Casirivimab/imdevimab and Its Use in Pediatrics

Introduction

Casirivimab and imdevimab are monoclonal antibodies that have been developed as a combination therapy for the treatment and prevention of COVID-19. This clinical note provides a comprehensive overview of this antibody cocktail, with a specific focus on its application in pediatric populations. As pediatricians, it is crucial to understand the mechanisms, efficacy, safety profile, and current recommendations for the use of casirivimab/imdevimab in children and adolescents.

Background and Development

Casirivimab and imdevimab were developed by Regeneron Pharmaceuticals as part of their COVID-19 response efforts. The combination, known by the trade name REGEN-COV, received Emergency Use Authorization (EUA) from the U.S. Food and Drug Administration (FDA) in November 2020 for the treatment of mild to moderate COVID-19 in patients aged 12 years and older weighing at least 40 kg who are at high risk for progressing to severe COVID-19.

These monoclonal antibodies were specifically designed to target the spike protein of SARS-CoV-2, the virus responsible for COVID-19. By binding to non-overlapping epitopes on the receptor binding domain (RBD) of the spike protein, casirivimab and imdevimab work synergistically to neutralize the virus and prevent its entry into human cells.

Mechanism of Action

The mechanism of action of casirivimab and imdevimab is based on their ability to mimic the body's natural immune response to SARS-CoV-2. As monoclonal antibodies, they are laboratory-produced molecules engineered to serve as substitute antibodies that can restore, enhance, or mimic the immune system's attack on pathogens.

Specifically:

• Casirivimab (REGN10933) and imdevimab (REGN10987) bind to different, non-overlapping epitopes of the SARS-CoV-2 spike protein RBD.
• This binding prevents the attachment of the virus to the human ACE2 receptor, which is the primary entry point for SARS-CoV-2 into human cells.
• By blocking viral entry, the antibodies effectively neutralize the virus, preventing infection of host cells and subsequent viral replication.
• The use of two antibodies targeting different epitopes reduces the potential for mutational escape by the virus, as it would need to simultaneously mutate at two distinct sites to evade both antibodies.

This dual-antibody approach provides a broader and more robust defense against the virus compared to single monoclonal antibody treatments.

Pharmacokinetics in Pediatric Populations

Understanding the pharmacokinetics of casirivimab and imdevimab in pediatric populations is crucial for determining appropriate dosing and administration strategies. While data specific to children are limited, extrapolations from adult studies and ongoing pediatric trials provide some insights:

• Distribution: Following intravenous administration, casirivimab and imdevimab are thought to distribute throughout the body in a manner similar to endogenous IgG antibodies. This includes distribution to the respiratory tract, which is the primary site of SARS-CoV-2 infection.
• Metabolism: As protein molecules, casirivimab and imdevimab are not metabolized by cytochrome P450 enzymes. Instead, they are likely catabolized throughout the body, similar to endogenous IgG.
• Elimination: The exact elimination half-life in pediatric patients has not been fully characterized. In adults, the estimated median elimination half-life is approximately 30 days for both casirivimab and imdevimab. It is reasonable to expect similar half-lives in adolescents, but younger children may have slightly different pharmacokinetics due to their developing immune systems and differing body compositions.
• Dosing adjustments: Current recommendations suggest weight-based dosing for pediatric patients, which helps account for the differences in body size and composition between children and adults. However, age-specific pharmacokinetic studies are needed to fully optimize dosing across different pediatric age groups.

It is important to note that ongoing studies are continually refining our understanding of the pharmacokinetics of casirivimab and imdevimab in pediatric populations. Pediatricians should stay informed about the latest research and guidelines as they become available.

