Summary Basis of Decision for Casirivimab and Imdevimab

 

The application for authorization of casirivimab and imdevimab was reviewed under the Interim Order Respecting the Importation, Sale, and Advertising of Drugs for Use in Relation to COVID-19 (Interim Order), which permitted a rolling submission and rolling review. The initial clinical data included results derived from Phases I and II of Study R10933-10987-COV-2067 (Study COV-2067 hereafter). Subsequently, the sponsor updated the submission with Phase III study results, also from Study COV-2067, which was the pivotal study assessing the safety, tolerability, and efficacy of the anti-spike severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies casirivimab and imdevimab administered together for the treatment of ambulatory patients with coronavirus disease 2019 (COVID-19).

Following review, terms and conditions were imposed on the interim authorization of casirivimab and imdevimab to ascertain the continued quality, safety, and efficacy of the products.

Clinical Pharmacology

Casirivimab and imdevimab act together as a combination monoclonal antibody therapy. Both are non-competing, fully human immunoglobulin G1 (IgG1 variant) antiviral monoclonal antibodies, which are unmodified in the fragment crystallizable (Fc) region. Each antibody targets and binds specifically to the receptor-binding domain of the spike glycoprotein 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. The blockage of the spike protein interaction with ACE2 receptors leads to the inhibition of infection of host cells. When administered together, casirivimab and imdevimab exhibit neutralization activity, with a concentration of 31.0 pM (0.005 μg/mL) providing inhibition of 50% of viral infection in a plaque-reduction neutralization test (PRNT50).

Casirivimab was isolated from Regeneron’s VelocImmune human antibody mouse platform. Imdevimab was isolated from the B cells of a human donor previously infected with SARS-CoV-2. 

Clinical pharmacology data and analyses were limited. Based on responses to information requests posed by the United States Food and Drug Administration (FDA) and provided in the submission, the sponsor confirmed the use of a validated bioanalytical method in the measurement of serum concentrations from the Phase III pharmacokinetic substudy. At the time of review, the sponsor had not conducted an exposure-response analysis. Summary pharmacokinetic parameters that included the maximum serum concentrations (C_max) at the end of infusion and 28 days after dosing were provided. These data suggested exposure increased in a dose-proportional manner for the single 1,200 mg to 8,000 mg intravenous doses (600 mg to 4,000 mg of each antibody), consistent with linear pharmacokinetics. The metabolic pathways of casirivimab and imdevimab have not been characterized. As human monoclonal IgG1 antibodies, both casirivimab and imdevimab are expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.

Study COV-2067 evaluated the combination of casirivimab and imdevimab in ambulatory patients with COVID-19 at combined doses of 1,200 mg (600 mg casirivimab + 600 mg imdevimab), 2,400 mg (1,200 mg casirivimab + 1,200 mg imdevimab), and 8,000 mg (4,000 mg casirivimab + 4,000 mg imdevimab). Patients treated with casirivimab and imdevimab, administered together, demonstrated a statistically significant reduction in the least squares mean viral load (log10 copies/mL) from baseline to Day 7 compared to placebo (-0.71 log10 copies/mL for 1,200 mg and -0.86 log10 copies/mL for 2,400 mg). Consistent effects were observed for the 1,200 mg and 2,400 mg treatment groups, indicating the absence of a dose effect.

The effects of age, renal impairment, or hepatic impairment on the pharmacokinetics of casirivimab and imdevimab are unknown. Renal impairment is not expected to impact the pharmacokinetics of casirivimab and imdevimab, as monoclonal antibodies with a molecular weight >50 kDa are known not to undergo renal elimination. Similarly, dialysis is not expected to impact the pharmacokinetics of casirivimab and imdevimab.

In pediatric patients 12 years of age and older and weighing at least 40 kg, the recommended dosing regimen is expected to result in serum exposures of casirivimab and imdevimab comparable to those observed in adults, since adults with similar body weight were included in Study COV-2067.

There are limited data on the safety and efficacy of patients ≥65 years of age. Of the 4,567 patients randomized in Study COV-2067, 14% were ≥65 years of age, and 4% were ≥75 years of age. The difference in the pharmacokinetics of casirivimab and imdevimab in geriatric patients compared to younger patients is unknown.

The clinical pharmacology data support the use of the combination of casirivimab and imdevimab for the recommended indication.

