Pandemic Influenza Planning: The Reality of Implementation in the Southeast

1. 1 Pandemic Influenza Planning: The Reality of Implementation in the Southeast Vaccines – Producing an Adequate Supply SECEBT Emory Conference Center 10TH November 2005 James T. Matthews, Ph.D Senior Director Health and Science Policy Public Policy and Government Relations US

2. 2 Agenda Influenza Vaccine Production Seasonal and pandemic – interrelatedness The Pandemic to come – dimensions of the problem Sanofi pasteur – our influenza vaccines and global presence - implications Importance of Health Authorities’ Immunization Recommendations – market growth and expanding capacity Key Challenges – capacity, current technology and others Meeting the Challenge – Sanofi pasteur’s Pandemic Preparedness Working Group (PPWG) Specific Activities within the French (EU) Business Unit Specific Activities within the US Business Unit Integrated overview of sanofi pasteur’s PPWG Activities and Conclusions

3. 3 Influenza Vaccine Production Seasonal Vaccine (Interpandemic) vaccine – most is inactivated, injectable, most currently produced in European Union with some local producers, in recent years – trivalent formulation consisting of an H1N1, H3N2 and B strain – updated semi-annually (Northern and Southern Hemisphere formulations) “Pandemic” vaccine – expected to be monovalent formulation but will use existing processes and capacity – there will be no time to either develop a vaccine or expand capacity The Implication ….

4. 4 PANDEMIC PHASES(From WHO Global Influenza Preparedness Plan - 2005)

5. 5 PANDEMIC PHASES(From WHO Global Influenza Preparedness Plan - 2005)

6. 6 Pandemic Preparedness and Interpandemic Vaccine Activities and Production are Intimately Related Interpandemic Period Pandemic Period Pandemic Alert

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8. 8 Flu pandemic : the « big picture » through significant figures ? 40 M ??? M 6.2 B 300 M doses 900 M doses 1 or 2 doses? ? 2 years ? 6 months 9 countries Estimated Number of deaths in 1918 Number of people that a 1918 like-pandemic could kill The current world population The worldwide capacity of trivalent current vaccine! The theoretical equivalent in monovalent but issues regarding Yield? / adjuvant? / process used? / antigen content? Number of doses needed to efficiently prevent (compliance / logistics…?) The expected duration of a pandemic Estimation of time between pandemic declaration and first doses available Number of countries with local production (large scale production) USA / Canada / Australia / Japan / France / UK /Germany / Netherlands / Italy 70% of doses produced in Europe Substantial pressure on Europe for “equitable allocation”

9. 9 First, let me start with a rapid description of the basic research and discovery centers working on Oncology projects around the world with Aventis. In North America... In Europe... As you can see, a large share of our research/discovery effort is taking place in North America, and it is important to you, as I will be speaking later about partnership and how important it is to develop the links between basic research, clinical development and practicing physicians. First, let me start with a rapid description of the basic research and discovery centers working on Oncology projects around the world with Aventis. In North America... In Europe... As you can see, a large share of our research/discovery effort is taking place in North America, and it is important to you, as I will be speaking later about partnership and how important it is to develop the links between basic research, clinical development and practicing physicians.

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11. 11 Current Influenza Immunization Rates Are Very Different Around the World (as of 2003)

12. 12 Public Recommendations by Health Authorities Accelerate Market Growth

13. 13 Market Growth is Dependent on Two Key Factors:Policy Recommendations and Reliability of Supply

14. 14 We must Focus on Rebuilding the Influenza Vaccine Marketplace

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16. 16 US Market Outlook is Positive as long as Supply Supports Market Growth Expected to grow from 85+M doses to over 150M doses by 2010 Stronger recommendations will drive market growth Supply constraints limit recommendation changes Product distribution begins in September Product distribution completed by end of October Product distribution begins in September Product distribution completed by end of October

