Summary Basis of Decision for Bamlanivimab for Injection
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Bamlanivimab for Injection is located below.
Recent Activity for Bamlanivimab for Injection
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 Bamlanivimab for Injection
Updated:
The following table describes post-authorization activity for bamlanivimab for injection. 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 and the Information and Application Requirements for Drugs Authorized under the Interim Order: Guidance Document.
Drug Identification Number (DIN):
- DIN 02508176 - 700 mg/20 mL, solution, intravenous administration
Post-Authorization Activity Table (PAAT)
Summary Basis of Decision (SBD) for Bamlanivimab for Injection
Date SBD issued: 2021-01-05
The following information relates to the interim authorization of Bamlanivimab for Injection.
Bamlanivimab
Drug Identification Number (DIN):
- DIN 02508176 - 700 mg/20 mL, solution, intravenous administration
Eli Lilly Canada Inc.
Application Control Number: 244947
On November 20, 2020, Health Canada issued an authorization under the Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19 (Interim Order) to Eli Lilly Canada Inc. for the drug product bamlanivimab for injection (bamlanivimab). The Interim Order, signed by the Minister of Health on September 16, 2020, establishes new authorization pathways with the intent to expedite the authorization for the importation, sale and advertising of drugs used in relation to coronavirus disease 2019 (COVID-19), while taking into consideration urgent public health needs caused by COVID-19.
The interim authorization of bamlanivimab was based on limited quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Following review of the available information, Health Canada considers that sufficient evidence has been provided to support the conclusion that the potential benefits associated with bamlanivimab outweigh the risks, having regard to the uncertainties relating to the benefits and risks and the necessity of addressing the urgent public health need related to COVID-19. Based on these considerations, the benefit risk-profile of bamlanivimab is considered favourable for the treatment of adults and pediatric patients 12 years of age or older with mild to moderate COVID-19 who weigh at least 40 kg and who are at high risk of progressing to severe COVID-19 illness and/or hospitalization.
The interim authorization of bamlanivimab is subject to terms and conditions that need to be met by the sponsor to ascertain the continued quality, safety, and efficacy of the product. The terms and conditions may be amended at any time. Furthermore, this authorization may be revoked if new information would not support the safe and effective use of the product.
For further information on authorization under this pathway, refer to Health Canada's Interim Order Respecting the Importation, Sale, and Advertising of Drugs for Use in Relation to COVID-19 (Interim Order) and the Information and Application Requirements for Drugs Authorized under the Interim Order: Guidance Document.
1 What was approved?
Bamlanivimab is a monoclonal antibody against the spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19).
Bamlanivimab is indicated for the treatment of adults and pediatric patients 12 years of age or older with mild to moderate COVID-19, who weigh at least 40 kg and who are at high risk of progressing to severe COVID-19 illness and/or hospitalization.
Patients at high risk of progressing to severe COVID-19 illness and/or hospitalization are defined as those who meet at least one of the following criteria:
- Are 65 years of age and older
- Have a body mass index (BMI) ≥35 for patients 18 years of age and older
- Have chronic kidney disease
- Have diabetes
- Have immunosuppressive disease
- Are currently receiving immunosuppressive treatment
- Are 55 years of age and older and have
- cardiovascular disease, or
- hypertension, or
- chronic obstructive pulmonary disease/other chronic respiratory disease
- Are 12 to 17 years of age and have
- BMI ≥85th percentile for their age and gender, or
- sickle cell disease, or
- congenital or acquired heart disease, or
- neurodevelopmental disorders, for example, cerebral palsy, or
- a medical-related technological dependence, for example, tracheostomy, gastrostomy, or positive pressure ventilation (not related to COVID-19), or
- asthma, reactive airway or other chronic respiratory disease that requires daily medication for control
Bamlanivimab should not be used in patients hospitalized with severe COVID-19 respiratory disease, as benefit of treatment has not been observed in this setting. Bamlanivimab, a monoclonal antibody, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high-flow oxygen or mechanical ventilation.
The authorization of bamlanivimab under the Interim Order Respecting the Importation, Sale, and Advertising of Drugs for Use in Relation to COVID-19 (Interim Order) is supported by a numerical reduction in hospitalization or emergency room visits in high-risk patients treated with bamlanivimab compared to high-risk patients treated with placebo.
Based on the data submitted to and reviewed by Health Canada, the safety and efficacy of bamlanivimab in pediatric patients have not been established. However, because the mechanism of action of bamlanivimab, as a neutralizing immunoglobulin G1 (IgG1) monoclonal antibody against the spike protein of SARS-CoV-2, directly affects the virus and not the host response to the viral infection, it is reasonable to anticipate similar function in adolescents compared to adults. In addition, considering the acceptable safety profile observed in adults who weigh at least 40 kg, treating physicians may consider the use of bamlanivimab for adolescents 12 years of age or older who weigh at least 40 kg and who are at high risk of developing severe COVID-19 symptoms and/or hospitalization. Close monitoring in this patient population is highly recommended.
Based on preliminary population pharmacokinetic analyses, there is no difference in the pharmacokinetics of bamlanivimab in geriatric patients (65 years of age and older) compared to patients younger than 65 years of age.
