Pre-exposure prophylaxis (prevention) trial
reduced risk of symptomatic COVID-19, with no severe disease or
COVID-19-related deaths in EVUSHELD group
Data published in the New England Journal of
Medicine
Detailed results from the PROVENT Phase III pre-exposure
prophylaxis (prevention) trial showed that AstraZeneca’s EVUSHELD™
(tixagevimab and cilgavimab), formerly AZD7442, reduced the risk of
developing symptomatic COVID-19 by 77% in the primary analysis and
by 83% in the six-month follow-up analysis, compared to placebo.1
There were no cases of severe disease or COVID-19 related deaths in
the EVUSHELD group through the six-month follow-up.1
More than 75% of PROVENT participants at baseline had
co-morbidities that put them at high risk for severe COVID-19 if
they were to become infected, including people who are
immunocompromised and may have an inadequate immune response to
vaccination.1
Additional pharmacokinetic data showed that EVUSHELD
concentrations remained elevated in serum for six months after
administration, supporting that a single dose could provide
long-term protection against COVID-19 lasting at least six
months.1
The data were published online today in the New England Journal
of Medicine.
Myron J. Levin, MD, Professor of Pediatrics and Medicine,
University of Colorado School of Medicine, US, and PROVENT
principal investigator on the trial, said: “While COVID-19 vaccines
have been highly effective at reducing hospitalization and death,
cases continue to surge and many individuals remain at high risk,
including immunocompromised individuals and those who cannot be
vaccinated. These important data now published in the New England
Journal of Medicine provide confidence that one easily administered
intramuscular dose of EVUSHELD could provide vulnerable populations
long-lasting protection. In addition, EVUSHELD has been shown to
neutralize BA.2, currently the dominant circulating COVID-19
variant.”
Mene Pangalos, Executive Vice President, BioPharmaceuticals
R&D, AstraZeneca, said: "These data add to the growing body of
evidence supporting the use of EVUSHELD to help prevent symptomatic
and severe COVID-19, especially for those individuals who can’t
respond adequately to vaccination and need additional protection.
EVUSHELD is now available in many countries around the world, and
we are progressing filings in pre-exposure prophylaxis, as well as
mild-to-moderate treatment.”
In the primary efficacy analysis, a single 300mg intramuscular
(IM) dose of EVUSHELD reduced the risk of developing symptomatic
COVID-19 compared to placebo by 77% (95% confidence interval [CI]
46, 90; p<0.001) at a median follow up of 83 days. Symptomatic
COVID-19 occurred in 8/3441 (0.2%) and 17/1731 (1.0%) participants
in the EVUSHELD and placebo groups, respectively.1
Compared to the primary analysis, the extended follow-up
analysis demonstrated greater reduction in COVID-19 incidence in
the EVUSHELD group, with an 83% relative risk reduction (95% CI 66,
91) with EVUSHELD compared to placebo at a median follow up of 196
days. Symptomatic COVID-19 occurred in 11/3441 (0.3%) and 31/1731
(1.8%) participants in the EVUSHELD and placebo groups,
respectively. Efficacy was generally consistent across participant
subgroups, where evaluable.1
There were no cases of severe/critical COVID-19,
COVID-19-related deaths or hospitalizations in the EVUSHELD group
by the six-month follow-up analysis; there were five cases of
severe/critical disease, seven hospitalizations and two
COVID-19-related deaths in the placebo group.1
EVUSHELD was generally well tolerated in PROVENT, and no safety
issues were identified at either the primary or six-month analysis.
Adverse events accrued at similar rates in the EVUSHELD and placebo
groups. The most common adverse event was injection-site reaction,
occurring in 2.4% of participants in the EVUSHELD group and 2.1% of
participants in the placebo group.1
Approximately 2% of the global population is considered at
increased risk of an inadequate response to COVID-19 vaccination
and may particularly benefit from pre-exposure prophylaxis with
EVUSHELD.2,3 This population includes people who are
immunocompromised, such as those with cancer or transplant patients
or anyone taking immunosuppressive medicines. People at increased
risk of exposure to the SARS-CoV-2 virus could also benefit from
protection with EVUSHELD.4–8
AstraZeneca previously announced positive high-level results
from the TACKLE Phase III trial in the treatment of
mild-to-moderate COVID-19. Full results are being presented at the
upcoming European Congress of Clinical Microbiology &
Infectious Diseases (ECCMID) and have been submitted for
publication in a peer-reviewed medical journal.9
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.
Visit EVUSHELD.com to learn more.
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
PROVENT
PROVENT is a Phase III, randomized, double-blind,
placebo-controlled, multi-center trial assessing the efficacy and
safety of a single IM 300mg dose of EVUSHELD compared to placebo
for the prevention of SARS-CoV-2 RT-PCR positive symptomatic
COVID-19 in participants who did not have a SARS-CoV-2 infection at
baseline. The trial was conducted at 87 sites in the US, UK, Spain,
France and Belgium. 5,197 participants were randomized in a 2:1
ratio to receive a single IM dose of either 300mg of AZD7442 (n =
3,460) or saline placebo (n = 1,737), administered in two separate,
sequential IM injections. It is the first Phase III trial
prospectively designed to evaluate a monoclonal antibody for
pre-exposure prophylaxis of symptomatic COVID-19, with targeted
inclusion of participants at increased risk of inadequate response
to vaccination or were at high risk for severe COVID-19
disease.
