Summary Basis of Decision for mNexspike

Clinical Pharmacology

The nucleoside-modified messenger ribonucleic acid (mRNA) in mNexspike, formulated in lipid particles, encodes the membrane-bound, linked N-terminal domain (NTD) and receptor-binding domain (RBD) of the spike glycoprotein from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains. These are known to contain the immuno-dominant epitopes for neutralizing antibody immune responses. After intramuscular injection, cells take up the lipid nanoparticle, effectively delivering the mRNA sequences into cells for expression of the SARS-CoV-2 RBD and NTD subdomains of the spike antigen. The delivered mRNA does not enter the cellular nucleus or interact with the genome, is nonreplicating, and is expressed transiently. The proteins undergo posttranslational modification and trafficking resulting in properly folded, RBD-NTD proteins that are inserted into the cellular membrane of the expressing cells. The vaccine elicits an immune response to the NTD and RBD of the spike antigen, which contributes to protection against coronavirus disease 2019 (COVID-19).

Pharmacokinetic studies are typically not required for vaccines. Immunogenicity was assessed as part of the clinical efficacy evaluation of mNexspike.

At the time of authorization, there were no data on the use of mNexspike with other vaccines.

For further details, please refer to the Product Monograph for mNexspike, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.

Clinical Efficacy

The data reviewed to evaluate the clinical efficacy of mNexspike were provided from the following studies:

• the Phase III studies: mRNA-1283-P301 main study (Part 1) and mRNA-1283-P301 (Japan addendum),

• the Phase IIa study mRNA-1283-P201, and

• the Phase I study mRNA-1283-P101.

The pivotal study, mRNA-1283-P301 (Part 1), (hereafter referred to as Study P301) is ongoing, and was designed to investigate the relative vaccine efficacy, safety, and immunogenicity of mNexspike (mRNA-1283) versus Spikevax (mRNA-1273; produced by the same manufacturer) in participants 12 years of age and older for the prevention of COVID-19. Participants (number of participants [n] = 11,454) were randomized 1:1, stratified by age groups (adolescents [12 to 17 years of age], adults [18 to 64 years of age], and seniors [65 years of age and older]). One treatment group received 10 mcg mNexspike (a bivalent vaccine containing the original SARS-CoV-2 [D614G] and Omicron BA.4/BA.5 subvariant antigen) (n = 5,706), and the other received 50 mcg Spikevax (a bivalent vaccine containing the original SARS-CoV-2 and Omicron BA.4/BA.5 subvariant antigen) (n = 5,711). Each of the vaccines was administered as a single dose. Dose selection was based on results from the mRNA-1283-P201 and mRNA-1283-P101 studies. All participants, except one in the mNexspike group, had previously received at least one dose of a COVID-19 vaccine. The median interval from last prior dose of COVID-19 vaccine to study vaccination was 9.8 months (range: 0.1 to 37.9 months). Participants were to be followed for one year to evaluate efficacy and safety.

The per-protocol set for efficacy (the primary efficacy analysis population) included 11,366 participants who received either mNexspike (n = 5,679) or Spikevax (n = 5,687). Female participants comprised 54.3% of the per-protocol set for efficacy, while 82.2% of participants were White, 13.1% identified as Hispanic or Latino, 11.1% were African American, 3.6% were Asian, and 2.3% were of other racial groups. The median age of participants was 56 years (range: 12 to 96 years) and 28.7% of participants were 65 years of age and older. There were no notable differences in demographic characteristics between participants who received mNexspike and those who received the comparator vaccine.

The population in which relative vaccine efficacy was analyzed included participants 12 years of age and older enrolled from March 28, 2023, and followed for the development of COVID-19 through January 31, 2024. The median duration of follow-up was 7.6 months (range: 0.1 to 9.5 months).

