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

Abstract

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.

Clinicaltrialsgov 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.

Figure 1. CS2 (phase 1b/2a open-label) and CS12 (extension) study designs and patient disposition

(A) Study designs: ^aOverall enrollment. ^bPatients received treatment on days 1 and 85 only. (B) Patient disposition: The CS2-CS12 integrated efficacy analysis included 28 children from CS2 who received their first dose of nusinersen in CS2 and could have been treated in CS12. The total number of nusinersen doses administered in CS2 was 2 (cohort 3) or 3 (cohorts 1, 2, and 4), and the total number of nusinersen doses administered in CS12 was 4. D = day; SMA = spinal muscular atrophy.

Figure 2. Mean change from baseline in Hammersmith Functional Motor Scale–Expanded (HFMSE) score

Due to the gap between CS2 and CS12 and windowing of visit days, some windowed visits do not contain all children. SE = standard error; SMA = spinal muscular atrophy.

Figure 3. Mean change from baseline in Upper Limb Module (ULM) score and 6-Minute Walk Test (6MWT) distance

(A) ULM: Assessed only in nonambulant participants. (B) 6MWT: Assessed only in ambulant participants. Due to the gap between CS2 and CS12 and windowing of visit days, some windowed visits do not contain all children. SE = standard error.

Figure 4. Mean change from baseline in compound muscle action potential (CMAP) amplitude, CMAP area, and motor unit number estimation (MUNE) value

(A) CMAP amplitude, (B) CMAP area, and (C) MUNE value. Due to the gap between CS2 and CS12 and windowing of visit days, some windowed visits do not contain all children. SE = standard error; SMA = spinal muscular atrophy.