Immunocompromised children may have increased risk for severe respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI), potentially leading to prolonged hospitalization, intensive care, and death. The open-label phase II MUSIC trial evaluated the safety and pharmacokinetics of nirsevimab, an extended half-life monoclonal antibody against RSV, in immunocompromised children aged ≤24 months.
Participants received a single intramuscular injection of nirsevimab (first RSV season: 50 mg if <5 kg/100 mg if ≥5 kg; second season: 200 mg). Safety, antidrug antibodies, and pharmacokinetics were evaluated to day 361.
Participants (n = 100) had ≥1 immunocompromising conditions: primary immunodeficiency (n = 33), previous transplantation (n = 16), HIV infection (n = 8) or treatment with high-dose systemic corticosteroids (n = 29), immunosuppressive chemotherapy (n = 20), or other immunosuppressive therapies (n = 15). Six children experienced eight treatment-related adverse events (none categorized as serious). Three deaths occurred, all were unrelated to treatment. Eleven children, developed antidrug antibodies, with minimal effects on pharmacokinetics and no apparent impact on safety. Nirsevimab serum concentrations at day 151 were similar to those effective in preventing medically attended RSV LRTI in healthy infants. Fourteen children had increased nirsevimab clearance. No protocol-defined medically attended RSV LRTIs occured through day 151.
Among immunocompromised children aged ≤24 months, nirsevimab was well tolerated with no safety concerns and serum concentrations were supportive of efficacy. A subset of children with increased nirsevimab clearance, had conditions potentially associated with protein loss; however, the impact on efficacy is unknown.
What’s Known on This Subject:
Immunocompromised children may be at increased risk for severe respiratory syncytial virus lower respiratory tract infection, resulting in prolonged hospitalization, a need for intensive care with or without mechanical ventilation, and increased mortality compared with otherwise healthy children.
What This Study Adds:
When administered as a single dose to immunocompromised children aged ≤24 months, nirsevimab, an extended half-life monoclonal antibody against respiratory syncytial virus, was well tolerated, with no safety concerns over 360 days postdose and achieved serum concentrations supportive of efficacy.
Children who are immunocompromised because of congenital or acquired immunodeficiencies, transplantation, or immunosuppressive therapy may be at increased risk for severe outcomes of respiratory syncytial virus (RSV) infection1 including prolonged hospitalization, intensive care admission, and mechanical ventilation requirements, versus immunocompetent children.2–5 Furthermore, RSV-associated mortality rates can reach 10% in some children with immunodeficiencies, compared with <0.5% in otherwise healthy infants.2,6 Because children who are immunocompromised may be unable to develop immunologic memory, this increased risk may persist beyond their first RSV season.
Nirsevimab is an extended half-life recombinant human immunoglobulin G1 κ monoclonal antibody targeting the prefusion conformation of the RSV fusion protein.7 The extended half-life is a result of a triple amino acid substitution (M257Y/S259T/T261E [YTE]) in the Fc region, which increases the affinity to neonatal fragment crystallizable receptor, resulting in a >3-fold increase in half-life versus unmodified monoclonals.8,9 In a pooled analysis of healthy infants from the phase IIb (≥29 to <35 weeks’ gestational age [wGA], subset of infants <5 kg only)10 and phase III MELODY primary cohort (≥35 wGA, all infants)11,12 trials, the efficacy of nirsevimab against medically attended (MA) RSV lower respiratory tract infection (LRTI) was 79.5%.13 Moreover, in the phase II/III MEDLEY trial of infants with chronic heart disease, congenital lung disease or born <35 wGA,14,15 nirsevimab was found to have a safety profile similar to palivizumab and serum concentrations consistent with those observed in healthy infants in whom efficacy was established, thereby supporting extrapolation of efficacy.13 Nirsevimab is approved in the United States for the prevention of RSV lower respiratory tract disease in neonates and infants born during or entering their first RSV season and in children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season.16
Here, we present data from the MUSIC trial, a 12-month, phase II, open label trial of nirsevimab, designed to evaluate the safety, pharmacokinetics (PK), and emergence of antidrug antibodies (ADA) in children with immunocompromised states who remain vulnerable to severe RSV disease through their second RSV season.
Methods
Participants
Full inclusion and exclusion criteria can be found in Supplemental Information. Key inclusion criteria included children aged ≤24 months with ≥1 immunocompromising condition entering their first or second RSV season. Key exclusion criteria, intended to identify those eligible to receive palivizumab, included participants born ≤28 wGA and aged ≤12 months; born at 29–35 wGA and aged ≤6 months; or aged ≤24 months with a history of bronchopulmonary dysplasia and/or hemodynamically significant congenital heart disease that required medical management within the past 6 months.