17. 17 Optimizing Coverage during the Interpandemic Period

18. 18 Key Challenges regarding Pandemic Vaccine Development and Production Existing Manufacturing Capacity The Manufacturing Cycle (most vaccine is currently Egg-based) Several Unknowns as of today: Vaccine characteristics: The pandemic strain Quantity of antigen / dose Vaccination schedule: 1 dose or 2 doses Adjuvanted or not? Production yield and stability of the pandemic strain The pandemic vaccine will not be tested at large-scale ahead of the pandemic situation, as the pandemic strain will not be known in advance (safety)

19. 19 Generalized Influenza Vaccine Global Production Timetable (NH - Representative Year) See contract See contract

20. 20 Pandemic Preparedness within sanofi pasteur - Meeting the ChallengePandemic Planning Working Group (PPWG)Specific Activities based in France (EU) Specific Activities based in the US Business Unit

21. 21 PPWG Key Activities A first draft of a Pandemic Situation Readiness Plan had been developed in 2004, and it helped organize work flow and define priority activities within sanofi pasteur Each part of the plan led to specific activities in the different areas identified and dedicated groups have been put in place in each department. The necessity for an Industrial Pandemic Emergency Plan has also been highlighted and this initiative is now taking place under the leadership of the Industrial Product leader – expected to be completed by Q1, 2006

22. 22 Some Priority Actions for Pandemic Readiness Activities Dependent on Vaccine Characteristics Determine Vaccine Characteristics Prepare for the EMEA registration of a mock-up vaccine (core or mock dossier) or license within the US Pursue EU and US egg-based production projects – evaluate production at commercial scale and stability of bulk vaccine Activities Independent of Vaccine Characteristics Finalize Industrial Operations Emergency plan and develop a full contingency plan for sanofi pasteur globally Pursue Cell Culture, Adjuvant and Delivery Technology Development – diversify/develop alternatives to egg-based technology and intramuscular administration

23. 23 Pandemic Situation Readiness Plan Pandemic Situation Work Flow

24. 24 Sanofi pasteur’s pandemic preparedness in France Research program initiated since 2002 NIAID research grant: Egg-based H5N1 vaccine production FLUPAN EU/NIBSC contract: Cell-based H7N1 vaccine production. Originally Vero based. Currently, production of H7N1 vaccine in PER.C6? cells (Crucell NV) for clinical study with and without adjuvant. Currently at preclinical stage with safety and immunogenicity Phase 1 study in Q2, 2006. Pilot scale egg-based production of H5N1 vaccines since 2004 Bulk production according to Vaxigrip? manufacturing using a scaled-down process in BSL2+ GMP pilot scale facilities (Marcy l’Etoile, France) Doses released in May 2005 Large-scale egg-based production pandemic vaccine development (in preparation since 2004) Large-scale production of several Million doses completed in Q3, 2005 in Val de Reuil, France will enable sanofi pasteur to respond to some Governments’ requests in Europe Large-scale H5N1 vaccine production planned in 2006

25. 25 Submission of core dossier for mock–up Vaxigrip-like vaccine to EMEA (1) First clinical study (Phase 1) based on EMEA criteria: Start Q2, 2005 Aimed at selecting the optimal dosage regimen and evaluating the safety profile In healthy adults (18-40 years), 2 injections three weeks apart Use A/Vietnam/1194 NIB RG 14 strain provided by NIBSC Novel – unlike conventional reasortants – in EU – issues relating to GMO Various dosages, with or without adjuvant (Al Hydroxide) (7.5, 15, 30 mcg). Results expected Q4,2005

26. 26 Submission of core dossier for mock–up Vaxigrip-like vaccine to EMEA (2) Second clinical study (Phase 2) with the selected formulation: Start Q2, 2006 Aimed at documenting the safety profile Nearly 300 subjects of 18-75 years of age (50% of subjects aged over 60 years), 2-dose regimen Core mock-up dossier (CTD format) submission in 2007