Efficacy in Pediatric Populations

The efficacy of casirivimab and imdevimab in pediatric populations has been extrapolated from adult studies and supported by limited pediatric-specific data. The following points summarize the current understanding of the efficacy of this antibody cocktail in children and adolescents:

1. Treatment of Mild to Moderate COVID-19:
   • In the phase 3 portion of an adaptive trial (NCT04425629) that included patients 12 years and older, REGEN-COV significantly reduced COVID-19-related hospitalization or all-cause death compared to placebo.
   • The trial demonstrated a 70.4% reduction in the composite endpoint of COVID-19-related hospitalization or all-cause death through day 29 in patients treated with REGEN-COV 1200 mg IV compared to placebo.
   • While the number of adolescents included in this trial was limited, the results were considered applicable to the pediatric population aged 12 and above, weighing at least 40 kg.
2. Post-Exposure Prophylaxis:
   • A phase 3 trial (NCT04452318) evaluated REGEN-COV for prevention of COVID-19 in household contacts of infected individuals, including adolescents 12 years and older.
   • The study showed an 81% reduction in symptomatic SARS-CoV-2 infections in individuals who received REGEN-COV compared to placebo.
   • While specific data on the pediatric subgroup were not reported separately, the overall results were considered applicable to adolescents meeting the eligibility criteria.
3. Viral Load Reduction:
   • Across various studies, including those with pediatric participants, REGEN-COV has consistently demonstrated rapid and significant reductions in viral load compared to placebo.
   • This reduction in viral load is associated with faster symptom resolution and potentially reduced risk of transmission, which is particularly relevant in household and school settings where children may be in close contact with others.
4. Efficacy Against Variants:
   • In vitro studies have shown that casirivimab and imdevimab maintain neutralizing activity against many SARS-CoV-2 variants of concern, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2).
   • However, reduced potency has been observed against some variants, particularly the Omicron (B.1.1.529) variant and its sublineages.
   • Ongoing surveillance is crucial to monitor the efficacy of REGEN-COV against emerging variants, especially in pediatric populations where the immune response may differ from adults.

It is important to note that while these results are promising, the data specific to pediatric populations remain limited. Pediatricians should consider the most current evidence and guidelines when making treatment decisions for their patients.

Safety Profile in Pediatric Populations

The safety profile of casirivimab and imdevimab in pediatric populations is an area of ongoing research. While the overall safety data from adult studies have been reassuring, it is crucial to consider the unique physiological characteristics of children when evaluating the safety of this antibody cocktail. The following points summarize the current understanding of the safety profile in pediatric patients:

1. General Safety Observations:
   • In clinical trials that included adolescents 12 years and older, the safety profile of REGEN-COV was generally similar to that observed in adult populations.
   • The most common adverse events reported were infusion-related reactions and injection site reactions, which were typically mild to moderate in severity.
2. Infusion-Related Reactions:
   • Infusion-related reactions have been reported in approximately 1-2% of patients receiving REGEN-COV.
   • Symptoms may include fever, chills, nausea, headache, bronchospasm, hypotension, angioedema, throat irritation, rash, myalgia, and dizziness.
   • In pediatric patients, close monitoring during and after infusion is essential, as children may not be able to articulate symptoms as clearly as adults.
3. Anaphylaxis and Severe Hypersensitivity Reactions:
   • While rare, anaphylaxis and other severe hypersensitivity reactions have been reported with REGEN-COV use.
   • Pediatricians should be prepared to recognize and manage such reactions promptly, including having appropriate resuscitation equipment and medications readily available.
4. Long-Term Safety:
   • As a relatively new therapeutic, long-term safety data in pediatric populations are limited.
   • Theoretical concerns include the potential for interference with the development of natural immunity to SARS-CoV-2, although this has not been observed in studies to date.
   • Ongoing surveillance and long-term follow-up studies are crucial to identify any potential delayed effects, particularly in growing and developing children.
5. Special Considerations for Pediatric Patients:
   • Children with a history of severe allergic reactions or anaphylaxis to any component of REGEN-COV should not receive the treatment.
   • Caution is advised in children with thrombocytopenia or any coagulation disorder, as intramuscular injection may pose a risk of hematoma formation.
   • The impact on various pediatric conditions, such as autoimmune disorders or primary immunodeficiencies, requires further study.
6. Monitoring and Reporting:
   • Close monitoring of pediatric patients receiving REGEN-COV is recommended, with particular attention to vital signs, oxygen saturation, and any signs of allergic or infusion-related reactions.
   • Pediatricians are encouraged to report any adverse events to the appropriate regulatory authorities and participate in post-marketing surveillance programs to enhance the safety database for pediatric use.

