TIDMAZN
RNS Number : 9133B
AstraZeneca PLC
15 June 2021
15 June 2021 07:00 BST
Update on AZD7442 STORM CHASER trial
in post-exposure prevention of symptomatic COVID-19
AstraZeneca today announced results from the STORM CHASER trial
assessing the safety and efficacy of AZD7442, a long-acting
antibody (LAAB) combination, for the prevention of symptomatic
COVID-19 in participants recently exposed to the SARS-CoV-2 virus.
The trial did not meet the primary endpoint of post-exposure
prevention of symptomatic COVID-19 with AZD7442 compared to
placebo.
Trial participants were unvaccinated adults 18 years and over
with confirmed exposure to a person with a case of the SARS-CoV-2
virus within the past eight days. In the overall trial population,
AZD7442 reduced the risk of developing symptomatic COVID-19 by 33%
(95% confidence interval (CI): -26, 65) compared to placebo, which
was not statistically significant (Table 1).
The trial included 1,121 participants in a 2:1 randomisation
AZD7442 to placebo, with 23 cases of symptomatic COVID-19 accrued
in the AZD7442 arm (23/749) and 17 cases accrued in the placebo arm
(17/372). All participants had a negative SARS-CoV-2 antibody test
on the day of dosing to exclude prior infection, and a
nasopharyngeal swab was also collected and subsequently analysed
for SARS-CoV-2 by RT-PCR to detect virus.
Given the importance of finding therapies for COVID-19 and to
help interpret trial results during the pandemic, additional
analyses were performed and are being communicated (Table 1).
In a pre-planned analysis of SARS-CoV-2 PCR positive (detectable
virus) and PCR negative (no detectable virus) participants, AZD7442
reduced the risk of developing symptomatic COVID-19 by 73% (95% CI:
27, 90) compared with placebo, in participants who were PCR
negative at time of dosing. In a post-hoc analysis, in participants
who were PCR negative at baseline, AZD7442 reduced the risk of
developing symptomatic COVID-19 by 92% (95% CI: 32, 99) versus
placebo more than seven days following dosing, and by 51% (95% CI:
-71, 86) up to seven days following dosing.
Myron J. Levin, MD, Professor of Pediatrics and Medicine,
University of Colorado School of Medicine, US, and principal
investigator on the trial, said: "The results of STORM CHASER
suggest that AZD7442 may be useful in preventing symptomatic
COVID-19 in individuals not already infected. The PROVENT trial
will give us more clarity in this patient population. While
COVID-19 vaccination efforts have been successful, there is still a
significant need for prevention and treatment options for certain
populations, including those unable to be vaccinated or those who
may have an inadequate response to vaccination."
Mene Pangalos, Executive Vice President, BioPharmaceuticals
R&D, said: "While this trial did not meet the primary endpoint
against symptomatic illness, we are encouraged by the protection
seen in the PCR negative participants following treatment with
AZD7442. We await results from PROVENT, our pre-exposure prevention
trial and TACKLE, our treatment trial in preventing more severe
disease, to understand the potential role of AZD7442 in protecting
against COVID-19."
Table 1: STORM CHASER analyses
Baseline subgroup Onset of case Number of cases / Relative risk reduction
post dose number of participants (95% confidence
interval)
--------------- -------------------------- ------------------------
AZD7442 (300mg Placebo
IM)
--------------- --------------- --------- ------------------------
All participants All cases 23 / 749 17 / 372 33% reduction(a)
(Primary analysis) (-26 to 65)
--------------- --------- ------------------------
PCR-negative(b) All cases 6 / 715 11 / 358 73% reduction
(Pre-planned
subgroup analysis) (27 to 90)
--------------- --------- ------------------------
PCR-negative(b) <=7 days 5 / 715 5 / 358 51% reduction
(Post hoc
subgroup analysis) (-71 to 86)
--------------- --------- ------------------------
92% reduction
>7 days 1 / 710 6 / 353 (32 to 99)
-------------------------------------- --------------- --------- ------------------------
a: Not statistically significant.
b: Includes 974 participants (15 cases) confirmed PCR negative
at baseline and 99 participants (2 cases) with PCR status
missing at baseline.
48 participants were confirmed PCR positive at baseline with
23 cases (AZD7442: 17/34; placebo: 6/14).
AZD7442 was well tolerated in the trial. Preliminary analyses
show similar adverse events in the placebo and treatment arms.
Full results from STORM CHASER will be submitted for publication
in a peer-reviewed medical journal and presented at a forthcoming
medical meeting.
Financial considerations
On 16 March 2021, AstraZeneca announced an extended agreement
with the US Government to supply up to 500,000 additional doses of
AZD7442 for $205m, contingent on AZD7442 receiving Food and Drug
Administration Emergency Use Authorisation in post-exposure
prophylaxis. Discussions regarding next steps with the US
Government are ongoing.
STORM CHASER
STORM CHASER is a Phase III, randomised, double-blind,
placebo-controlled, multi-centre trial assessing the safety and
efficacy of a single 300mg dose of AZD7442 compared to placebo for
the post-exposure prevention of COVID-19. The trial was conducted
in 59 sites in the UK and US. 1,121 participants were randomised in
a 2:1 ratio to receive a single intramuscular (IM) dose of either
300mg of AZD7442 (n=749) or saline placebo (n=372), administered in
two separate, sequential IM injections. The primary efficacy
endpoint is the first case of SARS-CoV-2 RT-PCR-positive
symptomatic illness occurring post dose to Day 183. The primary
analysis was to be conducted 30 days after 25 events meeting the
primary efficacy endpoint definition had occurred. This primary
analysis includes data and additional events accumulated up to 7
April 2021, 30 days after the symptom assessment date of the 25th
event; participants will continue to be followed for 15 months.
