Safety and Efficacy of IV Onasemnogene Abeparvovec for Pediatric Patients With Spinal Muscular Atrophy: The Phase 3b SMART Study

Safety and efficacy of IV onasemnogene abeparvovec has been demonstrated for patients with spinal muscular atrophy (SMA) weighing 13-17, and >17-21 kg), administered onasemnogene abeparvovec, and followed for 52 weeks. Corticosteroids were initiated 24 hours before infusion with dose increases in response to adverse events (AEs) and subsequent tapering at investigator discretion. The primary objective was safety. Secondary objective was efficacy (motor function/motor milestones). Twenty-four participants were enrolled; the majority had SMA type 2 (n = 11), 3 copies (n = 18), and prior treatment (n = 21). All participants completed the study; no deaths occurred. All participants had ≥1 treatment-related AE(s), 7 of 24 (29%) had serious treatment-related AEs, and 23 of 24 (96%) had ≥1 AE of special interest. Twenty of 24 participants (83%) had asymptomatic hepatotoxicity events, which were primarily transaminase elevations. No participant had bilirubin elevations >2× upper limit of normal, developed symptomatic hepatotoxicity, or met Hy law criteria. Transient asymptomatic thrombocytopenia events were reported in 17 of 24 participants (71%); all resolved spontaneously with no related bleeding events reported. Three of 24 participants (13%) had cardiac AEs (all unrelated to treatment). No thrombotic microangiopathy or dorsal root ganglionopathy-related AEs were reported. AE frequency and severity were similar across weight groups, although corticosteroid exposure was greater for the 2 heavier cohorts (median 135.0, 201.0, and 194.0 days, respectively) with 37% and 33% still on corticosteroids at the study end. By week 52, most participants maintained or improved motor function (Hammersmith Functional Motor Scale-Expanded 16/18; Revised Upper Limb Module 15/17); 4 participants (all 3 copies) achieved new motor milestones. Onasemnogene abeparvovec safety profile was similar across weight groups in this heterogenous participant population. Frequency and duration of asymptomatic aminotransferase elevations and thrombocytopenia are notable findings. Most participants demonstrated mainten