Summary Basis of Decision for Beyfortus

As described above, the clinical review of the bioanalytical methods specified in the New Drug Submission for Beyfortus was conducted as per Method 1 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The clinical package for Beyfortus included data from six studies: Study 1, Study 2, Study 3, MELODY, MEDLEY, and MUSIC.

Study 1 was a Phase I, randomized, double-blind, placebo-controlled, dose-escalation, first-in-human study performed to evaluate the safety, tolerability, and pharmacokinetics of Beyfortus in healthy adults aged 18 to 49 years. Subjects were administered either a single, fixed intravenous 300, 1,000, or 3,000 mg dose of Beyfortus, a single intramuscular 100 or 300 mg dose of Beyfortus, or placebo.

Study 2 was a Phase Ib/IIa, randomized, double-blind, placebo-controlled, dose-escalation study to evaluate the safety, tolerability, and pharmacokinetics of Beyfortus in healthy preterm infants who had a gestational age between 32 and 35 weeks and were entering their first RSV season. Subjects were administered as a single, fixed intramuscular 10, 25, or 50 mg dose of Beyfortus or placebo.

Study 3 was a pivotal, Phase IIb, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of Beyfortus against RSV in healthy preterm infants who had a gestational age between 29 and 35 weeks and were entering their first RSV season and were not eligible to receive RSV prophylaxis per local or national guidelines. Subjects were administered a single intramuscular 50 mg dose of Beyfortus or placebo.

MELODY is an ongoing, pivotal, Phase III, multicentre, randomized, double-blind, placebo-controlled, single-dose study to evaluate the efficacy and safety of Beyfortus against RSV in term and late preterm infants (gestational age ≥35 weeks). Subjects were entering their first RSV season and would not be eligible to receive RSV prophylaxis per local or national guidelines. Subjects received either a single, fixed intramuscular 50 mg (body weight <5 kg) or 100 mg (body weight ≥5 kg) dose of Beyfortus or placebo.

MEDLEY is an ongoing Phase II/III, randomized, double-blind, palivizumab-controlled study to evaluate the safety and descriptive efficacy of Beyfortus against RSV in individuals at higher risk for severe RSV disease, including preterm infants entering their first RSV season and children with chronic lung disease of prematurity or hemodynamically significant congenital heart disease entering their first and second RSV season. For the first season, subjects were administered a single intramuscular 50 mg (body weight <5 kg) or 100 mg (body weight ≥5 kg) dose of Beyfortus, followed by 4 once-monthly doses of placebo. The control group received a 15 mg/kg dose of palivizumab once a month for 5 months. During the second season, subjects were administered a 200 mg intramuscular dose of Beyfortus, followed by 4 once-monthly doses of placebo. The control group received a 15 mg/kg dose of palivizumab once a month for 5 months.

MUSIC is an ongoing Phase II, open-label, uncontrolled, single-dose study to assess the safety and tolerability, pharmacokinetics, occurrence of anti-drug antibodies (ADAs), and efficacy of Beyfortus in immunocompromised children who are 24 months of age or less. Subjects entering their first RSV season were administered Beyfortus as a single, fixed intramuscular 50 mg (body weight <5 kg) or 100 mg (body weight ≥5 kg) dose. Subjects entering their second RSV season were administered Beyfortus as a single, fixed intramuscular 200 mg dose.

Clinical Pharmacology

The clinical pharmacology package consisted of data from Study 1, Study 2, and three population pharmacokinetic models derived from data from all six studies (Study 1, Study 2, Study 3, MELODY, MEDLEY, and MUSIC).

The observed data from Study 1 suggest that a top intravenous 3,000 mg dose of Beyfortus (nirsevimab), corresponding to a maximum plasma concentration (C_max) of 1,163 mcg/mL, appeared to be well tolerated in healthy adults. Post hoc population pharmacokinetic exposure estimates predict a C_max of approximately 120 mcg/mL in infants in the first RSV season, and a mean (standard deviation [SD]) C_max of 194 (42.2) mcg/mL in the second RSV season. The predicted mean half-life of nirsevimab was approximately 71 days and consistent between the first and second RSV season. Nirsevimab exposures increased in an approximately dose-proportional fashion following intramuscular administration in both adults and infants, with the relative bioavailability of nirsevimab between intramuscular and intravenous dosing predicted to be 85%.

An exposure-response analysis for efficacy was performed on data from Study 3 and MELODY following nirsevimab dosing in the first season. The use of medically attended RSV lower respiratory tract infection (MA RSV LRTI) as a response endpoint was consistent with the primary efficacy endpoint for these studies (see Clinical Efficacy section). The exposure-response analysis suggests that nirsevimab exposures above a serum area under the concentration-time curve (AUC) based on clearance at baseline (AUC_baselineCL) of 12.8 mg*day/mL are likely to be efficacious in infants for both the first and second RSV season. The mean post hoc predicted population pharmacokinetic AUC_baselineCL following dosing during the first season was approximately 22 mg*day/mL. For the second season, a mean (SD) AUC_baselineCL of 23.6 (7.85) mg*day/mL is predicted.

