Summary Basis of Decision for Evusheld

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Evusheld is located below.

Recent Activity for Evusheld

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Evusheld

Updated:  2024-01-19

The following table describes post-authorization activity for Evusheld, a product which contains the medicinal ingredients tixagevimab and cilgavimab. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Drug Identification Number (DIN):

DIN 02526271 - 150 mg/1.5 mL tixagevimab, solution, and 150 mg/1.5 mL cilgavimab, solution, co-packaged, intramuscular administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities

Risk Management Plan update

Control # 277310
2023-07-18 Review completed 2023-11-02 The updated Core Risk Management Plan (RMP) version 5 and the Canadian Addendum succession 4 version 1 were filed as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. The information was reviewed and found acceptable. No further action was required.
PBRER # 277342 2023-07-19 Review completed 2023-10-27 Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. PBRER #3 for the period 2022-11-14 to 2023-05-13. The information was reviewed and found acceptable. No further action was required.
NC # 277416 2023-07-21 Issued NOL 2023-09-11 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to extend the shelf life of the drug substances. The submission was reviewed and considered acceptable, and an NOL was issued.
PBRER # 271339 2023-01-12 Review completed 2023-06-27 Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. PBRER #2 for the period 2022-05-14 to 2022-11-13. The information was reviewed and found acceptable. No further action was required.
SNDS # 273952 2023-04-03 Issued NOC 2023-05-30 Submission filed as a Level II – Supplement (Safety) to update the PM with neutralizing activity of Evusheld against the Omicron XBB.1.5 variant. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Microbiology section of the PM. An NOC was issued.
NC # 273300 2023-03-14 Issued NOL 2023-05-15 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to extend the shelf life of the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 271993 2023-02-01 Issued NOC
2023-03-09

Submission filed as a Level II – Supplement (Safety) to update the PM with a change in language for hypersensitivity and anaphylaxis. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, and Adverse Reactions sections of the PM. An NOC was issued.

PBRER # 266241 2022-07-21 Review completed
2023-02-17

Submission filed in response to commitments made as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. PBRER #1 for the period 2021-11-14 to 2022-05-13. The information was reviewed and found acceptable. No further action was required.

Risk Management Plan update Control # 268894 2022-10-20 Review completed
2023-02-07

The Canadian Addendum to the Risk Management Plan (RMP) succession #4 dated October 2022 and the draft protocol for a pregnancy study were filed as per the terms and conditions imposed on the authorization issued under the Food and Drug Regulations. The information was reviewed and found acceptable. No further action was required.

Health Professional Risk Communication Not applicable Posted
2023-01-17

Health Professional Risk Communication posted (Evusheld [tixagevimab and cilgavimab for injection] - Risk of Prophylaxis or Treatment Failure due to Antiviral Resistance to specific SARS-CoV-2 Subvariants), containing new safety information for health professionals.

SNDS # 270214 2022-11-30 Issued NOC
2023-01-12

Submission filed as a Level II – Supplement (Safety) to update the PM with in vitro neutralization data for several Omicron subvariants. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Microbiology section of the PM. An NOC was issued.

NC # 270665 2022-12-15 Issued NOL
2023-01-09

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to transfer quality control testing of the drug product to a different site. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 270075 2022-11-25 Issued NOL
2022-12-07

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to transfer quality control testing of the drug substance to a different site. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 266528 2022-07-28 Issued NOC
2022-11-09

Submission filed as a Level I – Supplement to change the dosing regimen for the pre-exposure prophylaxis of COVID-19 from a single 300 mg dose (150 mg tixagevimab and 150 mg cilgavimab) to a 600 mg dose (300 mg tixagevimab and 300 mg cilgavimab) every 6 months. The information was reviewed and considered acceptable. An NOC was issued.

Health Professional Risk Communication Not applicable Posted
2022-10-26

Health Professional Risk Communication posted (Evusheld [tixagevimab and cilgavimab for injection] - Risk of Prophylaxis or Treatment Failure due to Antiviral Resistance), containing information about product safety for health professionals.

SNDS # 265382 2022-06-22 Issued
2022-10-18

Submission filed as a Level I – Supplement for a new indication. The indication authorized was: the treatment of mild to moderate COVID-19 in adult and adolescent patients (≥12 years of age weighing at least 40 kg). The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.

NC # 265906 2022-07-08 Issued NOL
2022-07-15

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to extend the shelf life of lot CAAN from 18 to 24 months when stored at 2 oC to 8 oC. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 265693 2022-06-30 Issued NOC
2022-07-28

Submission filed as a Level I – Supplement to add an alternate manufacturing site for the production of the cilgavimab and tixagevimab drug substances. There were no changes to the manufacturing process for the drug substances. The information was reviewed and considered acceptable. An NOC was issued.

Drug product (DIN 02526271) market notification Not applicable Date of first sale:
2022-04-19
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
Health Product Risk Communication Not applicable Posted
2022-04-14
Health Professional Risk Communication posted (Distribution of Evusheld [tixagevimab and cilgavimab for injection] with English-Only Vial and Carton Labels), containing important information about labelling and supply for healthcare professionals.
NDS # 258295 2021-11-03 Issued NOC (subject to terms and conditions)
2022-04-14
NOC issued for New Drug Submission. Terms and conditions were imposed on the authorization.
Summary Basis of Decision (SBD) for Evusheld

Date SBD issued: 2022-06-15

The following information relates to the New Drug Submission for Evusheld.

Tixagevimab and Cilgavimab

Drug Identification Number (DIN):

  • DIN 02526271 - 150 mg/1.5 mL tixagevimab, solution, and 150 mg/1.5 mL cilgavimab, solution, co-packaged, intramuscular administration

AstraZeneca Canada Inc.

New Drug Submission Control Number: 258295

 

On April 14, 2022, Health Canada issued a Notice of Compliance (NOC), subject to terms and conditions, to AstraZeneca Canada Inc. for the drug product Evusheld.

The Food and Drug Regulations were amended on March 18, 2021 to incorporate flexibilities into the existing new drug submission (NDS) regulatory pathway, thereby facilitating the regulatory process for authorization of new drugs that treat or prevent coronavirus disease 2019 (COVID-19). The modified requirements allow an NDS for a designated COVID-19 drug to be filed through a rolling submission process, i.e., as the information becomes available. Sponsors are responsible for completing the required documentation and providing the necessary evidence to Health Canada. Health Canada will issue an NOC for a COVID-19 drug if it is determined that the benefits and risks of the product are supported by evidence of the safety, efficacy, and consistent quality of the drug.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit-risk profile of Evusheld is favourable for the pre-exposure prophylaxis of COVID-19 in adults and adolescents (12 years of age and older weighing at least 40 kg), who have not had a known recent exposure to an individual infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and:

  • who are immune compromised and unlikely to mount an adequate immune response to COVID-19 vaccination; or
  • for whom COVID-19 vaccination is not recommended.