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

Clinical Efficacy

Interim clinical data from the pivotal Study COV-2067 were available to evaluate the clinical efficacy of the combination of casirivimab and imdevimab for the treatment of patients with mild to moderate COVID-19.

Pivotal Study

Study COV-2067 is an ongoing Phase III, randomized, double-blinded, placebo-controlled clinical study of the combination of casirivimab and imdevimab for the treatment of adult patients with mild or moderate COVID-19 who are not hospitalized, but are considered at high risk for hospitalization and/or death due to COVID-19 progression. High-risk patients were those with one or more of the following protocol-defined risk factors: age ≥50 years; obesity (body mass index ≥30 kg/m²); cardiovascular disease, including hypertension; chronic lung disease, including asthma; type 1 or 2 diabetes mellitus; chronic kidney disease, including patients on dialysis; chronic liver disease; and patients who, in the opinion of the investigator, were immunosuppressed.

The study included adult patients (≥18 years of age) who had a positive SARS-CoV-2 diagnostic test within 72 hours prior to randomization, were not hospitalized, and had at least one or more COVID-19 symptoms that were considered mild or moderate in severity. The onset of symptoms should not have occurred >7 days before randomization, and treatment was to be initiated within 3 days of obtaining a positive SARS-CoV-2 viral test result. Key exclusion criteria included: admission to hospital for COVID-19 prior to randomization, or hospitalization for any reason at randomization; prior positive SARS-CoV-2 serologic test; and/or prior positive SARS-CoV-2 antigen or molecular diagnostic test from a sample collected ≥72 hours prior to randomization.

The study population was well-balanced between the treatment arms. The median age was 50 years (range: 18 to 96 years), with 14% of patients ≥65 years of age. Furthermore, 52% of patients were female, 84% were Caucasian, 5% were Black and all patients had one or more predefined risk factors for severe COVID-19.

In Phase III (cohort 1), 4,567 patients were randomized to receive a single intravenous infusion of the 1,200 mg combination (600 mg casirivimab + 600 mg imdevimab; number of patients [n] = 838), the 2,400 mg combination (1,200 mg casirivimab + 1,200 mg imdevimab; n = 1,529), the 8,000 mg combination (4,000 mg casirivimab + 4,000 mg imdevimab; n = 700), or placebo (n = 1,500). Initially, patients were randomized to receive either placebo, or the 2,400 mg or 8,000 mg combination of casirivimab with imdevimab. However, based on the analyses of Phase I/II data suggesting that the 2,400 mg and 8,000 mg treatment arms reduced viral load similarly, the Phase III protocol was amended to compare the 2,400 mg and 1,200 mg doses vs. placebo. Data from the 8,000 mg treatment arm were presented as a descriptive analysis only, with no formal comparison to the placebo treatment arm. Comparisons were conducted between patients randomized to specific casirivimab with imdevimab doses and patients concurrently randomized to placebo.

The full analysis set (FAS) included all randomized patients with COVID-19 symptoms, regardless of whether they had risk factors for severe COVID-19; however, the study protocol was amended to enroll only patients who were considered at high risk based on the presence of one or more protocol-defined risk factors. Consequently, the statistical analysis plan was also amended to specify that the primary and key secondary outcomes would be analyzed considering the modified FAS (mFAS), which included all patients who were in the FAS with detectable SARS-CoV-2 ribonucleic acid (RNA) by quantitative reverse transcription polymerase chain reaction (RT-qPCR) in nasopharyngeal swabs at randomization and who had one or more predefined risk factors (as listed above) for severe COVID-19. The pooled mFAS (n = 4,057) included the 8,000 mg treatment arm. As mentioned above, the mFAS excluded patients who did not have detectable SARS-CoV-2 RNA by RT-qPCR of nasopharyngeal samples taken at randomization. Health Canada requested further analysis with these patients included, and it was determined that their exclusion did not affect the study conclusions. The mFAS was used to analyze the primary and key secondary endpoints.

Considering the mFAS, 1,355 patients received the 2,400 mg combination, 736 patients received the 1,200 mg dose, and 1,341 patients received placebo. Importantly, the 1,200 mg treatment arm was only compared to concurrently enrolled placebo patients (n = 748) who were a subset of the overall placebo group. Given the dynamics of the pandemic in terms of expected event rates at different times, this approach was considered reasonable.

