Summary Basis of Decision (SBD) for Arexvy

As outlined in the What steps led to the approval of Arexvy? section, the clinical review of the New Drug Submission for Arexvy was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Clinical Pharmacology

Arexvy is designed to enhance antigen-specific humoral immune response and cellular immune response including neutralizing antibodies against respiratory syncytial virus (RSV) subtypes A and B. The fusion (F) glycoprotein is the main surface virus antigen which facilitates entry into the host cell and is highly conserved across RSV‑A and RSV‑B subtypes. The F glycoprotein vaccine antigen has been engineered to maintain the prefusion form (RSVPreF3), as it elicits more potent neutralizing antibodies compared to the post‑fusion form. The AS01_E adjuvant in Arexvy facilitates the recruitment and activation of the RSVPreF3 antigen‑presenting cells carrying vaccine‑derived antigens in the draining lymph node. This in turn leads to the generation and enhancement of RSVPreF3‑specific cluster of differentiation 4-positive (CD4+) T cells.

Immunogenicity was assessed as part of the clinical efficacy evaluation of Arexvy. Traditional pharmacokinetic studies would not be informative to support the assessment of the efficacy or safety of the vaccine. Pharmacodynamic evaluations in clinical studies comprised the humoral and cell‑mediated immune responses to the vaccine.

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

Clinical Efficacy

The clinical efficacy of Arexvy was evaluated based on results from the ongoing Phase III study RSV OA=ADJ‑006 (Study 006), in which a single dose and annual revaccination doses of Arexvy were administered to adults 60 years of age and older. This study is being conducted in 17 countries across the Northern and Southern hemispheres and is planned to follow participants for up to 36 months (i.e., up to three consecutive RSV seasons) in the Northern hemisphere. Study 006 is randomized, placebo-controlled, and observer-blind. Adults with pre-existing chronic but stable diseases, with or without specified treatment, such as diabetes, hypertension, or cardiac disease were allowed to participate in the study if they were considered by the investigator to be medically stable at the time of vaccination. The vaccine formulation and schedule used (120 mcg of RSVPreF3 recombinant antigen adjuvanted with AS01_E, administered as a single dose) was selected based on results from a Phase I/II study (RSV OA=ADJ‑002).

The efficacy analysis was conducted in adults 60 years of age and older who received one dose of Arexvy or placebo, and who did not report an RSV‑confirmed acute respiratory illness prior to Day 15 after vaccination (referred to as the modified Exposed Set). Acute respiratory illness was defined by the presence of at least two respiratory symptoms/signs for at least 24 hours, or at least one respiratory symptom/sign and one systemic symptom/sign (fever or feverishness, fatigue, body aches, headache, decreased appetite) for at least 24 hours. In total, 24,960 participants were randomized to receive one dose of Arexvy (number of participants [n] = 12,466) or placebo (n = 12,494).

In the modified Exposed Set, the median age of participants was 69 years (range: 59 to 102 years), with approximately 74% over 65 years of age, approximately 44% over 70 years of age, and approximately 8% over 80 years of age. About 52% of participants were female. The majority of participants in both groups were White (79.4%), 8.7% were Black, 7.6% were Asian, and 4.3% were of other racial or ethnic groups, including 5.5% of participants who were of Hispanic or Latino ethnicity. Participants living in the general community accounted for 98.8% of the modified Exposed Set, and 1.2% of participants were living in a long-term care facility.

At baseline, 39.3% of study participants had at least one comorbidity of interest. Underlying cardiorespiratory conditions (i.e., chronic obstructive pulmonary disease, asthma, any chronic respiratory/pulmonary disease, or chronic heart failure) affected 19.7% of study participants, and endocrinometabolic conditions (i.e., diabetes [Type I/II], advanced liver or renal disease) affected 25.8% of study participants.