Study Design
This was a 12-month, phase II, open-label, uncontrolled, single-dose trial of nirsevimab (Supplemental Fig 4). Participants received a single intramuscular injection of nirsevimab (study day 1; 0 days postdose) either when entering their first RSV season (50 mg if <5 kg or 100 mg if ≥5 kg) or when entering their second RSV season (all participants, 200 mg). The study began enrolling in Japan on August 19, 2020, before being amended to include global enrollment (Belgium, Poland, South Africa, Spain, United Kingdom, Ukraine, and the United States), starting in October 2021. The last participant’s last visit was February 17, 2023; analysis is based on the final database lock, April 18, 2023.
Endpoints
The primary objective was to evaluate the safety and tolerability of nirsevimab, including treatment emergent adverse events (AEs), serious AEs (SAEs), AEs of special interest (AESIs; immediate hypersensitivity [including anaphylaxis], immune complex disease [eg, vasculitis, endocarditis, neuritis, glomerulonephritis, serum sickness, arthralgias], or thrombocytopenia), and new-onset chronic disease (NOCDs), through 360 days postdose. AEs were graded by severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0, and coded according to the Medical Dictionary for Regulatory Activities, version 25.0.
Secondary endpoints included evaluation of nirsevimab PK and ADAs over 360 days postdose, along with incidence of MA RSV LRTI and hospitalization because of RSV LRTI over 150 days postdose (RSV positive by central or local reverse transcriptase polymerase chain reaction testing; see Supplemental Table 3 for protocol definition of RSV LRTI).
Exploratory endpoints included evaluation and correlation of total anti-RSV neutralizing antibody serum levels with nirsevimab serum concentration.
Nirsevimab Pharmacokinetics
Serum samples were collected before dosing; on days 8 (Japan only), 31, 151, and 361; and whenever participants required hospitalization for respiratory illnesses. Nirsevimab serum concentrations were measured using a validated enzyme-linked immunosorbent assay (MedImmune, Gaithersburg, MD, USA). Participants with ≥1 quantifiable PK sample were evaluated; the lower limit of quantification was 0.5 µg/mL.
Antidrug Antibodies
ADA assessments were performed using a validated electrochemiluminescence assay, as described previously.17
Neutralizing antibodies
RSV neutralizing antibody levels were measured using fluorescence-tagged recombinant RSV18 and quantified by interpolating from a serially diluted pooled serum reference standard curve calibrated to the First International World Health Organization RSV Reference Standard; RSV-National Institute for Biological Standards and Control 16/284.19,20
Statistical Analysis
No formal statistical comparisons were performed. AEs, SAEs, AESIs, and NOCDs were summarized using descriptive statistics. Categorical data were summarized by the number and percentage of participants in each category. Continuous variables were summarized by mean, median, SD, minimum, and maximum. Data analyses were conducted using the SAS System version 9.4 or higher (SAS Institute Inc, Cary, NC) in an SAS GRID environment.
PK data were summarized graphically and using descriptive statistics. Extrapolation of nirsevimab efficacy based on PK, with the assumption of a similar exposure–response relationship across pediatric populations, has been described previously.13 Nirsevimab serum concentrations on day 151 were compared with those in healthy infants in the MELODY trial.11
The percentage of ADA-positive participants were calculated using the number of participants with any ADA result at baseline and/or postbaseline during the trial as the denominator. Participants were considered ADA positive if they had a titer >50 at any time; missing ADA results were not imputed.
Ethics
The MUSIC trial was performed in accordance with the principles of the Declaration of Helsinki and the International Council for Harmonization Good Clinical Practice guidelines. Each site had approval from an institutional ethics review board or ethics committee, and appropriate written informed consent was obtained for each participant.
Results
Of 106 participants screened, 100 were enrolled from 8 countries (10 from Japan during 2020, 90 globally during 2021–2022; Table 1). Mean age at dosing was 13.0 months, with a median of 39.0 wGA at birth (range, 31.0 − 42.0 weeks); at the time of dosing, 46 (46%) participants were entering their first RSV season (aged <12 months; 7 were <5 kg and received 50 mg nirsevimab and 39 ≥ 5 kg and received 100 mg nirsevimab) and 54 (54%) were entering their second RSV season (aged ≥12 months; all were planned to receive 200 mg, but 2 participants received only 100 mg nirsevimab, both were <10 kg). Immunocompromising conditions included primary immunodeficiency (n = 33), systemic high-dose corticosteroid therapy (n = 29), immunosuppressive chemotherapy (n = 20), history of organ or bone marrow transplantation (n = 16), other immunosuppressive therapy (n = 15), and HIV infection (n = 8); some participants had >1 condition.