Pre-exposure prophylaxis with Evusheld is not a substitute for vaccination in individuals for whom COVID-19 vaccination is recommended.

Evusheld is authorized in accordance with the Food and Drug Regulations, subject to terms and conditions that need to be met by the sponsor. Terms and conditions may be imposed or amended at any time. Additionally, failure to comply with the terms and conditions may result in compliance and enforcement actions being taken by Health Canada.

For further information on the amended regulatory pathway, refer to the Guidance on Amendments to the Food and Drug Regulations for Drugs for Use in Relation to COVID-19.

1 What was approved?

Evusheld contains two active substances, tixagevimab and cilgavimab, which are both long-acting human immunoglobulin G1 monoclonal antibodies. They bind to non-overlapping epitopes on the receptor binding domain of the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and block its interaction with the human angiotensin-converting enzyme 2 (ACE2) receptor. As the human ACE2 receptor mediates cell entry, blocking the interaction of the spike protein with the ACE2 receptor inhibits infection of the host cell.

Evusheld was authorized for the pre-exposure prophylaxis of coronavirus disease 2019 (COVID-19) in adults and adolescents (12 years of age and older weighing at least 40 kg), who have not had a known recent exposure to an individual infected with SARS-CoV-2 and:

  • who are immune compromised and unlikely to mount an adequate immune response to COVID-19 vaccination; or
  • for whom COVID-19 vaccination is not recommended.

Pre-exposure prophylaxis with Evusheld is not a substitute for vaccination in individuals for whom COVID-19 vaccination is recommended.

Circulating SARS-CoV-2 viral variants may be associated with resistance to monoclonal antibodies. Healthcare professionals should therefore review the antiviral resistance information provided in the Evusheld Product Monograph (microbiology section) regularly, in conjunction with literature and local guidelines, for details regarding specific variants and resistance.

Evusheld is not authorized for use in individuals younger than 12 years of age or adolescents weighing less than 40 kg. The safety and efficacy of Evusheld has not been assessed in pediatric populations (younger than 18 years of age) in clinical studies. An allometric scaling approach (which accounted for the effect of body weight changes associated with age on clearance and volume of distribution) was applied to serum exposure data from adults. In patients 12 to 17 years of age and weighing at least 40 kg, the recommended dosing regimen is expected to result in comparable serum exposures of Evusheld.

Evusheld is contraindicated in individuals who have a history of severe hypersensitivity reactions, including anaphylaxis, to these drugs or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

Tixagevimab and cilgavimab are presented as two separate solutions. Each solution must be administered as a single intramuscular injection, preferably one injection in each gluteal muscle. Each Evusheld carton contains one 150 mg/1.5 mL vial of tixagevimab co-packaged with one 150 mg/1.5 mL vial of cilgavimab. In addition to the medicinal ingredients, each solution also contains the following non-medicinal ingredients: L-histidine, L-histidine hydrochloride monohydrate, polysorbate 80, sucrose, and water.

Evusheld was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Evusheld Product Monograph is available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.

For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

2 Why was Evusheld approved?

Health Canada considers that the benefit-risk profile of Evusheld is favourable for the pre-exposure prophylaxis of coronavirus disease 2019 (COVID-19) in adults and adolescents (12 years of age and older weighing at least 40 kg), who have not had a known recent exposure to an individual infected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and:

  • who are immune compromised and unlikely to mount an adequate immune response to COVID-19 vaccination; or
  • for whom COVID-19 vaccination is not recommended.

Pre-exposure prophylaxis with Evusheld is not a substitute for vaccination in individuals for whom COVID-19 vaccination is recommended. Evusheld is authorized in accordance with the Food and Drug Regulations, subject to terms and conditions that need to be met by the sponsor.

Coronavirus disease 2019 is the infectious disease caused by the novel coronavirus SARS-CoV-2, which has spread rapidly and globally since its emergence in late 2019. In Canada, there have been 3,604,789 confirmed cases of COVID-19 and approximately 38,165 deaths as of April 14, 2022, the date of authorization of Evusheld.

Severe acute respiratory syndrome coronavirus 2 is a highly transmissible and pathogenic coronavirus. Coronavirus disease 2019 is predominantly a respiratory illness that can affect other organs. People with COVID 19 can be asymptomatic, or can experience a range of symptoms from mild to severe illness. Symptoms may appear 1 to 14 days after exposure to the virus. Symptoms may include fever (≥38 °C) or chills, cough, shortness of breath, fatigue, muscle or body aches, headache, loss of taste or smell, sore throat, runny nose, nausea or vomiting, and diarrhea. Severe COVID-19 can progress to include pneumonia, severe acute respiratory syndrome, multi-organ failure, and death. The highest disease burden is in older adults and individuals with certain underlying medical conditions such as high blood pressure, obesity, heart disease, chronic kidney disease, diabetes, cancer, and pulmonary obstructive disease.

Health Canada has authorized the following vaccines for protection against COVID-19: Comirnaty (previously Pfizer-BioNTech COVID-19 Vaccine), Spikevax (previously COVID-19 Vaccine Moderna, Vaxzevria (previously AstraZeneca COVID-19 Vaccine), Covishield, Janssen COVID-19 Vaccine, Nuvaxovid, and Covifenz. Available treatments include antiviral medications Veklury (remdesivir), and Paxlovid (nirmatrelvir and ritonavir) and therapeutic monoclonal antibodies bamlanivimab, casirivimab/imdevimab, and sotrovimab.

Prior to the authorization of Evusheld, there were no non-vaccine products authorized in Canada for the prophylaxis of COVID-19. Therefore, there remains an unmet clinical need for immune compromised individuals who are unlikely to mount an adequate immune response to vaccination or for whom vaccination is not recommended. Evusheld is not a substitute for vaccination in individuals for whom COVID-19 vaccination is recommended.

Evusheld is a combination of two fully humanized Fc-modified immunoglobulin G1 monoclonal antibodies (tixagevimab and cilgavimab) that attach to the spike protein of SARS-CoV-2 at two different sites, thereby blocking the virus from binding to the angiotensin-converting enzyme 2 (ACE2) receptor and preventing viral entry into host cells.

