Meningococcal A,C,Y,W135 Conjugate Vaccine MenactraTM

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Meningococcal A,C,Y,W135 Conjugate Vaccine
(MenactraTM)
Aventis Pasteur, Inc.
Vaccines and Related Biological Products Advisory
Committee Meeting September 22, 2004

• Lucia H. Lee
• CBER, FDA

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Outline

• Proposed Basis for Licensure 11-55 years old
• Clinical Studies
• Efficacy (Immunogenicity)
• MTA-02, MTA-09
• Safety
• MTA-04, MTA-09
• Concomitant vaccines
• MTA-12
• Study Results
• Questions for the Committee

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Proposed Basis for Licensure 11-55 years old

• Efficacy inferred from immunogenicity data
• Non-inferiority to Menomune, a U.S. licensed
  meningococcal ACYW135 polysaccharide vaccine
• Immune correlate serum bactericidal antibody
• Demonstration of safety
• Non-inferiority to Menomune
• Demonstration of lot consistency

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Immunogenicity StudiesMTA-02 and MTA-09

• Participants Enrolled
• Study Age (yrs) Menactra Menomune
• MTA-02 11-18y 440 441
• 84 81
• MTA-09 18-55y 1384 1170
• 50 50

• Serum bactericidal assay- baby rabbit complement
• Menactra bactericidal antibody responses compared
  to Menomune, using baby rabbit C and human C

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Immunogenicity Menactra Compared to Menomune,
using SBA

• Serum bactericidal assay- baby rabbit complement
  (SBA-BR)
• Serum bactericidal assay- human complement
  (SBA-H)
• Study MTA-02 (11-18 years old)
• C, Y, W135
• A (Menactra n50, Menomune n52)
• Study MTA-09 (18-55 years old)
• Y, W135
• Reverse cumulative distribution curves
• Seroresponse Rate
• Seroconversion Rate

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Menactra Compared to MenomuneReverse
Cumulative Distribution Curves of Antibody Titer
Post-vaccination SBA-BR
Serogroup A
Serogroup C
11-18 years old
Serogroup Y
Serogroup W135
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Menactra Compared to MenomuneReverse
Cumulative Distribution Curves ofAntibody Titer
Post-vaccination SBA-H
Serogroup A
Serogroup C
Serogroup Y
Serogroup W135
11-18 years old
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Menactra Compared to MenomuneSeroresponse Rate
(11-18 years old) SBA-BR
SBA-BR response defined as 4-fold Increase in
antibody titer post-vaccination, compared to
baseline
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Menactra Compared to MenomuneSeroresponse Rate
(11-18 years old) SBA-H
SBA-H response defined as an antibody titer 1
4 post-vaccination
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Menactra Compared to Menomune, using SBA

• Serum bactericidal assay
• Menactra and Menomune bactericidal antibody
  response, using BR or H complement, supported the
  same conclusion.
• RCD curves overlapped, for Menactra and Menomune
  antibody titers measured post-vaccination, with
  each source of complement
• Similar seroresponse and seroconversion rate
• Similar immunogenicity profile in adults

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Meningococcal A,C,Y W135 Conjugate
Vaccine(MenactraTM)

• Immunogenicity
• Study MTA-02 11-18 years old
• Study MTA-09 18-55 years old

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ImmunogenicityMTA-02 and -09 Study Design

• Design
• Randomized, modified double blind, multi-center
  (USA), active-controlled trial
• Enrollment
• MTA-02 11-18 years old
• MTA-09 18-55 years old
• Vaccine administration
• Menactra single dose, IM
• Menomune single dose, SC
• Serum samples were obtained pre- and 28 days
• post-vaccination.

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ImmunogenicityMTA-02 and -09 Endpoints

• Primary endpoint
• Proportion of participants with a 4-fold rise in
  SBA-BR titer 28 days post-vaccination, compared
  to baseline, for each serogroup
• Other measurements of immune response
• SBA-BR geometric mean titer
• Seroconversion rate
• IgG and IgM, measured by ELISA (MTA-02)

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ImmunogenicityStatistical Hypothesis

• Primary Hypothesis
• To demonstrate that 28 days after vaccination,
  Menactra is non-inferior to Menomune
• MTA-02 Upper limit of the 1-sided 95 CI of
  pMenomune pMenactra is
• MTA-09 Upper limit of the 2-sided 95 CI of
  pMenomune pMenactra is
• p proportion of seroresponders
• participants with a 4-fold rise in SBA-BR titer
  28 days after vaccination, as compared to
  baseline, for each serogroup

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Study MTA-02 (11-18 years old)Results- Primary
Immunogenicity Analysis
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Study MTA-09 (18-55 years old)Results- Primary
Immunogenicity Analysis
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Meningococcal A,C,Y W135 Conjugate
Vaccine(MenactraTM)

• Safety

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Meningococcal A,C,Y W135 Conjugate
Vaccine(MenactraTM)
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Meningococcal A,C,Y W135 Conjugate
Vaccine(MenactraTM)
ITT population for safety included randomized
participants who received one dose of any study
vaccine. Analysis was performed according to the
vaccine received.
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Safety StudiesMTA-04 and MTA-09
Participants Enrolled Study Description
Age (yrs) Menactra Menomune MTA-04 Safety 11-18
y 2270 972 15-18y 75 75
MTA-09 Safety Immunogenicity 18-55y 1384 117
0 18-25y 60 60
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SafetyMTA-04 and -09 Study Design

• Primary Objective To compare the relative
  frequency of a solicited severe systemic reaction
  among Menactra and Menomune recipients
• Vaccine administration
• Menactra IM, Menomune SC
• Study personnel administering the vaccine
  differed from personnel collecting the safety data

