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Casirivimab/imdevimab

Introduction to Casirivimab/Imdevimab

Casirivimab and imdevimab are two recombinant human IgG1 monoclonal antibodies that bind to non-overlapping epitopes of the spike protein receptor binding domain (RBD) of SARS-CoV-2. This combination, developed by Regeneron Pharmaceuticals, is also known by the brand name REGEN-COV. It received Emergency Use Authorization (EUA) from the FDA in November 2020 for the treatment of mild-to-moderate COVID-19 in high-risk patients and later for post-exposure prophylaxis. However, as of April 2024, its EUA status may have changed due to the emergence of resistant variants.

Mechanism of Action

Casirivimab and imdevimab work synergistically through the following mechanisms:

  1. Virus Neutralization: Both antibodies bind to different sites on the SARS-CoV-2 spike protein RBD, blocking viral attachment and entry into human cells. This dual action enhances the potential for neutralization and may reduce the likelihood of viral escape.
  2. Fc-mediated Effector Functions: The Fc regions of the antibodies can engage immune system components, potentially leading to clearance of virus-infected cells through mechanisms such as antibody-dependent cell-mediated cytotoxicity (ADCC) and phagocytosis.

The use of two antibodies targeting different epitopes was designed to maintain efficacy even if mutations occur in one of the target sites. However, certain variants have shown resistance to this combination.

Indications

As of April 2024, the indications for casirivimab/imdevimab have evolved due to the changing landscape of SARS-CoV-2 variants:

  • Original EUA (November 2020):
    • Treatment of mild to moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progressing to severe COVID-19 and/or hospitalization.
  • Expanded EUA (July 2021):
    • Post-exposure prophylaxis of COVID-19 in individuals who are at high risk for progression to severe COVID-19, including hospitalization or death, and are:
      1. Not fully vaccinated or not expected to mount an adequate immune response to vaccination, AND
      2. Have been exposed to an individual infected with SARS-CoV-2 or
      3. Are at high risk of exposure to an individual infected with SARS-CoV-2 in institutional settings.
  • Revised EUA (April 2024): The FDA has limited the use of casirivimab/imdevimab only in regions where it is likely to retain activity against circulating SARS-CoV-2 variants. Healthcare providers should monitor the FDA website for information on specific variants and geographic regions where this combination is currently authorized.

Note: The exact status and indications may have changed after April 2024. Healthcare providers should always refer to the most current FDA guidance.

Administration

When authorized for use, casirivimab/imdevimab is administered as follows:

  • Treatment Dosage: 600 mg of casirivimab and 600 mg of imdevimab
  • Prophylaxis Dosage:
    • Initial dose: 600 mg of casirivimab and 600 mg of imdevimab
    • Subsequent doses: 300 mg of casirivimab and 300 mg of imdevimab every 4 weeks for duration of ongoing exposure
  • Routes:
    • Intravenous (IV) infusion (preferred method)
    • Subcutaneous (SC) injection when IV infusion is not feasible and would lead to delay in treatment
  • Timing: Should be given as soon as possible after positive SARS-CoV-2 test and within 10 days of symptom onset for treatment, or as soon as possible after exposure for prophylaxis

Important notes:

  • Must be diluted and administered together when given intravenously
  • Patients should be monitored during and for at least 1 hour after IV infusion or 4 subcutaneous injections
  • Should be administered in a setting where severe hypersensitivity reactions can be managed

Efficacy and Safety

Efficacy:

  • Treatment: In the phase 3 trial, reduced risk of COVID-19-related hospitalization or all-cause death by 70% compared to placebo in high-risk non-hospitalized patients
  • Prophylaxis: 81% reduced risk of symptomatic SARS-CoV-2 infection in close contacts of infected individuals
  • Efficacy against emerging variants has varied, leading to changes in authorization status

Safety:

  • Most common adverse events: Infusion-related reactions, injection site reactions
  • Serious adverse events: Hypersensitivity reactions including anaphylaxis have been reported rarely

Limitations:

  • Decreased efficacy against certain SARS-CoV-2 variants
  • Not authorized for patients hospitalized due to COVID-19 or who require oxygen therapy due to COVID-19
  • Not a substitute for vaccination against COVID-19

Pediatric Use

Casirivimab/imdevimab use in pediatric patients has been limited:

  • Authorized for use in patients 12 years and older weighing at least 40 kg
  • Safety and efficacy in pediatric patients under 12 years of age have not been established
  • Limited data available on use in pregnant adolescents

Considerations for pediatric use:

  • Benefit-risk assessment should be conducted for each patient, considering the changing landscape of SARS-CoV-2 variants
  • Pediatricians should stay informed about the latest FDA guidance on casirivimab/imdevimab's authorization status
  • Other treatment options may be preferred in pediatric patients, depending on current guidelines and variant prevalence
  • Special attention should be given to dosing and administration in adolescents, ensuring weight-based criteria are met

Special Considerations

- Variant Monitoring: Healthcare providers must stay informed about the prevalence of SARS-CoV-2 variants in their region and casirivimab/imdevimab's activity against them.
- Pregnancy and Lactation: Limited data available. Should be used during pregnancy only if the potential benefit outweighs the potential risk for the mother and fetus.
- Drug Interactions: No formal drug interaction studies have been conducted.
- Vaccination: COVID-19 vaccines may be less effective if administered within 90 days of casirivimab/imdevimab treatment.
- Antiviral Resistance: The potential for treatment-emergent resistance should be considered, especially in immunocompromised patients.
- Long-term Effects: As a relatively new therapy, long-term effects are not yet fully known and patients should be monitored accordingly.
- Cost and Availability: These factors may influence treatment decisions, especially given the changing authorization status.
- Storage and Handling: Specific temperature requirements and preparation instructions must be followed to maintain product integrity and efficacy.



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