Evusheld has been shown to be efficacious for the prevention of symptomatic COVID-19 in adults and adolescents without prior history of COVID-19 and who had not received COVID-19 vaccination. The market authorization was based primarily on efficacy data from the Phase III, randomized, double-blind, placebo-controlled PROVENT study. This study assessed the efficacy and safety of a single 300 mg dose of Evusheld compared to placebo for the pre-exposure prevention of COVID-19.

The primary efficacy endpoint was the first case of SARS-CoV-2 symptomatic laboratory-confirmed illness (a positive result using real-time reverse transcriptase polymerase chain reaction [RT-PCR] test) occurring following the administration of Evusheld or placebo and prior to Day 183. The primary analysis included 5,172 participants who were negative for SARS-CoV-2 at baseline (confirmed by RT-PCR), of which 3,441 received Evusheld and 1,731 received placebo. The median follow-up time post-administration was 83 days. The results from the PROVENT study showed a statistically significant reduction in the percentage of participants who developed symptomatic laboratory-confirmed COVID-19 with Evusheld 0.2% (8/3,441) compared to placebo 1.0% (17/1,731). The relative risk reduction was 76.7% (95% confidence interval [CI] 46.1, 90.0, p <0.001).

The clinical safety profile of a single dose of Evusheld 300 mg is based on data from two Phase III studies: the pre-exposure prophylaxis PROVENT study and the STORM CHASER study (a double-blind, placebo-controlled clinical trial for the post-exposure prophylaxis of COVID-19, an indication for which Evusheld is not approved). A total of 4,210 adult participants were included in the safety data with the median duration for safety follow-up being 137 days for PROVENT and 121 days for STORM CHASER.

Across the two safety studies, the administration of a single dose of 300 mg Evusheld by intramuscular injection was well-tolerated. The adverse reactions associated with use of Evusheld included hypersensitivity, injection site, and anaphylactic reactions. These reactions were generally mild and reported in a small number of participants. While infrequent overall, a small increase in serious cardiac disorders (including myocardial infarction and cardiac failure) and thromboembolic events occurred in participants who received Evusheld compared to those who received placebo. Most participants with these events had risk factors for cardiac disease or a history of cardiovascular disease prior to receiving Evusheld. A relationship between Evusheld and these events has not been established.

No adolescents (12 years of age and older) were included in the clinical studies of Evusheld. The inclusion of adolescents (12 years and older and weighing at least 40 kg) in the authorized indication was based on population pharmacokinetic modeling. Weight (36 to 177 kg) was not found to have a clinically significant effect on the pharmacokinetics of Evusheld based on an allometric scaling method and therefore a 40 kg weight limitation was considered reasonable.

A Core Risk Management Plan (RMP) and a Canadian RMP Addendum for Evusheld were submitted by AstraZeneca Canada Inc. to Health Canada. The RMP is designed to describe known and potential safety issues, to present the post-authorization monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. Upon review, the RMP was considered to be acceptable with revisions to include specific follow-up questionnaires for specific adverse reactions. The RMP included appropriate monitoring activities and risk minimization measures based on the known safety profile of Evusheld. The RMP will be updated to reflect additional safety information as it is collected. 

The submitted inner and outer labels and the Patient Medication Information section of the Evusheld Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

Based on the submitted information, the benefit-risk profile of Evusheld is considered favourable for the target population. Appropriate warnings and precautions are in place in the Evusheld Product Monograph to address the identified safety concerns. Additional efficacy and safety data from ongoing studies and post-market safety monitoring data will be submitted to Health Canada, as specified in the terms and conditions imposed in respect of Evusheld. These data will be submitted to Health Canada when available.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has issued an NOC pursuant to section C.08.004 of the Food and Drug Regulations. The NOC in respect of Evusheld is accompanied by terms and conditions imposed in accordance with section C.01.014.21 of the Food and Drug Regulations. Of note, terms and conditions may be imposed or amended at any time. All terms and conditions are enforceable under section 21.7 of the Food and Drugs Act. Failure to comply with the terms and conditions may result in compliance and enforcement actions being taken by Health Canada.

For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Evusheld?

The Food and Drug Regulations were amended on March 18, 2021 to incorporate flexibilities into the existing new drug submission (NDS) regulatory pathway, thereby facilitating the regulatory process for authorization of new drugs that treat or prevent coronavirus disease 2019 (COVID-19). For example, to expedite the review process, the modified requirements allow an NDS for a designated COVID-19 drug to be filed through a rolling submission process, i.e., as the information becomes available. This in turn allows Health Canada to commence a rolling review process of the information submitted. As outlined in the Guidance on amendments to the Food and Drug Regulations for drugs for use in relation to COVID-19, Health Canada will begin its review using the information submitted by the sponsor and accept new evidence as it becomes available until the submission is deemed complete. The rolling process can reduce the time it takes to authorize these critical new drugs while maintaining appropriate standards of safety, efficacy, and quality. Sponsors are responsible for completing the required documentation and providing the necessary evidence to Health Canada. Health Canada will issue a Notice of Compliance (NOC) for a COVID-19 drug if it is determined that the benefits and risks of the product are supported by evidence of the safety, efficacy, and consistent quality of the drug. Importantly, the amended regulations also allow the use of terms and conditions in order to ensure appropriate oversight, manage uncertainties or mitigate risks related to the drug in the context of the public health need due to COVID-19.

The information for this NDS was provided on a rolling basis. Following an expedited review of the data submitted, Health Canada determined that sufficient evidence was provided to support the conclusion that the benefits of Evusheld outweigh the risks under the conditions of use recommended, with consideration given to the uncertainties relating to those benefits and risks as well as the public health need related to COVID-19. Health Canada issued an NOC for Evusheld, with imposed terms and conditions, on April 14, 2022.

The review of the quality, non-clinical, and clinical components of the New Drug Submission (NDS) for Evusheld was based on a critical assessment of the data package submitted to Health Canada. The reviewers also considered documents and/or sponsor’s responses to information requests made by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) as added references.

For further information on the amended regulatory pathway, refer to the Guidance on Amendments to the Food and Drug Regulations for Drugs for Use in Relation to COVID-19.

 

Submission Milestones: Evusheld

Submission Milestone Date
Pre-submission meeting 2021-10-26
Initial New Drug Submission filed by sponsor 2021-11-03
Initial non-clinical data submitted by sponsor 2021-11-03
Screening Acceptance Letter issued 2021-11-12
Initial clinical data submitted by sponsor 2022-02-02
Risk Management Plan submitted by sponsor 2022-02-02
Initial quality data submitted by sponsor 2022-02-09
Health Canada quality evaluation completed 2022-04-06
Health Canada Risk Management Plan evaluation completed 2022-04-07
Health Canada labelling evaluation completed 2022-04-12
Health Canada non-clinical evaluation completed 2022-04-12
Health Canada clinical/medical evaluation completed 2022-04-12
Terms and conditions finalized by Health Canada 2022-04-12
Final Product Monograph (English) submitted by sponsor 2022-04-12
Final Product Monograph (French) submitted by sponsor 2022-04-12
Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate 2022-04-14
4 What follow-up measures will the company take?

