New York Product Development Partnerships for Global Health: The Global Alliance for TB Drug Development Gerald J. Siu

1. New York Product Development Partnerships for Global Health: The Global Alliance for TB Drug Development Gerald J. Siuta, Ph.D. Consultant, Business Development New York Biotechnology Association 17th Annual Meeting New York City, NY May 20, 2008

2. One-third of the world’s population is infected with Mycobacterium tuberculosis (M.tb.) 2 billion people 8-9 million develop active disease annually 2 million deaths occur each year 1 person dies every 15 seconds 400,000 cases of MDR-TB each year Leading cause of death in HIV-positive people 12 Million people are TB/HIV co-infected Global Tuberculosis Epidemic TB’s economic toll: $16 billion a year

3. Active TB Standard therapy – 4 drugs (isoniazid, rifampin, pyrazinamide & ethambutol) for 2 months, followed by isoniazid and rifampin for 4 months Latent TB Standard therapy – isoniazid for 9 months Multi-Drug Resistant TB (MDR-TB) Individualized, prolonged therapy, few available drugs, poorly tolerated and difficult to administer TB/HIV Co-Infection Treatment as in active TB, but drug interactions with antiretroviral agents make simultaneous therapy difficult Extensively Drug Resistant TB (XDR-TB) No treatment available Current TB Drug Therapy

4. Complex 6-9 months treatment with a 4 drug combination regimen No new anti-TB drug in over 40 years TB/HIV co-infections fueling each other MDR-TB is on the rise Unattractive market for private sector No capitalization of public sector research The Need for New TB Drugs

5. Cape Town Declaration – February 2000 Hosts: Rockefeller Foundation and the Medical Research Council of South Africa Over 120 organizations (health, science, philanthropy and private industry) Results Support goals of Stop TB Initiative Create Scientific Blueprint Develop Pharmacoeconomic Analysis History of the TB Alliance Build a Global Alliance for TB Drug Development

6. Independent, international Product Development Partnership founded in October 2000 Non-profit organization Headquarters in New York City Offices in Brussels and Cape Town Entrepreneurial, virtual R&D approach Out-source R&D to public and private partners Pro-active fundraising Over US $200 million raised Support ~ 200 FTE worldwide and 35 FTE in-house The TB Alliance

7. Develop an entirely new therapeutic regimen that will shorten or simplify the treatment of tuberculosis Coordinate and act as catalyst for global TB drug development activities Ensure Affordability, Adoption and Access (AAA Strategy) Our Mission

8. Affordability Appropriate pricing in developing countries Adoption Ensure that new drugs are incorporated into existing treatment programs Access Procurement and distribution to those patients who need them most AAA Strategy

9. FDCs Our Vision 10 Days 2 Months 6 Months

10. Shorten treatment to less than 2 months Novel mechanism of action (MDR/XDR-TB) Orally active Once daily or intermittent therapy Compatible with HIV treatment Low cost of goods Profile of a New TB Drug

11. Bill and Melinda Gates Foundation Rockefeller Foundation Netherlands Ministry for Development Cooperation United States Agency for International Development (USAID) Governments of Great Britain and Ireland Financial Support

12. In-Licensing IP Assignment Sponsored R&D Collaborative R&D Freedom to Operate Clinical Trials Types of Deals

13. TB Alliance Portfolio CLINICALDEVELOPMENT TB ALLIANCE PROGRAMS DISCOVERY Lead Identification Lead Optimization Preclinical Phase I Phase II Phase III Moxifloxacin PA-824 Quinolones Nitroimidazoles Pleuromutilins Mycobacterial Gyrase Inhibitors InhA Inhibitors Multifunctional Molecules Riminophenazines GSK Focused Screening Phenotypic Screening Malate Synthase Inhibitors Protease Inhibitors Energy Metabolism Inhibitors

14. PA-824 – A novel nitroimidazole Discovered by Pathogenesis, Inc. Distinct mechanism of action Potent activity against both active and slow growing M.tb. Possesses both bactericidal and sterilizing activity Chiron/Novartis