Bamlanivimab is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
Bamlanivimab for injection (bamlanivimab 700 mg/20 mL [35 mg/mL]) is presented as a solution. In addition to the medicinal ingredient, the solution contains L-histidine, L-histidine hydrochloride monohydrate, sodium chloride, sucrose, polysorbate 80, and water for injection. The solution has a pH range of 5.5 to 6.5.
For more information, refer to the Clinical, Non‑clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the bamlanivimab Product Monograph, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID‑19 vaccines and treatments portal.
2 Why was Bamlanivimab for Injection approved?
Health Canada considers that sufficient evidence has been provided to support the conclusion that the potential benefits associated with bamlanivimab outweigh the risks, having regard to the uncertainties relating to the benefits and risks and the necessity of addressing the urgent public health need related to coronavirus disease 2019 (COVID-19). Based on these considerations, the benefit risk-profile of bamlanivimab is deemed favourable for the treatment of adults and pediatric patients 12 years of age or older with mild to moderate COVID-19 who weigh at least 40 kg and who are at high risk of progressing to severe COVID-19 illness and/or hospitalization. The sale of bamlanivimab in Canada is permitted under an authorization issued in accordance with section 5 of the Interim Order Respecting the Importation, Sale, and Advertising of Drugs for Use in Relation to COVID-19 (Interim Order). The interim authorization is subject to terms and conditions that need to be met by the sponsor to ascertain the continued quality, safety, and efficacy of the product.
Coronavirus disease 2019 (COVID-19) is the infectious disease caused by the most recently discovered coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In Canada, there have been 320,719 confirmed cases of COVID-19 and 11,334 deaths as of November 20, 2020, the date of authorization of bamlanivimab. This new virus and disease were unknown before the outbreak began in December 2019 and have since spread around the world. In most cases, COVID-19 presents as a mild to moderately severe, acute respiratory illness with fever, cough, shortness of breath and breathing difficulties. The majority of patients infected with SARS-CoV-2 recover without significant sequelae. However, significant risk factors such as age and underlying medical issues (e.g., high blood pressure, obesity, heart problems or diabetes) increase the likelihood of developing severe disease, including pneumonia, severe acute respiratory syndrome, multiple organ failure, and death.
Currently, there are no drugs available that are specifically authorized for the treatment of mild to moderate COVID-19 illness in the outpatient setting. Veklury (remdesivir) was issued a Notice of Compliance with condition (NOC/c) under the NOC/c policy by Health Canada on July 27, 2020 for the treatment of COVID-19 in adults and adolescents (aged 12 years and older with body weight at least 40 kg) with pneumonia requiring supplemental oxygen.
Bamlanivimab (also referred to as LY3819253 or LY-CoV555) is a neutralizing immunoglobulin G1 (IgG1) monoclonal antibody directed against the spike protein of SARS-CoV-2. The monoclonal antibody can block the attachment of the spike protein to human angiotensin-converting enzyme 2 (ACE2) receptors, thereby preventing subsequent viral entry into human cells and viral replication.
The authorization of bamlanivimab under the Interim Order was based on interim results of one ongoing, Phase II, placebo-controlled, double-blind, randomized, single-dose study of escalating doses of bamlanivimab in outpatients diagnosed with mild to moderate COVID-19 (BLAZE-1). The study aimed to demonstrate that bamlanivimab treatment was associated with a reduction in viral load, as measured by viral ribonucleic acid (RNA) in samples taken by a nasopharyngeal swab at day 11 post infusion. Such an effect was not demonstrated, partially due to the fact that all study arms, including those in which placebo was administered, had significantly reduced viral RNA by this time point.
However, secondary outcomes supported the potential efficacy of bamlanivimab and included comparisons of the absolute rates of COVID-19-related hospitalization or emergency room visits occurring up to and including day 29 post infusion. A numerical reduction, albeit not statistically significant, in the proportions of patients requiring hospitalization or emergency room visits was consistently observed when comparing the proposed dose of 700 mg to placebo and also when comparing the 2,800 mg and 7,000 mg doses to placebo. This suggests that there might be no additional benefit associated with higher doses and supports 700 mg as the recommended dose. Importantly, the findings with respect to COVID-19-related hospitalization or emergency room visits appear to be driven mainly by patients who are within the target population, which encompasses patients with risk factors associated with progression to severe COVID-19 or hospitalization.
Time to symptom improvement was an additional secondary outcome. There was a numerical reduction in the median time to symptom improvement for patients who received the proposed 700 mg bamlanivimab dose (median time of 6 days), compared to those who received placebo (median time of 8 days). This reduction was consistently observed across monotherapy doses of bamlanivimab when compared to placebo.
The interim results of BLAZE-1 suggest that the safety profile of a single dose of bamlanivimab 700 mg is relatively unremarkable. Doses of up to 7,000 mg were also administered without any notable increase in the rates of treatment-emergent adverse events or serious adverse events. The most important adverse reactions associated with bamlanivimab are infusion reactions. Hypersensitivity and anaphylactic events may also occur during the treatment. These types of reactions are of concern for monoclonal antibodies in general, and were rarely observed in the clinical study. Only infusion reactions were reported at a higher rate in the treatment arms. The Product Monograph provides warnings regarding each of these potential adverse reactions and advises prescribers that the product should only be administered in a setting where health care professionals have the necessary means to treat such severe reactions.
