RSV Management with Nirsevimab:

Singing a New MELODY

Emily Harvath, PharmD
PGY1 Pharmacy Resident
Conflict of Interests
I have no actual or potential conflict of interest in relation to this
presentation​

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Accessing CE
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Objectives
Demonstrate appropriate prevention strategies for RSV based on
current recommendations
Compare benefits of using palivizumab versus nirsevimab
Evaluate potential impact of nirsevimab on current practice

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 Respiratory Syncytial Virus (RSV) Background
Most common cause of bronchiolitis & pneumonia in children <1
Treatment is primarily supportive care
High Risk Populations:
Age <1 Age <2
Born <29 weeks gestation Chronic Lung Disease

Born <32 weeks gestation Immunocompromised

with chronic lung disease

Congenital Heart Disease

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Centers for Disease Control. Updated October 24, 2022. https://www.cdc.gov/rsv/about/symptoms.html
Riley PAS Prescriber Guidance Palivizumab 2020-2021. Available at team.myiuhealth.org
 RSV Season Duration and Peak
2015-2016

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Centers for Disease Control and Prevention. MMWR. 2018;67(2):71–76.
 RSV Landscape Post-COVID
Winter 2020-2021
Summer 2021
Reduction in RSV
Winter 2021-2022
Atypical RSV
Cases 99% lower surge Reduced activity
than expected in compared to
England pre-pandemic RSV
seasons

*Potential risk of immunity debt as restrictions are lifted

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Bardsley et al. Lancet Infect Dis. 2023 Jan;23(1):56-66.
Garg et al. Infect Dis Rep. 2022 Jul 24;14(4):558-568.
Current RSV Management

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 Palivizumab (Synagis®)
Humanized monoclonal antibody
Binds to the F-protein of RSV, preventing the virus from binding to
host cells
Recommended Dose: 15 mg/kg given monthly by intramuscular
injection
Common Adverse Reactions: fever, rash

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Palivizumab. Package insert. Swedish Orphan Biovitrum AB; 2021.
 Palivizumab Studies
IMpact-RSV, 1998
• Population: ≤6 months & GA ≤35 weeks, or ≤2 years & BPD
• Endpoint: Hospitalization with RSV(+) antigen test
• Results: 55% reduction in hospitalization (P=0.00004)

Feltes et al, 2003

• Population: Infants with congenital heart disease
• Endpoint: Hospitalization with RSV(+) antigen test
• Results: 45% relative reduction in hospitalization (P=0.003)
Feltes et al. J Pediatr. 2003 Oct;143(4):532-40. 10
The IMpact-RSV Study Group. Pediatrics. 1998 Sep;102(3 Pt 1):531-7.
 American Academy of Pediatrics Recommendations

Eligible for Max of 5 doses Eligible for Max of 3 doses

<2 years with CLD GA 32+0 through 34+6 with 1
risk factor, born 3 months
<2 years with CHD
before or during
9/2/2021 Update: Strongly supports consideration ofRSV season during
palivizumab
Premature Infants interseasonal RSV spread
Neuromuscular disease or
airway abnormalities

Chronic Lung Disease (CLD), Congenital Heart Disease (CHD), Gestational Age (GA)

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Committee on Infectious Diseases. Pediatrics. 2009;124(6):1694–1701.
Updated Guidance: Use of Palivizumab Prophylaxis During 2021-2022 RSV Season. www.aap.org
Learning Assessment Question 1
Which of these patients qualifies for palivizumab?

A. 1 yoF with hypoplastic left heart syndrome

B. 2 yoM born at GA 31+2
C. 2 month old born at GA 38+0
D. 3 yoF with seizure disorder

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Nirsevimab

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 Nirsevimab (Beyfortus®)
Recombinant human monoclonal antibody with similar mechanism
on F protein of RSV
Shows greater potency at inhibiting RSV than palivizumab in vitro
Fc region engineered to have extended half-life in vivo
Given as a single dose of intramuscular injection
Studied Dose:
Patients <5 kg: 50mg
Patients ≥5 kg: 100mg
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Hammit et al; MELODY Study Group. N Engl J Med. 2022 Mar 3;386(9):837-846.
 Safety and Tolerability Studies
No treatment-associated serious adverse events
Aliprantis et al – healthy adult patients
Mean half-life 73 to 88 days
Serum neutralizing antibodies peaked at 14 days
Domachowske et al – healthy preterm infants
Estimated half-life 62.5-72.9 days
20/71 patients developed anti-drug antibodies
⎻No difference in drug concentrations
Aliprantis et al. Clin Pharmacol Drug Dev. 2021 May;10(5):556-566. 15
Domachowske et al. Pediatr Infect Dis J. 2018 Sep;37(9):886-892.
 Nirsevimab in Preterm Infants
Randomized, placebo-controlled trial
• Included: healthy, <1 year old, born preterm
• Excluded: meets criteria for or received palivizumab
Patients • Enrolled Nov 2016 - Dec 2017

• Primary: Medically attended RSV-associated LRTI*

• Secondary: Hospitalization for RSV-associated LRTI*
Endpoints
*LRTI = Lower Respiratory Tract
Infection
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Griffin et al. N Engl J Med 2020; 383: 415-25.
 Nirsevimab in Preterm Infants
Medically attended RSV-associated LRTI occurred in 2.6% of
nirsevimab group & 9.5% of placebo group
70.1% relative difference (95% CI 52.3 to 81.2; P<0.001)
Hospitalization for this condition occurred in 0.8% of nirsevimab
group & 4.1% of placebo group
72.9% relative difference (95% CI 56.5 to 83.1; P<0.001)
5 patients admitted to PICU for RSV – all placebo group
Adverse events related to study drug:
Rash (4 patients) and petechiae (1 patient) 17
Griffin et al. N Engl J Med 2020; 383: 415-25.
 Nirsevimab in Term Infants – MELODY Trial
Randomized, double blind, placebo-controlled, Phase III Clinical
Trial

