Clinical Overview: Evusheld for Pre-Exposure Prophylaxis of COVID-19

The FDA has authorized the use of Evusheld for pre-exposure prophylaxis for prevention of COVID-19 under an Emergency Use Authorization (EUA).¹ Tixagevimab co-packaged with cilgavimab (Evusheld) is a SARS-CoV-2 spike protein-directed attachment inhibitor.

The EUA does not allow tixagevimab/cilgavimab to treat COVID-19 or for post-exposure prophylaxis of COVID-19.

Adults and children 12 years of age or older who weigh at least 40 kg may receive tixagevimab/cilgavimab. Individuals must not have COVID-19 or have been in contact with an individual with COVID-19. They must be moderately to severely immunocompromised with an inadequate immune response to COVID-19 vaccination or unable to complete their vaccination series due to a severe adverse reaction to a COVID-19 vaccine or any components.²

Tixagevimab/cilgavimab is not a substitute for any COVID-19 vaccinations in unvaccinated individuals who are able to receive and respond appropriately to COVID-19 vaccination.

Clinical Studies

The phase 3 trial, PROVENT, supports the EUA. PROVENT is a randomized (2:1), double-blind, placebo controlled clinical trial studying tixagevimab/cilgavimab’s efficacy for pre-exposure prophylaxis of COVID-19.

All subjects selected had at least 1 elevated risk factor for COVID-19, including age (over 60 years), comorbidities, or residential or occupational status. Of the 3441 patients given 150 mg of tixagevimab plus 150 mg cilgavimab, only 8 (0.2%) developed symptomatic COVID-19. Seventeen (1.0%) of the 1731 patients administered placebo developed symptomatic COVID-19. The results show a relative risk reduction of 77%.

Detailed results from the pre-exposure prophylaxis trial showed that the treatment reduced the risk of developing symptomatic COVID-19 by 77% in the primary analysis and by 83% in the 6-month follow-up analysis, versus placebo. There were no cases of severe disease or COVID-19 related deaths in the tixagevimab/cilgavimab group through the 6-month follow-up.³

Mechanism of Action

Tixagevimab and cilgavimab are both human immunoglobulin G1 (IgG1k) monoclonal antibodies. The antibodies are produced in Chinese hamster ovary cells via recombinant DNA technology.

In combination, tixagevimab and cilgavimab bind to the receptor binding domain of spike protein and block its interaction with human ACE2 (the SARS-CoV-2 receptor), which prevents virus attachment to the receptor.

Dosage and Preparation

Tixagevimab/cilgavimab consists of 2 separate consecutive intramuscular injections of 300 mg of tixagevimab and 300 mg of cilgavimab. Currently, there are no recommendations to repeat dosages. A qualified health care provider must prepare and administer both injections, and monitor the patient for at least an hour after injections.

The provider must inspect the vials to ensure proper color and absence of particulates before withdrawal. The solutions are colorless to slightly yellow and clear to opalescent, and must not be shaken.

Tixagevimab and cilgavimab are packaged separately in 150 mg/1.5 mL (100 mg/mL) single-dose vials. The injection requires 2 vials of each drug, for a total of 3 mL (300 mg).

Providers must use a separate syringe for each drug. Both products contain no preservatives, so they require immediate administration and must be discarded if they are not administered within 4 hours.

Administration

Providers should administer tixagevimab and cilgavimab as 2 separate, consecutive intramuscular injections. The provider should give the injections in different injection sites, preferably 1 in each gluteal muscle to account for the appropriate volume of 3 mL per injection.

A health care professional must monitor the patient for at least 1 hour after the injections. Patients who have received a COVID-19 vaccination must wait at least 2 weeks before they can receive tixagevimab/cilgavimab.

Previous Administration

Some individuals have initially received 150 mg of tixagevimab and 150 mg of cilgavimab from the previously authorized dose. Those patients should receive a second dose of 150 mg tixagevimab and 150 mg cilgavimab as soon as possible. All other individuals should receive an initial dose of 300 mg of tixagevimab and 300 mg of cilgavimab.

Adverse Events (AEs)

The most common AEs include headache, fatigue, and cough. Local injection site reactions including pain, bruising of the skin, and soreness are possible.

Warnings and Precautions

A health care professional should monitor the patient for at least an hour after the injections in case of serious hypersensitivity reactions. This includes anaphylaxis, which can occur with IgG1 monoclonal antibody use.

Providers should use caution when administering to patients with thrombocytopenia or other coagulation disorder. They must consider the benefit/risk ratio in patients who are at high risk for cardiovascular AEs, as clinical trials have reported a higher proportion of subjects who experienced cardiovascular AEs.

Pregnancy and Lactation

There are insufficient data to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.¹ Patients should only use Evusheld during pregnancy if the potential benefit outweighs the potential risk factors. It is unknown whether tixagevimab or cilgavimab are present in breastmilk.

About the Author

Greta Staubly is a 2024 PharmD candidate at the University of Connecticut.

References

1. Fact Sheet for Healthcare Providers: Emergency Use Authorization for Evusheld (tixagevimab co-packaged with cilgavimab). AstraZeneca. Accessed March 7, 2022. https://den8dhaj6zs0e.cloudfront.net/50fd68b9-106b-4550-b5d0-12b045f8b184/6d1d5fea-2532-46e9-a1d4-1504f6dd41b2/6d1d5fea-2532-46e9-a1d4-1504f6dd41b2_viewable_rendition__v.pdf
2. Prevention of SARS-CoV-2 Infection. National Institutes of Health. Accessed March 7, 2022. https://www.covid19treatmentguidelines.nih.gov/overview/prevention-of-sars-cov-2/
3. EVUSHELD™ significantly protected against symptomatic COVID-19 for at least six months in PROVENT Phase III trial in high-risk populations. AstraZeneca. April 20, 2022. https://finance.yahoo.com/news/evusheld-significantly-protected-against-symptomatic-221200107.html