Demographics and Baseline Characteristics (as-Treated Population)
| Characteristic | Total (n = 100) | |
|---|---|---|
| Age at dosing | Mean months (SD) | 13.0 (6.2) |
| <12 mo, n (%) | 46 (46) | |
| ≥12 mo, n (%) | 54 (54) | |
| Sex, n (%) | Female | 35 (35) |
| Male | 65 (65) | |
| Weight group on day 1, n (%) | <5 kg (all 50 mg) | 7 (7) |
| ≥5 kg and <10 kg (n = 41, 100 mg; n = 26, 200 mga) | 67 (67) | |
| ≥10 kg (all 200 mg) | 26 (26) | |
| Gestational age | Median weeks (min−max) | 39.0 (31.0 − 42.0) |
| Race, n (%) | Asian | 28 (28) |
| American Indian or Alaskan Native | 1 (1) | |
| Black or African American | 20 (20) | |
| White | 45 (45) | |
| Other | 4 (4) | |
| Multiple categories | 2 (2) | |
| Ethnicity, n (%) | Not Hispanic or Latino | 93 (93) |
| Hispanic or Latino | 7 (7) | |
| Country of origin, n (%) | Belgium | 6 (6) |
| Japan | 26 (26) | |
| Poland | 3 (3) | |
| South Africa | 14 (14) | |
| Spain | 10 (10) | |
| Ukraine | 21 (21) | |
| United Kingdom | 1 (1) | |
| United States | 19 (19) | |
| Conditions of immunocompromise,bn (%) | Primary immunodeficiency | 33 (33) |
| Receiving systemic high-dose corticosteroid therapyc | 29 (29) | |
| Receiving immunosuppressive chemotherapy | 20 (20) | |
| History of solid organ or bone marrow transplantation | 16 (16) | |
| Receiving other immunosuppressive therapyd | 15 (15) | |
| HIV infectione | 8 (8) | |
| Characteristic | Total (n = 100) | |
|---|---|---|
| Age at dosing | Mean months (SD) | 13.0 (6.2) |
| <12 mo, n (%) | 46 (46) | |
| ≥12 mo, n (%) | 54 (54) | |
| Sex, n (%) | Female | 35 (35) |
| Male | 65 (65) | |
| Weight group on day 1, n (%) | <5 kg (all 50 mg) | 7 (7) |
| ≥5 kg and <10 kg (n = 41, 100 mg; n = 26, 200 mga) | 67 (67) | |
| ≥10 kg (all 200 mg) | 26 (26) | |
| Gestational age | Median weeks (min−max) | 39.0 (31.0 − 42.0) |
| Race, n (%) | Asian | 28 (28) |
| American Indian or Alaskan Native | 1 (1) | |
| Black or African American | 20 (20) | |
| White | 45 (45) | |
| Other | 4 (4) | |
| Multiple categories | 2 (2) | |
| Ethnicity, n (%) | Not Hispanic or Latino | 93 (93) |
| Hispanic or Latino | 7 (7) | |
| Country of origin, n (%) | Belgium | 6 (6) |
| Japan | 26 (26) | |
| Poland | 3 (3) | |
| South Africa | 14 (14) | |
| Spain | 10 (10) | |
| Ukraine | 21 (21) | |
| United Kingdom | 1 (1) | |
| United States | 19 (19) | |
| Conditions of immunocompromise,bn (%) | Primary immunodeficiency | 33 (33) |
| Receiving systemic high-dose corticosteroid therapyc | 29 (29) | |
| Receiving immunosuppressive chemotherapy | 20 (20) | |
| History of solid organ or bone marrow transplantation | 16 (16) | |
| Receiving other immunosuppressive therapyd | 15 (15) | |
| HIV infectione | 8 (8) | |
WHO, World Health Organization.
Two children aged ≥12 mo who were planned to receive 200 mg only received 100 mg; both were <10 kg.
Children may have been in >1 category of immunocompromising condition.
High-dose systemic corticosteroid therapy was defined as prednisone equivalent to ≥0.5 mg/kg every other day.
