Regulatory Decision Summary for Comirnaty Omicron XBB.1.5

The purpose of this submission is to seek authorization for a new mRNA-based vaccine formulation Comirnaty Omicron XBB.1.5 (raxtozinameran, mRNA COVID-19 vaccine, monovalent), for active immunization against coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) in individuals 6 months of age and older. The recommended dosing regimen is proposed to be 3 doses for 6 months to <5 years of age not previously immunized (or complete the 3-dose regimen if they received one or two doses only) and one dose across all age groups, if immunized. Individuals over 12 years of age receive one dose regardless of immunization status at an interval of at least 3 to 6 months following the most recent dose of a COVID-19 vaccine. Individuals 5 to <12 years of age receive one dose regardless of immunization status at an interval of at least 6 months following the most recent dose of a COVID-19 vaccine.

Only non-clinical data was supplied to Health Canada to support the market authorization of the herein product. The safety and effectiveness of Comirnaty Omicron XBB.1.5 is extrapolated based on the following data, taken within the context of the current epidemiological context:

• Safety and effectiveness of Comirnaty (administered as a primary series and booster doses) in individuals 5 years of age and older.

• Extrapolation of safety data for participants ≥5 years to <12 years of age in Group 2 - Substudy D of Study C4591048 following administration of Comirnaty Original & Omicron BA.4/BA.5 vaccine at 10 mcg as a booster (fourth dose).

• Preliminary immunogenicity and safety data from participants in Cohort 2 (≥12 years of age) and Cohort 3 (≥18 years of age) of Study C4591044 following administration of Comirnaty Original & Omicron BA.4/BA.5 vaccine at 30 or 60 mcg as a booster (fourth dose).

• Preliminary immunogenicity and safety data for a subset of participants ≥6 months to <5 years of age in Group 2 - Substudy B of Study C4591048 following administration of Comirnaty Original & Omicron BA.4/BA.5 at 3 mcg as a booster (fourth dose).

• Estimates of current seroprevalence rates.

• Preclinical data.

Comirnaty

The safety and immunogenicity of the primary series and booster doses of Comirnaty has been extensively characterized in several clinical studies conducted globally. These data were previously supplied to Health Canada to support the authorization of Comirnaty as a 2-dose primary series and as a booster dose across several age groups. For further details, refer to the Regulatory Decision Summary (Food and Drug Regulations) documents dated (in chronological order): 2020-12-09, 2021-05-05, 2021-09-16, 2021-11-09, 2021-11-19, 2022-06-01, and 2022-09-09 respectively.

Comirnaty Original & Omicron BA.4/BA.5

The safety and immunogenicity booster doses of Comirnaty Original & Omicron BA.4/BA.5 has been characterized in several clinical studies. These data were previously supplied to Health Canada to support the authorization of Comirnaty Original & Omicron BA.4/BA.5 as a 2-dose primary series (in individuals >5 years of age) or as a 3-dose primary series (in children >6 months ≤5 years of age) and as a booster dose across several age groups. For further details, refer to the Regulatory Decision Summary (Food and Drug Regulations) documents dated (in chronological order): 2022-10-07, 2022-12-09, 2023-07-06, 2023-08-31.

The Comirnaty Omicron XBB.1.5 product is formulated and manufactured in the same way as the currently approved Comirnaty mono- and bivalent products in the Tris/Sucrose formulation. Overall, the similarities in the formulations are reflected in the coherence of the safety results across the clinical development program studies. Given the nearly identical formulations (variation only within the coding sequence), the safety of Comirnaty may be extrapolated to an mRNA platform directed against the variant of concern, subject to the herein submission, Comirnaty Omicron XBB.1.5.

Immunogenicity data accrued with the monovalent formulation, Comirnaty, alongside preliminary data accrued with the bivalent formulations, particularly Comirnaty Original & Omicron BA.4/BA.5, administered as booster doses suggest that Comirnaty Omicron XBB.1.5 will induce neutralizing antibodies against the currently circulating Omicron sub-lineages. Furthermore, through analogy, it is expected that this updated formulation will induce superior antibody responses to Omicron XBB.1.5 strain and non-inferior responses to the reference strain when compared to the previously approved formulations, as well as, it is expected to provide broader antibody response against circulating and emerging variants, while retaining cross-reactive immunity and cross-protection from severe illness caused by the reference strain and other variants.