27. 27 Pandemic Situation Readiness Planbecause of GMO Issues within the EU Very active in development of Biosafety guidelines for large scale production (GMO; Biosafety): collaboration between producers and WHO Biosafety experts: objective end of October 2005 for finalization of the guidelines Need to ensure that guidelines are adequate but allow production under existing manufacturing conditions

28. 28 Pandemic Preparedness Working Group Activities in US Business Unit

29. 29 The Next Influenza Pandemic: A Cause for Concern Estimates of the effect of Pandemic in the US alone* 1-2 yrs in duration Overwhelming strain on limited medical resources: 18M – 42M outpatient visits 314K – 734K hospitalizations 89K – 207K deaths 20M – 47M additional illnesses $71B - $167B in economic damages

30. 30 The US Government Has Implemented Several Types of Initiatives to Ensure Preparedness US Congress earmarked $100M under FY '05 appropriations bill for pandemic preparedness initiatives – actually have spent more than this amount to date Strategic Reserves of Interpandemic influenza vaccine Appropriated funding for stockpiles of routine pediatric vaccines Stockpiles of influenza antivirals

31. 31 Importance of sanofi pasteur’s US Business Unit’s Participation in US Government Pandemic Planning Initiatives US market leader with over 55% market share (prior to 2004 Chiron shortage) Provides opportunity to prepare company for disruption in normal activity Strengthens partnership position with government in protecting public health As only domestic manufacturer, it is critical to be responsive to government pandemic preparedness initiatives

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33. 33 Update on Individual Contracts (1) DHHS-NIH-NIAID (Development and Production of an Investigational Inactivated H5N1 (2004) Influenza Vaccine for Use in Phase1/2 Clinical Trials) Key Deliverables: 4000 single-dose vials (each) of two different formulations of Fluzone-like vaccine (15mcg and 45mcg/dose, thimerosal-free, no adjuvant) One of two Contracts awarded in May, 2004 Sanofi pasteur (as manufacturer) only provided CMC information for NIAID’s IND - no direct role in first Clinical trial Used reverse genetics-derived strain (rg A/Vietnam/1203/2004) produced by St.Jude/Webster provided to us by NIAID under MTA No opportunity to evaluate and compare NIBSC (A/Vietnam/1194/2004) seed All lots produced in our pilot scale facility - approx. 4000 eggs per lot, using “scaled-down” version of commercial process. Yields Low but over 4000 doses of each formulation were available. Current Status: vaccine was manufactured in Q4, 2004; vaccine filled, labeled, packaged, released and transferred to NIAID in Q1, 2005. NIAID has completed first of several planned clinical studies in the VTEUs Stability on Bulk and Final Container for additional two years

34. 34 HHS/CDC (H5N1 Influenza Vaccine Services) Sanofi pasteur awarded contract in September, 2004 for the production of 2 Million doses of H5N1 vaccine (dose is operationally defined as 15mcg/dose or a dose-equivalent) As with pilot-scale lots, vaccine produced using Webster rg virus (sanofi pasteur early seed passes) at commercial scale All full scale lots completed in October, 2004. Yields relatively low but higher than pilot-scale Egg supply at time was not yet transitioned to support year round maximized production Vaccine is stored as bulk concentrate (2-8oC) US Government recently authorized Contract amendment to include aluminum hydroxide formulation – six formulations in preparation – to be available Q1, 2006 – Clinical study to begin Q2, 2006 – This is not a standard formulation – will require Toxicology Study Further enhancement of internal Medical/Regulatory Team – pursue activities analogous to “core or mock” dossier Final container and bulk concentrate will be assayed for potency for 3 and 2 years, respectively Update on Individual Activities (2)