Comprised immunosuppressive therapies other than chemotherapy or systemic high-dose corticosteroid therapy (eg, azathioprine, methotrexate, mizoribine, mycophenolate mofetil, cyclophosphamide, cyclosporine, tacrolimus, cytokine inhibitors).
Based on WHO Clinical Staging of HIV/AIDS, six children were clinical Stage 1, one was Stage 3, and one was Stage 4.
Treatment-Emergent Adverse Events
Overall, 81 (81.0%) participants experienced ≥1 AE (Table 2). Six (6%) experienced ≥1 treatment-related AE, all of which were grade 1 or 2 severity. Thirty-five (35.0%) participants experienced ≥1 AE of grade ≥3, the majority of which occurred >30 days after dosing (24, 24.0%). Treatment-emergent AEs within 1 day of dosing were reported by 6 participants (pyrexia, n = 4; abdominal pain, n = 1; rash, n = 1; Supplemental Table 4). Within 30 days of dosing, AEs were reported by 54 participants, the most common of which (reported in ≥4% of participants) were pyrexia (n = 13), upper respiratory tract infection (n = 9), and vomiting (n = 8). Six participants experienced 8 treatment-related AEs (pyrexia, n = 4; abdominal pain, n = 1; erythema, n = 1; rash, n = 2); all were grade 1, except 1 event of grade 2 pyrexia that occurred within 7 days of dosing and resolved within 3 days of onset (Supplemental Table 5). Thirty-two (32.0%) participants experienced ≥1 SAE, and 31 (31.0%) experienced ≥1 SAE of grade ≥3 severity; no treatment-related SAEs or NOCDs were observed. Six AESIs were reported in 5 participants; all were grade 1 hypersensitivity events limited to cutaneous findings (food allergy, n = 2; contrast media allergy, n = 1; urticaria, n = 2; erythema, n = 1), with 1 considered treatment-related (erythema). Three deaths occurred as a result of non-RSV LRTI (an RSV test was negative; Gram-positive cocci were observed), septic shock (Klebsiella pneumoniae was isolated), and suspected tumor hemorrhage; these events were not considered to be related to treatment (see Supplemental Table 6 for case narratives).
Overall Summary of Adverse Events Through 360 Days Postdose (as-Treated Population)
| Participants witha | Number of participants (%) (N = 100) |
|---|---|
| ≥1 AE | 81 (81.0) |
| Within 1 d of dosing | 4 (4.0) |
| Within 3 d of dosing | 9 (9.0) |
| Within 7 d of dosing | 23 (23.0) |
| Within 14 d of dosing | 34 (34.0) |
| Within 30 d of dosing | 54 (54.0) |
| ≥1 treatment-related AE | 6 (6.0) |
| ≥1 AE of grade 3b severity or higher | 35 (35.0) |
| Within 1 d of dosing | 0 |
| Within 3 d of dosing | 1 (1.0) |
| Within 7 d of dosing | 6 (6.0) |
| Within 14 d of dosing | 8 (8.0) |
| Within 30 d of dosing | 11 (11.0) |
| ≥1 treatment-related AE of grade 3b severity or higher | 0 |
| Any AE with outcome death | 3 (3.0) |
| ≥1 SAEc | 32 (32.0) |
| ≥1 treatment-related SAEc | 0 |
| ≥1 SAEc of grade 3b severity or higher | 31 (31.0) |
| ≥1 treatment-related SAEc of grade 3b severity or higher | 0 |
| ≥1 AESId based on investigator assessment | 5 (5.0) |
| ≥1 treatment-related AESId based on investigator assessment | 1 (1.0) |
| ≥1 NOCD | 0 |
| Participants witha | Number of participants (%) (N = 100) |
|---|---|
| ≥1 AE | 81 (81.0) |
| Within 1 d of dosing | 4 (4.0) |
| Within 3 d of dosing | 9 (9.0) |
| Within 7 d of dosing | 23 (23.0) |
| Within 14 d of dosing | 34 (34.0) |
| Within 30 d of dosing | 54 (54.0) |
| ≥1 treatment-related AE | 6 (6.0) |
| ≥1 AE of grade 3b severity or higher | 35 (35.0) |
| Within 1 d of dosing | 0 |
| Within 3 d of dosing | 1 (1.0) |
| Within 7 d of dosing | 6 (6.0) |
| Within 14 d of dosing | 8 (8.0) |
| Within 30 d of dosing | 11 (11.0) |
| ≥1 treatment-related AE of grade 3b severity or higher | 0 |
| Any AE with outcome death | 3 (3.0) |
| ≥1 SAEc | 32 (32.0) |
| ≥1 treatment-related SAEc | 0 |
| ≥1 SAEc of grade 3b severity or higher | 31 (31.0) |
| ≥1 treatment-related SAEc of grade 3b severity or higher | 0 |
| ≥1 AESId based on investigator assessment | 5 (5.0) |
| ≥1 treatment-related AESId based on investigator assessment | 1 (1.0) |
| ≥1 NOCD | 0 |
Database lock: April 18, 2023. Severity of AEs was graded according to the National Cancer Center Institute Common Terminology Criteria for Adverse Events.
