem S * BTZ-043* Telacebec (Q203*) TBI-166 OPC * GSK-656* (070) TBA-7371* SQ-109* Contezolid (MRX-4/MRX-1) Delpazolid (LCB ) Sutezolid (PNU100480) *New chemical class. Known chemical classes for any indication are color coded: fluoroquinolone, rifamycin, oxazolidinone, nitroimidazole, diarylquinoline, benzothiazinone, imidazopyridine amide, beta-lactam. 1 New Molecular Entities not yet approved, being developed for TB or only conditionally approved for TB. Showing most advanced stage reported for each. Details for projects listed can be found at Ongoing projects without a lead compound series identified: Bedaquiline* (TMC-207) Delamanid* (OPC-67683) Pretomanid* (PA-824) Underline = new to Phase since March Updated: October 2018

3 2018 Global New TB Drug Pipeline 1 Preclinical Development Clinical Development Early Stage GMP/ GLP Tox. Phase 1 Phase 2 Phase 3 Caprazene nucleoside CPZEN-45* Spectinamide 1810* Gyrase inhibitor SPR720* Pyrazolopyridine carboxamide TB-47* TBAJ-587 TBAJ-876 GSK-286* TBI-223 Sanfetrinem S * BTZ-043* TBI-166 OPC * GSK-656* (070) TBA-7371* Telacebec (Q203*) Delpazolid (LCB ) Sutezolid (PNU100480) SQ-109* Bedaquiline* Delamanid* Pretomanid* Global Market Contezolid (MRX-4/MRX-1) Underline = new to Phase since March 2018 New chemical class* Known chemical classes for any indication are color coded: fluoroquinolone, rifamycin, oxazolidinone, nitroimidazole, diarylquinoline, benzothiazinone, imidazopyridine amide, beta-lactam. 1 New Molecular Entities not yet approved, being developed for TB or only conditionally approved for TB. Showing most advanced stage reported for each. Details for projects listed can be found at Ongoing projects without a lead compound series identified: Updated: October 2018

4 2018 Milestones in TB Drug Research Advances in Registration/Phase 3 landscape CROI 2018 BRIEF-TB/A5279 reported prevention of TB in HIV+ TB infected individuals with 1 month of INH/rifapentine (1HP) TB Alliance Nix TB (Pa BDQ LZD) study continues in followup with updated results to be presented. TB Alliance ZeNix clinical trial (Pa BDQ LZD) begins enrollment to optimize LZD. TB Alliance New Drug Application (NDA) for Pretomanid in preparation. Sanofi/CDC TBTC Study 31/ACTG 5349 Phase 3 rifapentine-containing regimes for treatment shortening is approaching full enrollment with 2487 patients to date.

5 2018 Milestones in TB Drug Research Advances in Phase 2 landscape Boston University/TBTC 32/NIAID Levofloxacin for MDR-TB (Opti-Q) Phase 2 in data analysis. TRUNCATE Trial Adaptive Phase 2c begins enrollment March Two-month regimens using novel combinations (Singapore, Philippines). TB Alliance Begins enrollment in Phase 2c/3 Simplici- TB trial (B Pa M Z) open label, 4-month, July 2018 Qurient Phase 2 EBA of Telacebec (Q203) begins enrolling in South Africa, July 2018 LegoChem Phase 2 of oxazolidinone Delpazolid (LCB ) begins enrolling in Korea.

6 2018 Milestones in TB Drug Research Advances in Phase 1 landscape TB Alliance Completes Phase 1a study of aza-indole TBA-7371, targeting DprE1. Otsuka - Completes Phase 1a of OPC , targeting DprE1. GSK Completes Phase 1 of oxaborole candidate GSK (GSK-070). Institute of Materia Medica, Beijing Begins Phase 1 study of TBI-166, an improved analog of clofazimine. Innovative Medicines for Tuberculosis - Completes Phase 1a of Macozinone comparing two formulations, targeting DprE1. University of Munich - Begins Phase 1a of BTZ-043, targeting DprE1.

