Accelerating the development of faster acting and affordable drug combinations to fight...
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Transcript of Accelerating the development of faster acting and affordable drug combinations to fight...
Tuberculosis (TB)
• Tuberculosis, an ancient and relentless pandemic, continues to ravage continents, societies and families.
• Yet today the world still depends on outdated drugs delivered in a complex multi-drug regimen for six or more months.
• No new drugs have been introduces in 30 years
Global Epidemic
• 2 billion people are infected with M. tb• 9 million new active TB cases a year• 2 million people die/year; 1/15 sec• ~ 400,000 new cases of MDR-TB a year• 12 million persons are TB/HIV co-infected• Biggest killer of women of childbearing age• Economic toll: $12 billion a year
Current TB therapy, though efficacious, is inadequate to control the global TB epidemic - too long and too complex
Factors Contributing to Current TB Epidemic
• HIV epidemic
• failing public health infrastructures
• increasing poverty and homelessness
• IV drug use (living conditions)
Tuberculosis (TB)
• A disease caused by a bacterium (bug): Mycobacterium tuberculosis (M. tb; MTB)
• 50 years after introduction of an effective drug, TB remains 2nd only to AIDS as the leading infectious cause of death in the world
Clinical Presentations
• Latent TB Infection• Pulmonary TB
– Smear positive (cavitating)– Smear negative
• Extra Pulmonary TB• TB in children
– Miliary TB– TB meningitis– Pulmonary TB– Other
State of the Field
• Lengthy - 6-8 months of 4 drugs taken in combination
• Outdated – drugs discovered in 1940s, 1950s, armamentarium dwindling
• Cumbersome - direct monitoring by healthcare workers, <50% of smear+ cases receive standard of care
• Poor results - Incomplete treatment results in drug-resistant strains, and relapse
• TB and HIV treatment not easily co-administered
We need a new treatment!
TB and HIV• A total of 12 million people worldwide are co-
infected with both diseases, with a majority of them living in Southern Africa.
• In sub-Saharan Africa, two-thirds of TB patients are co-infected with AIDS.
• When someone with latent TB becomes co-infected with HIV, the risk of developing active TB increases by a factor of 30 - 50.
• For those who are HIV+, risk is almost 10% per year. (In some countries, over 70% of TB patients are also HIV+)
TB and HIVThe are several important associations between
epidemics of HIV and TB:
• TB is harder to diagnose in HIV positive people • TB progresses faster in HIV-infected people • TB in HIV positive people is more likely to be fatal if
undiagnosed or left untreated • TB occurs earlier in the course of HIV infection than
other opportunistic infections • TB is the only major AIDS-related opportunistic infection
that poses a risk to HIV-negative people.
History of the TB Alliance• Cape Town Declaration – Feb 2000
– Hosts: Rockefeller Foundation & MRC S. Africa– Over 120 organizations (health, science,
philanthropy and private industry)
• Results
– Support goals of Stop TB Initiative– Create Scientific Blueprint– Develop Pharmacoeconomic Analysis
Build a global alliance forTB drug development
The TB Alliance
• International Public-Private Partnership (PDP)
• Independent, not-for-profit organization
• Based in New York, Brussels and Pretoria
• Entrepreneurial, virtual R&D approach– Out-source R&D to public or private partners
The TB Alliance
Mission
Develop new, better drugs for TB
Ensure affordability, access and adoption (AAA)
Coordinate and catalyze TB drug development activities worldwide
Affordability, Access and Adoption (AAA)
• Develop cost effective, affordable new anti-tuberculosis drugs for all those who need them most
• Ensure equitable access of new TB treatments, especially for patients in high-burden countries.
