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Technological Leapfrogging: A TB Imperative

Technological Leapfrogging: A TB Imperative. Mel Spigelman. Dublin, Ireland Irish Forum/Royal College of Physicians 6 March 2014. Global Tuberculosis Epidemic. TB’s economic toll: >$16 billion a year. 2 billion people are infected with M.tb 9 million new active TB cases per year

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Technological Leapfrogging: A TB Imperative

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  1. Technological Leapfrogging: A TB Imperative Mel Spigelman Dublin, Ireland Irish Forum/Royal College of Physicians 6 March 2014

  2. Global Tuberculosis Epidemic • TB’s economic toll: >$16 billion a year • 2 billion people are infected with M.tb • 9 million new active TB cases per year • 1 million pediatric TB cases per year • 1.7 million people die per year • 0.5 million cases of MDR-TB per year (prevalent person to person transmission) • Virulent XDR-TB spreading • 12 million people are M.tb/HIV co-infected • Biggest infectious killer of HIV patients and women of childbearing age Primarily affects the poorest of the poor

  3. TB Toll in Europe • 502,763 cases of TB and more than 44,000 TB deathsin the WHO European region in 2011 (4% of global burden) • 78,000 MDR-TB cases in the region • Treatment success rates of only 67.2%, 49.2% and 48.5% among new, previously treated and MDR-TB cases respectively • Concentrated in 18 priority countries:Armenia, Azerbaijan, Belarus, Bulgaria, Estonia, Georgia, Kazakhstan, Kyrgyzstan, Latvia, Lithuania, Moldova, Romania, Russia, Tajikistan, Turkey, Turkmenistan, Ukraine and Uzbekistan. • But even in EU countries: • Direct treatment costs/year: €536 890 315 ($712,260,000). • Indirect costs/year: An additional €5.3 billion euros ($7 billion)

  4. TB Therapeutics – Unmet Medical Needs Current Therapy Unmet Needs Formulations with correct dosing Technological Leapfrogging: A TB Imperative

  5. TB Alliance $1 donated=$1.6 leveraged funds from other partners • Founded in 2000 • Not-for-profit Product Development Partnership (PDP); offices in New York and South Africa • Entrepreneurial, virtual approach to drug discovery and development; ~ 50 full time employees • Largest portfolio of TB drug candidates in history Technological Leapfrogging: A TB Imperative

  6. TB Alliance Mission Technological Leapfrogging: A TB Imperative

  7. “AAA” Mandate Our Access Strategy Technological Leapfrogging: A TB Imperative

  8. TB Alliance Vision Current Treatment New Treatments in Development Aspirational Goal 6-30Months 2-4Months 7-10Days Success will require novel drug combinations Technological Leapfrogging: A TB Imperative

  9. 2014 Q1 Discovery Late Development Early Development Phase 4 Phase 3 Lead identification Lead Optimization PRECLINICAL DEVELOPMENT Phase 1 Phase 2A Phase 2B NC-003 Optimized Pediatric Formulations NC-002 REMox-TB TB Alliance R&D Partners: AstraZeneca (AZ) Bayer Healthcare AG (Bayer) Beijing Tuberculosis and Thoracic Tumor Research Institute Calibr Daiichi Sankyo Eisai GlaxoSmithKline (GSK) Institute of MateriaMedica(IMM) IMPAACT Janssen [Johnson & Johnson] Johns Hopkins University (JHU) Medical Research Council (MRC) Novartis Institute for Tropical Diseases (NITD) New York Medical College Rutgers University Sanofi Shionogi Stellenbosch University Takeda Pharmaceuticals University College London (UCL) University of Auckland University of Illinois at Chicago (UIC) University of Pennsylvania School of Medicine Yonsei University Confidential

  10. TB Alliance: Major Collaborators SELECTED PARTNERS: DonorsPharmaTrial SitesAcademiaNat’l Research InstitutesStakeholders Technological Leapfrogging: A TB Imperative

  11. Changing the Way TB Drugs are Developed • For the first time in history, a significant clinical TB drug pipeline is available • All presently utilized TB drugs have either poor pharmaceutical profiles or significant existing resistance • Optimized novel regimens are needed to address requirements for meaningful treatment improvements for drug sensitive and resistant disease • Current TB drug development approach replaces or adds one drug at a time, requiring decades to introduce a new regimen • New paradigm needed for rational selection and development of new TB therapies Technological Leapfrogging: A TB Imperative Technological Leapfrogging: A TB Imperative 11

