By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has issued an emergency use authorization (EUA) to Regeneron Pharmaceuticals, Inc. for its monoclonal antibody cocktail for the treatment of mild to moderate COVID-19.1 Casirivimab and imdevimab are recombinant human IgG1 monoclonal antibodies that target the receptor-binding domain of the spike protein of SARS-CoV-2.2 Binding the viral spike protein reduces the attachment and entry of the virus into human cells. This combination gained early publicity when it was administered to President Trump after he tested positive for COVID-19 in October. The U.S. Department of Health and Human Services will make allocations to the states and territories, while AmerisourceBergen will distribute for the U.S. government.2
Casirivimab/imdevimab should be used to treat mild to moderate COVID-19 in adults and patients ≥ 12 years of age weighing at least 40 kg who have tested positive for SARS-CoV-2. These patients also would be considered high risk for developing severe COVID-19 or winding up in the hospital.2
The authorized dose is 1,200 mg of casirivimab and 1,200 mg of imdevimab, administered together as one intravenous infusion over at least one hour.2 Administer this combination as soon as possible after a positive viral test for SARS-CoV-2 (molecular or antigen) and within 10 days of the onset of symptoms. Casirivimab injection and imdevimab injection are available in separate 300 mg/2.5 mL increments.
The two monoclonal antibody combination approach may offer an advantage over the single monoclonal antibody (i.e., bamlanivimab). SARS-CoV-2 may mutate to viral variants with reduced susceptibility to either casirivimab or imdevimab because of different spike protein amino acid substitutions. These mutations have resulted in reduced susceptibility to one monoclonal antibody, but retained susceptibility to the other. This has led to maintained combination effectiveness.2
Casirivimab/imdevimab should not be used for patients who are hospitalized or require oxygen because of COVID-19.2 The combination also should not be used for those who are on chronic oxygen therapy and require a higher baseline oxygen flow rate because of COVID-19.2 Hypersensitivity, including anaphylaxis and infusion-related reactions (e.g., fever, chills, bronchospasm, hypotension, urticaria, and pruritus), may occur.2
Data supporting the EUA were drawn from a randomized, double-blind, placebo-controlled Phase I/II trial that included 799 nonhospitalized adults with mild to moderate COVID-19 symptoms.2 Subjects were randomized to 1,200 mg of casirivimab and 1,200 mg of imdevimab (n = 266), 4,000 mg of casirivimab and 4,000 mg of imdevimab (n = 267), or placebo (n = 266), initiated within three days of a positive test. The prespecified primary endpoint was average change in viral load from baseline. The secondary endpoint was medically attended visits related to COVID-19 (hospitalization, ED visit, urgent care visits, office/telemedicine visits) within 28 days after treatment.
Casirivimab/imdevimab (pooled doses) produced a significant reduction in viral load from day 1 through day 7, with the largest reduction occurring in subjects with high viral load or who were seronegative at baseline.2 No difference was observed between the two active doses. No difference in median time to symptom improvement was observed (five days for antibodies vs. six days for placebo). The most significant observation was with the secondary endpoint (hospitalization/ED visits in subjects at higher risk of hospitalization). The frequency was 3% for casirivimab/imdevimab (n = 151) and 9% for placebo (n = 78), a 67% reduction. In the overall study population, including those not at high risk for hospitalization (n = 665), the outcomes were not significantly different (2% for casirivimab/imdevimab vs. 4% for placebo).
Casirivimab/imdevimab provides a second treatment option under an EUA for nonhospitalized COVID-19 patients with mild to moderate disease, after bamlanivimab. Both received an EUA based on their ability to reduce the risk of hospitalization/ED visits in patients at higher risk for hospitalization (based on age, BMI, and comorbidities). Bamlanivimab showed a similar reduction (70%) in a related study population.3 There may be a theoretical advantage with a polyclonal vs. a monoclonal antibody in terms of development of antiviral resistance. (For more information about bamlanivimab, please read the Pharmacology Update section of the December 15 issue of Internal Medicine Alert here.)
- U.S. Food & Drug Administration. Coronavirus (COVID-19) update: FDA authorizes monoclonal antibodies for treatment of COVID-19. Nov. 21, 2020.
- U.S. Food & Drug Administration. Frequently asked questions on the emergency use authorization of casirivimab + imdevimab. Nov. 21, 2020.
- U.S. Food & Drug Administration. Coronavirus (COVID-19) update: FDA authorizes monoclonal antibody for treatment of COVID-19. Nov. 9, 2020.