FluMist Influenza Virus Vaccine Live, Intranasal

1
FluMistInfluenza Virus Vaccine Live, Intranasal
Edward Connor, M.D. Executive VP, Clinical
Development Chief Medical Officer

• MedImmune
• Gaithersburg, Maryland

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
Sponsor Presentation

• Introduction and Overview
• Data on efficacy of FluMist in children lt5 years
  of age
• Data on safety of FluMist in children lt5 years of
  age
• Post-marketing studies
• Conclusions

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
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 lt5 years
  of age
• Single manufacturer for children lt4 years of age

Thompson et al, J Am Med Assoc 289179, 2003
Poehling et al, N Engl J Med 35531, 2006 ACIP
Recommendations MMWR 55RR-10, 2006 AAP
Recommendations Pediatrics 119 846, 2007 AAFP
Practice Guidelines Am Fam Phys 74665, 2006
6
FluMist Product Characteristics

• 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 2-8ºC (refrigerator)
• Contains no preservatives (e.g., no thimerosal)

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
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

1 Izurieta et al, J Am Med Assoc 2942720, 2005
2 Baxter et al, PAS 2007
9
FluMist Rationale for Lower Age Limit in
Initial Approval

• MedImmune did not seek an indication in children
  lt5 years
• Wheezing signal in placebo-controlled safety
  study
• Further data needed to understand the signal

Study AV019 Post Hoc Analysis of Diagnostic Codes
Bergen et al, Pediatr Infect Dis J 23138, 2004
Belshe et al, Clin Infect Dis 39920, 2004
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 (N2187)1 6-17 yrs
  with asthma (N2229)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 lt59 months of age
• Study AV006 (NIH CRADA with Aviron)
• Study D153-P501 (Wyeth)
• Study MI-CP111

1 Ashkenazi et al, Pediatr Infect Dis J 25870,
2006 2 Fleming et al, Pediatr Infect Dis J
25860, 2006
11
FluMist Principal Findings for Children lt5
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
FluMist Proposed Expanded Indicated Population

• Children 12 to 59 months of age without a
  history of wheeze/asthma

13
EfficacyFluMist in Children lt5 Years of Age

• 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

14
Studies AV006 and D153-P501Placebo-Controlled
Efficacy Studies
Two placebo-controlled studies assessed efficacy
vs. all three influenza subtypes, including
mismatched A/H3N2
1 Belshe et al. N Engl J Med. 3381405-1412,
1998 2 Belshe et al. J Pediatr. 136168-175,
2000 3 Tam et al. Pediatr Infect Dis J. In press.
15
FluMist Efficacy in Vaccine-naïve Children Year
One Efficacy by Strain (Matched)
Efficacy estimates are for matched strains, the
studies primary endpoint
Study AV0061
Study D153-P5012
96.0
93.4
90.5
90.0
80.9
72.9
44.3
Efficacy () with 95 CI
Influenza Strain
1 Belshe et al. N Engl J Med. 3381405-1412,
1998 2 Tam et al. Pediatr Infect Dis J. In press.
16
FluMist Efficacy in Previously Vaccinated
Children Year Two Efficacy by Strain
AV006 estimates are for all strains because 94
of strains were mismatched D153-P501 estimates
are for matched strains
Study AV0061
Study D153-P5012
86.3
87.0
86.7
84.3
Efficacy () with 95 CI
Influenza Strain
1 Belshe et al. N Engl J Med. 3381405-1412,
1998 2 Tam et al. Pediatr Infect Dis J. In press.
17
Study MI-CP111Pivotal Comparative Trial in
Children lt5 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

Belshe et al, N Engl J Med 356685, 2007
18
Study MI-CP111Design

• Randomized, double-blind, TIV-controlled,
  multinational
• Children 6-59 months of age (N8,475)
• 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 gt3
  wheezing illnesses
• Stratification of 24-35 months to balance
  children receiving different TIV licensed dosages
  (children lt3 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

Belshe et al, N Engl J Med 356685, 2007
19
Study MI-CP111Design

• Primary efficacy endpoint was culture-confirmed
  modified CDC influenza-like illness (mCDC-ILI)
  against matched strains
• Increased temperature (?100ºF 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