While the available data suggest a favorable safety profile for casirivimab and imdevimab in adolescents, more research is needed to fully characterize the safety in younger children and infants. Pediatricians should weigh the potential benefits against the risks when considering REGEN-COV for their patients, taking into account individual clinical circumstances and the latest safety information.

Current Recommendations and Guidelines for Pediatric Use

The recommendations and guidelines for the use of casirivimab and imdevimab in pediatric populations have evolved as more data have become available. However, it is important to note that these guidelines may change rapidly in response to new evidence and the emergence of viral variants. The following summarizes the current recommendations as of the last update:

1. FDA Emergency Use Authorization (EUA):
   • The FDA has authorized the emergency use of REGEN-COV for the treatment of mild to moderate COVID-19 in patients aged 12 years and older weighing at least 40 kg.
   • The authorization also covers post-exposure prophylaxis in individuals who are at high risk for progression to severe COVID-19, including hospitalization or death.
2. Eligibility Criteria:
   • Pediatric patients must have a positive SARS-CoV-2 viral test and be within 10 days of symptom onset to be eligible for treatment.
   • For post-exposure prophylaxis, patients must have been exposed to an individual infected with SARS-CoV-2 and be at high risk for progression to severe COVID-19.
3. High-Risk Criteria for Pediatric Patients:
   • Obesity or being overweight (BMI ≥85th percentile for age and gender)
   • Sickle cell disease
   • Congenital or acquired heart disease
   • Neurodevelopmental disorders
   • Medical-related technological dependence
   • Asthma or other chronic respiratory disease that requires daily medication for control
   • Diabetes mellitus (type 1 or type 2)
   • Immunosuppressive disease or treatment
4. Dosing and Administration:
   • The recommended dose is 600 mg of casirivimab and 600 mg of imdevimab administered together as a single intravenous infusion.
   • For patients who meet criteria for subcutaneous injection and in whom IV infusion would lead to delay in treatment, four subcutaneous injections (2.5 mL per injection) may be given.
   • Dosing is the same for both treatment and post-exposure prophylaxis indications.
5. Timing of Administration:
   • For treatment, REGEN-COV should be administered as soon as possible after a positive viral test for SARS-CoV-2 and within 10 days of symptom onset.
   • For post-exposure prophylaxis, it should be given as soon as possible following exposure to SARS-CoV-2.
6. Monitoring:
   • Patients should be monitored during the infusion and observed for at least 1 hour after the completion of the infusion.
   • For subcutaneous injections, patients should be observed for at least 1 hour after the injections.
7. Limitations of Use:
   • REGEN-COV is not authorized for use in patients hospitalized due to COVID-19.
   • It is not recommended for patients who require oxygen therapy due to COVID-19.
   • The treatment has not been studied in patients younger than 12 years of age or weighing less than 40 kg.
8. Variant Considerations:
   • The use of REGEN-COV should be tailored to the local prevalence of SARS-CoV-2 variants and their susceptibility to the antibody cocktail.
   • In regions where variants with reduced susceptibility to REGEN-COV are prevalent, alternative therapies should be considered.
9. Combination with Other Therapies:
   • There is limited data on the use of REGEN-COV in combination with other COVID-19 therapies in pediatric populations.
   • Pediatricians should exercise caution and consider potential drug interactions when using REGEN-COV alongside other treatments.
10. Vaccination Considerations:
    • REGEN-COV administration should be deferred for at least 90 days in individuals who have received a COVID-19 vaccine, to avoid potential interference with vaccine-induced immune responses.
    • Conversely, COVID-19 vaccination should be deferred for at least 90 days following REGEN-COV administration.

It is crucial for pediatricians to stay informed about the latest guidelines and recommendations, as they may be updated frequently based on emerging evidence and the evolving landscape of SARS-CoV-2 variants.