The primary efficacy objective in this study was to demonstrate the non-inferior vaccine efficacy of mNexspike against COVID-19 starting 14 days after administration relative to the comparator vaccine (Spikevax). The primary endpoint was defined as any symptomatic COVID-19 case confirmed by reverse transcription-polymerase chain reaction (RT-PCR) using a validated assay. In addition to confirmation by RT-PCR, at least one of the following symptoms had to be present: fever (temperature higher than 38 °C), or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle aches, or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea, or vomiting or diarrhea.

The statistical criterion to demonstrate non-inferiority required that the lower bound of the 99.4% confidence interval (CI) be greater than -10% for relative vaccine efficacy. The prespecified primary efficacy objective of non-inferiority was met, as the relative vaccine efficacy and 99.4% CI (alpha-adjusted) was 9.31% (-6.58%, 22.83%). A descriptive subgroup analysis by age revealed that efficacy results were driven by data in the two adult subgroups (18 to 64 years and 65 years and over). The same analysis revealed that in participants 12 to 17 years of age, there were 29 COVID-19 cases (5.9%) in the mNexspike group (incidence rate of 1.016 per 100 person-months) and 23 COVID-19 cases (4.7%) in the Spikevax group (incidence rate of 0.791 per 100 person-months). The hazard ratio-based relative vaccine efficacy was -29.17% (95% CI: -123.27%, 25.27%). In participants 18 to 64 years of age, there were 382 COVID-19 cases (10.7%) in the mNexspike group (incidence rate 1.447 per 100 person-months), and 422 COVID-19 cases (11.8%) in the Spikevax group (incidence rate 1.602 per 100 person-months). The hazard ratio-based relative vaccine efficacy was 9.66% (95% CI: -3.75%, 21.34%). In participants 65 years of age and older, there were 149 COVID-19 cases (9.1%) in the mNexspike group (incidence rate 1.292 per 100 person-months), and 172 COVID-19 cases (10.5%) in the Spikevax group (incidence rate 1.491 per 100 person-months). The hazard ratio-based relative vaccine efficacy was 13.54% (95% CI: -7.67%, 30.57%). In the adolescent subgroup (12 to 17 years of age), a meaningful interpretation of the relative vaccine efficacy point estimate was not possible due to the limited number of COVID-19 cases (none of which were considered serious infections) and the corresponding wide confidence intervals.

The primary immunogenicity analysis population included 621 participants who received mNexspike and 568 participants who received the comparator vaccine. The non-inferiority primary immunogenicity objective was met, and the neutralizing antibody responses against the variants contained in the study vaccines were observed to be higher with mNexspike versus Spikevax. The endpoint of geometric mean concentration (GMC) ratio (GMCR) of Day 29 neutralizing antibodies against Omicron BA.4/BA.5 and D614G met the prespecified non-inferiority criterion, which was that the lower bound of the 95% CI of the GMCR (mNexspike versus Spikevax) had to be greater than 0.667 against both virus strains. The GMCRs for the neutralizing antibodies against Omicron BA.4/BA.5 were 1.048 (95% CI: 0.839, 1.309) in participants 12 to 17 years of age, 1.277 (95% CI: 1.100, 1.482) in participants 18 to 64 years of age, and 1.763 (95% CI: 1.401, 2.219) in participants 65 years of age and older. The GMCRs for the neutralizing antibodies against D614G were 1.098 (95% CI: 0.920, 1.309) in participants 12 to 17 years of age, 1.180 (95% CI: 1.040, 1.339) in participants 18 to 64 years of age, and 1.534 (95% CI: 1.259, 1.871) in participants 65 years of age and older. A clear relationship was observed between the age of participants and the GMCRs for both the neutralizing antibodies against Omicron BA.4/BA.5 and the neutralizing antibodies against D614G; namely, increasing GMCRs were noted with increasing age, from adolescents to older adults.