The post hoc analysis looked at cases of symptomatic COVID-19 in
the PCR-negative group occurring seven days or less after dosing
and more than seven days after dosing. This was based on the known
incubation period of SARS-CoV-2. Cases occurring more than seven
days after dosing are likely to be due to infection that occurred
after dosing rather than before.(1)
Participants were adults 18 years and over with potential
exposure, within eight days, to a specific identified individual
with laboratory-confirmed SARS-CoV-2 virus, symptomatic or
asymptomatic, and who were therefore assessed at the time of
enrolment to be at appreciable risk of imminently developing
COVID-19. Such individuals included, but were not limited to, those
who shared a household, those living in institutional residences
(military lodging, dormitories, etc.), health care workers,
long-term care facility workers, and workers in occupational or
industrial settings in which close contact is common.
AZD7442
AZD7442 is a combination of two LAABs - tixagevimab (AZD8895)
and cilgavimab (AZD1061) - d erived 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 protein(2) and were optimised by
AstraZeneca with half-life extension and reduced Fc receptor
binding. The half-life extension approximately triples the
durability of its action compared to conventional antibodies and
could afford six to 12 months of protection from COVID-19 following
a single administration.(3-6) The reduced Fc receptor binding aims
to minimise the risk of antibody-dependent enhancement of disease -
a phenomenon in which virus-specific antibodies promote, rather
than inhibit, infection and/or disease.(7)
AZD7442 is currently being tested in several additional COVID-19
prevention and treatment trials: PROVENT (8) Phase III trial of
over 5,000 participants in pre-exposure prophylaxis; TACKLE
COVID-19 (9) Phase III treatment trial in outpatient setting; and
collaborator treatment trials in outpatient and hospitalised
settings. AZD7442 is being assessed in both IM and intravenous
administration routes.
AZD7442 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.
Preliminary 'in vitro' findings from investigators at Oxford
University and Columbia University also demonstrate that AZD7442
neutralises recent emergent SARS-CoV-2 viral variants.(10-14)
Data published in Nature in July 2020 showed that in
pre-clinical experiments, the LAABs were able to block the binding
of the SARS-CoV-2 virus to host cells and protect against infection
in cell and animal models of disease.(15)
Under the terms of the licensing agreement with Vanderbilt,
AstraZeneca will pay single-digit royalties on future net
sales.
AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led
biopharmaceutical company that focuses on the discovery,
development and commercialisation of prescription medicines in
Oncology 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.
Please visit astrazeneca.com and follow the Company on Twitter
@AstraZeneca.
Contacts
For details on how to contact the Investor Relations Team,
please click here . For Media contacts, click here .
References
1. Guan WJ, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020;382(18):1708. Epub 2020 Feb 28.
2. 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.
3. 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;57:6147-53.
4. 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:e01714-16.
5. Yu XQ, et al. Safety, Tolerability, and Pharmacokinetics of MEDI4893, an Investigational, Extended-Half-Life, Anti-Staphylococcus aureus Alpha-Toxin Human Monoclonal Antibody, in Healthy Adults. Antimicrob Agents Chemother. 2016;61:e01020-16.
6. 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;37:886-892.
Dejnirattisai W, et al. Antibody evasion by the Brazilian P.1
strain of SARS-CoV-2. bioRxiv. 2021;
https://doi.org/10.1101/2021.03.12.435194 .
7. van Erp EA, et al. Fc-Mediated Antibody Effector Functions
During Respiratory Syncytial Virus Infection and Disease. Front
Immunol. 2019; 10: 548.
8. Clinicaltrials.gov. Phase III Double-blind,
Placebo-controlled Study of AZD7442 for Pre-exposure Prophylaxis of
COVID-19 in Adult. (PROVENT). Available at:
https://clinicaltrials.gov/ct2/show//NCT04625725 . [Last accessed:
7 April 2021].
9. Clinicaltrials.gov. Phase III Study of AZD7442 for Treatment
of COVID-19 in Outpatient Adults (TACKLE). Available at:
https://clinicaltrials.gov/ct2/show//NCT04723394 . [Last accessed:
7 April 2021].
10. Zhou D, et al. Evidence of escape of SARS-CoV-2 variant
B.1.351 from natural and vaccine induced sera. Cell. 2021; 184 (9):
2348-2361.e6.
11. Dejnirattisai W, et al. Antibody evasion by the Brazilian
P.1 strain of SARS-CoV-2. bioRxiv. 2021;
https://doi.org/10.1101/2021.03.12.435194 .
12. Wang P, et al. Antibody resistance of SARS-CoV-2 variants
B.1.351 and B.1.1.7. Nature 2021;593:130-135.
13. Chen RE, et al. Resistance of SARS-CoV-2 variants to
neutralization by monoclonal and serum-derived polyclonal
antibodies. Nat Med 2021; 27, 717-726.
https://doi.org/10.1038/s41591-021-01294-w.
14. Wang P, Nair MS, Liu L. et al. Antibody resistance of
SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature 2021 Mar 8. doi:
10.1038/s41586-021-03398-2. Epub ahead of print. PMID:
33684923.
15. Zost SJ, et al. Potently neutralizing and protective human
antibodies against SARS-CoV 2. Nature. 2020;584:443-449.
Adrian Kemp
Company Secretary
AstraZeneca PLC
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