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

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 S...

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Autores principales: Walter, Maggie C., Wenninger, Stephan, Thiele, Simone, Stauber, Julia, Hiebeler, Miriam, Greckl, Eva, Stahl, Kristina, Pechmann, Astrid, Lochmüller, Hanns, Kirschner, Janbernd, Schoser, Benedikt
Formato: Online Artículo Texto
Lenguaje:English
Publicado: IOS Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918909/
https://www.ncbi.nlm.nih.gov/pubmed/31594243
http://dx.doi.org/10.3233/JND-190416
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author Walter, Maggie C.
Wenninger, Stephan
Thiele, Simone
Stauber, Julia
Hiebeler, Miriam
Greckl, Eva
Stahl, Kristina
Pechmann, Astrid
Lochmüller, Hanns
Kirschner, Janbernd
Schoser, Benedikt
author_facet Walter, Maggie C.
Wenninger, Stephan
Thiele, Simone
Stauber, Julia
Hiebeler, Miriam
Greckl, Eva
Stahl, Kristina
Pechmann, Astrid
Lochmüller, Hanns
Kirschner, Janbernd
Schoser, Benedikt
author_sort Walter, Maggie C.
collection PubMed
description 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.
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spelling pubmed-69189092019-12-20 Safety and Treatment Effects of Nusinersen in Longstanding Adult 5q-SMA Type 3 – A Prospective Observational Study Walter, Maggie C. Wenninger, Stephan Thiele, Simone Stauber, Julia Hiebeler, Miriam Greckl, Eva Stahl, Kristina Pechmann, Astrid Lochmüller, Hanns Kirschner, Janbernd Schoser, Benedikt J Neuromuscul Dis Research Report 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. IOS Press 2019-10-31 /pmc/articles/PMC6918909/ /pubmed/31594243 http://dx.doi.org/10.3233/JND-190416 Text en © 2019 – IOS Press and the authors. All rights reserved https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License (https://creativecommons.org/licenses/by-nc/4.0/) , which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Report
Walter, Maggie C.
Wenninger, Stephan
Thiele, Simone
Stauber, Julia
Hiebeler, Miriam
Greckl, Eva
Stahl, Kristina
Pechmann, Astrid
Lochmüller, Hanns
Kirschner, Janbernd
Schoser, Benedikt
Safety and Treatment Effects of Nusinersen in Longstanding Adult 5q-SMA Type 3 – A Prospective Observational Study
title Safety and Treatment Effects of Nusinersen in Longstanding Adult 5q-SMA Type 3 – A Prospective Observational Study
title_full Safety and Treatment Effects of Nusinersen in Longstanding Adult 5q-SMA Type 3 – A Prospective Observational Study
title_fullStr Safety and Treatment Effects of Nusinersen in Longstanding Adult 5q-SMA Type 3 – A Prospective Observational Study
title_full_unstemmed Safety and Treatment Effects of Nusinersen in Longstanding Adult 5q-SMA Type 3 – A Prospective Observational Study
title_short Safety and Treatment Effects of Nusinersen in Longstanding Adult 5q-SMA Type 3 – A Prospective Observational Study
title_sort safety and treatment effects of nusinersen in longstanding adult 5q-sma type 3 – a prospective observational study
topic Research Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918909/
https://www.ncbi.nlm.nih.gov/pubmed/31594243
http://dx.doi.org/10.3233/JND-190416
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