Summary Basis of Decision for Prehevbrio

Clinical Pharmacology

Prehevbrio contains the full antigenic structure of the hepatitis B virus surface antigen, including the small (S), middle (pre-S2), and large (pre-S1) hepatitis B surface antigens. Prehevbrio confers seroprotection against hepatitis B virus infection through the stimulation of a specific immune response, as measured by the induction of anti‑hepatitis B titres at a level ≥10 mIU/mL. Post‑vaccination antibody concentrations ≥10 mIU/mL to hepatitis B surface antigens are recognized as conferring protection against infection caused by all known subtypes of the hepatitis B virus.

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

For further details, please refer to the Prehevbrio Product Monograph, approved by Health Canada and available through the Drug Product Database. Prehevbrio demonstrated a good immune response against hepatitis B surface antigen, as shown by anti-hepatitis B geometric mean antibody concentrations and seroprotection rate.

Clinical Efficacy

The support for efficacy of Prehevbrio was based on two Phase III randomized, active‑controlled, double‑blinded, multicentre clinical studies (Sci‑B‑Vac-001 and Sci‑B‑Vac‑002) which included a total of 4,445 adult participants 18 years of age and older. In both Phase III pivotal studies, the immunogenicity of Prehevbrio was assessed by comparing Prehevbrio against a licensed hepatitis B vaccine, Engerix-B. Prehevbrio and Engerix‑B were administered as a three‑dose regimen with vaccinations given at 0, 1, and 6 months. A total of 2,920 individuals received at least one dose of Prehevbrio in the two Phase III pivotal clinical studies. Enrolled participants had no history of hepatitis B vaccination or infection.

Study Sci-B-Vac-001: Adults 18 years of age and older

The Sci‑B‑Vac‑001 study was a comparative study against a licensed hepatitis B vaccine, Engerix‑B. The study included two co‑primary endpoints. The first co‑primary endpoint was to demonstrate that the seroprotection rate following three doses of Prehevbrio was non‑inferior to the seroprotection rate induced by three doses of the approved hepatitis B vaccine Engerix‑B at Day 196. The second co‑primary endpoint was to demonstrate that the seroprotection rate following Prehevbrio administration was statistically higher than Engerix-B at Day 196 in adults 45 years of age and older. The seroprotection rate was defined as the percentage of subjects with anti-hepatitis B titre levels of ≥10 mIU/mL.

A total of 2,472 participants were screened for the study and 1,607 adult subjects were subsequently enrolled and randomized in a 1:1 ratio to receive either Prehevbrio (number of subjects [n] = 796) or Engerix‑B (n = 811; the active control). Enrolled subjects were stratified by age group into three categories (18 to 44 years; 45 to 64 years; and 65 years or older) with 81% of participants aged 45 years or older and 37.2% aged 65 years or older. Subjects with controlled common chronic conditions were also eligible and enrollment was targeted to be 20% of participants 18 to 44 years of age.

Most subjects in both treatment groups completed the study as planned, including 756 (95.0%) in the Prehevbrio treatment arm and 769 (94.8%) in the Engerix‑B treatment arm. Early discontinuation from treatment was reported for 40 (5.0%) subjects in the Prehevbrio treatment arm and 42 (5.2%) subjects in the Engerix‑B treatment arm. The most common reasons for treatment discontinuation were lost to follow‑up and withdrawal of consent. Treatment discontinuation due to non‑serious adverse events or serious adverse events was uncommon, reported in 1 (0.1%) subject in the Prehevbrio treatment arm and 3 (0.4%) subjects in the Engerix‑B treatment arm.

Results

The results from the Sci‑B‑Vac‑001 study demonstrated that both co‑primary endpoints were met. The estimated difference in the seroprotection rate was 14.9% (95% confidence interval [CI]: 11.2, 18.6), meeting the non‑inferiority margin of -5%. The estimated difference in the seroprotection rate in adults 45 years of age and older was 16.4% (95% CI: 12.2, 20.7%), meeting the superiority criteria.

Study Sci-B-Vac-002: Adults 18 to 45 years of age

The Sci‑B‑Vac‑002 study was a lot‑to‑lot consistency study designed to establish the manufacturing consistency of Prehevbrio. The study included two co‑primary endpoints. The first co‑primary endpoint was to demonstrate manufacturing equivalence based on a pairwise comparison between three lots of Prehevbrio as determined by adjusted geometric mean concentration ratios of anti-hepatitis B titres at Day 196. The second co‑primary endpoint was to demonstrate non‑inferiority of Prehevbrio compared to Engerix‑B at Day 196, based on seroprotection rate.

A total of 4,452 participants were screened for the study and 2,838 adult subjects were subsequently enrolled and randomized. A total of 712 subjects were randomized to the Engerix‑B treatment arm, and 2,126 subjects were randomized to one of three Prehevbrio treatment arms (711 to Lot A, 709 to Lot B, and 706 to Lot C). Of the 2,838 subjects, 2,836 (99.9%) subjects received their assigned treatment. Two subjects were randomized to receive Prehevbrio but did not receive the vaccination. Of these two subjects, one subject withdrew consent before receiving any vaccination and the other subject was discontinued due to non-compliance with the study procedures.