The Notice of Compliance issued in respect of Evusheld is accompanied by terms and conditions imposed on the drug identification number assigned to Evusheld in accordance with section C.01.014.21 of the Food and Drug Regulations. Of note, terms and conditions may be imposed or amended at any time. Failure to comply with the terms and conditions may result in compliance and enforcement actions being taken by Health Canada.

These terms and conditions set out requirements relating to clinical information, risk management plan (RMP) elements, and labelling, and were put in place to ascertain the continued efficacy and safety of the product.

The terms and conditions include (but are not limited to) the requirements listed below.

The sponsor is required to submit the following when the data become available:

  • Final study reports for PROVENT, STORM CHASER, and TACKLE.
  • Final study report for the PROVENT repeat-dose sub-study: A Phase III Multicentre, Open-label Sub-study in Adults to Assess the Safety, Pharmacokinetic, and Immunogenicity of Repeat Doses of AZD7442, a Combination Product of Two Monoclonal Antibodies (AZD8895 and AZD1061) (The PROVENT Repeat Dose Sub-study) (D8850C002A01).
  • Interim analysis results through Day 28 for the first 50 subjects to receive a second dose from the PROVENT repeat-dose sub-study.
  • Data from baseline and all subsequent study visits, of the following biomarkers from the PROVENT repeat-dose sub-study: d-dimer, P-selectin, thrombin, and Factor VIII.
  • Topline data, to include safety, pharmacokinetic, anti-drug antibodies, and biomarker results for thrombotic events from the first 9 months of the PROVENT repeat-dose sub-study.
  • Results, and any interim analysis, of the randomized, dose-ranging clinical trial investigating safety, immunogenicity, pharmacokinetics, pharmacodynamics and efficacy in individuals with moderate to severe immunocompromise who may not mount an adequate immune response to coronavirus disease 2019 (COVID-19) vaccination evaluating the following dosing regimens for COVID-19 pre-exposure prophylaxis:
    • Evusheld (300 mg tixagevimab and 300 mg cilgavimab) administered as two consecutive intramuscular (IM) injections followed 3 months later by Evusheld (150 mg tixagevimab and 150 mg cilgavimab) administered as two consecutive IM injections with subsequent redosing every 3 months.
    • Evusheld (600 mg tixagevimab and 600 mg cilgavimab) administered as intravenous infusion followed 6 months later by Evusheld (300 mg tixagevimab and 300 mg cilgavimab) administered as two consecutive IM injections with subsequent re-dosing every 6 months.
  • Final report of the study evaluating the potential for tixagevimab and cilgavimab to mediate antibody-dependent enhancement of infection using sub-saturating concentrations of each monoclonal antibody.
  • Regular updates to Health Canada regarding the activity and/or clinical efficacy/effectiveness of tixagevimab and cilgavimab against the current and future variants of concern and variants of interest identified by the World Health Organization (WHO).

Additionally, the sponsor is required to:

  • Submit final snapshots of all components of the electronic platform containing the approved Canadian-specific information for Evusheld in French and English for Health Canada’s review and records, prior to launch of the electronic platform, and for each subsequent update.
  • Submit an updated Canadian-specific Risk Management Plan (RMP) Addendum. The Canadian RMP addendum shall address the following:
    • lack of efficacy - in particular related to effectiveness against circulating variants of concern;
    • cardiac disorders;
    • embolic and thrombotic events;
    • exposure during pregnancy.
  • Submit Periodic Benefit Risk Evaluation Reports every 6 months.
  • Implement Canadian-specific bilingual labelling for Evusheld once supplies are transitioned to Canadian-dedicated supplies. Health Canada should be kept informed of estimated timelines and proposed strategies concerning the implementation of Canadian-specific bilingual labels.
6 What other information is available about drugs?

Up-to-date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

The New Drug Submission for Evusheld (tixagevimab and cilgavimab) was submitted and reviewed in accordance with the Food and Drug Regulations, which permitted a rolling submission and review process. Following review of the provided information, a Notice of Compliance was issued in relation to Evusheld, with accompanying terms and conditions to manage any uncertainties or mitigate risks related to the drug.

Clinical Pharmacology

Evusheld is a combination monoclonal antibody therapy consisting of two human monoclonal antibodies (tixagevimab and cilgavimab) that bind to the receptor-binding domain of the spike protein of SARS-CoV-2. This action neutralizes virus infectivity by blocking the ability of the virus to bind to angiotensin-converting enzyme 2 (ACE2) receptors. Blocking the interaction of the spike protein with ACE2 receptors inhibits the infection of host cells. When administered together, tixagevimab and cilgavimab neutralize SARS-CoV-2 infection (USA-WA1/2020 isolate) with a half maximal inhibitory concentration (IC50) of 10 ng/mL.

The safety, tolerability, pharmacokinetics, and pharmacodynamics of Evusheld were evaluated in a first in-human study in healthy adult participants 18 to 55 years of age who received a single 300 mg dose of Evusheld intravenously (number of individuals [n] = 10) or intramuscularly (n = 10). The values for the geometric mean of the maximum serum concentration (Cmax) following each intramuscular injection were similar for tixagevimab and cilgavimab at 16.52 µg/mL and 15.27 µg/mL, respectively. The median time to reach the maximum concentrations for both antibodies was 14 days. The bioavailability of Evusheld was 68.5% for tixagevimab and 65.8% for cilgavimab calculated as the geometric mean of exposure as measured by the area under the concentration-time curve extrapolated to infinity (AUCinf) after intramuscular injection compared to intravenous injection. The half-lives were 88 and 83 days for tixagevimab and cilgavimab, respectively.

The effectiveness of Evusheld was demonstrated by the strong neutralization potential of this combination antibody therapy in the serum of healthy volunteers administered this product using a live virus assay.

A population pharmacokinetic analysis of pooled Phase I and III data was performed to characterize the pharmacokinetics of Evusheld and to evaluate the impact of covariates such as demographics and renal and liver function tests on the pharmacokinetic exposure. A two-compartmental model adequately described the data, with first-order absorption and first-order elimination for tixagevimab, cilgavimab, and Evusheld pharmacokinetics following intravenous and intramuscular administration. In total, 7,450 serum pharmacokinetic samples from a total of 2,560 participants administered Evusheld were available for inclusion in this analysis.