No adolescents (12 years of age and older) were included in the available clinical trials with bamlanivimab. The indication for this group of patients was supported by the acceptable safety profile observed in adults and an extrapolation approach for efficacy based on exposure matching. Preliminary population pharmacokinetic modelling and simulation predicted similar pharmacokinetic exposures following a 700 mg dose in adolescent patients weighing over 40 kg to those observed in adult patients.
The study results for bamlanivimab are associated with some uncertainties or limitations. Factors such as the small sample size, the lack of control for type I error for endpoints that suggest a benefit, and the fact that the trial enrolled a population of patients with different risks for progression to severe COVID-19 or hospitalization contribute to the uncertainties. Further, the clinical significance of the lack of viral load reduction remains unknown.
Results of ongoing trials are pending to confirm the clinical benefit of bamlanivimab.
A Risk Management Plan (RMP) for bamlanivimab was submitted by Eli Lilly Canada Inc. to Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. According to the terms and conditions imposed on this interim authorization, the sponsor is required to collect and assess safety information on an ongoing basis, submit safety reports, and provide an updated Canadian Addendum RMP.
Terms and conditions relating to developing and implementing Canadian-specific labelling have also been put in place.
Overall, despite uncertainty arising from the submission of limited data, Health Canada considers that bamlanivimab offers potential benefits with an acceptable safety profile and a favourable benefit-risk balance for the indicated patient population. The unmet medical need and the emergency context of the COVID-19 pandemic were taken into account in assessing whether the potential benefits outweigh the potential risks associated with bamlanivimab.
Pursuant to Section 5 of the Interim Order, the drug product bamlanivimab for injection has been authorized for sale in Canada, with associated terms and conditions set out to ascertain the continued quality, safety, and efficacy of the product. At any time, the terms and conditions may be amended. In addition, the authorization may be revoked if new information would not support the safe and effective use of the product.
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 Bamlanivimab for Injection?
The application for authorization of bamlanivimab was filed on October 12, 2020, in accordance with section 3 of the Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19 (Interim Order).
The intent of the Interim Order (signed by the Minister of Health on September 16, 2020) is to expedite the authorization of COVID-19 drugs. The Interim Order allows the Minister to account for the urgent public health needs relating to COVID-19 in deciding whether to authorize a COVID-19 drug based on the provided evidence of safety, efficacy, and quality. As outlined in the Information and Application Requirements for Drugs Authorized under the Interim Order: Guidance Document, the clinical, non-clinical, and quality (chemistry and manufacturing) information submitted in an application for authorization under the Interim Order may not be as comprehensive as that contained in a typical drug submission. The Interim Order sets out a modified set of application requirements with the potential for a rolling submission of information, which allows Health Canada to begin its assessment using the information submitted by the applicant and accept new evidence as it becomes available until the application is deemed complete. This process can reduce time to authorization for these important drugs while maintaining appropriate standards of safety, efficacy, and quality.
The information for this application was provided on a rolling basis. Following an expedited review of the limited clinical, non-clinical, and quality data submitted, Health Canada determined that sufficient evidence was provided to support the conclusion that the potential benefits associated with bamlanivimab outweigh the potential risks, having regard to the uncertainties relating to the benefits and risks and the necessity of addressing the urgent public health need related to COVID-19. An authorization for the sale of bamlanivimab, with imposed terms and conditions, was issued by Health Canada on November 20, 2020.
Submission Milestones: Bamlanivimab for Injection
The Canadian authorization decision was based on a critical assessment of the data package submitted to Health Canada. The reviewers also considered the sponsor's responses to information requests made by the United States Food and Drug Administration (FDA) and the fact sheet for health care providers on the FDA's emergency use authorization of bamlanivimab.
For further information on authorization under this pathway, refer to Health Canada's Interim Order Respecting the Importation, Sale, and Advertising of Drugs for Use in Relation to COVID-19 and the Information and Application Requirements for Drugs Authorized under the Interim Order: Guidance Document.
4 What follow-up measures will the company take?
In accordance with section 10 of the Interim Order Respecting the Importation, Sale, and Advertising of Drugs for Use in Relation to COVID-19 (Interim Order), terms and conditions were imposed on the authorization issued in respect of bamlanivimab (also referred to as LY3819253 or LY-CoV555). These terms and conditions set out requirements relating to clinical information, quality (chemistry and manufacturing), risk management plan elements, and labelling, and were put in place to ascertain the continued quality, safety, and efficacy of the product.
Briefly, the terms and conditions include (but are not limited to) the following:
- The sponsor will provide results, if, and when they become available, from:
- BLAZE-2, a Phase III randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of LY3819253 (LY-CoV555) in preventing SARS-CoV-2 infection and COVID-19 in skilled nursing and assisted living facility residents and staff;
- ACTIV-2, a study for outpatients with COVID-19;
- the treatment arms containing adolescents (i.e., treatment arms 7 to 10) of BLAZE-1, a Phase II randomized, double-blind, placebo-controlled trial to evaluate LY3819253 (LY-CoV555) and LY3832479 (LY-CoV016) in participants with mild to moderate COVID-19 illness.
