Summary Basis of Decision for mResvia

Clinical Pharmacology

mResvia is a messenger ribonucleic acid (mRNA)-based vaccine, in which the mRNA encodes the membrane-anchored respiratory syncytial virus (RSV) fusion (F) glycoprotein stabilized in the prefusion conformation (hereafter referred to as mRNA-1345). The F protein exists in two primary conformational states, prefusion and post-fusion. The prefusion state facilitates entry into the host cell through a conformational change to the post-fusion state. The prefusion F glycoprotein is the target of potent neutralizing antibodies that mediate protection against RSV‑associated respiratory tract disease.

mResvia stimulates the production of RSV‑A and RSV‑B neutralizing antibodies and the induction of antigen-specific cellular immune responses.

Clinical pharmacology studies were not conducted and are typically not required for vaccines. The pharmacodynamics of mResvia was assessed through the analysis of immunogenicity described in the Clinical Efficacy section.

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

Clinical Efficacy

The clinical efficacy of mResvia was evaluated in Study 1 (mRNA-1345-301, NCT05127434), the ongoing pivotal Phase II/III study which included 35,088 participants 60 years of age and older with or without underlying medical conditions. mResvia was administered to 17,572 participants, and placebo (normal saline) was administered to 17,561 participants. This study was conducted in 22 countries across North America, Europe, Central/Latin America, Africa, and Asian/Pacific regions. Participants were followed for up to a year after vaccination. The median follow-up time was 3.7 months for the primary analysis, and 8.6 months for the extended analysis.

There were no notable differences in demographics or pre-existing medical conditions between participants in the two groups. In total, 6.9% of participants had protocol-defined lower respiratory tract disease (LRTD) risk factors (congestive heart failure [CHF] and/or chronic obstructive pulmonary disease [COPD]), and 29.3% of participants had one or more comorbidity of interest (COPD, asthma, chronic respiratory disease, diabetes, CHF, advanced liver disease, or advanced renal disease). In the per-protocol efficacy set, 21.8% of participants scored “vulnerable” or “frail” according to the Edmonton Frail Scale.

The primary efficacy endpoints were the prevention of a first episode of RSV-LRTD with 2 or more or with 3 or more signs/symptoms between 14 days and 12 months post injection. Primary efficacy was evaluated after a median of 3.7 months of follow-up (range: 15 to 379 days). Both primary efficacy endpoints met the predefined success criterion (lower bound of the alpha-adjusted confidence interval [CI] of vaccine efficacy [VE] greater than 20%). Vaccine efficacy against RSV-LRTD with 2 or more signs/symptoms was 83.7% (95.88% CI: 66.0%, 92.2%; 9 cases in the mResvia group and 55 cases in the placebo group). Vaccine efficacy against RSV‑LRTD with 3 or more signs/symptoms was 82.4% (96.36% CI: 34.8%, 95.3%; 3 cases in the mResvia group and 17 cases in the placebo group).

The extended efficacy analysis was evaluated after a median of 8.6 months (range: 15 to 530 days), and both primary endpoints met the same predefined success criterion as with the primary analysis. Vaccine efficacy against RSV-LRTD with 2 or more signs/symptoms was 63.3% (95% CI: 48.7%, 73.7%; 47 cases in the mResvia group and 127 cases in the placebo group). Vaccine efficacy against RSV‑LRTD with 3 or more signs/symptoms was 63% (95% CI: 37.3%, 78.2%; 19 cases in the mResvia group and 51 cases in the placebo group).

Indication

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

Clinical Safety

The safety profile of mResvia was characterized based on data from Study 1. All study participants are to be followed for up to 24 months as part of the safety analysis.

Local and systemic adverse reactions were solicited in an electronic diary from 7 days following injection (i.e., the day of injection and 6 subsequent days). The most commonly reported (in at least 20% of participants) solicited local adverse reaction was injection site pain, which was more common in mResvia recipients (55.9%) than in placebo recipients (13.8%). The most commonly reported solicited systemic adverse reactions, in the mResvia and placebo groups respectively, were fatigue (30.8% and 20.0%), headache (26.7% and 18.8%), myalgia (25.6% and 14.4%), and arthralgia (21.7% and 14.0%). For all solicited reactions, the median onset and duration were approximately 2 days, with most graded mild or moderate in severity. Severe (Grade 3) solicited adverse reactions were reported for 5.9% of participants in the mResvia group and 3.8% of participants in the placebo group.

