FORM 6-K
SECURITIES
AND EXCHANGE COMMISSION
Washington,
D.C. 20549
Report
of Foreign Issuer
Pursuant
to Rule 13a-16 or 15d-16 of
the
Securities Exchange Act of 1934
For the
month of September 2022
Commission
File Number: 001-11960
AstraZeneca PLC
1
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Cambridge
Biomedical Campus
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United
Kingdom
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AstraZeneca PLC
INDEX
TO EXHIBITS
1.
Nirsevimab recommended for approval in EU by
CHMP
16 September 2022 07:00 BST
Beyfortus
(nirsevimab) recommended for approval in the EU by CHMP for the
prevention of RSV lower respiratory tract disease in
infants
Recommendation is based on the Beyfortus clinical trial programme
which demonstrated protection against RSV disease during the RSV
season with a single dose
If approved by the European Commission, Beyfortus would be the
first preventative option for the broad newborn and infant
population
AstraZeneca and Sanofi's
Beyfortus (nirsevimab)
has been recommended for marketing authorisation in the European
Union (EU) for the prevention of respiratory syncytial virus (RSV)
lower respiratory tract disease in newborns and infants during
their first RSV season. If approved,
Beyfortus would
be the first and only single-dose passive immunisation for the
broad infant population, including those born healthy, at term or
preterm, or with specific health conditions.
The Committee for Medicinal Products for Human Use (CHMP) of the
European Medicines Authority based its positive opinion on results
from the
Beyfortus clinical development programme, including the
MELODY Phase III, MEDLEY Phase II/III, and Phase IIb
trials.1-8
In the MELODY and Phase IIb trials,
Beyfortus met
its primary endpoint of reducing the incidence of medically attended lower
respiratory tract infections (LRTI) caused by RSV during the RSV
season vs. placebo with a single dose.1-6 No
clinically meaningful differences in safety results between
the
Beyfortus and
placebo groups were seen.
Beyfortus also
demonstrated a comparable safety and tolerability profile to
Synagis (palivizumab) in the MEDLEY Phase II/III trial,
with occurrence of treatment emergent adverse events (TEAEs) or
treatment emergent serious adverse events (TESAEs) similar between
groups.7-8
Iskra Reic, Executive Vice President, Vaccines and Immune
Therapies, AstraZeneca, said: "This positive CHMP opinion
underscores
Beyfortus'potential
as a ground breaking, first-in-class passive immunisation that
could transform the medical community's approach to respiratory
syncytial virus prevention in infants."
Jean-François Toussaint, Global Head of Research and
Development Vaccines, Sanofi, said: "Today's positive CHMP opinion
is one of the most significant public health achievements in
respiratory
syncytial virus in decades and has the potential to alleviate the
enormous physical and emotional burden that RSV can place on
families and healthcare systems. With this endorsement, we are one
step closer to achieving our goal of protecting all infants against
RSV with a single dose."
RSV is the most common cause of LRTIs and a leading cause of
hospitalisation in all infants.9-11 RSV-related
direct medical costs, globally -
including hospital, outpatient and follow-up care
- were estimated at €4.82 billion in 2017.12
The current standard of care for the prevention of
serious LRTIs caused by RSV focuses on to preterm infants and
infants at higher risk of severe disease, and treatment is limited
to symptomatic relief.13-14
Notes
Beyfortus
Beyfortus (nirsevimab),
an investigational long-acting antibody designed for all infants
for protection against RSV disease from birth through their first
RSV season with a single dose, is being developed jointly by
AstraZeneca and Sanofi using AstraZeneca's YTE
technology.
Beyfortus has been developed to offer newborns and infants
direct RSV protection via an antibody to help prevent LRTI caused
by RSV. Monoclonal antibodies do not require the activation of the
immune system to help offer timely, rapid and direct protection
against disease.15 The
recommended dose of
Beyfortus is
a single intramuscular injection of 50 mg for infants with body
weight <5 kg and a single intramuscular injection of 100 mg for
infants with body weight ≥5 kg.