- BLAZE-2, a Phase III randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of LY3819253 (LY-CoV555) in preventing SARS-CoV-2 infection and COVID-19 in skilled nursing and assisted living facility residents and staff;
- The sponsor will submit updated and comprehensive population pharmacokinetic and pharmacokinetic/pharmacodynamic modelling and simulation reports at the time of filing a new drug submission for bamlanivimab.
- The drug product to be sold in Canada will be tested in accordance with the updated specifications, and the drug substance will be tested at sites noted by the sponsor.
- The sponsor will provide information, as it becomes available, regarding any failed or aborted drug substance or drug product lots, and a detailed description of the issue(s), including a discussion on any potential impact on quality, safety, and efficacy.
- Within one week of filing a Biologics License Application to the United States Food and Drug Administration (FDA), the sponsor will file an amendment(s) to this interim authorization to provide:
- process validations related to drug substance and drug product manufacturing;
- any available stability data from lots included in the application for this interim authorization, indicating the new data points and any extensions to drug substance or drug product expiry date;
- any supporting studies, as filed to the FDA.
- Bamlanivimab has been placed in the Lot Release Evaluation Group 3 of Health Canada's Lot Release Program. Products in the Lot Release Evaluation Group 3 require review by Health Canada and issuance of a formal lot release decision letter prior to their release for sale on the Canadian market.
- The sponsor will:
- Collect and assess safety information on an ongoing basis, determine whether there has been a significant change in what is known about the risks and benefits of bamlanivimab, and notify Health Canada without delay of such changes.
- Submit to Health Canada reports of any serious expected and unexpected adverse drug reaction that has occurred in Canada and any serious unexpected adverse drug reaction that has occurred outside Canada within 15 days of receiving the information (as per section C.01.017 of the Food and Drug Regulations).
- After authorization and commencing on January 30, 2021, submit monthly safety reports for the period of this interim authorization, unless otherwise determined by Health Canada.
- At any time, prepare an issue-related summary report (as per section C.01.019 of the Food and Drug Regulations), should an emerging issue be identified.
- Provide an updated Canadian Addendum Risk Management Plan (RMP), no later than after two months on the market, that should include the following:
- close monitoring activities on pediatric patients in Canada;
- updated pregnancy questionnaire;
- information regarding studies (ongoing or planned) and timelines for evaluation of long-term safety.
- Provide an updated Canadian Addendum RMP in a timely manner if a signal of safety issue is observed in post-authorization surveillance.
- Develop and distribute a Dear Health Care Professional Letter in French and English, upon Health Canada's approval, to inform health care professionals about the authorization of bamlanivimab under the Interim Order with English-only vial and carton labels, to expedite the global supply of the drug in the context of the pandemic. The letter should point health care professionals to the website where they can find information about Canadian-specific labelling in both official languages and should be issued before the product is distributed.
- Commit to inform Health Canada on the plans to develop and implement Canadian-specific labelling and work towards developing such labelling at a point when the global supply and pandemic situation will allow it.
- Collect and assess safety information on an ongoing basis, determine whether there has been a significant change in what is known about the risks and benefits of bamlanivimab, and notify Health Canada without delay of such changes.
6 What other information is available about drugs?
Health Canada is committed to providing up‑to‑date information related to vaccines and treatments for COVID‑19. Up‑to‑date information can be found at the following links:
- See the Health Canada COVID‑19 vaccines and treatments portal for information on vaccines and treatments authorized for COVID‑19, as well as those currently under review.
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Drug Product Database (DPD) for the most recent Product Monographs for drugs that have been approved for use in Canada.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision
The clinical data initially provided in the application for authorization of bamlanivimab under the Interim Order Respecting the Importation, Sale, and Advertising of Drugs for Use in Relation to COVID-19 (Interim Order) included protocols, summaries and data tables related to the interim analysis of one clinical study, BLAZE-1 (PYAB), considered pivotal for the application. Subsequently, as part of a rolling submission of information allowed under the Interim Order, the sponsor provided several clinical information requests made by the United States Food and Drug Administration and responded to by the sponsor, to help inform the review. In addition, an interim population pharmacokinetic/pharmacodynamic report containing high-level details of the modelling and simulation conducted in support of the dose selection and extrapolation to adolescents was included in the application.
Following review, terms and conditions were imposed on the interim authorization of bamlanivimab to ascertain the continued quality, safety, and efficacy of the product.
Clinical Pharmacology
Bamlanivimab is a neutralizing immunoglobulin G1 (IgG1) monoclonal antibody directed against the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The monoclonal antibody can block the attachment of the spike protein to human angiotensin-converting enzyme 2 (ACE2) receptors, thereby preventing subsequent viral entry into human cells and viral replication.
The pharmacokinetics of bamlanivimab was assessed by a preliminary population pharmacokinetic analysis that pooled data from one Phase I study (PYAA) and one Phase II study (PYAB [BLAZE-1]) conducted in patients with coronavirus disease 2019 (COVID-19). Based on this preliminary analysis, the pharmacokinetics of bamlanivimab was not affected by age (age range of 18 to 86 years), sex, race, and disease severity.
