Only antibody therapy authorized in US for
pre-exposure prophylaxis
Pivotal phase III data showed robust
efficacy and long-term protection with one dose in high-risk
population
AstraZeneca's EVUSHELD (tixagevimab co-packaged with
cilgavimab), a long-acting antibody (LAAB) combination, has
received emergency use authorization (EUA) in the US for the
pre-exposure prophylaxis (prevention) of COVID-19, with first doses
expected to become available very soon.
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The Food and Drug Administration (FDA) granted the EUA for
EVUSHELD for pre-exposure prophylaxis of COVID-19 in adults and
adolescents (aged 12 and older who weigh 40kg or more) with
moderate to severe immune compromise due to a medical condition or
immunosuppressive medications and who may not mount an adequate
immune response to COVID-19 vaccination, as well as those
individuals for whom COVID-19 vaccination is not recommended.
Recipients should not be currently infected with or had recent
known exposure to a person infected with SARS-CoV-2.
Myron J. Levin, MD, Professor of Pediatrics and Medicine,
University of Colorado School of Medicine, US, and principal
investigator on the PROVENT trial, said: “Millions of people in the
US and around the world remain at serious risk for COVID-19 because
their immune systems do not generate a sufficient immune response,
even after receiving all recommended doses of vaccine. I am excited
to offer my patients EVUSHELD as an easily-administered new option
that provides long-lasting protection that could help them return
to their everyday lives.”
Mene Pangalos, Executive Vice President, BioPharmaceuticals
R&D, AstraZeneca, said: “We are proud to play a leading role in
fighting the COVID-19 pandemic and, with EVUSHELD, we now have the
first antibody therapy authorized in the US to prevent COVID-19
symptoms before virus exposure, while also providing long lasting
protection with a single dose. EVUSHELD neutralizes all previous
SARS-CoV-2 variants to date, and we are working quickly to
establish its efficacy against the new Omicron variant. We thank
our clinical trial participants, the investigators, scientists, and
government agencies and our colleagues at AstraZeneca who have all
contributed to the development of EVUSHELD.”
Brian Koffman, MDCM (retired), MS Ed, Co-Founder, Executive Vice
President and Chief Medical Officer of the CLL (Chronic Lymphocytic
Leukemia) Society, US, said: “One of the primary questions I keep
getting asked by patients is ‘When can I hug my grandchildren
again?’ As a physician and person with a weakened immune system, l
am filled with hope now that EVUSHELD will soon be available to
those who can’t count on vaccination alone to provide the
protection they need.”
EVUSHELD is a combination of two long-acting monoclonal
antibodies and is the only antibody therapy authorized in the US
for COVID-19 pre-exposure prophylaxis and the only COVID-19
antibody delivered as an intramuscular dose (150mg tixagevimab and
150mg cilgavimab).
About 2% of the global population is considered at increased
risk of an inadequate response to a COVID-19 vaccine.1,2 About
seven million people in the US are immunocompromised and may
benefit from EVUSHELD for pre-exposure prophylaxis of
COVID-19.1,3,4 This includes people with blood cancers or other
cancers being treated with chemotherapy, and those taking
medications after an organ transplant or who are taking
immunosuppressive drugs for conditions including multiple sclerosis
and rheumatoid arthritis.5-9
The primary data supporting the EVUSHELD EUA are from the
ongoing PROVENT Phase III pre-exposure prevention trial, which
showed a statistically significant reduction (77% at primary
analysis, 83% at median six-month analysis) in the risk of
developing symptomatic COVID-19 compared to placebo, with
protection from the virus continuing for at least six months. More
follow-up is needed to establish the full duration of protection
provided by EVUSHELD. Data from the Phase III STORM CHASER
post-exposure trial and the EVUSHELD Phase I trial also supported
the EUA. EVUSHELD was well-tolerated in the trials.