Three covariates (i.e., age, gender, diabetes) were found to affect the pharmacokinetics of Evusheld. Participants 65 years of age or older showed slightly lower absorption compared to participants less than 65 years of age. Male participants were found to have a faster absorption rate and a lower central volume of distribution and therefore a slightly lower exposure compared to female participants. Participants with diabetes were found to have a modestly higher clearance of 20% and a higher volume of distribution of 43% and so the presence of diabetes as a co-morbidity resulted in lower Evusheld concentrations (32% lower exposure based on the area under the concentration-time curve [AUC]) due to faster clearance and higher volume of distribution.

Evusheld was authorized for use in individuals who are immunocompromised where administration of a SARS-CoV-2 vaccine is not considered a viable option or where the administered SARS-CoV-2 vaccine is not expected to produce an adequate immune response. In the sponsor's analysis, an immunosuppressive or immunocompromised state resulted in a small increase in clearance (8%) that was not considered to be clinically meaningful. Health Canada acknowledges this small effect and at this time supports the sponsor’s position but will assess this further as the population pharmacokinetic is updated with more pharmacokinetic data points in future iterations of this model.

In the clinical studies of Evusheld, only participants aged 18 years or older were included in clinical studies; however, the recommended indication also includes adolescent patients 12 to 17 years of age and weighing at least 40 kg. As per the population pharmacokinetic model, weight from 36 to 177 kg was not found to have a clinically significant affect on the pharmacokinetics of Evusheld based on an allometric scaling method and therefore a 40 kg weight limitation is considered reasonable. Furthermore, Evusheld consists of two monoclonal antibodies that are not expected to be affected by differential expression profiles in cytochrome P450 (CYP) or other enzymes between adults and adolescents and therefore their metabolism will not be altered based on any differences in the populations. The safety and efficacy profile of Evusheld is not expected to be altered in adolescents who meet the weight requirements.

Overall, the clinical pharmacology program is considered sufficient for authorization of Evusheld. The data provided demonstrated strong neutralization potential of Evusheld in the serum of healthy volunteers administered this combination antibody product using a live virus assay and there was a direct correlation between neutralization potential and serum concentrations. Health Canada considers that some uncertainties remain (i.e., diabetes and body mass index effects) when taking into account the evolving SARS-CoV-2 variants that overcome in part the neutralization by Evusheld at the recommended clinical dose. The authorization of Evusheld is therefore accompanied by terms and conditions to address these uncertainties and mitigate risks.

Viral Dynamic Model

In order to extrapolate efficacy findings to the Omicron variant, the sponsor used viral dynamic modeling. The predictions of viral load time-course profiles based on various doses and potency of Evusheld to Omicron variants were considered during the review.

Population pharmacokinetic model-based simulations, which incorporates the viral dynamic model derived minimal required inhibition, were available during the review that sought to predict the percentage of individuals who would attain the minimum protective concentration of Evusheld following 300 mg and 600 mg doses against the Omicron sub-variants BA.1 and BA1.1. The predictions indicated that the 600 mg dose may improve the probability of achieving the minimum protective concentration against BA.1 and BA.1.1 while the 300 mg dose may be sub-optimal for protection against these strains.

For further details, please refer to the Evusheld Product Monograph, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.

Clinical Efficacy

The efficacy of Evusheld for the pre-exposure prophylaxis of COVID-19 in adults) was primarily supported by the pivotal study PROVENT.

PROVENT is an ongoing Phase III, randomized, double-blind, placebo-controlled, multicentre clinical study assessing the safety and efficacy of a single 300 mg dose of Evusheld (two intramuscular injections) compared to placebo for the pre-exposure prevention of COVID-19. The participants were adults (18 years of age and older) considered at increased risk for inadequate response to active immunization (due to age of 60 years or older, co-morbidity, pre-existing chronic illness, immunocompromised state, or intolerance to vaccination), or at increased risk of SARS-CoV-2 infection (due to their location or circumstances at time of enrolment). The study excluded participants with a history of laboratory-confirmed SARS-CoV-2 infection, SARS-CoV-2 antibody positivity at screening, and any prior receipt of investigational or licensed COVID-19 vaccine. Due to the deployment of COVID-19 vaccines during the study, the protocol was amended to permit unblinding and allow participants to make an informed choice on vaccine timing and to receive COVID-19 vaccination. Participants were randomized (2:1) to receive either a single dose of Evusheld 300 mg or placebo by intramuscular injection.

The primary efficacy endpoint was the first case of SARS-CoV-2 symptomatic laboratory-confirmed illness (a positive result using a real-time reverse transcriptase polymerase chain reaction [RT-PCR] test) occurring post-dose and prior to day 183 based on the full pre-exposure analysis set. Only events that occurred prior to unblinding or vaccine receipt were included. Participants who became unblinded or received COVID-19 vaccine were censored for the analysis of the primary efficacy endpoint.

Baseline demographics were well balanced across the Evusheld and placebo arms. The median age was 57 years (with 43% of participants aged 60 years or older), 46% of participants were female, 73% were White, 3.3% were Asian, 17% were Black/African American, and 15% were Hispanic/Latino. Of the 5,197 participants, 78% had baseline co-morbidities or characteristics associated with an increased risk for severe COVID-19, including obesity (42%), diabetes (14%), cardiovascular disease (8%), cancer, including a history of cancer (7%), chronic obstructive pulmonary disease (5%), chronic kidney disease (5%), chronic liver disease (5%), immunosuppressive medications (3%) and immunosuppressive disease (<1%).

The primary efficacy analysis included 5,172 participants and was conducted after a median follow-up time of 83 days for both the Evusheld and placebo arms. A statistically significant benefit was reported with Evusheld compared to placebo for the first occurrence of SARS-CoV-2 RT-PCR-positive symptomatic illness. A total of 8 (0.2%; 8/3,441) participants who received Evusheld and 17 (1.0%; 17/1,731) participants who received placebo were reported with a first occurrence of symptomatic laboratory-confirmed COVID-19. The relative risk reduction was 76.7% (95% confidence interval [CI] 46.1, 90.0, p <0.001).

Two key supportive analyses of the primary efficacy endpoint were included within a hierarchical multiple testing strategy. In the first key supportive analysis, which included participants regardless of unblinding or receipt of COVID-19 vaccine, the relative risk reduction for the first case of SARS-CoV-2 RT-PCR-positive symptomatic illness was 77.3% (95% CI 52.0, 89.3). In the second key supportive analysis of the incidence of SARS-CoV-2 RT-PCR-positive symptomatic illness or death from any cause, the relative risk reduction was 68.8% (95% CI 35.6, 84.9).