In Study BLAZE-1, bamlanivimab doses over a range of 1 to 10 times the recommended dose (700 mg to 7,000 mg) were evaluated in patients with mild to moderate COVID-19 symptoms. Based on preliminary population pharmacokinetic analysis modelling and simulation, a flat exposure-response relationship for viral load reduction was identified for bamlanivimab within the studied dose range. In addition, body weight had no clinically meaningful effect on viral load reduction in adults with COVID-19 over the body weight range of 41 kg to 173 kg. These findings support the single intravenous infusion of 700 mg bamlanivimab as the recommended dose. The preliminary results further suggest that patients who receive treatment early relative to the onset of symptoms are expected to have improved viral clearance compared to patients who receive placebo within the same time period. As such and with consideration to the design of Study BLAZE-1, the Product Monograph indicates that treatment with bamlanivimab should be initiated as soon as possible after a positive SARS-CoV-2 test (using a direct SARS-CoV-2 validated testing method) and should be administered within 10 days following the onset of clinical signs and symptoms of infection.
Consistent with the available non-clinical data, the sponsor identified SARS-CoV-2 variants in patients following administration of bamlanivimab that were not present in baseline nasal swabs. In the high-risk patient population enrolled in BLAZE-1, SARS-CoV-2 resistant variants were identified more frequently at ≥15% and ≥50% allele fractions in bamlanivimab-treated patients (14% and 9.3%, respectively) compared to placebo-treated patients (2.4% and 0%, respectively). The clinical relevance of these findings is not known.
No adolescents (12 years of age and older) were included in the available clinical trials with bamlanivimab. The indication for this group of patients was supported by data derived from the preliminary population pharmacokinetic analysis modelling and simulation. The modelling approach accounted for the effect of age-associated body weight changes on pharmacokinetic parameters and predicted similar pharmacokinetic exposures following a 700 mg dose in adolescent patients weighing more than 40 kg to those observed in adult patients.
A number of uncertainties were considered in the assessment of the clinical pharmacology data. The correlation between viral load and clinical outcomes is presently unknown. Furthermore, the extent and handling of missing data as well as the validity of the modelling assumptions were not addressed in this application, but the sponsor committed to submitting updated and comprehensive modelling and simulation reports at the time of filing a new drug submission for bamlanivimab (see What follow-up measures will the company take?).
For further details, refer to the bamlanivimab 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
Interim clinical data from Study BLAZE-1 were available to evaluate the clinical efficacy of bamlanivimab for the treatment of patients with mild to moderate COVID-19.
Study BLAZE-1 is an ongoing Phase II, placebo-controlled, double-blind, randomized single-dose study of bamlanivimab alone or in combination with etesevimab, another anti-SARS-CoV-2 spike protein IgG1 monoclonal antibody, in participants with mild to moderate COVID-19 who have not been hospitalized. The application for authorization of bamlanivimab under the Interim Order sought authorization of the monotherapy only.
The study enrolled adult patients who had at least one COVID-19 symptom of mild or moderate severity and were not hospitalized. Patients must have had a SARS-CoV-2 positive test based on a sample taken no more than 3 days prior to drug infusion. Randomization to placebo or one of three bamlanivimab treatment arms (700 mg, 2,800 mg or 7,000 mg) was stratified by days (≤8 days vs. >8 days) since symptom onset. Treatment arms were well balanced with respect to the reported baseline patient characteristics.
The study objective was to evaluate the impact of bamlanivimab on viral clearance and clinical outcomes. The primary outcome was to demonstrate a statistically significant reduction in SARS-CoV-2 viral load at day 11 (±4 days), as measured by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) of samples taken via nasopharyngeal swabs. Important secondary outcomes included the proportion of patients who required hospitalization or emergency room visits by day 29, time to symptom improvement, and time to SARS-CoV-2 clearance. Improvement on the National Institute of Allergy and Infectious Diseases eight-point ordinal scale at various days post infusion was an exploratory objective. Of note, the results provided in the application were limited to those related to viral load, hospitalizations or emergency room visits, and symptom improvement.
The study was unsuccessful in demonstrating a statistically significant improvement in SARS-CoV-2 viral load at day 11 for any of the monotherapy treatment arms in comparison to placebo. In the subgroup of high-risk patients (the target population), a difference in viral clearance was not apparent between treatment arms. It was noted during review that viral clearance in the nasopharynx might not accurately reflect the potential of bamlanivimab to have a meaningful impact on clinical outcomes. While the utility of viral load in the role of a clinical endpoint is not clear, non-clinical data from the African green monkey and rhesus macaque models of SARS-CoV-2 infection (see Non-Clinical Basis for Decision) suggested that testing based on nasal or throat sampling was not completely reflective of viral load as measured in the lungs. This suggests that nasopharyngeal sampling may not accurately reflect the effect of the drug on the virus and further, that the viral load may not be a robust predictor of clinical outcomes.
The most promising evidence of a potential benefit related to bamlanivimab is with respect to the proportion of patients who required hospitalization or emergency room visits by study day 29. A numerical reduction in the proportion of patients requiring hospitalization or emergency room visits was observed among all treated patients. In the placebo, 700 mg, 2,800 mg, 7,000 mg and combined bamlanivimab groups, the proportions of patients requiring hospitalization or emergency room visits were 5.8%, 1.0%, 1.9%, 2.0% and 1.6%, respectively. Within the subgroup of patients who met the high-risk criteria, as per the recommended indication, the proportions of patients requiring hospitalization or emergency room visits in the placebo, 700 mg, 2,800 mg, 7,000 mg, and combined bamlanivimab groups were 10.1%, 2.2%, 2.2%, 4.5%, and 2.9%, respectively. These data suggest that the numerical reduction in the rate of hospitalizations and emergency room visits observed between placebo- and bamlanivimab-treated patients is mainly driven by patients who are at high risk of progressing to severe COVID-19 or hospitalization.
