Summary Basis of Decision for Sotrovimab

 

Clinical Basis for Decision

The application for authorization of sotrovimab was submitted and reviewed in accordance with 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 of information and rolling review.

The initial clinical data on sotrovimab were derived from an interim analysis of the seamless Phase II/III pivotal study, COMET-ICE (described in the Clinical Efficacy section) and were submitted to Health Canada on April 1, 2021. Of note, due to evidence of safety and efficacy, enrollment of patients in this study was stopped in March of 2021 upon the recommendation of an independent data monitoring committee, which assessed data from the prespecified first interim analysis (with a cut-off date of March 4, 2021) for safety, efficacy, and futility in approximately 41% (583) of the planned number of subjects (1,360) to be recruited.

The sponsor subsequently provided summary findings from all 1,057 participants who had been randomized at the time when the enrollment was closed. Given the limitations associated with early data cut-off and relatively low numbers of participants in the dataset of the prespecified first interim analysis (868 patients for safety analysis and 583 patients for efficacy analysis), the post hoc analysis of the 1,057 participants has also been reviewed by Health Canada and relevant information has been included in the Product Monograph for sotrovimab.

Following review of the submitted information, an interim authorization of sotrovimab has been issued in accordance with section 5 of the Interim Order, with associated terms and conditions set out to ascertain the continued quality, safety, and efficacy of the product.

Clinical Pharmacology

The pivotal study (COMET-ICE, described in the Clinical Efficacy section) was the primary source of clinical pharmacology data on sotrovimab.

Pharmacokinetics and Pharmacodynamics

Sotrovimab is a fully human immunoglobulin G (IgG1) monoclonal antibody directed against a highly conserved epitope on the receptor-binding domain of the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The Fc region of the antibody was engineered to contain two amino acid substitutions, M438L and N444S, which enhance the neonatal Fc receptor (FcRn) binding and extend the antibody half-life.

The clinical pharmacokinetics of a single 500 mg dose of sotrovimab (administered by intravenous infusion over one hour) was analyzed using non-compartmental analyses following intensive pharmacokinetic sampling carried out in 9 subjects from the lead-in phase and sparse pharmacokinetic sampling conducted in 69 subjects from the expansion phase of the COMET-ICE study. Neither group of patients has undergone pharmacokinetic sampling of sufficient duration to allow characterization of the elimination phase for sotrovimab. This is reflected by the high percentage of the area under the concentration-time curve (AUC) from time 0 to infinity (AUC_inf) that is extrapolated (38.4%). However, the geometric mean serum concentration (34 µg/mL) of sotrovimab observed on day 29 of the study is consistent with an extended half-life monoclonal antibody.

At present, the only meaningful pharmacokinetic parameters that have been included in the Product Monograph for sotrovimab are the geometric mean maximum serum concentration (C_max) at the end of the one-hour infusion and the geometric mean serum concentration on day 29. Notably, predicted and observed geometric mean serum concentrations of sotrovimab on day 29 were similar and are expected to exceed the estimated lung-tissue adjusted 90% effective concentration (EC₉₀) of sotrovimab by at least 15 times for 28 days in at least 97.5% of patients.

The effect of hepatic insufficiency on the pharmacokinetics of sotrovimab has not been established. Renal impairment is not expected to impact the pharmacokinetics of sotrovimab since monoclonal antibodies with molecular weight over 69 kDa do not undergo renal elimination. Similarly, dialysis is not expected to impact the pharmacokinetics of sotrovimab. The effect of other covariates (e.g., age, sex, race, body weight, disease severity) on the pharmacokinetics of sotrovimab is unknown.

The pharmacodynamics of sotrovimab, in terms of the impact on nasopharyngeal viral load was investigated in the COMET-ICE study. However, the data are incomplete and it is still early to draw conclusions concerning the impact of sotrovimab on viral load over time and in comparison with placebo. No exposure-response or exposure-safety analyses have been submitted to Health Canada.

Antiviral Resistance

Data from sequence analysis of the SARS-CoV-2 spike gene were available for baseline nasal samples from 189 patients and post-baseline nasal samples from 76 patients. A sample was determined to be positive for a variant if the variant was present at an allelic frequency of greater than 5%.

