Summary Basis of Decision for Nimenrix

Clinical Pharmacology

Invasive meningococcal disease is an acute and serious illness caused by the bacterium Neisseria (N.) meningitidis. Invasive disease may lead to meningitis, in which the bacteria infect the fluids and membranes (called meninges) covering the brain and the spinal column, or septicemia. In Canada, five of the N. meningitidis (A, B, C, W-135, and Y) are responsible for the majority of disease.

Anti-capsular meningococcal antibodies protect against meningococcal diseases via complement-mediated bactericidal killing. Nimenrix induces the production of bactericidal antibodies against capsular polysaccharides of serogroups A, C, W-135 and Y when measured by assays using either rabbit complement serum bactericidal assay (rSBA) or human complement serum bactericidal assay (hSBA). By conjugating capsular polysaccharide to a protein carrier that contains T-cell epitopes, meningococcal conjugate vaccines like Nimenrix change the nature of immune response to capsular polysaccharide from T-cell independent to T-cell dependent.

The pharmacodynamics of Nimenrix were assessed through the analysis of immunogenicity described in the Clinical Efficacy section. Pharmacokinetic studies are not directly applicable to vaccines.

For further details, please refer to the Nimenrix Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

Invasive disease caused by the N. meningitidis serogroups A, C, W-135 and Y occurs at relatively low rates as endemic disease and in unpredictable and short-lived outbreaks of epidemic illness thus making pre-authorization efficacy trials unfeasible. The World Health Organization's (WHO) position paper (Meningococcal vaccines, November 2011) indicated that "Due to the relatively low incidence of meningococcal disease, pre-authorization clinical efficacy studies may not be feasible. Meningococcal polysaccharide and protein conjugate vaccines are authorized based on evidence of an immune response in vaccinated subjects using serum bactericidal activity (SBA) as the immunologic correlate of protection". Therefore, meningococcal conjugate vaccines have been authorized based on immunological correlates of protection.

The efficacy of Nimenrix was inferred from the demonstration of immunologic non-inferiority to authorized meningococcal vaccines. Immunogenicity was measured by using rSBA or hSBA which are biomarkers for protective efficacy against meningococcal serogroups A, C, W-135 and Y.

Pivotal Studies

Four pivotal studies provided evidence of immunogenicity in support of the authorization of Nimenrix. All four studies were open, randomized, and active-controlled primary vaccination studies designed to demonstrate in four different age groups the non-inferiorities and safety of Nimenrix as compared to the comparator vaccines below:

1. Study 039: Nimenrix versus (vs.) Meningitec in toddlers (12-23 months of age).
2. Study 081: Nimenrix vs. Menjugate in children (2-10 years of age).
3. Study 071: Nimenrix vs. Menactra in adolescents and adults (10-25 years of age).
4. Study 035: Nimenrix vs. Mencevax-ACWY in adults (18-55 years of age).

Study 039 - Toddlers (12-23 months of age)

The co-primary objectives of Study 039 for immunogenicity were:

• to demonstrate the non-inferiority of Nimenrix conjugate vaccine as compared to Meningitec (a conjugate vaccine for N. meningitidis serogroup C), in terms of serogroup C serum bactericidal antibodies (rSBA-MenC);and
• to demonstrate the immunogenicity of Nimenrix for the N. meningitides serogroups A, W-135, and Y, in terms of bactericidal antibodies to N. meningitides serogroups A, W-135, and Y.

The criterion for non-inferiority for serogroup C was that the lower limit of the two-sided standardized asymptotic 95% confidence interval (CI) for the group difference in the percentages of subjects with rSBA-MenC titre ≥1:8 was greater than or equal to the pre-defined limit of  -10%. The criterion for immunogenicity for serogroups A, W-135, and Y was that the lower limit of the two-sided exact 95% CI for the Nimenrix group proportion of subjects with rSBA titre ≥1:8 was greater than or equal to the pre-defined limit of 90%. Both non-inferiority objectives were met.