Patient Population Endpoints

Included: Healthy Infants <1 Primary: Medically attended

year old, born at ≥GA 35 weeks RSV-associated LRTI

Excluded: meets criteria for or Secondary: Hospitalization due

has received palivizumab to RSV-associated LRTI
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Hammit et al; MELODY Study Group. N Engl J Med. 2022 Mar 3;386(9):837-846.
 MELODY Trial Outcomes
• Medically-attended RSV-associated LRTI in 12/994
nirsevimab patients (1.2%) vs 25/496 placebo patients
Primary (5.0%)
• Efficacy of 74.5% (95% CI 49.6 to 87.1; P<0.001)
• NNT = 27

• Hospitalization for RSV-associated LRTI in 6/994

nirsevimab patients (0.6%) vs 8/496 placebo patients
Secondary (1.6%)
• Efficacy 62.1% (95% CI -8.6 to 86.8; P=0.07)
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Hammit et al; MELODY Study Group. N Engl J Med. 2022 Mar 3;386(9):837-846.
 MELODY Trial Additional Outcomes
Northern hemisphere: 1,027 patients, 2019-2020 RSV season
Southern Hemisphere: 462 patients, 2020 RSV season
0/462 had primary outcome event
Safety
Serious adverse events: 6.8% nirsevimab and 7.3% placebo
None considered associated with study treatment
Pharmacokinetics
All infants had nirsevimab levels associated with protection at
Day 151 20
Hammit et al; MELODY Study Group. N Engl J Med. 2022 Mar 3;386(9):837-846.
Learning Assessment Question 2
In healthy term infants, single-dose nirsevimab has
been found to:
A. Significantly reduce hospitalization for RSV-associated LRTI
B. Cause severe adverse events in many patients
C. Significantly reduce medically-attended RSV-associated
LRTI
D. Result in nirsevimab levels that were too low to provide
efficacy
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 Kiefer 2022 Journal of Infectious Diseases
pharmacoeconomic study (US data)
Modeled US birth cohort to estimate nirsevimab impact on RSV
outcomes and cost
Based on uptake rates of:
71% in term/preterm infants
80% in palivizumab-eligible infants
Outcome (annual) Standard of Care Nirsevimab
Medically-attended LRTI 529,915 cases 239,741 cases
Hospitalizations 47,281 cases 22,295 cases
Economic Burden $1.2 billion $588 million 22
Kieffer et al. J Infect Dis. 2022 Aug 15;226(Suppl 2):S282-S292. doi: 10.1093/infdis/jiac216.
Palivizumab vs Nirsevimab
Palivizumab Nirsevimab
5 monthly doses Single dose
Primary endpoint – Primary endpoint – Medically-
RSV hospitalization attended RSV LRTI
Population recommendations Potential utility in healthy,
term infants
Cost: $3,947.86 per Potentially significant cost
100mg/mL savings
Insurance Coverage Unknown
Difficulties
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Learning Assessment Question 3
Which of the following is a potential advantage of
nirsevimab over palivizumab?
A. Affordability
B. Improved efficacy compared to palivizumab
C. Efficacy for hospitalization reduction in term infants
D. Single-dose administration

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Future Directions

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 Nirsevimab in Heart or Lung Disease - MEDLEY
Ongoing phase 2-3 trial
Patient Population:
MidpointPreterm infants, eligibleRSV
Medically-Attended for palivizumab
LRTIs
Cohorts with and
Nirsevimab without CHD or
Group CLD(0.6%)
4/616
Treatment Groups:
Palivizumab nirsevimab vs palivizumab
Group 3/309 (1.0%)
Midpoint Safety Analysis:
Adverse event incidence similar across treatment groups
Events of interest in nirsevimab group:
⎻Heparin-induced thrombocytopenia (1 patient)
⎻Maculopapular rash after placebo (1 patient) 26
Domachowske et al. MEDLEY Study Group. N Engl J Med. 2022 Mar 3;386(9):892-894.
Nirsevimab in All Infants - HARMONIE
Currently ongoing Phase 3 trial
Patient Population: Age <12 months & don’t qualify for
palivizumab
Estimated enrollment: 28,860 participants
Treatment Groups: Nirsevimab vs placebo
Primary Endpoint: hospitalization for RSV LRTI

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Nirsevimab in Immunocompromise (NCT04484935)
Currently ongoing Phase 2 trial, evaluating safety & efficacy
Patient Population: Age <2 years & immunosuppressed
Treatment Group: Nirsevimab
50-100mg if 1st RSV season
200mg if 2nd RSV season
Primary Endpoint: safety & tolerability of nirsevimab

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Anticipated Application to Practice
Nirsevimab may provide benefit for a population previously
ineligible for palivizumab
Increased convenience with nirsevimab – single dose
Cost comparisons unknown
Potential difficulty with buy-in from providers and patient family
May feel that a “healthy” infant isn’t at high enough risk for
severe RSV to warrant
Outcomes from MEDLEY will likely help identify place in therapy
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RSV Management with Nirsevimab:
Singing a New MELODY
Emily Harvath, PharmD
PGY1 Pharmacy Resident