# Presentation: 665782

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

**Lucia H. Lee**
**CBER, FDA**

**Vaccines and Related Biological Products**
**Advisory Committee Meeting**
**September 22, 2004**

- Aventis Pasteur, Inc.

## 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**

## 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_

## Immunogenicity Studies:MTA-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’

## 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

- 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

**Immunogenicity: ****Menactra Compared to Menomune****®****, using SBA**

## Menactra Compared to Menomune®:Reverse Cumulative Distribution Curves of Antibody Titer Post-vaccination [SBA-BR]

**11-18 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]

**11-18 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 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**

## Menactra Compared to Menomune®:Seroresponse Rate (11-18 years old) SBA-H 

**SBA-H response: defined as an antibody titer **_**>**_**1: 4 post-vaccination**

## 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

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

- 			**Immunogenicity**
- Study MTA-02: 11-18 years old
- Study MTA-09: 18-55 years old

## 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.

## 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)

- 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

## 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

- 	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

**Immunogenicity:**Statistical Hypothesis

## 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 |  
Difference  | 
Upper Limit of the | 
Upper Limit of the |
| Serogroup | N= 423 | N= 423 | (pMenomune® - | 1-sided 95% CI | 2-sided 95% CI |
|   | pMenomune® | pMenactra | pMenactra) | of the Difference | of the Difference |
| A | 0.924 | 0.926 | -0.002 | 0.027 | 0.033 |
| C | 0.886 | 0.917 | -0.031 | 0.003 | 0.009 |
| Y | 0.801 | 0.818 | -0.017 | 0.028 | 0.036 |
| W-135 | 0.952 | 0.966 | -0.014 | 0.008 | 0.013 |

## 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 |
| Serogroup | N= 1098 | N= 1280 | Difference | 2-sided 95% CI |
|   | pMenomune® | pMenactra | (pMenomune® - pMenactra) | of the Difference |
| A | 0.846 | 0.805 | 0.041 | 0.072 |
| C | 0.897 | 0.885 | 0.012 | 0.037 |
| Y | 0.794 | 0.735 | 0.059 | 0.093 |
| W-135 | 0.944 | 0.894 | 0.050 | 0.072 |

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

- 			**Safety**

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

| Overall Safety Database |  |   |  |
| --- | --- | --- | --- |
|   | # Participants enrolled |  |  |
| Age group
  | Menactra |  | Menomune |
|  | n |  | n |
| 11-14 years | 1636 |  | 490 |
| 15-25 years | 4078 |  | 1578 |
| 26-55 years | 1957 |  | 973 |
| Total for 11-55y | 7672 |  | 3041 |

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

## 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.**

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

## Safety Studies:MTA-04 and MTA-09

**Safety Studies:**MTA-04 and MTA-09

- 				_# Participants Enrolled_
- Study 	Description 	Age (yrs)	Menactra	Menomune®
**MTA-04**	**Safety**	**11-18y**		**2270**			**972**
**	****	****	**[**15-18y****	****	****~75%****	****	****~75%**]
**MTA-09**	**Safety + Immunogenicity****	****18-55y**		**1384**		**1170**
**	****	****	**[**18-25y****	****	****~60%****	****	****~60% **]

## 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

_**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

## Local reactions
Pain, induration, erythema, swelling

Systemic reactions
Fever (oral temperature), headache, fatigue, malaise, chills, arthralgia, anorexia, vomiting, diarrhea,  seizures, rash 

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

**Safety:** MTA-04 and -09

## 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

_**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

## 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

- 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

**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 

- 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

## Study Results:
MTA-04 (11-18 years old)

- MTA-04 (11-18 years old)

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

## Study MTA-04: Ages 11-18 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**

|   |   | Menactra  |  | Menomune® |  |
| --- | --- | --- | --- | --- | --- |
|   |   | N= 2264 |  | N= 970 |  |
| Reaction | Severity | % | 95% CI | % | 95% CI |
| Pain | Any | 59.2* | 57.1, 61.2 | 28.7 | 25.8, 31.6 |
|  | Mild | 46.2* | 44.1, 48.2 | 26.1 | 23.3, 29.0 |
|  | Moderate | 12.8* | 11.4, 14.2 | 2.6 | 1.7, 3.8 |
|  |  |   |   |   |   |
| Induration | Any | 15.7* | 14.2, 17.2 | 5.2 | 3.9, 6.7 |
| Redness | Any | 10.9* | 9.7, 12.3 | 5.7 | 4.3, 7.3 |
| Swelling  | Any | 10.8* | 9.6, 12.2 | 3.6 | 2.5, 5.0 |

## Study MTA-04: Ages 11-18 years oldIncidence 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

## Study MTA-04: Ages 11-18 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 11-18 Years Old With At Least One Severe Solicited Systemic Reaction  |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- |
| Menactra |  | 
Menomune® |  |   | Upper Limit of  | Upper Limit of  |
| N= 2265 |  | N= 970 |  | Ratio   | the 2-sided 90% CI | the 2-sided 95% CI |
| n | pMenactra | n | pMenomune® | (pMenactra / 
pMenomune® ) | of the Ratio | of the Ratio |
| 97 | 0.043 | 25 | 0.026 | 1.7 | 2.4 | 2.6 |

