1. Maria C. Freire, Ph.D. August 23, 2012 Bethesda, Maryland Engaging Communities in Drug Development: Observations from the Field A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N

2. Overview Background – Drug Development 101 Case Study: Tuberculosis AAA Strategy Lessons Learned 2

3. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N 3 PRE- DISCOVERY 5,000 – 10,000 250 COMPOUNDS 5 1 FDA- APPROVED DRUG DISCOVERY PRE-CLINICAL FDA REVIEW PHASE I PHASE II PHASE III 3 – 6 YEARS 6 – 7 YEARS 0.5 – 2 YEARS NUMBER OF VOLUNTEERS 20 - 100100 - 5001,000 – 5,000 IND NDA MFG POST MARKETING SURVEILLANCE PHASE IV Drug Development Pipeline

4. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N Drug Development Pipeline 4 PRE- DISCOVERY DISCOVERY PRE-CLINICAL FDA REVIEW PHASE I PHASE II PHASE III 3 – 6 YEARS 6 – 7 YEARS 0.5 – 2 YEARS MFG

5. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N Drug Development Pipeline 5 PRE- DISCOVERY DISCOVERY PRE-CLINICAL FDA REVIEW PHASE I PHASE II PHASE III 3 – 6 YEARS 6 – 7 YEARS 0.5 – 2 YEARS IND NDA MFG POST MARKETING SURVEILLANCE PHASE IV

6. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N Drug Development Pipeline 6 PRE- DISCOVERY DISCOVERY PRE-CLINICAL FDA REVIEW PHASE I PHASE II PHASE III 3 – 6 YEARS 6 – 7 YEARS 0.5 – 2 YEARS IND NDA MFG POST MARKETING SURVEILLANCE PHASE IV NUMBER OF VOLUNTEERS 20 - 100100 - 5001,000 – 5,000

7. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N 7 PRE- DISCOVERY DISCOVERY PRE-CLINICAL FDA REVIEW PHASE I PHASE II PHASE III 3 – 6 YEARS 6 – 7 YEARS 0.5 – 2 YEARS NUMBER OF VOLUNTEERS 20 - 100100 - 5001,000 – 5,000 IND NDA MFG POST MARKETING SURVEILLANCE PHASE IV Drug Development Pipeline

8. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N 8 PRE- DISCOVERY 5,000 – 10,000 250 COMPOUNDS 5 1 FDA- APPROVED DRUG DISCOVERY PRE-CLINICAL FDA REVIEW PHASE I PHASE II PHASE III 3 – 6 YEARS 6 – 7 YEARS 0.5 – 2 YEARS NUMBER OF VOLUNTEERS 20 - 100100 - 5001,000 – 5,000 IND NDA MFG POST MARKETING SURVEILLANCE PHASE IV Drug Development Pipeline

9. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N Drug Development Costs 9 Millions (Constant $Year 2000) $800M $1.3B Source: J. DiMasi and H. Grabowski

10. 10 Case Study: Tuberculosis

11. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N Tuberculosis 2 billion people are infected with M.tb 8 million new active TB cases a year 1.4 million people die a year – 1 person per 25 sec. ~ 400,000 cases of MDR-TB a year 12 million persons are TB/HIV co- infected Biggest infectious killer of TB/HIV patients and women of childbearing age A Disease of Poverty

12. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N Current TB Drug Therapy Active TB 6 months of therapy (INH, rifampin, pyrazinamide, ethambutol ) MDR-TB Individualized, prolonged therapy, few available drugs, poorly tolerated and difficult to administer XDR-TB Individualized, prolonged therapy – when one exists TB/HIV co-infection Treatment as in active TB, but drug interactions with ARVs make simultaneous therapy difficult Latent TB 9 months of INH therapy Lengthy and Cumbersome

13. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N TB Drug Development Pipeline 13 PRE- DISCOVERY DISCOVERY PRE-CLINICAL FDA REVIEW PHASE I PHASE II PHASE III 3 – 6 YEARS 6 – 7 YEARS 0.5 – 2 YEARS IND NDA MFG POST MARKETING SURVEILLANCE PHASE IV X X X

14. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N TB Drug Development 2001 Landscape 14 PRE- DISCOVERY DISCOVERY PRE-CLINICAL FDA REVIEW PHASE I PHASE II PHASE III MFG

15. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N TB Drug Development 2001 Landscape 15 PRE- DISCOVERY DISCOVERY PRE-CLINICAL FDA REVIEW PHASE I PHASE II PHASE III MFG Usual actors: Academia Government Biotech Pharma Biotech Pharma Government Biotech Pharma Government Pharma Academia Government Biotech Pharma NIH/NIAID Institut Pasteur Albert Einstein UCLA UCSF Others?... NIH/NIAID TAACF (SRI, GNL, HDC, CSU, RTI) NIH TBTC CDC WHO Aventis Novartis Lupin Other Indian Pharma Pharmacia AHP Glaxo Daiichi Local producers In TB: Source:: Boston Consulting Group Primary Involvement Secondary Involvement

16. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N TB Drug Development 2001 Landscape 16 PRE- DISCOVERY DISCOVERY PRE-CLINICAL FDA REVIEW PHASE I PHASE II PHASE III MFG Usual actors: Academia Government Biotech Pharma Biotech Pharma Government Biotech Pharma Government Pharma Academia Government Biotech Pharma NIH/NIAID Institut Pasteur Albert Einstein UCLA UCSF Others?... NIH/NIAID TAACF (SRI, GNL, HDC, CSU, RTI) NIH TBTC CDC WHO Aventis Novartis Lupin Other Indian Pharma Pharmacia AHP Glaxo Daiichi Local producers In TB: Source:: Boston Consulting Group Primary Involvement Secondary Involvement

17. The Intervention – a PDP 17

18. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N

19. Types of PPPs Basic Knowledge/Research –SNP Consortium Product Development Partnerships (PDPs) –TB Alliance Improvement of Access to Health Products –GAVI Global Coordinating/Funding Mechanisms –Global Fund ATM Health Services Strengthening –Global Campaign for Microbicides Public Education and Advocacy –Corporate Council on Africa Regulation, Quality and Standards –Anti-Counterfeit Drug Initiative www.ippph.org

20. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N NYO-TBX001-20061206-RD2 TB Alliance: a PDP Operates as a virtual company 1 Develops drug candidates and novel regimens that represent a sufficient improvement to change the field 2 Fosters discovery & development of new treatments by all stakeholders 3 Ensures AAA 4 Operating Principles

21. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N 10 days Vision 2 months 6 months Faster and Simpler Treatment for TB FDCs

22. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N Profile of the New Drug/Combination Simplify/shorten treatment < 2 months Effective against drug resistant-TB Co-administered with ARVs Shorten/improve latent TB treatment Easily adopted in the field Novel drug combinations are required

23. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N 23 Strategy In-license, support or form partnerships with owners of IP to develop TB drugs; Provide funding, know-how and project management; Outsource development worldwide – CROs and/or Partners, public and private (US, New Zealand, South Africa, India, Switzerland, Spain, etc.) ; Funding from private sources and governments; Governed by AAA Novel Drug Development Paradigm

24. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N TB Drug Development 24 PRE- DISCOVERY DISCOVERY PRE-CLINICAL FDA REVIEW PHASE I PHASE II PHASE III MFG Usual actors: Academia Government Biotech Pharma Biotech Pharma Government Biotech Pharma Government Pharma Academia Government Biotech Pharma NIH/NIAID Institut Pasteur Albert Einstein UCLA UCSF Others?... NIH/NIAID TAACF (SRI, GNL, HDC, CSU, RTI) NIH TBTC CDC WHO Aventis Novartis Lupin Other Indian Pharma Pharmacia AHP Glaxo Daiichi Local producers In TB: Source:: Boston Consulting Group Primary Involvement Secondary Involvement 2001 Landscape

25. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N TB Drug Development 25 PRE- DISCOVERY DISCOVERY PRE-CLINICAL FDA REVIEW PHASE I PHASE II PHASE III MFG Usual actors: Academia Government Biotech Pharma Biotech Pharma Government Biotech Pharma Government Pharma Academia Government Biotech Pharma Source:: Boston Consulting Group Sequella: SQ-109 TBTC-Pfizer- several Univ: Linezolid Lupin: LL-3858 Otsuka: OPC-67683 TBA: PA-824 TBTC-Sanofi Aventis: Rifapentine Tibotec (J&J): TMC-207 OFLOTUB- EC-Lupin-TDR: Gatifloxacin TBA-Bayer-TBTC- JHU-BMRC-UCL: Moxifloxacin TBTC-VA: Latent Infection Aventis Novartis Lupin Other Indian Pharma Pharmacia AHP Glaxo Daiichi Local producers NIH/NIAID Institut Pasteur Albert Einstein UCLA UCSF Others?... Astra-Zeneca IDRI JHU Lilly NITD (Novartis) Rutgets –HHMI-NIH Sequella (3) TAACF – NIAID –SRI TBA-IDRI TBA-IMCAS TBA-IMM-BTTTRI-UIC TBA-GSK (4) TBA-GSK-TXA&M TBA-UA-CS TBA-UIC-Penn UIC (2) Vertex (3) Lilly JATA CSRI SA Sequella (3) TBA TBA-UA-UIC PFIZER In TB: 10 years later

26. Available, Affordable, A dopted: The AAA Strategy 26

27. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N AAA Strategy Develop cost effective, affordable new anti-tuberculosis therapies; Ensure equitable availability of new TB treatments especially for patients in high-burden countries: Work closely with communities, governments and National TB Program coordinators to ensure the future drugs will be adopted into TB Programs.

28. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N NYO-TBX001-20061206-RD2 28 AAA Strategy Consider cost of goods and manufacturing to focus on developing regimens which are likely affordable for governments and patients. Affordability Availability Adoption Promote regimen accessibility in country without duplicating existing efforts and within existing infrastructure where possible. Only acting in roles where the Alliance can build credibility, capacity and capability to act. Focus on developing markedly improved treatments. Engage the community, advocates, patients and other key opinion leaders. Engage international community on guidelines and support conversations with local experts as required. The Alliance will:

29. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N Known Bottlenecks and Hurdles 29 Insufficient engagement of local communities and key clinical opinion leaders in clinical development; Lack of political will; Lack of clear and robust investment case to guide global and national decision making; Inadequate knowledge and awareness by key decision makers, including patients and advocates; Inaccurate demand forecasting leading to unreliable and insufficient supply; Increase in projected cost; Negative impact on incumbent businesses (e.g., generic manufacturers); Negative impact on other health programs and local capacity; Other… Key examples

30. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N Stage I – Development to policy Successful Adoption strategy Stage II – Policy to implementation Ensure processes and policies are in place to allow for the quick introduction of new regimen Deliver reliable supply of regimen to patients in need Ensure patient and physician compliance and efficacy of regimen delivery 5 6 Identify key desirable characteristics of treatment regimen from perspective of end- users and policy makers, and ensure these are reflected in research and development goals and activities. Build fact base and inform key decision-makers, patients, advocates, public and private sector thought leaders of new regimen profile and value. Help ensure regulatory approval and global and national guideline adoption. NYO-TBX001-20061206-RD2 Adoption Strategy 1 2 3 4 Examples of Activities

31. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N NYO-TBX001-20061206-RD2 Factors shaping Adoption Lessons learned Decreasing ability to inform clinical development Increasing ability to accurately forecast demand and market environment. Consistent need throughout to develop stakeholder and community awareness and engagement 1 2 3 Pre-clinical Reg. Approval

32. Thank you! 32

33. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N Building a Portfolio Public Announcement BOD – Formal Review Portfolio Committee SAC, Consultants BD, RFAs, Unsolicited Proposals DEAL Investment Approval Due Diligence & Negotiations Scientific and Technical Review Proactive Scouting Non-blocked IP positions for all projects

34. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N Deals structured depending on stage of development, investment, burden of activity, etc.  KRICT  Chiron/Novartis  GSK  NITD  JHU  Abbott  Bayer, CDC, JHU, EDCTP IP Assignment In-licensing Sponsored R&D Collaborative R&D Research Tools Freedom to Operate Multi-Party/CT Sample deal structures Product Development Partnerships

35. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N Substitution to Revolution

36. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N Target Distribution Areas of Investment

37. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N Substitution Strategy 6 years 24 years ABCD EFG ABCDBCDECDEDEFEFG EA 6 years B FC GD Conventional TB Clinical Development Paradigm

38. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N Alternative TB Clinical Development Paradigm ABCDBCDE EA CDE B EFG CDFG 6 - 10 years ABCDEFG From Substitution to Revolution

39. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N TB Alliance Portfolio TARGET OR CELL-BASED SCREENING Natural Products IMCAS Whole-Cell Hit to Lead Program GSK Nitroimidazoles U. of Auckland/ U. Ill Chicago PA-824 Novartis Moxifloxacin (+ H, R, Z) Bayer Topoisomerase I Inhibitors AZ/NYMC Whole-Cell Hit to Lead Program AZ Mycobacterial Gyrase Inhibitors GSK InhA Inhibitors GSK TMC207 Tibotec Moxifloxacin (+ R, Z, E) Bayer Protease Inhibitors IDRI Phenotypic Hit to Lead Program U. Ill Chicago Diarylquinolines Tibotec/U. of Auckland PA-824/Pyrazinamide TB Drug Discovery Portfolio NITD Riminophenazines IMM/BTTTRI TMC207/Pyrazinamide Gyrase B Inhibitors AZ Pyrazinamide Analogs Yonsei PA-824/ Moxifloxacin/ Pyrazinamide Folate Biosynthesis Inhibitors AZ Malate Synthase Inhibitors GSK/TAMU RNA Polymerase Inhibitors AZ Menaquinone Biosynthesis Inhibitors CSU Energy Metabolism Inhibitors AZ/U. Penn LEAD IDENTIFICATIONLEAD OPTIMIZATION CLINICAL PHASE ICLINICAL PHASE IICLINICAL PHASE III Preclinical TB Regimen Development JHU/U. Ill Chicago  AstraZeneca (AZ)  Bayer Healthcare AG (Bayer)  Beijing Tuberculosis and Thoracic Tumor Research Institute (BTTTRI)  Colorado State University (CSU)  GlaxoSmithKline (GSK)  Infectious Disease Research Institute (IDRI)  Institute of Materia Medica (IMM)  Institute of Microbiology, Chinese Academy of Sciences (IMCAS)  Johns Hopkins University (JHU)  Johnson & Johnson / Tibotec (Tibotec)  New York Medical College (NYMC)  Novartis Institute for Tropical Diseases (NITD)  Novartis Pharmaceutical (Novartis)  Texas A&M University (TAMU)  University of Auckland (U. of Auckland)  University of Illinois at Chicago (U. Ill Chicago)  University of Pennsylvania School of Medicine (U. Penn)  Yonsei University (Yonsei) Novel TB regimen development Current first-line TB treatment consists of Isoniazid (H) + rifampicin (R) + pyrazinamide (Z) + ethambutol (E) Clinical DevelopmentDiscovery OUR R&D PARTNERS Preclinical Development The largest ever Courtesy Mel Spigelman

40. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N PA-824 Case Study

41. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N PA-824 Novel nitromidazole (-pyran) Distinct mechanism of action In-licensed from Chiron in 2002

42. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N Chiron-TB Alliance Deal The Technology: –Novel anti-TB family –Developed by Pathogenesis, Inc. –Issued patents The Deal: –In-licensing deal for all patent rights to TB –Upfront fees and royalty sharing –Defined scientific milestones –Grant-Back option –Manufacturing rights –No royalties in Developing World

43. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N Outsourcing of PA-824 Development *

44. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N Moxifloxacin Case Study

45. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N Moxifloxacin Fluoroquinolone antibiotic Orally active Once-a-day dosage Approved in 104 countries for the treatment of bacterial respiratory and skin infections

46. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N 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

47. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N Bayer/TB Alliance Partnership Clinically assess the efficacy and safety of moxifloxacin as a front-line agent for the treatment of TB If successful, register moxifloxacin for a TB indication Committed to making the product affordable and accessible to patients in the developing world

48. A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N Evaluated Clinical Trial Sites