Most subjects (93%) completed study treatment as planned. Early discontinuation from treatment was reported in 159 (7.5%) subjects who received Prehevbrio and in 41 (5.8%) subjects who received Engerix‑B. The most common reason for treatment discontinuation was lost to follow‑up or withdrawal of consent by the subject.

Results

The results from study Sci‑B‑Vac‑002 demonstrated that both co‑primary endpoints were met. The lot‑to‑lot manufacturing consistency of Prehevbrio was demonstrated. Additionally, the non‑inferiority of Prehevbrio compared to Engerix‑B, based on seroprotection rate, was established. The estimated difference in seroprotection rate at Day 196 was 4.49% (95% CI: 2.90, 6.63%).

Indication

The New Drug Submission for Prehevbrio was filed by the sponsor with the following indication, which Health Canada subsequently approved:

Prehevbrio (3‑antigen, recombinant Hepatitis B vaccine) is indicated for active immunization against infection caused by all known subtypes of hepatitis B virus in adults 18 years of age and older.

It can be expected that hepatitis D will also be prevented by immunization with Prehevbrio as hepatitis D (caused by the delta agent) does not occur in the absence of hepatitis B infection.

Additionally, at Health Canada’s request the sponsor included the following statement:

The National Advisory Committee of Immunization provides additional guidance on the use of hepatitis B vaccines in Canada, including a list of recommended individuals for vaccination against hepatitis B. Please refer to the Canadian Immunization Guide.

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

Clinical Safety

The clinical safety profile of Prehevbrio is mainly based on two Phase III pivotal clinical studies (Sci‑B‑Vac‑001 and Sci‑B‑Vac‑002), previously described in the Clinical Efficacy section. A total of 2,920 adults received at least one dose of Prehevbrio.

The safety evaluation comprised an assessment of local and systemic reactogenicity monitored from days 0 to 7 after vaccination, with unsolicited adverse events and serious adverse events monitored within 28 days of any vaccine dose.

Pain and tenderness at the injection site were the most commonly reported solicited local symptoms after Prehevbrio administration. Both events were reported in a majority of subjects and at greater frequencies in the Prehevbrio treatment group than in the Engerix‑B treatment group.

Myalgia, headache, and fatigue were the most commonly reported solicited systemic symptoms after Prehevbrio administration. Myalgia was the only solicited adverse event reported at a clinically significantly higher frequency in the Prehevbrio group compared to the Engerix‑B group. Grade 3 myalgia and fever were uncommon in both treatment groups.

No clinically significant differences in reactogenicity were identified between the three lots of Prehevbrio.

No clinical studies were conducted specifically to assess the safety of Prehevbrio in pregnancy. A total of 18 pregnancies were reported in subjects receiving Prehevbrio, including 3 pregnancies in the Sci‑B‑Vac‑001 study and 15 pregnancies in the Sci-B-Vac-002 study. There were no adverse outcomes of pregnancies or birth anomalies that could be associated with the exposure to Prehevbrio. Pharmacovigilance periodic safety reports published since Prehevbrio’s initial approval in Israel in 2000 have not identified any safety concerns associated with the use of Prehevbrio during pregnancy.

Overall, while there are some limitations in the submitted safety data (e.g., no data available in special populations such as pregnant and breastfeeding women), these limitations have been managed through appropriate labeling and the Risk Management Plan. The sponsor is also expected to add a pregnancy outcomes registry as a post-marketing commitment.

The safety data submitted demonstrates an acceptable safety profile for Prehevbrio and appropriate warnings and precautions are in place in the approved Prehevbrio Product Monograph to address any safety concerns. Although Prehevbrio was moderately more reactogenic than Engerix-B, the vast majority of reactions were mild or moderate in severity and resolved quickly. There were no serious adverse events considered causally related to Prehevbrio. Therefore, the benefit‑risk assessment for Prehevbrio is favorable and supports the use of Prehevbrio in subjects aged 18 years and older.

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

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

The non‑clinical program for Prehevbrio included studies to assess the pharmacological properties and toxicity profile of Prehevbrio components (Chinese hamster ovary cell-derived S, pre-S2, and pre-S1 hepatitis B surface antigens). The primary pharmacodynamic studies investigated the seroconversion of the Prehevbrio components (S, pre-S2 and pre-S1) in mice when compared to the marketed, yeast-derived hepatitis B virus vaccines, Engerix-B and H-B-Vax II, which contain only non-glycosylated ‘S’ hepatitis B surface antigens. Balb/C mice were used for testing, as well as B10/S and B10/M mice, which are known to be less responsive to the ‘S’ antigen.

The ability of the current formulation of Prehevbrio to induce a strong immune response was established in another study in Balb/C mice to which doses were administered by intraperitoneal injection on Day 0 and Day 21. In this study, adjuvanted Prehevbrio was found to elicit stronger responses than unadjuvanted Prehevbrio or a yeast-derived hepatitis B vaccine after one dose. One month after the second dose, a 100% seroconversion rate was observed for adjuvanted Prehevbrio, which was almost three times the seroconversion rate noted with unadjuvanted Prehevbrio (37.5%).