In baseline sequencing data, variants of the epitope that is the target of sotrovimab were detected in 3 placebo- and 5 sotrovimab-treated patients. Notably, there were 8 patients in the sotrovimab treatment arm and 1 patient in the placebo treatment arm who had epitope variants in the post-baseline samples, suggesting that sotrovimab might exert selective pressure on the virus. Of the 8 sotrovimab-treated patients with an epitope variant detected after treatment, 4 patients carried SARS-CoV-2 with the E340K amino acid substitution in the spike protein and 1 patient carried SARS-CoV-2 with the E340A substitution, both of which have been shown to increase the EC₉₀ (i.e., reduce the effectiveness) of sotrovimab substantially in models of SARS-CoV-2 infection. One sotrovimab-treated patient (a 96-year-old man) who carried SARS-CoV-2 with the E340K mutation required hospitalization on day 22, but subsequently recovered. The E340K substitution has been demonstrated to confer resistance to sotrovimab in in vitro assays. However, E340K is not a substitution that has been observed in commonly circulating SARS-CoV-2 variants of concern and variants of interest (as designated by the World Health Organization).

With respect to circulating variants of SARS-CoV-2 in the study population, among the 189 participants for whom baseline sequencing of viral genomes were available, there were 3 and 5 patients in the sotrovimab and placebo treatment arms, respectively, who were infected with the novel CAL.20C variant (which emerged in Southern California). One sotrovimab-treated patient (the same 96-year-old man who also carried the E340K variant) required hospitalization on day 22, and subsequently recovered. No patient samples were positive for the variants of concern B.1.1.7 (Alpha), B.1.351 (Beta) or P.1 (Gamma). Other single amino acid substitutions detected among baseline sequences included L425R (2 placebo-treated patients, with no disease progression), N501Y (1 placebo-treated patient, with no disease progression), S477N (4 placebo-, 3 sotrovimab-treated patients, with no disease progression).

Overall, the clinical sequencing data provided are not sufficient to allow for a determination of the impact of specific SARS-CoV-2 variants on the efficacy of sotrovimab. The key clinical findings regarding SARS-CoV-2 resistance to sotrovimab are the E340K and E340A mutations, which were shown to reduce the virus susceptibility to neutralization by sotrovimab in vitro. In several patients, the E340K mutation has been detected after treatment with sotrovimab, suggesting that sotrovimab has the potential to select for variants with mutations in the target epitope.

Immunogenicity

Treatment with any therapeutic protein is accompanied by the risk of immunogenicity (i.e., the development of anti-drug antibodies, which have the potential to neutralize the biological activity of the drug). The immunogenicity of sotrovimab has not been evaluated in patients. The sponsor has indicated that anti-drug antibody assays are being developed and validated for screening, confirmation, and neutralization. Given the single‑dose treatment regimen proposed for sotrovimab, the risk of potential adverse impact on the efficacy or safety of sotrovimab due to immunogenicity appears to be low. Therefore, the absence of immunogenicity data for this application under the Interim Order is acceptable. As per the terms and conditions imposed on the interim authorization of sotrovimab, the sponsor is required to submit a complete reporting of the COMET-ICE study, including immunogenicity information, upon finalization of the study.

Dosing of sotrovimab in pediatric patients 12 years of age and older and weighing at least 40 kg

Sotrovimab has not been evaluated in pediatric (i.e., younger than 18 years of age) patients. The proposed use of sotrovimab to prevent progression of COVID-19 among high-risk pediatric patients who are at least 12 years of age and weigh at least 40 kg is based on extrapolation of the safety and efficacy findings in adult patients from the COMET-ICE study. Based on allometric scaling, the range of sotrovimab exposure in pediatric patients (with a 40 kg weight cut‑off) is expected to overlap the range of adult exposures by 67%, with the pediatric range of exposure shifted higher. Compared to an adult with a body weight of 49 kg and assuming a fixed allometric scaling power of 0.75 for clearance, an adolescent who weighs 40 kg is predicted to have 1.16 times higher average exposure (approximated by the AUC from time 0 to 28 days [AUC_0-28d]), and thus, no dosing adjustment is considered necessary. It should be noted that, since the clearance of sotrovimab is based on estimates predicted from non-clinical data, the allometric estimates may be subject to significant error. However, it is reasonable to consider the use of sotrovimab among high-risk pediatric patients, who are at least 12 years of age and weigh at least 40 kg, given that the product does not bind to any receptor in human tissues and is associated with a relatively benign safety profile as observed in adults. As per the terms and conditions imposed on the authorization of sotrovimab, the sponsor will provide data from the COMET-PACE study, which is planned to assess the pharmacokinetics and safety of sotrovimab in children from birth to 17 years of age with mild to moderate COVID-19 at high risk of disease progression.

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

Clinical Efficacy

Limited clinical data from the pivotal study, COMET-ICE, were available to evaluate the clinical efficacy of sotrovimab for the treatment of patients with mild to moderate COVID-19.

The COMET-ICE study was a seamless, randomized, double-blind, placebo-controlled Phase II/III clinical trial of sotrovimab for the treatment of adult (18 years of age and older) patients with mild or moderate COVID-19 who were not hospitalized, but who were considered at high risk for hospitalization and/or death due to disease progression.