35. 35 “Egg” based contract (HHS/CDC) awarded to sanofi pasteur in October, 2004 (Base Year and 4 Option years – all options have now been exercised) Key Deliverables: Egg-related - restructure flock management to assure a year-round supply of embryonated eggs to maintain full production and establish contingency flocks (final number 20% of current flocks), maintain essential supplies – important positive impact on current commercial-scale production Produce Investigational lots (3,000 doses – dose range to be specifically defined) of pandemic-like vaccine annually Current Status: All Major Milestones on track (capacity for full-scale, year-round production, contingency flocks in Q4, 2006) DHHS has identified an H7N7 strain (conventional reassortant produced at the CDC) for pilot scale clinical lots this year (pilot lot production is on-going) Contract now being amended to include aluminum hydroxide formulations

36. 36 Update on Individual Activities (4) HHS/CDC-Acquisition of H5N1 Avian Influenza Vaccine for the Strategic National Stockpile Contract for production of up to 20 Million doses of H5N1 awarded Q3, 2005 Use 2004 viral working seed (strain not updated) - but evaluating later seed passes – some improvement in yields Vaccine to be produced at commercial scale prior to and without interference with trivalent, seasonal vaccine production Vaccine currently being produced and to be released by end-Q4, 2005/early Q1, 2006 Vaccine will be held in bulk concentrate for up to 2 years or formulated according to results of (second) NIAID clinical trial Formulated vaccine to be stored and tested for up to 2 years

37. 37  Cell RFP (HHS/CDC 2004-N-01102) awarded (US$ 97M) to sanofi pasteur March 31ST, 2005 – To accelerate development and US licensure of a cell-derived influenza vaccine Purpose: to diversify technology/increase capacity Initial contract for three year program - based on PER.C6? -very aggressive timelines: process definition and intermediate scale-up, Phase 2 clinical studies, production of Phase 3 clinical lots – all milestones on track – Phase 1 Q3, 2006 Early stage of development to be conducted in Marcy, leading to US licensure from our Marcy intermediate scale facility at 1500 L Includes plans for facility design and eventual construction in US (actual construction not funded)

38. 38 Update on Individual Contracts (6) DHHS-ORDC-VB-05-13 Acquisition of H5N1 Avian Influenza Vaccine for the Strategic National Stockpile Contract (HHS0100200500004C) for production of up to 20 Million doses of H5N1 awarded Q3, 2005 (US$100 M base) Use same or related seed virus as used in 2004 (strain not updated) Vaccine to be produced prior to and without interference with manufacturing of trivalent, seasonal vaccine at full commercial scale Vaccine currently being produced – to be available in bulk by end-Q4, 2005 Vaccine will be held in bulk for up to 2 years or formulated according to results of (second) NIAID clinical trial Formulated vaccine to be stored and tested for up to 2 years

39. 39 HHS/CDC (US National Pandemic Plan) to be finalized in 2005 US Congress earmarked $7.1B under FY '06 appropriations bill for pandemic preparedness initiatives - includes funding for construction HHS published three pre-solicitation notices related to influenza vaccine production – RFPs to be published on/about 1ST November Cell and Recombinant Influenza vaccine production (Not applicable) Influenza Vaccine Process Improvement Dose-sparing strategies – adjutants and delivery devices (e.g. ID syringe) Sanofi pasteur worked closely to educate Congress on importance of Pandemic liability protection/public compensation legislation Recent Government and sanofi pasteur Initiatives to Ensure Pandemic Preparedness

40. 40 Pandemic Preparedness Working Group Integrated Overview of sanofi pasteur activities

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42. 42 Conclusion regarding Sanofi pasteur’s involvement in Pandemic Preparedness Sanofi pasteur and our parent company, sanofi-aventis, are fully committed to pandemic preparedness through internal preparation, and through collaborations with external bodies – many of these activities report directly to the CEO Sanofi pasteur actively participates in all groups that collaborate, in order to accelerate pandemic preparedness: EVM, IVS International Task Force, IOM, … Sanofi pasteur is a key partner in all initiatives developed by various organizations such as WHO, DHHS, NIAID, CDC, the EU … and welcomes opportunities to share our experience with others to help better manage or reduce this impending global health threat.