First and only RSV preventive option for broad infant population authorised for use in Japan.

AstraZeneca and Sanofi's Beyfortus (nirsevimab), a long-acting monoclonal antibody, has been approved in Japan for the prophylaxis of lower respiratory tract disease (LRTD) caused by respiratory syncytial virus (RSV) in all neonates, infants and children entering their first RSV season, and the prevention of RSV LRTD in neonates, infants and children at risk of serious RSV infection[ ]entering their first or second RSV season.[1] Beyfortus is anticipated to be available for the upcoming 2024/25 RSV season, in line with existing Japanese guidelines.

Beyfortus is the first preventive option developed to protect a broad infant population against RSV LRTD, including protecting those infants born healthy at term, or preterm, or with specific health conditions that make them vulnerable to severe disease. The approval by the Japanese Ministry of Health, Labour and Welfare is based on three Beyfortus pivotal late-stage clinical trials. Across all clinical endpoints, a single dose of Beyfortus demonstrated consistent efficacy against RSV LRTD extending through five months, the duration of a typical RSV season.[2-5]

More than 100,000 cases of RSV LRTD in infants are reported every year in Japan including healthy infants born at term.[6]

Dr. Hiroyuki Moriuchi, Professor and Head of Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, said: "This is an important milestone in the fight against RSV in infants. Almost all children are affected by RSV by the age of two and all infants, including those born healthy and at term, can be at risk. RSV causes a significant burden for children, their families and to the medical system potentially leading to long-term consequences of severe infection in infancy. Beyfortus can protect infants across the RSV season and its approval represents a crucial contribution to the prevention and control of RSV disease in Japan."

Iskra Reic, Executive Vice President, Vaccines and Immune Therapies, AstraZeneca, said: "The approval of Beyfortus means it is possible for the first time to prevent serious respiratory disease due to RSV for all infants in Japan and reduce the infectious disease burden on healthcare systems. Beyfortus reflects AstraZeneca's commitment to the scientific development of preventive options to support the most vulnerable patient populations and we look forward to making Beyfortus available in Japan for the 2024/25 season." 

Beyfortus has received approval in the European Union, US and China.

Notes

Japan Beyfortus indication[1]
The following groups of neonates, infants or children at risk of serious RSV infection entering their first or second RSV season, should meet at least one of the following criteria:

• In the early stage of first RSV season
• Infants born at 28 weeks' gestation or earlier and less than 12 months of age

• Infants born at 29 to 35 weeks' gestation and less than 6 months of age

• In the early stage of first and second RSV season

• Neonates, infants or children less than 24 months of age who have received one treatment against chronic lung disease within the past 6 months
• Neonates, infants or children less than 24 months of age with hemodynamically significant congenital heart disease
• Neonates, infants or children less than 24 months of age with immunocompromised conditions
• Neonates, infants or children less than 24 months of age with Down syndrome

The Beyfortus dosing regimen was determined based on further exploration of the Phase IIb data and was used in subsequent trials as a single 50mg dose for those who weigh less than 5kg, or a single 100mg dose for those who weigh 5kg or greater.[1,4]

The MELODY Phase III study (Trial 04) was a randomised, double-blind, placebo-controlled trial conducted across 21 countries designed to determine efficacy of Beyfortus against medically attended LRTI through 150 days after dosing, versus placebo, in healthy term and late preterm infants (35 weeks gestational age or greater) entering their first RSV season.[1-3]

The MEDLEY (Trial 05) was a Phase II/III, randomised, double-blind, Synagis (palivizumab)-controlled trial with the primary objective of assessing safety and tolerability for Beyfortus in preterm infants of less than 35 weeks gestational age and infants with congenital heart disease (CHD) and/or chronic lung disease of prematurity (CLD) eligible to receive Synagis. Between July 2019 and May 2021, a total of 925 infants entering their first RSV season were randomised (2:1) in each of the preterm and CLD/CHD cohorts to receive Beyfortus or Synagis. A total of 262 children up to 24 months of age from the CLD/CHD cohort continued in the trial for a second RSV season. Safety was assessed by monitoring the occurrence of adverse events through 360 days post-dose.

