Background: Onasemnogene abeparvovec (OA) is a one-time gene replacement therapy for SMA. While clinical trials of OA included patients with two or three SMN2 gene copies, patients with ≥4 copies may be treated in clinical practice. Natural history and outcomes following SMA treatment have not been well-characterized for these patients.
Objective: We sought to describe clinical outcomes after OA monotherapy for patients with ≥4 SMN2 copies in RESTORE, a comprehensive, noninterventional spinal muscular atrophy (SMA) registry.
Methods: We evaluated baseline characteristics, and post-treatment motor function, motor milestone achievement, use of ventilatory/nutritional support, and adverse events (AEs) (as of May 23, 2022, data cut). Patients evaluable for motor function or milestone achievement had ≥2 assessments, with ≥1 after OA.
Results: Nine children with four SMN2 copies and five with ≥4 copies were included. All 14 cases were identified by newborn screening in the United States and treated presymptomatically. Median age at OA administration was 3.5 (range, 1–11) months. All six children with evaluable motor milestone assessments achieved new milestones. All four children evaluable for CHOP INTEND maintained/achieved the maximum score of 64 points. One child was evaluable for HINE-2 and achieved a ≥2-point increase. One child was evaluable for HFMSE and achieved a ≥3-point increase. Six children with recorded AE data had ≥1 treatment-emergent AE. Two children reported AEs ≥Grade 3 (one had otitis media and one with history of fetal stroke had seizure ~3.5 months post-OA). No deaths or use of ventilatory/nutritional support were reported.
Conclusions: Patients with ≥4 SMN2 gene copies attained improvements in motor function and achieved new milestones after treatment with OA. SMA presentation with ≥4 SMN2 copies is heterogeneous, and laboratory determination of SMN2 copy number may be unreliable, highlighting the importance of early identification and intervention to optimize outcomes for all SMA patients.