The primary objective of Study 006 was to demonstrate the efficacy of a single dose of Arexvy in the prevention of a first episode of confirmed RSV‑A- and/or RSV-B-associated lower respiratory tract disease (LRTD) during the first season following vaccination. The case definition of RSV‑associated LRTD involved both the presence of predefined lower respiratory tract symptoms and/or signs and a swab sample positive for RSV confirmed by reverse transcription polymerase chain reaction (RT-PCR). The primary endpoint for vaccine efficacy was the first occurrence of RT‑PCR‑confirmed RSV-A‑ and/or RSV-B-associated LRTD with an onset from 15 days after vaccination.

The primary vaccine efficacy analysis was case-driven, and was performed with 47 cases of RSV-confirmed LRTD accrued in the primary cohort for efficacy. All 47 cases were identified in participants from the Northern hemisphere, with 7 cases in the group treated with Arexvy and 40 cases in the placebo group. At the time of the primary efficacy analysis, study participants had been followed for the development of RSV-associated LRTD for up to 10 months, with a median time of 6.7 months.

The primary objective of the study was achieved. In participants 60 years of age and older, the vaccine efficacy of a single dose of Arexvy against RSV‑confirmed LRTD was 82.6% (96.95% confidence interval [CI]: 57.9, 94.1), with the lower limit of the two‑sided CI well above the predefined threshold of 20%. Compared with placebo, Arexvy significantly reduced the risk of developing RSV‑associated LRTD in participants 60 years of age and older.

The vaccine efficacy against RSV-A-associated LRTD cases and RSV-B-associated LRTD cases was 84.6% (95% CI: 32.1, 98.3), and 80.9% (95% CI: 49.4, 94.3), respectively. Compared with placebo, Arexvy significantly reduced the risk of developing RSV-associated LRTD by 84.4% (95% CI: 46.9, 97.0) in participants 70 years of age and older. The results for secondary objectives consistently showed the efficacy of Arexvy against RSV‑confirmed LRTD by RSV subtype (RSV‑A and RSV‑B), by age category, by time of vaccination, and by baseline comorbidities. In the subgroup of participants 80 years of age and older, vaccine efficacy could not be determined due to the low number of total cases accrued (2 cases in 1,016 participants treated with Arexvy and 3 cases in 1,028 participants who received placebo).

Severe RSV‑associated LRTD was defined as either RT‑PCR‑confirmed RSV‑associated LRTD with at least two lower respiratory signs, or an RT‑PCR‑confirmed RSV‑associated LRTD episode assessed as severe by the investigator. Among 18 RSV-LRTD cases with at least two lower respiratory signs or which prevented everyday activities, there were 4 cases of severe RSV-LRTD, requiring supplemental oxygen in the placebo group, and none in the Arexvy group.

Immunogenicity

No correlation has been established of protection with immunogenicity of Arexvy.

Immunogenicity in Adults 60 Years of Age and Older

The Phase III study RSV OA=ADJ-004 (NCT04732871) was designed to evaluate the immunogenicity, safety, reactogenicity, and long-term persistence of immune response of Arexvy in adults 60 years of age and older. The humoral immune response was assessed at Month 1 post‑vaccination (n = 940 for RSV‑A and n = 941 for RSV‑B) and at Month 6 post‑vaccination (n = 928 for RSV‑A and n = 929 for RSV‑B). Cell‑mediated immune responses were also evaluated pre‑vaccination (n = 471), at Month 1 post-vaccination (n = 410), and at Month 6 post‑vaccination (n = 440).

The geometric mean increases of RSV‑A and RSV‑B neutralizing titers at Month 1 post‑vaccination were 10.5‑fold (95% CI: 9.9, 11.2) and 7.8‑fold (95% CI: 7.4, 8.3) higher than pre‑vaccination levels, respectively. At Month 6 post‑vaccination, these values were 4.4‑fold (95% CI: 4.2, 4.6) and 3.5‑fold (95% CI: 3.4, 3.7) higher than pre‑vaccination levels, respectively.

The median frequency (percentile [25^th, 75^th]) of the RSVPreF3-specific CD4+ T-cells (per million CD4+ T cells) was 191.0 (71.0, 365.0) pre-vaccination, 1,339.0 (829.0, 2136.0) at Month 1 post‑vaccination and 666.0 (428.0, 1049.5) at month 6 post‑vaccination.

