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FDA News: Issue 1-2, January 2022

Author: [AUTHOR] Published on 1/14/2022 5:00:00 AM


FDA Authorizes Evusheld, New Long-Acting Monoclonal Antibodies, for Pre-exposure Prevention of COVID-19 in Certain Individuals

On December 8, 2021, the US Food and Drug Administration issued an emergency use authorization (EUA) for AstraZeneca’s Evusheld (tixagevimab co-packaged with cilgavimab) for the pre-exposure prophylaxis (prevention) of COVID-19 in certain adults and pediatric individuals (12 years of age and older weighing at least 40 kilograms [about 88 pounds]). The product is only authorized for those individuals who are not currently infected with the SARS-CoV-2 virus and who have not recently been exposed to an individual infected with SARS-CoV-2. The authorization also requires that individuals either 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 (examples of such medical conditions or treatments can be found in the fact sheet for health care providers) or
  • a history of severe adverse reaction (e.g., a severe allergic reaction) to a COVID-19 vaccine(s) and/or COVID-19 vaccine component(s), where vaccination with any available COVID-19 vaccine, according to the approved or authorized schedule, is not recommended.

The dosage of Evusheld for emergency use is 150 mg of tixagevimab and 150 mg of cilgavimab administered as two separate consecutive intramuscular injections. One dose of Evusheld, administered as two separate consecutive intramuscular injections (one injection per monoclonal antibody, given in immediate succession), may be effective for pre-exposure prevention for six months. Evusheld is not authorized for individuals for the treatment of COVID-19 or for post-exposure prevention of COVID-19. Patients should talk with their health care provider to determine whether Evusheld is an appropriate pre-exposure prevention option for them. Pre-exposure prevention with Evusheld is not a substitute for vaccination in individuals for whom COVID-19 vaccination is recommended.

Mechanism of Action (MOA) and Pharmacokinetics (PK)
MOA: Tixagevimab and cilgavimab are long-acting monoclonal antibodies that are specifically directed against the spike protein of SARS-CoV-2, designed to block the virus’ attachment and entry into human cells.
General PK: A summary of PK parameters and properties for tixagevimab and cilgavimab following a single intramuscular dose of Evusheld (150 mg of tixagevimab and 150 mg of cilgavimab) is presented below.

PK Parameters Tixagevimab Cilgavimab
Cmax (µg/mL)* 16.5 (35.6) 15.3 (38.5)
Tmax (day) 14.0 (3.1 – 30) 14.0 (3.1 – 60)
C1 (µg/mL) 4.4 (92.2) 3.9 (94.4)
C150 (µg/mL)§ 6.6 (25.6) 5.5 (35.2)
C210 (µg/mL) 4.0 (31.6) 3.9 (37.1)
AUCinf (day•µg/mL) 2529 (30.2) 2133 (31.7)
Absorption
Bioavailability (%)# 68.5 65.8
Distribution
Apparent Volume of Distribution (L)# 7.7 (1.97) 8.7 (2.73)
Elimination
Half-life (days)# 87.9 (13.9) 82.9 (12.3)
Apparent Clearance (L/day)# 0.062 (0.019) 0.074 (0.028)
Metabolism Catabolic pathways; Same manner as endogenous IgG
Excretion Not likely to undergo renal excretion

* Geomean (geometric %CV), Median (range), Observed geomean (geometric %CV) concentration 1 day after dosing, § Observed geomean (geometric %CV) concentration 150 days after dosing, Observed geomean (geometric %CV) concentration 210 days after dosing, # Arithmetic mean (SD)

Use in Specific Populations
The PK profile of tixagevimab and cilgavimab were not affected by sex, age, race or ethnicity. Body weight had no clinically relevant effect on the PK of tixagevimab and cilgavimab in adults over the range of 36 kg to 177 kg. Tixagevimab and cilgavimab are not eliminated intact in the urine, and renal impairment is not expected to affect the exposure of tixagevimab and cilgavimab. Similarly, dialysis is not expected to impact the PK of tixagevimab and cilgavimab. No specific studies have been conducted to examine the effects of hepatic impairment on the PK of tixagevimab and cilgavimab, and the impact of hepatic impairment on the PK of tixagevimab and cilgavimab is unknown.