## Study MTA-04: Ages 11-18 years oldSevere Systemic Reactions (Days 0-7)

|   | Menactra | Menomune® |
| --- | --- | --- |
|   | N= 2265 | N= 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% | 0.1% |
|     3 severe systemic AEs | 0.4% | 0.1% |
|     2 severe systemic AEs  | 0.4% | 0.1% |

## Study Results:
MTA-09 (18-55 years old)

- MTA-09 (18-55 years old)

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

## 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**

|   |   | Menactra |  | Menomune® |  |
| --- | --- | --- | --- | --- | --- |
| Local Pain | Severity | % | 95% CI | % | 95% CI |
| Age 18-25 years | Any | 61.1 | 57.5, 64.5 | 51.8 | 47.9, 55.6 |
|   | Mild | 45.8 | 42.3, 49.4 | 47.9 | 44.1, 51.8 |
|   | Moderate | 15.2 | 12.9, 18.0 | 3.7 | 2.5, 5.5 |
|   | Severe | 0.0 | 0.0, 0.0 | 0.2 | 0.0, 0.9 |
| Age 26-55 years | Any | 45.1 | 41.2, 49.1 | 43.6 | 39.4, 47.9 |
|   | Mild | 38.2 | 34.4, 42.1 | 40.9 | 36.7, 45.2 |
|   | Moderate | 6.5 | 4.8, 8.7 | 2.7 | 1.6, 4.5 |
|   | Severe | 0.5 | 0.2, 1.4 | 0.0 | 0.0, 0.7 |

## Study MTA-09: Ages 18-55 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 18-55 Years Old With At Least One Severe Solicited Systemic Reaction |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- |
| Menactra |  | 
Menomune® |  |   | Upper Limit of  | Upper Limit of  |
| N= 1371 |  | N= 1159 |  | 
Ratio  | the 2-sided 90% CI | the 2-sided 95% CI |
| n | pMenactra | 
n | 
pMenomune® | (pMenactra / 
pMenomune® ) | of the Ratio | of the Ratio |
| 52 | 0.038 | 30 | 0.026 | 1.5 | 2.1 | 2.3 |

## Study MTA-09: Ages 18-55 years oldSevere Systemic Reactions (Days 0-7)

|   | Menactra | Menomune® |
| --- | --- | --- |
|   | N= 1371 | N= 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% | 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% |

## Serious Adverse events 
(all trials combined)

- (all trials combined)

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

## 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. 

- 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.

**Safety:**
- Serious Adverse Events (all trials submitted to BLA)

## Concurrent Immunizations
Study MTA-12: Td

- Study MTA-12: Td

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

## Concurrent Immunizations:Study MTA-12

**11-17 years old**

## Study MTA-12: Td
	Antibody response to meningococcal components

- 	Antibody response to meningococcal components

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

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

| Percentage  of Participants 11-17 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=478 | N=465 |  |
|   | % | % | % |
| A | 90.1 | 90.6 | 0.5% |
| C | 91.2 | 82.4 | -8.8% |
| Y | 85.8 | 65.1 | -20.7% |
| W-135 | 96.3 | 87.7 | -8.7% |

## Study MTA-12: Ages 11-17 years oldSBA-BR GMT, 28d after Menactra vaccination

| SBA-BR GMT, 28 Days after Menactra Vaccination |  |  |
| --- | --- | --- |
|   | Group A | Group B |
|  | Td + Menactra | Td, then Menactra |
| A | 11313 | 10391 |
| C | 5059 | 2136 |
| Y | 3391 | 1331 |
| W135 | 4195 | 1339 |

## Study MTA-12: Td
	Safety

- 	Safety

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

## 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, |  | Td + Menactra, |  |
|   |  | Then Placebo |  | Then Placebo |  |
|   |  | Menactra
Injection site |  | Td 
Injection site |  |
| Reaction | Severity | % | 95% CI | % | 95% CI |
| Pain |   |  |  |   |   |
|   | Any | 52.9 | 48.4, 57.3 | 70.9 | 66.7, 74.8 |
|   | Mild | 42.2 | 37.8, 46.6 | 48.3 | 43.9, 52.8 |
|  
  | Moderate | 10.7 | 8.1, 13.7 | 22.4 | 18.8, 26.3 |
|  | Severe | 0.0 | 0.0, 0.7 | 0.2 | 0.0, 1.1 |

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

| 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 |  |  |
| Reaction | Severity | % | 95% CI | % | 95% CI |  |
| Redness | Any | 12.1 | 9.4, 15.2 | 11.1 | 8.5, 14.2 |  |
| Swelling | Any | 11.7 | 9.0, 14.8 | 13.1 | 10.3, 16.3 |  |
| Induration | Any | 17.0 | 13.9, 20.6 | 15.4 | 12.4, 18.9 |  |
| Pain | Any | 52.9 | 48.4, 57.3 | 53.5 | 49.0, 57.9 |  |
|  |  |  |  |  |  |  |

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

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

## Summary

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

## 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.

## 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

- 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