The results of MELODY, MEDLEY Phase II/III and the Phase IIb trials demonstrate that a single dose of Beyfortus helps protect infants during their first RSV season against RSV disease. This broad infant population includes healthy term, late preterm and preterm infants, as well as infants with specific health conditions that make them vulnerable to severe RSV disease.[1,5]

These trials formed the basis of regulatory submissions which began in 2022.

Results

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. The event rates were 2.6% in treatment arm vs 9.5% in placebo arm. 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. Data were published in NEJM in July 2020.[1,4]

In a prespecified secondary endpoint, Beyfortus reduced medically attended RSV LRTI with hospitalisation by 78.4% (95% CI 51.9, 90.3) versus placebo. Observed events were 0.8% in treatment arm vs 4.1% in placebo arm.[1] A subgroup analysis by body weight indicated a lower efficacy in infants >5 kg vs <5kg. The resulting post-hoc analysis of the Phase IIb study that applied the recommended 50mg dose in a subgroup of infants weighing less than 5kg showed the efficacy of Beyfortus against medically attended RSV LRTI and medically attended RSV LRTI with hospitalisation was 86.2% (95% CI 68.0, 94.0) and 86.5% (95% CI 53.5, 96.1) respectively.[1,7 ]

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% confidence interval (CI) 49.6, 87.1; P<0.001) compared to placebo.[3] The event rates were 1.2% in treatment arm vs 5% in placebo arm. The Beyfortus dosing regimen was determined based on further exploration of the Phase IIb data and was 50mg<5kg and 100 mg >=5kg. The efficacy of Beyfortus against the secondary endpoint of hospitalisation was 62.1% (95% CI: -8.6, 86.8). Observed events were 0.6% in treatment arm vs 1.6% in placebo arm. Between July 2019 and March 2020, 1,490 infants were randomised to receive either Beyfortus or placebo at the RSV season start. Initial data from the MELODY Primary Cohort were published in NEJM in March 2022.[1,5]

MEDLEY Phase II/III trial (Trial 05)
Serum levels of Beyfortus 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. In the first RSV season, the incidence of medically attended RSV LRTI through 150 days post dose was 0.6% (4/616) in the Beyfortus group and 1.0% (3/309) in the Synagis group. In the second RSV season, there were no cases of medically attended RSV LRTI through Day 150 in children who received either Beyfortus or Synagis. Data were published in the New England Journal of Medicine (NEJM) in March 2022.[1,5]

The safety profile of Beyfortus was similar to Synagis in the MEDLEY Phase II/III trial and consistent with the safety profile in healthy term and preterm infants studied in the MELODY and Phase IIb trials. While uncommon, the most reported adverse reactions were: rash 14 days post-dose (the majority of which were mild to moderate); non-serious injection site reactions within 7 days post-dose.[1,3,5]

Beyfortus
Beyfortus (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.  Beyfortus, provided directly to newborns and infants as a single dose, offers rapid protection via an antibody to help prevent LRTD caused by RSV, without requiring activation of the immune system. 

Beyfortus administration can be timed to the start of the RSV season or during the season for those infants born in season.[1]

Beyfortus has been granted regulatory 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).

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 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.

Beyfortus will be co-promoted by AstraZeneca and Sanofi in Japan.

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 social media @AstraZeneca (https://www.linkedin.com/company/astrazeneca/).

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References

1. Japan Ministry of Health, Labour and Welfare indication
2. 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
3. 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
4. Griffin P, MD et al. Single-Dose Nirsevimab for Prevention of RSV in Preterm Infants. N Engl J Med. 2020;383: 415-425. DOI: 10.1056/NEJMoa1913556
5. 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)
6. Ishiwada, N. et al. Guidelines for the Management of Respiratory Infectious Diseases in Children in Japan 2022. The Pediatric Infectious Disease Journal. Volume 42, Issue 10, October 2023. DOI: 10.1097/INF.0000000000004041
7. Supplement to 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; published online Jan 9. https://doi.org/10.1016/S2352-4642(22)00321-2.