In participants who received mResvia, the reporting of solicited adverse reactions was lower among older participants than younger participants. Solicited local adverse reactions were reported for 61.2% of participants 60 to 69 years of age, 55.4% of participants 70 to 79 years of age, and 46.3% of participants 80 years of age and older. Solicited systemic adverse reactions were reported for 48.8% of participants 60 to 69 years of age, 46.4% of participants 70 to 79 years of age, and 40.1% of participants 80 years of age and older. In the placebo group, no consistent trends for solicited adverse reaction incidence were observed based on age group.

Participants were monitored for all unsolicited treatment-emergent adverse events (TEAEs) up to 28 days following the administration of mResvia or placebo. Unsolicited TEAEs considered related to the study vaccination were numerically higher in mResvia recipients (5.7%) than in the placebo recipients (4.4%), primarily attributed to solicited adverse reactions that persisted beyond Day 7. The incidence of hypersensitivity events was similar between the mResvia and placebo groups (0.6% and 0.5%, respectively). However, there was a numerically higher incidence of events of urticaria in the mResvia group (15 participants, <0.1%) with an onset ranging from 1 to 20 days post vaccination with a duration ranging from 3 to 188 days. The incidence of urticaria in the placebo group was 5 participants (<0.1%), with an onset ranging from 1 to 21 days post vaccination with a duration ranging from 1 to 18 days.

Participants were monitored for all serious adverse events (SAEs) and protocol-defined adverse events of special interest (AESI) throughout the study, for up to 24 months following the administration of mResvia or placebo. Throughout the study, similar incidences of SAEs were reported in the two groups (6.1% of mResvia recipients and 6.0% of placebo recipients). The incidence of AESIs was balanced between mResvia recipients and placebo recipients (0.2% for each group). One participant in the mResvia group had an SAE of facial paralysis with an onset of four days after vaccination. This event was assessed as being related to mResvia, lasted 113 days (3.7 months), and required treatment. Within 28 days and 42 days post vaccination, there was no imbalance in reports of facial paralysis (including Bell’s palsy) between treatment groups. There were no other notable patterns or numerical imbalances between treatment groups among categories of SAEs or AESIs that would suggest a causal relationship to mResvia.

Adverse events leading to death were reported in 84 participants (0.5%) in the mResvia group and 83 participants (0.5%) in the placebo group. None of these deaths were assessed as being related to study intervention. Adverse events leading to withdrawal from the study were similar in the mResvia and placebo groups (99 [0.5%] and 105 [0.6%] participants, respectively). Most discontinuations in both groups were due to fatal events.

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

Non-clinical pharmacology studies were conducted in mice and cotton rats, which followed a prime-boost immunization schedule for the administration of the messenger ribonucleic acid (mRNA) encoding RSV glycoprotein F stabilized in the prefusion conformation, 5′(m7G-5′-ppp-5′-Gm) cap, 100-nucleotide 3′ poly(A) tail. This mRNA encodes the membrane-anchored respiratory syncytial virus (RSV) fusion (F) glycoprotein stabilized in the prefusion conformation, and will be referred to hereafter as mRNA-1345.

Robust responses were observed with respect to RSV-specific binding and functional dose-dependent neutralizing antibody responses, which significantly increased after a second dose of mRNA-1345. In mice, T helper (Th) 1-directed antigen-specific cluster of differentiation (CD) 4+ and CD8+ T-cell responses were observed. When mRNA-1345 was administered to cotton rats according to a prime-boost schedule at 30 mcg or 3 mcg, full protection from viral challenge was observed in the lower respiratory tract. Additionally, mRNA-1345 did not promote vaccine-associated enhanced respiratory disease (VAERD). This was demonstrated by balanced Th1/Th2-directed immune responses in mice and cotton rats, the absence of increased lung pathology, and controlled viral replication after viral challenge when mRNA-1345 was administered at doses predicted to be fully (optimal dose) or partially (suboptimal dose) protective in cotton rats. Based on these findings, mRNA-1345 was found to be immunogenic and provide protection from RSV challenge.

