Safety, Tolerability, and Pharmacokinetics of Nirsevimab for the Prevention of RSV Disease in Immunocompromised Children Aged ≤24 Months: Music, an Open Label, Phase 2 Trial

Abstract

Background Immunocompromised children are at increased risk for severe respiratory syncytial virus (RSV)-associated lower respiratory tract infections (LRTIs), which can lead to poor outcomes, including death. Nirsevimab, an extended half-life monoclonal antibody that targets the RSV prefusion F protein, is approved in Canada, the EU, Great Britain, and the US for the prevention of RSV lower respiratory tract disease in neonates and infants during their first RSV season. In Canada and the US, approval extends to the second season for children remaining at higher risk for severe RSV disease. Here, we present the full analysis of the MUSIC trial (NCT04484935), a 12-month, Phase 2, open-label, uncontrolled, single-dose study of nirsevimab, designed to evaluate the safety, pharmacokinetics (PK), and emergence of antidrug antibodies (ADA) in immunocompromised children ≤24 months of age. Methods Children aged ≤24 months with ≥1 immunocompromising condition received a single intramuscular injection of nirsevimab 50 mg (if weight <5 kg) or 100 mg (if weight ≥5 kg) prior to their first RSV season or 200 mg if entering their second RSV season (Table 1). Safety, ADA, and PK were evaluated to Day 361 (final database lock April 18, 2023). Adverse events of special interest (AESIs) included immediate hypersensitivity (including anaphylaxis), immune complex disease, or thrombocytopenia. Results One hundred children (first RSV season n=46, second RSV season n=54) were enrolled from 8 countries (Table 1). 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 human immunodeficiency virus infection (n=8; children may have had more than one condition). Six children experienced 8 treatment-related adverse events (AEs; pyrexia n=4, abdominal pain n=1, erythema n=1, rash n=2); all were Grade 1 severity , except 1 event of Grade 2 pyrexia, and occurred within 7 days of dosing. No treatment-related serious AEs or new onset chronic diseases were observed. Six AESIs were reported in 5 children; 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 (LRTI, septic shock, and suspected tumor hemorrhage); all were determined to be unrelated to treatment. Eleven children developed treatment-emergent ADAs (median titer 200.0; Day 31 n=1, Day 151 n=1, and Day 361 n=9); none experienced a treatment-related serious AE, AESI, or skin hypersensitivity reaction. Of the children who were ADA-positive on Day 361, 1 experienced a treatment-related AE (Grade 1 pyrexia within 60 minutes of dosing), and 1 experienced a Grade 1 rash on Day 104, determined to be unrelated to treatment. Children who were ADA-positive on Day 361 were more likely to have nirsevimab levels below the limit of detection versus ADA-negative children, suggesting an influence of ADA on PK between Days 151 and 361. Nirsevimab serum exposures at Day 151 were similar to levels demonstrated to be effective in preventing medically attended RSV LRTI in healthy children enrolled in the Phase 3 MELODY trial (Figure 1). Fourteen children demonstrated a rapid decline in serum concentrations through Day 151 compared with the rest of the children; a review of their medical histories revealed evidence for protein-losing conditions, including graft versus host disease, chronic liver disease, and nephrotic syndrome, in 9 of the 14 children. Although none met protocol-defined case criteria for medically attended RSV LRTI, 3 children had an RSV-positive LRTI (central or local test) requiring medical attendance (in an inpatient or outpatient setting; all after Day 151), of whom 1 was hospitalized. Conclusions In immunocompromised children aged ≤24 months, a single dose of nirsevimab was well tolerated and no safety concerns arose over 361 days. Levels of ADA were low, with minimal effects on PK and no apparent impact on safety outcomes. Nirsevimab serum exposure was consistent with previous studies in healthy children and supportive of efficacy in this population at risk of severe RSV disease. Some children with underlying protein-losing conditions had a rapid decline in nirsevimab serum concentrations.