Study 081 - Children (2-10 years of age)

The primary objective of Study 081 was to demonstrate non-inferiority of Nimenrix compared to the conjugate vaccine Menjugate in terms of serum bactericidal antibody vaccine response to N. meningitidis serogroup C.

The non-inferiority of Nimenrix compared to Menjugate in terms of serum bactericidal antibody vaccine response to rSBA-MenC, one month after vaccination was demonstrated as the lower limit of the 95% CIs on the difference between Nimenrix and the Menjugate group was -5.25%, which was above the pre-specified non-inferiority limit of -10%. Note: Nimenrix met the criterion for non-inferiority for serogroup C only, as Menjugate is a meningococcal serogroup C conjugate vaccine.

Study 081 demonstrated the non-inferiority of Nimenrix when compared to Menjugate for rSBA-MenC titres and significantly higher rSBA antibody responses were induced against serogroups A, W-135 and Y.

Study 071 - Adolescents and Adults (10-25 years of age)

The primary objective of Study 071 was to demonstrate the non-inferiority of Nimenrix when compared to Menactra (vaccine for N. meningitidis serogroups A, C, W-135, and Y)in terms of the percentage of subjects with serum bactericidal activity (using human complement) against N.meningitidis serogroup A (hSBA-MenA), hSBA-MenC, hSBA-MenW-135, and hSBA-MenY with respect to vaccine response one month after vaccination. Vaccine response was defined as an hSBA titre of ≥1:8 in subjects initially seronegative (hSBA titre <1:4) and as a 4-fold increase in titre in subjects initially seropositive (hSBA titre >1:4).

For each serogroup, the criterion for non-inferiority was that the lower limit of the two-sided 95% CI for the percentage of subjects with hSBA vaccine response one month after vaccination (Nimenrix - Menactra) was greater than or equal to the pre-defined clinical limit of -10%.

Nimenrix was demonstrated to be immunologically non-inferior to Menactra in terms of the percentage of subjects with hSBA-MenA, hSBA-MenC, hSBA-Men-W-135, and hSBA-MenY vaccine response one month after vaccination (all the lower limits of the two-sided 95% CI for the difference between groups were ≥-10%).

Study 035 - Adults (18-55 years of age)

Study 035 had multiple primary objectives including the demonstration of non-inferiority of the bactericidal antibody (rSBA) vaccine response induced by Nimenrix (from the 3 manufactured lots pooled) compared to Mencevax (vaccine for N. meningitidis serogroups A, C, W-135, and Y).

Nimenrix met the criteria for non-inferiority when compared to Mencevax-ACWY in terms of the percentage of subjects with rSBA-MenA, rSBA-MenC, rSBA-MenW-135 and rSBA-MenY vaccine response one month after the vaccination (all the lower limits of the two-sided 95% CI for the difference between groups were ≤10%).

Supportive Studies

Co-administration with Other Vaccines

Additional data from the pivotal studies as well as further supportive studies supported the use of Nimenrix when administered concomitantly with other common vaccines, including: Fluarix (seasonal influenza vaccine); Twinrix (hepatitis A and hepatitis B vaccine); Synflorix (10-valent pneumococcal conjugate vaccine); and Priorix Tetra (measles, mumps, rubella, and varicella vaccine). Nimenrix can also be given concomitantly with combined diphtheria-tetanus-acellular pertussis vaccines in the second year of life, including combination DTPa vaccines with hepatitis B, inactivated polio or Haemophilus influenza Type b, such as Infanrix hexa (combined DTPa, Hepatitis B, Poliovirus and Haemophilus Influenzae Type b vaccine).

The immunogenicity and safety of Nimenrix was evaluated when sequentially administered or co-administered with Infanrix hexa (DTPa-HBV-IPV/Hib vaccine) in the second year of life. The administration of Nimenrix one month after Infanrix hexa resulted in lower MenA, MenC and MenW-135 rSBA geometric meant titres (GMTs). The clinical relevance of this observation is unknown, as ≥99.4% of subjects (n = 178) had rSBA titres ≥8 for each group (A, C, W-135, Y).

