Safety of Re-dosing Nirsevimab Prior to RSV Season 2 in Children With Heart or Lung Disease

Abstract In children with congenital heart disease and/or chronic lung disease entering their second respiratory syncytial virus (RSV) season, 200 mg nirsevimab had a similar safety profile to that of palivizumab and resulted in nirsevimab serum exposures associated with efficacy in healthy infants, supporting efficacy in this population at risk of severe RSV disease.

Nirsevimab, a monoclonal antibody with an extended halflife, has been developed to protect infants against lower respiratory tract infection due to respiratory syncytial virus (RSV) [1,2].Following a single dose of nirsevimab before the first RSV season, efficacy was demonstrated and safety described in otherwise healthy preterm infants in the Phase 2b (≥29 to <35 weeks gestational age [GA]) and Phase 3 MELODY (≥35 weeks GA) trials [3][4][5].Extrapolation of efficacy based on pharmacokinetics (PK) is an established means of extending label claims to other populations [6].Based on the mechanism of action of nirsevimab, efficacy was extrapolated to infants with congenital heart disease (CHD), chronic lung disease of prematurity (CLD), and those born extremely preterm [7] in the Phase 2/3 MEDLEY trial (NCT03959488) [8].Furthermore, the nirsevimab safety profile was similar to that of palivizumab during the first RSV season in MEDLEY [8].Here we report the safety and PK extrapolation of efficacy among children with CHD or CLD following administration of a second nirsevimab dose prior to their second RSV season.

METHODS
The methodology of the MEDLEY trial has been described previously [8].In brief, infants were required to be eligible to receive palivizumab in accordance with local or national guidelines; eligibility for participation in a second season was restricted to infants with CHD or CLD in accordance with these guidelines.Before their first RSV season, participants were randomly assigned to receive nirsevimab in a single intramuscular dose of 50 mg (if weight <5 kg) or 100 mg (if weight ≥5 kg), followed by four once-monthly doses of placebo, or five once-monthly intramuscular doses of palivizumab (15 mg/ kg weight per dose) (Supplementary Figure 1).Prior to the second season, participants with CHD or CLD randomized to nirsevimab before the first season received 200 mg nirsevimab followed by four once-monthly doses of placebo (N/N); those randomized to palivizumab were re-randomized 1:1 to either 200 mg nirsevimab followed by four once-monthly doses of placebo (P/N) or five once-monthly intramuscular doses of palivizumab (15 mg/kg weight per dose) (P/P).Adverse events (AEs), antidrug antibodies (ADA), and nirsevimab serum concentrations were assessed through 360 days post first Season 2 dose, representing the active nirsevimab dose for the P/N and N/N groups and the first of five active palivizumab doses for the P/P group.PK was evaluated, and area under the curve data were derived, as previously described [7].The success criterion for PK extrapolation was 80% of participants achieving the previously defined nirsevimab exposure target associated with efficacy (12.8 day•mg/mL) [7].AEs of special interest (Type I hypersensitivity [including anaphylaxis], immune complex disease, and thrombocytopenia) were assessed by investigators.Data from an interim analysis are presented, including safety, ADA, and PK evaluation ≥150 days post first Season 2 dose (corresponding to a typical 5-month RSV season).Data for this analysis were collected from July 28, 2020-April 30, 2022.The safety analysis included an assessment of AEs through 30 days post first dose to permit an evaluation of AEs relative to receiving nirsevimab compared with one palivizumab dose.