The difference between mNexspike and Spikevax in seroresponse rates against Omicron BA.4/BA.5 and D614G met the prespecified non-inferiority criterion of the lower bound of the 95% CI of the difference in seroresponse rates being greater than -10%. Seroresponse in a participant is defined as an antibody value change from baseline below the lower limit of quantitation (LLOQ) to at least 4 times the LLOQ, or at least a 4-fold rise if baseline is less than or equal to the LLOQ and less than 4 times the LLOQ, or at least a 2-fold rise if baseline is at least four times the LLOQ, where baseline refers to pre-dose levels.

Indication

Sponsor's proposed indication	Health Canada-approved indication
mNexspike (COVID-19 mRNA vaccine) is indicated for active immunization against coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus in individuals 12 years of age and older.	mNexspike (COVID-19 mRNA vaccine) is indicated for active immunization against coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus in previously vaccinated individuals 18 years of age and older.

The approved indication is based on observations from the clinical studies. The proposed indication was modified due to several factors:

• As the pivotal study did not include vaccine-naïve participants, the target population was limited only to individuals with a previous history of COVID-19 immunization, regardless of the number of doses received.

• The relative vaccine efficacy could not be established for adolescents due to the small sample size in the pivotal study (P301), which resulted in insufficient statistical power to formally evaluate the non-inferiority of mNexspike compared to Spikevax. Additionally, the effectiveness of the comparator during the course of the trial in the adolescent age group was not demonstrated.

• Based on the data reviewed, the greatest benefit of mNexspike is expected to be in adults 65 years of age and older, while the greatest risk is expected for individuals 12 to 24 years of age, especially adolescents. Given the well-established increased relative risk of adverse events of special interest (e.g., myocarditis and pericarditis) in adolescent and young adult males, exposure of fewer than 500 adolescent participants to mNexspike in this submission was considered insufficient to draw conclusions on the risk-benefit profile of mNexspike in this age group.

• Clear baseline differences were identified between adolescents and older adults (65 years of age and older) with respect to SARS-CoV-2 serostatus rates (approximately 90% in adolescents versus approximately 65% in older adults), despite fewer previously received COVID-19 vaccine doses at screening (2-3 versus 4-5), fewer boosters received (0 versus 3 or more), and nearly twice the median interval since the previous COVID-19 vaccine (16.03 months versus 8.80 months). These findings suggest that adolescents either maintain detectable immunity to a greater degree than older adults, and/or receive enduring immunity from natural infections that are asymptomatic or mildly symptomatic. None of the COVID-19 cases in adolescents in the pivotal study were serious.

For more information, refer to the Product Monograph for mNexspike, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.

Clinical Safety

The safety profile of mNexspike was characterized based on data generated from the safety analysis of the ongoing pivotal Study P301, Part 1 (described in the Clinical Efficacy section). The safety analysis relied solely on this study, as 5,706 of the 6,268 mNexspike injections (91%) administered across the three clinical studies (P301, P201, and P101) were administered in Study P301 at the proposed 10 mcg dose of mNexspike.

All study participants in Study P301 (Part 1) are to be followed for up to 12 months. At the time of data cut-off, the median duration of follow-up for safety analysis was 8.8 months in adults (18 years of age and older) who received a study vaccine, and 6.5 months in adolescents (12 to 17 years of age). With the exception of 9 participants, the overall study population received 2 or more prior COVID-19 vaccine doses. The median interval from the last dose of a COVID-19 vaccine to administration of the study vaccination was 9.8 months. However, the median interval was nearly twice as long in adolescents (16.03 months) than in older adults (65 years of age and older) (8.80 months). At baseline, 88.5% of adolescents and 66.9% of older adults in the mNexspike group, and 91.7% of adolescents and 62.8% of older adults in the Spikevax group were SARS-CoV-2 seropositive. Other demographic characteristics were similar between participants who received mNexspike and participants who received Spikevax.

