TIDMAZN
RNS Number : 1813C
AstraZeneca PLC
09 June 2023
9 June 2023
Nirsevimab unanimously recommended by FDA Advisory Committee for
the prevention of RSV lower respiratory tract disease in
infants
If approved, nirsevimab would be the first preventive option
specifically designed to protect the broad infant population
through its first RSV season
Across all clinical endpoints, a single dose of nirsevimab
delivered consistent and sustained efficacy against RSV disease vs
placebo
The US Food and Drug Administration (FDA) Antimicrobial Drugs
Advisory Committee (AMDAC) has voted unanimously 21 to 0 that
AstraZeneca and Sanofi's nirsevimab has a favourable benefit risk
profile for the prevention of respiratory syncytial virus (RSV)
lower respiratory tract disease (LRTD) in newborns and infants born
during or entering their first RSV season. The Committee also voted
19 to 2 in support of nirsevimab's favourable benefit risk profile
for children up to 24 months of age who remain vulnerable to severe
RSV disease through their second RSV season.
Nirsevimab has the potential to protect the broad infant
population through its first RSV season, including those born
healthy at term or preterm, or with specific health conditions that
make them vulnerable to RSV disease. The single dose can be
flexibly administered at the beginning of the RSV season or at
birth for newborns born during the RSV season.
The FDA accepted the Biologics License Application (BLA) for
nirsevimab in 2022 and the agency has indicated it will work to
expedite its review. The Prescription Drug User Fee Act date is in
the third quarter of 2023. If approved by that time, nirsevimab
will be available in the US ahead of the 2023-2024 RSV season.
Dr William Muller, Associate Professor, Pediatrics, Northwestern
University Feinberg School of Medicine and Scientific Director,
Clinical and Community Trials, Ann & Robert H. Lurie Children's
Hospital of Chicago, Illinois, US said: "RSV remains the most
common cause of bronchiolitis and pneumonia in infants, and the
inability to predict which infants will develop severe RSV disease
leads to uncertainty for new parents and for physicians. The
innovation of nirsevimab as a long-acting antibody that can be
conveniently administered to a broad infant population with a
single-dose at the time protection is most needed is a significant
public health advancement that could have far-reaching impact on
the well-being of our families and healthcare systems in the
US."
Iskra Reic, Executive Vice President, Vaccines and Immune
Therapies, AstraZeneca, said: "We are delighted that the
Antimicrobial Drugs Advisory Committee has unanimously recognised
the favourable benefit risk profile of nirsevimab as the first
preventative option against RSV for a broad infant population.
Nirsevimab builds on AstraZeneca's strong science, leadership in
RSV and commitment to addressing the needs of the most vulnerable.
We look forward to continuing to work with the FDA to complete
their expedited review, and we hope to see nirsevimab available as
soon as possible given the significant burden of RSV in
infants."
Thomas Triomphe, Executive Vice President, Vaccines, Sanofi,
said: "Most babies hospitalised with RSV are born at term and
healthy, which is why interventions specifically designed to
protect all infants are likely to result in the greatest impact. We
are encouraged by the Advisory Committee's positive vote based on
the compelling clinical development program supporting nirsevimab
and its breakthrough potential to reduce the magnitude of annual
RSV burden."
RSV is a very contagious virus that can lead to serious
respiratory illness, according to the Centers for Disease Control
and Prevention (CDC).(1) In the US, RSV is the leading cause of
hospitalisation for babies under one.(2) About 75% of infants
hospitalised for RSV in the US were born at term with no underlying
conditions.(3)
The AMDAC based its recommendation on the nirsevimab clinical
development programme spanning three pivotal late-stage clinical
trials, including results from the MELODY Phase III trial recently
published in the New England Journal of Medicine .(4-8) Across all
clinical endpoints, a single dose of nirsevimab demonstrated
sustained and consistent reduction in RSV LRTD requiring medical
care vs placebo through the entire RSV season. Nirsevimab was
generally well tolerated with a favourable safety profile that was
consistent across all clinical trials. The overall rates of adverse
events were comparable between nirsevimab and placebo and the
majority of adverse events were mild or moderate in severity. The
most common adverse events were rash, fever and injection site
reactions.(4-10)
Notes
Antimicrobial Drugs Advisory Committee (AMDAC)
AMDAC reviews and evaluates available data concerning the safety
and effectiveness of marketed and investigational human drug
products for use in the treatment of infectious diseases and
disorders and makes appropriate recommendations to the Commissioner
of Food and Drugs. The AMDAC's recommendation, while not binding,
will be considered by the FDA during its review of the BLA for
nirsevimab.
