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TB Drugs in the Pipeline

TB Drugs in the Pipeline. Carl M. Mendel, MD TB Alliance IUATLD Meeting San Antonio, February 24, 2012. TB Alliance. Founded in 2000 Not-for-profit Product Development Partnership (PDP) headquartered in New York, with office in Pretoria

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TB Drugs in the Pipeline

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  1. TB Drugs in the Pipeline Carl M. Mendel, MD TB Alliance IUATLD Meeting San Antonio, February 24, 2012

  2. TB Alliance Founded in 2000 Not-for-profit Product Development Partnership (PDP) headquartered in New York, with office in Pretoria Entrepreneurial, virtual approach to drug discovery and development Largest portfolio of TB drug candidates in history GOVERNMENTS PHARMA BIOTECH TB Alliance ACADEMIA INSTITUTES FOUNDATIONS

  3. TB Alliance Mission Develop new, better treatments for TB that are: Faster-acting and less complex Compatible with anti-retrovirals for HIV/AIDS coinfection Active against drug sensitive and drug resistant strains Ensure that new regimens are affordable, adopted for use, and made widely available Coordinate and act as catalyst for global TB drug discovery and development activities

  4. TB Alliance Portfolio Discovery Clinical Development Preclinical Development Lead identification Lead Optimization Target Or Cell-Based Screening Clinical Phase I Clinical Phase II Clinical Phase III TBA-354U. of Auckland/ U. Ill Chicago Moxifloxacin (+ H, R, Z) Bayer Natural Products IMCAS Whole-Cell Hit to Lead Program GSK Mycobacterial Gyrase Inhibitors GSK PA-824 Novartis Preclinical TB Regimen Development JHU/U. Ill Chicago TMC207 Tibotec Moxifloxacin (+ R, Z, E) Bayer TB Drug Discovery Portfolio NITD THPP Series GSK Gyrase B Inhibitors AZ Topoisomerase I Inhibitors AZ/NYMC PA-824/Pyrazinamide Pyrazinamide Analogs Yonsei TMC207/Pyrazinamide Folate Biosynthesis Inhibitors AZ Diarylquinolines Tibotec/U. of Auckland PA-824/TMC207 Riminophenazines IMM/BTTTRI Whole-Cell Hit to Lead Program AZ RNA Polymerase Inhibitors AZ PA-824/Moxifloxacin/Pyrazinamide Energy Metabolism Inhibitors AZ/U. Penn Novel TB regimen development Current first-line TB treatment consists of: isoniazid (H) + rifampicin (R) + pyrazinamide (Z) + ethambutol (E)

  5. TB Drug/RegimenDiscovery and Development Process Discovery Single Compound Preclinical Development  Phase I  EBA Phase II  Phase III Compound 1 Compound 2 Drug Candidate Pool Regimen A Compound 3 Regimen B Compound 4 Regimen Identification Compound 5 Regimen C Identification of New Drug Candidates Selection of Potential New Regimens

  6. Modes of Action • DNA Gyrase • Gatifloxacin • Moxifloxacin • Multiple Targets • PA-824 • OPC-67683 Bio- reduction • Cell-Wall • Synthesis • SQ-109 • RNA Polymerase • Rifapentine DNA Reactive Species mRNA H+ ADP ATP Peptide • Ribosome • PNU-100480 • AZD-5847 • ATP Synthase • TMC-207

  7. TB Regimen Testing: A New Approach

  8. Approach to Novel Regimen Development • Use animal model(s) to identify most promising combinations • Conduct full preclinical, Phase I and Phase II EBA evaluations of each drug singly • Explore drug-drug interactions and, as appropriate, preclinical tox of the combination • Take combination (regimen) into clinical development (Phase II, III)

  9. NC-001

  10. NC-001: Use of EBA to Test Principles Learned From Animal Models and to Begin Clinical Development of Novel Regimens NC-001 (first novel combination EBA study) J-Z synergy Pa-Z additivity Pa-J antagonism Pa-M-Z an enhanced novel regimen EBA = early bactericidal activity Pa = PA-824; M = moxifloxacin; Z = pyrazinamide; J = TMC207

