FluMist Influenza Virus Vaccine Live, Intranasal

1. 1 FluMist�Influenza Virus Vaccine Live, Intranasal MedImmune Gaithersburg, Maryland

2. 2 Sponsor Team Sponsor Project Team Robert Walker, M.D. FluMist Project Director George Kemble, Ph.D. Head of Research, MedImmune Vaccines Iksung Cho, MS Head of Biostatistics Micki Hultquist, MS FluMist Project Lead Statistician External Investigators/Advisors Robert Belshe, M.D. Professor, Internal Medicine/Infectious Disease Director, Center for Vaccine Development Saint Louis University School of Medicine Kathryn Edwards, M.D. Professor of PediatricsVice Chair for Clinical Research in PediatricsDirector of Pediatric Clinical Research Division of Pediatric Infectious Diseases Vanderbilt University School of Medicine Dereck Weycker, Ph.D. Policy Analysis, Inc. Janet Wittes, Ph.D. Statistics Collaborative, Inc. Pamela Zeitlin, M.D., Ph.D. Professor of Pediatrics and Physiology Director, Pediatric Respiratory Sciences Johns Hopkins University School of Medicine

3. 3 Sponsor Presentation Introduction and Overview Data on efficacy of FluMist in children <5 years of age Data on safety of FluMist in children <5 years of age Post-marketing studies Conclusions

4. 4 Influenza and Vaccination Influenza is the leading cause of vaccine-preventable mortality and morbidity in the U.S. Vaccination is the primary method for preventing illness and severe complications related to influenza Antigenic mismatch between vaccines and circulating strains is common and complicates influenza prevention

5. 5 Influenza in Children Rates of influenza infection are highest among children Hospitalization rates among young children similar to elderly Significant burden of outpatient clinic visits and ER visits Annual vaccination is recommended for all children 6-59 months of age in the U.S. Trivalent inactivated vaccine (TIV) is the only currently licensed product for children <5 years of age Single manufacturer for children <4 years of age

6. 6 Live, cold-adapted, temperature-sensitive, attenuated influenza virus vaccine Trivalent (A/H1N1, A/H3N2, B) 107 FFU of each strain per dose Dose: 0.2 mL intranasal spray (0.1 mL per nostril) Storage: 2-8�C (refrigerator) Contains no preservatives (e.g., no thimerosal)

7. 7 FluMist� Regulatory Milestones 2003 FluMist (frozen) approved for healthy individuals 5 to 49 years of age 2003-2007 Commercial product available January 2007 Refrigerated FluMist approved for healthy individuals 5 to 49 years of age

8. 8 FluMist� Post Licensure Safety (5-49 years of age) Approximately 7M doses have been distributed for commercial use from 2003 to 2007 No new safety signals have been identified since licensure VAERS data from first 2 seasons1 Post-marketing safety study (N = 45,000) 2002-20062

9. 9 FluMist� Rationale for Lower Age Limit in Initial Approval

10. 10 FluMist� Background for Expansion of Indicated Population Two published studies suggested better efficacy of FluMist compared to TIV in children 6-71 mos with recurrent RTI (N=2187)1 & 6-17 yrs with asthma (N=2229)2 53% & 35% fewer cases of influenza (predominantly matched B) No safety signals identified Open-label, not conducted under US IND IND studies of efficacy and safety of FluMist in children <59 months of age Study AV006 (NIH CRADA with Aviron) Study D153-P501 (Wyeth) Study MI-CP111

11. 11 FluMist� Principal Findings for Children <5 years (IND Studies) Efficacy High levels of efficacy against influenza Significantly higher efficacy compared to TIV in MI-CP111 Cross-protection against mismatched A/H3N2, including better cross-protection compared to TIV in MI-CP111 Safety Further evaluation is needed in children 6-11 months of age and in children 12-59 months with a history of wheeze/asthma For children without a history of wheeze/asthma Safety established in children 24-59 months of age Risk-benefit warrants availability for children 12-23 months of age

12. 12 FluMist� Proposed Expanded Indicated Population Children 12 to 59 months of age without a history of wheeze/asthma