The median time to symptom improvement as recorded in a trial-specific daily symptom diary was 6 days for bamlanivimab-treated subjects, as compared with 8 days for placebo-treated subjects. Symptoms assessed were cough, shortness of breath, feeling feverish, fatigue, body aches and pains, sore throat, chills, and headache.
The data reviewed are associated with a number of uncertainties. In particular, the proportions of patients needing hospitalization or emergency room visits was a secondary outcome that was not controlled for type I error. Another uncertainty is related to the lack of a clear link between viral load and clinical outcomes. However, it is unclear whether nasopharyngeal viral load over time is predictive of clinical outcomes. Uncertainty also exists with respect to the assessment of symptom scores since this was also a secondary endpoint with no control of type I error. The reliability of patient-reported outcomes and the extent of missing data as well as the handling of missing data are additional confounders in interpreting the data.
Despite these uncertainties and limitations, the numerical reduction in the rates of hospitalization or emergency room visits among bamlanivimab-treated patients is suggestive of a clinical benefit of bamlanivimab when used in the target patient population.
Results of ongoing trials are pending to confirm the clinical benefit of bamlanivimab.
Indication
The sponsor filed the application for authorization of bamlanivimab under the Interim Order with the following indication:
- Bamlanivimab is indicated for the treatment of mild to moderate COVID-19 in adults and pediatric patients 12 years or older, who weigh at least 40 kg and who are at high risk of progressing to COVID-19 illness or hospitalization.
- High risk is defined as patients who meet at least one of the following criteria:
- Are ≥65 years of age
- Have a body mass index (BMI) ≥35
- Have chronic kidney disease
- Have diabetes
- Have immunosuppressive disease
- Are currently receiving immunosuppressive treatment
- Are ≥55 years of age and have
- cardiovascular disease, or
- hypertension, or
- chronic obstructive pulmonary disease/other chronic respiratory disease
- Bamlanivimab should not be used in patients hospitalized with severe COVID-19 respiratory disease.
Health Canada revised the proposed indication to include additional risk criteria, which define the adolescent patients (12 to 17 years of age) for whom bamlanivimab may be appropriate. The criteria are aligned with those listed in the United States Food and Drug Administration (FDA) fact sheet for health care providers on the FDA's emergency use authorization of bamlanivimab. Importantly, bamlanivimab has not been tested in pediatric subjects and the utility of these risk criteria in treatment stratification are unknown. The sponsor provided a written discussion on the epidemiology and pathophysiology of COVID-19 among pediatric patients suggesting that pediatric patients who required admission to intensive care were likely to have a significant risk factor for progression to severe COVID-19 illness.
In the revised indication, Health Canada also highlighted the lack of observed benefit of treatment with bamlanivimab in patients hospitalized with severe COVID-19 respiratory disease and the limited clinical evidence that supported the interim authorization.
Accordingly, Health Canada approved the following indication:
- Bamlanivimab is indicated for the treatment of adults and pediatric patients 12 years of age or older with mild to moderate coronavirus disease 2019 (COVID-19), who weigh at least 40 kg and who are at high risk of progressing to severe COVID-19 illness and/or hospitalization.
- High risk is defined as patients who meet at least one of the following criteria:
- Are ≥65 years of age
- Have a body mass index (BMI) ≥35 for patients ≥18 years of age
- Have chronic kidney disease
- Have diabetes
- Have immunosuppressive disease
- Are currently receiving immunosuppressive treatment
- Are 55 years of age and older and have
- cardiovascular disease, or
- hypertension, or
- chronic obstructive pulmonary disease/other chronic respiratory disease
- Are 12 to 17 years of age and have
- BMI ≥85th percentile for their age and gender, or
- sickle cell disease, or
- congenital or acquired heart disease, or
- neurodevelopmental disorders, for example, cerebral palsy, or
- a medical-related technological dependence, for example, tracheostomy, gastrostomy, or positive pressure ventilation (not related to COVID-19), or
- asthma, reactive airway or other chronic respiratory disease that requires daily medication for control
- Bamlanivimab should not be used in patients hospitalized with severe COVID-19 respiratory disease, as benefit of treatment has not been observed in this setting. Bamlanivimab, a monoclonal antibody, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high-flow oxygen or mechanical ventilation.
- Interim authorization is supported by a numerical reduction in hospitalization or emergency room visits in high-risk patients treated with bamlanivimab compared to high-risk patients treated with placebo.
For more information, refer to the bamlanivimab 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
In Study BLAZE-1 (described in the Clinical Efficacy section), 309 outpatients with mild to moderate COVID-19 received one administration of bamlanivimab at a dose of 700 mg (number of subjects [n] = 101), 2,800 mg (n = 107) or 7,000 mg (n = 101). An additional 112 patients received bamlanivimab 2,800 mg in combination with etesevimab 2,800 mg. Placebo was administered to 156 patients. The median follow-up time post exposure was 29 days. More than 98% of monotherapy-treated subjects were followed for longer than 22 days.
