Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3

Abstract

ObjectiveTo retrospectively investigate safety and efficacy of nusinersen in a large cohort of adult Italian patients with spinal muscular atrophy (SMA).MethodsInclusion criteria were: (1) clinical and molecular diagnosis of SMA2 or SMA3; (2) nusinersen treatment started in adult age (>18 years); (3) clinical data available at least at baseline (T0-beginning of treatment) and 6 months (T6).ResultsWe included 116 patients (13 SMA2 and 103 SMA3) with median age at first administration of 34 years (range 18–72). The Hammersmith Functional Rating Scale Expanded (HFMSE) in patients with SMA3 increased significantly from baseline to T6 (median change +1 point, p<0.0001), T10 (+2, p<0.0001) and T14 (+3, p<0.0001). HFMSE changes were independently significant in SMA3 sitter and walker subgroups. The Revised Upper Limb Module (RULM) in SMA3 significantly improved between T0 and T14 (median +0.5, p=0.012), with most of the benefit observed in sitters (+2, p=0.018). Conversely, patients with SMA2 had no significant changes of median HFMSE and RULM between T0 and the following time points, although a trend for improvement of RULM was observed in those with some residual baseline function. The rate of patients showing clinically meaningful improvements (as defined during clinical trials) increased from 53% to 69% from T6 to T14.ConclusionsOur data provide further evidence of nusinersen safety and efficacy in adult SMA2 and SMA3, with the latter appearing to be cumulative over time. In patients with extremely advanced disease, effects on residual motor function are less clear.

Pilot Study on Quantitative Cervical Cord and Muscular MRI in Spinal Muscular Atrophy: Promising Biomarkers of Disease Evolution and Treatment?

“…Even though SMA is generally described as a symmetric disorder, it is not uncommon to see asymmetrical weakness: Kang et al (46) reported three female type 3 SMA patients with asymmetrical weakness, showing also upper motor neuron signs that have always been absent in our patient. Despite the small sample size considered here and the relatively short observation period, our results are in line with those reported by the German and Italian studies (47,48). It should also be noted that all patients reported some further improvement in motor function, which could not be captured by their repeated functional scores possibly because of the discrete nature of such scales.…”

Safety, Tolerability, and Effect of Nusinersen Treatment in Ambulatory Adults With 5q-SMA

“…Similarly, the study by Maggi et al reported a mean change among SMA type 3 walkers in the HFMSE was 2.38 ± 2.71 (median 2, range −3 to 8) in 40 subjects at 10 months and 2.37 ± 2.22 (median 2, range −2 to 6) in 27 subjects at 14 months (17). The percent increase in HFMSE of ≥3 points was 43 and 48% after 10 and 14 months of treatment (17). In our study, the impact of nusinersen on the 6MWT was less robust as compared with the studies by Hagenacker et al (11) and Maggi et al (17) 17).…”

“…Nusinersen was approved for all types of SMA, but approval was primarily based on evidence in infants and children ages 2-15 (7)(8)(9). There is emerging data supporting the use of nusinersen in adults with SMA (10)(11)(12)(13)(14)(15)(16)(17). However, there is a limited understanding of how delayed or late SMN restoration may result in improved function.…”

A Canadian Adult Spinal Muscular Atrophy Outcome Measures Toolkit: Results of a National Consensus using a Modified Delphi Method

“…Sansone et al recently recommended OM in adult SMA based upon expert opinion of international neuromuscular experts [13] and their results align with the findings of the present study, with differences only in the selection of the SMAFRS and the TUG. Similarly, Hagenacker et al, Walter et al and Maggi et al studied the effects of nusinersen (an SMN2-targeted anti-sense oligonucleotide [6]) in an adult SMA population and all utilized the HFMSE, RULM, and 6MWT [25][26][27] in evaluation of therapy effectiveness and safety. In 2016, Mercuri et al selected the HFMSE as the primary outcome measure when reporting upon the natural progression of SMA in children and adults [28].…”