Summary Basis of Decision for Menveo ™

The clinical development plan was built upon prior regulatory guidance and published information reported for clinical studies with licensed polysaccharide and conjugate vaccines for Streptococcus pneumoniae, Haemophilus influenzae type b and N. meningitidis, as well as upon the sponsor's previous experience with Menjugate and also an early generation meningococcal A/C vaccine. The clinical development plan also took into consideration recent data used to register Menactra^® in the United States for subjects aged 2 years and older.

Approval of Menactra^® was based upon demonstration of immunologic equivalence between Menactra^® and the licensed quadrivalent polysaccharide vaccine, Menomune^®, using serum bactericidal antibody responses as the measure of immunogenicity and inferred vaccine efficacy. Because of the relatively low incidence of meningococcal disease, the effectiveness of meningococcal vaccines is demonstrated through an assay which measures the serum bactericidal activity from the serum of vaccine recipients. This in vitro assay tests the ability of vaccine-induced bactericidal antibodies to kill meningococci, when in the presence of human complement. The original studies that identified the protective threshold of ≥1:4 against meningococcal disease were conducted with assays based on human complement. Accordingly, the human serum bactericidal assay (hSBA) was used exclusively in the development of the MenACWY vaccine.

3.3.1 Clinical Efficacy

The New Drug Submission for licensing of Menveo contained seventeen completed and two ongoing clinical studies. Immunogenicity data establishing clinical efficacy was derived from four main studies, two pivotal and two supportive studies, for the proposed indication. There were three primary immunogenicity objectives for these studies:

• Assess non-inferiority versus a licensed comparator (Menomune^® or Menactra^®);
• Establish clinical lot consistency for Menveo;
• Establish non-interference with age-appropriate vaccines on the immunogenicity of Menveo due to:
  1. concomitant vaccination with Tetanus/Diphtheria/acellular Pertussis (Tdap) and Human Papillomavirus (HPV) vaccine;
  2. sequential vaccination one month following the Tdap vaccine.

In all studies conducted, serum bactericidal activity using hSBA was selected in determining immunogenicity against the four meningococcal serogroups included in the Menveo vaccine. The following endpoints were included in the analyses of all studies conducted:

• Immunogenicity response one month after vaccination, defined as:
  1. for a subject with a pre-vaccination hSBA titre <1:4 at baseline (i.e. seronegative), immunogenicity was defined as a post-vaccination hSBA titer ≥1:8;
  2. for a subject with a pre-vaccination hSBA titre ≥1:4 (i.e. seropositive), immunogenicity was defined as a post-vaccination hSBA titre of at least four times the pre-vaccination titre;
• hSBA titre ≥1:8;
• hSBA titre ≥1:4;
• hSBA Geometric Mean Titers (GMTs);
• Reverse Cumulative Distribution Function (RCDF) curves.

The first pivotal study (V59P13) was a phase III, observer-blind, comparative study versus a licensed control, Menactra^®, conducted in adolescents aged 11 to 18 years and adults aged 19 to 55 years. The objective of the study was to demonstrate consistency of an immune response amongst three lots of Menveo, as measured by hSBA, at one month post-vaccination following a single-dose administration in healthy subjects 11 to 18 years of age. In addition, this study also sought to compare the immunogenicity of a single dose of Menveo to that of Menactra^® (quadrivalent meningococcal conjugated vaccine) by assessing the percentage of subjects with a seroresponse directed against N. meningitidis serogroups A, C, W-135, and Y, at one month post-vaccination. A superiority analysis was prespecified in the protocol in the event that non-inferiority was demonstrated.

The study design consisted of 3539 subjects (2663 Menveo subjects and 876 Menactra^® subjects) randomized to receive either Menveo Lot 1, Menveo Lot 2, Menveo Lot 3, or Menactra^®. One 0.5 mL dose of Menveo or 0.5 mL dose of Menactra^® (4 µg of polysaccharie conjugated to diphteria toxoid) was administered by intramuscular injection. Study findings showed a consistent immunogenicity response across the three different Menveo lots for all four serogroups A, C, W-135, and Y, based on the ratio of GMTs for each of the pairwise comparisons. In addition, when comparing the immunogenicity efficacy between the Menveo vaccine to that of the Menactra^® vaccine, Menveo demonstrated to be non-inferior to Menactra^® for all four serogroups in both adolescents and adults using the primary endpoint (hSBA seroresponse). Furthermore, statistically higher seroresponse rates were demonstrated for serogroups A, W, and Y in subjects aged 11 to 18 years and for serogroups C, W and Y in subjects aged 19 to 55 years. It should be noted however, an observed statistically higher immune response does not necessarily imply a clinical superiority, that is to say a difference in clinical efficacy.

