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Observational Study
. 2019;6(4):453-465.
doi: 10.3233/JND-190416.

Safety and Treatment Effects of Nusinersen in Longstanding Adult 5q-SMA Type 3 - A Prospective Observational Study

Free PMC article
Observational Study

Safety and Treatment Effects of Nusinersen in Longstanding Adult 5q-SMA Type 3 - A Prospective Observational Study

Maggie C Walter et al. J Neuromuscul Dis. .
Free PMC article


Objective: Spinal muscular atrophy (SMA) is a progressive autosomal recessive motor neuron disease caused by loss of the SMN1 gene. Based on randomized clinical trials in children with SMA type 1 and 2, Nusinersen has been approved as the first treatment for all types of SMA, including adults with SMA type 3.

Methods: We evaluated the safety and treatment effects of Nusinersen in longstanding adult 5q-SMA type 3. Patients were treated with intrathecal loading doses at day 1, 14, 28 and 63, followed by maintenance dose every four months up to 300 days. We monitored the patients within SMArtCARE, a prospective open-label outcome study for disease progression, side effects and treatment efficacy, encompassing clinical examination including MRC sum score, vital capacity in sitting position (VC, VC % pred.), ALS Functional Rating Scale (ALS-FRS), 6-Minute-Walk-Test (6MWT), Revised Upper Limb Module (RULM), and Hammersmith Functional Rating Scale (HFMSE). We also measured biomarkers in the spinal fluid (phosphorylated neurofilament heavy chain pNFH, neuron-specific enolase NSE, proteins, ß-Amyloid 1-40, ß-Amyloid 1-42, tau and phospho-tau) and creatine kinase (CK). Assessments were performed at baseline, day 63 (V4), day 180 (V5) and day 300 (V6). For statistical analysis, we compared baseline to V4, V5 and V6, using the paired sample t-test. When there were significant differences, we added cohen's d and effect size r for evaluation of clinical meaningfulness.

Results: 19 patients were included, 17 of them have completed the observation period of 10 months (day 300, V6). Patients were aged 18 to 59 years with disease duration ranging from 6 to 53 years. Except for the 6MWT, the RULM and the peak cough flow, there were no relevant significant changes in all functional outcome assessments at V4, V5 or V6, compared to baseline. For the 6MWT, there was a statistically significant improvement at visit 5 and at visit 6. RULM-score increased significantly at V6, and peak cough flow at visit 5. In biomarker studies, there was a significant decline in NSE and pTAU as well as a slight increase in proteins. In safety analysis, overall, Nusinersen applications were well tolerated. Eleven patients reported adverse events that were related to the study procedures, comprising back pain in seven patients and post-lumbar-puncture headache following intrathecal administration in four patients. Post-lumbar-puncture headache was reported in three females and one male, in total eleven times of 108 punctures (10%). No serious adverse events occurred.

Conclusions: This prospective observational study indicates a mild treatment effect in adults with long-standing SMA3 after 10 months of treatment with Nusinersen, which had never occurred in the natural history of the disease. In our cohort, the most significant outcome measures were the 6MWT with statistically significant changes after day 180 and day 300, RULM after day 300 and peak cough flow after day 180.

Keywords: Nusinersen; prospective observational study; safety; spinal muscular atrophy; treatment.

Conflict of interest statement

Simone Thiele, Julia Stauber, Miriam Hiebeler, Eva Greckl, Kristina Stahl report no disclosures.

Astrid Pechmann received funding from Biogen for educational activities.

Hanns Lochmüller: Consultancy and financial support for research projects and clinical trials from AMO Pharma, Biogen, Desitin, GW Pharma, Pfizer, PTC Therapeutics, Roche, Santhera, Sarepta, Satellos and Ultragenyx. Editor-in-chief for the Journal of Neuromuscular Disease (IOS Press)

Benedikt Schoser has served on advisory boards for Amicus Therapeutics, Audentes, Nexien, Lupin, Valerion, Vertex, and Sanofi Genzyme; he has undertaken contracted unrestricted research for Greenovation Biopharm, Sanofi Genzyme, Nexien; and has received honoraria from Octapharm and Kedrion, and travel expenses from Amicus and Sanofi Genzyme.

Janbernd Kirschner received funding from Avexis, Biogen, and Roche for advisory activities and clinical research activities related to spinal muscular atrophy.

Maggie C. Walter has served on advisory boards for Avexis, Biogen, Novartis, Roche, Santhera, Sarepta, PTC Therapeutics, Ultragenyx, Wave Sciences, received funding for Travel or Speaker Honoraria from Novartis, Biogen, Ultragenyx, Santhera, PTC Therapeutics, and worked as an ad-hoc consultant for AskBio, Audentes Therapeutics, Biogen Pharma GmbH, Fulcrum Therapeutics, GLG Consult, Guidepoint Global, Gruenenthal Pharma, Novartis, PTC Therapeutics.

Stephan Wenninger has served on advisory boards for Alexion Pharma, CSL Behring and Sanofi Genzyme GmbH. He received funding for Travel or Speaker Honoraria from Sanofi-Aventis Germany GmbH; SH Glykogenose Gesellschaft, Germany; AbbVie Germany GmbH; Recordati Pharma GmbH, Germany; CSL-Behring GmbH, Germany; Alexion Pharma Germany GmbH; Desitin Germany.


Age of symptom onset, age at diagnosis and duration of disease for patients with 3 and 4 SMN2 copies. Boxplots of symptom onset, age at diagnosis and duration of disease for patients with 3 and 4 SMN2 copies. Black circles indicate outliers with patient numbers. There were no significant differences between the groups with 3 or 4 SNM2 copies in the age of onset, age at diagnosis and disease duration until the start of first treatment with Nusinersen (α> 0.05).
Scatterplots of baseline motor function tests. RULM = Revised Upper Limb Module; HFMSE = Hammersmith Functional Motor Scale Expanded; ALSFRS = Amyotrophic Lateral Sclerosis Functional Rating Scale; MRC = Medical Research Council score for assessing muscle weakness. The MRC sum score was calculated by summing 14 muscles/regions, which ranges from 0 (complete paralysis) to 160 (normal strength): neck flexors and extensors, deltoid, biceps brachii, triceps brachii, hand extensors and hand flexors, finger extensors and finger flexors, iliopsoas, quadriceps, hamstring muscles, as well as foot extensors and flexors.
Boxplot 6MWT [meters]. Boxplots of the 6MWT at baseline, visit 4, visit 5 and visit 6. There were statistically significant differences between baseline compared to visit 5 and visit 6.
A and B: Levels of (A) pTau and (B) NSE at baseline, visit 4, visit 5 and visit 6. Boxplots of the levels of (A) neuron specific enolase (NSE) and (B) phosphorylated TAU-Protein (pTau) at baseline, visit 4, visit 5 and visit 6, both measured in cerebral fluid. For pTAU, there was a significant decrease between baseline and visit 4 as well as visit 6. For NSE, we could detect a significant decrease in all visits compared to baseline.

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