Beyfortus has
been granted regulatory designations to facilitate expedited
development by several major regulatory agencies around the world.
These include Breakthrough Therapy Designation by The China Center
for Drug Evaluation under the National Medical Products
Administration;
Breakthrough Therapy Designation
from
the US Food and Drug Administration; access granted to the European
Medicines Agency (EMA)
PRIority Medicines (PRIME) scheme ; and named "a medicine
for prioritized development" under the Project for Drug Selection
to Promote New Drug Development in Pediatrics by the Japan Agency
for Medical Research and Development (AMED). The safety and
efficacy of
Beyfortus was
evaluated under an accelerated assessment procedure by the
EMA.
Beyfortus has
not been approved by any regulatory authority.
Pivotal clinical trials
The Phase IIb study was a randomised, placebo-controlled trial
designed to measure the efficacy of
Beyfortus
(nirsevimab)
against medically attended LRTI through 150 days postdose. Healthy
preterm infants of 29-35 weeks' gestation were randomised (2:1) to
receive a single 50mg intramuscular injection of
Beyfortus or placebo.3-4
The dosing regimen was recommended based on further exploration of the Phase IIb
data.3 The
subsequent Phase III study, MELODY, applied the recommended dosing
regimen.2
The MELODY Phase III study was a randomised, placebo-controlled
trial conducted across 21 countries designed to determine efficacy
of
Beyfortus against medically attended LRTI due to RSV
confirmed by reverse transcriptase polymerase chain reaction
testing through 150 days after dosing, versus placebo, in healthy
late preterm and term infants (35 weeks gestational age or greater)
entering their first RSV season.1-2
MEDLEY was a Phase II/III, randomised, double-blind,
Synagis-controlled
trial with the primary objective of assessing safety and
tolerability for
Beyfortus in
preterm infants and infants with congenital heart disease (CHD)
and/or chronic lung disease of prematurity (CLD) eligible to
receive
Synagis.7-8 Between
July 2019 and May 2021 approximately 918 infants entering their
first RSV season were randomised to receive a single 50mg (in
infants weighing <5kg) or 100mg (in infants weighing ≥5kg)
intramuscular injection of
Beyfortus or
Synagis. Safety was assessed by monitoring the occurrence
of TEAEs and TESAEs through 360 days post-dose.7-8 Serum
levels of nirsevimab following dosing (on day 151) in this trial
were comparable with those observed in the MELODY Phase III trial,
indicating similar protection in this population to that in the
healthy term and late preterm infants is likely.7 Data
was published in the
New England Journal of Medicine (NEJM) in
March 2022. The results of MELODY, MEDLEY Phase II/III and the
Phase IIb trials demonstrate that
Beyfortus helps protect infants during their first RSV
season against RSV disease with a single dose.1-8 This
all-infant population includes preterm, healthy late preterm and
term infants, as well as infants with specific
conditions.
These trials form the basis of regulatory submissions which began
in 2022.
Results from the Phase IIb trial
The primary endpoint of the
Phase IIb study
was
met, reducing the incidence of medically attended LRTI, caused by
RSV by 70.1% (95% CI: 52.3, 81.2) compared to
placebo.
Between
November 2016 and December 2017, 1,453 infants were randomised
(Beyfortus,
n=969; placebo, n=484) at the RSV season start. Research was
conducted by AstraZeneca in both hemispheres, at 164 sites in 23
countries.3-4 Data
was published in
NEJM
in
July 2020.