AE, adverse event; AESI, adverse events of special interest; NOCD, new-onset chronic disease; SAE, serious adverse event.
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.
An AE of grade 1 denotes a mild event, grade 2 a moderate event, grade 3 a severe event, grade 4 a life-threatening event, and grade 5 a fatal event.
SAE criteria: death, life-threatening, required inpatient hospitalization, prolongation of existing hospitalization, persistent or significant disability/incapacity, important medical event, congenital anomaly/birth defect.
Includes type I hypersensitivity (including anaphylaxis), immune complex disease, and thrombocytopenia.
Nirsevimab Pharmacokinetics
Nirsevimab serum concentrations were available for 97 (97%) participants. Nirsevimab concentrations decreased monoexponentially after day 31 (Fig 1). At day 151, mean nirsevimab serum concentrations were higher in participants who received 200 mg nirsevimab (33.2 µg/mL, SD 19.3 µg/mL) than in those who received 50 mg/100 mg nirsevimab (25.6 µg/mL, SD 13.4 µg/mL), but with substantial overlap between the 2 groups. Fourteen (14.0%) participants had increased clearance of nirsevimab compared with the other participants (Fig 1); a subsequent detailed review of the medical histories of these children found that they all had ≥1 condition that may be associated with protein loss giving rise to hypogammaglobulinemia:21 chronic liver disease (n = 5), malignancy (n = 3), graft versus host (GVH) disease (n = 2), Omenn syndrome (n = 2; 1 child had both GVH disease and Omenn syndrome), HIV (n = 2), and nephrotic syndrome (n = 1). Based on all participants, mean nirsevimab serum concentrations on day 151 were lower than those in healthy infants in the MELODY trial11 (Fig 2) where efficacy against MA RSV LRTI was established. When excluding participants with increased nirsevimab clearance, mean nirsevimab serum concentrations were similar to those in the MELODY trial.
Nirsevimab serum concentrations to day 360 postdose.
Nirsevimab serum concentrations were available for 97 (97%) participants. Samples below the lower limit of quantification were not included.
Nirsevimab serum concentrations to day 360 postdose.
Nirsevimab serum concentrations were available for 97 (97%) participants. Samples below the lower limit of quantification were not included.
Nirsevimab serum concentrations across MUSIC RSV season 1 and RSV season 2 compared with MELODY in (A) all participants and (B) excluding participants with increased clearance of nirsevimab (as-treated population).
Points represent individual participants; boxes represent IQRs; central lines correspond to the medians; whiskers extend to the largest and smallest values no further than 1.5 × IQR. The gray band represents the IQR of healthy infants at day 151 in the MELODY trial.11 At day 151, 39 recipients of nirsevimab 50 mg or 100 mg and 44 recipients of nirsevimab 200 mg had available PK measurements. (B) Data from 14 participants were excluded from the analysis because of increased clearance of nirsevimab through day 151. Two participants aged 12.2 months who were planned to receive 200 mg nirsevimab only received 100 mg; both were <10 kg.
IQR, interquartile range; PK, pharmacokinetics; RSV, respiratory syncytial virus.
Nirsevimab serum concentrations across MUSIC RSV season 1 and RSV season 2 compared with MELODY in (A) all participants and (B) excluding participants with increased clearance of nirsevimab (as-treated population).
Points represent individual participants; boxes represent IQRs; central lines correspond to the medians; whiskers extend to the largest and smallest values no further than 1.5 × IQR. The gray band represents the IQR of healthy infants at day 151 in the MELODY trial.11 At day 151, 39 recipients of nirsevimab 50 mg or 100 mg and 44 recipients of nirsevimab 200 mg had available PK measurements. (B) Data from 14 participants were excluded from the analysis because of increased clearance of nirsevimab through day 151. Two participants aged 12.2 months who were planned to receive 200 mg nirsevimab only received 100 mg; both were <10 kg.