7 2018 Milestones in TB Drug Research Significant changes in development landscape TB Alliance Begins GLP/GMP studies of TBAJ-587 and TBAJ- 876 as improved diarylquinolines. GSK Announces development of Sanfetrinem, a tricyclic beta-lactam, for TB treatment. GSK Selects an inhibitor of Mtb cholesterol metabolism GSK-286 as a drug development candidate. Johnson & Johnson Partnership with CSIR-IMTECH, India plans to develop combinations halting energy metabolism in M. tuberculosis Shinogoni Begins clinical development of S (novel nitroimidazole) with partner in China and in-licenses imidazole pyrimidines from Hsiri/University of Notre Dame Sanofi Moves R&D for TB to Evotec AG

8 2018 Global TB Drug and Regimen Clinical Research 1 Ongoing Clinical Development Research: Strategy / Optimization / Regimen Development Phase 2 Phase 3 Regimens Optimization/Post Market Bedaquiline-Delamanid (ACTG 5343) Bedaquiline-Pretomanid- Moxifloxacin-PZA (SimpliciTB Trial, NC-008) Bedaquiline - Pretomanid Moxifloxacin - Pyrazinamide (BPaMZ) (NC-005) Levofloxacin with OBR for MDR-TB (OPTI-Q) Linezolid Dose-Ranging Nitazoxanide Beta-Lactams High Dose Rifampicin (PANACEA) TB PRACTECAL - regimens with Bedaquiline-Pretomanid-Linezolid Known chemical classes are color coded: fluoroquinolone, rifamycin, oxazolidinone, nitroimidazole, diarylquinoline, benzothiazinone, imidazopyridine amide, beta-lactam. 1 Strategy trials, regimen development, open label, repurposed drug studies. Details for projects listed can be found at 2 OBR = Optimized Background Regimen Bedaquiline-STREAM MDR-TB Trial Stage 2 with oral OBR (9 mo) or OBR with injectables (6 mo) Bedaquiline-Pretomanid-Linezolid (NiX-TB) Delamanid with OBR for MDR-TB High Dose Rifampicin for DS-TB (RIFASHORT) Rifapentine - Moxifloxacin for DS- TB (CDC TBTC 31) Pretomanid-Moxifloxacin- Pyrazinamide (STAND) Bedaquiline-Linezolid with OBR for MDR-TB (NExT Trial) endtb 5-Regimen Trial for MDR TB PredictTB PET/CT, biomarkers DS-TB, 4 mo TRUNCATE-TB Trial, 2 mo Updated: October 2018

9 2018 Global TB Drug Discovery Pipeline 1 Hit-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 (GATB, TBDA, J&J/CSIR-Imtech, Univ. of Notre Dame Isoprenoid Biosynthesis Inhibitors (Lilly DDI) Whole-Cell Hit-to-Lead (GATB, Evotec) RNA Polymerase Inhibitors (GATB) ClpC/P1P2 (GATB) Diarylthiazoles (TBDA) InhA Inhibitors (GATB/GHDDI) Spectinamides (St. Jude, U Tenn, CSU, UZ, Microbiotix) Macrolides (GATB, Evotec) Clp (SPRINT TB / A* Star) Indolcarboxamides / MmpL3 inhibitors (GATB, TBDA) Oxazolidinones (IMM) Aryl Sulfonamides (GATB, GSK, TBDA) PKS13 inhibitors (GATB, DDU, TAMU, GSK, TBDA) Squaramides (GATB, TBDA, Evotec) 1 Details for projects listed can be found at and clinical development projects can be viewed at Abbreviations of Developers: A*Star- Agency for Science 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; TBDA-TB Drug Accelerator; U- University; U ILL-University of Illinois; UPenn-University of Pennsylvania; U Tenn-University of Tennessee; UZ-University of Zurich Updated: October 2018

10 2018 Global New TB Drug Pipeline 1 Preclinical Development Small Pharma Non Profits Clinical Development Early Stage GMP/ GLP Tox. Phase 1 Phase 2 Phase 3 Caprazene nucleoside CPZEN-45* Spectinamide 1810* Gyrase inhibitor SPR720* Pyrazolopyridine carboxamide TB-47* TBAJ-587 TBAJ-876 GSK-286* TBI-223 Sanfetrinem S * BTZ-043* TBI-166 OPC * GSK-656* (070) TBA-7371* Contezolid (MRX-4/MRX-1) Telacebec (Q203*) Delpazolid (LCB ) Sutezolid (PNU100480) SQ-109* New chemical class* Known chemical classes for any indication are color coded: fluoroquinolone, rifamycin, oxazolidinone, nitroimidazole, diarylquinoline, benzothiazinone, imidazopyridine amide, beta-lactam. 1 New Molecular Entities not yet approved, being developed for TB or only conditionally approved for TB. Showing most advanced stage reported for each. Details for projects listed can be found at Ongoing projects without a lead compound series identified: Bedaquiline* Delamanid* Pretomanid* Global Market Underline = new to Phase since March Updated: October 2018