The second pivotal study V59P18, which is currently ongoing, is a Phase III, single-centre, open-label, controlled, randomized study designed to evaluate the immunogenicity of Menveo when administered either alone or concomitantly with a combined tetanus, reduced diphteria toxoid, acellular pertussis vaccine (Tdap) Boostrix^® and a quadrivalent human papillomavirus recombinant vaccine (HPV) Gardasil^®. Based on the interim report provided, this study was conducted in a total of 1620 adolescents aged 11 to 18 years of age who were randomized to one of the three following groups:

• Group 1 received Menveo concomitantly with Tdap and HPV (first injection only) all on Day 1. The second and third HPV injections were administered two and six months after the first injection (Day 1).
• Group 2 received Menveo on Day 1, then Tdap on Day 31. The first injection of the HPV vaccine was administered on Day 61 followed by the second and third injections given at two and six months following the first HPV injection.
• Group 3 received Tdap at Day 1, then Menveo at Day 31. The first injection of the HPV vaccine was administered on Day 61 followed by the second and third injections given at two and six months following the first HPV injection.

Prior to and one month after vaccination with either Menveo or Tdap, serum samples were collected to assess antibody responses. Results showed immune responses to A, C, and Y were non-inferior but immune responses to serogroup W were statistically lower when Menveo was administered with Tdap and HPV. Moreover, responses to serogroups W and Y were statistically lower when Menveo was administered sequentially one month after receipt of Tdap. However, despite the non-inferiority criterion was not met for serogroup W among subjects lacking bactericidal antibodies at baseline (baseline hSBA titer < 1:4), the percentage of immunogenicity in subjects who received Menveo one month after Tdap was high (90%). In addition, one month following Menveo administration, 95% of subjects having received Menveo one month after Tdap had an hSBA titer ≥ 1:8 for serogroup W versus 99% of subjects receiving Menveo one month before Tdap.

In terms of the Tdap immunogenicity analyses, non-inferiority of concomitant administration of Tdap and Menveo to Tdap alone has not been established. Concomitant administration of Menveo and Tdap vaccines compared to Tdap administered alone demonstrated non-inferiority for the diphtheria toxoid (DT), tetanus toxoid (TT), and the pertussis toxoid (PT), but not for filamentous haemagglutinin (FHA) and pertactin (PRN). A reduction in antibody levels for PT and PRN was also seen within the analysis of another supportive study (V59P11) conducted by the sponsor. These two studies suggest a possible interference in the immune response to pertussis antigens with co-administration of Menveo and/or HPV with Tdap. However, although the concomitant non-inferiority criterion was not met for FHA and PRN, the antipertussis GMCs were robust for all pertussis antigens both when Tdap was administered concomitantly and when it was administered alone. Furthermore, the immunogenicity of the HPV vaccine, Gardasil^®, was not yet evaluated in this study. Given the V59P18 study results are based upon interim data only, and the study did not control type I error rate for testing three primary non-inferior hypotheses, caution should be taken when interpreting these study results.

Study V59P6 was a Phase II, randomized, single-blind, non-inferiority study conducted among adolescents aged 11 to 17 years. The objective of this supportive study was to compare the immune response of one dose of either adjuvanted Menveo or unadjuvanted Menveo (final formulation) compared to the immunogenicity of a single dose of a licensed comparator vaccine, Menomune^®. In addition, this study also sought to assess persistence of the immune response at one year post-vaccination.

The study design consisted of subjects receiving either one injection of Menveo (with or without aluminum phosphate adjuvant) or one injection of the Menomune^® vaccine. Immune responses were assessed at one month and at one year post-vaccination. Study findings showed that at twenty-eight days post-vaccination, Menveo did demonstrate non-inferiority to Menomune^® for all four serogroups, based on seroresponse, hSBA titre ≥ 1:8 and GMTs. In addition, Menveo was also statistically superior to Menomune^® for all serogroups, based on seroresponse and GMTs. However, it should be noted once again that an observed statistically higher immune response does not necessarily imply a clinical superiority in terms of efficacy.