IQR, interquartile range; PK, pharmacokinetics; RSV, respiratory syncytial virus.
On further exploration of the full MUSIC population, there were 30 additional participants who had a condition potentially associated with protein loss, including chronic liver disease (n = 3), malignancy (n = 18), GVH disease (n = 2), HIV (n = 6), and nephrotic syndrome (n = 1); see Supplemental Tables 7 and 8 and Supplemental Fig 5 for additional details; however, these participants did not exhibit rapid clearance of nirsevimab.
Antidrug Antibodies
Eleven (11%) participants developed treatment-emergent ADAs any time through day 361 (median titer, 200.0; day 31, n = 1, day 151, n = 1; and day 361, n = 9). All were positive for YTE, and one was positive for neutralizing ADAs. Of the participants who were ADA-positive on day 361, 1 experienced a treatment-related AE (grade 1 pyrexia within 60 minutes of dosing on day 1), and 1 experienced a grade 1 rash on day 104 assessed as unrelated to treatment; none experienced a treatment-related SAE or AESI. Participants who were ADA-positive on day 361 were more likely to have nirsevimab levels below the lower limit of quantification compared with participants who were ADA negative (nirsevimab 50 mg/100 mg ADA positive: 1/2 participants ADA negative: 6/27; 200 mg ADA positive 4/7, ADA negative 6/31).
Neutralizing Antibodies
RSV neutralizing antibody levels were higher in 200 mg nirsevimab recipients than in 50 mg/100 mg nirsevimab recipients, but with substantial overlap between the 2 groups (Fig 3). At day 151, 82 participants with evaluable data had a geometric mean (GM) neutralizing antibody concentration of 8074.9 IU/mL (95% confidence interval [CI], 6869.7–9454.3), giving a GM fold-rise from baseline of 63.7 (95% CI, 43.9–92.4). At day 361, 65 participants with evaluable data had a lower GM concentration of 835.3 IU/mL (95% CI, 567.4–1229.5); however, this still constituted a GM fold-rise of 7.7 (95% CI, 4.9–12.0). Among participants with increased clearance of nirsevimab, 13 of the 14 participants had neutralizing antibody concentrations >1000 IU/mL at day 151 (GM neutralizing antibody concentration levels can be found in Supplemental Fig 6).
Geometric mean concentration of serum RSV neutralizing antibodies (as-treated population).
Error bars represent 95% confidence interval.
Geometric mean concentration of serum RSV neutralizing antibodies (as-treated population).
Error bars represent 95% confidence interval.
Clinical Disease Incidence
No cases of protocol-defined MA RSV LRTI occurred through day 151, the observation period in which efficacy has been established. However, 3 participants had an MA RSV LRTI after day 151 that did not meet the protocol definition, 1 of whom required hospitalization (2 did not have an objective measure of disease severity and 1 had a positive RSV reverse transcriptase polymerase chain reaction test performed at a local laboratory that was not confirmed at a central laboratory). None of the 3 had increased clearance of nirsevimab.
Discussion
In this phase II trial of immunocompromised children aged ≤24 months at risk for severe RSV disease, a single dose of nirsevimab was well tolerated, with no safety concerns over 361 days postdose. The ADA incidence of 11% was associated with minimal effects on PK and no apparent impact on safety outcomes. Overall, nirsevimab serum concentration was consistent with previous studies in healthy infants and supportive of efficacy in this population.
The nature and severity of AEs that occurred during the trial were consistent with expectations for a population of immunocompromised children aged ≤24 months. All AEs considered causally related to nirsevimab by investigators were mild to moderate in severity and the majority were indicative of systemic reactogenicity. AESIs occurred infrequently and included mild cutaneous hypersensitivity events, 1 of which was considered causally related to nirsevimab by the investigator; those remaining had identifiable triggers (eg, radiocontrast media). Notably, no AESIs occurred among participants who were ADA positive. There were no reports of anaphylaxis or other serious allergic reactions, no reports of immune complex disease, and no thrombocytopenia attributed to nirsevimab. Three fatal events during the trial were not attributed to RSV and none was considered related to nirsevimab. Thus, overall, the safety profile of nirsevimab in this trial was consistent with that established in other controlled trials of nirsevimab.10,11,14,22
The incidence of ADA was similar to that in previous nirsevimab trials, with no impact of ADA on safety observed.11,14 Based on data from children with congenital heart disease or chronic lung disease dosed in 2 consecutive RSV seasons in the MEDLEY trial,22 there was no evidence of priming or boosting of ADA to nirsevimab. Furthermore, no serious hypersensitivity reactions were observed with repeat dosing, including among participants who were ADA positive at the end of the first season.22 As observed during the phase I trial of nirsevimab in healthy preterm infants,17 the finding that participants who were ADA positive on day 361 were more likely to have nirsevimab levels below the limit of detection versus ADA-negative participants, suggests that there may be an effect of ADA on PK between days 151 and 361. However, there was no indication of an ADA effect on nirsevimab serum concentrations through day 151 (ie, the length of a typical RSV season).