In the overall study population, the incidence of any solicited adverse reactions through 7 days post vaccination was slightly lower in the mNexspike group (80.2%) than in the Spikevax group (83.8%). The majority of adverse reactions were Grade 1 in severity, whereas Grade 2 adverse reactions were the second most common in both groups. Eight percent (8.0%) of adverse reactions in the mNexspike group and 6.9% in the Spikevax group were Grade 3 in severity. The observed imbalance in local reactogenicity, particularly for injection site pain, can be partially attributed to the higher injection volume and total ribonucleic acid (RNA) content of Spikevax (0.5 mL dose, 50 mcg RNA) compared to mNexspike (0.2 mL dose, 10 mcg RNA). The most frequently reported solicited adverse reactions in both groups included injection site pain, fatigue, headaches, and myalgias.

The pattern of solicited adverse reactions was different in adolescents and in older adults. Higher rates of axillary swelling and tenderness were observed in adolescents (34.6% in the mNexspike group and 27.1% in the Spikevax group) than in older adults (10.7% in the mNexspike group and 10.0% in the Spikevax group). Chills were also observed at higher rates in adolescents (31.6% in the mNexspike group and 31.9% in the Spikevax group) than in older adults (16.5% in the mNexspike group and 12.8% in the Spikevax group). Among study participants, any solicited (local and systemic) adverse reactions reported following vaccine administration had a median onset of 2 days after vaccination and a median duration of 3 days for the mNexspike vaccine group compared with a median onset of 1 day after vaccination and a median duration of 3 days for Spikevax.

Unsolicited adverse events that occurred within 28 days following injection were reported by 701 participants (12.3%) who received mNexspike and 680 participants (11.9%) who received Spikevax. Adverse events assessed by investigators as vaccine-related were uncommon (45 participants [0.8%] in the mNexspike group and 51 participants [0.9%] in the Spikevax group).

Through the data cut-off date, serious adverse events were reported in 156 participants (2.7%) who received mNexspike and 151 participants (2.6%) who received Spikevax. Five deaths had been reported in the mNexspike group. All of these occurred beyond 28 days of administration of the study injection (range: Day 82 to Day 251), and were assessed as not related to the study injection. One case of autoimmune meningitis was detected in a 17-year-old male recipient of mNexspike. Clinical information leading up to the diagnosis was limited, and therefore a causal relationship to the vaccine could not be established or ruled out. This condition will be monitored in the post-market period.

Increased risks of myocarditis and pericarditis were identified through data from authorized COVID-19 vaccines, particularly within the first week after vaccination. The observed risk is highest in adolescent and young adult males. Considering that mNexspike is a new COVID-19 vaccine product, a total exposure of less than 500 adolescents to the vaccine is not considered sufficient for an adequate safety analysis for this age group. Based on these factors, the benefit-risk profile of mNexspike in adolescents could not be determined from the data provided in the submission.

Risk Management Plan

A core Risk Management Plan (RMP) and a Canadian Addendum were submitted as part of the New Drug Submission for mNexspike. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and to describe measures that will be put in place to minimize risks associated with the product, when needed.

The safety concerns listed in the Canadian Addendum to the RMP for mNexspike include “myocarditis” and “pericarditis” as important potential risks. “Use in pregnancy”, “long-term safety”, “use in unvaccinated individuals”, “coadministration with other vaccines”, and “use in individuals 12 to under 18 years of age” were listed as missing information.

Routine pharmacovigilance activities will be carried out by the sponsor, including adverse reaction reporting and signal detection. For the first two 6-month periods after market introduction of mNexspike in Canada, the sponsor was requested to submit Periodic Safety Update Reports (PSURs)/Periodic Benefit-Risk Evaluation Reports (PBRERs). Studies have also been proposed to further characterize the risks presented in the RMP.

Important potential risks and areas identified as missing information are included in the Canadian Product Monograph for mNexspike, as part of routine risk minimization procedures.

Upon review, the RMP documents were found to be acceptable with respect to the intended use of mNexspike in individuals 18 years of age and older.

For more information, refer to the Product Monograph for mNexspike, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.