13. 13 EfficacyFluMist� in Children <5 Years of Age

14. 14 Studies AV006 and D153-P501Placebo-Controlled Efficacy Studies

15. 15 FluMist� Efficacy in Vaccine-na�ve Children Year One Efficacy by Strain (Matched)

16. 16 FluMist� Efficacy in Previously Vaccinated Children: Year Two Efficacy by Strain

17. 17 Study MI-CP111Pivotal Comparative Trial in Children <5 Years of Age Pivotal trial to evaluate safety and efficacy of FluMist compared to TIV Allows assessment of the benefits and risks of both vaccines in children 6-59 months of age

18. 18 Study MI-CP111Design Randomized, double-blind, TIV-controlled, multinational Children 6-59 months of age (N=8,475) Excluded only recent wheezing, history of severe asthma, immunocompromised Stratification factors Age (6-23, 24-35, 36-59 months), country, previous influenza vaccination, and history of >3 wheezing illnesses Stratification of 24-35 months to balance children receiving different TIV licensed dosages (children <3 years receive 0.25 mL) Pre-specified analyses for children 6-23 months and 24-59 months Enrollment of children 6-23 months was increased to enable robust subgroup analysis

19. 19 Study MI-CP111Design Primary efficacy endpoint was culture-confirmed modified CDC influenza-like illness (mCDC-ILI) against matched strains Increased temperature (?100�F oral or equivalent) plus cough, sore throat or runny nose/nasal congestion on same or consecutive days Symptoms must be within +/- 7 days of positive culture According to protocol (ATP) and intent-to-treat (ITT) analyses

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22. 22 Study MI-CP111Influenza Strains in the General Population, 2004-2005

23. 23 Study MI-CP111All Culture-Confirmed Modified CDC-ILI

24. 24 Study MI-CP111 Efficacy Comparison: Primary and Secondary Endpoints � ATP and ITT

25. 25 Study MI-CP111 Efficacy Comparison by Strain

26. 26 Study MI-CP111 Efficacy Comparison by Age: Matched Strains

27. 27 Study MI-CP111 Efficacy Comparison by Age: All Strains

28. 28 Study MI-CP111Other Efficacy Endpoints

29. 29 Overall Efficacy ConclusionsChildren <5 Years of Age

30. 30 SafetyFluMist in Children <5 Years of Age

31. 31 FluMist Safety in Children <5 Years Reactogenicity and Adverse Events Mortality Serious Adverse Events Wheezing Outcomes Risk-benefit Summary

32. 32 Study MI-CP111: Reactogenicity

33. 33 Study MI-CP111Adverse Events (AE) Through 28 Days Approximately 30% of children in both groups had >1 AE Adverse events with difference >1% between groups: Events higher with FluMist: sneezing (1.1%) Events higher with TIV: diarrhea (1.1%), AOM (1.5%), and rash (1.3%) Severe AE and related AE were balanced between treatment groups A small number of children in each group did not receive a second vaccination because of an AE or RE 27/3247 (0.8%) TIV, 37/3269 (1.1%) FluMist

34. 34 2 deaths occurred on study, both were unrelated 1 FluMist: 1 year-old due to foreign body (toy) aspiration 1 TIV: 2 year-old due to a house fire

35. 35 Overall SAE rates were similar: 3.1% TIV, 3.3% FluMist 94% of all SAEs were hospitalizations Increased hospitalization rate with FluMist in 6-11 months Study MI-CP111SAE/Hospitalizations Through 180 Days Post Last Dose

36. 36 Overall SAE rates were similar: 3.1% TIV, 3.3% FluMist 94% of all SAEs were hospitalizations Increased hospitalization rate with FluMist in 6-11 months Study MI-CP111SAE/Hospitalizations Through 180 Days Post Last Dose

37. 37 Study MI-CP111Hospitalizations in Children 6-11 Months of Age

38. 38 Study MI-CP111Additional Exploratory Safety Analysis Multiple additional factors were evaluated for association with safety parameters Prior history of wheeze/asthma was prospectively collected and identified by either parent or investigator 21% of children had a history of wheeze/asthma reported 85% by parent 15% by health care provider only Prior history of wheeze/asthma was associated with higher rates of hospitalization