EVUSHELD and SARS-CoV-2 variants
Studies are underway to provide information on the impact of the
new Omicron variant (B.1.1.529) on EVUSHELD.10,11 Of the Omicron
binding site substitutions relevant to EVUSHELD that have been
tested to date in preclinical assays, none have been associated
with escape from EVUSHELD neutralization.10,11 In vitro findings
demonstrate EVUSHELD neutralizes other recent emergent SARS-CoV-2
viral variants, including the Delta and Mu variants.10
EVUSHELD is being developed with support from the US government,
including federal funds from the Department of Health and Human
Services; Office of the Assistant Secretary for Preparedness and
Response; Biomedical Advanced Research and Development Authority in
partnership with the Department of Defense; Joint Program Executive
Office for Chemical, Biological, Radiological and Nuclear Defense,
under Contract No. W911QY-21-9-0001.
AstraZeneca has agreed to supply the US government with 700,000
doses of EVUSHELD. The US government has indicated that it plans to
distribute these doses to states and territories at no cost and on
a pro rata basis.
AstraZeneca is progressing with filings around the globe for
potential emergency use authorization or conditional approval of
EVUSHELD in both COVID-19 prophylaxis and treatment.
EVUSHELD is authorized only for the duration of the declaration
that circumstances exist justifying the authorization of the
emergency use of EVUSHELD under Section 564(b)(1) of the Food, Drug
and Cosmetic Act, 21 U.S.C. § 360bbb-3(b)(1), unless the
authorization is terminated or revoked sooner.
IMPORTANT SAFETY INFORMATION
EVUSHELD (tixagevimab co-packaged with cilgavimab) has not been
approved, but has been granted an Emergency Use Authorization (EUA)
by FDA. There are limited clinical data available and serious and
unexpected adverse events may occur that have not been previously
reported with EVUSHELD use.
Contraindication:
EVUSHELD is contraindicated in individuals with previous severe
hypersensitivity reactions, including anaphylaxis, to any component
of EVUSHELD.
Warnings and
Precautions:
Hypersensitivity Including Anaphylaxis
Serious hypersensitivity reactions, including anaphylaxis, have
been observed with IgG1 monoclonal antibodies like EVUSHELD. If
signs and symptoms of a clinically significant hypersensitivity
reaction or anaphylaxis occur, immediately discontinue
administration and initiate appropriate medications and/or
supportive therapy. Clinically monitor individuals after injections
and observe for at least 1 hour.
Clinically Significant Bleeding Disorders
As with any other intramuscular injection, EVUSHELD should be
given with caution to individuals with thrombocytopenia or any
coagulation disorder.
Cardiovascular Events
A higher proportion of subjects who received EVUSHELD versus
placebo reported myocardial infarction and cardiac failure serious
adverse events. All of the subjects with events had cardiac risk
factors and/or a prior history of cardiovascular disease at
baseline. A causal relationship between EVUSHELD and these events
has not been established. Consider the risks and benefits prior to
initiating EVUSHELD in individuals at high risk for cardiovascular
events, and advise individuals to seek immediate medical attention
if they experience any signs or symptoms suggestive of a
cardiovascular event.
Adverse Reactions:
The most common adverse events are headache, fatigue and
cough.
Use in Specific
Populations:
Pregnancy
There are insufficient data to evaluate a drug-associated risk
of major birth defects, miscarriage, or adverse maternal or fetal
outcomes. EVUSHELD should only be used during pregnancy if the
potential benefit outweighs the potential risk for the mother and
the fetus.
Lactation
There are no available data on the presence of tixagevimab or
cilgavimab in human milk or animal milk, the effects on the
breastfed infant, or the effects of the drug on milk production.
Maternal IgG is known to be present in human milk.
Pediatric Use
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.
AUTHORIZED USE
EVUSHELD (tixagevimab co-packaged with cilgavimab) is authorized
for use under an EUA for the pre-exposure prophylaxis of COVID-19
in adults and pediatric individuals (12 years of age and older
weighing at least 40 kg):
- Who are not currently infected with SARS-CoV-2 and who have not
had a known recent exposure to an individual infected with
SARS-CoV-2 and
- 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
- 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 COVID-19
vaccine component(s).
EVUSHELD has been authorized by FDA for the emergency use
described above. EVUSHELD is not FDA-approved for any use,
including use for pre-exposure prophylaxis of COVID-19.
EVUSHELD is authorized only for the duration of the declaration
that circumstances exist justifying the authorization of the
emergency use of EVUSHELD under section 564(b)(1) of the Act, 21
U.S.C. § 360bbb-3(b)(1), unless the authorization is terminated or
revoked sooner.