Belshe et al, N Engl J Med 356685, 2007
20
Study MI-CP111Baseline Characteristics
ITT Population
Baseline characteristics were balanced between
the treatment groups
21
Study MI-CP111Follow-up of Subjects
ITT Population
Follow-up was also balanced between the treatment
groups
22
Study MI-CP111Influenza Strains in the General
Population, 2004-2005
High proportion of mismatched A/H3N2 circulated
as well as some mismatched B and alternate
lineage B
Source U.S. Centers for Disease Control and
Prevention, European Influenza Surveillance
Scheme (EISS)
No strain-specific data available for
Asia Mismatched strains shown in blue italics
matched and mismatched B/Yamagata strains
circulated
23
Study MI-CP111All Culture-Confirmed Modified
CDC-ILI
Culture-confirmed Modified CDC-ILI Caused by Any
Wild-type Strain (Matched and Mismatched)
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4
.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
338 cases
TIV
Percent
1st immunizations completed by 10/29/04
FluMist
153 cases
01 NOV 04
01 DEC 04
01 JAN 05
01 FEB 05
01 MAR 05
01 APR 05
01 MAY 05
24
Study MI-CP111 Efficacy Comparison Primary and
Secondary Endpoints ATP and ITT
Comparative Efficacy Against Culture-confirmed
Modified CDC-ILI
ATP
ITT
58.2 (Plt0.001)
56.6 (Plt0.001)
TIV
7
FluMist
6.2
6.0
44.5 (Plt0.001)
46.0 (Plt0.001)
6
5
0.7
0.7
Attack Rate ()
Solid bars matched Hatched bars mismatched
4
2.4
2.4
2.6
3
2.6
2
1.4
1.3
1
0
Mismatched Strains
Matched Strains
Mismatched Strains
Matched Strains
No. of Cases
93
53
102
245
55
100
111
255
TIV N4232, FluMist N4243
TIV N3936, FluMist N3916
25
Study MI-CP111 Efficacy Comparison by Strain
Comparative Efficacy Against Culture-confirmed
Modified CDC-ILI (ATP Population)
54.9 (Plt0.001)
10
TIV (N3936)
9
8.6
FluMist (N3916)
8
79.2 (Plt0.001)
7
16.1 (PNS)
Solid bars matched Hatched bars mismatched
6
5
Attack Rate ()
4.5
3.9
4
3.5
89.2 (Plt0.001)
2.9
3
2
0.9
0.7
1
0.1
0
All Strains
H1N1
H3N2
B
Strain
338
153
3
27
37
178
115
136
No. of Cases
26
Study MI-CP111 Efficacy Comparison by Age
Matched Strains
Comparative Efficacy Against Culture-confirmed
Modified CDC-ILI (ATP Population)
TIV N1852, 6-23 mos N2084, 24-59 mos
10
FluMist N1834, 6-23 mos N2082,
24-59 mos
9
8
7
Attack Rate ()
52.5 (Plt0.001)
6
29.1 (PNS)
5
4
2.9
3
1.7
1.4
2
1.3
1
0
6-23 mos
24-59 mos
Age Group
32
23
61
30
No. of Cases
27
Study MI-CP111 Efficacy Comparison by Age All
Strains
Comparative Efficacy Against Culture-confirmed
Modified CDC-ILI (ATP Population)
TIV N1852, 6-23 mos N2084, 24-59 mos
54.4 (Plt0.001)
9.8
55.7 (Plt0.001)
10
FluMist N1834, 6-23 mos N2082,
24-59 mos
9
8
7.2
7
Solid bars matched Hatched bars mismatched
Attack Rate ()
6
4.5
5
4
3.2
3
2
1
0
6-23 mos
24-59 mos
Age Group
133
59
205
94
No. of Cases
28
Study MI-CP111Other Efficacy Endpoints
Illness associated with a positive culture for
all strains regardless of match
50.6 (Plt0.001)
10.0
10
TIV (N3936)
9
8
FluMist (N3916)
7
Solid bars matched Hatched bars mismatched
6
5.0
Attack Rate ()
5
50.6 (P0.003)
4
45.9 (P0.046)
3
2
1.4
0.8
0.7
1
0.5
0
Symptomatic Influenza
LRI
AOM
393
195
18
33
26
54
No. of Cases
29
Overall Efficacy ConclusionsChildren lt5 Years of
Age

