Abstract
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.