• Working closely with communities, governments and National TB Programme coordinators to ensure the future drugs will be adopted into TB Programmes
1. Active disease
2. TB/HIV co-infection
3. MDR-TB
4. Latent infection (LTBI)
TB Alliance Priorities Based on impact and feasibility
Active TB – Near Term Goal
130 doses130 doses
Shorten: 6 months to 2-3 months
Simplify: daily to weekly
10 doses10 doses
Long-term Goal Active Disease
7-10 days of treatment
But - very difficult to achieve without advances in understanding the biology of
“persistence”
TB Alliance PortfolioDiscovery Preclinical Clinical Testing
Nitroimidazole Analogs (University of Auckland/Novartis Institute for Tropical Diseases/National Institute of Allergy & Infectious Diseases)
Quinolones (KRICT/Yonsei University)
Nitroimidazole PA-824 (Chiron)
Co
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ou
nd
s, A
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og
s an
d D
eri
vati
ves
Contracted Program
Program in discussion
Screening and Target Identification (AstraZeneca)
Nitroimidazole OPC-67683 (Otsuka)
Moxifloxacin (Bayer)
Global Alliance for TB Drug Development www.tballiance.org March 2006
InhA Inhibitors(GlaxoSmithKline)
Isocitrate Lyase Inhibitors(GlaxoSmithKline)
Focused Screening (GlaxoSmithKline)
Pleuromutilins (GlaxoSmithKline)
Nitroimidazole Backup Compound (Otsuka)
Oxazolidinones(Pfizer)
Bifunctional Molecules(Cumbre)
Macrolides (University of Illinois at Chicago)
Malate Synthase Inhibitors(GlaxoSmithKline/Rockefeller University)
Protease Inhibitors(Medivir)
Riminophenazines(Institute of Materia Medica)
Capuromycins(Sankyo/Sequella)
Diamine SQ-109(Sequella)
New Targets(University of Pennsylvania/Evotec)
Proteasome Inhibitors(Cornell University)
Quinolone DW-224(Dongwha)
Global TB Drug PortfolioSeptember 2005
Discovery Preclinical Clinical Testing
Dihydrolipoamide Acyltransferase InhibitorsCornell University, NIAID
InhA InhibitorsGlaxoSmithKline, TB Alliance
Isocitrate Lyase Inhibitors (ICL) GlaxoSmithKline, TB Alliance
MacrolidesTB Alliance, University of Illinois at Chicago
Methyltransferase InhibitorsAnacor Pharmaceuticals
Translocase I InhibitorsSequella Inc., Sankyo
Synthase Inhibitor FAS20013FASgen Inc.
Moxifloxacin Bayer Pharmaceuticals, CDC TBTC, Johns Hopkins University, NIAID TBRU, TB Alliance
Diarylquinoline TMC207Johnson & Johnson
Nitroimidazo-oxazole OPC-67683 Otsuka
Natural Products Exploration BIOTEC, California State University, ITR, NIAID, TAACF, University of Auckland
Dipiperidines (SQ-609) Sequella Inc.
Diamine SQ-109Sequella Inc.
GatifloxacinOFLOTUB Consortium, Lupin, NIAID TBRU, Tuberculosis Research Centre, WHO TDR
Cell Wall InhibitorsColorado State University, NIAID
Novel Antibiotic ClassGlaxoSmithKline, TB Alliance
Picolinamide ImidazolesNIAID, TAACF)
PleuromutilinsGlaxoSmithKline, TB Alliance
QuinolonesKRICT/ Yonsei University, NIAID, TAACF, TB Alliance
Screening and Target IdentificationAstraZeneca
Thiolactomycin AnalogsNIAID, NIH
Nitroimidazole Analogs NIAID, Novartis Institute for Tropical Diseases, TB Alliance
Nitrofuranylamides NIAID, University of Tennessee
Pyrrole LL-3858Lupin Limited
Nitroimidazole PA-824Chiron Corporation, TB Alliance
Non-Fluorinated QuinoloneTaiGen
CarboxylatesTB Alliance, Wellesley College
Nitroimidazo-oxazole Back-up Otsuka
STOP TB New Drugs Working Group
TB and HIV
While policymakers are currently developing better technical
frameworks to improve today’s strategies for TB control in HIV
hotspots, better drugs that eliminate TB in HIV patients are key to halting
the dual infection.
Antituberculosis drugs and HIV
• Rifampicin should be avoided because of its strong inducing effect resulting in an increased risk of virological failure and development of resistance.
• Serious side effects can occur in combination with Protease inhibitors
• Rifampin should be avoided if concurrent ART with NNRTIs (nucleoside reverse transcriptase inhibitors.)