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A New Paradigm for TB Drug Development

A New Paradigm for TB Drug Development. Mel Spigelman, M.D. Stakeholders’ Association Meeting October 17, 2005. TB Alliance Drug Portfolio 2004. Discovery. Preclinical. Clinical Testing. Compounds, Analogs and Derivatives. Nitroimidazole Analogs

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A New Paradigm for TB Drug Development

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  1. A New Paradigm for TB Drug Development Mel Spigelman, M.D. Stakeholders’ Association Meeting October 17, 2005

  2. TB Alliance Drug Portfolio 2004 Discovery Preclinical Clinical Testing Compounds, Analogs and Derivatives Nitroimidazole Analogs (Novartis Institute for Tropical Diseases, NIAID) Nitroimidazole PA-824 (Chiron) Moxifloxacin (Bayer Pharmaceutical, EDCTP) Carboxylates (Wellesley College) Pyrrole LL-3858 (Lupin Limited) Novel chemical entities Quinolones (KRICT/Yonsei University) Non-Fluorinated Quinolone (Procter & Gamble) Macrolides (University of Illinois at Chicago) Quinolone KRQ-10018 (KRICT/ Yonsei University) Novel Targets (Partner to be announced) New Compound Classes (Partner to be announced) Methyltransferase inhibitors (Anacor Pharmaceuticals) Rifalazil Analogs (ActivBiotics) Under contract In discussion/finalization stages Terminated TB Alliance support

  3. Global TB Drug PortfolioSeptember 2005 Discovery Preclinical Clinical Testing Carboxylates TB Alliance, Wellesley College Nitrofuranylamides NIAID, University of Tennessee Diamine SQ-109 Sequella Inc. Diarylquinoline TMC207 Johnson & Johnson Dipiperidines (SQ-609) Sequella Inc. Gatifloxacin OFLOTUB Consortium, Lupin, NIAID TBRU, Tuberculosis Research Centre, WHO TDR Cell Wall Inhibitors Colorado State University, NIAID Nitroimidazole Analogs NIAID, Novartis Institute for Tropical Diseases, TB Alliance Non-Fluorinated Quinolone TaiGen Moxifloxacin Bayer Pharmaceuticals, CDC TBTC, Johns Hopkins University, NIAID TBRU, TB Alliance Dihydrolipoamide Acyltransferase Inhibitors Cornell University, NIAID Novel Antibiotic Class GlaxoSmithKline, TB Alliance Synthase Inhibitor FAS20013 FASgen Inc. Nitroimidazole PA-824 Chiron Corporation, TB Alliance InhA Inhibitors GlaxoSmithKline, TB Alliance Picolinamide Imidazoles NIAID, TAACF) Translocase I Inhibitors Sequella Inc., Sankyo Nitroimidazo-oxazole OPC-67683 Otsuka Isocitrate Lyase Inhibitors (ICL) GlaxoSmithKline, TB Alliance Pleuromutilins GlaxoSmithKline, TB Alliance Nitroimidazo-oxazole Back-up Otsukai Pyrrole LL-3858 Lupin Limited Macrolides TB Alliance, University of Illinois at Chicago Quinolones KRICT/ Yonsei University, NIAID, TAACF, TB Alliance Methyltransferase Inhibitors Anacor Pharmaceuticals Screening and Target Identification AstraZeneca Natural Products Exploration BIOTEC, California State University, ITR, NIAID, TAACF, University of Auckland Thiolactomycin Analogs NIAID, NIH

  4. The Challenge and Opportunity of Success

  5. Active TB - Strategy Shorten: 6 months to 2-3 months then Simplify: daily to weekly 130 doses 10 doses

  6. Long-term Goal Active Disease 7-10 days of treatment But - very difficult to achieve without advances in understanding the biology of “persistence”

  7. “TB Crystal Ball” All present first-line drugs (HRZE) have suboptimal profiles • pharmacokinetics • cytochrome P450 interactions • poor sterilizing activities (except R) • antagonistic interactions (E with HRZ; H with RZ) None of present first-line drugs will ultimately be part of an “optimized” regimen H = isoniazid; R = rifampin; Z = pyrazinamide; E = ethambutol

  8. Conventional TB Clinical Paradigm • Goal of a development program is to substitute one new drug for one of the conventional drugs HRZE MRZE or HRZM • Approximate (aggressive) timelines: Phase I 1 year Phase II 2 years Phase III 3 years 6 years H = isoniazid; R = rifampin; Z = pyrazinamide; E = ethambutol; M = moxifloxacin

  9. DilemmaConventional TB Clinical Development Paradigm E A F B G C H D ABCD BCDE CDEF DEFG EFGH 6 years 6 years 6 years 6 years ABCD 24 years EFGH

  10. Strategic Shift Advancing novel COMBINATIONS rather than single drugs through the later drug development pipeline.

  11. Alternative TB Clinical Development Paradigms EF AB GH CD #1: ABCD CDEF EFGH 6 years 6 years ABCD 12 years EFGH

  12. Alternative TB Clinical Development Paradigms EFGH ABCD #2: ABCD EFGH 6 years ABCD 6 years EFGH

  13. “Milestones” of Combination Development Paradigm • All preclinical candidates potentially included in combination in vitro/in vivo studies • Compounds tested individually through standard Phase I and EBA studies • Phase I combination studies • EBA combination studies • Phase II and III combination studies

  14. The Unfolding Solution

  15. CFU Counts after 2 Months’ Treatment

  16. Meeting the Regulatory ChallengeTB Drug Development Forum • December 6-7, 2005 in DC area • Co-sponsored by TB Alliance, STOP TB Working Group on New Drugs and Bill and Melinda Gates Foundation • Funded primarily by unrestricted grant from AstraZeneca • Significant FDA participation; EMEA and SA MCC invited

  17. A New TB Drug Development Paradigm • Process begins at the preclinical stage once individual compounds meet preset criteria • Feasible with present technologies • Engage major regulatory authorities • Think and act “comprehensively”– all compounds are part of one large portfolio new concepts of partnerships

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