Immunogenicity following concomitant vaccination

The open‑label Phase III study RSV OA=ADJ‑007 (NCT04841577) was designed to evaluate the immunogenicity of Arexvy with concomitant vaccination with an influenza vaccine. Adult participants 60 years of age and older received one dose of Arexvy and one dose of the Fluarix Quadrivalent inactivated seasonal influenza vaccine (containing a combined total of 60 mcg hemagglutinin per dose) at Month 0 (n = 442), or one dose of Fluarix Quadrivalent at Month 0 followed by one dose of Arexvy at Month 1 (n = 443).

The criteria for non‑inferiority of the immune responses in the group that received the two vaccines separately versus the co‑administration group were met. The two‑sided 95% CI upper limits on the group geometric mean titer ratios were below 1.50 for the RSV‑A neutralizing antibodies and hemagglutinin inhibition antibodies against the strains Flu A/Hong Kong/H3N2, Flu A/Victoria/H1N1, Flu B/Phuket/Yamagata, and Flu B/Washington/Victoria. There was no evidence for statistically significant interference in the immune response to any of the antigens contained in both co‑administered vaccines. However, RSV‑A and RSV‑B neutralising titres and influenza A and B hemagglutination inhibition titres were numerically lower when Arexvy and inactivated seasonal influenza vaccine were co-administered than when they were administered separately. The clinical relevance of this finding is unknown.

Indication

Health Canada approved the following indication:

Arexvy (respiratory syncytial virus vaccine recombinant, adjuvanted) is a vaccine indicated for the prevention of lower respiratory tract disease caused by respiratory syncytial virus in adults 60 years of age and older.

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

Clinical Safety

In the pivotal Phase III Study 006 (described in the Clinical Efficacy section), a solicited safety set consisting of a small subset (approximately 7%) of the entire exposed study population was monitored for solicited adverse reactions. These data were collected using standardized paper diary cards during the first 4 days (i.e., the day of vaccination and the next 3 days) following a dose of Arexvy or placebo. The local administration site and systemic adverse reactions reported with Arexvy were transient and of short duration. Overall, there was an observed imbalance of local and systemic reactogenicity rates for Arexvy.

The most commonly reported solicited adverse reactions (Arexvy versus [vs.] placebo) were injection site pain (60.9% vs. 9.3%), followed by fatigue (33.6% vs. 16.1%), myalgia (28.9% vs. 8.2%), headaches (27.2% vs. 12.6%), and arthralgia (18.1% vs. 6.4%). Other solicited adverse reactions were far less common. There were few Grade 3 (severe) solicited adverse events, with fatigue (1.7%), myalgia (1.4%), and headaches and arthralgia (1.3% each) reported in Arexvy recipients. Local and systemic solicited adverse reactions were reported less frequently in participants 80 years of age and older (e.g., 42.1% for injection site pain and 15.9% for headache) compared with participants 60 to 69 years of age (e.g., 67.5% for injection site pain and 30.9% for headache), suggesting that reactogenicity decreases with advancing age.

Unsolicited adverse events were assessed in Study 006 in the entire exposed study population (i.e., all participants who received Arexvy) using paper diary cards during the 30-day period following vaccination (i.e., the day of vaccination and the next 29 days). A higher frequency of unsolicited adverse events was reported among participants who received Arexvy compared to participants who received placebo (33.0% and 17.8%, respectively). This observation was primarily attributed to events that are consistent with local and systemic reactogenicity within the first 4 days post-vaccination. Reports of these events were collected as unsolicited adverse events in the entire exposed study population (93% of all study participants), who were not included in the solicited safety set. It is possible that some non‑reactogenic adverse events were included within the high rates of local and systemic reactions reported in the first 4 days post‑vaccination. However, the rates reported in the Arexvy and placebo groups started balancing in the period from Day 5 to Day 30 without obvious imbalances clustering around specific categories.