Overall, treatment-emergent adverse events were reported by 26.3% of placebo-treated patients compared to 23.0% of patients treated with bamlanivimab monotherapy. The rates of treatment-emergent adverse events observed across monotherapy doses were similar. The majority of treatment-emergent adverse events were graded as mild to moderate in all study arms, with no apparent differences observed. Treatment-emergent adverse events graded as severe were observed in 1.9% of placebo-treated subjects compared to 2.9% of bamlanivimab monotherapy-treated patients. One patient (1.0%) who received bamlanivimab at the proposed dose of 700 mg experienced a severe treatment-emergent adverse event of dyspnea.
One serious adverse event was reported in the placebo arm, while no serious adverse events were observed among any of the bamlanivimab monotherapy arms.
No deaths were reported in the placebo and treatment arms.
The most important adverse reactions associated with bamlanivimab are infusion reactions, hypersensitivity reactions and anaphylactic reactions. These types of reactions are of concern for therapeutic monoclonal antibodies in general. Notably, there was no clear increase in hypersensitivity or anaphylactic reactions based on narrow and broad standardized Medical Dictionary for Regulatory Activities (MedDRA) queries when the monotherapy treatment arms were compared to placebo. With regard to infusion reactions, the sponsor's search strategy identified six likely cases in the bamlanivimab group compared to one likely case in the placebo group. The Product Monograph provides warnings regarding each of these potential adverse reactions and advises prescribers that the product should only be administered in a setting where health care providers have the necessary means to treat such severe reactions.
Overall, the results of BLAZE-1 suggest that the safety profile of a single dose of bamlanivimab 700 mg is relatively unremarkable. Single doses of up to 7,000 mg were also administered without any notable increase in the rate of treatment-emergent adverse events or serious adverse events. This may be partially due to the mechanism of action, which involves direct binding to the spike protein of the SARS-CoV-2 and not to any receptor expressed in human tissue. Furthermore, a single-dose administration may also reduce the incidence of hypersensitivity and anaphylactic reactions as compared to a regimen requiring repeated administrations.
For more information, refer to the bamlanivimab 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 initial non-clinical data contained in the application for authorization of bamlanivimab under the Interim Order Respecting the Importation, Sale, and Advertising of Drugs for Use in Relation to COVID-19 included four primary pharmacodynamic reports, four pharmacokinetic reports, one repeat-dose toxicity study, and one tissue cross-reactivity study. Subsequently, the sponsor provided a summary of resistant variant data from non-clinical studies and an amended non-clinical pharmacology-toxicology report prepared for the United States Food and Drug Administration.
In vitro characterization of bamlanivimab activity demonstrated high-affinity binding to the receptor-binding domain (RBD) on the spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and showed that bamlanivimab blocks interaction between the spike protein and the angiotensin-converting enzyme 2 (ACE2) receptor, the known receptor for the RBD. Integrated statistical evaluation of multiple in vitro viral neutralization assays demonstrated a 50% maximal activity (half-maximal inhibitory concentration, IC50) at 0.03 µg/mL and 90% maximal activity (IC90) at 0.09 µg/mL with the Washington viral isolate.
In vivo, in a rhesus monkey prophylaxis model of SARS-CoV-2 infection, bamlanivimab administered as an intravenous dose of 1, 2.5, 15, or 50 mg/kg 24 hours prior to viral challenge demonstrated maximal neutralization of SARS-CoV-2 infection at the dose levels of 2.5 through 50 mg/kg.
Additional studies were conducted to determine if SARS-CoV-2 resistant variants could be isolated when cultured in the presence of bamlanivimab. In the assays employed, using serial passage of SARS-CoV-2 and directed evolution of the spike protein, four key SARS-CoV-2 variants were identified: E484K, F490S, Q493R, and S494P. These variants contain amino acid substitutions in the RBD of the spike protein and had reduced susceptibility to bamlanivimab as determined in neutralization assays using SARS-CoV-2 (F490S and S494P variants: >485-fold and >71-fold reduction, respectively) and/or vesicular stomatitis virus-based pseudovirus (all variants: >100-fold reduction).
The sponsor also assessed whether pre-treatment of rhesus macaques and African green monkeys with bamlanivimab was efficacious against SARS-CoV-2 and if potential paradoxical findings of antibody-dependent enhancement of infection were evident. No negative effects related to antibody-dependent enhancement of infection were noted, but importantly, the results indicated that bamlanivimab reduced viral load more effectively in the lungs (assessed in bronchoalveolar lavage samples) compared to samples taken from the throat and nasal passage. These non-clinical findings suggest that pre-treatment with bamlanivimab is efficacious against SARS-CoV-2 and that nasopharyngeal sampling may not accurately reflect the effect of the drug on the virus, which could complicate interpretations of clinical findings when viral load from nasal swabs is used as a clinical endpoint (see Clinical Efficacy).
A tissue cross-reactivity study assessed the binding of bamlanivimab to human, rat and monkey tissues. The binding pattern observed in monkey tissues was dissimilar to that in the human and rat tissues, and unexpected given the lack of viral antigen target in the analyzed tissues. Based on the tissue cross-reactivity data, the sponsor considers that the ongoing repeat-dose toxicity study in rats provides an adequate toxicology assessment of bamlanivimab and does not plan to initiate a monkey toxicity study of this monoclonal antibody.
