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Tuberculosis Program at NIAID Christine Sizemore, PhD* & Barbara Laughon, PhD # *Program Officer for Tuberculosis, Leprosy and Other Mycobacterial Diseases.

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Presentation on theme: "Tuberculosis Program at NIAID Christine Sizemore, PhD* & Barbara Laughon, PhD # *Program Officer for Tuberculosis, Leprosy and Other Mycobacterial Diseases."— Presentation transcript:

1 Tuberculosis Program at NIAID Christine Sizemore, PhD* & Barbara Laughon, PhD # *Program Officer for Tuberculosis, Leprosy and Other Mycobacterial Diseases # Chief, Complications and Co-Infections Research Branch, TRP Division of Microbiology and Infectious Diseases (DMID) Division of Acquired Immunodeficiency Syndrome (DAIDS) National Institute of Allergy and Infectious Diseases (NIAID) National Institutes of Health (NIH) US Department of Health and Human Services (DHHS) NIAID – WHO TB/HIV February 14-15, 2005

2 New Concepts for Therapeutics In Vitro Spectrum In Vivo Efficacy Pharmacology Toxicology Direct Assistance and Interaction with the Scientific Community Basic Research Preclinical Development Clinical Trials Multi-center Clinical Studies NIAID TBRU TB Alliance CDC TBTC ACTG International Sites IUATLD Growth Inhibition Screening Drug Libraries Mechanism- Based Screening In Vivo Evaluation, Chemical Synthesis, Reagent Support, Data Bases New Therapeutics for Tuberculosis / HIV Co-infections NIH Roadmap Initiatives

3 NIAID Project Officer: Robert Goldman, www.taacf.org

4 Geographical Distribution of Compound Suppliers

5 Candidates Advancing >75,000 unique structures in database 7,157 active at < 6.25 ug/ml 2,000 MIC < 4 ug/ml 20 Actives in Gamma Knock Out Mouse 11 Actives in Standard Model 3 Actives in both GKO and Standard 182 Compounds in queue for in vivo testing Candidates = Compounds with SI >= 10, structural novelty, supportive assay results, meet drug-like criteria. NIAID Project Officer: Robert Goldman, www.taacf.org

6 Global Alliance for TB Drug Development (TB Alliance) TB Alliance founded in 2000 TB Alliance founded in 2000 Global public private partnership Global public private partnership NIAID - a founding stakeholder, in kind contributor NIAID - a founding stakeholder, in kind contributor NIAID staff – Board of Directors, Scientific Advisory Committee NIAID staff – Board of Directors, Scientific Advisory Committee

7 Advanced Drug Development Moxifloxacin (Bayer) Moxifloxacin (Bayer) R207910 Diarylquinoline Johnson & Johnson R207910 Diarylquinoline Johnson & Johnson PA-824 (TB Alliance) PA-824 (TB Alliance) Oxazolidinone Ranbaxy Research Labs Oxazolidinone Ranbaxy Research Labs LL-3858 Lupin Pharmaceuticals LL-3858 Lupin Pharmaceuticals SQ-109 Sequella, Inc SQ-109 Sequella, Inc KRQ-10018 KRICT/TB Alliance KRQ-10018 KRICT/TB Alliance OSA FASgen, Inc OSA FASgen, Inc PD Fluoroquinolone PD Fluoroquinolone Thiolactomycin -GlaxoSmithKline/NIAID/St. Jude Childrens Hospital Thiolactomycin -GlaxoSmithKline/NIAID/St. Jude Childrens Hospital ActivBiotics ActivBiotics

8 PA-824: Efficacy Review Bactericidal against replicating MTB Bactericidal against replicating MTB New mechanism of action New mechanism of action Active against MDR strains of MTB Active against MDR strains of MTB Potency similar to INH Potency similar to INH Other analogs show greater in vitro activity than PA-824, less in vivo Other analogs show greater in vitro activity than PA-824, less in vivo Orally bioavailable with formulation Orally bioavailable with formulation