Pharmacokinetic evaluations included biodistribution, metabolism, and excretion studies in Sprague-Dawley rats. A biodistribution study was conducted using a surrogate mRNA vaccine, formulated in the same 4 lipids as mRNA-1345. This is acceptable, as the biodistribution of mRNA-based vaccines formulated in lipid nanoparticles (LNPs) is predicted to be driven primarily by the characteristics of the LNPs. The mRNA distributed mainly to the site of intramuscular injection, the proximal and distal lymph nodes, and the spleen. Lower levels were detected in plasma and other tissues, with the exception of the kidneys, and concentrations were observed to decrease thereafter. At 5 days post-dosing, mRNA was detected only in the major distribution sites, the bone marrow, and the jejunum. Based on observations with the surrogate mRNA vaccine, the average half-life (t_½) was 14.9 hours in the injection site muscle, 34.8 hours in the proximal lymph nodes, 31.3 hours in the distal lymph nodes, and 63.0 hours in the spleen.

Non-clinical toxicology studies evaluated the repeat-dose toxicity, genotoxicity, and reproductive/developmental toxicity associated with mRNA-1345 or surrogate mRNA vaccines, formulated in the same 4 lipids as mRNA-1345. In repeat-dose Good Laboratory Practices (GLP)-compliant toxicity studies in Sprague-Dawley rats, surrogate mRNA-LNP vaccines were well tolerated. The surrogate vaccines were administered up to four times (once every two weeks) by intramuscular injection, at doses ranging from 8.9 mcg to 150 mcg, followed by a two-week recovery period. Repeat-dose toxicity studies were also conducted in Sprague-Dawley rats with mRNA-1345, with two doses administered by intramuscular injection at 98 mcg/dose (GLP-compliant study) or 15 mcg/dose, 50 mcg/dose, or 100 mcg/dose (non-GLP-compliant study) once every three weeks. In the GLP-compliant study, administration of mRNA-1345 was associated with lower mean body weight gain and food consumption. This resulted in a lower body weight in males only, and changes in clinical pathology parameters that were consistent with a local and/or systemic inflammatory/immune system response.

In the GLP-compliant study with mRNA-1345, clinical signs, including limited use of the hind limb and/or hind paw and skin discolouration were attributed to the inflammatory reaction induced by the injection of mRNA-1345. All edema and/or erythema and clinical signs (including the hind limb and/or hind paw and skin discoloration) resolved within 6 days after administration of the first dose. Target organ effects related to mRNA-1345 indicated an inflammatory response, and were limited to the injection site, the iliac, inguinal, and popliteal lymph nodes, connective tissue surrounding the sciatic nerve, and the spleen. There was no recovery group in the toxicity studies conducted with mRNA-1345. Therefore, whether the observed changes would be recovered and the scope of any recovery are unknown. However, the toxicological results from studies with mRNA-1345 are consistent with toxicity data obtained from the GLP-compliant study with surrogate vaccines.

In the GLP-compliant reproductive and developmental toxicity study, four doses of mRNA-1345 (96 mcg each) were administered to female rats by intramuscular injection on study days 1 and 15 (28 and 14 days prior to mating, respectively) and gestation days 1 and 13. No signs were observed of maternal toxicity related to mRNA-1345 or adverse effects on pre- and postnatal development. Anti-RSV antibodies were present in serum samples from females administered mRNA-1345 following the dose administration on study day 1 and continuing through lactation day 21. Anti-RSV antibodies were also present in milk samples obtained on lactation days 13 and 21, in fetal serum obtained on gestation day 21, and in pup serum obtained on lactation days 13 and 21.