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Safety MTA-04 and -09

• Local reactions
• Pain, induration, erythema, swelling
• Systemic reactions
• Fever (oral temperature), headache, fatigue,
  malaise, chills, arthralgia, anorexia, vomiting,
  diarrhea, seizures, rash

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SafetyMTA-04 and -09 Statistical Analysis Plan

• Primary Hypothesis
• To demonstrate that Menactra is non-inferior to
  Menomune
• p proportion of participants with at least one
  severe systemic reaction during the 7 day period
  following vaccination
• Upper limit of the two-sided 90 CI of pMenactra
  / pMenomune is less than 3
• Current CBER requirements two-sided 95 CI

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SafetyMTA-04 and -09 Statistical Analysis Plan

• Severe Systemic Reaction
• Fever
• T40.0C (oral)
• Headache, fatigue, malaise, chills, arthralgia
• Disabling, requiring bed rest or analgesics
• Anorexia, vomiting
• 3 episodes
• Diarrhea
• 5 episodes
• Seizures
• Any
• Rash
• For analysis purposes, all rashes (Days 0-7) were
  designated as severe

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SafetyMTA-04 and -09 Statistical Analysis Plan

• Intent-to-treat Population for Safety
• Randomized participants who received one dose of
  vaccine
• Safety information was available
• Analyses were performed according to the vaccine
  received

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Meningococcal A,C,Y W135 Conjugate
Vaccine(MenactraTM)

• Study Results
• MTA-04 (11-18 years old)

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Study MTA-04 Ages 11-18 years oldIncidence of
Any Local Reactions (Days 0-7)
non-overlapping 95 CI between the two vaccine
groups Pain 0none 1 (mild) symptom present,
but arm movement not affected 2 (moderate)
limits usual arm movement
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Study MTA-04 Ages 11-18 years oldIncidence of
Rash (Days 0-7)

• N51 (37 Menactra, 14 Menomune)
• Local rash
• Injection site n 14 (11 Menactra, 3 Menomune)
• Non-specific local rash
• Extremities trunk neck or face
• Median duration 2 days (range 40 minutes to 2
  months)
• Generalized rash n3
• Itchy, blanching (1 Menactra, 1 Menomune)
• Non-blanching, red, raised

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Study MTA-04 Ages 11-18 years oldResults-
Primary Safety Analysis
Note For analysis purposes, all rashes were
counted as severe solicited systemic reactions.
Also, for each reaction, each participant is
counted no more than once.
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Study MTA-04 Ages 11-18 years oldSevere
Systemic Reactions (Days 0-7)
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Meningococcal A,C,Y W135 Conjugate
Vaccine(MenactraTM)

• Study Results
• MTA-09 (18-55 years old)

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Study MTA-09 Incidence of Local Pain (Days
0-7)Ages 18-25 and 26-55 years old
Pain 0none 1 (mild) symptom present, but arm
movement not affected 2 (moderate) limits usual
arm movement 3 (severe) disabling
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Study MTA-09 Ages 18-55 years oldResults-
Primary Safety Analysis
Note For analysis purposes, all rashes were
counted as severe solicited systemic reactions.
Also, for each reaction, each participant is
counted no more than once.
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Study MTA-09 Ages 18-55 years oldSevere
Systemic Reactions (Days 0-7)
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Meningococcal A,C,Y W135 Conjugate
Vaccine(MenactraTM)

• Serious Adverse events
• (all trials combined)

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Safety Serious Adverse Events (all trials
submitted to BLA)

• Two deaths
• 25-year old woman
• Motor vehicle accident 109 days following
  Menactra vaccination
• 35-year old man
• Cardiopulmonary arrest following drug overdose 72
  days after Menomune vaccination
• Investigator considered event possibly related to
  vaccination
• 17- year old Menactra participant with severe
  esophagitis
• Hospitalized six days following immunization. A
  plausible cause for the event included a history
  of a sports-related back injury, four weeks prior
  to enrollment, and extensive NSAID use
  thereafter.

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Meningococcal A,C,Y W135 Conjugate
Vaccine(MenactraTM)

• Concurrent Immunizations
• Study MTA-12 Td

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Concurrent ImmunizationsStudy MTA-12
11-17 years old
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Meningococcal A,C,Y W135 Conjugate
Vaccine(MenactraTM)

• Study MTA-12 Td
• Antibody response to meningococcal components

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Study MTA-12 with SBA-BR Four-fold Increase
in SBA-BR Antibody Titer
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Study MTA-12 Ages 11-17 years oldSBA-BR GMT,
28d after Menactra vaccination
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Meningococcal A,C,Y W135 Conjugate
Vaccine(MenactraTM)

• Study MTA-12 Td
• Safety

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Study MTA-12 Local Pain after Td Menactra
vaccination (Days 0-7)
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Study MTA-12 Menactra local reactions after 1st
(Group A) and 2nd (Group B) vaccination
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Study MTA-12 Diphtheria GMT (Day 0, 28 days
after Td)
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Meningococcal A,C,Y W135 Conjugate
Vaccine(MenactraTM)

• Summary

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Summary

• Primary immunogenicity hypotheses to demonstrate
  non-inferiority of Menactra compared to Menomune
  were achieved, for each serogroup.
• Proportion of participants with 4-fold increase
  in SBA-BR titer, 28 days after vaccination,
  compared with baseline
• A difference in antibody response to
  meningococcal components was noted in the group
  receiving Td prior to Menactra, and the group
  receiving Menactra and Td concomitantly.

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Cont. Summary

• Increased frequency of local and systemic
  reactions was observed in Menactra participants,
  compared to Menomune.
• Difference in of participants with multiple
  severe systemic reactions was not statistically
  significant
• Safety hypotheses to demonstrate non-inferiority
  of Menactra to Menomune were achieved