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Summary

Tixagevimab/cilgavimab (Evusheld) is a combination of two human monoclonal antibodies, tixagevimab and cilgavimab derived from B-cells donated by convalescent patients after infection with the SARS-CoV-2 virus.

The U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) PDF on December 8, 2021 for Evusheld to be used as pre-exposure prophylaxis for adults and pediatric individuals (12 years of age and older weighing at least 40 kg) if they meet the following criteria:

1. Are not currently infected with SARS-CoV-2 and who have not had a known recent exposure to an individual infected with SARSCoV-2 and:
1. Who have moderate to severe immune compromise due to a medical condition or receipt of immunosuppressive medications or treatments and may not mount an adequate immune response to COVID-19 vaccination; OR
2. For whom vaccination with any available COVID-19 vaccine, according to the approved or authorized schedule, is not recommended due to a history of severe adverse reaction (e.g., severe allergic reaction) to a COVID-19 vaccine(s) and/or COVID19 vaccine component(s).

Due to decreased neutralization activity of Evusheld against the Omicron subvariants BA.1 and BA.1.1,  the FDA revised the EUA on February 24, 2022 to change the initial dose from 150 mg of tixagevimab and 150 mg of cilgavimab to 300 mg of tixagevimab and 300 mg of cilgavimab. The new dose is based on pharmacokinetic/pharmacodynamic modeling for the Omicron BA.1 and BA.1.1 subvariants. Individuals who have already received the previously authorized dose (150 mg of tixagevimab and 150 mg of cilgavimab) should receive an additional dose of Evusheld as soon as possible. The additional dose should be administered based on the following:

• If the patient received their initial dose less than or equal to 3 months ago, the patient should receive a dose of 150 mg of tixagevimab and 150 mg of cilgavimab.
• If the patient received their initial dose longer than 3 months ago, the patient should receive a dose of 300 mg of tixagevimab and 300 mg of cilgavimab.

Clinical Trial Data

On June 15, 2021, AstraZeneca announced that Evusheld had failed to meet the primary endpoint of post-exposure prevention of symptomatic COVID-19 (STORM CHASER trial). On August 20, 2021, AstraZeneca announced Evusheld demonstrated a statistically significant reduction in the risk of developing symptomatic COVID-19 in the PROVENT Phase III pre-exposure prevention trial. The PROVENT trial enrolled individuals having increased risk for inadequate response to immunization or having increased risk for SARS-CoV-2 infection. The drug reduced the risk of developing symptomatic COVID-19 by 77% (95% confidence interval (CI): 46, 90) compared to placebo. At the time of analysis, the median follow-up time post-administration was 83 days (range 3 to 166 days). On October 11, 2021, AstraZeneca announced the results of TACKLE, a Phase III trial assessing the safety and efficacy of a single dose of Evusheld compared to placebo for the outpatient treatment of COVID-19. Evusheld given by intramuscular injection reduced the risk of developing severe COVID-19 or death (from any cause) by 50% compared to placebo in outpatients who had been symptomatic for seven days or less.

Evusheld and SARS-CoV-2 Variants

Evusheld is expected to be effective against all variants currently circulating in California, including Omicron. However there is decreased neutralization activity of Evusheld against the Omicron BA.1 and BA.1.1 subvariants and the authorized dosage of Evusheld has been increased by the FDA to account for this decrease. The neutralization activity of Evusheld against the Omicron BA.2 subvariant is minimally impacted. It is likely that Evusheld dose recommendations will be regularly updated as the circulating variants change and providers should review the FDA's Fact Sheet for Healthcare Providers.

Additional Use Considerations

Evusheld is authorized for pre-exposure prophylaxis against COVID-19 only. The Fact Sheet for Health Care Providers (PDF), which includes criteria for the full authorization of use, contraindications, and drug interactions should be reviewed prior to administration of the medication. 

The following should be considered:

• Evusheld is not authorized for the treatment of COVID-19 or for post-exposure prophylaxis of COVID-19 in individuals who have been exposed to someone infected with SARS-CoV-2.
• Vaccination remains the most effective way to prevent SARS-CoV-2 infection and should be considered the first line of prevention. Evusheld should not be considered a replacement for vaccination in individuals who would be expected to respond to the COVID-19 vaccine.
• Evusheld may only be prescribed by a healthcare provider licensed or authorized under state law to prescribe drugs in the therapeutic class for an individually identified patient. 
  
• Evusheld is administered via two intramuscular injections given at the same time.
• Individuals who qualify may be redosed every 6 months with Evusheld. Evusheld has only been studied in clinical trials as a 1-time combination therapy; therefore, no safety or efficacy data exist for repeat dosing.
  
• Through the additional data cut-off in the PROVENT trial (median follow-up 6.5 months), a higher proportion of subjects who received Evusheld reported cardiac severe adverse events compared to placebo. There was no clear temporal pattern, with events reported from several hours after Evusheld receipt through the end of the follow-up period. All subjects who experienced cardiac severe adverse events had cardiac risk factors and/or a prior history of cardiovascular disease.
  

Patient Prioritization During Times of Limited Supply

The National Institutes of Health (NIH) treatment guidelines on prioritization should be followed during times when supply is limited. Additionally, NIH has published a guide on use of Evusheld.

Acquiring Evusheld

Allocation of Evusheld is made to U.S. states and territories by the US Department of Health and Human Services (HHS). The California Department of Public Health (CDPH) will be allocating Evusheld directly to local health jurisdictions. 

The number of courses allocated to each region is determined using the overall population within the four different quartiles of the Healthy Places Index (HPI).

Prescribing healthcare providers can locate sites where COVID-19 therapeutics are available using the HHS Therapeutics Locator. The Therapeutics Locator is based on shipments and reported utilization and is not a guarantee of availability. Providers should communicate with facilities to ensure that supply exists.

Originally published on January 19, 2022