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

OBJECTIVE: To report results of intrathecal nusinersen in children with later-onset spinal muscular atrophy (SMA). METHODS: Analyses included children from a 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 2–15 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), 6-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 1,150 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. CLINICALTRIALS.GOV IDENTIFIER: NCT01703988 (ISIS-396443-CS2); NCT02052791 (ISIS-396443-CS12). CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that nusinersen improves motor function in children with later-onset SMA.