9 NIAID-supported TB HIV Co-infection Studies R Chaisson – Novel TB Prevention Regimens for HIV-Infected Adults, Hopkins, University of the Witwatersrand. R Chaisson – Novel TB Prevention Regimens for HIV-Infected Adults, Hopkins, University of the Witwatersrand. R Oberhelman – Practical Diagnostics for AIDS-Related Pediatric TB, Peru, Tulane, Instituto de Salud del Nino, Lima. R Oberhelman – Practical Diagnostics for AIDS-Related Pediatric TB, Peru, Tulane, Instituto de Salud del Nino, Lima. R Semba – Adjunct Vitamin Therapy for TB and HIV/AIDS, Hopkins, Zomba Central Hospital, Malawi R Semba – Adjunct Vitamin Therapy for TB and HIV/AIDS, Hopkins, Zomba Central Hospital, Malawi C Whalen – Punctuated ARV Therapy, Case Western, Uganda JCRC, Kampala, Uganda C Whalen – Punctuated ARV Therapy, Case Western, Uganda JCRC, Kampala, Uganda A Salim Karim – CIPRA:CAPRISA – Implementing ARV therapy in resource constrained settings, Durban. A Salim Karim – CIPRA:CAPRISA – Implementing ARV therapy in resource constrained settings, Durban. D Havlir – AACTG 5221 "A Phase IV study of immediate versus delayed initiation of antiretroviral therapy for HIV-infected adults presenting with pulmonary tuberculosis. D Havlir – AACTG 5221 "A Phase IV study of immediate versus delayed initiation of antiretroviral therapy for HIV-infected adults presenting with pulmonary tuberculosis. Sok Thim – A Cambodian Clinical Research Network for HIV, CAMELIA, Cambodian Health Committee (NGO), ANRS, Institute Pasteur Cambodia, Harvard. Sok Thim – A Cambodian Clinical Research Network for HIV, CAMELIA, Cambodian Health Committee (NGO), ANRS, Institute Pasteur Cambodia, Harvard. J Pape – A randomized clinical trial to determine the efficacy of early versus delayed antiretroviral therapy in HIV-infected adults with CD4+ T cell counts between 200 and 350 cells/mm3, GHESKIO, Haiti J Pape – A randomized clinical trial to determine the efficacy of early versus delayed antiretroviral therapy in HIV-infected adults with CD4+ T cell counts between 200 and 350 cells/mm3, GHESKIO, Haiti PACTG 1041 – A Phase II/III Randomized DB Trial to Determine the Efficacy of INH in TB Disease in South African Infants Perinatally exposed to HIV, University of the Witwatersrand, South Africa. PACTG 1041 – A Phase II/III Randomized DB Trial to Determine the Efficacy of INH in TB Disease in South African Infants Perinatally exposed to HIV, University of the Witwatersrand, South Africa. J McIntyre – CIPRA: The Effect of ART on Rates and Transmission of TB in a peri-urban community in South Africa J McIntyre – CIPRA: The Effect of ART on Rates and Transmission of TB in a peri-urban community in South Africa

10 TB HIV Co-Infection Treatment Issues Appropriate treatment of both infections Appropriate treatment of both infections When to Start ARVs in active TBWhen to Start ARVs in active TB What ARVs to Start – CYP interactions with PIs and with RIFWhat ARVs to Start – CYP interactions with PIs and with RIF How to effectively protect against infection (or re- infection) of HIV+ How to effectively protect against infection (or re- infection) of HIV+ Extended INH over 6 monthsExtended INH over 6 months Lifetime INHLifetime INH RifapentineRifapentine Management and better understanding of the IRIS reaction in HIV/TB co-infections Management and better understanding of the IRIS reaction in HIV/TB co-infections

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13 NIAIDs TB and other Mycobacterial Diseases Program BasicResearchTargetIdentification Research Grants Contracts TargetValidationCandidateIdentification OptimizationScale-up GLP Pharm GLP Tox Formulation IND Studies Partners Preclinical Efficacy Safety Clinical Trials Fundamental and Clinical Science VaccinesDrugsDiagnostics


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