Pediatric Population
Evusheld is not authorized for use in pediatric individuals under 12 years of age or weighing less than 40 kg. The safety and effectiveness of Evusheld have not been established in pediatric individuals. The dosing regimen is expected to result in comparable serum exposures of tixagevimab and cilgavimab in individuals 12 years of age and older and weighing at least 40 kg as observed in adults, since adults with similar body weight have been included in the clinical trials.

Drug Interaction Studies
Drug-drug interaction studies have not been performed. Tixagevimab and cilgavimab are not renally excreted or metabolized by cytochrome P450 (CYP) enzymes; therefore, interactions with concomitant medications that are renally excreted or that are substrates, inducers, or inhibitors of CYP enzymes are unlikely.

Efficacy and Safety
The issuance of an EUA is different than an FDA approval. In determining whether to issue an EUA, the FDA evaluates the totality of available scientific evidence and carefully balances any known or potential risks with any known or potential benefits of the product. Based on the FDA’s review of the totality of the scientific evidence available, the agency has determined that it is reasonable to believe that Evusheld may be effective for use as pre-exposure prevention in certain adults and pediatric individuals (12 years of age and older weighing at least 40 kilograms). The agency has also determined that the known and potential benefits of Evusheld, when used consistent with the terms and conditions of the authorization, outweigh the known and potential risks of the product. There are no adequate, approved and available alternatives to Evusheld for the pre-exposure prevention of COVID-19 in the authorized population.

Efficacy
The primary data supporting this EUA for Evusheld are from PROVENT, a randomized, double-blind, placebo-controlled clinical trial in adults greater than age 59 or with a prespecified chronic medical condition or at increased risk of SARS-CoV-2 infection for other reasons who had not received a COVID-19 vaccine and did not have a history of SARS-CoV-2 infection or test positive for SARS-CoV-2 infection at the start of the trial. The main outcome measured in the trial was whether a trial participant had a first case of COVID-19 after receiving Evusheld or placebo and before day 183 of the trial. In this trial, 3,441 people received Evusheld and 1,731 received a placebo. In the primary analysis, Evusheld recipients saw a 77% reduced risk of developing COVID-19 compared to those who received a placebo, a statistically significant difference. In additional analyses, the reduction in risk of developing COVID-19 was maintained for Evusheld recipients through six months. The safety and effectiveness of Evusheld for use in the pre-exposure prevention of COVID-19 continue to be evaluated.

Safety
Possible side effects of Evusheld include: hypersensitivity reactions (including anaphylaxis), bleeding at the injection site, headache, fatigue and cough. Serious cardiac adverse events were infrequent in PROVENT. However, more trial participants had serious cardiac adverse events (such as myocardial infarction and heart failure) after receiving Evusheld compared to placebo. These participants all had risk factors for cardiac disease or a history of cardiovascular disease before participating in the clinical trial. It is not clear if Evusheld caused these cardiac adverse events.

Additional Information
The Fact Sheet for Health Care Providers provides essential information about using Evusheld in treating COVID-19 as authorized and is available at https://go.usa.gov/xtaRv. A fact sheet for patients, parents, and caregivers is available at https://go.usa.gov/xtaRs and contains information for understanding the potential risks and potential benefits of taking Evusheld, including side effects.

The EUA authority allows FDA to help strengthen the nation’s public health protections against chemical, biological, radiological, and nuclear threats by facilitating the availability and use of medical countermeasures needed during public health emergencies. For additional information on the EUA authority and EUAs for COVID-19, please visit https://go.usa.gov/xs8x4.

The FDA is working with sponsors of all currently authorized therapeutics to assess the activity against any global SARS-CoV-2 variant(s) of interest and is committed to communicating with the public as we learn more.


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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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