Accelerating

1. Accelerating the development of faster acting and affordable drug combinationsto fight tuberculosis.

2. Community Advocacy for New Tools and Strategies to Address TB/HIV: TB TreatmentChristo van Niekerk

3. 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 • Yet today the world still depends on outdated drugs delivered in a complex multi-drug regimen for six or more months.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

4. 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

5. Factors Contributing to Current TB Epidemic • HIV epidemic • failing public health infrastructures • increasing poverty and homelessness • IV drug use (living conditions)

6. 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

7. Natural History of TB(in the absence of HIV infection) 50% 50% 10% 90%

8. 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

9. State of the Field • Lengthy - 6-8 months of 4 drugs taken in combination • Outdated – drugs discovered in 1940s, 1950s,armamentarium dwindling • Cumbersome - direct monitoring by healthcare workers, 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!

10. 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+)

11. TB and HIV The 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.

12. 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 for TB drug development

13. 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

14. The TB Alliance Mission • Develop new, better drugs for TB • Ensure affordability, access and adoption (AAA) • Coordinate and catalyze TB drug development activities worldwide

15. 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

16. TB Alliance Priorities • Active disease • TB/HIV co-infection • MDR-TB • Latent infection (LTBI) Based on impact and feasibility

17. Active TB – Near Term Goal Shorten: 6 months to 2-3 months Simplify: daily to weekly 130 doses 10 doses

18. Long-term Goal Active Disease 7-10 days of treatment But - very difficult to achieve without advances in understanding the biology of “persistence”

19. TB Alliance Portfolio Compounds, Analogs and Derivatives Discovery Preclinical Clinical Testing Nitroimidazole Backup Compound (Otsuka) Nitroimidazole Analogs (University of Auckland/Novartis Institute for Tropical Diseases/ National Institute of Allergy & Infectious Diseases) Nitroimidazole PA-824 (Chiron) Diamine SQ-109 (Sequella) Moxifloxacin (Bayer) Quinolones (KRICT/Yonsei University) Quinolone DW-224 (Dongwha) Nitroimidazole OPC-67683 (Otsuka) Macrolides (University of Illinois at Chicago) InhA Inhibitors (GlaxoSmithKline) Isocitrate Lyase Inhibitors (GlaxoSmithKline) Pleuromutilins (GlaxoSmithKline) Focused Screening (GlaxoSmithKline) Screening and Target Identification (AstraZeneca) Oxazolidinones (Pfizer) Bifunctional Molecules (Cumbre) Malate Synthase Inhibitors (GlaxoSmithKline/Rockefeller University) Protease Inhibitors (Medivir) Riminophenazines (Institute of Materia Medica) Contracted Program Capuromycins (Sankyo/Sequella) Program in discussion New Targets (University of Pennsylvania/Evotec) Global Alliance for TB Drug Development www.tballiance.orgMarch 2006 Proteasome Inhibitors (Cornell University)

20. Global TB Drug PortfolioSeptember 2005 Discovery Preclinical Clinical Testing Carboxylates TB Alliance, Wellesley College Nitrofuranylamides NIAID, University of Tennessee Diamine SQ-109 Sequella Inc. Diarylquinoline TMC207 Johnson & Johnson Dipiperidines (SQ-609) Sequella Inc. Gatifloxacin OFLOTUB Consortium, Lupin, NIAID TBRU, Tuberculosis Research Centre, WHO TDR Cell Wall Inhibitors Colorado State University, NIAID Nitroimidazole Analogs NIAID, Novartis Institute for Tropical Diseases, TB Alliance Non-Fluorinated Quinolone TaiGen Moxifloxacin Bayer Pharmaceuticals, CDC TBTC, Johns Hopkins University, NIAID TBRU, TB Alliance Dihydrolipoamide Acyltransferase Inhibitors Cornell University, NIAID Novel Antibiotic Class GlaxoSmithKline, TB Alliance Synthase Inhibitor FAS20013 FASgen Inc. Nitroimidazole PA-824 Chiron Corporation, TB Alliance InhA Inhibitors GlaxoSmithKline, TB Alliance Picolinamide Imidazoles NIAID, TAACF) Translocase I Inhibitors Sequella Inc., Sankyo Nitroimidazo-oxazole OPC-67683 Otsuka Isocitrate Lyase Inhibitors (ICL) GlaxoSmithKline, TB Alliance Pleuromutilins GlaxoSmithKline, TB Alliance Nitroimidazo-oxazole Back-up Otsuka Pyrrole LL-3858 Lupin Limited Macrolides TB Alliance, University of Illinois at Chicago Quinolones KRICT/ Yonsei University, NIAID, TAACF, TB Alliance 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 STOP TB New Drugs Working Group

21. 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.

22. 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.)

23. Accelerating the development of faster acting and affordable drug combinationsto fight tuberculosis.