Practical Considerations for Pediatric Use

When considering the use of casirivimab and imdevimab in pediatric patients, several practical aspects need to be taken into account:

1. Patient Selection:
   • Carefully assess the patient's risk factors for severe COVID-19 progression.
   • Consider the timing of symptom onset or exposure, as REGEN-COV is most effective when administered early.
   • Evaluate the patient's ability to comply with the administration protocol and follow-up requirements.
2. Facility Requirements:
   • Ensure that the healthcare facility is equipped to administer intravenous infusions or subcutaneous injections to pediatric patients.
   • Have appropriate emergency equipment and medications available to manage potential infusion reactions or anaphylaxis.
3. Consent and Assent:
   • Obtain informed consent from parents or legal guardians, explaining the potential benefits and risks of REGEN-COV treatment.
   • When appropriate, involve the pediatric patient in the decision-making process and obtain assent.
4. Administration Challenges:
   • Consider the potential difficulty of establishing intravenous access in younger children.
   • For subcutaneous administration, be aware that multiple injection sites may be required, which can be distressing for some pediatric patients.
5. Monitoring and Follow-up:
   • Develop a robust follow-up plan to monitor for delayed adverse effects and assess treatment efficacy.
   • Consider the need for repeat viral testing to evaluate viral clearance, especially in immunocompromised patients.
6. Patient and Family Education:
   • Provide clear instructions on monitoring for potential side effects at home.
   • Emphasize the importance of continued infection prevention measures, as REGEN-COV does not provide long-term immunity.
7. Resource Allocation:
   • Be aware of potential supply limitations and follow institutional or regional guidelines for prioritizing patients when resources are scarce.
8. Cost and Insurance Considerations:
   • While the U.S. government has purchased doses for distribution, be prepared to address potential insurance and cost concerns from families.

Ongoing Research and Future Directions

The field of COVID-19 therapeutics, including the use of monoclonal antibodies in pediatric populations, is rapidly evolving. Several areas of ongoing research and future directions are particularly relevant for pediatricians:

1. Pediatric-Specific Clinical Trials:
   • Ongoing and planned studies are focusing on the safety and efficacy of REGEN-COV in younger age groups, including infants and children under 12 years of age.
   • These trials aim to provide more robust data on optimal dosing, pharmacokinetics, and potential age-specific considerations.
2. Long-Term Follow-up Studies:
   • Research is underway to assess the long-term impacts of monoclonal antibody treatment on pediatric immune system development and natural immunity to SARS-CoV-2.
   • These studies will help inform future guidelines on the use of REGEN-COV in children, particularly in the context of vaccination strategies.
3. Combination Therapies:
   • Investigations are ongoing to evaluate the potential synergistic effects of combining REGEN-COV with other COVID-19 treatments in pediatric patients.
   • This research may lead to more effective treatment protocols, especially for high-risk pediatric populations.
4. Variant Surveillance and Antibody Engineering:
   • Continuous monitoring of SARS-CoV-2 variants and their impact on REGEN-COV efficacy is crucial.
   • Researchers are working on developing next-generation antibodies that may offer broader protection against emerging variants.
5. Novel Administration Routes:
   • Studies are exploring alternative routes of administration, such as inhaled formulations, which could be particularly beneficial for pediatric patients.
   • These novel approaches may improve treatment adherence and reduce the need for healthcare facility visits.
6. Predictive Biomarkers:
   • Research is ongoing to identify biomarkers that can predict which pediatric patients are most likely to benefit from REGEN-COV treatment.
   • This could lead to more personalized treatment approaches and improved resource allocation.
7. Real-World Effectiveness Studies:
   • Large-scale observational studies are being conducted to assess the real-world effectiveness of REGEN-COV in diverse pediatric populations.
   • These studies will provide valuable insights into the treatment's impact on hospitalizations, disease progression, and long-term outcomes in children.
8. Integration with Vaccination Strategies:
   • Research is needed to optimize the use of REGEN-COV in the context of expanding vaccination programs for children and adolescents.
   • Studies are exploring how monoclonal antibody treatment may complement or interact with vaccine-induced immunity in pediatric populations.

As pediatricians, staying informed about these ongoing research efforts and future directions is crucial. The landscape of COVID-19 treatment is likely to continue evolving, and new evidence may significantly impact clinical practice guidelines for the use of casirivimab and imdevimab in pediatric patients.

Further Reading

• FDA Fact Sheet for Healthcare Providers: Emergency Use Authorization for REGEN-COV
• REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19
• REGEN-COV Antibody Combination and Outcomes in Outpatients with Covid-19
• CDC: Information for Pediatric Healthcare Providers
• Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19