39. 39 Study MI-CP111Hospitalization by Age and History of Wheeze/Asthma, Through 180 Days Post Last Dose

40. 40 Further evaluation is needed in children 6-11 months of age 12-59 months of age with a history of wheeze/asthma No SAE/hospitalization increase in children 12-59 months of age without a history of wheeze/asthma Study MI-CP111SAE/Hospitalization Conclusions

41. 41 Protocol-defined Medically Significant Wheezing (MSW) Wheeze on physical examination plus at least one of the following: new daily bronchodilator use, respiratory distress or hypoxemia Parents instructed to have child evaluated by HCP for any respiratory illness including wheezing Treatment left to physician discretion Any wheeze Not a pre-specified case definition in the protocol Any wheeze event reported by parent or investigator Includes MSW and other wheeze events Study MI-CP111Wheezing Outcomes

42. 42 Study MI-CP111Wheezing Outcomes Through 42 Days Post Last Dose

43. 43 Study MI-CP111Protocol-Defined Wheezing (MSW) within 42 Days Post Last Dose By Age at Study Entry

44. 44 Study MI-CP111Severity of MSW* in Children <24 Months MSW occurred in 192 children 75 TIV, 117 FluMist 14 children were hospitalized for MSW 4/75 TIV vs. 10/117 FluMist 3 in each group had a pathogen identified No ICU admission or mechanical ventilation because of MSW 69% of TIV cases and 75% of FluMist cases had new daily bronchodilator use but no respiratory distress or hypoxemia Rates of recurrent wheezing through 180 days post last dose At least 1 additional episode: 21/75 (28%) TIV vs. 38/117 (32%) FluMist At least 2 additional episodes: 4/75 (5%) TIV vs. 5/117 (4%) FluMist

45. 45 Study MI-CP111Severity of MSW* in Children 12-23 Months Without a History of Wheeze/Asthma

46. 46 Wheezing is not increased in children >24 months of age There appears to be an increase in wheezing in children 12-23 months of age without a prior history of wheeze/asthma Study MI-CP111Wheezing Conclusions

47. 47 Study MI-CP111Risk-Benefit Summary Assess overall risks/benefits of FluMist relative to TIV Data display: Rate differences (FluMist-TIV) per 1000 children Safety endpoints from randomization through 42 & 180 days after last vaccination Culture-confirmed modified CDC-ILI from randomization through 180 days after last vaccination based on all cases (matched and mismatched) Summaries for 12-23 months and 24-59 months without a history of wheeze/asthma

48. 48 Study MI-CP111 Event Rate Differences (FluMist-TIV) per 1000 Children with 95% CI in Children Without a History of Wheeze/Asthma

49. 49 Safety Summary Reactogenicity of FluMist as expected Further evaluation is needed in children 6-11 months of age 12-59 months of age with a history of wheeze/asthma Based on risk-benefit profile for the 77% of children in MI-CP111 who were 12-59 months without a history of wheeze/asthma For children 24-59 months, significant benefit and no increase in wheezing or hospitalization For children 12-23 months, significant benefit but there appears to be a residual increase in wheeze within 42 days post-vaccination

50. 50 Proposed Post-marketing Initiatives Proposed observational safety study in children 12-59 months of age Similar to ongoing post-marketing safety study in healthy children and adults 5-49 years of age Planned enrollment of at least 20,000 FluMist recipients Including assessment of hospitalizations and wheezing Passive surveillance Education & outreach Risks included in package insert Appropriate language in FluMist Vaccine Information Statement (VIS) Targeted outreach to healthcare practitioners and to parents/guardians of children vaccinated with FluMist

51. 51 Overall ConclusionsChildren <5 Years of Age Influenza causes significant morbidity in children on an annual basis Influenza vaccine options are limited for young children FluMist represents a highly efficacious vaccine in children <5 years 73 to 93% efficacy in placebo-controlled studies 55% fewer cases of influenza illness than TIV in MI-CP111 Significant cross-protection against mismatched A/H3N2, including better cross-protection compared to TIV Safety of FluMist established in children 24-59 months without a history of wheeze/asthma FluMist risk-benefit profile in children 12-23 months without a history of wheeze/asthma also warrants vaccine licensing in this population

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