Within 30 days after vaccination, atrial fibrillation was reported in 10 participants who received Arexvy and 4 participants who received placebo. Seven of the 10 cases in participants who received Arexvy and 1 of the 4 cases in participants who received placebo were found to be serious. The onset of symptoms ranged from 1 to 30 days post‑vaccination. The information currently available on atrial fibrillation is insufficient to determine a causal relationship to the vaccine.

Participants in Study 006 were monitored for all potential immune‑mediated diseases (pIMDs), serious adverse events, and deaths that occurred during the 6‑month period following the administration of Arexvy or placebo. New onset pIMDs or exacerbation of existing pIMDs within 6 months following vaccination were reported for 0.3% of participants who received Arexvy and 0.3% of participants who received placebo. Serious adverse events with an onset 6 months following vaccination were reported in 4.2% of participants who received Arexvy and 4.0% of participants who received placebo. Within 6 months after vaccination, serious events of atrial fibrillation were reported in 13 participants who received Arexvy and 15 participants who received placebo. From the time of vaccination through the first interim analysis of Study 006, adverse events leading to death were reported for 49 participants (0.4%) who received Arexvy and 58 participants (0.5%) who received placebo. The causes of death among study participants were consistent with those generally reported in adult and elderly populations.

In the supportive Study RSV OA=ADJ‑004, one case of Guillain‑Barré syndrome beginning 9 days after Arexvy vaccination was reported in a participant enrolled at a study site in Japan.

In the supportive study RSV OA=ADJ‑007, a suspected case of acute disseminated encephalomyelitis was reported in one participant enrolled at a study site in South Africa. The onset of symptoms was 22 days post‑vaccination. The event was non‑fatal. The participant received Arexvy concomitantly with Fluarix Quadrivalent.

The number of discontinuations due to adverse events was low and comparable between participants who received Arexvy and those who received placebo (0.6% of total study participants in both groups). The adverse events leading to discontinuations were reported across multiple system organ classes, high level terms, and preferred terms, with no obvious clustering or pattern.

The available data regarding vaccine efficacy are currently limited to approximately 6 months post‑vaccination. At the time of authorization, no information is available regarding the long‑term protection of Arexvy, and the need for revaccination remains to be determined. Additionally, the available data are not sufficient to establish the efficacy of Arexvy in adults 80 years of age and older. Reliable vaccine efficacy estimates against severe LRTD and hospitalization caused by RSV could not be established.

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

As outlined in the What steps led to the approval of Arexvy? section, the review of the non-clinical component of the New Drug Submission for Arexvy was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Studies conducted in naïve mice showed that the RSVPreF3 antigen formulated with various AS01 doses was able to induce targeted humoral and cellular immune responses. These results supported the choice of AS01 as an adjuvant system for clinical evaluation in the Phase I/II RSV OA=ADJ‑002 clinical study.

Repeat‑dose toxicity studies revealed no potential hazards and indicated that the vaccine candidate formulated with a higher adjuvant concentration was generally well tolerated in rabbits at antigen levels at or above the proposed clinical levels, and showed the expected effects from the stimulation of the immune response.

Arexvy has not been evaluated for carcinogenic or mutagenic potential as per current international guidelines. Non‑clinical reproductive and developmental studies with Arexvy have not been evaluated and the impacts on fertility, pregnancy, embryo‑foetal development, parturition, or postnatal development are not known.

Overall, the non‑clinical data served to establish the chosen antigen and the chosen adjuvant and provided evidence for the need for the adjuvant in the formulation. The results of the non-clinical studies as well as the potential risks to humans have been included in the Arexvy Product Monograph. Considering the intended use of Arexvy, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

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

As outlined in the What steps led to the approval of Arexvy? section, the review of the quality component of the New Drug Submission for Arexvy was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Characterization of the Drug Substance

Arexvy consists of two components: the RSVPreF3 antigen (lyophilized) and the AS01_E adjuvant (liquid suspension). The RSVPreF3 antigen is an engineered version of the respiratory syncytial virus (RSV) fusion (F) surface protein, stabilized in the pre‑fusion conformation.