A post-hoc analysis of the primary efficacy endpoint was provided after a median follow-up of 6.5 months. The relative risk reduction of SARS-CoV-2 RT-PCR-positive symptomatic illness was 82.8% (95% CI 65.8, 91.4) with 11 (0.3%; 11/3,441) events in the Evusheld arm and 31 (1.8%; 31/1,731) events in the placebo arm.

Limitations or gaps in the available clinical data for Evusheld have been identified:

  • No clinical data are available on its effectiveness against the currently dominant Omicron sub-variants.
  • The benefit in a vaccinated population is unclear.
  • There are limited clinical data available in immunocompromised individuals.
  • There are insufficient data to support its benefit in the prevention of COVID-19 related hospitalization or death.
  • There are no safety and efficacy data available on repeat dosing.
  • At the current authorized 300 mg dose, clinical data did not demonstrate the effectiveness of Evusheld as a prophylaxis therapy in individuals who have been exposed to an active SARS-CoV-2 infection.

Despite the noted uncertainties, considering the statistically significant reduction in SARS-CoV-2 RT-PCR-positive symptomatic disease with Evusheld compared to placebo, and the generally well-tolerated safety profile, and taking into account the public health need for a pre-exposure prophylaxis option for COVID-19, in immunocompromised individuals who may not mount an adequate immune response to vaccination or individuals for whom vaccination is not recommended, Health Canada considers that Evusheld has an overall favourable benefit-risk profile for the authorized indication. The authorization is accompanied by terms and conditions to manage uncertainties and mitigate risks related to the drug. Appropriate warnings and precautions are in place in the Evusheld Product Monograph to address the identified risks.

Indication

The New Drug Submission for Evusheld was filed by the sponsor with the following indication:

Evusheld (tixagevimab and cilgavimab) is indicated for the prophylaxis of coronavirus disease 2019 (COVID-19) in adults and adolescents (≥12 years of age weighing at least 40 kg).

Health Canada approved the following indication:

Evusheld (tixagevimab and cilgavimab) is indicated for the pre-exposure prophylaxis of coronavirus disease 2019 (COVID-19) in adults and adolescents (≥12 years of age weighing at least 40 kg) who have not had a known recent exposure to an individual infected with SARS-CoV-2:

  • who are immune compromised and unlikely to mount an adequate immune response to COVID-19 vaccination; or
  • for whom COVID-19 vaccine is not recommended.

Pre-exposure prophylaxis with Evusheld is not a substitute for vaccination in individuals for whom COVID-19 vaccination is recommended.

The proposed indication was revised by Health Canada, as the Phase III clinical trials submitted only demonstrated the benefit of Evusheld for the pre-exposure prophylaxis of COVID-19. Based on the availability of COVID-19 vaccinations in Canada, and the totality of the evidence, the indication was revised to target a population with an unmet medical need who may benefit from passive immunization.

For more information, refer to the Evusheld Product Monograph, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.

Clinical Safety

The evidence of safety for Evusheld 300 mg is based primarily on data from the pivotal study PROVENT (described in the Clinical Efficacy section) and STORM CHASER (a double-blind, placebo-controlled clinical trial for the post-exposure prophylaxis of COVID-19, an indication for which EVUSHELD is not approved). The safety data from a Phase III clinical study, TACKLE, was also reviewed as part of the safety evaluation in support of a 600 mg dosing option.

PROVENT

The safety data reviewed from the PROVENT study is based on 3,461 participants who received Evusheld and 1,736 participants who received placebo. The median duration of follow-up in the study was 137 days for the Evusheld arm and 135 days for the placebo arm.

Overall, the proportion of participants who experienced adverse events was balanced between the two arms (41% Evusheld and 40% placebo). The most frequently reported adverse events included, headache, fatigue, and cough.

Serious adverse events occurred in a small proportion of participants in each treatment arm (3% Evusheld and 2% placebo). Of the participants with at least one adverse event, the majority were mild or moderate in intensity and balanced between treatment arms.

Supportive safety data was provided after a median follow-up of 196 days in both treatment arms. A higher proportion of participants who received Evusheld versus placebo reported serious cardiac disorders (0.7% Evusheld versus 0.3% placebo), notably myocardial and cardiac failure. A small imbalance was also observed for serious thromboembolic events (0.5% Evusheld versus 0.2% placebo). Most participants who experienced these events had cardiovascular risk factors and/or a prior history of cardiovascular disease, and there was no clear temporal pattern. An underlying mechanism is not clear and a causal relationship has not been established. The potential risk of cardiac or thromboembolic events has been included under the Warnings and Precautions section of the Evusheld Product Monograph. Healthcare practitioners should consider the risks and benefits prior to initiating Evusheld in individuals at high risk for cardiovascular or thromboembolic events, and advise individuals to seek immediate medical attention if they experience any signs or symptoms suggestive of a cardiovascular or thromboembolic event.

Adverse events resulting in death were reported for 9 (0.3%) participants in the Evusheld arm and 7 (0.4%) in the placebo arm. None of the deaths were considered related to Evusheld by the study investigator. Four deaths in the Evusheld arm and 0 deaths in the placebo arm were due to cardiac disorders (including arrhythmia, congestive cardiac failure, cardio-respiratory arrest and myocardial infarction). All of these participants had cardiac risk factors or a history of cardiovascular disease at baseline.

Treatment-emergent anti-tixagevimab, anti-cilgavimab and anti-Evusheld antibodies were detected in 0.8% (6/716), 1.1% (7/644) and 1.3% (10/743) of the anti-drug antibody evaluable participants who received Evusheld. The number of participants with treatment-emergent anti-drug antibodies was too low to establish a potential impact on pharmacokinetics, safety, or efficacy.

STORM CHASER

A second Phase III study, STORM CHASER, was submitted in support of the use of Evusheld for post-exposure prophylaxis of COVID-19. However, the results from the STORM CHASER study did not support the benefit of Evusheld in participants with a known exposure to SARS-CoV-2. Therefore, the approved indication is specific to the pre-exposure prophylactic setting, as supported by the PROVENT study. The safety data from the STORM CHASER study was included as part of the safety evaluation for the 300 mg Evusheld dose. The safety data reviewed are based on 749 participants who received Evusheld and 372 participants who received placebo. The median duration of follow-up was 121 days.

Overall, the safety profile from STORM CHASER was generally similar to that reported in PROVENT. The proportion of participants who experienced adverse events was 31% in Evusheld-treated subjects and 40% in placebo-treated subjects.

