Nirsevimab : Clinical Experience

Study Design

Preclinical trials

2014	Phase 1a¹ NCT02114268	*“1^st Time in Healthy Adults”*	Phase 1b/2a² NCT02290340	*“1^stTime 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 3^4,5 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 2/3^6-8 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 2^9,31 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 3^b10 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
	Ph2b³ 29-<35 wGA		MELODY⁴ ≥35 wGA		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

	HARMONIE^10,11		MUSIC⁹	MEDLEY Second season¹²
	HARMONIE^10,11		MUSIC⁹	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	31.7	10%	7.8%
Adverse events of special interest (AESI)	<0.1	<0.1	6.7%	6.7%	0.0%	0%
Deaths	0	0	1	1	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 2b^3,15	(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 RSV^16-21.
	Nirsevimab is designed to provide protection for all infants for the length of typical RSV season with a single dose^3,22.
	Nirsevimab has demonstrated an efficacy of 79% against RSV-MA-LRTI (MELODY/Ph2b pooled), and 83% against hospitalizations (HARMONIE), for 150 days^5,10.
	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 season^23-25.

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

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.

Griffin MP, et al. Antimicrob Agents Chemother. 2017;61(3):e01714-16.
Domachowske JB, et al. Pediatr Infect Dis J. 2018;37(9):886-892.
Griffin MP, et al; N Engl J Med. 2020;383(5):415-425.
Muller WJ, et al. N Engl J Med. 2023;388(16):1533-1534.
Nirsevimab for the prevention of RSV in all infants Accessed October 2023.
Domachowske J, et al. N Engl J Med. 2022;386(9):892-894.
NCT03959488. Accessed October 2023.
Domachowske JB. et al. ReSViNET’s 7th Conference (RSVVW 2023), 22- 24 February 2023.
Mori et al. Asian Congress of Pediatric Infectious Diseases, 26-28 October 2022, Seoul, Korea.
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.
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
Domachowske JB, et al. J Pediatric Infect Dis Soc. 2023;12(8):477-480.
Beyfortus. Summary of Product Characteristics. November 2022.
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.
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.
Leader S, et al. Pediatr Infect Dis J. 2002;21(7):629-632.
Karron R. Plotkin’s Vaccines. 7th ed. Philadelphia, PA : Elsevier;2018:943- 949.
Glezen WP, et al. Am J Dis Child. 1986;140(6):543-546.
Hall CB, et al. N Engl J Med. 2009;360(6):588-598.
Hall CB, et al. Pediatrics. 2013;132(2):e341-e348.
Rha B, et al. Pediatrics. 2020;146(1):e20193611.
Hammitt LL, et al. N Engl J Med. 2022;386(9):837-846.
Sanofi presentation to US Advisory Committee on Immunization Practices. 20 October 2022. Accessed October 2023.
FDA approves Beyfortus™(nirsevimab-alip) to protect infants against RSV disease. Accessed October 2023.
European Medicines Agency. Nirsevimab. EMEA/H/C/005304. Accessed October 2023.
Medicines & Healthcare products Regulatory Agency (MHRA). MHRA- 100067-PIP01-21-M01. Accessed October 2023.
Health Canada approves BEYFORTUS™ (nirsevimab) for the prevention of RSV disease in infants Accessed October 2023.
Jones JM, et al. MMWR Morb Mortal Wkly Rep. 2023;72(34):920-925.
HAS | BEYFORTUS (nirsevimab) - Respiratory syncytial virus Accessed October 2023.
Recomendaciones de utilización de nirsevimab frente a virus respiratorio sincitial para la temporada 2023-2024 Accessed October 2023.
History of Changes for Study - NCT04484935 Accessed October 2023.