The primary endpoint was the rate of hospitalizations and/or all-cause death occurring through Day 29 in the mFAS. Type I error was controlled via a hierarchical testing scheme, which specified testing the 2,400 mg arm vs. placebo first. In the event that statistical significance was demonstrated, the 1,200 mg arm was to be formally tested against the group of placebo-treated patients who were enrolled concurrently with the patients in the 1,200 mg arm. Further statistical tests were also pre-specified in the statistical analysis plan. However, these tests were not considered as supportive of the recommended indication since they were limited to subgroup analyses defined by the arbitrary cut-offs for nasopharyngeal viral load or by serology status, none of which were clearly related to the rate of hospitalization or death.

In the 2,400 mg combination vs. placebo comparison, fewer events of hospitalization/death were observed among treated patients. The rate of events among patients in the placebo arm was 4.6% (62/1,341 patients) compared to 1.3% (18/1,355 patients) in the 2,400 mg treated arm. This represents an absolute risk reduction of 3.3% and a relative risk reduction of 71.3% in the number of patients with a COVID-19-related hospitalization or all-cause death (95% confidence interval [CI]: 51.7%, 82.9%, p <0.0001). The calculated number needed to treat (NNT) to prevent one hospitalization or death was 30.35 (95% CI: 29.97, 30.73). Considering the 1,200 mg treatment arm in comparison to concurrently enrolled placebo patients, the event rate among patients in the placebo arm was 3.2% (24/748 patients) compared to 1.0% (7/732 patients) in the 1,200 mg treatment arm. The absolute risk reduction was 2.2% and the relative risk reduction was 70.4% (95% CI: 31.6%, 87.1%, p = 0.0024). The calculated NNT for the 1,200 mg arm, compared to placebo was 44.30 (95% CI: 43.40, 45.22).

Overall, most events were hospitalizations related to COVID-19. In the placebo group, there were three deaths through Day 29 and two additional deaths that occurred after Day 29, for a total of five deaths through the end of study follow-up. There was one death in each treatment group.

Clinical findings from the Phase I and II portions of the study support a direct effect of casirivimab and imdevimab on viral load. Statistically significant differences were observed between the placebo and each of the 2,400 mg and 8,000 mg treatment arms in the time-weighted average reduction in viral load from baseline when compared to placebo up to Day 7 after treatment. These findings were confirmed among high-risk patients enrolled in the Phase III portion of the study who received either placebo, the 1,200 mg casirivimab and imdevimab combination or the 2,400 mg casirivimab and imdevimab combination.

Indication

The sponsor filed the application for authorization of casirivimab and imdevimab under the Interim Order with the following indication:

• Casirivimab and imdevimab are indicated for the treatment of mild to moderate coronavirus disease 2019 (COVID-19) in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with laboratory-confirmed SARS-CoV-2 infection and who are at high risk of severe COVID-19.
•  
• High risk is defined as patients who meet at least one of the following criteria:
  • Age ≥60 years
  • Obesity
  • Cardiovascular disease, including hypertension
  • Chronic lung disease, including asthma
  • Type 1 or type 2 diabetes mellitus
  • Chronic kidney disease, including those on dialysis
  • Chronic liver disease
  • Immunosuppressed, based on investigator’s assessment. Examples include: cancer treatment, bone marrow or organ transplantation, immune deficiencies, HIV (if poorly controlled or evidence of AIDS), sickle cell anemia, thalassemia, and prolonged use of immune-weakening medications.

Health Canada revised the proposed indication to refer to patients who are at high risk of progression to hospitalization or death, instead of referring to progression to severe COVID-19. This better aligns with the dataset provided, in which the primary outcome demonstrated a statistically significant reduction in the rate of hospitalizations or deaths among treated patients compared to placebo. Health Canada also considered the inclusion of a defined set of risk factors in the indication, but determined that patient selection criteria, guided by protocol-defined risk factors in the pivotal clinical study, would be most appropriately provided within the Dosage and Administration section of the Product Monograph for casirivimab and imdevimab rather than within the indication. This approach supports health care professionals in applying clinical judgement with respect to identifying patient risk factors, which may change as new data are gathered throughout the pandemic, while providing information on the risk factors considered in the selection of patients for the pivotal clinical study. Accordingly, Health Canada approved the following indication:

• Casirivimab and imdevimab, to be administered together, are indicated for the treatment of mild to moderate coronavirus disease 2019 (COVID-19), confirmed by direct SARS-CoV-2 viral testing, in adults and adolescents (aged 12 years of age and older weighing at least 40 kg) who are at high risk for progressing to hospitalization and/or death.

