Tuberculosis Program at NIAIDTuberculosis 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

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

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

Geographical DistributionGeographical Distributionof Compound Suppliersof Compound Suppliers

Candidates AdvancingCandidates Advancing

>75,000 unique structures in database7,157 active at < 6.25 ug/ml2,000 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

Global Alliance for TB Drug Global Alliance for TB Drug Development (TB Alliance)Development (TB Alliance)

TB Alliance founded in 2000TB Alliance founded in 2000 Global public private partnership Global public private partnership NIAID - a founding stakeholder, in NIAID - a founding stakeholder, in

kind contributorkind contributor NIAID staff – Board of Directors, NIAID staff – Board of Directors,

Scientific Advisory CommitteeScientific Advisory Committee

Advanced Drug Development Advanced Drug Development Moxifloxacin (Bayer)Moxifloxacin (Bayer)

R207910 Diarylquinoline Johnson & JohnsonR207910 Diarylquinoline Johnson & Johnson

PA-824 (TB Alliance)PA-824 (TB Alliance)

Oxazolidinone Ranbaxy Research LabsOxazolidinone Ranbaxy Research Labs LL-3858 Lupin PharmaceuticalsLL-3858 Lupin Pharmaceuticals SQ-109 Sequella, IncSQ-109 Sequella, Inc KRQ-10018 KRICT/TB AllianceKRQ-10018 KRICT/TB Alliance OSA FASgen, IncOSA FASgen, Inc PD Fluoroquinolone PD Fluoroquinolone

Thiolactomycin -GlaxoSmithKline/NIAID/St. Jude Children’s Thiolactomycin -GlaxoSmithKline/NIAID/St. Jude Children’s HospitalHospital

ActivBioticsActivBiotics

PA-824: Efficacy ReviewPA-824: Efficacy Review Bactericidal against replicating MTBBactericidal against replicating MTB New mechanism of actionNew mechanism of action Active against MDR strains of MTBActive against MDR strains of MTB Potency similar to INHPotency similar to INH Other analogs show greater Other analogs show greater in vitroin vitro

activity than PA-824, less activity than PA-824, less in vivoin vivo Orally bioavailable with formulationOrally bioavailable with formulation

NIAID-supported TB HIV Co-infection StudiesNIAID-supported TB HIV Co-infection Studies R ChaissonR Chaisson – “Novel TB Prevention Regimens for HIV-Infected Adults”, Hopkins, University of the – “Novel TB Prevention Regimens for HIV-Infected Adults”, Hopkins, University of the

Witwatersrand.Witwatersrand.

R OberhelmanR Oberhelman – “Practical Diagnostics for AIDS-Related Pediatric TB, Peru”, Tulane, Instituto de – “Practical Diagnostics for AIDS-Related Pediatric TB, Peru”, Tulane, Instituto de Salud del Nino, Lima.Salud del Nino, Lima.

R SembaR Semba – “Adjunct Vitamin Therapy for TB and HIV/AIDS”, Hopkins, Zomba Central Hospital, – “Adjunct Vitamin Therapy for TB and HIV/AIDS”, Hopkins, Zomba Central Hospital, MalawiMalawi

C WhalenC Whalen – “Punctuated ARV Therapy”, Case Western, Uganda JCRC, Kampala, Uganda – “Punctuated ARV Therapy”, Case Western, Uganda JCRC, Kampala, Uganda

A Salim KarimA Salim Karim – “CIPRA:CAPRISA – Implementing ARV therapy in resource constrained – “CIPRA:CAPRISA – Implementing ARV therapy in resource constrained settings”, Durban. settings”, Durban.

D HavlirD Havlir – AACTG 5221 "A Phase IV study of immediate versus delayed initiation of antiretroviral – AACTG 5221 "A Phase IV study of immediate versus delayed initiation of antiretroviral therapy for HIV-infected adults presenting with pulmonary tuberculosis.“therapy for HIV-infected adults presenting with pulmonary tuberculosis.“

Sok ThimSok Thim – “A Cambodian Clinical Research Network for HIV”, CAMELIA, Cambodian Health – “A Cambodian Clinical Research Network for HIV”, CAMELIA, Cambodian Health Committee (NGO), ANRS, Institute Pasteur Cambodia, Harvard.Committee (NGO), ANRS, Institute Pasteur Cambodia, Harvard.

J PapeJ Pape – “A randomized clinical trial to determine the efficacy of early versus delayed – “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 antiretroviral therapy in HIV-infected adults with CD4+ T cell counts between 200 and 350 cells/mm3”, GHESKIO, Haiticells/mm3”, GHESKIO, Haiti

PACTG 1041PACTG 1041 – “A Phase II/III Randomized DB Trial to Determine the Efficacy of INH in TB – “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, Disease in South African Infants Perinatally exposed to HIV”, University of the Witwatersrand, South Africa.South Africa.

J McIntyreJ McIntyre – “CIPRA: The Effect of ART on Rates and Transmission of TB in a peri-urban – “CIPRA: The Effect of ART on Rates and Transmission of TB in a peri-urban community in South Africa”community in South Africa”

TB HIV Co-Infection Treatment IssuesTB HIV Co-Infection Treatment Issues Appropriate treatment of both infectionsAppropriate 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 What ARVs to Start – CYP interactions with PIs and

with RIFwith RIF How to effectively protect against infection (or re-How to effectively protect against infection (or re-

infection) of HIV+infection) of HIV+• Extended INH over 6 monthsExtended INH over 6 months• Lifetime INHLifetime INH• RifapentineRifapentine

Management and better understanding of the IRIS Management and better understanding of the IRIS reaction in HIV/TB co-infectionsreaction in HIV/TB co-infections

NIAID’s TB and other Mycobacterial Diseases NIAID’s TB and other Mycobacterial Diseases ProgramProgram

BasicBasicResearcResearc

hh

TargetTargetIdentificationIdentification

Research GrantsResearch Grants

ContractsContracts

TargetTargetValidationValidation

Candidate Candidate IdentificationIdentification

OptimizationOptimizationScale-up Scale-up GLP PharmGLP PharmGLP ToxGLP ToxFormulationFormulationIND StudiesIND StudiesPartnersPartners

PreclinicaPreclinical Efficacy l Efficacy SafetySafety

Clinical TrialsClinical Trials

Fundamental and Clinical ScienceFundamental and Clinical ScienceVaccinesVaccinesDrugsDrugs DiagnosticsDiagnostics