Observed and population pharmacokinetic-predicted nirsevimab exposures obtained from infants with congenital heart disease or chronic lung disease enrolled in MEDLEY suggest a pharmacokinetic profile consistent with infants enrolled in MELODY. While the data from immunocompromised infants in MUSIC is limited at this time, the pharmacokinetic data in this population appears consistent with that observed in MELODY.

A robust increase in anti-RSV neutralizing antibodies (nAbs) is observed at the first sampling timepoint (Day 31) after nirsevimab dosing in MELODY and MEDLEY. A correlation between the anti-RSV nAb titer and nirsevimab exposure is observed in the data as a whole, with lower anti-RSV nAb titers observed with lower nirsevimab exposures.

The incidence of anti-nirsevimab antibodies (anti-drug antibodies [ADAs]) was 5.6% (84/1,498 infants) across Study 3 and MELODY. This was also consistent across all studies. The proportion of ADA-positive subjects tended to increase between Day 151 and Day 361 and was correlated with lower nirsevimab concentrations measured at Day 361 in ADA-positive subjects compared to ADA-negative subjects. Overall, there was no clinically relevant impact of ADA positivity on nirsevimab clearance. Immunogenicity had no apparent effect on the efficacy of nirsevimab in the first season of RSV.

The clinical virology data suggest that the incidence of amino acid substitutions that confer nirsevimab resistance in the fusion (F) protein of both RSV subtype A and B strains was low; however, surveillance for the occurrence of substitutions conferring nirsevimab resistance should be maintained.

Overall, the clinical pharmacology data support the use of Beyfortus for the recommended indication.

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

Clinical Efficacy

The indication for use in the first RSV season was supported by efficacy and safety results from Study 3 and MELODY (see Clinical Basis for Decision). A total of 2,943 term and preterm infants (gestational age ≥29 weeks) entering their first RSV season were randomized to receive Beyfortus (50 mg or 100 mg) or placebo. The primary endpoint was the incidence of MA RSV LRTI through 150 days post dosing.

Both studies met their primary efficacy endpoint; the relative risk reduction for infants who received Beyfortus compared to placebo was 70.1% (95% confidence interval [CI]: 52.3%, 81.2%) in Study 3, and 74.5% (95% CI: 49.6%, 87.1%) in MELODY. The pooled results for these two studies showed that preterm and term infants receiving Beyfortus at the recommended dose (50 mg if <5 kg and 100 mg if ≥5 kg) or placebo (n = 2,350) had a 79.5% relative risk reduction for MA RSV LRTI compared to placebo. The secondary endpoint was MA RSV LRTI with hospitalization through 150 days post dosing. The results of the pre-specified pooled analysis of Study 3 and MELODY showed a statistically significant relative risk reduction of MA RSV LRTI with hospitalization of 77.3% (95% CI: 50.3%, 89.7%) in the Beyfortus group compared to the placebo group.

The indication for use in the second RSV season was supported by safety information from MEDLEY, which included high-risk infants who were treated with either Beyfortus or standard of care during their first and second RSV season. Additional safety information was available from MUSIC, which enrolled immunocompromised infants who were then treated with Beyfortus. The efficacy of Beyfortus during the second RSV season in infants and children (≤24 months of age) who remained vulnerable to severe RSV disease was demonstrated in MEDLEY and MUSIC. Pharmacokinetic extrapolation of the data from these studies suggests that this population achieved nirsevimab exposures associated with RSV protection, as they were above those that were demonstrated to be efficacious in Study 3 and MELODY.

Indication

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

Beyfortus (nirsevimab injection) is indicated for the prevention of Respiratory Syncytial Virus (RSV) lower respiratory tract disease in:

• Neonates and infants during their first RSV season.

• Children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season, which may include but is not limited to children with:

• Chronic lung disease of prematurity (CLD)

• Hemodynamically significant congenital heart disease (CHD)

• Immunocompromised states

• Down syndrome

• Cystic fibrosis

• Neuromuscular disease

• Congenital airway anomalies.

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

Clinical Safety

The safety profile of Beyfortus was evaluated across all six studies (see Clinical Basis for Decision). The safety profile in 4,441 subjects (2,966 received Beyfortus and 1,475 received placebo) evaluated in the pooled pivotal Study 3/MELODY studies, including 2,570 subjects who received the recommended dose of Beyfortus (compared with 1,284 who received placebo), was considered acceptable and no specific safety signals of concern were identified. The types and frequencies of adverse events were generally balanced between the Beyfortus and placebo groups through 360 days post dosing and within immediate post-dose timepoints (1, 3, 7, 14, and 30 days). The majority of events were nonserious or mild/moderate in severity. During the 7‑day post-dosing period, the percentage of subjects with adverse events associated with reactogenicity measures of injection site reaction or pyrexia was low (<1%) for the Beyfortus and placebo groups. Similarly, the percentage of subjects with drug-related skin reactions and investigator-assessed skin hypersensitivity reactions was low and balanced between the treatment groups. The time course for immediate hypersensitivity reactions is typically within minutes to several hours of exposure to a causative agent. Cutaneous manifestations typically include urticaria, angioedema, or both. There were no events of urticaria or angioedema within 7 days post intramuscular dosing.