With respect to the proposed posology, an analysis of immunogenicity data from COVID-19 vaccine-naïve subjects ≥18 to ≤85 years of age who had evidence of prior SARS-CoV-2 infection after a single 30 mcg dose of an investigational variant (Alpha/Delta)-modified bivalent Comirnaty (B.1.1.7 + B.1.617.2) formulation, encoding spike antigens for the Alpha and Delta SARS-CoV-2 variants, was provided from two clinical studies:

Study BNT162-17: “Phase II trial to evaluate the safety and immunogenicity of SARS-CoV-2 monovalent and multivalent RNA-based vaccines in healthy subjects”, which includes evaluation of the safety and immunogenicity of multivalent and monovalent Comirnaty in subjects ≥18 to ≤85 years of age.

Study C4591001: “Phase 1/2/3, placebo-controlled, randomized, observer-blind, dose-finding study to evaluate the safety, tolerability, immunogenicity, and efficacy of SARS-CoV-2 mRNA vaccine candidates against COVID-19 in healthy individuals”, which includes evaluation of the safety and immunogenicity of Comirnaty in subjects ≥12 years of age.

These data showed robust immune responses against the reference strain and Alpha, Delta and Omicron BA.5 variants. Notwithstanding the limitations of the cross-study comparisons, based on the variant neutralization results, a single dose of a more closely matched formulation in seropositive COVID-19 vaccine-naïve individuals would perform at least as well against the XBB-matched strain. And, given the current seroprevalence rates in Canada, immunization with a single dose of the XBB-targeted formulation is expected to lead to significant increases in serum neutralizing antibody responses and memory B-cell expansion against the Omicron XBB sub-lineages, as well as other emerging variants. The aforementioned limitations of the supportive data will be risk mitigated via the agreed upon Terms and Conditions imposed on the Drug Identification Number.

The proposed dosing intervals are supported by the reviewed clinical evidence within the context of the current seroprevalence rates. Based on this considerate, the current ‘on label’ dosing interval for the previous formulations is sustained.

Overall, safety data accrued with Comirnaty mono- and bivalent formulations suggests that, the safety profiles of Comirnaty, Comirnaty Original & Omicron BA.1 and Comirnaty Original & Omicron BA.4/BA.5 (primary series or booster doses) are comparable dose per dose and vaccination scheme per vaccination scheme. By extension, it is assumed that the safety profile of Comirnaty Omicron XBB.1.5 will be no different from that of the previously-approved formulations encoding for variants of concern Comirnaty Original & Omicron BA.1 and Comirnaty Original & Omicron BA.4/BA.5, respectively.

Inference of clinical data is in line with the current clinical considerations for COVID-19 mRNA-based formulations which incorporate the addition of a change to the coding sequence (active substance) related to the new variant of concern (Omicron XBB.1.5) to the current sequence (reference strain). No new safety concerns were identified in studies using the Comirnaty Original & Omicron BA.1 and Comirnaty Original & Omicron BA.4/BA.5 formulations when compared to Comirnaty. No deaths or adverse events of special interest including cases of myocarditis or pericarditis occurred. It should be noted that, the safety profile of Comirnaty and Comirnaty Original & Omicron BA.4/BA.5 is well characterized in the post-market setting. Based on these safety profiles it is anticipated that the safety of Comirnaty Omicron XBB.1.5 will bear no differences to these formulations. Safety concerns remain as those captured in the Comirnaty Omicron XBB.1.5 label.

Estimates of current seroprevalence rates

Cumulative data on comparative protection of immunity relative to previous infection only, vaccination only, and hybrid immunity suggests that individuals with hybrid immunity have the highest magnitude and durability of protection against all outcomes. Overall, rapidly accumulating epidemiologic and immunogenetic evidence pertaining to hybrid protection against Omicron infection suggests that vaccination among individuals with prior heterologous SARS-CoV-2 infection provides the greatest protection against severe outcomes as a result of reinfection with Omicron sub-lineages. Given the ever-evolving epidemiological context, an updated vaccine composition that contains constructs encoding the spike protein for Omicron XBB sub-lineages (the most antigenically distinct SARS-CoV-2 variant of concern to date), may provide a broader antibody response against circulating and emerging variants, while retaining cross-protective immunity against severe disease. In this respect, the XBB.1.5 formulation (Omicron XBB.1.5) incorporates the change to the coding sequence (Omicron sub-lineage, active substance) related to the new variant of concern (XBB.1.5).