RSV
RSV is a very contagious virus that can lead to serious
respiratory illness for infants, according to the CDC.(1) Two out
of three infants are infected with RSV during their first year of
life and almost all infants are infected by their second
birthday.(11) In the US, RSV is the leading cause of
hospitalisation in infants under 12 months.(2) Approximately 75% of
infants hospitalised for RSV were born healthy and at term with no
underlying conditions in a study conducted from 2014-2015.(3) RSV
symptoms can include runny nose, coughing, sneezing, fever,
decrease in appetite, and wheezing.(1) Each year RSV infection
leads to approximately 500,000 emergency department visits in the
US by children under 5 years of age, which represents 1 in 4 of all
RSV-related doctor visits, according to the CDC.(12)
Nirsevimab
Nirsevimab is a single dose long-acting antibody, developed and
commercialised in partnership by AstraZeneca and Sanofi using
AstraZeneca's YTE technology. It is designed to protect infants
born during or entering their first RSV season and for children up
to 24 months of age who remain vulnerable to severe RSV disease
through their second RSV season. Nirsevimab, provided directly to
newborns and infants as a single dose, offers RSV protection via an
antibody to help prevent LRTD caused by RSV. Monoclonal antibodies
do not require the activation of the immune system to help offer
timely, rapid and direct protection against disease.(13)
Nirsevimab has been granted regulatory and other designations to
facilitate expedited development by several major regulatory
agencies around the world. These include Breakthrough Therapy
Designation and Priority Review 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). Nirsevimab was approved in
the European Union in October 2022.
Pivotal clinical trials
The Phase IIb study (Trial 03) was a randomised,
placebo-controlled trial designed to measure the efficacy of
nirsevimab against medically attended Lower Respiratory Tract
Infection (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 nirsevimab or placebo.(6)
The dosing regimen was recommended based on further exploration
of the Phase IIb data.(6) The subsequent Phase III study, MELODY
(Trial 04) applied the recommended dosing regimen.(4,5)
The MELODY Phase III study was a randomised, placebo-controlled
trial conducted across 21 countries designed to determine efficacy
of nirsevimab 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.(4,5)
MEDLEY (Trial 05) was a Phase II/III, randomised, double-blind,
Synagis-controlled trial with the primary objective of assessing
safety and tolerability for nirsevimab in preterm infants and
infants with congenital heart disease (CHD) and/or chronic lung
disease of prematurity (CLD) eligible to receive Synagis.(7)
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 nirsevimab or Synagis. Safety was
assessed by monitoring the occurrence of TEAEs and TESAEs through
360 days post-dose.(7) 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 safety profile of nirsevimab was similar to Synagis in the
MEDLEY Phase II/III and consistent with the safety profile in term
and preterm infants studied in the MELODY Phase III trial.(4,5,7)
While uncommon, the most reported adverse reactions were: rash 14
days post-dose, (the majority of which were mild to moderate);
pyrexia (fever) within 7 days post-dose; non-serious injection site
reactions within 7 days post-dose.
The results of MELODY, MEDLEY Phase II/III and the Phase IIb
trials demonstrate that a single dose of nirsevimab helps protect
infants during their first RSV season against RSV disease.(4-8)
This broad infant population includes preterm, healthy late preterm
and term infants, as well as infants with specific conditions.
These trials formed the basis of regulatory submissions which
began in 2022.
Results from the MELODY Phase III trial (Trial 04)
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
nirsevimab or placebo. Between July 2019 and March 2020, 1,490
infants were randomised to receive either nirsevimab or placebo at
the RSV season start.(4,5) Data was published in NEJM in March
2022.
Following the analysis of the initial 1,490 infants within the
MELODY primary cohort, additional infants continued to be enrolled.
