1. Gerald J. Siuta, Ph.D. Business Development May 3, 2007
TB Drug Development
Gerald J. Siuta, Ph.D.
Business Development
May 3, 2007

2. Tuberculosis
One-third of the world’s population is infected with Mycobacterium tuberculosis
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

3. Current TB Drug Therapy
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)
Prolonged therapy, few available drugs, poorly tolerated and difficult to administer
TB/HIV Co-Infection
Drug interactions with antiretroviral agents - simultaneous therapy difficult

4. The Need for New TB Drugs
Complex 6-9 months treatment with a drug combination regimen
No new anti-TB drug in over 30 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

5. 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

6. The TB Alliance International Public-Private Partnership
Non-profit organization
Based in New York City, Brussels and Cape Town
Entrepreneurial, virtual R&D approach
Out-source R&D to public or private partners
Pro-active fundraising

7. Public-Private Partnership
An organization that pursues a social mission by employing the best practices of the private sector and drawing upon resources from the public and private realms

8. TB Alliance Mission To ensure equitable access
to a faster tuberculosis cure
that will advance global health
and prosperity

9. Profile of New TB Drug
Shorten the duration of TB treatment or otherwise simplify its completion
Be effective against multi-drug resistant tuberculosis (MDR-TB)
Improve the treatment of latent TB
Be compatible with HIV treatment

10. Goals and Objectives
Develop an entirely new therapeutic regimen that will shorten or simplify the treatment of tuberculosis
Coordinate and catalyze TB drug development activities worldwide
Ensure Affordability, Adoption and Access (AAA Strategy)

11. AAA Strategy Affordability Adoption Access
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

12. Financial Support 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

13. Types of Deals/Agreements
Licensing
Sponsored Projects
Outsourcing/Contracts
Co-Development
Co-Investments
Partnerships
Others

14. Compounds, Analogs and Derivatives
TB Alliance Portfolio
Discovery
Preclinical
Clinical
Compounds, Analogs and Derivatives
Nitroimidazole Analogs
(University of Auckland, Novartis ITD, NIAID)
Moxifloxacin
(Bayer HealthCare AG)
Quinolones
(KRICT/Yonsei University)
Nitroimidazole PA-824
(Chiron/Novartis)
Multi-Functional Molecules
(Cumbre)
Bacterial Topoisomerase Inhibitors
(GlaxoSmithKline)
InhA Inhibitors
(GlaxoSmithKline)
Pleuromutilins
(GlaxoSmithKline)
Focused Screening – Two Projects
(GlaxoSmithKline)
Riminophenazines
(Institute of Materia Medica)
Active TB Alliance program
Malate Synthase Inhibitors
(GlaxoSmithKline/Texas A&M)
TB Alliance in discussion
Proteasome Inhibitors
(Cornell University)
New Targets
(University of Pennsylvania)

15. Chiron Novel anti-TB compound (PA-824)
Discovered by Pathogenesis, Inc.
Exclusive worldwide license
Defined scientific milestones
Grant-back option
Manufacturing rights
No royalties in high endemic countries

16. PA-824 Novel nitroimidazole
Potent activity against both active and slow growing M.tb.
Possesses both bactericidal and sterilizing activity
Phase I clinical trials began June 3, 2005
Preclinical development completed in 3 years

17. University of Auckland
Synthesis of PA-824 analogs
Joint program with:
Novartis Institute of Tropical Diseases (Singapore)
National Institute of Allergy and Infectious Diseases
Aims to discover new nitroimidazopyrans that may have improved profiles over PA-824

18. GlaxoSmithKline
Joint drug discovery program at GSK’s Diseases of the Developing World facility in Tres Cantos, Spain
Four individual projects:
Bacterial topoisomerase inhibitors
InhA inhibitors
Pleuromutilins
Focused screening (two projects)

19. Korea Research Institute of Chemical Technology (KRICT)
Daejeon, South Korea
Three year research funding
Quinolones, pyridones & quinolizines
Chemical synthesis at KRICT
In vitro and in vivo biological testing at Yonsei University College of Medicine in Seoul, South Korea
Clinical compound selection in progress

20. Cumbre Pharmaceuticals
Joint program on the design, synthesis and optimization of two different classes of multi-functional antibiotics
The TB Alliance will have exclusive rights to these compounds for the treatment of tuberculosis and other neglected diseases
Cumbre will retain the rights to pursue the compounds for use in other infectious diseases

21. Institute of Materia Medica
Member of the Chinese Academy of Medical Sciences that is one of the primary institutions for drug research in China
Joint research partnership for the design, synthesis and evaluation of a class of compounds known as riminophenazines
Originally discovered to be active against TB in the 1950s
Has not been used due to side effect profile
The collaboration will utilize IMM's expertise and integrated capabilities in chemistry, pharmacology and manufacture

22. The TB Alliance-Bayer
Moxifloxacin Deal

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

24. Moxifloxacin for TB
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

25. October 18, 2005
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

26. The Partnership
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

27. Moxifloxacin Clinical Trials
Phase II program will 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
Nearly 2,500 TB patients are being enrolled

28. Bayer Commitments 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

29. TB Alliance Commitments
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)

30. Special Recognition

31. Licensing Executives Society
On September 13, 2006, the Licensing Executives Society Industry/University and Government Laboratory Transactions Industry Sector presented the TB Alliance and Bayer its Deals of Distinction Award which recognizes worthy transactions involving licensing and transfer of intellectual property and promote creative and innovative solutions to business issues

32. Scrip – World Pharmaceutical News
The TB Alliance-Bayer deal was also one of six finalists for the Scrip 2006 Best Partnership Alliance Award which recognizes the importance of partnerships involving pharmaceutical and/or biotech companies, focusing on deals that require strong strategic input from both partners, are mutually beneficial to both parties, hold promise to address an unmet medical need and demonstrate strategic potential as well as an innovative business model

33. Global Alliance for TB Drug Development