  12. Novel TB Drug Regimen Development Discovery Phase II  Phase III Single Compound Preclinical Development  Phase I  EBA Compound 1 Drug Candidate Pool Compound 2 Regimen A Compound 3 Regimen B Compound 4 Regimen C Compound 5 Regimen Identification in Mice Identification of New Drug Candidates Selection of Potential New Regimens Discovery and Development Process Technological Leapfrogging: A TB Imperative

  13. Novel TB Drug Regimen Development (Unified Drug Sensitive/Drug Resistant Development Path) Stage Pre clinical Phase 1 Phase 2 Phase 3 Testing Model Study Attributes Go/No-Go Criteria: PK to support daily dosing As good as HRZE standard Clear effect to reduce CFU count Better Than HRZE Technological Leapfrogging: A TB Imperative

  14. Novel Regimen Development:General Approach • Use animal models to identify most promising combinations (relapse models) • Conduct full preclinical, Phase I and Phase II EBA evaluations of each drug singly • Dose ranging in EBA study • Explore drug-drug interactions and, as appropriate, preclinical toxicology of the combination • Take combination (regimen) into clinical development (Phase II, III) • Data from each step in development justifies proceeding to next step • Unite “DS” and “MDR” development paths when makes sense Technological Leapfrogging: A TB Imperative

  15. Launch of the Critical Path to TB Drug Regimens (CPTR) Technological Leapfrogging: A TB Imperative

  16. Innovative Paradigm: From Drugs to Regimens TB Alliance is searching for the best combinations of novel drugs • Multi-drug combinations prevent the development of resistance • A critical mass of novel TB compounds are available to enable novel regimen development • Potential to reduce R&D timelines from decades to years Technological Leapfrogging: A TB Imperative

  17. CPTR Structure Technological Leapfrogging: A TB Imperative

  18. Pa824 – Moxifloxacin – Pyrazinamide(PaMZ) Regimen Development (a case study)

  19. PaMZ Value Proposition • Effective against DS and MDR-TB • ARV Compatible • Oral, FDC-Compatible Regimen • Marked reduction in time for MDR-TB therapy (75%) • Marked reduction in cost of MDR-TB therapy (>90%)

  20. Bactericidal Activity of Different Treatment Regimens in the Mouse Log10 CFU in Lungs R = rifampin H = isoniazid Z = pyrazinamide Pa = PA-824 M = moxifloxacin Weeks Technological Leapfrogging: A TB Imperative

  21. PA-824 Two-week Monotherapy (logCFU) Error Bar Plot Over Treatment for Mean EBA Regression Technological Leapfrogging: A TB Imperative

  22. PA-824 based Regimen Phase 2A: NC-001 Pa = PA-824: M = moxifloxacin; Z = pyrazinamide; J = TMC207 • Pa = PA-824: M = moxifloxacin; Z = pyrazinamide; J = TMC207 Pa-Z-(M pbo) Pa-M-Z J-Z 2 weeks of treatment J -(Z pbo) J-Pa Rifafour Technological Leapfrogging: A TB Imperative

  23. All Treatment Groups: Bi-linear Regression Mean of LogCFU Over Day; Change from Baseline (Day X – Day 0) Technological Leapfrogging: A TB Imperative

  24. NC-002: First Novel Combination “SSCC” StudyIn patients with TB sensitive to Pa, M, and Z Participants with newly diagnosed smear positive DS TB, and MDR TB Pa(200mg)-M-Z N=60 Pa(100mg)-M-Z N=60 DS Rifafour N=60 2 months of treatment Pa(200mg)-M-Z N=50 Randomize DR Serial 16 hour pooled sputum samples for CFU Count Z = pyrazinamide at 1500mg Pa = PA-824 M = moxifloxacin Technological Leapfrogging: A TB Imperative

