Nusinersen in later-onset spinal muscular atrophy

Abstract

ObjectiveTo report results of intrathecal nusinersen in children with later-onset spinal muscular atrophy (SMA).MethodsAnalyses 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.ResultsTwenty-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.ConclusionsNusinersen 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 identifierNCT01703988 (ISIS-396443-CS2); NCT02052791 (ISIS-396443-CS12).Classification of evidenceThis study provides Class IV evidence that nusinersen improves motor function in children with later-onset SMA.

Treatment expectations and patient-reported outcomes of nusinersen therapy in adult spinal muscular atrophy

“…Noteworthy, a 3-year follow-up study on nusinersen treatment in later-onset children with SMA and recently published studies conducted in adult SMA patients, observed significant improvements in motor function. In line with our data, these results provide evidence for the long-term benefits of nusinersen in later-onset SMA [11,30,31]. In our cohort, however, we also identified three patients who reported a deterioration of symptoms during the treatment (1 SMA type 2 and 2 SMA type 3) in line with a decline in quantitative motor function scores.…”

Biomarkers and the Development of a Personalized Medicine Approach in Spinal Muscular Atrophy

“…CMAP could therefore be adjunctive to longitudinal changes in functional motor scores to assess treatment response to therapeutic intervention (18). In children with later onset SMA, treatment with nusinersen over several years produced improvements in motor function, concomitant with stable CMAP readings (79). Further detailed neurophysiological assessments may provide a deeper understanding of treatment response.…”

“…Standardized operating protocols are essential to ensure the CMAP is a feasible, valid, reliable, and reproducible outcome measure. Limiting factors such as background noise, inconsistent electrode placement and contact, may produce large errors, particularly in the small CMAP measurements evident in late disease stages (75, 79, 80). Patient tolerance and cooperation (to avoid movement and EMG artifact) is also critical to success.…”

Antisense Oligonucleotide in LNA-Gapmer Design Targeting TGFBR2—A Key Single Gene Target for Safe and Effective Inhibition of TGFβ Signaling

“…Thus, Antisense technology is gaining upcoming relevance in the field of therapeutic applications [2,[4][5][6][7][8]. A recent example is Nusinersen, a successful FDA-approved ASO and the first compound for treating spinal muscular atrophy [7][8][9][10][11].…”