Medically Attended LRTI and Hospitalisation for RSV LRTI Through
150 Days Postdose (ITT population)
|
Endpoints and analyses, n (%)
|
Nirsevimab(N = 969)
|
Placebo(N = 484)
|
Efficacy
(95% CI)
|
P value
|
|
Medically attended RSV LRTI
|
|
|
70.1 (52.3, 81.2)
|
<0.001
|
|
Observed events
Participants requiring imputation of data*
|
25 (2.6)
24 (2.5)
|
46 (9.5)
11 (2.3)
|
|
|
|
Hospitalisation for RSV LRTI
Observed events
Participants requiring imputation of data*
|
8 (0.8)
24 (2.5)
|
20 (4.1)
11 (2.3)
|
78.4 (51.9, 90.3)
|
<0.001
|
*Data
were imputed for participants who had no events and were not
followed through 150 days postdose. Analyses were conducted using
Poisson regression with robust variance. CI, confidence interval;
ITT, intent-to-treat; LRTI, lower respiratory tract infection; RRR,
relative risk reduction; RSV, respiratory syncytial
virus.
Results from the MELODY Phase III trial
The primary endpoint of the MELODY
Phase
III trial
was
met, reducing the incidence of medically attended LRTI, such as
bronchiolitis or pneumonia, caused by RSV by 74.5% (95% CI 49.6,
87.1; P<0.001) compared to placebo. Infants
were randomised (2:1) to receive a single 50mg (in infants weighing
<5kg) or 100mg (in infants weighing ≥5kg) intramuscular
injection of
Beyfortus or
placebo. Between July 2019 and March 2020, 1,490 infants were
randomised to either
Beyfortus or placebo at the RSV season
start.1-2 Data
was published in
NEJM
in
March
2022.
Medically Attended LRTI and Hospitalisation for RSV LRTI Through
150 Days Postdose (ITT population)
|
Endpoints and analyses, n (%)
|
Nirsevimab(N = 994)
|
Placebo(N = 496)
|
Efficacy
(95% CI)
|
P value
|
|
Medically attended RSV LRTI
|
|
|
74.5 (49.6, 87.1)
|
<0.001
|
|
Observed events
Participants requiring imputation of data*
|
12 (1.2)
15 (1.5)
|
25 (5.0)
6 (1.2)
|
|
|
|
Hospitalisation for RSV LRTI
Observed events
Participants requiring imputation of data*
|
6 (0.6)
15 (1.5)
|
8 (1.6)
6 (1.2)
|
62.1 (-8.6, 86.8)
|
0.07
|
*Data
were imputed for participants who had no events and were not
followed through 150 days postdose. Analyses were conducted using
Poisson regression with robust variance. CI, confidence interval;
ITT, intent-to-treat; LRTI, lower respiratory tract infection; RRR,
relative risk reduction; RSV, respiratory syncytial
virus.
Results from the pre-specified pooled analysis of the Phase IIb and
MELODY trials
A prespecified pooled analysis of the MELODY Phase III trial and
the recommended dose from the Phase IIb trial, in which an efficacy
(relative risk reduction versus placebo) of 79.5% (95% CI 65.9,
87.7; P<0.0001) was seen against medically attended LRTI, such
as bronchiolitis or pneumonia, caused by RSV in infants born at
term or preterm entering their first RSV season.5 The
pooled analysis studied healthy preterm and term infants who
received the recommended dose of Beyfortus based on weight compared
to placebo through Day 151 and showed an efficacy of 77.3% (95% CI
50.3, 89.7; P<0.001) against RSV LRTI
hospitalisations.1,5
Medically Attended LRTI and Hospitalisation for RSV LRTI Through
150 Days Postdose (ITT population)
|
Endpoints and analyses, n (%)
|
Nirsevimab(N = 1564)
|
Placebo(N = 786)
|
Efficacy (Relative
Risk
Reduction)(95% CI)
|
P value
|
|
Medically attended RSV LRTI
|
|
|
79.5 (65.9, 87.7)
|
<0.0001
|
|
Participants with observed events n (%)
Participants requiring imputation of data* n
(%)
|
19 (1.2)
25 (1.6)
|
51 (6.5)
10 (1.3)
|
|
|
|
Hospitalisation for RSV LRTI
|
|
|
77.3 (50.3, 89.7)
|
<0.001
|
|
Participants with observed events n (%)
Participants requiring imputation of data* n
(%)
|
9 (0.6)
25 (1.6)
|
21 (2.7)
10 (1.3)
|
|
|
*Data
were inputed for participants who had no events and were not
followed through 150 days postdose. Analyses were conducted using
Poisson regression with robust variance. CI, confidence interval;
ITT, intent-to-treat; LRTI, lower respiratory tract infection; RRR,
relative risk reduction; RSV, respiratory syncytial
virus.