The non-inferiority of Nimenrix co-administered (co-ad) with Infanrix hexa compared to Nimenrix administered alone was demonstrated: the lower limit of the two-sided standardized asymptotic 95% CI for the group difference (Co-ad minus Nimenrix) in the percentages of subjects with rSBA titre ≥8 was above the pre-defined clinical limit of -10% for the four serogroups.

The non-inferiority of Infanrix hexa co-administered with Nimenrix compared to Infanrix hexa alone in terms of GMCs of antibodies to pertussis toxoid (PT), filamentous haemagglutinin (FHA) and pertactin (PRN) was demonstrated as the lower limit of the two-sided 95% CI on the adjusted GMC ratios for anti-PT, anti-FHA and anti-PRN were above the pre-defined limit of 0.67. The non-inferiority of the co-administration was also demonstrated in terms of percentages of subjects with antibody concentrations to anti-PRP antibody concentration for Haemophilus influenza type b vaccine ≥1.0 mg/mL and to hepatitis B surface antigen (HBsAg) ≥10 mIU/mL the lower limit of the two-sided 95% CI around the difference between groups (Co-ad minus Infanrix hexa) was above the pre-specified limit of -10%.

As the data suggest that the immune response to Nimenrix may be lowered when it is administered one month after Infanrix hexa, recommendations have been included in the Product Monograph for Nimenrix suggesting that whenever possible, Nimenrix and a tetanus toxoid (TT) containing vaccine, such as a DTPa-HBV-IPV/Hib vaccine, should be co-administered or Nimenrix should be administered at least one month before the TT-containing vaccine.

The Product Monograph for Nimenrix also states that one month after co-administration with Synflorix (a 10-valent pneumococcal conjugate vaccine), lower Geometric Mean antibody Concentrations (GMCs) and opsonophagocytic assay (OPA) antibody GMTs were observed for one pneumococcal serotype (18C conjugated to tetanus toxoid carrier protein). The clinical relevance of this observation is unknown. This finding is not unexpected when many vaccine antigens are co-administrated. There was no impact on the co-administration of the other nine pneumococcal serotypes.

Persistence and Immune Memory Studies

In Study 059, the persistence of the immune response was evaluated by hSBA after vaccination with Nimenrix compared to vaccination with Menactra in adolescents and adults 11-25 years of age primed in Study 052.

At one year following the primary vaccination 76% of the subjects were included in the evaluation. The percentage of subjects 11-25 years of age with hSBA antibody titres ≥1:8 in serogroups MenC, MenW-135, and MenY ranged from 94.9% to 98.5% for those subjects that received Nimenrix. In comparison, subjects that received Menactra had MenC, MenW-135, and MenY hSBA titres ≥1:8 that ranged from 73.3%-86.7%. In the MenA serogroup, the percentage of subjects with hSBA antibody titres ≥1:8 was 29.1% in the Nimenrix group and 31.3% in the Menactra group.

For all four serotypes (A, C, W, Y), the persistence of the antibodies elicited by Nimenrix and Menactra was comparable.

Study 021, subjects previously vaccinated with a plain meningococcal polysaccharide vaccine were immunized with Nimenrix, and an increase in rSBA GMTs were observed for all four serogroups in these individuals.

Ongoing Studies

Ongoing extension studies will monitor persistence of the immune response.

In addition, ongoing Study 085 is currently underway to evaluate the immunogenicity of Nimenrix in adults >55 years of age.

The immunogenicity and safety of a booster dose 4 years after vaccination of Nimenrix will be evaluated in study 039 follow up period.

Special Populations

It may be expected that in patients receiving immunosuppressive treatment or patients with immunodeficiency, an adequate immune response may not be elicited.

Immunogenicity has not been assessed in patients with increased susceptibility to meningococcal infection due to conditions such as terminal complement deficiencies and anatomic or functional asplenia. In these individuals, an adequate immune response may not be elicited.

The immunogenicity in patients under the age of 12 months and over the age of 55 years has not been established.

