Population-based assessment of nusinersen efficacy in children with spinal muscular atrophy: a 3-year follow-up study

Abstract

Nusinersen (Spinraza®) improves survival of infants with hereditary proximal spinal muscular atrophy and motor function in children up to 12 years. Population-based assessments of treatment efficacy are limited and confined to select cohorts of patients. We performed a nationwide, population-based, single-center cohort study in children with spinal muscular atrophy younger than 9.5 years at start of treatment in line with reimbursement criteria in the Netherlands. We assessed age-relevant motor function scores, the need for tube feeding, hours of ventilatory support and documented adverse events. We used linear mixed modeling to assess treatment effects. We compared motor function during treatment with natural history data and to individual trajectories of muscle strength and motor function before the start of treatment. We included 71 out of 72 Dutch children who were treated (median age 54 months; range 0-117) and followed them for a median of 38 months (range 5-52). We observed improvement of motor function in 72% and stabilization in another 18% of the symptomatic children, which differed from the natural disease course in a matched cohort of which we had previously collected natural history data. Longitudinal analysis showed that motor function improved up to a median of 24 months (range 12-30) of treatment after which it stabilized. Shorter disease duration at start of treatment resulted in better treatment efficacy (p < 0.01). Sixteen children (23%) achieved new motor milestones. Bulbar and respiratory function did not improve significantly during treatment. In 15 patients from whom treatment-naïve data were available, the pre-treatment trajectory of motor function decline changed to stabilization or improvement after the start of treatment. We documented 82 adverse events after 934 injections (9%) in 45 patients. None of the adverse events led to treatment discontinuation. Intrathecal nusinersen treatment is safe and improves or stabilizes motor function in 90% of young children with spinal muscular atrophy types 1c–3a. We did not observe improvement of respiratory and bulbar functions.

Nusinersen demonstrates effectiveness in treating spinal muscular atrophy: findings from a three-year nationwide study in Korea

“…In patients with type 2 SMA, steady improvements in the HFMSE score were observed at 1 and 2 years of follow-up, with a mean increase of 4.7 from baseline to the first year and 2.2 in the second year of treatment. These results were consistent with those observed in previous studies, reporting mean HFMSE score changes of 2.8-4.3 at year 1 from baseline and 0.8-1.5 from the first to the second year of follow-up (3,11,19). From the second to the third of year follow-up, a slow but steady increase in HFMSE score (mean 0.4) was observed in 12 patients who reached 3 years of follow-up.…”

“…This finding aligns with previous short-term follow-up studies, which reported a mean HINE-2 score increase of 2.2-3.2 from baseline to the first year and 0.9-1.9 from the first year to the second year (12,(16)(17)(18). The plateauing of motor function improvement between years 2 and 3 (mean 0.8 HINE-2 score improvement) in this study was consistent with findings from a recently published 3-year follow-up Dutch study, which reported a mean increase of 0.6 in HINE-2 scores between years 2 and 3 (11). In patients with type 2 SMA, steady improvements in the HFMSE score were observed at 1 and 2 years of follow-up, with a mean increase of 4.7 from baseline to the first year and 2.2 in the second year of treatment.…”

“…Subsequent to regulatory approval, many observational studies have reported its beneficial effects on motor function across all types of SMA (3,(7)(8)(9)(10). Nevertheless, the limited number of population-based studies has prevented clinicians from referring to real-world data (11,12).…”

New therapies for spinal muscular atrophy: where we stand and what is next

“…A recent meta-analysis on motor function in type II and III patients treated with nusinersen including all the real-world data available in the literature [45] shows that in all studies nusinersen treatment was associated with a favorable benefit in motor function that could be observed even when subdividing the results according to age and type of assessment. These results were different from those observed in natural history untreated cohorts who consistently showed negative changes [34,46]. New developments An ongoing phase 2/3 study, DEVOTE (NCT04089566), is currently exploring efficacy, safety, and PK of higher doses of nusinersen.…”

Consensus from the Brazilian Academy of Neurology for the diagnosis, genetic counseling, and use of disease-modifying therapies in 5q spinal muscular atrophy

“…Subsequent real-life studies with type 1 SMA patients, including those using the drug in an expanded access program, further confirmed the positive effects of nusinersen on motor and respiratory function, as well as on the survival of patients with long-term illness and varying respiratory conditions. [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] The CHERISH trial was a placebo-randomized study that enrolled 126 patients with late-onset SMA aged 2 to 12 years. 41 The study demonstrated that patients who received nusinersen experienced clinically significant improvements in motor function compared to the control group.…”