Risk factors for disease progression, as defined by the study protocol, included age ≥55 years, diabetes, obesity (body mass index >35 kg/m²), chronic kidney disease, congestive heart failure, chronic obstructive pulmonary disease, and moderate to severe asthma.

The study randomized adult subjects who had a positive SARS-CoV-2 diagnostic test, onset of symptoms within 5 days of enrollment, oxygen saturation of at least 94% on room air, and one or more specific COVID-19 symptoms (fever, chills, cough, sore throat, malaise, headache, joint or muscle pain, change in smell or taste, vomiting, diarrhea, and/or shortness of breath on exertion). Pregnant women and severely immunocompromised patients were excluded from the study. The study also excluded patients who were hospitalized or likely to require hospitalization in the next 24 hours, patients with symptoms consistent with severe COVID-19 as defined by shortness of breath at rest, or respiratory distress, or requiring supplemental oxygen, and patients who, in the judgement of the investigator, were likely to die in the next 7 days. Additionally, individuals who had received a SARS-CoV-2 vaccine at any time prior to randomization, or those who had received convalescent plasma from a recovered COVID-19 patient or other anti-SARS-CoV-2 monoclonal antibodies within 3 months prior to randomization, were not included in the study.

Eligible patients were randomized 1:1 to receive a single intravenous infusion of either sotrovimab (500 mg) or placebo over 60 minutes.

A short, lead-in phase of the study included 10 patients in each treatment arm and was followed by an expansion phase, which had a planned enrollment of 670 patients per treatment arm.

The prespecified first interim analysis, with a data cut-off date of March 4, 2021, was conducted after 583 randomized patients (291 in the sotrovimab treatment arm and 292 in the placebo treatment arm) had the opportunity to complete at least day 29 of the COMET-ICE study. Baseline demographic and disease characteristics were well balanced between the treatment arms. The median age of the analyzed population (also referred to as intention-to-treat population at interim analysis 1 [ITT-IA1]) was 53 years (range: 18 to 96 years) and 22% of patients were 65 years of age or older.

The full efficacy analysis set encompassed patients (ITT population) who were still being followed in the study after further patient enrollment was stopped in March 2021. The enrollment was halted upon the recommendation of an independent data monitoring committee, which found evidence of safety and efficacy after assessing the results of the first prespecified interim analysis for safety, efficacy, and futility. In total, 1,057 patients (529 treated with sotrovimab and 528 treated with placebo) were included in the full efficacy analysis. There were no follow-up efficacy data for 7 (1%) patients in the sotrovimab arm and 5 (<1%) in the placebo arm. These subjects withdrew consent to participate in the study often because of the lengthy infusion procedure.

In both analyzed populations (ITT-IA1 and ITT), the primary outcome was the rate of hospitalizations involving more than 24 hours of acute care management or death from any cause occurring through study day 29. Secondary outcomes of clinical importance included hospitalization regardless of duration and death from any cause, viral load reductions, and safety endpoints.

Based on results of the prespecified first interim analysis, fewer events of hospitalization for over 24 hours of acute care management, or death from any cause through day 29 were observed in the sotrovimab group as compared to the placebo group. The rate of events was 1.0% (3/291) in the sotrovimab group versus 7.2% (21/292) in the placebo group. These findings represent an adjusted risk difference of -8.05% and an adjusted relative risk ratio of 0.15 (97.24% confidence interval [CI]: 0.04, 0.56) indicating a relative risk reduction of 85%. Similarly, in the full analysis population, the rate of events was 1.2% (6/528) in the sotrovimab group compared to 5.7% (30/529) in the placebo group, representing an adjusted risk difference of -6.34% and adjusted relative risk ratio of 0.21 (97.25% CI: 0.08, 0.56). The latter translates to a relative risk reduction of 79%.

A secondary endpoint, related to the rate of hospitalization regardless of duration of acute care management or death from any cause, was considered a more realistic endpoint for clinical effectiveness than the primary endpoint. A hospitalization for 23 hours, even if related to COVID-19, would not be counted as an event in the primary endpoint, whereas an unrelated admission for 25 hours would be counted as one, thus leading to the risk of misclassification by introducing information bias. Analysis of this secondary endpoint also revealed fewer events of all-cause hospitalization or death from any cause in the sotrovimab group compared with the placebo group. The rate of events among the sotrovimab-treated patients was 1.3% (7/528) compared with 5.7% (30/529) in the placebo-treated patients. These findings represent an adjusted relative risk ratio of 0.23 (95% CI: 0.10, 0.51), indicating a relative risk reduction of 77%.

Data on viral load reduction and time to symptom resolution from the pivotal study were incomplete. However, there is no current evidence to suggest an association or correlation between these secondary endpoints and the primary efficacy outcomes of reducing hospitalization or death due to COVID-19.