Pre-clinical data

Pre-clinical data indicate that while the T-cell response is not as impacted by variant-specific mutations, Comirnaty Omicron XBB.1.5 formulation induced the strongest neutralizing antibody response against all strains tested, and was higher in naïve animals compared to vaccine experienced animals. The data provide proof-of-concept for clinical use that XBB.1.5-modified vaccines administered in vaccine experienced or naïve animals produced an immune response against matched and antigenically related strains, including the currently circulating EG.5 Omicron variant. Collectively, the non-clinical package was considered supportive of the proposed drug product for use in the clinical setting. The vaccine is anticipated to elicit potent immune responses, particularly those mediated by neutralizing antibodies, with high frequencies of T cells whether administered as booster dose or a primary series. As well, a more closely strain-matched vaccine formulation is anticipated to generate the most potent immune responses that are likely to translate into improved effectiveness, with no new safety concerns from a preclinical perspective. Across the data generated to date with the Comirnaty portfolio mono- and bivalent formulations, pre-clinical data have reliably predicted the immunological responses trends in humans, and this speaks to the translatability of the non-clinical data as supportive to use in naïve and/or vaccine experienced humans.

Given the aforementioned data from the Comirnaty Original & Omicron BA.4/BA.5 formulations administered in individuals 6 months of age and older, combined with accumulated experience with the Comirnaty monovalent formulation, along with the understanding that the Comirnaty Omicron XBB.1.5 vaccine is manufactured by the same process as the currently approved formulations, it is reasonable to generalize the inferred safety and effectiveness of Comirnaty Omicron XBB.1.5 across the age groups for which the indication is being sought.

Clinical data will be submitted by the Sponsor at a later date in support of the herein authorization. These flexibilities are justifiable given that it is not feasible to conduct clinical studies rapidly enough to respond to the emergence of SARS-CoV-2 variants that may evade the immune response conferred by previously approved vaccines. This is important in light of the overall rapidly evolving epidemiological context which supports the need for a dose of a targeted formulation to protect against the circulating variant of concern, XBB.1.5.

Planned post-market studies are expected to provide additional validation of the immune response. Data outcomes from Study C4591048, substudies A and E and Study C4591054, substudies A and B conducted with the specific XBB.1.5 formulation will be required as Terms and Conditions for the herein authorization:

• Study C4591048, Substudy A: Evaluates the safety, tolerability, and immunogenicity of a 3-dose series of Comirnaty Original & Omicron BA.4/BA.5 and a 4^th dose of XBB.1.5 at 3, 6 or 10 mcg in 6 months through 5 years of age in COVID-19 vaccine-naïve subjects.

• Study C4591048, Substudy E: Evaluates the immunogenicity and safety of a single dose of the age-appropriate authorized dose of Comirnaty Omicron XBB.1.5 in infants and children 2 to <12 years.

• Study C4591054: Is a Phase 2/3 study that will investigate the safety, tolerability, and immunogenicity of BNT162b2 RNA-based vaccine candidates for SARS-CoV-2 new variants in healthy individuals.

Risk Management Plan

An updated Core Risk Management Plan (RMP) and a Canadian RMP Addendum were included in the submission for Comirnaty Omicron XBB.1.5. The RMP is designed to describe known and potential safety issues, to present the monitoring plan and when needed, to describe measures that will be put in place to minimize risks associated with the product. Upon review, the RMP was considered to be acceptable and identified appropriate monitoring (pharmacovigilance) activities and risk minimization measures for Comirnaty Omicron XBB.1.5 based on the known safety profiles of Comirnaty, Comirnaty Original/Omicron BA.1 and Comirnaty Original & Omicron BA.4/BA.5. This included providing information in the Product Monograph and identifying populations where more data are needed. The RMP will be updated to reflect additional safety information as this is collected. In addition to regulatory requirements for post-market monitoring, Terms and Conditions have been imposed for the submission of periodic safety update reports/periodic benefit risk evaluation reports and RMPs to Health Canada. Results related to safety and effectiveness from ongoing and planned studies will be submitted as they become available.

Conclusion

Based on the totality of the information, the benefit-risk profile for Comirnaty Omicron XBB.1.5 is considered favorable in individuals >6 months of age.

For further details about Comirnaty Omicron XBB.1.5, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.