Summary Basis of Decision for Capvaxive

Clinical Pharmacology

Immune responses following pneumococcal vaccination can be determined through the assessments of opsonophagocytic activity (OPA) responses to assess functional antibodies capable of opsonizing pneumococcal capsular polysaccharides for presentation to phagocytic cells for engulfment and subsequent killing. Opsonophagocytic activity responses are considered an important immunologic surrogate measure of protection against pneumococcal disease in adults. Specific threshold values that correlate with protection in adults have not been defined. There is a positive correlation between OPA responses and anti-capsular immunoglobulin G (IgG) responses.

Serotype-specific immune responses (OPA and IgG) for the 21 serotypes contained in Capvaxive and two cross-reactive serotypes (15B and 6C) were measured using a validated multiplexed opsonophagocytic assay (MOPA) and pneumococcal electrochemiluminescence (Pn ECL) assay. Serotype 15C represents the immune response to the deOAc15B polysaccharide, as the molecular structure for deOAc15B and 15C are similar.

As with any vaccine, Capvaxive may not protect all vaccine recipients.

The pharmacodynamics of Capvaxive was assessed through the analysis of immunogenicity described in the Clinical Efficacy section.

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

Clinical Efficacy

Five clinical studies were submitted to support the use of Capvaxive in individuals 18 years of age and older:

• Study P003, the pivotal Phase III study evaluating immunogenicity and safety in pneumococcal vaccine-naïve individuals 18 years of age and older.

• Study P004, a Phase III lot-to-lot consistency study in individuals 18-49 years of age.

• Study P005, a Phase III study with concomitant administration of influenza vaccine in individuals 50 years of age and older.

• Study P006, a Phase III immunogenicity and safety study in individuals 50 years of age and older who previously received a pneumococcal vaccine.

• Study P001, a Phase I/II safety, immunogenicity, and dose-finding study in individuals 18 years of age and older.

Results from the dose-finding study (P001) showed that the dose of 4 mcg of each of the polysaccharide serotypes (in total, 84 mcg of pneumococcal polysaccharide antigen) was well tolerated and generated serotype-specific immune responses. This dose was selected for further studies. A single dose of Capvaxive was used in all the Phase III clinical studies.

A total of 4,556 adults with and without prior pneumococcal vaccination received Capvaxive in the clinical studies.

Study P003

The immunogenicity (effectiveness) of Capvaxive in pneumococcal vaccine-naïve adults was primarily assessed using clinical data from the pivotal Study P003. This study was conducted based on comparative immunogenicity to Prevnar 20 (PCV20), which is indicated for the prevention of invasive pneumococcal disease in individuals 6 weeks and older and pneumococcal pneumonia in individuals 18 years of age and older. In the double-blind study, participants 50 years of age and older (Cohort 1, number of participants [n] = 2,362) were randomized in a 1:1 ratio and participants 18 to 49 years of age (Cohort 2, n = 301) were randomized in a 2:1 ratio to receive a single dose of either Capvaxive or PCV20. Immunogenicity was assessed by serotype-specific opsonophagocytic activity (OPA) and immunoglobulin G (IgG) responses at one month post vaccination, using a validated assay. The co-primary immunogenicity endpoints were OPA geometric mean titers (GMTs) and the proportion of individuals who achieved a 4 fold or higher rise in OPA responses from baseline (prior to vaccination) to one month post vaccination.

The immunogenicity data for Capvaxive indicated that in adults 50 years of age and older (Cohort 1), Capvaxive was non-inferior to PCV20 for the 10 common serotypes as assessed by the GMT ratio, as the lower bound of the two-sided 95% confidence interval (CI) for non-inferiority was greater than the pre-defined value of 0.5. Capvaxive was superior to PCV20 for 10 of the 11 serotypes unique to Capvaxive, as the lower bound of the two-sided 95% CI for superiority was greater than 2.0. Serotype 15C did not meet the criterion for statistical significance. The lower bound of the two-sided 95% CI for serotype 15C was 1.77, which missed the margin for superiority slightly. There is no established minimum threshold for OPA titer that predicts protection against invasive pneumococcal disease. The clinical relevance of differences in immune response levels is unknown.

In individuals 18 to 49 years of age (Cohort 2), the immune response was assessed using immunobridging. This allowed for comparison of the immune response in this study group to the response observed in individuals 50 to 64 years of age, for whom the immunogenicity of Capvaxive was demonstrated. The vaccine successfully immunobridged serotype-specific immune responses for each of the vaccine serotypes, as the lower bound of the two-sided 95% CI for non-inferiority for the GMT ratio for each serotype was greater than the pre-defined value of 0.5. Immunoglobulin G antibody responses (geometric mean concentrations [GMCs]) to Capvaxive at 30 days post vaccination were consistent with the results of the primary analysis of OPA GMTs. Additionally, Capvaxive elicited an immune response (provided cross-protection) to serotype 15B (cross-reactive to serotype 15C) and serotype 6C (cross-reactive to serotype 6A), which are not contained in the vaccine.