Based on the mechanism of action, any potential risks defined for Beyfortus were based primarily on the generic safety risks associated with any immunoglobulin (including monoclonal antibodies) and were the focus of the safety assessments conducted throughout the clinical program. These included immediate hypersensitivity (including anaphylaxis) and immune complex disease. Thrombocytopenia was also included as a potential risk as events of thrombocytopenia were reported during post-approval use of palivizumab, a monoclonal antibody with a similar mechanism of action as Beyfortus.

Appropriate warnings and precautions are in place in the approved Beyfortus Product Monograph to address the identified safety concerns, including:

• As with any other intramuscular injections, Beyfortus should be given with caution to individuals with thrombocytopenia, any coagulation disorder, or to individuals on anticoagulation therapy. Serious hypersensitivity reactions, including anaphylaxis, have been observed rarely with other human immunoglobulin G1 monoclonal antibodies. If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue administration, and initiate appropriate medicinal products and/or supportive therapy.

• The safety and effectiveness of Beyfortus in children older than 24 months of age have not been established. The safety and efficacy of Beyfortus in infants with a body weight below 1.6 kg have not been established. Dosing in infants with a body weight from 1.0 kg to less than 1.6 kg is based on extrapolation.

• The efficacy of Beyfortus in infants who remain vulnerable to severe RSV disease during their first or second RSV season has not been directly established and is based on extrapolation of exposure only.

• There is limited information available in extremely preterm (gestational age <29 weeks) infants less than 8 weeks of age, and no clinical data are available in infants with a postmenstrual age (gestational age at birth plus chronological age) of 32 weeks. Limited data are available in infants with Down syndrome (n = 13), cystic fibrosis (n = 5), congenital airway anomalies (n = 9), and neuromuscular disease (n = 0, not evaluated in clinical trials).

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

As described above, the review of the non-clinical component of the New Drug Submission for Beyfortus was conducted as per Method 1 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

No significant findings were observed from a repeat-dose toxicity study in cynomolgus monkeys at Beyfortus dose levels of up to 300 mg/kg administered intravenously or 300 mg administered intramuscularly, which were considered to be the no-observed-adverse-effect level. In accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidance S6 (R1), no studies were conducted or are planned to evaluate the effects of Beyfortus on fertility or embryo-foetal and pre/postnatal development. This is because Beyfortus binds a viral-specific target that is not expressed in non-clinical models or in humans, and the intended clinical population (infants and children) does not include women of childbearing potential. There were no safety concerns identified on the basis of non-clinical safety data, and no further non-clinical studies were considered necessary.

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

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

The Beyfortus drug substance (nirsevimab) is a human immunoglobulin G1 monoclonal antibody that targets the pre-fusion conformation of the fusion (F) protein of respiratory syncytial virus (RSV). Binding of nirsevimab to the F protein prevents the infection of cells by RSV.

The Beyfortus drug product is a sterile, single-dose, preservative-free solution for intramuscular injection. It is provided as two strengths: 50 mg/0.5 mL or 100 mg/1.0 mL in a 1 mL pre-filled syringe.

Characterization of the Drug Substance

Characterisation studies for the drug substance were performed using a reference standard representative of the commercial product. These studies provided assurance that the drug substance consistently exhibits the desired characteristic structure and biological activity.

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

The drug substance is manufactured in Chinese hamster ovary cells at commercial scale. The commercial process consists of a series of steps which include cell expansion, purification through a series of chromatography steps, viral inactivation and removal, final filtration, and filling into storage containers.

Controls of critical steps of the drug substance manufacturing process were established during manufacturing development, based on a risk assessment and the results of process characterization. Process validation was conducted on multiple lots of drug substance manufactured at the commercial scale. The results of the process validation study demonstrate the manufacturing process is capable of consistently manufacturing drug substance with the desired product quality.

The drug product manufacturing process consists of thawing and mixing of the drug substance, bioburden reduction, sterile filtration, filling, stoppering, labelling, and packaging.

Controls of critical steps of the drug product manufacturing process were established during manufacturing development, based on a risk assessment and the results of process characterization. Process validation demonstrated that the manufacturing process is capable of consistently manufacturing drug product with the desired product quality.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of nirsevimab 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 suitable reference standards to verify that they meet approved specifications, and analytical procedures are validated and in compliance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines.

All drug product batches met the release and stability acceptance criteria through the proposed shelf-life.

Beyfortus 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 24‑month shelf life at 2 to 8 ºC for Beyfortus 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.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facility and equipment that are involved in the production of the of the drug product and drug substance are considered suitable for the activities and products manufactured.

Based on a risk assessment score determined by Health Canada, on-site evaluations of the drug product and drug substance manufacturing facilities were not deemed necessary.

Adventitious Agents Safety Evaluation

The manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Purification process steps designed to remove and inactivate viruses are adequately validated and in compliance with ICH guidelines.