Analysis of Efficacy

The recommended total dose of 2,400 mg (1,200 mg casirivimab + 1,200 mg imdevimab) administered as a single intravenous infusion over 1 hour is supported by the statistically significant reduction, compared to placebo, in hospitalizations and deaths up to Day 29 in the Phase III, cohort 1 (adults with risk factors) portion of the pivotal Study COV-2067. A third treatment arm employed a 1,200 mg total dose (600 mg casirivimab + 600 mg imdevimab), which also showed a statistically significant reduction in hospitalizations and deaths compared to placebo over the same time period. The treatment effect was considered moderate, but potentially meaningful, with absolute risk reductions (for hospitalization/death) of 2.2% and 3.3% for the 1,200 mg and 2,400 mg treatment arms, respectively, when compared to placebo. The relative risk reductions were 71.3% (2,400 mg vs. placebo) and 70.4% (1,200 mg vs. placebo).

Health Canada recommends that the 2,400 mg combined dose of casirivimab and imdevimab be maintained at least until such time that it can be confirmed that lower doses retain efficacy against variants of concern, which were not widely circulating during the examined period of the ongoing pivotal clinical study. In addition, while no comparison was made, there appeared to be a trend towards a greater reduction in hospitalizations in the 2,400 mg treatment group compared to the 1,200 mg treatment group both in the primary outcome analyses and in the landmark analyses. This may have been due to imprecision in the 1,200 mg treatment group outcomes associated with a lower sample size or due to changing event rates over time (the 1,200 mg arm was initiated late in the trial), but the reasons for the difference are uncertain. In the face of an evolving infectious agent, Health Canada is of the opinion that maximum neutralization capacity of the authorized antiviral products (as exhibited by the 2,400 mg dose) should be maintained. Notably, the 2,400 mg dose was not associated with a greater risk of adverse reactions compared to lower doses.

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

Clinical Safety

Pivotal Study COV-2067 Phase I, II, and III (Cohort 1)

Throughout the ongoing Study COV-2067 (described in the Clinical Efficacy section), the sponsor conducted a safety assessment that was limited to the collection of targeted treatment emergent adverse events (TEAEs). During Phases I, II, and III (cohort 1), targeted safety reporting included serious adverse events (SAEs), Grade 2 or higher infusion-related reactions, and Grade 2 or higher hypersensitivity reactions. In Phase I only, TEAEs that were Grade 3 or higher were recorded. In Phase III only, TEAEs that led to a medically attended visit (hospitalization, emergency room visit, physician’s office, telemedicine) were recorded. This limited safety reporting may have risked the under-reporting of certain adverse reactions, for example, Grade 1 infusion-related reactions or hypersensitivity reactions; however, important adverse reactions would be expected to be captured by focussing on higher-grade adverse events of special interest (AESIs), SAEs and events that led patients to seek medical care. Importantly, the following safety summary is limited to the adult population.

Phase I and II (combined safety)

The safety analysis sets included all patients who were randomized and received any study drug. In Phase I and II combined, 262 patients received placebo, 258 patients received the 2,400 mg combination (1,200 mg casirivimab + 1,200 mg imdevimab) and 260 patients received the 8,000 mg combination (4,000 mg casirivimab + 4,000 mg imdevimab). Serious adverse events occurred in 6 (2.3%) placebo patients, 4 (1.6%) patients treated with 2,400 mg casirivimab and imdevimab, and 2 (0.8%) patients treated with 8,000 mg casirivimab and imdevimab. Adverse events of special interest (≥Grade 2 infusion-related reactions/hypersensitivity reactions) were infrequent across treatment arms and occurred among 0.8% of placebo patients, 0% of 2,400 mg casirivimab and imdevimab patients and 1.5% of 8,000 mg casirivimab and imdevimab patients. Grade 3-4 TEAEs were observed with similar frequencies across treatment arms, with the highest proportion observed among placebo-treated patients at 1.5%. Serious adverse events reported in more than one patient were hypoxia and pneumonia, which each occurred in two patients who received placebo. Pneumonia was also reported in one patient who received 2,400 mg casirivimab and imdevimab.

