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 Aventis Pasteur, Inc.

2 Outline  Proposed Basis for Licensure: years old  Clinical Studies  Efficacy (Immunogenicity) MTA-02, MTA-09 MTA-02, MTA-09  Safety MTA-04, MTA-09 MTA-04, MTA-09  Concomitant vaccines MTA-12 MTA-12  Study Results  Questions for the Committee

3 Proposed Basis for Licensure: 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

4 Immunogenicity Studies: MTA-02 and MTA-09 # Participants Enrolled Study Age (yrs)MenactraMenomune ® MTA y MTA y  Serum bactericidal assay- baby rabbit complement  Menactra bactericidal antibody responses compared to Menomune ®, using baby rabbit C’ and human C’

5 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 C, Y, W135 A (Menactra n=50, Menomune ® n=52) A (Menactra n=50, Menomune ® n=52)  Study MTA-09 (18-55 years old) Y, W135 Y, W135  Reverse cumulative distribution curves Seroresponse Rate Seroconversion Rate Immunogenicity: Menactra Compared to Menomune ®, using SBA

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

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

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 RCD curves overlapped, for Menactra and Menomune antibody titers measured post-vaccination, with each source of complement Similar seroresponse and seroconversion rate Similar seroresponse and seroconversion rate Similar immunogenicity profile in adults Similar immunogenicity profile in adults

11 Meningococcal A,C,Y W135 Conjugate Vaccine (Menactra TM ) Immunogenicity  Study MTA-02: years old  Study MTA-09: years old

12 Immunogenicity: MTA-02 and -09 Study Design  Design:  Randomized, modified double blind, multi-center (USA), active-controlled trial  Enrollment:  MTA-02: years old  MTA-09: years old  Vaccine administration: Menactra: single dose, IM Menactra: single dose, IM Menomune ® : single dose, SC Menomune ® : single dose, SC  Serum samples were obtained pre- and 28 days post-vaccination.

13  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) Immunogenicity: MTA-02 and -09 Endpoints

14 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 p Menomune® – p Menactra is <0.10  MTA-09: Upper limit of the 2-sided 95% CI of p Menomune® – p Menactra 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 participants with a >4-fold rise in SBA-BR titer 28 days after vaccination, as compared to baseline, for each serogroup Immunogenicity: Statistical Hypothesis

15 Study MTA-02 (11-18 years old) Results- Primary Immunogenicity Analysis Proportion of Participants with > Four-fold Increase in SBA-BR 28 Days Post-vaccination, Compared to Baseline Menomune ® Menactra DifferenceUpper Limit of the SerogroupN= 423 (p Menomune® -1-sided 95% CI2-sided 95% CI p Menomune® p Menactra p Menactra )of the Difference A C Y W

16 Study MTA-09 (18-55 years old) Results- Primary Immunogenicity Analysis Proportion of Participants with > Four-fold Increase in SBA-BR 28 Days Post-vaccination, Compared to Baseline Menomune ® Menactra Upper Limit of the SerogroupN= 1098N= 1280Difference2-sided 95% CI p Menomune® p Menactra (p Menomune® - p Menactra ) of the Difference A C Y W

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

18 Overall Safety Database # Participants enrolled Age group MenactraMenomune nn years years years Total for 11-55y Meningococcal A,C,Y W135 Conjugate Vaccine (Menactra TM )

19 * ITT population for safety included randomized participants who received one dose of any study vaccine. Analysis was performed according to the vaccine received. Meningococcal A,C,Y W135 Conjugate Vaccine (Menactra TM )

20 Safety Studies: MTA-04 and MTA-09 # Participants Enrolled Study Description Age (yrs)MenactraMenomune ® MTA-04Safety11-18y [15-18y~75%~75%] MTA-09Safety + Immunogenicity18-55y [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  Local reactions  Pain, induration, erythema, swelling  Systemic reactions  Fever (oral temperature), headache, fatigue, malaise, chills, arthralgia, anorexia, vomiting, diarrhea, seizures, rash Safety: MTA-04 and -09

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 p Menactra / p Menomune® is less than 3  Current CBER requirements: two-sided 95% CI

24  Severe Systemic Reaction:  Fever T>40.0C (oral) T>40.0C (oral)  Headache, fatigue, malaise, chills, arthralgia Disabling, requiring bed rest or analgesics Disabling, requiring bed rest or analgesics  Anorexia, vomiting >3 episodes >3 episodes  Diarrhea >5 episodes >5 episodes  Seizures Any Any  Rash For analysis purposes, all rashes (Days 0-7) were designated as severe For analysis purposes, all rashes (Days 0-7) were designated as severe Safety: MTA-04 and -09 Statistical Analysis Plan

25  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 Safety: MTA-04 and -09 Statistical Analysis Plan

26 Study Results:  MTA-04 (11-18 years old) Meningococcal A,C,Y W135 Conjugate Vaccine (Menactra TM )

27 Study MTA-04: Ages years old Incidence 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 MenactraMenomune ® N= 2264N= 970 ReactionSeverity % 95% CI % PainAny 59.2*57.1, , 31.6 Mild 46.2*44.1, , 29.0 Moderate 12.8*11.4, , 3.8 IndurationAny 15.7*14.2, , 6.7 RednessAny 10.9*9.7, , 7.3 Swelling Any 10.8*9.6, , 5.0

