REG - AstraZeneca PLC - nirsevimab recommended for infant RSV protection

AstraZenecaAnnouncement

09/06/2023 07:15

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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 (https://www.nejm.org/doi/full/10.1056/NEJMc2214773) .(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
(https://www.astrazeneca.com/media-centre/press-releases/2019/us-fda-grants-breakthrough-therapy-designation-for-potential-next-generation-rsv-medicine-medi8897.html)
 from the US Food and Drug Administration; access granted to the European
Medicines Agency (EMA) PRIority Medicines
(https://www.astrazeneca.com/media-centre/press-releases/2019/ema-grants-prime-eligibility-for-potential-next-generation-rsv-medicine-medi8897-05022019.html)
(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) (https://www.nejm.org/doi/full/10.1056/NEJMc2112186) 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
(https://www.nejm.org/doi/full/10.1056/NEJMoa2110275) 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, n (%)                  Nirsevimab  Placebo     Efficacy           P value

(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 of data(*)   15 (1.5)    6 (1.2)

 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
(https://www.nejm.org/doi/full/10.1056/nejmoa1913556)  in July 2020.

 

Medically Attended LRTI and Hospitalisation for RSV LRTI Through 150 Days
Postdose (ITT population)

 

 Endpoints and analyses, n (%)                  Nirsevimab  Placebo     Efficacy           P value

(N = 969)
(N = 484)

                                                                        (95% CI)
 Medically attended RSV LRTI                                            70.1 (52.3, 81.2)  <0.001
 Observed events                                25 (2.6)    46 (9.5)

 Participants requiring imputation of data(*)   24 (2.5)    11 (2.3)

 Hospitalisation for RSV LRTI                                           78.4 (51.9, 90.3)  <0.001

 Observed events                                8 (0.8)     20 (4.1)

 Participants requiring imputation of data(*)   24 (2.5)    11 (2.3)

(*)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
(https://www.astrazeneca.com/media-centre/press-releases/2017/medimmune-and-sanofi-pasteur-form-alliance-to-develop-and-commercialise-potential-next-generation-respiratory-syncytial-virus-antibody-medi8897-030317.html)
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
(https://www.astrazeneca.com/media-centre/press-releases/2023/update-to-arrangements-with-sobi-and-sanofi.html)
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
(https://www.astrazeneca.com/media-centre/press-releases/2018/astrazeneca-to-divest-us-synagis-rights-to-sobi131120180.html)
2018
(https://www.astrazeneca.com/media-centre/press-releases/2018/astrazeneca-to-divest-us-synagis-rights-to-sobi131120180.html)
.

 

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 (http://www.astrazeneca.com/) and follow the
Company on Twitter @AstraZeneca (https://twitter.com/AstraZeneca) .

 

Contacts

For details on how to contact the Investor Relations Team, please click here
(https://www.astrazeneca.com/investor-relations.html#Contacts) . For Media
contacts, click here (https://www.astrazeneca.com/media-centre/contacts.html)
.

 

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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