LIMITATIONS OF AUTHORIZED USE
- EVUSHELD is not authorized for use in individuals:
- For 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
- Pre-exposure prophylaxis with EVUSHELD is not a substitute for
vaccination in individuals for whom COVID-19 vaccination is
recommended. Individuals for whom COVID-19 vaccination is
recommended, including individuals with moderate to severe immune
compromise who may derive benefit from COVID-19 vaccination, should
receive COVID-19 vaccination
- In individuals who have received a COVID-19 vaccine, EVUSHELD
should be administered at least two weeks after vaccination
See Full Fact Sheet for Healthcare Providers for examples of
medical conditions or treatments that may result in moderate to
severe immune compromise and an inadequate immune response to
COVID-19 vaccination, the justification for emergency use of drugs
during the COVID-19 pandemic, information on available
alternatives, and additional information on COVID-19.
The FDA Letter of Authorization is available for reference, as
well as the Fact Sheet for Patients, Parents And Caregivers.
SARS-CoV-2 Viral Variant
There is a potential risk of treatment failure due to the
development of viral variants that are resistant to tixagevimab and
cilgavimab administered together. Prescribing healthcare providers
should consider the prevalence of SARS-CoV-2 variants in their
area, where data are available, when considering prophylactic
treatment options.
Reporting Adverse Events
The prescribing healthcare provider and/or your designee must
report all SERIOUS ADVERSE EVENTS and MEDICATION ERRORS potentially
related to EVUSHELD within 7 calendar days from the healthcare
provider’s awareness of the event (1) by submitting FDA Form 3500
online, (2) by downloading FDA Form 3500 and then submitting by
mail or fax, or (3) contacting the FDA at 1-800-FDA-1088 to request
this form.
In addition, please fax a copy of all FDA MedWatch forms to
AstraZeneca at 1-866-742-7984.
Report adverse events by visiting
https://contactazmedical.astrazeneca.com, or calling AstraZeneca at
1-800-236-9933.
Notes
EVUSHELD
EVUSHELD, formerly known as AZD7442 is a combination of two
LAABs - tixagevimab (AZD8895) and cilgavimab (AZD1061) - derived
from B-cells donated by convalescent patients after SARS-CoV-2
virus. Discovered by Vanderbilt University Medical Center and
licensed to AstraZeneca in June 2020, the human monoclonal
antibodies bind to distinct sites on the SARS-CoV-2 spike protein13
and were optimized by AstraZeneca with half-life extension and
reduced Fc receptor and complement C1q binding. The half-life
extension more than triples the durability of its action compared
to conventional antibodies and could afford up to 12 months of
protection from COVID-19 following a single administration;14-16
data from the Phase III PROVENT trial show protection lasting at
least six months.17 The reduced Fc receptor binding aims to
minimize the risk of antibody-dependent enhancement of disease - a
phenomenon in which virus-specific antibodies promote, rather than
inhibit, infection and/or disease.18 EVUSHELD is delivered as an IM
dose of 150mg tixagevimab and 150mg cilgavimab administered in two
separate, consecutive injections.
In August 2021, AstraZeneca announced that EVUSHELD demonstrated
a statistically significant reduction in the risk of developing
symptomatic COVID-19 in the PROVENT trial; efficacy was 83%
compared to placebo in a six-month analysis announced on November
18, 2021. In October 2021, AstraZeneca announced positive
high-level results from the EVUSHELD TACKLE Phase III outpatient
treatment trial. EVUSHELD is also being studied as a potential
treatment for hospitalized COVID-19 patients as part of the
National Institute of Health’s ACTIV-3 trial and in an additional
collaborator hospitalization treatment trial.
Under the terms of the licensing agreement with Vanderbilt,
AstraZeneca will pay single-digit royalties on future net
sales.
About AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company
that focuses on the discovery, development and commercialization of
prescription medicines in Oncology, Rare Diseases and
BioPharmaceuticals, including Cardiovascular, Renal &
Metabolism, and Respiratory & Immunology. Based in Cambridge,
UK, AstraZeneca operates in over 100 countries, and its innovative
medicines are used by millions of patients worldwide. For more
information, please visit www.astrazeneca-us.com and follow us on
Twitter @AstraZenecaUS.