  11. First Novel Combo EBA: NC-001 Pa-Z-(M pbo) Pa-M-Z J-Z 2 weeks of treatment J -(Z pbo) J-Pa Rifafour Pa = PA-824: M = moxifloxacin; Z = pyrazinamide; J = TMC207

  12. All Treatment Groups: Bi-linear Regression Mean of LogCFU Over Day; Change from Baseline (Day X – Day 0)

  13. All Treatment Groups: Bi-linear Regression Mean of TTP Over Day; Change from Baseline (Day X – Day 0)

  14. NC-001 Conclusions Validation of mouse data: J-Z synergy, Pa-Z additivity, Pa-J antagonism Pa-M-Z an enhanced novel regimen in 2-wk study All three compounds contribute to observed effect EBA can distinguish between treatments Just as it has previously distinguished between doses CFU and TTP give similar results Pa = PA-824; M = moxifloxacin; Z = pyrazinamide; J = TMC207

  15. Post NC-001 Study: Next Steps Develop Pa-M-Z for both DS- and DR-TB (in setting of appropriate resistance testing) 2-month “SSCC” study (NC-002) as next step In patients whose M.tb is sensitive to Pa, M, and Z Build on J-Z and Pa-Z backbones Explore J-Pa building block Continue to examine potential regimens in mouse models and bring promising new regimens into clinical development Pa = PA-824; M = moxifloxacin; Z = pyrazinamide; J = TMC207

  16. NC-002: First Study to Examine DS- and MDR-TB Together Using the Same Treatment for Both

  17. NC-002 Objectives • Pa-M-Z vsRifafour in DS-TB • Pa-M-Z in MDR-TB consistent with Pa-M-Z in DS-TB • DS vs MDR in 2-wk EBA • 2-wk EBA vs 2-mo “SSCC” • Feasibility of multicenter “EBA” study Pa = PA-824; M = moxifloxacin; Z = pyrazinamide

  18. First Novel Combo SSCC: NC-002In patients with M.tb sensitive to Pa, M, and Z Pa(200mg)-M-Z Pa(100mg)-M-Z 2 months of treatment (plus 2-wk EBA substudy) Rifafour Pa = PA-824; M = moxifloxacin; Z = pyrazinamide Pa(200mg)-M-Z (MDR) Z dose = 1500mg

  19. Unified DS/DR Development Path

  20. Current MDR Development Path Issues • Requires separate development program from DS-TB • Standard of care (SOC) treatment (control group) for MDR-TB is • Lengthy (24+ months) • Toxicity-prone / difficult • Of limited efficacy • Expensive • A new regimen for MDR-TB could be much shorter than SOC, but the timepoint for comparison will still be defined by the SOC control group

  21. Unified DS/DR Development Path:Paradigm Shift • Indication: “Drugs X, Y, and Z in combination are indicated for the treatment of tuberculosis caused by M.tb strains that are sensitive to drugs X, Y, and Z.” • Patients should be treated based on what they are sensitive to--rather than what they are resistant to • “MDR” label doesn’t apply in setting of new chemical entities

  22. Unified DS/DR Regimen Development Path Better than HRZE Complete regimens as good as HRZE SD, MD; DDI if needed 2-wk Combo EBA Mouse model 2-wk EBA 2-mo SSCC Ph3 cidalsterilizing DS + DR sensitive to test regimen DS vs HRZE MDR not randomized Best doses used in combos All final regimens tested here MDR also 2-4 mos DS vs HRZE MDR for consistency Dose ranging here for single drugs DS only Dose ranging in cidal Only combos in sterilizing

  23. Coming This Year • SQ109 EBA study results • PNU100480 EBA study results • NC-002 (Pa-M-Z x 2 mos in DS and MDR pts) • NC-003 • 2-wk EBA study examining four new regimens: J-Pa-Z, J-Pa-C, J-Z-C, J-Pa-Z-C • TBA-354 (nitroimidazole) FIM study • Expansion of biobanking initiative • GatifloxacinPh 3 results

  24. Thank You!And Thank You To Our: Funders Partners Stakeholders Staff Patients

  25. TB Alliance Supporters Bill & Melinda Gates Foundation United States Food and Drug Administration European Union United Kingdom Department for International Development United States Agency for International Development

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