Phase III (Cohort 1)

In the safety analysis set of Phase III (cohort 1), 1,843 patients received placebo, 827 patients received the 1,200 mg combination (600 mg casirivimab + 600 mg imdevimab), 1,849 patients received the 2,400 mg combination (1,200 mg casirivimab + 1,200 mg imdevimab), and 1,012 patients received the 8,000 mg combination (4,000 mg casirivimab + 4,000 mg imdevimab). Serious adverse events occurred in 74 (4.0%) patients treated with placebo, 9 (1.1%) patients treated with 1,200 mg casirivimab and imdevimab, 24 (1.3%) patients treated with 2,400 mg casirivimab and imdevimab, and 17 (1.7%) patients treated with 8,000 mg casirivimab and imdevimab. Adverse events of special interest (Grade ≥2 infusion-related reactions/hypersensitivity reactions) were infrequent across treatment arms, occurring in fewer than 0.5% of patients in any given treatment arm. Tabulation of SAEs by system organ class was provided in the data summary. Notably, SAEs appeared to mainly be the consequence of COVID-19 (e.g., hypoxia, dyspnea, and pneumonia), rather than due to treatment, with a greater rate of SAEs observed among patients who received placebo as compared to treated patients. Five patients (0.3%) in the placebo group died as did one patient (0.1%) in each of the casirivimab and imdevimab groups. None of the deaths were considered to be related to study treatment.

Overall, the combination of casirivimab and imdevimab appears to be well tolerated across the dosing range studied. Given the nature of the products (recombinant monoclonal antibodies), there is potential for hypersensitivity and/or anaphylactic reactions. In addition, administration by intravenous infusion is associated with the risk of infusion reactions. For these reasons, these specific risks have been included under the Warnings and Precautions of the Product Monograph for casirivimab and imdevimab.

Supportive Study

At the time of review, Study COV-20145 was an ongoing, randomized, double-blind, placebo-controlled, parallel-group study to assess the dose-response profile of single intravenous or subcutaneous doses of casirivimab and imdevimab in outpatients with SARS-CoV-2 infection. Eligible patients, consisting of adults that were either asymptomatic or had COVID-19 but no risk factors for severe COVID-19, were randomized equally to receive a single dose of the combination of casirivimab and imdevimab or placebo by either subcutaneous injection or intravenous infusion. The study enrolled 1,164 patients of whom 803 are included in the analysis.

Safety variables collected included: TEAEs, treatment-emergent SAEs, and treatment-emergent AESIs (Grade ≥2 infusion-related reactions, Grade ≥3 injection-site reactions, Grade ≥2 hypersensitivity reactions, and any TEAE that led to a hospitalization or emergency room visit, regardless of whether the visit was related to COVID-19).

Although the results of the study were not relevant with respect to efficacy for the indicated population, from a safety perspective, the study did not show any concerning safety signals. The rate of TEAEs was similar between intravenous placebo and intravenous casirivimab and imdevimab. The rate of TEAEs experienced in the subcutaneous treatment arms also appeared similar to that observed in the intravenous treatment arms. Infusion-related reactions, injection-site reactions, and hypersensitivity were not observed in this study.

Analysis of Safety

The safety of the combination of casirivimab and imdevimab was based on limited reporting of the ongoing Phase II/III Study COV-2067. Serious and unexpected adverse events that have not been previously reported with the use of the combination (casirivimab and imdevimab) may occur. At the time of authorization, the results of the study suggest that the safety profile of a single combined dose of 2,400 mg (1,200 mg casirivimab + 1,200 mg imdevimab) is relatively unremarkable.

Serious hypersensitivity reactions, including anaphylaxis, as well as infusion-related reactions have been reported with the administration of the combination of casirivimab and imdevimab. These reactions may be severe or life-threatening. In addition, a potential risk of treatment failure exists, as circulating SARS-CoV-2 viral variants may be associated with resistance to monoclonal antibodies such as casirivimab and/or imdevimab. Health care professionals should routinely review the antiviral resistance information in the Product Monograph for casirivimab and imdevimab (Section 15 - Microbiology) for details regarding specific variants and resistance, as it may be updated regularly.

Appropriate warnings and precautions are in place in the approved Product Monograph for casirivimab and imdevimab to address the identified safety concerns.

There are limited data from the use of casirivimab with imdevimab in pregnant women. The combination therapy of casirivimab and imdevimab should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the fetus considering all associated health factors.

There are no available data on the presence of casirivimab and/or imdevimab in human milk or animal milk, the effects on the breastfed infant, or the effects of the drug on milk production. Maternal immunoglobulin G (IgG) is known to be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for the combination of casirivimab and imdevimab and any potential adverse effects on the breastfed child from either casirivimab and imdevimab or from the underlying maternal condition.

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