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Arbaclofen extended-release tablets for spasticity in multiple sclerosis: open-label extension study
Baclofen, a racemic γ-aminobutyric acid B receptor agonist, is commonly used for the management of multiple sclerosis–related spasticity but is associated with frequent dosing and poor tolerability. Arbaclofen, the active R-enantiomer of baclofen, exhibits 100- to 1000-fold greater specificity for t...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9968651/ https://www.ncbi.nlm.nih.gov/pubmed/36861013 http://dx.doi.org/10.1093/braincomms/fcad026 |
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author | Okuda, Darin T Kantor, Daniel Jaros, Mark deVries, Tina Hunter, Samuel |
author_facet | Okuda, Darin T Kantor, Daniel Jaros, Mark deVries, Tina Hunter, Samuel |
author_sort | Okuda, Darin T |
collection | PubMed |
description | Baclofen, a racemic γ-aminobutyric acid B receptor agonist, is commonly used for the management of multiple sclerosis–related spasticity but is associated with frequent dosing and poor tolerability. Arbaclofen, the active R-enantiomer of baclofen, exhibits 100- to 1000-fold greater specificity for the γ-aminobutyric acid B receptor compared with the S-enantiomer and ∼5-fold greater potency compared with racemic baclofen. Arbaclofen extended-release tablets allow a dosing interval of 12 h and have shown a favourable safety and efficacy profile in early clinical development. A 12-week, randomized, placebo-controlled Phase 3 trial in adults with multiple sclerosis–related spasticity demonstrated that arbaclofen extended-release 40 mg/day significantly reduced spasticity symptoms compared with placebo and was safe and well tolerated. The current study is an open-label extension of the Phase 3 trial designed to evaluate the long-term safety and efficacy of arbaclofen extended-release. In a 52-week, open-label, multicentre study, adults with a Total Numeric-transformed Modified Ashworth Scale score ≥2 in the most affected limb received oral arbaclofen extended-release titrated over 9 days up to 80 mg/day based on tolerability. The primary objective was assessment of arbaclofen extended-release safety and tolerability. Secondary objectives included an assessment of efficacy using the Total Numeric-transformed Modified Ashworth Scale-most affected limb, the Patient Global Impression of Change and Expanded Disability Status Scale. Of 323 patients enrolled, 218 (67.5%) completed 1 year of treatment. Most patients (74.0%) achieved an arbaclofen extended-release maintenance dose of 80 mg/day. At least one treatment-emergent adverse event was reported by 278 patients (86.1%). The most common adverse events were [n patients (%)]: urinary tract disorder [112 (34.7)], muscle weakness [77 (23.8)], asthenia [61 (18.9)], nausea [70 (21.7)], dizziness [52 (16.1)], somnolence [41 (12.7)], vomiting [29 (9.0)], headache [24 (7.4)] and gait disturbance [20 (6.2)]. Most adverse events were of mild–moderate severity. Twenty-eight serious adverse events were reported. One death occurred during the study, a myocardial infarction that was considered by investigators as unlikely to be related to treatment. Overall, 14.9% of patients discontinued due to adverse events, primarily muscle weakness, multiple sclerosis relapse, asthenia and nausea. Evidence of improvement in multiple sclerosis–related spasticity was observed across arbaclofen extended-release dosages. Arbaclofen extended-release treatment (up to 80 mg/day) was well tolerated and reduced symptoms of spasticity in adult patients with multiple sclerosis for 1 year. Clinical Trial Identifier: ClinicalTrials.gov, NCT03319732 |
format | Online Article Text |
id | pubmed-9968651 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-99686512023-02-28 Arbaclofen extended-release tablets for spasticity in multiple sclerosis: open-label extension study Okuda, Darin T Kantor, Daniel Jaros, Mark deVries, Tina Hunter, Samuel Brain Commun Original Article Baclofen, a racemic γ-aminobutyric acid B receptor agonist, is commonly used for the management of multiple sclerosis–related spasticity but is associated with frequent dosing and poor tolerability. Arbaclofen, the active R-enantiomer of baclofen, exhibits 100- to 1000-fold greater specificity for the γ-aminobutyric acid B receptor compared with the S-enantiomer and ∼5-fold greater potency compared with racemic baclofen. Arbaclofen extended-release tablets allow a dosing interval of 12 h and have shown a favourable safety and efficacy profile in early clinical development. A 12-week, randomized, placebo-controlled Phase 3 trial in adults with multiple sclerosis–related spasticity demonstrated that arbaclofen extended-release 40 mg/day significantly reduced spasticity symptoms compared with placebo and was safe and well tolerated. The current study is an open-label extension of the Phase 3 trial designed to evaluate the long-term safety and efficacy of arbaclofen extended-release. In a 52-week, open-label, multicentre study, adults with a Total Numeric-transformed Modified Ashworth Scale score ≥2 in the most affected limb received oral arbaclofen extended-release titrated over 9 days up to 80 mg/day based on tolerability. The primary objective was assessment of arbaclofen extended-release safety and tolerability. Secondary objectives included an assessment of efficacy using the Total Numeric-transformed Modified Ashworth Scale-most affected limb, the Patient Global Impression of Change and Expanded Disability Status Scale. Of 323 patients enrolled, 218 (67.5%) completed 1 year of treatment. Most patients (74.0%) achieved an arbaclofen extended-release maintenance dose of 80 mg/day. At least one treatment-emergent adverse event was reported by 278 patients (86.1%). The most common adverse events were [n patients (%)]: urinary tract disorder [112 (34.7)], muscle weakness [77 (23.8)], asthenia [61 (18.9)], nausea [70 (21.7)], dizziness [52 (16.1)], somnolence [41 (12.7)], vomiting [29 (9.0)], headache [24 (7.4)] and gait disturbance [20 (6.2)]. Most adverse events were of mild–moderate severity. Twenty-eight serious adverse events were reported. One death occurred during the study, a myocardial infarction that was considered by investigators as unlikely to be related to treatment. Overall, 14.9% of patients discontinued due to adverse events, primarily muscle weakness, multiple sclerosis relapse, asthenia and nausea. Evidence of improvement in multiple sclerosis–related spasticity was observed across arbaclofen extended-release dosages. Arbaclofen extended-release treatment (up to 80 mg/day) was well tolerated and reduced symptoms of spasticity in adult patients with multiple sclerosis for 1 year. Clinical Trial Identifier: ClinicalTrials.gov, NCT03319732 Oxford University Press 2023-02-07 /pmc/articles/PMC9968651/ /pubmed/36861013 http://dx.doi.org/10.1093/braincomms/fcad026 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Article Okuda, Darin T Kantor, Daniel Jaros, Mark deVries, Tina Hunter, Samuel Arbaclofen extended-release tablets for spasticity in multiple sclerosis: open-label extension study |
title | Arbaclofen extended-release tablets for spasticity in multiple sclerosis: open-label extension study |
title_full | Arbaclofen extended-release tablets for spasticity in multiple sclerosis: open-label extension study |
title_fullStr | Arbaclofen extended-release tablets for spasticity in multiple sclerosis: open-label extension study |
title_full_unstemmed | Arbaclofen extended-release tablets for spasticity in multiple sclerosis: open-label extension study |
title_short | Arbaclofen extended-release tablets for spasticity in multiple sclerosis: open-label extension study |
title_sort | arbaclofen extended-release tablets for spasticity in multiple sclerosis: open-label extension study |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9968651/ https://www.ncbi.nlm.nih.gov/pubmed/36861013 http://dx.doi.org/10.1093/braincomms/fcad026 |
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