Data from: Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies

Objective: Report results of intrathecal nusinersen in children with later-onset spinal muscular atrophy (SMA). Methods: Analyses included children from the phase 1b/2a study (ISIS-396443-CS2; NCT01703988) who first received nusinersen during that study and were eligible to continue treatment in the extension study (ISIS-396443-CS12; NCT02052791). The phase 1b/2a study was a 253-day, ascending dose (3, 6, 9, 12 mg), multiple-dose, open-label, multicenter study that enrolled children with SMA aged 2 to 15 years. The extension study was a 715-day, single-dose level (12 mg) study. Time between studies varied by participant (196–413 days). Assessments included the Hammersmith Functional Motor Scale–Expanded (HFMSE), Upper Limb Module (ULM), Six-Minute Walk Test (6MWT), compound muscle action potential (CMAP), and quantitative multipoint incremental motor unit number estimation. Safety also was assessed. Results: Twenty-eight children were included (SMA Type II, n = 11; SMA Type III, n = 17). Mean HFMSE scores, ULM scores, and 6MWT distances improved by the day 1150 visit (HFMSE: SMA Type II, +10.8 points; SMA Type III, +1.8 points; ULM: SMA Type II, +4.0 points; 6MWT: SMA Type III, +92.0 meters). Mean CMAP values remained relatively stable. No children discontinued treatment due to adverse events. Conclusions: Nusinersen treatment over ~3 years resulted in motor function improvements and disease activity stabilization not observed in natural history cohorts. These results document the long-term benefit of nusinersen in later-onset SMA, including SMA Type III. Classification of evidence: This study provides Class IV evidence that nusinersen improves motor function in children with later-onset SMA