Serious adverse events were reported in 1% of Evusheld-treated subjects and 2% in placebo-treated subjects. Of the participants with at least one adverse event, the majority were mild or moderate in intensity.

No serious cardiac disorders were reported. However, the study population in STORM CHASER had fewer participants with baseline cardiovascular disease compared to the study population in PROVENT (2.9% versus 8.1%, respectively).

TACKLE

The available clinical trial data to support the authorization of Evusheld was collected prior to the emergence of the Omicron sub-variants. In vitro laboratory studies showed reduced neutralizing activity of Evusheld against Omicron sub-variants BA.1 (fold reduction: 12-183) and BA.1.1 1 (fold reduction: 176-424). Due to this reduced activity, a 600 mg dosing option (300 mg of tixagevimab and 300 mg of cilgavimab) is recommended in regions where BA.1 and BA.1.1 strains are circulating. Safety data from the TACKLE study was therefore submitted to support the 600 mg dosing option.

The safety of Evusheld 600 mg is based on a total of 452 non-hospitalized adult patients with mild to moderate COVID-19 who received 300 mg of tixagevimab and 300 mg of cilgavimab, via intramuscular injection (within ≤7 days of symptom onset), in the TACKLE study. The TACKLE study is a Phase III, double-blind, placebo-controlled clinical trial for the treatment of adult patients with mild to moderate COVID-19 (an indication for which Evusheld is not approved by Health Canada). The median duration for safety follow-up was 84 days.

The overall safety profile in participants who received 600 mg Evusheld was generally similar to that reported in participants who received 300 mg Evusheld. The most frequently reported adverse reaction in TACKLE was injection site reaction (2.4%). Adverse events were reported more frequently in the placebo arm compared to the Evusheld arm (36% vs 29%, respectively).

Serious adverse events occurred in 7% of participants who received Evusheld compared to 12% who received placebo. Four participants reported serious cardiac events. Acute myocardial infarction was reported for two participants who received Evusheld (one of whom also experienced cardiac failure leading to death) and sudden cardiac death was reported for one participant who received Evusheld. One participant in the placebo group experienced a serious event of arrhythmia. All participants had cardiac risk factors and/or a prior history of cardiovascular disease at baseline.

Special Populations

There is limited data from the use of Evusheld (tixagevimab and cilgavimab) in pregnant women. Non-clinical reproductive toxicity studies have not been performed with tixagevimab and cilgavimab. In a tissue cross reactivity study with tixagevimab and cilgavimab using human fetal tissues, no binding of clinical concern was detected. Human immunoglobulin G1 antibodies are known to cross the placental barrier; therefore, tixagevimab and cilgavimab have the potential to be transferred from the mother to the developing fetus. Evusheld should only be used during pregnancy if the potential benefit outweighs the potential risk for the mother and the fetus.

There are no data available on whether tixagevimab and cilgavimab are excreted in human milk. Exposure to the breastfed infant cannot be excluded. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Evusheld and any potential adverse effects on the breastfed infant from Evusheld or from the underlying maternal condition.

No specific studies have been conducted to examine the effects of hepatic impairment on the pharmacokinetics of tixagevimab and cilgavimab. The impact of hepatic impairment on the pharmacokinetics of tixagevimab and cilgavimab has not been established and it is unknown whether a dose adjustment is needed in these individuals.

Overall, Evusheld was generally well tolerated, as shown in the PROVENT, STORM CHASER, and TACKLE studies. The most frequently reported adverse reaction in the pooled analysis of PROVENT and STORM CHASER was injection site reaction (1.3%). No serious hypersensitivity reactions were reported in the provided clinical studies.

A small imbalance was observed for serious cardiac disorders (0.7% Evusheld versus 0.3% placebo) and serious thromboembolic events (0.5% Evusheld versus 0.2% placebo) in the pivotal study PROVENT. Most participants who experienced these events had cardiovascular risk factors and/or prior cardiovascular disease. The potential risk of cardiac or thromboembolic events has been included in the Warnings and Precautions section of the Product Monograph. Given the nature of the products (recombinant monoclonal antibodies), there is a potential for hypersensitivity and/or anaphylactic reactions. In addition, administration by intramuscular injection may be associated with clinically significant bleeding disorders in individuals with thrombocytopenia or any coagulation disorder. For these reasons, these specific risks are also included under the Warnings and Precautions section of the Product Monograph for Evusheld.

Additional safety data from ongoing studies (including data from the final study reports of PROVENT, STORM CHASER, and TACKLE) and post-market safety monitoring data will be submitted to Health Canada, as specified in the terms and conditions imposed in respect of Evusheld to address the uncertainties in reference to the clinical safety evidence available at the time of the review.

For more information, refer to the Evusheld Product Monograph, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.

7.2 Non-Clinical Basis for Decision

The New Drug Submission for Evusheld (tixagevimab and cilgavimab) was submitted and reviewed in accordance with the Food and Drug Regulations, which permitted a rolling submission and review process. Following review of the provided information, a Notice of Compliance was issued in relation to Evusheld, with accompanying terms and conditions to manage any uncertainties or mitigate risks related to the drug.

Evusheld is a combination product containing two drug substances, tixagevimab and cilgavimab. Tixagevimab and cilgavimab are recombinant human immunoglobulin G1 monoclonal antibodies. In vitro characterization studies showed that tixagevimab and cilgavimab bind with high affinity to non-overlapping epitopes on the receptor binding domain of the spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and block its interaction with the human angiotensin-converting enzyme 2 receptor, which mediates cell entry.

The two antibodies were engineered with amino acid substitutions in the Fc region to extend antibody half-life, reduce antibody effector function, and reduce the potential risk of antibody-dependent enhancement of disease.

In a SARS-CoV-2 virus neutralization assay on Vero E6 cells, tixagevimab, cilgavimab and the combination of the two antibodies neutralized SARS-CoV-2 (USA-WA1/2020 isolate) with half-maximal inhibitory concentration values of 9 ng/mL, 32 ng/mL and 10 ng/mL, respectively.

The potential of tixagevimab and cilgavimab to mediate antibody-dependent viral entry was assessed in FcγRII-expressing Raji cells co-incubated with recombinant virus pseudotyped with SARS-CoV-2 spike protein, with antibody concentrations at a range of 6.6 nM (1 µg/mL) to 824 pM (125 ng/mL). Tixagevimab, cilgavimab and their combination did not mediate entry of pseudovirus into these cells.