For more information, refer to the Nimenrix Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety evaluation for Nimenrix was based on a pooled analysis of 8,108 subjects who had been vaccinated with one dose of Nimenrix in clinical studies. The pooled analysis included data from 2,237 toddlers (12 months to 23 months), 1,809 children (2 to 10 years), 2,011 adolescents (11 to 17 years), and 2,051 adults (>18 years).

Pivotal Studies

The pivotal clinical studies are described in the Clinical Efficacy section.

Study 039 - Toddlers (12-23 months)

In Study 039, healthy toddlers 12 through 23 months of age were administered either:

• 1 dose of Nimenrix.
• 1 dose of Nimenrix co-administered with a first dose of Priorix-Tetra (measles, mumps, rubella, and varicella vaccine).
• 1 dose of Priorix-Tetra.
• 1 dose of Meningitec (a conjugate vaccine for N. Meningitidis serogroup C).

The safety data of Nimenrix was comparable with Meningitec in toddlers 12 to 23 months, except for local reactions: redness >30 mm (4.4% - Nimenrix vs. 0.8% - Meningitec); and swelling >30 mm (4.1% - Nimenrix vs. 0.8% - Meningtec).

Irritability was the most frequently reported solicited general symptom in the 4 groups (50.7% in the Nimenrix + Priorix-Tetra group; 43.5% in the Meningitec group; 40.9% in the Nimenrix group; and 38.7% in the Priorix-Tetra group).

Study 081 - Children (2-10 years)

In Study 081, healthy children 2 to 10 years of age were administered 1 dose of Nimenrix or 1 dose of Menjugate (a conjugate vaccine for N. Meningitidis serogroup C).

2 to 5 years

In subjects 2 to 5 years of age, the reactogenicity profile of Nimenrix was comparable with Menjugate. During the 4-day post-vaccination period, redness was the most frequently reported solicited local symptom in each group (35.2% - Nimenrix and 39.6% - Menjugate).

Irritability was the most frequently reported solicited general symptom in each group (15.4% - Nimenrix and 11.3% - Menjugate). Drowsiness was also reported (14.2% - Nimenrix and 11.3% - Menjugate). Fever ≥37.5°C was reported by 5.6% of the subjects in the Nimenrix group and 5.7% of the subjects in the Menjugate group. The majority of fevers were measured by the rectal route (66.7% - Nimenrix group and 100% - Menjugate).

6 to 10 years

In subjects 6 to 10 years of age, the reactogenicity profile of Nimenrix was comparable with Menjugate with the exception of headache (16.2% - Nimenrix and 4.0% - Menjugate).

During the 4-day post-vaccination period, pain was the most frequently reported solicited local symptom in each group (43.9% - Nimenrix and 54.0% - Menjugate).

Fatigue was the most frequently reported solicited general symptom in each group (22.3% - Nimenrix and 22.0% - Menjugate). Fever ≥37.5°C was reported in 6.8% of the subjects in the Nimenrix group and 2.0% of the subjects in the Menjugate group.

Study 071 - Adolescents and Adults (10-25 years)

In Study071, healthy subjects 10 to 25 years of age were administered 1 dose of Nimenrix or 1 dose of Menactra (ACWY).

The reactogenicity profile of Nimenrix was comparable with Menactra with the exception of Grade 3 pain (2.4% Nimenrix and 0.6% - Menactra).

The most common solicited local symptom during the 4-day post-vaccination period was pain at the injection site, reported by 51.4% and 55.4% of subjects in the Nimenrix and Menactra groups, respectively.

The incidence of redness at the injection site was 25.8% and 20.3% of subjects in the Nimenrix and Menactra groups, respectively. The incidence of swelling was 19.1% in the Nimenrix group and 13.5% in the Menactra group. The majority of these events were Grade 1 in intensity. Grade 3 events of redness (i.e. >50 mm in diameter) were reported by 3 and 6 subjects in the Nimenrix and Menactra groups, respectively. Grade 3 events of swelling (i.e. >50 mm in diameter) were reported by 3 subjects for each of the two vaccine groups.