A comprehensive set of non-clinical studies were reviewed as part of the New Drug Submission (NDS) for mNexspike. Many of the study reports provided consisted of data obtained using other messenger ribonucleic acid (mRNA) vaccines formulated in lipid nanoparticles (LNPs), and had previously been submitted to Health Canada as part of different dossiers for other drug products. These studies were considered supportive in nature.

Pharmacodynamic studies in mice revealed that mRNA-1283 (the mRNA component of mNexspike, which encodes the N-terminal domain [NTD] and the receptor-binding domain [RBD] of the severe acute respiratory syndrome coronavirus [SARS-CoV-2] spike glycoprotein) elicited a robust immune response, with dose-dependent increases in binding antibody (bAb) and neutralizing antibody (nAb) titers, along with T-cell responses to the spike protein. Immune responses generated by the mRNA-1283 vaccines were directed by T helper 1 (Th-1) cells, and bAb titers correlated well with the measured nAb activity. These observations, along with the immune responses, suggest that enhanced respiratory disease is unlikely to occur following vaccination. Immune responses elicited by mRNA-1283 vaccines were comparable to those induced by mRNA-1273 (which encodes the full spike glycoprotein). Variant-containing mRNA-1283 vaccines were as effective or better at boosting variant-specific immune responses compared to mRNA-1273 vaccines. Additionally, mRNA-1283 vaccines were able to cross-neutralize antigenically similar strains, which indicates that the subfamily approach proposed for mRNA-1273 vaccines could be adapted to mRNA-1283 vaccines.

Following in vitro stimulation with a RBD peptide pool, NTD peptide pool, or two spike protein peptide pools (S1 and S2), the splenocytes from mRNA-1283-immunized mice produced more interferon (IFN)-γ, interleukin (IL)-2, or tumour necrosis factor (TNF)-α in cluster of differentiation (CD) 4+ T cells than IL-4, IL-5, or IL-13, and more IFN-γ in CD8+ T cells. However, compared with mRNA-1273, mRNA-1283 vaccination elicited increased IFN-γ–, IL-2–, and TNF-α–producing CD4+ T cells after stimulation with the S1 peptide pool, RBD peptide pool, and NTD peptide pool, but not with the S2 peptide pool. Additionally, mRNA-1283 elicited increases in IFN-γ in CD8+ T cells after stimulation with the S1 peptide pool and RBD peptide pool, but not with S2 peptide pool or NTD peptide pool, versus vaccination with mRNA-1273.

Pharmacokinetic studies were conducted using mRNA-LNP drug products comprised of the same 4 lipids and a generally similar lipid-to-mRNA ratio as in mRNA-1283. Tissues with the highest mRNA and SM-102 exposures were generally similar for both analytes. The highest exposures were found at the injection site, in lymph nodes, and in the spleen, all of which had greater exposures than in the serum or plasma. The highest levels of expressed protein were also detected at the injection site, in lymph nodes, and in the spleen and/or liver. A small fraction reached distant tissues and mRNA concentrations in most tissues became undetectable within 1 to 3 days, except at the injection site, lymph nodes, and spleen.

Repeat-dose toxicity studies were conducted in rats, including a Good Laboratory Practices (GLP)-compliant 4-week study of mRNA-1283.222 (2 doses, with a 2-week recovery period) and a non-GLP-compliant 3-week study of mRNA-1283 (2 doses). Primary findings were related to the local and/or systemic inflammatory or immune response, with the injection site and draining lymph nodes identified as the only microscopic target organs. At terminal necropsy, microscopic findings were observed at the injection sites and draining iliac lymph nodes. The primary finding was mixed-cell inflammation in the second injection site. Inflammation was minimal to moderate with secondary infiltration of neutrophils in the iliac (draining) lymph node of a few animals. Neutrophil infiltration in the lymph node was considered part of or secondary to the mixed-cell inflammation in the second injection site. At the first injection site, minimal fibrosis and mixed-cell inflammation were observed in a subset of animals, the latter of which was of the same character as that observed at the second site. This suggests that the fibrosis was likely secondary to the resolution of inflammation occurring previously at those sites. Injection site findings correlated with clinical pathology changes consistent with an inflammatory and/or acute phase response, including increases in neutrophil counts and/or fibrinogen concentrations. All microscopic and clinical pathology findings were partially or completely reversed by the end of the 2-week recovery period. The no-observed-adverse-effect level (NOAEL) was established at 10 mcg/dose (or 33.3 mcg/kg based on a rat body weight of 0.3 kg). When compared to the proposed marketed dose of mRNA-1283 (10 mcg/dose or 0.17 mcg/kg based on a conservative body weight estimate of 60 kg), the NOAEL represents a 195-fold safety margin.