The primary analysis reported on August 20, 2021 was based on
5,172 participants, with a data cut-off of May 5, 2021. The primary
efficacy endpoint was the first case of any SARS-CoV-2 RT-PCR
positive symptomatic illness occurring post dose prior to day 183.
The six-month assessment was conducted using a data cut-off of
August 29, 2021. Subjects will be followed for a total of 15
months. Participants who chose to get vaccinated at any timepoint
during the PROVENT trial were included in the efficacy analyses
until the day of vaccination.
Participants were adults 18 years-old and older who would
benefit from prevention with EVUSHELD, defined as having increased
risk for inadequate response to active immunization (predicted poor
responders to vaccines or intolerant to vaccination) or having
increased risk for SARS-CoV-2 infection, including those whose
locations or circumstances put them at appreciable risk of exposure
to the SARS-CoV-2 virus. Participants at the time of screening were
unvaccinated and had a negative point-of-care SARS-CoV-2 serology
test.
More than 75% of PROVENT participants had baseline
co-morbidities and other characteristics that are associated with
an increased risk for severe COVID-19 should they become infected,
including those with immunosuppressive disease or taking
immunosuppressive medications, diabetes, severe obesity or cardiac
disease, chronic obstructive pulmonary disease, chronic kidney and
chronic liver disease. Approximately 43% of participants were 60
years and over.
EVUSHELD
EVUSHELD, formerly known as AZD7442, is a combination of two
long-acting antibodies - tixagevimab (AZD8895) and cilgavimab
(AZD1061) - derived from B-cells donated by individuals previously
infected with the 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 protein10 and were optimized by AstraZeneca with
half-life extension and reduced Fc receptor and complement C1q
binding. 11The half-life extension more than triples the durability
of its action compared to conventional antibodies;12–14 data from
the Phase III PROVENT trial show protection lasting at least six
months.1 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.15
There is a growing body of evidence from multiple independent in
vitro and in vivo (animal model) studies supporting the potential
of EVUSHELD to protect against the BA.1, BA.1.1 and BA.2 Omicron
SARS-CoV-2 subvariants.16–18 Data from Washington University School
of Medicine demonstrated EVUSHELD retained neutralizing activity
against the highly transmissible BA.2 subvariant, which is
currently the dominant strain globally.18,19 This study also showed
that EVUSHELD reduced viral burden and limited inflammation in the
lungs (in vivo) across all Omicron variants.18
EVUSHELD has marketing authorization in the European Union and
was granted conditional marketing authorization by the Medicines
and Healthcare products Regulatory Agency (MHRA) in Great Britain
for pre-exposure prophylaxis of COVID-19. EVUSHELD is authorized
for emergency use for pre-exposure prophylaxis of COVID-19 in the
US. EVUSHELD is also authorized for use and being supplied in
several other countries around the world. Regulatory filings are
progressing in both prevention and treatment around the world.
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.
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
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(Tixagevimab–Cilgavimab) for Prevention of Covid-19. N Engl J Med.
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2. Harpaz R ,et al. Prevalence of Immunosuppression Among US
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doi:10.1001/JAMA.2016.16477
3. AstraZeneca Data on File
4. Centers for Disease Control and Prevention. ACIP Altered
Immunocompetence Guidelines for Immunizations.
https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/immunocompetence.html
5. 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.
doi:10.1001/JAMA.2021.4385
6. Rabinowich L, et al. Low immunogenicity to SARS-CoV-2
vaccination among liver transplant recipients. Journal of
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7. Deepak P, et al. Glucocorticoids and B Cell Depleting Agents
Substantially Impair Immunogenicity of mRNA Vaccines to SARS-CoV-2.
medRxiv. Published online April 9, 2021:2021.04.05.21254656.
doi:10.1101/2021.04.05.21254656
8. Simon D, et al. SARS-CoV-2 vaccination responses in
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severe COVID-19 or death in TACKLE Phase III outpatient treatment
trial.
https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2021/azd7442-phiii-trial-positive-in-covid-outpatients.html
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in humans. Science Translational Medicine.
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12. Robbie GJ, et al. A Novel Investigational Fc-Modified
Humanized Monoclonal Antibody, Motavizumab-YTE, Has an Extended
Half-Life in Healthy Adults. Antimicrobial Agents and Chemotherapy.
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13. 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. Antimicrobial Agents and
Chemotherapy. 2017;61(3). doi:10.1128/AAC.01714-16
14. 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.
doi:10.1097/INF.0000000000001916
15. van Erp EA, et al. Fc-Mediated Antibody Effector Functions
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16. Dejnirattisai W, et al. SARS-CoV-2 Omicron-B.1.1.529 leads
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2022;185(3):467-484.e15. doi:10.1016/J.CELL.2021.12.046
17. VanBlargan LA, et al. An infectious SARS-CoV-2 B.1.1.529
Omicron virus escapes neutralization by therapeutic monoclonal
antibodies. Nature Medicine 2022. Published online January 19,
2022:1-6. doi:10.1038/s41591-021-01678-y
18. Case JB, et al. Resilience of S309 and AZD7442 monoclonal
antibody treatments against infection by SARS-CoV-2 Omicron lineage
strains. bioRxiv. Published online March 18,
2022:2022.03.17.484787. doi:10.1101/2022.03.17.484787
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