RSV
RSV is the most common cause of LRTI, including bronchiolitis and
pneumonia, in infants.9 It
is also a leading cause of hospitalisation in all infants, with
most hospitalisations for RSV occurring in healthy infants born at
term.10-11,16-17 Globally,
in 2019, there were approximately 33 million cases of acute lower
respiratory infections leading to more than three million
hospitalisations, and it was estimated that there were 26,300
in-hospital deaths of children younger than five
years.18 RSV-related
direct medical costs, globally - including hospital, outpatient and
follow-up care - were estimated at €4.82 billion in
2017.12
Currently,
Synagis (palivizumab) is the only approved option for the
prevention of serious LRTIs caused by RSV in high risk and preterm
infants and requires up to five injections to cover a typical RSV
season.13
Sanofi Alliance
In March 2017, AstraZeneca and Sanofi announced an
agreement
to develop and commercialise nirsevimab. Under the terms of the
agreement, AstraZeneca leads all development and manufacturing
activities, and Sanofi will lead commercialisation activities and
record revenues. Under the terms of the global agreement, Sanofi
made an upfront payment of €120m, has paid a development
milestone of €30m and will pay up to a further €465m
upon achievement of certain development and sales-related
milestones. The two companies share all costs and profits. Revenue
from the agreement is reported as Collaboration Revenue in the
Company's financial statements.
Sobi agreement
Related, in November 2018, AstraZeneca divested US commercial
rights for
Synagis to
Swedish Orphan Biovitrum AB (publ) (Sobi) in addition to the right
to participate in payments that may be received by AstraZeneca from
the US profits or losses for nirsevimab. Under the
agreement AstraZeneca
received upfront consideration of $1.5bn, consisting of $1.0bn in
cash and $500m in ordinary shares of Sobi upon completion, and
received a total of $60m in non-contingent payments for nirsevimab
during 2019-2021. AstraZeneca will also receive up to $470m in
sales-related payments for Synagis
, a
$175m milestone following the submission of the Biologics License
Application (BLA) for nirsevimab and potential net payments of
approximately $110m on achievement of other nirsevimab profit and
development-related milestones. Upon payment of the $175m milestone
on BLA submission, Sobi's ongoing participation will amount to
AstraZeneca's share of profits or losses under the aforementioned
agreement with Sanofi for nirsevimab in the US. AstraZeneca will
continue to manufacture and supply nirsevimab globally and is
entitled to an additional royalty from Sobi if profits from
nirsevimab in the US exceed a pre-specified level.
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, 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. 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.
Hammitt LL, MD et al. Nirsevimab for Prevention of RSV in Healthy
Late -Preterm and Term Infants. N Engl J Med. 2022;386 (9):
837-846. doi: 10.1056/NEJMoa2110275.
2.
Clinicaltrials.gov. A Study to Evaluate the Safety and Efficacy of
MEDI8897 for the Prevention of Medically Attended RSV LRTI in
Healthy Late Preterm and Term Infants (MELODY).
https://clinicaltrials.gov/ct2/show/NCT03979313. Accessed September
2022.
3.
Clinicaltrials.gov. A Study to Evaluate the Safety and Efficacy of
MEDI8897 for the Prevention of Medically Attended RSV LRTI in
Healthy Preterm Infants. (MEDI8897 Ph2b).
https://clinicaltrials.gov/ct2/show/results/NCT02878330. Accessed
September 2022.
4.
