Download TB Alliance

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
New Therapeutics for Tuberculosis / HIV Co-infections
Basic Research
New
Concepts
for
Therapeutics
Preclinical Development
Growth Inhibition
Screening
Drug Libraries
MechanismBased Screening
Clinical Trials
In Vitro Spectrum
Multi-center Clinical Studies
In Vivo Efficacy
NIAID TBRU
Pharmacology
TB Alliance
Toxicology
CDC TBTC
ACTG International Sites
In Vivo Evaluation, Chemical Synthesis,
Reagent Support, Data Bases
NIH Roadmap Initiatives
Direct Assistance and Interaction with the Scientific Community
IUATLD
NIAID Project Officer: Robert Goldman, www.taacf.org
Geographical Distribution
of Compound Suppliers
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
Global Alliance for TB Drug
Development (TB Alliance)
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TB Alliance founded in 2000
Global public private partnership
NIAID - a founding stakeholder, in
kind contributor
NIAID staff – Board of Directors,
Scientific Advisory Committee
Advanced Drug Development
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Moxifloxacin (Bayer)
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R207910 Diarylquinoline Johnson & Johnson
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PA-824 (TB Alliance)
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Oxazolidinone Ranbaxy Research Labs
LL-3858 Lupin Pharmaceuticals
SQ-109 Sequella, Inc
KRQ-10018 KRICT/TB Alliance
OSA FASgen, Inc
PD Fluoroquinolone
Thiolactomycin -GlaxoSmithKline/NIAID/St. Jude Children’s
Hospital
ActivBiotics
PA-824: Efficacy Review
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Bactericidal against replicating MTB
New mechanism of action
Active against MDR strains of MTB
Potency similar to INH
Other analogs show greater in vitro
activity than PA-824, less in vivo
Orally bioavailable with formulation
NIAID-supported TB HIV Co-infection Studies
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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 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
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.“
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
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”
TB HIV Co-Infection Treatment Issues
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Appropriate treatment of both infections
• When to Start ARVs in active TB
• What ARVs to Start – CYP interactions with PIs
and with RIF
How to effectively protect against infection (or reinfection) of HIV+
• Extended INH over 6 months
• Lifetime INH
• Rifapentine
Management and better understanding of the IRIS
reaction in HIV/TB co-infections
NIAID’s TB and other Mycobacterial Diseases Program
Research Grants
Basic
Target
Research Identification
Contracts
Target
Validation
Fundamental and Clinical Science
Vaccines
Drugs
Diagnostics
Candidate
Identification
Preclinical
Efficacy
Safety
Optimization
Scale-up
GLP Pharm
GLP Tox
Formulation
IND Studies
Partners
Clinical Trials