P.37 Outcomes in patients with spinal muscular atrophy and four or more SMN2 copies treated with onasemnogene abeparvovec: Findings from RESTORE

Abstract

Onasemnogene abeparvovec (OA) is a one-time gene replacement therapy for spinal muscular atrophy (SMA). While clinical trials of OA included patients with two or three SMN2 gene copies, patients with four or more copies may be treated in clinical practice. Natural history and outcomes following SMA treatment have not been well-characterized for these patients. We sought to describe clinical outcomes after OA monotherapy for patients with four or more SMN2 copies in RESTORE, a prospective SMA registry. We evaluated baseline characteristics, and post-treatment motor function, motor milestone achievement, use of ventilatory/nutritional support, and adverse events (AEs). Patients evaluable for motor function or milestone achievement had ≥2 assessments, with ≥1 after OA. Seven children with four SMN2 copies and five with more than four copies were included. All 12 cases were identified by newborn screening in the United States and treated presymptomatically. Median age at OA was 3 months (range, 1–11). Two of three children with evaluable motor milestone assessments achieved new milestones. All three children evaluable for CHOP INTEND maintained or achieved the maximum score of 64 points. One child was evaluable for HINE and achieved a 6-point increase. Five children with recorded AE data had ≥1 treatment-emergent AE (mainly Grade 1 LFT and/or troponin elevations without relevant clinical signs). 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. Patients with four or more SMN2 gene copies attained improvements in motor function and achieved new milestones after treatment with OA. Presentation of SMA with four or more 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.