Study Design

Preclinical trials

2014 Phase 1a1
NCT02114268		 “1st Time in Healthy Adults”

Healthy adults aged 18 to 49 years (n=136)
Evaluation of pharmacokinetics and safety profile of
Nirsevimab before initiating a clinical study in infants
Phase 1b/2a2 NCT02290340 “1st Time in Healthy Preterm Infants”

Healthy preterm infants 32-35 wGA (n=89)
Evaluation of pharmacokinetics and safety profile of Nirsevimab in healthy preterm infants

Pivotal clinical trials

2016 Phase 2b3 NCT02878330 “Infants not eligible to receive Palivizumab as per AAP / other guidelines”

Healthy preterm infants in healthy infants 29-34 weeks 6 days wGA (n=1453)
Evaluation of nirsevimab for the prevention of RSV-associated lower respiratory tract infection in healthy infants
2019 Phase 34,5
NCT03979313

Healthy late preterm and term infants ≥ 35 wGA (n=3012)
Evaluation of efficacy and safety of nirsevimab in healthy late-preterm and term infants entering their first RSV season

Due to COVID-19, no RSV cases were observed. Therefore, a joint decision with health authorities was taken to analyze the primary endpoint (primary cohort). MELODY trial restarted to further characterize nirsevimab safety in this population (secondary cohort)

2019 Phase 2/36-8
NCT03959488		 ‘MEDLEY’
Preterm cohort
(n=615)
Evaluation of safety of nirsevimab in preterm infants with OR without CHD or CLD of prematurity
2019
CHD/CLD cohort
(n=310)		 Season 2† (n=262)
2020 Phase 29,31
NCT04484935		 ‘MUSIC’

Immunocompromised children who are ≤ 24 months of age at the time of dose administration. (n=100)
Evaluation of safety and tolerability, for nirsevimab in immunocompromised children
2022 Phase 3b10
NCT05437510		 ‘HARMONIE’

Healthy infants ≥29 wGA not eligible for palivizumab (n=8058)
Determination of efficacy and safety of nirsevimab for the prevention of hospitalizations due to RSV-LRTI in all palivizumab ineligible infants under 12 months

Key results from the clinical development program of nirsevimabs

Safety

Nirsevimab (N=3580): Favorable Safety Profile Across All Infants in pivotal studies
  Ph2b3
29-<35 wGA		 MELODY4
≥35 wGA		 MEDLEY First season6
Preterm CHD/CLD
Variables Placebo (N=479) Nirsevimab (N=968) Placebo (N=996) Nirsevimab (N=1998) Palivizumab (N=206) Nirsevimab (N=406) Palivizumab (N=98) Nirsevimab (N=208)
Serious adverse events 16.9% 11.2% 7.4% 6.3% 5.3% 6.9% 20.4% 19.2%
Adverse events of Grade 3 or higher 12.5% 8.0% 3.8% 3.1% 3.4 3.4% 13.3% 14.4%
Adverse events of special interest (AESI) 0.6% 0.5% 0.0% 0.2% 0.0% 0.2% 0.0% 0.5%
Deaths 3 2 0 4 0 2 1 3
  • None of the serious adverse events or deaths were considered as related to nirsevimab
  • Overall, incidence of nirsevimab antidrug antibody was low across studies with no safety concerns
    • MELODY: Four AESI cases of hypersensitivity limited to cutaneous signs and symptoms
    • MEDLEY: 2 AESIs (nirsevimab arm): Maculopapular rash (preterm cohort) 92 days post nirsevimab dose and heparin-induced thrombocytopenia (CHD/CLD cohort) unrelated to treatment
Clinical experience of nirsevimab continues with HARMONIE, MUSIC, and MELODY
  HARMONIE10,11 MUSIC9 MEDLEY Second season12
CHD/CLD
Variables No intervention (N=4020) Nirsevimab (N=4016) Nirsevimab (N=100) P/P (N=42) P/N (N=40) N/N (N=180)
Serious adverse events 1.7% 2.2% 30% 0% 10% 9.4%
Adverse events of Grade 3 or higher 1.1% 1.2% 31.7 2.4% 10% 7.8%
Adverse events of special interest (AESI) <0.1 <0.1 6.7% 0% 0.0% 0%
Deaths 0 0 1 0 0 0
  • Overall incidence of adverse events (AEs)13,14
    • Serious AEs and treatment-related AEs were balanced between Nirsevimab and placebo groups
    • No anaphylaxis or other serious allergic reactions
    • No thrombocytopenia attributed to study drug
    • No immune complex disease
  • Nonserious cutaneous hypersensibility reactions occurred in 0.2% of nirsevimab recipients
  • Levels of ADA were low
  • Incidence of deaths were low and similar between groups
    • None were considered treatment-related

Key results from the clinical development program

Phase
1a1		 Nirsevimab administration resulted in a 4X increase in neutralizing antibodies persisting until day 181
(ranging from 50% in 100 mg IM cohort to 83% in 3000 mg IV cohort)
Phase
1b/2a2		 The extended half-life and the demonstrated RSV-neutralizing activity supported the potential for protection against RSV
disease for the duration of a typical 5-month season with a single 50 mg IM dose of nirsevimab

Consistent efficacy against RSV-LRTI and associated hospitalizations

  RSV
MA-LRTI		 RSV LRTI
Hospitalization		 RSV Very severe
MA-LRTI		 All Cause LRTI
Hospitalization		 All Cause
MA-LRTI
Phase 2b3,15
(95% CI, 52.3-81.2)
(95% CI, 51.9-90.3)
(95% CI, 62.9, 95.8)
(95% CI, 16.3-60.5)
(95% CI, 7.1-37.0)

