Nirsevimab US regulatory submission accepted for the prevention of RSV lower respiratory tract disease in infants and children up to age 24 months

If FDA approved, nirsevimab would be the first single-dose RSV preventative option for the broad newborn and infant population in the US

Submission supported by comprehensive clinical trial programme, which demonstrated protection against RSV disease through the RSV season

LONDON, UK I January 5, 2023 I AstraZeneca’s Biologics License Application (BLA) for nirsevimab has been accepted for review by the US Food and Drug Administration (FDA) for the prevention of respiratory syncytial virus (RSV) lower respiratory tract disease in newborns and infants entering or during 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 is being developed and commercialised by AstraZeneca in collaboration with Sanofi and is the first single-dose preventative option for the broad infant population, including those born healthy, at term or preterm, or with specific health conditions. The FDA has indicated it will work to expedite its review.  The Prescription Drug User Fee Act date, the FDA target action date for its decision, is in the third quarter of 2023.  If approved at that time, nirsevimab will be available in the US for the 2023/2024 RSV season.

RSV is a very contagious virus that can lead to serious respiratory illness, according to the Centers for Disease Control and Prevention.¹ In the US, RSV is the leading cause of hospitalisation for babies under one.² Any infant can be hospitalised in their first RSV season and about 75% of infants hospitalised for RSV in the US were born at term with no underlying conditions.^3-5

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: “A substantial burden of disease from RSV affects infants, families, and healthcare providers every year. Effective interventions to prevent RSV are a critical need. This year in the US, we’ve seen first-hand how frightening the impact of this respiratory disease is on our patients and how stressful it is on the healthcare system, highlighting the urgency of addressing this problem.”

Iskra Reic, Executive Vice President, Vaccines and Immune Therapies, AstraZeneca, said: “This decision brings us a step closer to delivering a first-in-class preventative option for a broad infant population in the US. If approved, we believe nirsevimab may transform the medical community’s approach to respiratory syncytial virus prevention in infants and we are committed to working with the FDA to support completion of the review as quickly as possible.”

The BLA was based on results from the comprehensive nirsevimab clinical development programme, including the MELODY Phase III (primary cohort and all subjects), MEDLEY Phase II/III (first and second RSV season), and Phase IIb trials.^6-11 Data from the MELODY trial was published in the New England Journal of Medicine in March 2022 and demonstrated a reduction in the incidence of medically-attended lower respiratory tract infections (LRTI) caused by RSV by 74.5% (95% CI 49.6, 87.1; p<0.001) vs. placebo through day 151 (a typical RSV season) with a single dose.⁶ Nirsevimab 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.^10-11

In November 2022, nirsevimab was granted marketing authorisation in the European Union for the prevention of RSV lower respiratory tract disease in newborns and infants during their first RSV season, under the name Beyfortus.¹² Additional global regulatory submissions are underway.

Notes

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 entering or during 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 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.¹⁴

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 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). In November 2022, Beyfortus was approved by the European Commission and by the UK Medicines and Healthcare products Regulatory Agency (MHRA).^12-13

Pivotal clinical trials
The Phase IIb study was a randomised, placebo-controlled trial designed to measure the efficacy of 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 nirsevimab or placebo.^8-9

The dosing regimen was recommended based on further exploration of the Phase IIb data.⁸ The subsequent Phase III study, MELODY applied the recommended dosing regimen.^6-7

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.^6-7

MEDLEY 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.^10-11 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.^10-11 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.¹¹ 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.^6-7,10-11 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 nirsevimab helps protect infants during their first RSV season against RSV disease with a single dose.^6-11,15-16 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 first year 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 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.^6-7 Data was published in NEJMin March 2022.

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

^*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
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.^8-9 Data was published in NEJMin July 2020.

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

^*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.¹⁵ The pooled analysis studied healthy preterm and term infants who received the recommended dose of nirsevimab 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.¹⁵

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

^*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.

RSV
RSV is a very contagious virus that can lead to serious respiratory illness for infants, according to the Centers for Disease Control and Prevention (CDC).¹ 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 at term with no underlying conditions in a study conducted from 2014-2015.^3-5 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 by children under 5 years of age, which represents 1 in 4 of all RSV-related doctor visits, according to the CDC.¹⁷

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 leads commercialisation activities and records revenue. 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 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 agreed to sell US commercial rights for Synagis (palivizumab) 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 and also received non-contingent payments for nirsevimab during 2019-2021. AstraZeneca is also entitled to receive certain milestone payments for nirsevimab, including a $175m cash payment following the date on which the Biologics License Application (BLA) for nirsevimab was accepted for filing by the FDA and a $90m cash payment following the date on which BLA approval in the US occurs. 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.

References

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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.

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7. 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 January 2023.

8. 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 January 2023.

9. 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.

10. 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).

11. 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 January 2023.

12. European Commission. https://www.ema.europa.eu/en/documents/product-information/beyfortus-epar-product-information_en.pdf. Accessed January 2023.

13. Medicines & Healthcare products Regulatory Agency. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1119040/Marketing_authorisations_granted_1_-_14_November_2022.pdf. Accessed January 2023.

14. Centers for Disease Control and Prevention. Vaccines & Immunizations. August 18, 2017. https://www.cdc.gov/vaccines/vac-gen/immunity-types.htm. Accessed January 2023.

15. 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.

16. 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.

17. Hall, C. B. et al. The burden of respiratory syncytial virus infection in young children. New Engl J Medicine 360, 588–98 (2009)

SOURCE: AstraZeneca