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

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

Characterization of the Drug Substance

The mResvia vaccine is a dispersion of messenger ribonucleic acid (mRNA) encoding the fusion (F) glycoprotein of the respiratory syncytial virus (RSV) stabilized in the prefusion conformation (hereafter referred to as mRNA-1345), and encapsulated in a lipid nanoparticle (LNP) containing four distinct lipid types: SM-102 (a custom-manufactured, ionizable lipid), cholesterol, DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), and PEG2000-DMG (1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000).

The mRNA component mRNA-1345, the LNP, and the encapsulated mRNA-1345 LNP were considered as three separate drug substances. With the exception of the mRNA sequence, the manufacturing of the three drug substances follows the same processes as those for Spikevax, another mRNA vaccine manufactured by the same sponsor.

Detailed characterization studies were performed to provide assurance that the drug substances consistently exhibit their desired characteristic and meet their specifications.

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

The manufacturing processes for mRNA-1345 and the LNP are the same as those for the corresponding components of Spikevax, with the exception of mRNA sequence-specific steps and test methods. The blending process of the mRNA-1345 and LNP to form the encapsulated mRNA-1345 LNP is also identical to that which is used in the production of Spikevax.

The mRNA is synthesized enzymatically through an in vitro transcription (IVT) reaction. A linearized plasmid template specific for the sequence of interest is used to produce the desired full-length RNA with a polyadenylated tail. A cap is added to the RNA through an enzymatic cap reaction. Throughout the process, tangential flow filtration and chromatography steps are used to capture the RNA and remove process-related impurities. Following bioburden reduction clarification the resulting RNA is dispensed in containers and stored at temperatures established for operational flexibility at the manufacturing site. The mRNA is subsequently encapsulated in a mixture of four lipids to produce the mRNA-LNP intermediate, which is then formulated to produce the final drug product.

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 mRNA-1345-LNP drug substance with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The sponsor leveraged the knowledge gained through the development and manufacturing of the Spikevax vaccines to ensure that critical quality attributes of mRNA-1345 consistently remained within acceptable limits. Control strategies have been incorporated into the manufacturing processes, which were found to adequately ensure the consistent quality of the drug substances and drug product. All analytical procedures used for in-process, stability, and release testing of the drug substances and drug product were validated and qualified. The drug substances and drug product were tested against suitable reference standards to verify that they meet approved specifications.

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 risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy.)

mResvia is a Schedule D (biologic) drug and is subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs. For post‑approval monitoring, mResvia has been assigned to Lot Release Evaluation Group 2, as it is considered to require a high level of assessment. Before each lot is sold, a formal Release Letter from Health Canada is required to approve the sale of the lot in Canada. This assessment level also involves the review of testing protocols and samples. The risk level associated with a drug product is determined by factors including the nature of the product, its indication and target patient population, and the manufacturer's production and inspection history.

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. The mResvia drug product may be stored frozen at -40 °C to -15 °C for up to 18 months. Once thawed, the product must not be frozen again, and must be stored between 2 °C and 8 °C. Within the 18-month shelf life, the unopened vaccine may be stored refrigerated between 2 °C and 8 °C and protected from light for a maximum of 30 days. Unopened pre-filled syringes may be stored at 8 °C to 25 °C for a total of 24 hours after removal from refrigerated conditions. Thawed pre-filled syringes can be handled in room light conditions.

Additional storage and special handling instructions are included in the mResvia Product Monograph.

Facilities and Equipment

A risk assessment was conducted by Health Canada to determine whether on-site evaluations (OSEs) are needed for the drug substance and drug product manufacturing facilities. However, as the manufacturing of the drug substances and drug product will be moved to different facilities in 2025, it was determined that OSEs were not appropriate at the time of review. The need for OSEs will be reassessed following the move to the new manufacturing sites.

The information included in the submission provides sufficient assurance that the process and conditions of manufacture are suitable to ensure the drug product will not be unsafe for use as required by the Food and Drugs Act. Health Canada also requested and reviewed additional manufacturing site information and site inspection reports from foreign regulators.

Adventitious Agents Safety Evaluation

There are no materials of animal or human origin used in the manufacture of mResvia. All raw materials used in its production are under control, and the product is manufactured under good manufacturing practices (GMP) regulations. Therefore, there is a negligible risk of adventitious agents and no viral clearance studies were required.