In an embryo‑fetal developmental study, the vaccine administration did not have any effects on female productivity and fetal/embryonal development. No adverse effects of preweaning development were observed. There were no female reproductive effects and no effects on fetal/embryonal development and postnatal development up to Day 23.

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

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

Prehevbrio is a recombinant hepatitis B vaccine indicated for active immunization against infection caused by all known subtypes of hepatitis B virus in adults 18 years and older. Prehevbrio is comprised of three protein components (pre‑S1, pre‑S2, and S protein).

Prehevbrio is supplied as a sterile aqueous suspension in single‑dose (1.0 mL) glass vials. Each vial contains a dosage of 10 mcg/mL hepatitis B surface antigens adsorbed on aluminum hydroxide as an adjuvant, for intramuscular administration. The vaccine does not contain any preservatives. Prehevbrio is administered as a three-dose regimen with vaccinations given at 0, 1, and 6 months.

Characterization of the Drug Substance

Prehevbrio is characterized by the expression of three envelope proteins, pre‑S1 (6%), pre‑S2 (11%), and S (83%) hepatitis B surface antigens, derived from a transfected Chinese hamster ovary cell line. The hepatitis B surface antigen proteins are covalently linked to one another by intermolecular disulfide bonds between the S domains and partially embedded in the membrane lipids creating virus-like particles.

The cloning strategy and generation of this stable transfected Chinese hamster ovary cell line has been appropriately characterized. Genetic stability has been maintained over several years of production. The master cell bank and the working cell banks have been thoroughly analyzed for growth kinetics and hepatitis B surface antigen productivity. They also are regularly tested to ensure they are free from adventitious contaminants and endogenous viruses in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines.

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

Prehevbrio contains the full antigenic structure of the hepatitis B virus surface antigen. The drug substance is manufactured in a Chinese hamster ovary cell line using recombinant deoxyribonucleic acid technology and is based on a master and working cell bank system. The drug substance comes from transfected Chinese hamster ovary cells which are propagated initially in tissue culture flasks, roller bottles, and cell factories, and then grown in bioreactors. Meanwhile, the Chinese hamster ovary cells secrete particles carrying the three antigens into the harvest media, which is then collected. The harvest media is held for a certain time, then undergoes viral removal and bioburden testing prior to downstream processing. The harvest media is clarified and further concentrated. The concentrated harvest is then purified and undergoes inactivation steps. Finally, the purified harvest media is sterile filtered to obtain the hepatitis B surface antigens bulk drug substance.

The drug product manufacturing process includes formulation of the drug substance diluted in a buffer solution followed by sterile filtration, mixing, aseptic filling, capping, and crimping, which then is followed by visual inspection and storage.

The final drug product is presented as a sterile aqueous suspension supplied in single‑dose glass vials. Each vial contains 10 mcg/mL hepatitis B surface antigens formulated with aluminum hydroxide (0.5 mg/mL) as an adjuvant. The final drug product appears turbid when mixed, and forms a clear colorless upper solution and white precipitate upon settling. The final drug product composition includes buffers and adjuvant that are of pharmaceutical grade and are commonly used in the formulations of other vaccines.

Minor changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable upon review.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. All analytical procedures are adequate to control the quality of the intermediates for both the drug substance and drug product and have been validated appropriately. The control of the process and environment is assured with adequate specifications set for microbial contamination and endotoxin. The product was found to be stable over time at proposed storage conditions and thus the release and stability specifications are adequate.

During the submission review, issues were identified relating to the in vitro potency analytical procedure (enzyme‑linked immunosorbent assay) and the proposed acceptance criteria for drug product quality control release. However, following further discussion with the sponsor, both issues were then resolved.

Prehevbrio 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. The proposed 36-month shelf life when stored at 5 °C ± 3 °C for Prehevbrio is considered acceptable.

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.

Facilities and Equipment

Based on a risk assessment score determined by Health Canada and considering the drug product manufacturing facility had no history of on-site evaluations conducted by Health Canada, an on-site evaluation of the drug product manufacturing facility was planned. However, following the review of several inspection reports prepared by other regulators which indicated minimal issues were observed, Health Canada decided to pivot in favor of conducting a virtual site evaluation on August 12, 2022. Following completion of the virtual site evaluation, the facilities and equipment were deemed adequate.

Adventitious Agents Safety Evaluation

The sponsor has applied a comprehensive risk mitigation strategy in compliance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use to ensure the safety of the drug substance and drug product by minimizing the risk of adventitious agent contamination. Risks resulting from non‑viral as well as viral adventitious agents have been assessed and adequate testing for microbial and viral contaminants has been performed on raw materials and cell banks. Viral clearance studies have shown that the manufacturing process has sufficient capacity to inactivate and/or remove a broad range of viruses should they be present. Collectively, the information provided is sufficient to ensure product safety from adventitious agent contamination.