A GLP-compliant developmental and reproductive toxicology study revealed no mRNA-1283-related adverse effects on fertility or pre- and postnatal development when administered to female rats during the pre-mating (28 and 14 days prior to mating) and gestation periods (gestation days 1 and 13) via intramuscular injection at 80 mcg/dose. Immunoglobulin G antibodies were present in the maternal serum after dosing, and in the gestation and lactation periods. Antibodies were also present in maternal milk, and in fetal and pup serum during gestation and the postnatal period, respectively, demonstrating effective placental and lactation transfer of antibodies to offspring. The NOAEL was determined to be 80 mcg/dose.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Product Monograph for mNexspike. Considering the intended use of mNexspike, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Product Monograph for mNexspike, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.

Characterization of the Drug Substance

mNexspike (mRNA-1283) is a prophylactic vaccine developed for active immunization against coronavirus disease 2019 (COVID-19). The vaccine is a ribonucleic acid (RNA)-lipid complex dispersion containing messenger RNA (mRNA) that encodes the linked N-terminal domain (NTD) and receptor-binding domain (RBD) of the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), encapsulated in a lipid nanoparticle (LNP).

Spikevax (mRNA-1273) and mNexspike (mRNA-1283) both protect against COVID-19 and are manufactured by the same sponsor. The main difference between the two vaccines is the messenger RNA (mRNA) construct. The mRNA sequence in Spikevax encodes the full SARS-CoV-2spike glycoprotein, while the mRNA sequence in mNexspike encodes the membrane-bound NTD and RBD of the SARS-CoV-2 spike glycoprotein. The NTD and RBD regions of the spike antigen contain epitopes that elicit neutralizing antibody responses, which are known to correlate with protection against COVID-19. The membrane-binding function of the translated protein helps to ensure localized protein expression near the injection site. The design of mNexspike allows for a lower dose of RNA in mNexspike (10 mcg in 0.2 mL) than in Spikevax (50 mcg in 0.5 mL).

Detailed characterization studies were performed to provide assurance that the mRNA construct consistently exhibits the desired characteristic structure and biological activity.

Manufacturing Process of the Drug Substance and Drug Product and Process Controls

The pharmaceutical development of mNexspike is based on “platform approach” knowledge from the sponsor’s development experience with the currently authorized mRNA vaccines, sound scientific knowledge, prior experience with the development of mRNA‑LNP vaccines, and principles described in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines.

From a quality review perspective, the primary difference between drug products in this range is the mRNA sequence. Therefore, the review of the quality data submitted focused on processes and test methods that are unique to mNexspike, while verifying similarities to the other products.

The mNexspike drug substance (mRNA-1283) is manufactured through in vitro transcription reactions using a linearized plasmid deoxyribonucleic acid (DNA) template. The resulting RNAs are then mixed with lipid mixture (LMX-100) to produce the lipid nanoparticle (LNP) intermediate. The LNP intermediate is then buffered, filtered, frozen, and stored at a temperature between -90 ºC and -60 ºC.

