Evaluation of Children with SMA Type 1 Under Treatment with Nusinersen within the Expanded Access Program in Germany

Abstract

Background:Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by muscle weakness and muscle atrophy. Nusinersen acts as a splicing modifier and has recently been approved for intrathecal treatment of SMA.Objective:Prior to approval, nusinersen was provided to patients with SMA type 1 in Germany within an Expanded Access Program (EAP). In contrast to previous clinical trials, children of different age groups and different stages of the disease were treated with nusinersen.Methods:We conducted a prospective, longitudinal data collection of patients treated with nusinersen within the EAP in seven neuromuscular centers in Germany. Standardized assessments including CHOP-INTEND and HINE-2 motor milestones were performed at baseline and 60 and 180 days after start of treatment.Results:Data from 61 SMA type 1 patients (mean age 21.08 months, range 1–93) were available for analysis. After six months of treatment, 47 children (77.0%) improved by ≥4 points in CHOP INTEND score. Mean change in CHOP INTEND score was 9.0±8.0 points. Nineteen patients (31.1%) improved by ≥2 points in HINE-2 motor milestones. Regression analysis revealed age at onset of treatment as major determinant of change in CHOP INTEND from baseline.Conclusion:When analyzing a broad spectrum of SMA type 1 patients, many children showed an improvement of motor function after six months of treatment with nusinersen, which is generally not expected within the natural course of the disease. Long-term observation and follow-up of patients with later onset types of SMA are crucial to understand the clinical impact of treatment with nusinersen.

Sitting in patients with spinal muscular atrophy type 1 treated with nusinersen

“…We found that high baseline motor function and improvement in HINE‐2 score by more than 2 points after 6 months were positive predictive factors for the acquisition of a sitting position in patients with SMA1 treated with nusinersen. Previously, the only positive predictive factor of nusinersen treatment efficacy in SMA1 was the time between symptom onset and treatment initiation . Recent publicly disclosed follow‐up data from the open‐label extension study, SHINE, suggests that age at treatment initiation (<5.5mo) is the main predictive factor of motor improvement .…”

“…). In the German and Australian open‐label studies, 3.3% (2 of 61) and 3 of 16 patients treated with nusinersen were able to sit independently respectively after 6 months. Because of a longer follow‐up of 14 months, we observed a remarkably higher percentage of sitters (15 of 47) than reported for previous studies.…”

“…Choosing a scale for an objective evaluation of this cohort is challenging. Although the HINE‐2 was developed for infants aged 0 to 24 months, it has become a widely used assessment tool for patients with SMA . In contrast, the CHOP‐INTEND was validated in patients of a broad age range .…”

“…The maximum score on the HINE‐2 is 26 points. The scale is simple to implement and has been used in a number of SMA clinical trials and reports, with the exclusion of the voluntary grasp section . CHOP‐INTEND is a 16‐item motor scale with each item scored from 0 to 4 points.…”

Angewandte Genetik in der Pädiatrie

“…20.000 Gene, die sich auf 22 Chromosomen (Autosomen) und die 2 Geschlechtschromosomen des Zellkerns sowie die in hoher Kopienanzahl vorliegende ringförmige DNA der Mitochondrien verteilen. Die Ursachen genetischer Erkrankungen rangieren von der Substitution, Deletion oder Duplikation eines einzelnen Basenpaars ("single nucleotide variants", SNV) in einzelnen Genen (monogene Erkrankungen) über die veränderte Kopienzahl ("copy number variations", CNV) kleinerer oder größerer Chromosomenabschnitte bis hin zu veränderten Chromosomenanzahlen (z.…”