(95% CI, 62.3–85.2)
(95% CI, 49.4–89.4)
(95% CI, 48.8–91.0)
(95% CI, 6.3-60.2)
(95% CI, 23.7-50.0)
Phase 2b
+

(Pooled)5


(95% CI, 68.5-86.1)
(95% CI, 62.3-90.1)
(95% CI, 68.1-94.0)		    
 
(95% CI, 67.7-92.0)
(95% CI, 32.8-92.9)
(95% CI, 39.7-71.2)		  

 

All infants need protection from RSV16-21.
Nirsevimab is designed to provide protection for all infants
for the length of typical RSV season with a single dose3,22.
Nirsevimab has demonstrated an efficacy of 79% against RSV-MA-LRTI
(MELODY/Ph2b pooled), and 83% against hospitalizations (HARMONIE), for 150 days5,10.
Nirsevimab is the first-in-class and only prevention strategy approved by FDA and EMA
and is designed to protect all infants from RSV-LRTI in their first RSV season23-25.

Regulatory approvals

NITAGs Recommend Nirsevimab for All Infants

Advisory Committee on Immunization Practices28

  • First RSV Season: All infants below 8 months of age
  • Second RSV Season: Infants and children (8-19 months) at increased risk of severe RSV disease

Haute Autorité de santé29

  • First RSV Season: All infants with reimbursements

inisterio de Sanidad30

  • First RSV Season: All infants below 6 months of age
  • Second RSV Season: High risk under 24 months

Abbreviations

AAP: American Academy of Paediatrics; AESI: adverse event of special interest; CHD: Chronic Heart Disease; CLD: Chronic Ling Disease; FDA: Food and Drug Administration; EMA: European Medicines Agency; IM: Intramuscular; IV: Intravenous; LRTI: lower respiratory tract infection; RSV: respiratory syncytial virus; wGA: weeks of gestational age.

Useful Links

    1. Griffin MP, et al. Antimicrob Agents Chemother. 2017;61(3):e01714-16.
    2. Domachowske JB, et al. Pediatr Infect Dis J. 2018;37(9):886-892.
    3. Griffin MP, et al; N Engl J Med. 2020;383(5):415-425.
    4. Muller WJ, et al. N Engl J Med. 2023;388(16):1533-1534.
    5. Nirsevimab for the prevention of RSV in all infants Accessed October 2023.
    6. Domachowske J, et al. N Engl J Med. 2022;386(9):892-894.
    7. NCT03959488. Accessed October 2023.
    8. Domachowske JB. et al. ReSViNET’s 7th Conference (RSVVW 2023), 22- 24 February 2023.
    9. Mori et al. Asian Congress of Pediatric Infectious Diseases, 26-28 October 2022, Seoul, Korea.
    10. SB Drysdale, A Phase 3 randomized open-label study of nirsevimab (versus no intervention) in preventing hospitalizations due to respiratory syncytial virus (RSV) in infants (HARMONIE). ESPID 2023: Lisbon, Portugal.
    11. SN Faust, (2023, Oct 10-15th). The Impact of Nirsevimab on an RSV Season in All Infants: Data From The HARMONIE Study [Oral presentation]. ID Week 2023 Boston, MA, USA
    12. Domachowske JB, et al. J Pediatric Infect Dis Soc. 2023;12(8):477-480.
    13. Beyfortus. Summary of Product Characteristics. November 2022.
    14. Mankad V. Comprehensive summary of all safety data of nirsevimab in healthy infants: experience to date from pivotal trials. ESPID 2023 (May 8–12, 2023); Lisbon, Portugal.
    15. Muller WJ. Safety and efficacy of nirsevimab for prevention of medically attended RSV lower respiratory tract infection in all infants enrolled in the phase 3 melody trial [Oral presentation]. RSVVW 2023: Lisbon, Portugal. (February 22–24, 2023) : Lisbon, Portugal.
    16. Leader S, et al. Pediatr Infect Dis J. 2002;21(7):629-632.
    17. Karron R. Plotkin’s Vaccines. 7th ed. Philadelphia, PA : Elsevier;2018:943- 949.
    18. Glezen WP, et al. Am J Dis Child. 1986;140(6):543-546.
    19. Hall CB, et al. N Engl J Med. 2009;360(6):588-598.
    20. Hall CB, et al. Pediatrics. 2013;132(2):e341-e348.
    21. Rha B, et al. Pediatrics. 2020;146(1):e20193611.
    22. Hammitt LL, et al. N Engl J Med. 2022;386(9):837-846.
    23. Sanofi presentation to US Advisory Committee on Immunization Practices. 20 October 2022. Accessed October 2023.
    24. FDA approves Beyfortus™(nirsevimab-alip) to protect infants against RSV disease. Accessed October 2023.
    25. European Medicines Agency. Nirsevimab. EMEA/H/C/005304. Accessed October 2023.
    26. Medicines & Healthcare products Regulatory Agency (MHRA). MHRA- 100067-PIP01-21-M01. Accessed October 2023.
    27. Health Canada approves BEYFORTUS™ (nirsevimab) for the prevention of RSV disease in infants Accessed October 2023.
    28. Jones JM, et al. MMWR Morb Mortal Wkly Rep. 2023;72(34):920-925.
    29. HAS | BEYFORTUS (nirsevimab) - Respiratory syncytial virus Accessed October 2023.
    30. Recomendaciones de utilización de nirsevimab frente a virus respiratorio sincitial para la temporada 2023-2024 Accessed October 2023.
    31. History of Changes for Study - NCT04484935 Accessed October 2023.

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