It is notable that 14 participants demonstrated an increased clearance of nirsevimab. Given the spectrum of underlying diseases in these participants and following an extensive review of medical histories, although not conclusive, protein loss, which is a well-documented cause of hypogammaglobulinemia,21 appeared to be the most likely underlying mechanism. Five participants had chronic liver disease with evidence of cirrhosis, portal hypertension, or hepatic venous outflow obstruction that, through the formation of secondary intestinal lymphangiectasia, may lead to a protein-losing enteropathy. Two participants had GVH disease, which has the potential to damage the integrity of the intestinal mucosa and/or skin, leading to protein loss. Two participants had Omenn syndrome, a rare disease, with clinical features of severe erythroderma and protracted diarrhea that may be associated with protein loss from both the skin and the gut.23 Two participants had HIV infection, which can predispose patients to protein loss from injury to the kidneys and/or gastrointestinal tract secondary to antiretroviral therapy, opportunistic enteric infections, and myriad causes of chronic diarrhea.21 One participant had nephrotic syndrome, in which glomerular damage leads to heavy proteinuria. The 3 remaining participants had malignancies of retinoblastoma, choroid plexus carcinoma, and juvenile myelomonocytic leukemia with complex clinical courses. Interestingly, these diagnoses alone were insufficient to predict which children would experience pathologic protein loss or increased clearance of nirsevimab, indicating the need for further research. This also highlights the importance of obtaining a detailed clinical history to best assess or predict those who may be at high risk for clinically significant protein loss that could translate to more rapid clearance of nirsevimab than expected.
All but 1 of the 14 participants had RSV neutralizing antibody titers >1000 IU/mL at day 151. This is higher than for palivizumab (the only other approved RSV prophylactic), which has a neutralizing titer of 705 IU/mL (100 μg/mL serum concentration),24 and corresponds to the approximate peak levels observed after the first dose.25 Additionally, there were no protocol-defined MA RSV LRTIs through day 151 among the 14 participants, indicating that this subgroup of children may still benefit from nirsevimab, albeit acknowledging that the level of protection may be lower or of shorter duration than that seen in otherwise healthy infants.
Strengths of this trial include the broad range of serious complex immunocompromising conditions experienced by the participants. Consequently, the safety profile and ability to achieve nirsevimab serum concentrations to support efficacy using the standard dosing regimen already in place for approved indications, may be broadly extrapolated to this extremely vulnerable population at increased risk of severe RSV. In terms of study limitations, conduct of the trial overlapped with the onset of the COVID-19 pandemic in March 2020,26 which led to reduced RSV transmission during the 2020–2021 northern hemisphere season; however, this only impacted 10 participants enrolled in Japan because the remaining 90 participants were enrolled just before and during the 2021–2022 northern hemisphere season when RSV circulation was gradually returning to pre–COVID-19 levels. Logistical challenges presented by the pandemic were addressed by ensuring regular contact with participants via phone and telemedicine to minimize any impact on the collection of safety data. Additionally, no minimum duration of treatment with systemic corticosteroids or other immune compromising agents was specified in the inclusion criteria and there was no requirement to record the degree of immunocompromise of participants, such as CD4 levels. Finally, the lack of control group in this open-label clinical trial limits the interpretation of safety data.
In conclusion, a single dose of nirsevimab administered to immunocompromised children aged ≤24 months was well tolerated with no safety concerns arising over 361 days postdose. ADA incidence was 11%, with no apparent impact on safety outcomes. Infants and children with immunocompromising conditions achieved nirsevimab serum concentrations that were similar to those observed in healthy preterm and term infants who were enrolled in the phase III MELODY trial, where efficacy was established,11 and is therefore supportive of efficacy in this population. A subset of immunocompromised children had increased nirsevimab clearance that may be evidence of conditions associated with protein loss. The impact of this on efficacy in these children is unknown, but the potential for benefit is supported by the ability to achieve levels of RSV neutralizing antibodies in line with or higher than those achieved with palivizumab.