Overall, the pivotal Study P003 showed that the immune responses elicited by Capvaxive were comparable to those observed with PCV20 for the 10 common serotypes, and were higher than those observed with PCV20 for the 11 serotypes unique to Capvaxive. These findings are based on data from individuals 18 years of age and older with and without chronic medical conditions who were not previously vaccinated with any pneumococcal vaccines.

Study P005

Study P005 evaluated the safety and immunogenicity of Capvaxive when concomitantly administered with quadrivalent influenza vaccine (QIV) in participants 50 years of age and older (n = 1,080). The participants were randomized in a 1:1 ratio to receive Capvaxive and QIV either concomitantly or separately (concomitant group: Capvaxive and QIV administered concomitantly; sequential group: Capvaxive and QIV administered 30 days apart). Capvaxive administered concomitantly with QIV was non-inferior to Capvaxive administered alone for 20 of 21 serotypes (as the lower bound of the two-sided 95% CI of the GMT ratio was greater than 0.5). The lower bound for serotype 23B in Capvaxive was 0.44.

The QIV administered concomitantly with Capvaxive was non-inferior to QIV administered alone for 3 of 4 influenza strains as assessed by influenza strain-specific hemagglutination inhibition (HAI) GMTs (as the lower bound of the two-sided 95% CIs for HAI GMT ratios was greater than 0.67). The lower bound was 0.67 for the A/H3N2 influenza strain.

Overall, the immunogenicity of Capvaxive administered concomitantly with QIV was demonstrated. The immune responses to serotype 23B in Capvaxive and A/H3N2 influenza strain in QIV were lower when both vaccines were administered concomitantly, compared to QIV and Capvaxive administered separately. However, the clinical relevance of the differences in immune responses is unknown, and the benefit of co-administration of the vaccines outweighs the risk.

Study P006

Study P006 was conducted to assess the immunogenicity and safety of Capvaxive in individuals 50 years of age and older who previously received other pneumococcal vaccines at least one year prior to study entry. Capvaxive was immunogenic for all serotypes included in the vaccine in individuals who had been vaccinated with other pneumococcal vaccines at least one year prior, based on OPA GMTs and the proportion of individuals with a 4-fold rise or higher in OPA responses from baseline to one month postvaccination in the descriptive analyses.

Indication

Health Canada approved the following indication:

Capvaxive (pneumococcal 21-valent conjugate vaccine) is indicated for active immunization for the prevention of invasive pneumococcal disease (including sepsis, meningitis, bacteremic pneumonia, pleural empyema and bacteremia) caused by Streptococcus pneumoniae serotypes (3, 6A, 6C, 7F, 8, 9N, 10A, 11A, 12F, 15A, 15B, 15C, 16F, 17F, 19A, 20A, 22F, 23A, 23B, 24F, 31, 33F, and 35B) in adults 18 years of age and older.

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

Clinical Safety

The integrated safety analysis of Capvaxive is based on data collected from four clinical studies (the pivotal Study P003, and studies P004, P005, and P006). Data was pooled from approximately 4,500 participants who received Capvaxive (treatment group) and approximately 2,000 participants who received an active comparator (control group).

The median age was 55 years (range: 18 to 97), with 40.7% of participants aged 18 to 49 years, 59.2% older than 50 years, and 32.2% older than 65 years of age. Females constituted 57.3% of participants. Thirty-three percent of participants had one or more pre-specified medical conditions associated with an increased risk of pneumococcal disease. Approximately 86% of participants were vaccine-naïve.

The most commonly reported solicited adverse reactions, observed in more than 10% of individuals 50 years of age and older who received Capvaxive, were injection site pain (41.2%), fatigue (19.7%), and headache (11.0%).

The most commonly reported solicited adverse reactions, observed in more than 10% of individuals 18 to 49 years of age following vaccination with Capvaxive, were injection‑site pain (73.1%), fatigue (36.0%), headache (27.5%), myalgia (16.4%), injection‑site erythema (13.8%), and injection‑site swelling (13.3%).

Across the Phase III studies in individuals 18 years of age and older, the majority of local and systemic solicited adverse reactions were mild (based on intensity or size) and of short duration (3 days or less). Severe events (defined as an event that prevents normal daily activity, or size ˃10 cm) occurred in ≤1.0% of adults.

More than 67% of participants experienced one adverse event or more in the treatment and control groups. The proportions of solicited and unsolicited adverse events were generally comparable between groups, with the exception of injection site swellings, pain, and erythema, which were higher in the treatment group than in the control group. Rates of fatigue, headache, myalgia and pyrexia were also higher in the treatment group than in the control group. Unsolicited events were reported by 7.8% in the treatment group, and 6.1% in the control group. Apart from this observation, there is no specific concern regarding the overall proportions of adverse events in the treatment group versus the control group based on this information. Less common adverse reactions include lymphadenopathy, diarrhea, nausea, injection-site pruritus, chills and dizziness.

The frequency of serious adverse events was low and comparable between the treatment and comparator groups. Two events were considered to be related to the vaccine by the investigator: bronchospasm and injection-site cellulitis. There were nine deaths in the integrated population, none of which were considered to be related to study vaccine.