Indication

The sponsor filed the application for authorization of sotrovimab under the Interim Order with the following indication:

• Sotrovimab is indicated for the treatment of adults and adolescents (aged 12 years and older and weighing at least 40 kg) with mild to moderate coronavirus disease 2019 (COVID-19) who are at risk of progressing to severe COVID-19.
• The safety and efficacy of sotrovimab have not been demonstrated in patients:
  • who are hospitalized due to COVID-19, or
  • who require oxygen therapy due to COVID-19, or
  • who require an increase in baseline oxygen flow rate due to COVID-19 (in those on chronic oxygen therapy due to underlying non-COVID-19-related comorbidity).

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 is consistent 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. In addition, the text was edited to align with the wording of the indications of other authorized anti-SARS-CoV-2 monoclonal antibodies. Accordingly, Health Canada approved the following indication:

• Sotrovimab is 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 (12 years of age and older weighing at least 40 kg) who are at high risk for progressing to hospitalization and/or death.
• Sotrovimab is not authorized for use in patients:
  • who are hospitalized due to COVID-19, or
  • who require oxygen therapy due to COVID-19, or
  • who require an increase in baseline oxygen flow rate due to COVID-19 (in those on chronic oxygen therapy due to underlying non-COVID-19-related comorbidity).

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

 

 

Clinical Safety

Throughout the pivotal study (COMET-ICE, described in the Clinical Efficacy section), the sponsor conducted a safety assessment that was not limited to the collection of targeted treatment-emergent adverse events. The safety reporting encompassed: serious adverse events, adverse events of special interest including infusion-related reactions, reactions within 24 hours of infusion, adverse events potentially related to immunogenicity of sotrovimab and/or antibody-dependent enhancement. All adverse events were documented and then graded (1 to 5) as per the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (Corrected Version 2.1 ‑ July 2017).

Overall, median duration of follow-up of patients in the COMET-ICE study was 56 days (range: 5 to 190 days) for sotrovimab-treated patients and 55 days (range: 2 to 190 days) for placebo-treated patients. Of the 868 patients, who represented the safety population at the prespecified first interim analysis, 747 patients were followed for over 29 days (18 of whom were followed for up to 24 weeks).

The safety population at the first interim analysis included 430 patients who received sotrovimab and 438 patients who received placebo. The overall rate of adverse events was slightly lower in the patients treated with sotrovimab as compared to those treated with placebo.

Serious adverse events occurred in 2% of sotrovimab-treated patients and in 6% of placebo-treated patients. There were no fatal serious adverse events related to study treatment, and two fatalities during the follow-up through day 29 in the placebo group were attributed to deteriorating untreated COVID-19. Notably, serious adverse events (e.g., pneumonia, dyspnea, headaches) appeared mainly to be the consequence of COVID-19.

Of the adverse events reported in at least 1% of subjects, most events occurred more frequently in the placebo group. Only diarrhea was more commonly reported in the sotrovimab group accounting for 6 cases (1%) compared with 3 cases (<1%) in the placebo group. No events consistent with antibody-dependent enhancement were observed. All infusion-related reactions including hypersensitivity reactions were grade 1 or grade 2. Adverse events of special interest (infusion-related reactions including serious hypersensitivity reactions and reactions within 24 hours of infusion) occurred infrequently and at similar incidences in the sotrovimab (1%) and placebo (1%) groups.

A review of a broad range of laboratory test results, including those related to renal, cardiovascular or hepatic function, did not reveal any clear trends that might suggest a causal relationship between treatment with sotrovimab and laboratory abnormalities.

The post hoc safety analysis of 1,049 patients enrolled in the COMET-ICE study (or the intention-to-treat study population including patients still requiring follow-up through day 29 at the time of the interim analysis) showed similar results to those of the prespecified first interim analysis of safety data from 868 patients. The incidence of adverse events was similar between patients treated with sotrovimab (22%) and those given placebo (23%). Serious adverse events (reported at a rate of 2% in the sotrovimab group and 6% in the placebo group) and grade 3‑4 adverse events (reported at a rate of 3% in the sotrovimab group and 7% in the placebo group) were less commonly observed in patients treated with sotrovimab than in patients who received placebo. In the placebo group, there were 4 deaths (all related to COVID-19 pneumonia or respiratory complications) as can be anticipated in some patients with untreated deteriorating severe infection.

Overall, sotrovimab appeared to be well tolerated in the pivotal COMET-ICE study. Given the nature of the product (a monoclonal antibody), there is the potential for hypersensitivity and/or anaphylactic reactions. In addition, administration by intravenous infusion is associated with the risk of infusion-related reactions. These specific risks have been conveyed in the Warnings and Precautions section of the Product Monograph for sotrovimab.

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