RESULTS
Of 310 participants with CHD/CLD enrolled prior to the first season, 262 continued to the second season (42 P/P, 40 P/N, 180 N/N) and 252 completed ≥150 days follow-up, post first Season 2 dose (Supplementary Figure 2).The characteristics of children continuing to Season 2 were similar between treatment groups (Table 1).The incidence of AEs during the second season was similar across treatment groups (P/P: 29 [69.0%];P/N: 29 [72.5%];N/N: 126 [70.0%]), with no deaths or AEs of special interest reported (Table 2).The overall incidence of serious AEs and AEs of Grade 3 or greater severity was numerically higher among P/N and N/N recipients than P/P recipients (Table 2); these events were primarily due to infections or were related to underlying comorbid conditions and no trends or safety concerns were identified (Supplementary Tables 1 and 2).Within 30 days post first Season 2 dose, the incidence of serious AEs Prior to the second season, children with CHD/CLD randomized to nirsevimab in the first season received 200 mg nirsevimab followed by four once-monthly doses of placebo (N/N) and those randomized to palivizumab in the first season were re-randomized 1:1 to either 200 mg nirsevimab followed by four once-monthly doses of placebo (P/N) or five once-monthly intramuscular doses of palivizumab (15 mg/kg of body weight per dose) (P/P).The primary cardiac lesion as reported by the investigator is provided for participants with CHD; percentage of participants with specific lesions are calculated using the total number of participants with CHD as the denominator.
Abbreviations: CHD, congenital heart disease; CLD, chronic lung disease of prematurity; ITT, intent-to-treat; LPA, left pulmonary artery; N, nirsevimab; P, palivizumab; PDA, patent ductus arteriosus; RPA, right pulmonary artery; TGA, transposition of the great arteries; VSD, ventricular septal defect.and AEs of Grade 3 or greater severity was similar among the three treatment groups (Table 2).The incidence of AEs post first Season 2 dose by time relative to any dose was also similar (Supplementary Tables 3 and 4).
The ADA incidence was low in participants who received N/N, occurring in 1/90 participants (1.1%) at Day 31 and in 0/158 participants at Day 151; no participant with post baseline ADA in the first season had detectable ADA in the second season.The PK exposure target for efficacy extrapolation was met, with 98% of participants achieving target serum AUCs across the P/N and N/N treatment groups.No RSV lower respiratory tract infections occurred through Day 151.

DISCUSSION
In this study of children with CLD/CHD entering their second RSV season, the safety profile observed was favorable for nirsevimab and similar to that of palivizumab.Additionally, a second dose of nirsevimab was associated with a low incidence of ADA, and no Type I hypersensitivity was observed with re-exposure, including among participants who were ADA positive at the end of Season 1.
Participants with CHD/CLD who received a 200 mg dose of nirsevimab before their second RSV season achieved nirsevimab serum exposures known to be efficacious in preventing MA RSV LRTI in healthy term and preterm infants.Efficacy is, therefore, expected for children with CHD/CLD entering their second season.
One limitation is that the re-randomization of the palivizumab recipients in the first season meant that the P/P and P/N groups were relatively small.In addition, the trial enrolled and collected safety data during the coronavirus disease 2019 pandemic, which is known to have affected RSV circulation.Given the unpredictable situation in the face of the pandemic and the primary objective of the study being safety, it was decided to continue with the study as planned using historical conventions of seasonality in the respective regions where infants were enrolled (all but 4 of the 262  Prior to the second season, children with CHD/CLD randomized to nirsevimab in the first season received 200 mg nirsevimab followed by four once-monthly doses of placebo (N/N) and those randomized to palivizumab in the first season were re-randomized 1:1 to either 200 mg nirsevimab followed by four once-monthly doses of placebo (P/N) or five once-monthly intramuscular doses of palivizumab (15 mg per kilogram of body weight per dose) (P/P).Adverse events were coded by MedDRA Version 23.1 or higher, unless otherwise stated.There were no treatment-related serious adverse events or serious adverse events of Grade 3 or greater severity.
a Relative to the active nirsevimab dose for P/N and N/N groups and to the first of 5 active doses for the P/P group.
Participants with multiple events in the same category were counted once in that category; participants with events in >1 category were counted once in each of those categories.
c An adverse event of Grade 3 denotes a severe event, an adverse event of Grade 4 a life-threatening event, and an adverse event of Grade 5 a fatal event.
d Serious adverse event criteria: death, life-threatening, required inpatient hospitalization, prolongation of existing hospitalization, persistent or significant disability/incapacity, important medical event, congenital anomaly/birth defect.
e Includes Type I hypersensitivity (including anaphylaxis), immune complex disease, and thrombocytopenia.
f COVID-19-related adverse events were symptomatic or asymptomatic COVID-19 cases with a confirmatory diagnostic test positive for severe acute respiratory syndrome coronavirus 2 or suspected cases for which signs and symptoms were judged by the investigator to be highly suspicious for COVID-19 but for which a confirmatory diagnostic test was unavailable or negative.

a
Includes one participant with Down syndrome without CLD or CHD.b Participants with both CHD and CLD (n = 9; 1 in the P/P group, 8 in the N/N group) are counted in both the CLD and CHD subpopulations.