28 Study MTA-04: Ages years old Incidence of Rash (Days 0-7) N=51 (37 Menactra, 14 Menomune ® )  Local rash: Injection site: n= 14 (11 Menactra, 3 Menomune ® ) Injection site: n= 14 (11 Menactra, 3 Menomune ® ) Non-specific local rash 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 ® ) Itchy, blanching (1 Menactra, 1 Menomune ® ) Non-blanching, red, raised Non-blanching, red, raised

29 Study MTA-04: Ages years old Results- 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. Number and Proportion of Participants Years Old With At Least One Severe Solicited Systemic Reaction Menactra Menomune ® Upper Limit of N= 2265N= 970Ratio the 2-sided 90% CI the 2-sided 95% CI np Menactra np Menomune® (p Menactra / p Menomune® ) of the Ratio

30 Study MTA-04: Ages years old Severe Systemic Reactions (Days 0-7) MenactraMenomune ® N= 2265N= 970 % Severe systemic reactions (+ rash) 4.3%2.6% Severe systemic reactions (- rash) 2.7%1.2% Participants with multiple severe systemic AEs: 1.1%0.3% 5 severe systemic AEs 0.1%0.0% 4 severe systemic AEs 0.1% 3 severe systemic AEs 0.4%0.1% 2 severe systemic AEs 0.4%0.1%

31 Study Results:  MTA-09 (18-55 years old) Meningococcal A,C,Y W135 Conjugate Vaccine (Menactra TM )

32 Study MTA-09: Incidence of Local Pain (Days 0-7) Ages and years old Pain: 0=none 1= (mild) symptom present, but arm movement not affected 2= (moderate) limits usual arm movement 3= (severe) disabling MenactraMenomune ® Local PainSeverity % 95% CI % Age yearsAny , , 55.6 Mild , , 51.8 Moderate , , 5.5 Severe , , 0.9 Age yearsAny , , 47.9 Mild , , 45.2 Moderate , , 4.5 Severe , , 0.7

33 Study MTA-09: Ages years old Results- 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. Number and Proportion of Participants Years Old With At Least One Severe Solicited Systemic Reaction Menactra Menomune ® Upper Limit of N= 1371N= 1159Ratio the 2-sided 90% CI the 2-sided 95% CI np Menactra np Menomune® ( p Menactra / p Menomune ® ) of the Ratio

34 Study MTA-09: Ages years old Severe Systemic Reactions (Days 0-7) MenactraMenomune ® N= 1371N= 1159 % Severe systemic reactions (+ rash) 3.8%2.6% Severe systemic reactions (- rash) 2.6%1.9% Participants with multiple severe systemic AEs: 1.1%0.7% 7 severe systemic AEs 0.1%0.0% 5 severe systemic AEs 0.1% 4 severe systemic AEs 0.1%0.2% 3 severe systemic AEs 0.5%0.3% 2 severe systemic AEs 0.3%0.2%

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

36  Two deaths  25-year old woman Motor vehicle accident 109 days following Menactra vaccination Motor vehicle accident 109 days following Menactra vaccination  35-year old man Cardiopulmonary arrest following drug overdose 72 days after Menomune vaccination 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. Safety: Serious Adverse Events (all trials submitted to BLA)

37 Concurrent Immunizations  Study MTA-12: Td Meningococcal A,C,Y W135 Conjugate Vaccine (Menactra TM )

38 Concurrent Immunizations: Study MTA-12 Day 0 Day 28 Menactra + TdSaline placebo Td + saline placeboMenactra Group B: Group A: years old

39 Study MTA-12: Td  Antibody response to meningococcal components Meningococcal A,C,Y W135 Conjugate Vaccine (Menactra TM )

40 Study MTA-12: % with SBA-BR >Four-fold Increase in SBA-BR Antibody Titer Percentage of Participants Years Old with > 4-fold Increase in SBA-BR Antibody Titer, 28 days after Menactra vaccination, compared to Baseline Serogroup Group A Group B Difference (Group B- Group A) Td+ Menactra, Then Placebo Td + Placebo, Then Menactra N=478N=465 % % A % C % Y % W %

41 Study MTA-12: Ages years old SBA-BR GMT, 28d after Menactra vaccination SBA-BR GMT, 28 Days after Menactra Vaccination Group AGroup B Td + Menactra Td, then Menactra A C Y W

42 Study MTA-12: Td  Safety Meningococcal A,C,Y W135 Conjugate Vaccine (Menactra TM )

43 Study MTA-12: Local Pain after [Td + Menactra] vaccination (Days 0-7) Concomitant Vaccine Group: Td and Menactra Injection sites Group A N=505 Group A N=505 Td + Menactra, Then Placebo Menactra Injection site Td Injection site ReactionSeverity % 95% CI % Pain Any , , 74.8 Mild , , 52.8 Moderate , , 26.3 Severe , , 1.1

44 Menactra Local Adverse Reactions (Days 0-7) Group A (N= 505)Group B (N= 505) Td + Menactra, Td + Placebo, Then Placebo Then Menactra Menactra Injection site Menactra Injection site ReactionSeverity % 95% CI % RednessAny , , 14.2 SwellingAny , , 16.3 IndurationAny , , 18.9 PainAny , , 57.9 Study MTA-12: Menactra local reactions after 1 st (Group A) and 2 nd (Group B) vaccination

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

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

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  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 Cont. Summary