The most common solicited general symptom was fatigue with an incidence of 27.3% to 29.2% across the two vaccine groups. Headache was reported by 25.5% to 26.4% and gastrointestinal symptoms by 13.1% to 13.5% of subjects across the two vaccine groups.

Study 035 - Adults (18-55 years of age)

In Study035, healthy adults 18 through 55 years of age were administered either:

• 1 dose of Nimenrix;
• 1 dose of Mencevax-ACWY (polysaccharide) vaccine; or
• 1 dose of Nimenrix co-administered with an authorized influenza vaccine, Fluarix.

In subjects 18-55 years of age, the safety data for Nimenrix was comparable with Mencevax-ACWY in terms of Grade 3 general reactions. The reported Grade 3 solicited local reactions in terms of redness & swelling >50mm were 1.3% vs. 0% for Nimenrix and Mencevax ACWY, respectively.

During the 4-day post-vaccination period, pain was the most frequently reported solicited local symptom in each group (21.9% in the Nimenrix + Fluarix group, 19.4% in the Nimenrix group, and 13.5% in the Mencevax-ACWY group). Headache was the most frequently reported solicited general symptom in each group (16.3% - Nimenrix, 14.2% - Mencevax-ACWY, and 13.3% in the Nimenrix + Fluarix group).

Supportive Studies

Co-administration with Other Vaccines

Co-administration with other vaccines, including: Fluarix (unadjuvanted seasonal influenza vaccine); Twinrix (hepatitis A and hepatitis B vaccine); and Priorix Tetra (measles, mumps, rubella, and varicella vaccine) revealed a safety profile similar to that revealed a safety profile similar to that for the vaccines alone or Nimenrix alone.

Overall Analysis of Safety

Administration of the Nimenrix vaccine was shown to be generally well-tolerated and no safety signals were identified in the clinical program. All serious adverse events (SAEs) were considered not related to vaccination and resolved without sequelae, with exception of five SAEs reported in three subjects vaccinated with Nimenrix which were considered as causally related to vaccination. These five events were as follows: abdominal pain and gastritis; concussion and syncope; floppy infant; blighted ovum; and convulsion. No Guillain-Barré Syndrome (GBS) cases were reported during the clinical development of Nimenrix. One SAE reported during the conduct of clinical studies was that of death (i.e. drowning). This event was not considered related to vaccination.

There is limited experience with use of Nimenrix in pregnant women. Animal studies with Nimenrix do not indicate direct or indirect harmful effects with respect to fertility, pregnancy, embryo/fetal development, parturition or post-natal development; however, Nimenrix should be used during pregnancy only when clearly needed and in cases where the possible advantages outweigh the potential risks for the fetus.

The safety of Nimenrix when administered to breastfeeding women has not been evaluated. It is unknown whether Nimenrix is excreted in human breast milk; therefore, Nimenrix should only be used during breast-feeding when the possible advantages outweigh the potential risks.

Appropriate warnings and precautions are in place in the approved Nimenrix Product Monograph to address the general safety concerns.

Although Nimenrix contains tetanus toxoid, this vaccine does not substitute for tetanus immunization.

A more rapid waning of serum bactericidal antibody titres against MenA than for other serogroups (C, W-135, Y) has been observed when using human complement in the assay. In individuals expected to be at particular risk of exposure to MenA and who received a first dose of Nimenrix more than one year earlier, consideration may be given to administering a second dose of Nimenrix. Available data indicate that a second dose will elicit an anamnestic (memory) immune response to all four meningococcal types in the vaccine. Currently there is very limited information available on the safety of a second dose of Nimenrix.

For more information, refer to the Nimenrix Product Monograph, approved by Health Canada and available through the Drug Product Database.

A Risk Management Plan (RMP) for Nimenrix was submitted by GlaxoSmithKline Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will put in place to minimize risks associated with the product. Due to limited information regarding vaccine effectiveness, post-market surveillance will be particularly important. The need for a Risk Minimization Plan will be re-evaluated by GlaxoSmithKline Inc. should a safety signal be detected from any of the ongoing clinical studies as well as from the planned post-authorization pharmacovigilance activities described in this RMP.