Griffin P, MD et al. (2020). Single-Dose Nirsevimab for Prevention
of RSV in Preterm Infants. NEJM 2020; 383: 415-425. DOI:
10.1056/NEJMoa1913556.
5.
Simões, E, et al. Pooled efficacy of nirsevimab against RSV
lower respiratory tract infection in preterm and term infants.
ESPID 2022 Congress; 2022 May 9-13. Hybrid Congress.
6.
Wilkins, D, et al. Nirsevimab for the prevention of respiratory
syncytial virus infection: neutralizing antibody levels following a
single dose. ESPID 2022 Congress; 2022 May 9-13. Hybrid
Congress.
7.
Domachowske J, MD et al. Safety of Nirsevimab for RSV in Infants
with Heart or Lung Disease or Prematurity. N Engl J Med. 2022; 386
(9).
8.
Clinicaltrials.gov. A Study to Evaluate the Safety of MEDI8897 for
the Prevention of Medically Attended Respiratory Syncytial Virus
(RSV) Lower Respiratory Track Infection (LRTI) in High-risk
Children. https://clinicaltrials.gov/ct2/show/NCT03959488 (MEDLEY).
Accessed September 2022.
9.
R K. Respiratory Syncytial Virus Vaccines. Plotkin SA, Orenstein
WA, Offitt PA, Edwards KM, eds Plotkin's Vaccines 7th ed
Philadelphia. 2018;7th ed. Philadelphia:943-9.
10.
Leader S, Kohlhase K. Respiratory syncytial virus-coded pediatric
hospitalizations, 1997 to 1999. The Pediatric infectious disease
journal. 2002;21(7):629-32.
11.
McLaurin KK, Farr AM, Wade SW, Diakun DR, Stewart DL. Respiratory
syncytial virus hospitalization outcomes and costs of full-term and
preterm infants. Journal of Perinatology: official journal of the
California Perinatal Association. 2016;36(11):990-6.
12.
Zhang S, et al. Cost of Respiratory Syncytial Virus-Associated
Acute Lower Respiratory Infection Management in Young Children at
the Regional and Global Level: A Systematic Review and
Meta-Analysis. J Infect Dis. 2020;222(Suppl
7):S680-687.
13.
Synagis - Summary of Product Characteristics (SmPC) - (eMC)
[Internet]. Available from:
https://www.ema.europa.eu/en/documents/product-information/synagis-epar-product-information_en.pdf
Accessed September 2022.
14.
Respiratory Syncytial Virus Infection (RSV): Infants and Young
Children. Centers for Disease Control and Prevention.
https://www.cdc.gov/rsv/high-risk/infants-young-children.html.
Accessed September 2022.
15.
Centers for Disease Control and Prevention. Vaccines &
Immunizations. August 18, 2017.
https://www.cdc.gov/vaccines/vac-gen/immunity-types.htm. Accessed
September 2022.
16.
Rha B, et al. Respiratory Syncytial Virus-Associated
Hospitalizations Among Young Children: 2015-2016. Pediatrics.
2020;146:e20193611.
17.
Arriola CS, et al. Estimated Burden of Community-Onset Respiratory
Syncytial Virus-Associated Hospitalizations Among Children Aged
<2 Years in the United States, 2014-15. J Pediatric Infect Dis
Soc. 2020;9:587-595
18.
Li Y, et al. Global, regional, and national disease burden
estimates of acute lower respiratory infections due to respiratory
syncytial virus in children younger than 5 years in 2019: a
systematic analysis. Lancet 2022;399:92047-64.
Adrian Kemp
Company Secretary
AstraZeneca PLC
SIGNATURES
Pursuant
to the requirements of the Securities Exchange Act of 1934, the
Registrant has duly caused this report to be signed on its behalf
by the undersigned, thereunto duly authorized.
Date:
16 September 2022
|
|
By: /s/
Adrian Kemp
|
|
|
Name:
Adrian Kemp
|
|
|
Title:
Company Secretary
|
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