• 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

30
SafetyFluMist in Children lt5 Years of Age

• For children without a history of wheeze/asthma
• Safety established in children 24-59 months
• Risk-benefit warrants availability for children
  12-23 months

31
FluMist Safety in Children lt5 Years

• Reactogenicity and Adverse Events
• Mortality
• Serious Adverse Events
• Wheezing Outcomes
• Risk-benefit Summary

32
Study MI-CP111 Reactogenicity
Percent of Children with Events Days 010 Two
Dose Group, Post Dose 1
Each child received both an intranasal spray and
an intramuscular injection
33
Study MI-CP111Adverse Events (AE) Through 28 Days

• Approximately 30 of children in both groups had
  gt1 AE
• Adverse events with difference gt1 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
Study MI-CP111Mortality

• 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
Study MI-CP111SAE/Hospitalizations Through 180
Days Post Last Dose

• 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

Hospitalization Rates by Age
For all subjects
p0.002
36
Study MI-CP111SAE/Hospitalizations Through 180
Days Post Last Dose

• 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

37
Study MI-CP111Hospitalizations in Children 6-11
Months of Age
Temporal Distribution of Hospitalizations
Hospitalization by Diagnosis
TIV
FluMist
Days Following Randomization
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
Study MI-CP111Hospitalization by Age and History
of Wheeze/Asthma, Through 180 Days Post Last Dose
Without a history of wheezing (N6580)
With a history of wheezing (N1772)
p0.004
p0.039
40
Study MI-CP111SAE/Hospitalization Conclusions

• 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

41
Study MI-CP111Wheezing Outcomes

• 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

• Pre-specified interval randomization through 42
  days post last dose

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

• Wheezing increased in children 6-23 months of age
• No increase in children 24-59 months of age

Children 24-59 Months
Children 6-23 Months
p0.002
p0.002
For all subjects regardless of history of
wheeze/asthma
43
Study MI-CP111Protocol-Defined Wheezing (MSW)
within 42 Days Post Last Dose By Age at Study
Entry

• Higher rates of wheezing in FluMist recipients
  through 23 months of age

Protocol-Defined Wheezing (MSW) Rates by Age
6-23 Months
24-59 Months
44
Study MI-CP111Severity of MSW in Children lt24
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

Protocol-defined (MSW) within 42 days after
last vaccination
45
Study MI-CP111Severity of MSW in Children 12-23
Months Without a History of Wheeze/Asthma

• MSW occurred in 58 children
• 23 TIV, 35 FluMist
• 3 children were hospitalized for wheezing
• 1/23 TIV, 2/35 FluMist
• 1 in each group had a pathogen identified
• 74 of TIV cases and 86 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 5/23 (22) TIV vs.
  5/35 (14) FluMist
• At least 2 additional episodes 1/23 (4) TIV vs.
  1/35 (3) FluMist

Protocol-defined (MSW) within 42 days after
last vaccination
46
Study MI-CP111Wheezing Conclusions

• Wheezing is not increased in children gt24 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

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
Study MI-CP111 Event Rate Differences
(FluMist-TIV) per 1000 Children with 95 CI in
Children Without a History of Wheeze/Asthma
Wheeze endpoints
Hospitalization
Culture-Confirmed Modified CDC-ILI
24-59 Months
12-23 Months
FluMist N1053, TIV N1060
FluMist N1615, TIV N1625
-49
-35
Benefit
-8
-8
-6
-6
-8
-3
-3
4
1
7
12
18
Risk
Any wheeze
MSW
Hosp
Any wheeze
MSW
Hosp
mCDC- ILI
Through 42 Days PLD
Through 180 Days PLD
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
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
Overall ConclusionsChildren lt5 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 lt5 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

52
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