The F protein, which is conserved among RSV subtypes A and B, is a major surface protein of RSV that mediates the fusion between the viral and the host cell membrane, leading to pathological changes in the respiratory system. As the greatest neutralizing potency has been demonstrated against the pre‑fusion conformation of the F protein, specific mutations have been introduced into the RSVPreF3 antigen via genetic engineering to retain this conformation.

Comprehensive studies were performed to provide assurance that the RSVPreF3 antigen consistently exhibits the desired characteristic structure and biological activity. Several physico‑chemical tests were conducted to characterize the RSVPreF3 antigen, including tests to evaluate intact mass, peptide mapping, protein profile, secondary and tertiary structure, charge distribution, non-glycosylated variants, and oxidation/deamidation levels.

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

The recombinant RSVPreF3 antigen (the drug substance) is synthesized in Chinese hamster ovary (CHO) cells stably transfected with a deoxyribonucleic acid (DNA) plasmid bearing the sequence of the modified RSV F protein. The transfected CHO cells are initially propagated in shake flasks and then transferred to bioreactors as the cell cultures grow. The cells are induced to express the antigen when the cell cultures have reached a targeted volume/density. The antigen is secreted into the harvest media, which is clarified (i.e., separated from cells and debris) when the culture reaches its maximum volume. The clarified harvest is treated to control viral adventitious agents, and undergoes a series of chromatography and filtration steps to purify and concentrate the antigen. The drug substance is stored in sterile containers and frozen.

The manufacturing process for the vaccine drug product begins with thawing and formulation of the drug substance. The formulated final bulk solution is sterile filtered and filled into glass vials, partially stoppered, and lyophilized (freeze‑dried). The lyophilized vials are capped and visually inspected, and the final containers are stored at 2 °C to 8 °C until labelling and packaging.

The vaccine drug product vial is to be reconstituted with the accompanying vial of AS01_E adjuvant suspension at the time of use. The AS01_E adjuvant is a liquid suspension containing immunoenhancers which use liposomes as a vehicle.

Proper development and validation studies were conducted, and adequate controls are in place for the commercial process. Changes to the manufacturing process and formulation made throughout the pharmaceutical development of Arexvy are considered acceptable upon review.

None of the non-medicinal ingredients (excipients) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of the RSVPreF3 antigen with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The manufacturing processes include appropriate control strategies that adequately ensure the quality of the drug substance and drug product. All analytical procedures used for in-process, stability, and release testing of the drug substance and drug product were validated and qualified. The drug substance and drug product were tested against suitable reference standards to verify that they meet approved specifications.

Arexvy 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. The consistency test results support the suitability of the selected methods for their intended purpose and the consistency of the manufacturing process. For post‑approval monitoring, Arexvy 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 proposed shelf lives of 24 months at 2 °C to 8 °C for lyophilized RSVPreF3 and 36 months at 2 °C to 8 °C for the AS01_E liquid suspension are considered acceptable. The vials containing each of these components must not be frozen and must be stored in the original package to protect from light.

After reconstitution, Arexvy should be used promptly. If this is not possible, the vaccine should be stored in the refrigerator (2 °C to 8 °C) or at room temperature up to 25 °C. If not used within 4 hours, it should be discarded. Additional guidelines and special handling instructions are included in the Arexvy Product Monograph.

Facilities and Equipment

Based on a risk assessment determined by Health Canada, an on-site evaluation of the drug product manufacturing facility was not deemed necessary. This assessment was based on the inspection history of the manufacturing facility and the outcomes of previous evaluations for drug products manufactured through similar processes.

Adventitious Agents Safety Evaluation

The risks resulting from adventitious agents have been assessed and adequate testing for microbial and viral contaminants has been performed on raw materials and cell banks.

Steps for viral clearance are incorporated into the manufacturing process. Viral clearance studies show that these steps have sufficient capacity to inactivate and/or remove a broad range of viruses. Collectively, the information provided is sufficient to ensure product safety from adventitious agent contamination.

The biologic raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy (TSE) or other human pathogens.