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Nirsevimab : Clinical Experience

Study Design

Preclinical trials

2014 Phase 1a1
NCT02114268		 “1st Time in Healthy Adults” Phase 1b/2a2
NCT02290340		 “1stTime in Healthy Preterm Infants”

Healthy adults aged 18 to 49 years (n=136)

 Healthy preterm infants 32-35 wGA (n=89)
Evaluation of pharmacokinetics and safety profile of Nirsevimab before initiating a clinical study in infants 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” Evaluation of nirsevimab for the prevention of RSV-associated lower respiratory tract infection in healthy infants
Healthy preterm infants in healthy infants 29-34 weeks 6 days wGA (n=1453)
2019 Phase 34,5
NCT03979313		 Evaluation of efficacy and safety of nirsevimab in healthy late-preterm and term infants entering their first RSV season
Healthy late preterm and term infants ≥ 35 wGA (n=3012)

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’ Evaluation of safety of nirsevimab in preterm infants with OR without CHD or CLD of prematurity
Preterm cohort
(n=615)
2019 CHD/CLD cohort
(n=310)		 Season 2† (n=262)
2020 Phase 29,31
NCT04484935		 ‘MUSIC’ Evaluation of safety and tolerability, for nirsevimab in immunocompromised children
Immunocompromised children who are ≤ 24 months of age at the time of dose administration. (n=100)
2022 Phase 3b10
NCT05437510		 ‘HARMONIE’ Determination of efficacy and safety of nirsevimab for the prevention of hospitalizations due to RSV-LRTI in all palivizumab ineligible infants under 12 months
Healthy infants ≥29 wGA not eligible for palivizumab (n=8058)

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

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

References

  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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