REG - AstraZeneca PLC - Nirsevimab recommended for approval in EU by CHMP

AstraZenecaAnnouncement

16/09/2022 07:00

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RNS Number : 7319Z  AstraZeneca PLC  16 September 2022

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
(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 (PRIME) scheme
(https://www.astrazeneca.com/media-centre/press-releases/2019/ema-grants-prime-eligibility-for-potential-next-generation-rsv-medicine-medi8897-05022019.html)
; 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)
(https://www.nejm.org/doi/full/10.1056/NEJMc2112186) 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
(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.

 

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 (https://www.nejm.org/doi/full/10.1056/NEJMoa2110275) in
March 2022.

 

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 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   Placebo     Efficacy (Relative  P value

(N = 1564)
(N = 786)

                                                                               Risk

                                                                               Reduction)

(95% CI)
 Medically attended RSV LRTI                                                   79.5 (65.9, 87.7)    <0.0001
 Participants with observed events n (%)              19 (1.2)     51 (6.5)

 Participants requiring imputation of data(*) n (%)

                                                      25 (1.6)     10 (1.3)
 Hospitalisation for RSV LRTI                                                  77.3 (50.3, 89.7)    <0.001
 Participants with observed events n (%)              9 (0.6)      21 (2.7)

 Participants requiring imputation of data(*) n (%)

                                                      25 (1.6)     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
(https://nam12.safelinks.protection.outlook.com/?url=https%3A%2F%2Fwww.astrazeneca.com%2Fmedia-centre%2Fpress-releases%2F2017%2Fmedimmune-and-sanofi-pasteur-form-alliance-to-develop-and-commercialise-potential-next-generation-respiratory-syncytial-virus-antibody-medi8897-030317.html&data=04%7C01%7Celeanor.read%40edelman.com%7Ca3c20243fe85477f1b3808d90636596f%7Cb824bfb3918e43c2bb1cdcc1ba40a82b%7C0%7C0%7C637547652770793519%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C1000&sdata=ZcJELgHfl6iZMI7f3qCFUOW4miRNoLSrIxbCrVRDGzk%3D&reserved=0)
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
(https://www.astrazeneca.com/media-centre/press-releases/2018/astrazeneca-to-divest-us-synagis-rights-to-sobi131120180.html)
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 (https://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.   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

 

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