Developing New Drugs to Control TB

1. Developing New Drugs to Control TB William Wells, Ph.D. Director, Market Access Global Alliance for TB Drug Development (TB Alliance) Journalist to Journalist Project, IUATLD Meeting Cancun, Mexico, December 4, 2009

2. The need for new TB drugs The need to ensure adherence can put a huge burden on patients Shorter therapies equals > adherence, > cure, < burden on patients, and < emergence of drug resistance

3. Current TB Therapy and Unmet Needs Drug-sensitive TB 4 Drugs, ≥6 months M(X)DR-TB Few drugs (including injectables); ≥18 months; severe side effects TB/HIV co-infection Drug-drug interactions with ARVs (antiretroviral agents – i.e., HIV/AIDS drugs) Latent TB Infection 9 months of isoniazid Current Therapy Unmet Needs • Shorter therapy • More effective, safer drugs; shorter, simpler therapy • Co-administration with ARVs • Shorter therapy No new drugs for TB in 40 years; no market incentive

4. TB Alliance Founded in 2000 Not-for-profit Product Development Partnership (PDP) headquartered in New York, with offices in Brussels and Pretoria Entrepreneurial, virtual drug development approach Largest portfolio of TB drug candidates in history GOVERNMENTS PHARMA BIOTECH TB Alliance ACADEMIA INSTITUTES FOUNDATIONS

5. Operating Model In-licensing and independent development PA-824 (Chiron/Novartis) Collaborative R&D with affordability commitment Moxifloxacin (Bayer); GSK mini portfolio (GSK); TB drug portfolio (Novartis); TMC-207 (J&J) Contracted R&D with IP rights Quinolone (KRICT); Nitroimidazole (ACSRC); Riminophenazine (IMM); Phenotypic screening (UIC); Energy metabolism (UPenn); Protease (IDRI); Tryptanthrine (KRICT); RNAP (Rutgers); LeuRS (Anacor); Menaquinone (CSU); Topo I (NYMC); Natural products (IMCAS) A flexible, virtual R&D approach:

6. There is a “market failure” for diseases found solely or predominantly in low income countries Private sector: Cannot justify such large expenditure when the returns are so low Prior to the PDPs, most products that were useful only in low income countries were discovered by “accident” (e.g., veterinary product) or for military or tourists Academic researchers: Publicly funded Have the interest in pursuing neglected diseases But do not have the means to do so (large chemical libraries, screening facilities, networks of trials sites and the staff to run them) Why are PDPs needed?

7. Funding for all TB R&D (basic, drugs, diagnostics, vaccines, operational) is US$510m per year, compared to the US$2 billion per year estimated to be needed to reach Global Plan to Stop TB targets Private investment is not enough to support TB R&D TB R&D funding by sector, 2008

8. FDCs TB Alliance Vision 10 days 2 – 4 months Success will require novel multi-drug combinations 6 – 30 months

9. Global Clinical Portfolio - New TB Drugs in Registration Programs Oflotub, TDR Bayer, TB Alliance Tibotec, TB Alliance Otsuka TB Alliance Sequella Lupin Pfizer Phase I Phase II Phase III

10. Focused on the AAA strategy: Available (supply chain, forecasting, registration, distribution strategy); Affordable (pricing strategy, donor policies); Adopted (issues and evidence for key decision makers). Ensure that products are suited for, and wanted by, those in endemic markets. Formulate strategy, but work through partners and existing structures. Need to understand the process so we can facilitate coordination. WHO recommendation is essential. Existing Ministry of Health and NGO programs will deliver the drugs. TB Alliance Market Access

11. Define issues for users (Value Proposition Study) Demand Forecast (Moxi Demand Forecast) Understand the regimen change process (Country Introduction Study) Understand Existing Market (Market Study) • Devise local launch • strategy • Stakeholder and partner • mapping and engagement • Document resources for operational research, financing, TA, retraining Manufacturing Strategy Market Access Strategy IP agreements Pricing Strategy Consumer marketing Regulatory Strategy Support local decision-making (cost-benefit) Engage funding and procurement agencies Engage guideline- setting agencies (WHO and others)

12. Market Study Conducted with IMS HealthPublished May 2007 • Map TB drug market in 6 key high burden & 4 high income countries • Understand flow of drugs to prepare for launch • Fragmented, local markets • Size the existing global TB drug market • Estimate to inform TB Alliance deals and strategy • Global market of ~US$315m including all four first-line drugs

13. What Countries Want Value Proposition StudyPublished August 2009 • Most stakeholders would welcome treatment shortening as the primary goal. • Unacceptable trade-offs in all countries: • Decreased efficacy • Additional safety concerns or side effects requiring monitoring or expensive adjuvant therapies • Significant drug interactions with other commonly-used drugs (including ARVs) • Unacceptable trade-offs in some countries: • Treatment frequency significantly different from current TB program (e.g., India) • Unavailability in fixed-dose combination (FDC)

14. Summary Great need for new drugs to address the challenges and unmet needs in TB therapy Resurgence in TB drug R&D; up to 2-3 new drugs could reach registration by 2015 Increased funding is needed to support a stronger global TB drug pipeline and fulfill our vision

15. Thank You

16. REMoxTB Trial Design Randomized, double-blind; non-inferiority Treatment Duration (months) 1 2 3 4 5 6 Intensive Continuation 800 participants Standard regimen HRZE HR Placebos 800 participants Moxifloxacin for Ethambutol HRZM HRM Placebos 800 participants Moxifloxacin for Isoniazid MRZE MR Placebos All pts followed for 12 months post-treatment end