  25. NC-002 Summary of Key Results and Plans • Pa-M-Z Regimen was statistically significantly better than the HRZE control for the primary and 3/5 key secondary endpoints • Reduction in colony counts over 56 days • Time to culture conversion • Culture conversion to negative at 8 weeks • Safety comparable to control • Positive End-of Phase-2 meetings with FDA (1/23/14) • Positive EMA Scientific Advice (March 5, 2014) Technological Leapfrogging: A TB Imperative

  26. NC-006 (STAND): Phase 3 Trial of Pa-M-Z Participants with newly diagnosed smear positive DS- and MDR-TB Pa(200mg)-M-Z N= 350 Pa(100mg)-M-Z N=350 4months of treatment Pa(200mg)-M-Z N=350 12 & 24 mos f/u after randomization DS Rifafour N=350 Pa(200mg)-M-Z N= up to 350 6months of treatment Randomize DR Z = pyrazinamide at 1500mg Pa = PA-824 M = moxifloxacin Technological Leapfrogging: A TB Imperative

  27. Regimens Consisting Entirely of Novel Chemical Entities Nix – TB

  28. NiX-TB: Background • DS-TB is a curable disease; MDR-TB is a curable disease, although treatment harder to implement • Highly resistant TB offers opportunity to further speed up the testing of promising TB drug regimens • XDR / TDR-TB is a disease where existing treatment options are limited: >75% mortality in South Africa • Optimal therapy should consist of at least 3 drugs to which M.tb is susceptible • Critical mass of new chemical entities without pre-existing resistance are currently in development or just approved, but not readily available • Aim is to help XDR-TB patients now under carefully controlled conditions while advancing understanding of entirely novel regimens • Treat for cure in XDR-TB patients • Definitive treatment and follow up • Potentially most rapid path to approval • Simultaneously pursue forward development pathway in DS/DR Technological Leapfrogging: A TB Imperative

  29. NiX-TB Program • Initial regimen – universal sensitivity • Diarylquinoline – bedaquiline • Nitroimidazole – Pa-824 • Oxazolidinone – linezolid • Initiate study in 2014 with XDR-/TDR-TB at select centers with aim of cure • Highly selected centers - intensive data collection, long-term follow up with definitive outcomes • Value proposition • Universal regimen for all TB patients with active disease (no pre-existing resistance) • 3-4 month regimen pre-clinically • Oral, once daily • Affordable Technological Leapfrogging: A TB Imperative

  30. STEP-TB Speeding Treatments to End Pediatric- TB

  31. Childhood TB A Leading Cause of Childhood Mortality One of the top 10 causes of childhood deaths globally 530,000-810,000 pediatric TB cases annually: Possibly 20-40% of the burden in some countries Children with TB are the neglected of the neglected: Under-diagnosed Under-reported Inappropriately treated TB is a leading killer of children with HIV The young are susceptible to the deadliest forms of TB.

  32. Daily treatment for a TB-HIV co-infected child

  33. Current Efforts • Understand the global TB epidemic in kids • Incentivize global suppliers to enter the market • Integrate childhood TB into national TB control and child survival strategies • Ensure appropriate, improved treatments reach children in need • Advocate for an end to the neglect of childhood TB Manufacturer Engagement Market Understanding Clinical and Regulatory Understanding Policy and Uptake by Countries Establish Funding Information Exchange

  34. STEP-TB Update and Next Steps Market Intelligence: • 4 studies completed • Additional studies in 2014/2015 on barriers to manufacturer involvement, procurement in non-GDF countries, refinement of data on current and potential market size, etc. Ensuring Product Supply: • MOU with Svizera; Agreement with Macleods anticipated Q1 2014 • Negotiations progressing with Lupin, Sandoz, Sanofi Policy and Uptake: • WHO comprehensive treatment guidelines for pediatric TB to be finalized 1Q14 and rolled out in 2014 Advancing Development of Pediatric TB Treatments: • Under 5kg PK study (IMPAACT) • Accelerating development and regulatory pathways for novel drugs Technological Leapfrogging: A TB Imperative

  35. TB Alliance Supporters United States Agency for International Development Bill & Melinda Gates Foundation Irish Aid UK aid United States Food and Drug Administration National Institute of Allergy and Infectious Disease AIDS Clinical Trial Group European Commission Global Health Innovative Technology Fund UNITAID Australian AID Technological Leapfrogging: A TB Imperative

  36. Thank you!

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