References
- Oliver, S MD. Data and clinical considerations for additional
doses in immunocompromised people. ACIP Meeting July 22, 2021.
Available at:
https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-07/07-COVID-Oliver-508.pdf.
[Last accessed: December 2021].
- AstraZeneca data on file.
- Taken as percentage of US Population: 328.2m (2019).
- CDC: Lower range: adult pneumococcal vaccine (~25% ), mid
range: flu (~48%), upper range: COVID vaccine (~70%).
- Centers for Disease Control and Prevention. Altered
Immunocompetence. General Best Practice Guideline for Immunization:
Best Practices Guidance of the Advisory Committee on Immunization
Practices. [Online]. Available at:
https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/immunocompetence.html.
[Last accessed: December 2021].
- Boyarsky BJ, et al. Immunogenicity of a Single Dose of
SARS-CoV-2 Messenger RNA Vaccine in Solid Organ Transplant
Recipients. JAMA. 2021; 325 (17):1784-1786.
- Rabinowich L, et al. Low immunogenicity to SARS-CoV-2
vaccination among liver transplant recipients, Journal of
Hepatology (2021). doi: https://doi.org/10.1016/
j.jhep.2021.04.020.
- Deepak P, et al. Glucocorticoids and B Cell Depleting Agents
Substantially Impair Immunogenicity of mRNA Vaccines to SARS-CoV-2.
medRxiv [Preprint]. 2021 Apr 9:2021.04.05.21254656. doi:
10.1101/2021.04.05.21254656. PMID: 33851176; PMCID:
PMC8043473.
- Simon D, et al. SARS-CoV-2 vaccination responses in untreated,
conventionally treated and anticytokine-treated patients with
immune-mediated inflammatory diseases. Ann Rheum Dis. 2021 May 6:
annrheumdis-2021-220461. doi: 10.1136/annrheumdis-2021-220461. Epub
ahead of print. PMID: 33958324.
- ACTIV. National Center for Advancing Translational Sciences
Open Data Portal. SARS-CoV-2 Variants & Therapeutics, All
Variants Reported in vitro Therapeutic Activity. Available at:
https://opendata.ncats.nih.gov/variant/activity. [Last accessed:
December 2021].
- Bloom Labs. Available from:
https://twitter.com/jbloom_lab/status/1464005705891868702/photo/1
[Last accessed December 2021].
- AstraZeneca data on file.
- Dong J, et al. Genetic and structural basis for recognition of
SARS-CoV-2 spike protein by a two-antibody cocktail. bioRxiv. 2021;
doi: 10.1101/2021.01.27.428529.
- Robbie GJ, et al. A novel investigational Fc-modified humanized
monoclonal antibody, motavizumab-YTE, has an extended half-life in
healthy adults. Antimicrob Agents Chemother. 2013; 57 (12):
6147-53.
- Griffin MP, et al. Safety, tolerability, and pharmacokinetics
of MEDI8897, the respiratory syncytial virus prefusion F-targeting
monoclonal antibody with an extended half-life, in healthy adults.
Antimicrob Agents Chemother. 2017; 61(3): e01714-16.
- Domachowske JB, et al. Safety, tolerability and
pharmacokinetics of MEDI8897, an extended half-life single-dose
respiratory syncytial virus prefusion F-targeting monoclonal
antibody administered as a single dose to healthy preterm infants.
Pediatr Infect Dis J. 2018; 37(9): 886-892.
- AstraZeneca news release. New analyses of two AZD7442 COVID-19
trials in high-risk populations confirm robust efficacy and
long-term prevention. Available at:
https://www.astrazeneca.com/media-centre/press-releases/2021/new-analyses-of-two-azd7442-covid-19-phase-iii-trials-in-high-risk-populations-confirm-robust-efficacy-and-long-term-prevention.html.
[Last accessed: December 2021]
- van Erp EA, et al. Fc-mediated antibody effector functions
during respiratory syncytial virus infection and disease. Front
Immunol. 2019; 10: 548.
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