At one-year post-vaccination, study results showed that the persistence of bactericidal antibodies was maintained for all four serogroups. Conversely, results also showed that the percentage of adolescents with hSBA ≥ 1:4 for serogroup A over a 12-month decreased from 84% to 36% (48% drop) in the Menveo (final formulation) group, suggesting that the rapid waning of antibodies against serogroup A occurred. Similarly, the decrease in the responder rate in children from 1 to 12 months was most pronounced for serogroup A in two other supportive studies. All three of these studies suggest a rapid waning of antibodies against serogroup A occurring at 12 months in adolescents and children.

When comparing the difference in the immune response at one month between the adjuvanted and unadjuvanted formulations of Menveo, the result was minimal. Consequently, this observation provided further support to the choice of a non-adjuvanted vaccine as the final formulation.

Study V59P11 was a Phase III, multi-centre, observer blind, controlled randomized study conducted among healthy subjects aged 11 to 25 years. The objective of this supportive study was to compare the immunogenicity of the co-administration of one dose of Tdap Boostrix^® vaccine to one dose of the Menveo vaccine. A total of 1072 subjects were enrolled of whom 1069 were randomized to receive co-administrations of either Tdap and Menveo vaccines, or Tdap vaccine plus a placebo vaccine, or Menveo plus a placebo vaccine. Subjects were administered each of the concomitant vaccines in different arms. Serum samples were drawn before vaccination, at Day 1 and post-vaccination, at Day 29. From Day 30 to Day 181, only safety data was collected.

Study results showed for subjects who received the Tdap and Menveo vaccines concomitantly that there was no evidence of an effect on the immune response to the Menveo vaccine. However, in regards to the effect of co-administration of Menveo with Tdap on the immune response to the Tdap vaccine, results showed a lower response against the pertussis antigens which is in line with the findings indentified in the V5P18 study. The clinical significance of this observed difference remains unclear.

In study V59P7, a second vaccination with Menveo at 6 or 12 months after the first dose in children aged 36 to 59 months showed a robust booster response for all serogroups, which was higher when the interval for vaccination was 12 months compared to 6 months.

In conclusion, the above studies did demonstrate that Menveo was non-inferior to Menactra^® or Menomune^®, and there was consistent immunogenicity across different lots. In addition, Menveo can also be administered in combination with Tdap and HPV vaccines without interference in the immune response to Menveo. However, 12-month immunogenicity data suggested that a rapid waning of antibodies against serogroup A occurred with Menveo in healthy adolescents although the immunogenicity for serogroup A was comparable between Menveo and Menomune^® at 12 months post-vaccination. In addition, a single dose of the Menveo vaccine can effectively induce immunologic memory in children. Yet, the need for, and timing of a booster dose of the Menveo vaccine has not been determined.

The studies provide some evidence that MenACWY can be administered either concomitantly with Tdap and HPV, without a significant clinical impact on the immune response relative to MenACWY administered alone. The non-inferiority criteria of the sequential administration of Menveo after Tdap to Menveo alone were not met. The non-inferiority of concomitant administration of Tdap with Menveo to Tdap alone has not been shown as concomitant administration of MenACWY with Tdap led to a reduction in the antibody levels to pertussis antigens.

3.3.2 Clinical Safety

A total of 6724 subjects aged 11 to 65 years were exposed to Menveo as a single first vaccination or a second vaccination. Safety data for Menveo was analyzed from 6185 subjects aged 11 to 65 years, and comparisons were made with 1757 subjects who received Menactra^®, 209 subjects who received Menomune^® and 892 subjects receiving Tdap. Based on the safety data submitted, the following conclusions were drawn. The local reactogenicity profile of Menveo was comparable to Menactra^®, but severe local reactions (induration and erythema > 50 mm) were more often reported and duration of pain was possibly longer in the Menveo group. In addition, the local reactogenicity of Menveo showed no significant clinical impact when given with or after other routine administered vaccines, such as the Tdap and HPV vaccine. Overall, systemic reactions were generally mild and of short duration, similar to other licensed vaccines, and usually resolved within fourteen days post-vaccination. 

The incidence of unsolicited adverse events was considered unrelated to the study vaccine. The types of events and their frequencies were similar in the Menveo and the comparator vaccines. Only one serious adverse event (SAE) was reported as possibly related to Menveo, which was a spontaneous abortion that occurred on Day 44 post-vaccination. To enhance the pharmacovigilance monitoring of these events, the sponsor plans to establish a pregnancy registry to monitor foetal outcomes of pregnant women exposed to Menveo, after licensure. Data from this registry will be submitted to Health Canada on a regular basis.