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Testing Novel Combination Regimens
Mel Spigelman, M.D. Open Forum on Key Issues in TB Drug Development December 6-7, 2005 Arlington, VA We have completed several studies on PA-824 and analogues. Additional studies are underway and will be completed this month. As we have described before, the Development Plan has key go/no-go decision points to be guided by results of studies on PA-824 and analogues -- to assess its potential mutagenicity and feasibility of synthesis on a production scale. The results have been encouraging and we have passed the initial go/no-go decision(mutagenicity screening) to move to the next phase of the preclinical development plan (animal toxicology studies).
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what’s new ? what’s needed? what’s necessary?
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what’s new ?
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Global TB Drug Portfolio September 2005
Discovery Preclinical Clinical Testing Carboxylates TB Alliance, Wellesley College Nitrofuranylamides NIAID, University of Tennessee Diamine SQ-109 Sequella Inc. Diarylquinoline TMC207 Johnson & Johnson Cell Wall Inhibitors Colorado State University, NIAID Nitroimidazole Analogs NIAID, Novartis Institute for Tropical Diseases, TB Alliance Dipiperidines (SQ-609) Sequella Inc. Gatifloxacin OFLOTUB Consortium, Lupin, NIAID TBRU, Tuberculosis Research Centre, WHO TDR Dihydrolipoamide Acyltransferase Inhibitors Cornell University, NIAID Novel Antibiotic Class GlaxoSmithKline, TB Alliance Non-Fluorinated Quinolone TaiGen Moxifloxacin Bayer Pharmaceuticals, CDC TBTC, Johns Hopkins University, NIAID TBRU, TB Alliance InhA Inhibitors GlaxoSmithKline, TB Alliance Picolinamide Imidazoles NIAID, TAACF) Synthase Inhibitor FAS20013 FASgen Inc. Nitroimidazole PA-824 Chiron Corporation, TB Alliance Isocitrate Lyase Inhibitors (ICL) GlaxoSmithKline, TB Alliance Pleuromutilins GlaxoSmithKline, TB Alliance Translocase I Inhibitors Sequella Inc., Sankyo Nitroimidazo-oxazole OPC-67683 Otsuka Macrolides TB Alliance, University of Illinois at Chicago Quinolones KRICT/ Yonsei University, NIAID, TAACF, TB Alliance Nitroimidazo-oxazole Back-up Otsukai Pyrrole LL-3858 Lupin Limited 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
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what’s new ? AstraZeneca Bayer GlaxoSmithKline Johnson & Johnson Lupin
Novartis Otsuka Sequella Others Hope for a sustainable pipeline
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An Established Global Alliance for TB Drug Development
what’s new ? An Established Global Alliance for TB Drug Development
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what’s new ? Global TB Drug Facility Global Fund Stop TB Partnership
Invigorated DOTS Programs Strengthened National Treatment Programs Green Light Committee More rational systems for procurement, delivery, access and adoption of new therapies
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what’s new ? Funding of New Drug R&D Bill and Melinda Gates Foundation
Rockefeller Foundation Governments and government agencies Private sector
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what’s not new ? HIV/AIDS increasing, fueling TB epidemic
MDR increasing Poor understanding of present first line regimen does ethambutol or streptomycin contribute anything would therapy be more effective without isoniazid what is the optimal dose of rifampin Same old tools
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summary of what’s new ? Meaningful clinical pipeline with more to follow Increasing TB cases and deaths Better mechanisms in place for a more rational delivery of new therapies More money, but not enough, especially for clinical development
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what’s needed ?
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what’s needed ? Dramatic shortening and meaningful simplification of treatment of active disease Stop generating “MDR” Ability to treat TB and AIDS simultaneously Markedly improved therapy of latent infection
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what’s needed ? Replace all present first line drugs (? Z)
Present first-line drugs will not contribute to meeting present needs pharmacokinetics cytochrome P450 interactions (H and R) poor sterilizing activities (except R) not clear if H or E contribute to efficacy potentially even antagonistic interactions (E with HRZ; H with RZ) H = isoniazid; R = rifampin; Z = pyrazinamide; E = ethambutol
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what’s not needed ? Conventional Sequential Development
F B G C H D ABCD BCDE CDEF DEFG EFGH 6 years 6 years 6 years 6 years ABCD 24 years EFGH
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what’s not needed ? Multiple, minimally differentiable regimens with similar levels of activity Pressure on NTPs to change standard of care frequently for minimal incremental improvements
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summary of what’s needed ?
Make optimal use of every drug (whether “old” or “new”) Fixed dose combination products need to be prioritized whenever feasible
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Strategic Shift Advance optimal REGIMENS, independent of source or novelty of components, through the later stages of the development pipeline
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what’s necessary ?
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what’s necessary ? Cooperation amongst “sponsors”
“cultural shift” Nonclinical safety evaluation of drug combinations (generic FDA Draft Guidance January 2005) Extensive preclinical testing of all “reasonable” combinations identify synergistic regimens with potential for major impact on treatment shortening Path for clinical development,registration and adoption
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Clinical Development Paradigm
what’s necessary ? Clinical Development Paradigm predicated on extensive preclinical testing “standard” Phase I and EBA testing of all individual compounds identify pk, safety profiles, maximum tolerated doses, dose response, metabolic profiles of individual compounds Phase I combination studies potential pk interactions, tolerability
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Clinical Development Paradigm (cont)
“Sterilization” potential – Phase IIA EBA combination studies, SSCC, 2 month sputum conversion ??? Definitive Phase III studies on small number of optimized regimens
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Considerations Why would we not want to know the best (from a preclinical perspective) potentially available regimen ? no reason How different is it to advance clinically a regimen with multiple novel agents versus a regimen with only one novel drug minimally different; higher risk of failure for greater potential impact risk-benefit equation drives adoption, not just approval
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