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Meningococcal A,C,Y,W135 Conjugate Vaccine (Menactra TM )

Aventis Pasteur, Inc. Meningococcal A,C,Y,W135 Conjugate Vaccine (Menactra TM ). Lucia H. Lee CBER, FDA. Vaccines and Related Biological Products Advisory Committee Meeting September 22, 2004. Outline. Proposed Basis for Licensure: 11-55 years old Clinical Studies

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Meningococcal A,C,Y,W135 Conjugate Vaccine (Menactra TM )

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

  2. 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

  3. 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 ofsafety • Non-inferiority to Menomune® • Demonstration oflot consistency

  4. Immunogenicity Studies:MTA-02 and MTA-09 # Participants Enrolled Study Age (yrs) Menactra Menomune® MTA-0211-18y440441 84 81 MTA-0918-55y13841170 50 50 • Serum bactericidal assay- baby rabbit complement • Menactra bactericidal antibody responses compared to Menomune®, using baby rabbit C’ and human C’

  5. 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 n=50, Menomune® n=52) • Study MTA-09 (18-55 years old) • Y, W135 • Reverse cumulative distribution curves Seroresponse Rate Seroconversion Rate

  6. Menactra Menomune Menactra Compared to Menomune®:Reverse Cumulative Distribution Curves of Antibody Titer Post-vaccination [SBA-BR] Serogroup A Serogroup C Serogroup Y Serogroup W135 11-18 years old

  7. Menactra Menomune Menactra Compared to Menomune®:Reverse Cumulative Distribution Curves ofAntibody Titer Post-vaccination [SBA-H] Serogroup A Serogroup C Serogroup Y Serogroup W135 11-18 years old

  8. Menactra Compared to Menomune®:Seroresponse Rate (11-18 years old) SBA-BR SBA-BR response: defined as >4-fold Increase in antibody titer post-vaccination, compared to baseline

  9. Menactra Compared to Menomune®:Seroresponse Rate (11-18 years old) SBA-H SBA-H response: defined as an antibody titer >1: 4 post-vaccination

  10. 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

  11. Meningococcal A,C,Y W135 Conjugate Vaccine(MenactraTM) Immunogenicity • Study MTA-02: 11-18 years old • Study MTA-09: 18-55 years old

  12. Immunogenicity:MTA-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.

  13. Immunogenicity:MTA-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)

  14. Immunogenicity:Statistical 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 <0.10 • MTA-09: Upper limit of the 2-sided 95% CI of pMenomune®– pMenactra is <0.10 • 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

  15. Study MTA-02 (11-18 years old)Results- Primary Immunogenicity Analysis

  16. Study MTA-09 (18-55 years old)Results- Primary Immunogenicity Analysis

  17. Meningococcal A,C,Y W135 Conjugate Vaccine(MenactraTM) Safety

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

  19. 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.

  20. Safety Studies:MTA-04 and MTA-09 # Participants Enrolled Study Description Age (yrs) Menactra Menomune® MTA-04Safety11-18y2270972 [15-18y ~75% ~75%] MTA-09Safety + Immunogenicity 18-55y13841170 [18-25y ~60% ~60% ]

  21. Safety:MTA-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

  22. 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

  23. Safety:MTA-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

  24. Safety:MTA-04 and -09 Statistical Analysis Plan • Severe Systemic Reaction: • Fever • T>40.0C (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

  25. Safety:MTA-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

  26. Meningococcal A,C,Y W135 Conjugate Vaccine(MenactraTM) Study Results: • MTA-04 (11-18 years old)

  27. 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: 0=none 1= (mild) symptom present, but arm movement not affected 2= (moderate) limits usual arm movement

  28. Study MTA-04: Ages 11-18 years oldIncidence of Rash (Days 0-7) N=51 (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: n=3 • Itchy, blanching (1 Menactra, 1 Menomune®) • Non-blanching, red, raised

  29. 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.

  30. Study MTA-04: Ages 11-18 years oldSevere Systemic Reactions (Days 0-7)

  31. Meningococcal A,C,Y W135 Conjugate Vaccine(MenactraTM) Study Results: • MTA-09 (18-55 years old)

  32. Study MTA-09: Incidence of Local Pain (Days 0-7)Ages 18-25 and 26-55 years old Pain: 0=none 1= (mild) symptom present, but arm movement not affected 2= (moderate) limits usual arm movement 3= (severe) disabling

  33. 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.

  34. Study MTA-09: Ages 18-55 years oldSevere Systemic Reactions (Days 0-7)

  35. Meningococcal A,C,Y W135 Conjugate Vaccine(MenactraTM) Serious Adverse events (all trials combined)

  36. 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.

  37. Meningococcal A,C,Y W135 Conjugate Vaccine(MenactraTM) Concurrent Immunizations • Study MTA-12: Td

  38. Group A: Menactra + Td Saline placebo Day 28 Day 0 Td + saline placebo Menactra Group B: Concurrent Immunizations:Study MTA-12 11-17 years old

  39. Meningococcal A,C,Y W135 Conjugate Vaccine(MenactraTM) Study MTA-12: Td • Antibody response to meningococcal components

  40. Study MTA-12:% with SBA-BR >Four-fold Increase in SBA-BR Antibody Titer

  41. Study MTA-12: Ages 11-17 years oldSBA-BR GMT, 28d after Menactra vaccination

  42. Meningococcal A,C,Y W135 Conjugate Vaccine(MenactraTM) Study MTA-12: Td • Safety

  43. Study MTA-12: Local Pain after [Td + Menactra] vaccination (Days 0-7)

  44. Study MTA-12: Menactra local reactions after 1st (Group A) and 2nd (Group B) vaccination

  45. Study MTA-12:Diphtheria GMT (Day 0, 28 days after Td)

  46. Meningococcal A,C,Y W135 Conjugate Vaccine(MenactraTM) Summary

  47. 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.

  48. 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

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