Overall, Capvaxive was well tolerated in individuals 18 years of age and older with and without prior pneumococcal vaccination, with a safety profile generally comparable to the safety profile of other currently authorized pneumococcal vaccines.

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

Non-clinical pharmacology studies were conducted in mice and adult rhesus monkeys to evaluate the immunogenicity of Capvaxive. The results indicated that Capvaxive was immunogenic in both animal models and showed a dose-dependent immunogenicity response. A challenge study in mice showed that Capvaxive provided protection from intratracheal challenge with vaccine serotype 24F, a serotype unique to Capvaxive.

The safety of the vaccine was also evaluated in rats in a repeat-dose toxicity study and a developmental and reproductive toxicity (DART) study. In the repeat-dose toxicity study, two 42 mcg doses (one half of the full human dose) were administered by intramuscular injection three weeks apart. The results suggest that the vaccine was tolerated without evidence of systemic toxicity or adverse anatomic pathology findings. In the DART study, a 42 mcg dose was administered to female rats by intramuscular injection. No effects were observed on mating performance, fertility, or embryonic/fetal survival. Additionally, no malformations or adverse effects on pre-weaning development were observed.

No dedicated studies have been conducted to evaluate the carcinogenicity or genotoxicity of Capvaxive as these are not typically required for vaccines.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Capvaxive Product Monograph. Considering the intended use of Capvaxive, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product. For more information, refer to the Capvaxive Product Monograph, approved by Health Canada and available through the Drug Product Database.

Characterization of the Drug Substance

Capvaxive is a 21-valent pneumococcal conjugate vaccine that contains antigen from 21 Streptococcus pneumoniae polysaccharides (3, 6A, 7F, 8, 9N, 10A, 11A, 12F, 15A, de-O-acetylated serotype 15B [deOAc15B], 16F, 17F, 19A, 20A, 22F, 23A, 23B, 24F, 31, 33F, 35B).

The characterization of the Capvaxive drug substance and drug substance intermediates included attributes that have been shown to be linked to the efficacy of polysaccharide pneumococcal vaccines. Product- and process-related impurities were also characterized.

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

Twenty-one serotype-specific monovalent bulk conjugate (MBC) drug substances are used to formulate the Capvaxive drug product. Each MBC is created by covalently linking two types of drug substance intermediate: the serotype-specific pneumococcal polysaccharides (PnP), and the non-toxic variant of diphtheria toxin (CRM197) carrier protein.

Fourteen of the 21 PnPs drug substance intermediates (3, 6A, 7F, 8, 9N, 10A, 11A, 12F, 15B, 17F, 19A, 20, 22F and 33F) are already used in currently authorized pneumococcal vaccines manufactured by the same sponsor. The manufacture and control process for serotypes novel to Capvaxive (15A, 16F, 23A, 23B, 24F, 31 and 35B) is similar to that used for the production of PnPs used in the already licenced pneumococcal vaccines. The manufacture and control of the CRM197 drug substance intermediate is identical to that contained in some currently authorized vaccines and supported by extensive manufacturing/clinical experience.

Each serotype MBC drug substance is produced by independently conjugating serotype specific PnPs to the CRM197 carrier protein. The manufacturing processes for the production of MBC drug substances are similar to those already approved for other conjugate vaccines.

The manufacturing of the Capvaxive vaccine (drug product) involves the thawing and dilution of the 21 drug substances to a target concentration, producing the final bulk solution, followed by aseptic filling into single-dose syringes.

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 process parameters and in-process controls for the drug substances for the novel serotypes were based on those approved for the drug substances of a currently authorized vaccine. These were further refined throughout product development. The quality attributes of the commercial drug substance lots were shown to be comparable to those of the drug substance lots tested in Phase III clinical studies, which supports the use of the final commercial drug substance manufacturing process. In addition, hold times and release assays were appropriately validated.

The manufacturing experience with a currently authorized vaccine was leveraged to develop the Capvaxive drug product manufacturing process and control strategy. The intended formulation of Capvaxive was assessed during clinical development, and the drug product lots used in the clinical Phase III studies were manufactured at the intended commercial site. Minor differences between the processes used to manufacture Phase III lots and the commercial batches were evaluated and are considered unlikely to impact product quality. Hold times and release assays were appropriately validated.

Capvaxive 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.

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested. The results reflect the consistency of the manufacturing process.

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 18-month shelf life is acceptable when Capvaxive is stored between 2 °C and 8 °C and protected from light.

Facilities and Equipment

On-site evaluations (OSEs) were not recommended for the drug substance or drug product manufacturing sites. The manufacturing and testing activities at both sites are either identical or highly similar to those for a previously authorized vaccine. The submission included supporting data that provided sufficient assurance that the process and conditions of manufacture are suitable.

Adventitious Agents Safety Evaluation

Raw materials of animal origin used in the manufacturing process are adequately tested to ensure freedom from adventitious agents. These materials originate from sources with no or minimal risk of transmissible spongiform encephalopathy agents or other human pathogens. The excipients used in the drug product formulation are not of animal or human origin.

The manufacturing process of Capvaxive, including media and buffers used, does not support virus growth, therefore, there are no concerns with respect to viral safety.