The manufacture of the drug product involves the thawing of each LNP intermediate complex followed by pooling, dilution and filtration processes to produce the formulated drug product. The formulated drug product solution is then sterile filtered, aseptically filled into pre-filled syringes (PFS), plungers inserted, visually inspected, labelled, and then frozen and stored at a temperature between -40 ºC and -15 ºC.

The method of manufacturing and the controls used for the drug substance and the drug product were informed by the sponsor’s cumulative manufacturing history and experience with currently authorized mRNA vaccines. These methods and controls are considered to be adequately controlled within justified limits and all analytical methods are considered appropriately validated and qualified. Continual process verification activities informed updates to in-process controls. The in-process controls and lot release tests for the mNexspike drug substance and drug product are based on scientifically justified assays, and appropriate specifications are in place to monitor key quality attributes.

Changes made throughout development are considered acceptable upon review and the sponsor provided sufficient information to support the consistency of production.

Supportive release and extended characterization data were provided for all variant-specific drug substance and drug product batches.

The submitted information, along with the sponsor’s experience with the platform approach, is sufficient to support the authorization of mNexspike.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations. The compatibility of the medicinal ingredients with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against qualified reference standards to verify conformance to approved specifications. Analytical methods have been validated in compliance with relevant ICH guidelines. The sponsor applied a platform approach, leveraging information gained from development activities and cumulative manufacturing history of currently authorized mRNA vaccines, to streamline method validation. This platform approach strategy was determined to be acceptable based on method performance and product knowledge. Process validation studies demonstrated the consistency and robustness of the manufacturing process and provided sufficient analytical characterization data to assess any impacts of the mRNA sequence changes on the drug substance and drug product critical quality attributes. For sequence-agnostic quality attributes (e.g., lipid content), validated platform methods were leveraged. For sequence-specific quality attributes (e.g., identity), methods were re‑validated for the drug substance and drug product to confirm the consistent assay performance with the updated sequence. mNexspike‑specific reference materials were produced to support the analytical testing and ongoing control.

While there are some manufacturing differences and controls between the sponsor’s authorized mRNA vaccines, the overarching manufacturing processes remain the same and use the same equipment and methods. The manufacturing process and control strategies unique to mNexspike have been adequately described, and any differences to the manufacturing processes between these products would not reasonably be expected to impact the quality or quality assessment of mNexspike.

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risk of the formation or introduction of nitrosamine impurities in the drug substance and/or drug product is considered negligible or has been adequately addressed (e.g., with qualified limits and a suitable control strategy.)

mNexspike is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. mNexspike can be stored frozen between -40 °C and -15 °C for up to 12 months. The prefilled syringe should always be kept in the original packaging to protect from light. Within the 12-month period, once thawed, mNexspike can be stored in a refrigerator between 2 °C and 8 °C for up to 90 days and must not be frozen again. Prefilled syringes may be stored between 8 °C and 25 °C for up to 24 hours after removal from refrigerated conditions. Additional storage and special handling instructions are included in the Product Monograph for mNexspike.

Facilities and Equipment

Although the drug substance manufacturing site qualified for an on-site evaluation (OSE) based on the risk assessment conducted by Health Canada, the need for an OSE was mitigated by several factors. The site has an established production history, as the similar manufacturing process for the mNexspike drug substance is already being used for the drug substances of two other mRNA vaccines from the same sponsor, both of which are approved in Canada. Additionally, while the manufacturing site has no history of OSEs conducted by Health Canada, it is subject to oversight by the United States Food and Drug Administration.

To further mitigate the risk of not conducting an OSE, Health Canada requested from the sponsor to provide reports of site inspections conducted by other foreign regulators. The reports were reviewed and are considered to confirm the Good Manufacturing Practices (GMP) status and production capabilities of the manufacturing site.

Adventitious Agents Safety Evaluation

There are no materials of animal or human origin used in the manufacture of mNexspike. All raw materials used in its production are appropriately sourced and tested, and the product is manufactured according to GMP regulations. The manufacturing process incorporates adequate control measures to prevent introduction of adventitious agents.