A total of 3,012 healthy late preterm and term infants (35 weeks
gestational age or greater) entering their first RSV season were
randomised to receive nirsevimab (n=2,009) or placebo (n=1,003). In
this updated analysis of the full enrolment cohort, nirsevimab
demonstrated a 76.8% (95% CI: 49.4, 89.4) reduction in
hospitalisation-associated RSV LRTI vs placebo. Additionally,
nirsevimab reduced very severe MA RSV LRTI by 78.6% (95% CI: 48.8,
91.0) through an RSV season, and efficacy against MA RSV LRTI was
consistent with previous trials (76.4%; 95% CI: 62.3, 85.2). The
safety profile of nirsevimab was similar to placebo (nirsevimab,
1.3%; placebo, 1.5%).(4)
Medically Attended LRTI and Hospitalisation for RSV LRTI Through
150 Days Postdose (ITT population)
Endpoints and analyses, Nirsevimab Placebo Efficacy P value
n (%) (N = 994) (N = 496) (95% CI)
Medically attended RSV LRTI 74.5 (49.6, 87.1) <0.001
Observed events 12 (1.2) 25 (5.0)
Participants requiring imputation 15 (1.5) 6 (1.2)
of data(*)
Hospitalisation for RSV
LRTI 62.1 (-8.6, 86.8) 0.07
Observed events 6 (0.6) 8 (1.6)
Participants requiring imputation
of data(*) 15 (1.5) 6 (1.2)
(*) 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 Phase IIb trial (Trial 03)
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 (nirsevimab, n=969;
placebo, n=484) at the RSV season start. Research was conducted by
AstraZeneca in both hemispheres, at 164 sites in 23 countries.(6)
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, Nirsevimab Placebo Efficacy P value
n (%) (N = 969) (N = 484) (95% CI)
Medically attended RSV 70.1 (52.3, <0.001
LRTI 81.2)
Observed events 25 (2.6) 46 (9.5)
Participants requiring 24 (2.5) 11 (2.3)
imputation of data(*)
Hospitalisation for RSV 78.4 (51.9, <0.001
LRTI 90.3)
Observed events 8 (0.8) 20 (4.1)
Participants requiring 24 (2.5) 11 (2.3)
imputation of data(*)
(*) 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.
Sanofi Alliance
In March 2017, AstraZeneca and Sanofi announced an agreement to
develop and commercialise nirsevimab. Under the terms of the
agreement, AstraZeneca leads development and manufacturing
activities, and Sanofi leads commercialisation activities and
records revenue. The two companies share costs and profits in all
territories except in the US. AstraZeneca's revenue from the
agreement is reported as Alliance Revenue and Collaboration Revenue
in the Company's financial statements. Following a revision to the
profit-sharing arrangement relating to the development and
commercialisation of nirsevimab in the US between AstraZeneca,
Sanofi and Sobi, Sobi has entered into a direct relationship with
Sanofi, replacing the previous participation agreement with
AstraZeneca entered into in November 2018 .
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. Centers for Disease Control and Prevention. RSV in Infants
and Young Children. October 28, 2022.
https://www.cdc.gov/rsv/high-risk/infants-young-children.html.
Accessed June 2023.
2. Leader S, Kohlhase K. Recent trends in severe respiratory
syncytial virus (RSV) among US infants, 1997 to 2000. J Pediatr.
2003;143(5 Suppl):S127-S132. doi:10.1067/s0022-3476(03)00510-9.
3. Esposito S, et al. RSV Prevention in All Infants: Which Is
the Most Preferable Strategy? Front Immunol. 2022; 13: 880368. doi:
10.3389/fimmu.2022.880368.
4. Muller WJ, et al. Nirsevimab for Prevention of RSV in Term
and Late-Preterm Infants. N Engl J Med. April 5, 2023. doi:
10.1056/NEJMc2214773
5. Hammitt LL, 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.
6. Griffin P, et al. Single-Dose Nirsevimab for Prevention of
RSV in Preterm Infants. N Engl J Med. 2020;383: 415-425. doi:
10.1056/NEJMoa1913556.
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. AstraZeneca. Beyfortus (Nirsevimab) for the Prevention of RSV
Lower Respiratory Tract Disease in Infants and Children. Briefing
Document for US FDA Antimicrobial Drugs Advisory Committee Meeting.
June 6, 2023. https://www.fda.gov/media/169226/download. Accessed
June 2023.
9. Simões EAF, et al. Efficacy of nirsevimab against respiratory
syncytial virus lower respiratory tract infections in preterm and
term infants, and pharmacokinetic extrapolation to infants with
congenital heart disease and chronic lung disease: a pooled
analysis of randomised controlled trials. Lancet Child Adolesc
Health 2023. doi: 10.1016/S2352-4642(22)00321.
10. 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.
11. Walsh, EE. Respiratory Syncytial Virus infection: an illness
for all ages. Clin Chest Med. 2017; 38(1):29-36.
12. Hall, C. B. et al. The burden of respiratory syncytial virus
infection in young children. New Engl J Medicine 360, 588-98
(2009).
13. Centers for Disease Control and Prevention. Vaccines &
Immunizations. September 24, 2021.
https://www.cdc.gov/vaccines/vac-gen/immunity-types.htm. Accessed
June 2023.
Adrian Kemp
Company Secretary
AstraZeneca PLC
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