Acknowledgments
We thank the trial participants and their families; the team at IQVIA; the members of the independent data and safety monitoring committee (Larry Givner, MD [chair], William Blackwelder, PhD [biostatistician], and John Modlin, PhD); the members of the investigator teams; the full clinical team at AstraZeneca; and Rebecca A. Bachmann, PhD, for assistance with manuscript preparation. Medical writing support, under the direction of the authors, was provided by Richard Knight, PhD, CMC Connect, a division of IPG Health Medical Communications, in accordance with Good Publication Practice (GPP) 2022 guidelines (https://www.ismpp.org/gpp-2022; Ann Intern Med. 2022 doi:10.7326/M22-1460) and was funded by AstraZeneca. Nirsevimab is being developed in partnership between AstraZeneca and Sanofi.
Amanda Leach is a former employee of AstraZeneca and was an employee at the time of this analysis.
A list of the MUSIC Study Group members is provided in the Supplementary Appendix.
Dr Domachowske conceptualized and designed the study, collected data, and critically reviewed and revised the manuscript for important intellectual content; Dr Hamrén conceptualized and designed the study, carried out the pharmacokinetic analyses, and critically reviewed and revised the manuscript for important intellectual content; Ms Banu and Mr Basavaraju carried out the initial analyses and critically reviewed and revised the manuscript; Ms Baronio carried out the statistical analyses and critically reviewed and revised the manuscript; Mr Koen, Mr Mori, Ms Pannaraj, and Mr Soler-Palacin collected dat, and critically reviewed and revised the manuscript for important intellectual content; Ms Leach and conceptualized and designed the study, carried out the initial analyses, and critically reviewed and revised the manuscript for important intellectual content; Ms Villafana conceptualized and designed the study and critically reviewed and revised the manuscript for important intellectual content; Ms Mankad interpreted data and critically reviewed and revised the manuscript for important intellectual content; Ms Takas coordinated and supervised data collection and critically reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Clinical Trial Registration: Clinicaltrials.gov, NCT04484935, https://www.clinicaltrials.gov/study/NCT04484935.
Data Sharing Statement: Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Data for studies directly listed on Vivli can be requested through Vivli at www.vivli.org. Data for studies not listed on Vivli could be requested through Vivli at https://vivli.org/members/enquiries-about-studies-not-listed-on-the-vivli-platform/. AstraZeneca Vivli member page is also available outlining further details: https://vivli.org/ourmember/astrazeneca/.
FUNDING: This trial was supported by AstraZeneca and Sanofi. AstraZeneca was involved in the trial design; the collection, analysis, and interpretation of the data; and the writing of the manuscript. Nirsevimab is being developed and commercialized in partnership between AstraZeneca and Sanofi.
CONFLICT OF INTEREST DISCLOSURES: Dr Domachowske has received consulting fees from Sanofi; payment or honoraria from Sanofi; and has participated in data safety monitoring boards or advisory boards for AstraZeneca. Dr Hamrén, Dr Mankad, Ms Takas, and Ms Villafana are employees and shareholders of AstraZeneca. Ms Baronio is an employee of ClinChoice Inc and was contracted to AstraZeneca at the time of this analysis. Dr Basavaraju is a former employee of AstraZeneca. Drs Koen and Pannaraj have no conflicts of interest to declare. Dr Soler-Palacin has received research grants from Astellas, CSL Behring, Gilead, Grifols, Pfizer, Pharming, and Takeda; and consulting fees from CSL Behring, Grifols, Takeda, and UCB. Dr Mori has received grants from Abbvie GK, Asahi Kasei Pharma Corporation, Ayumi Pharmaceutical Corporation, CSL Behring K. K., Chugai Pharmaceutical Co. Ltd., Japan Blood Products Organization, Nippon Kayaku Co. Ltd., and UCB Japan Co. Ltd.; consulting fees from Daiichi Sankyo Company Ltd. and Taisho Pharmaceutical Co. Ltd; and payments or honoraria from AstraZeneca K. K., MSD K. K. and Sanofi K. K.
- ADA
antidrug antibodies
- AE
adverse event
- AESI
adverse event of special interest
- CI
confidence interval
- GM
geometric mean
- GVH
graft versus host
- LRTI
lower respiratory tract infection
- MA
medically attended
- NOCD
new onset chronic disease
- PK
pharmacokinetics
- RSV
respiratory syncytial virus
- SAE
serious adverse event
- wGA
weeks’ gestational age
- YTE
triple amino acid substitution
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