In the repeat-dose toxicology study in Sprague Dawley rats, bamlanivimab administered by intravenous injection at 70, 175, or 500 mg/kg/dose once weekly for three weeks was well tolerated at all dose levels. The bamlanivimab-related microscopic observations in the inguinal lymph node along with the hematology changes were considered non-adverse findings, based on their minimal severity and limited distribution. There were no bamlanivimab-related clinical observations or effects on body weights, food consumption, ocular assessments, coagulation, blood chemistry and urinalysis parameters, gross pathology, and organ weights. Based on the absence of adverse findings, the highest dose tested (500 mg/kg) was considered the no-observed-adverse-effect level (NOAEL).
Toxicology studies in juvenile animals were not conducted.
Overall, based on the available non-clinical data, bamlanivimab had an acceptable safety profile, demonstrated high-affinity binding to the SARS-CoV-2 spike protein, reduced viral load (in the lungs) and infectivity in pre-treated African green monkeys, and was a useful tool to identify SARS-CoV-2 variants that could develop resistance to this therapy. The non-clinical findings also suggested that bamlanivimab could reduce viral load more effectively in the lungs compared to the upper respiratory tract, indicating that nasopharyngeal sampling may not reflect the overall pharmacological effects of the drug on the virus.
For more information, refer to the bamlanivimab 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
Limited quality (chemistry and manufacturing) data were provided in the application for authorization of bamlanivimab under the Interim Order Respecting the Importation, Sale, and Advertising of Drugs for Use in Relation to COVID-19 (Interim Order). Of note, given the intent of the Interim Order to expedite the authorization of coronavirus disease 2019 (COVID-19) drugs, data submitted may not be as comprehensive as the data contained in a typical new drug submission. Following review, terms and conditions were imposed on the interim authorization of bamlanivimab to ascertain the continued quality, safety, and efficacy of the product.
Characterization of the Drug Substance
Bamlanivimab is a fully human immunoglobulin G1 (IgG1) variant monoclonal antibody, which consists of two identical light chain polypeptides composed of 214 amino acids each and two identical heavy chain polypeptides composed of 455 amino acids each. Its molecular mass is 146,439 Da. The antibody binds selectively to the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Detailed characterization studies were performed to provide assurance that bamlanivimab consistently exhibits the desired characteristic structure and biological activity.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
Bamlanivimab is produced using a genetically engineered Chinese hamster ovary (CHO) cell line. The bioprocess begins with a master cell bank or working cell bank that is scaled up prior to inoculating a production bioreactor. Following cell culture clarification, the cell culture harvest is purified through a series of chromatography, viral inactivation, and filtration steps. The drug substance is subsequently stored frozen.
Submitted data for bioreactor runs and drug substance lots derived from these runs show that the drug substance manufacturing process is consistently run within the proposed parameter ranges. Process performance information for the cell culture steps showed consistent cell density and viability across all runs. The results of all available release tests were consistent and met the defined criteria.
The drug product manufacturing process begins with thawing of the drug substance, followed by formulation to a target of 35 mg/mL, sterile filtration, filling and stoppering, inspections prior to labelling, and final packaging.
Submitted in-process data from drug product batches demonstrate that the process is consistently run within the process parameters. The available batch release data are consistent and meet the acceptance criteria, supporting consistency in the process and resulting product. The aseptic processing is monitored by routine release sterility testing and by periodic aseptic processing simulations.
Control of the Drug Substance and Drug Product
The results of all available release tests for the drug substance and the drug product were provided and consistently met the defined criteria.
Summary qualification data for all methods were provided in lieu of release method validation studies.
Bamlanivimab is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per Health Canada's Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs. It has been placed in Lot Release Evaluation Group 3 of the Lot Release Program. Products in Lot Release Evaluation Group 3 require review by the Biologic and Radiopharmaceutical Drugs Directorate and issuance of a formal release letter prior to their release for sale on the Canadian market.
Stability of the Drug Substance and Drug Product
Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product are considered acceptable.
The available stability data support the proposed shelf life of 12 months for the drug product when stored at a temperature of 2°C to 8°C, protected from light. Bamlanivimab is a preservative-free product and therefore, the prepared solution should be administered immediately. If immediate administration is not possible, the diluted solution may be stored for up to 48 hours at refrigerated temperature (2ºC to 8ºC) or up to 14 hours at room temperature (20ºC to 25ºC) including infusion time.
Facilities and Equipment
The design, operations, and controls of the facilities and equipment involved in the production are considered suitable for the activities and products manufactured.
Based on risk assessment scores determined by Health Canada, on-site evaluations of the drug substance and drug product manufacturing facilities were not deemed necessary.
The sites involved in production are compliant with Good Manufacturing Practices.
Adventitious Agents Safety Evaluation
The manufacturing process of bamlanivimab incorporates adequate control measures to prevent contamination and maintain microbial control. Acceptable viral clearance studies have been performed 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.
With the exception of the CHO cell line, no materials of animal or human origin are used for the production of the drug substance and drug product. The master and working cell banks were confirmed to be free of adventitious agents.