Summary Basis of Decision for Evusheld

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 (C_max) 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 (AUC_inf) 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.