15. Worldwide exclusive license for the treatment of tuberculosis Defined scientific milestones Grant-back option Manufacturing rights No royalties in developing world Chiron/Novartis

16. Phase I clinical trials began June 3, 2005 Preclinical development completed in 3 years Drug was well tolerated with no definitive dose-limiting adverse events Phase II extended Early Bactericidal Activity (EBA) study has begun in Cape Town, South Africa Development of PA-824

17. Synthesis of PA-824 analogs Identified many new pharmacophores, several of which have demonstrated potent activity against TB Optimization has led to nitroimidazole analogs that have in vitro activity greater than PA-824 University of Auckland

18. Joint drug discovery program at GSK’s Diseases of the Developing World facility in Tres Cantos, Spain Five individual projects: Mycobacterial gyrase inhibitors InhA inhibitors Malate synthase inhibitors Pleuromutilins Focused screening GlaxoSmithKline

19. Project oversight by Joint Steering Committee TB Alliance helps to support 25 full-time scientists at GSK working exclusively on the TB drug program GSK absorbs all remaining overhead costs GSK contributes a matching number of staff Any resulting medicines will be made affordable and accessible to those most in need GlaxoSmithKline

20. Located in Daejeon, South Korea Synthesized more than 600 quinolones, pyridones & quinolizines In vitro and in vivo biological testing at the Yonsei University College of Medicine in Seoul, South Korea Four lead compounds have been selected for further preclinical evaluation Korea Research Institute of Chemical Technology (KRICT)

21. Joint program on the design, synthesis and optimization of multifunctional antibiotics The TB Alliance has exclusive rights to these compounds for the treatment of tuberculosis and other neglected diseases Cumbre retains rights to pursue the compounds for use in other infectious disease areas Cumbre Pharmaceuticals

22. Joint research partnership for the design, synthesis and evaluation of a class of compounds known as riminophenazines Class was discovered in the 1950s The collaboration will utilize IMM's expertise and integrated capabilities in chemistry, pharmacology and manufacture Institute of Materia Medica

23. The TB Alliance-Bayer Moxifloxacin Deal

24. Fluoroquinolone antibiotic Orally active Once-a-day dosage Approved in 104 countries for the treatment of bacterial respiratory and skin infections Moxifloxacin

25. Novel mechanism of action: kills M.tb. by inhibition of DNA gyrase In vivo studies showed moxifloxacin reduced treatment time by two months when substituted for isoniazid Safe to use with antiretroviral agents since it is not metabolized by the cytochrome P-450 enzyme system Moxifloxacin for TB

26. TB Alliance and Bayer HealthCare announced a partnership to coordinate a global clinical trial program to study the potential of moxifloxacin to shorten the standard six-month treatment of TB October 18, 2005

27. Clinically assess the efficacy and safety of moxifloxacin as a front-line agent for the treatment of TB If clinical trials are successful, register moxifloxacin for a TB indication Committed to making the product affordable and accessible to patients in the developing world The Partnership

28. Evaluate whether substitution of moxifloxacin for one of the standard TB drugs (isoniazid or ethambutol) eliminates TB infection faster than current standard therapy Trials to be run in Brazil, Canada, South Africa, Spain, Tanzania, Uganda, the United States and Zambia More than 3,000 TB patients will be enrolled Moxifloxacin Clinical Trials

29. Donate moxifloxacin for each clinical trial site Cover costs of regulatory filings Provide moxifloxacin at an affordable price for patients with TB in the developing world Bayer Commitments

30. Coordinate and help cover the costs of the clinical trials Ensure coordination of information and results towards the goal of registration Leverage substantial support from: U.S. Centers for Disease Control and Prevention (CDC) Orphan Products Development Center of the U.S. Food & Drug Administration European and Developing Countries Clinical Trials Partnership (EDCTP) TB Alliance Commitments

31. Global Alliance for TB Drug Development www.tballiance.org