Evusheld demonstrated anti-viral activity in the prophylactic setting in animal models of SARS-CoV-2 infection (strain USA-WA1/2020). Intravascular administration in non-human primates prior to SARS-CoV-2 inoculation resulted in a dose-dependent improvement in total viral ribonucleic acid in the lungs or nasal mucosae, infectious virus levels in the lungs, and lung injury and pathology based on histology measurements.  In a Syrian hamster model, prophylactic administration of Evusheld prevented SARS-CoV-2 infection-induced weight loss, reduced viral load in the lungs, and reduced SARS-CoV-2 induced pathogenesis in the lungs compared to control-treated animals. No evidence of antibody-dependent enhancement of disease and/or infection was observed with sub-neutralizing doses of Evusheld in the non-clinical models.

There is a risk of resistance to monoclonal antibodies such as Evusheld due to the development of viral variants that are resistant to tixagevimab and cilgavimab. SARS-CoV-2 or recombinant vesicular stomatitis virus encoding SARS-CoV-2 spike protein were serially passaged in cell cultures in the presence of cilgavimab or tixagevimab individually, or tixagevimab and cilgavimab in combination. Escape variants were identified following passage with cilgavimab, but not with tixagevimab or tixagevimab and cilgavimab in combination. Variants which showed reduced susceptibility to cilgavimab alone included spike protein amino acid substitutions R346I (>200-fold), K444E (>200-fold), and K444R (>200-fold). All variants maintained susceptibility to tixagevimab alone, and tixagevimab and cilgavimab in combination.

In vitro neutralization assays using recombinant pseudovirus SARS-CoV-2 variants and/or authentic live variant strains showed that Evusheld retained activity against the variants of concern Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Delta (+K417N). A reduction in neutralization potency was reported for Evusheld against the Omicron sub-variants BA.1 (fold reduction: 12-183) and BA.1.1 (fold reduction: 176-424) while minimal change in activity was reported against BA.2 (fold reduction: 3.2-5.4) compared to the reference strain.

A single-dose toxicology study of 150 mg/kg (75 mg/kg of tixagevimab and cilgavimab by intramuscular injection) Evusheld in cynomolgus monkeys was conducted. After 8 weeks of follow-up, no Evusheld-related adverse effects were reported. The no-observed-adverse-effect level (NOAEL) was considered to be 150 mg/kg Evusheld.

Cross-reactivity studies of Evusheld were conducted using fetal human tissues and normal human or cynomolgus monkey tissues. No specific binding was reported.

Overall, the non-clinical pharmacology and toxicology profile of Evusheld (tixagevimab and cilgavimab) supports its proposed clinical use.

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

For more information, refer to the Evusheld Product Monograph, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.

7.3 Quality Basis for Decision

The New Drug Submission for Evusheld (tixagevimab and cilgavimab) was submitted and reviewed in accordance with the Food and Drug Regulations, which permitted a rolling submission and review process. Following review of the provided information, a Notice of Compliance was issued in relation to Evusheld, with accompanying terms and conditions to manage any uncertainties or mitigate risks related to the drug.

Characterization of the Drug Substance

Evusheld is a combination product containing two drug substances, tixagevimab and cilgavimab. Tixagevimab and cilgavimab are recombinant human immunoglobulin G1 monoclonal antibodies. Each antibody targets and binds specifically to the receptor-binding domain of the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This binding action neutralizes virus infectivity by blocking the ability of SARS-CoV-2 spike protein to bind to angiotensin-converting enzyme 2 receptors; the interaction which mediates cell entry and leads to the infection of host cells.

Detailed characterization studies were performed to provide assurance that tixagevimab and cilgavimab consistently exhibit the desired characteristic structure and biological activity. Primary and higher order structures, identity, molecular weight, size heterogeneity, post-translation modifications, binding, and biological activity were among the quality attributes assessed for both antibodies.

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

Tixagevimab and cilgavimab drug substances are manufactured by a common process, with the main difference being the specific cell banks used to produce each antibody.

The two monoclonal antibodies are produced in Chinese hamster ovary cells, which have been genetically engineered to express either tixagevimab or cilgavimab through use of recombinant deoxyribonucleic acid (DNA) technology. The cell culture is initiated with the thawing of cells from a master cell bank, and allowed to expand to commercial scale in bioreactors. As the cell culture expands, recombinant protein is expressed and secreted into the culture medium.

To retrieve the antibodies from the culture medium, the harvest from all bioreactors is first clarified and pooled. The harvested cell culture fluid then undergoes chromatography and viral reduction steps, followed by filtration, concentration, and formulation steps. The formulated drug substance is then filtered into containers using an appropriate aseptic technique and then stored under temperature-controlled conditions.

Manufacturing of the tixagevimab and cilgavimab drug products begins with thawing and mixing of the formulated drug substance, followed by bioburden reduction filtration and aseptic filling into glass vials. The vials are then stoppered, capped, visually inspected, individually labelled, co-packaged (one vial of tixagevimab and one vial of cilgavimab), and placed in a paperboard carton. The resulting product, Evusheld, is then stored in a refrigerator at 2 °C to 8 °C.

The process performance qualification data reviewed reflected consistency in the drug substance and drug product manufacturing processes for both tixagevimab and cilgavimab. All process parameters, process attributes, release testing results, and stability results met predefined criteria, acceptance limits, and specifications for all validation lots.

Control of the Drug Substance and Drug Product

To demonstrate control of the manufacturing processes, the sponsor provided a detailed overview of the approaches used to establish quality attribute criticality. The method of manufacturing and the controls used during the manufacturing process for both drug products (tixagevimab and cilgavimab) are validated and considered to be adequately controlled within justified limits.

Specifications were determined based on historical release and stability batch data, clinical experience, manufacturing history and capability, analytical method capability, regulatory expectations, safety, and compendial requirements for protein-based products. Further control is provided through release and stability trending programs.

Tixagevimab and cilgavimab are Schedule D (biologic) drugs and are, 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 both drug substances and final drug product are considered acceptable.

The available stability data support the proposed shelf life of 18 months for Evusheld when the vials are kept in their original carton, stored at a temperature of 2 °C to 8 °C, and protected from light.

Facilities and Equipment

Based on a risk assessment score determined by Health Canada and mitigating factors (extensive experience with the product type), an on-site evaluation of the drug product manufacturing facility was not deemed necessary. The design, operations, and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured.

Both sites involved in production are compliant with Good Manufacturing Practices.

Adventitious Agents Safety Evaluation

The manufacturing processes of tixagevimab and cilgavimab incorporate adequate control measures to prevent contamination and maintain microbial control. Acceptable viral clearance studies have been performed for each antibody to support the viral clearance capability of the process. Bioburden and endotoxin testing procedures are integrated in the control strategy and meet relevant guidelines and requirements.

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