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A study on the safety and efficacy of reveglucosidase alfa in patients with late-onset Pompe disease

BACKGROUND: Late-onset Pompe disease is a rare genetic neuromuscular disorder caused by lysosomal acid alpha-glucosidase (GAA) deficiency that ultimately results in mobility loss and respiratory failure. Current enzyme replacement therapy with recombinant human (rh)GAA has demonstrated efficacy in s...

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Autores principales: Byrne, Barry J., Geberhiwot, Tarekegn, Barshop, Bruce A., Barohn, Richard, Hughes, Derralynn, Bratkovic, Drago, Desnuelle, Claude, Laforet, Pascal, Mengel, Eugen, Roberts, Mark, Haroldsen, Peter, Reilley, Kristin, Jayaram, Kala, Yang, Ke, Walsh, Liron
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571484/
https://www.ncbi.nlm.nih.gov/pubmed/28838325
http://dx.doi.org/10.1186/s13023-017-0693-2
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author Byrne, Barry J.
Geberhiwot, Tarekegn
Barshop, Bruce A.
Barohn, Richard
Hughes, Derralynn
Bratkovic, Drago
Desnuelle, Claude
Laforet, Pascal
Mengel, Eugen
Roberts, Mark
Haroldsen, Peter
Reilley, Kristin
Jayaram, Kala
Yang, Ke
Walsh, Liron
author_facet Byrne, Barry J.
Geberhiwot, Tarekegn
Barshop, Bruce A.
Barohn, Richard
Hughes, Derralynn
Bratkovic, Drago
Desnuelle, Claude
Laforet, Pascal
Mengel, Eugen
Roberts, Mark
Haroldsen, Peter
Reilley, Kristin
Jayaram, Kala
Yang, Ke
Walsh, Liron
author_sort Byrne, Barry J.
collection PubMed
description BACKGROUND: Late-onset Pompe disease is a rare genetic neuromuscular disorder caused by lysosomal acid alpha-glucosidase (GAA) deficiency that ultimately results in mobility loss and respiratory failure. Current enzyme replacement therapy with recombinant human (rh)GAA has demonstrated efficacy in subjects with late-onset Pompe disease. However, long-term effects of rhGAA on pulmonary function have not been observed, likely related to inefficient delivery of rhGAA to skeletal muscle lysosomes and associated deficits in the central nervous system. To address this limitation, reveglucosidase alfa, a novel insulin-like growth factor 2 (IGF2)-tagged GAA analogue with improved lysosomal uptake, was developed. This study evaluated the pharmacokinetics, safety, and exploratory efficacy of reveglucosidase alfa in 22 subjects with late-onset Pompe disease who were previously untreated with rhGAA. RESULTS: Reveglucosidase alfa plasma concentrations increased linearly with dose, and the elimination half-life was <1.2 h. Eighteen of 22 subjects completed 72 weeks of treatment. The most common adverse events were hypoglycemia (63%), dizziness, fall, headache, and nausea (55% for each). Serious adverse events included hypersensitivity (n = 1), symptomatic hypoglycemia (n = 2), presyncope (n = 1), and acute cardiac failure (n = 1). In the dose-escalation study, all treated subjects tested positive for anti-reveglucosidase alfa, anti-rhGAA, anti-IGF1, and anti-IGF2 antibodies at least once. Subjects receiving 20 mg/kg of reveglucosidase alfa demonstrated increases in predicted maximum inspiratory pressure (13.9%), predicted maximum expiratory pressure (8.0%), forced vital capacity (−0.4%), maximum voluntary ventilation (7.4 L/min), and mean absolute walking distance (22.3 m on the 6-min walk test) at 72 weeks. CONCLUSIONS: Additional studies are needed to further assess the safety and efficacy of this approach. Improvements in respiratory muscle strength, lung function, and walking endurance in subjects with LOPD may make up for the risk of hypersensitivity reactions and hypoglycemia. Reveglucosidase alfa may provide a new treatment option for patients with late-onset Pompe disease. TRIAL REGISTRATION: ISRCTN01435772 and ISRCTN01230801, registered 27 October 2011. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13023-017-0693-2) contains supplementary material, which is available to authorized users.
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spelling pubmed-55714842017-08-29 A study on the safety and efficacy of reveglucosidase alfa in patients with late-onset Pompe disease Byrne, Barry J. Geberhiwot, Tarekegn Barshop, Bruce A. Barohn, Richard Hughes, Derralynn Bratkovic, Drago Desnuelle, Claude Laforet, Pascal Mengel, Eugen Roberts, Mark Haroldsen, Peter Reilley, Kristin Jayaram, Kala Yang, Ke Walsh, Liron Orphanet J Rare Dis Research BACKGROUND: Late-onset Pompe disease is a rare genetic neuromuscular disorder caused by lysosomal acid alpha-glucosidase (GAA) deficiency that ultimately results in mobility loss and respiratory failure. Current enzyme replacement therapy with recombinant human (rh)GAA has demonstrated efficacy in subjects with late-onset Pompe disease. However, long-term effects of rhGAA on pulmonary function have not been observed, likely related to inefficient delivery of rhGAA to skeletal muscle lysosomes and associated deficits in the central nervous system. To address this limitation, reveglucosidase alfa, a novel insulin-like growth factor 2 (IGF2)-tagged GAA analogue with improved lysosomal uptake, was developed. This study evaluated the pharmacokinetics, safety, and exploratory efficacy of reveglucosidase alfa in 22 subjects with late-onset Pompe disease who were previously untreated with rhGAA. RESULTS: Reveglucosidase alfa plasma concentrations increased linearly with dose, and the elimination half-life was <1.2 h. Eighteen of 22 subjects completed 72 weeks of treatment. The most common adverse events were hypoglycemia (63%), dizziness, fall, headache, and nausea (55% for each). Serious adverse events included hypersensitivity (n = 1), symptomatic hypoglycemia (n = 2), presyncope (n = 1), and acute cardiac failure (n = 1). In the dose-escalation study, all treated subjects tested positive for anti-reveglucosidase alfa, anti-rhGAA, anti-IGF1, and anti-IGF2 antibodies at least once. Subjects receiving 20 mg/kg of reveglucosidase alfa demonstrated increases in predicted maximum inspiratory pressure (13.9%), predicted maximum expiratory pressure (8.0%), forced vital capacity (−0.4%), maximum voluntary ventilation (7.4 L/min), and mean absolute walking distance (22.3 m on the 6-min walk test) at 72 weeks. CONCLUSIONS: Additional studies are needed to further assess the safety and efficacy of this approach. Improvements in respiratory muscle strength, lung function, and walking endurance in subjects with LOPD may make up for the risk of hypersensitivity reactions and hypoglycemia. Reveglucosidase alfa may provide a new treatment option for patients with late-onset Pompe disease. TRIAL REGISTRATION: ISRCTN01435772 and ISRCTN01230801, registered 27 October 2011. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13023-017-0693-2) contains supplementary material, which is available to authorized users. BioMed Central 2017-08-24 /pmc/articles/PMC5571484/ /pubmed/28838325 http://dx.doi.org/10.1186/s13023-017-0693-2 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Byrne, Barry J.
Geberhiwot, Tarekegn
Barshop, Bruce A.
Barohn, Richard
Hughes, Derralynn
Bratkovic, Drago
Desnuelle, Claude
Laforet, Pascal
Mengel, Eugen
Roberts, Mark
Haroldsen, Peter
Reilley, Kristin
Jayaram, Kala
Yang, Ke
Walsh, Liron
A study on the safety and efficacy of reveglucosidase alfa in patients with late-onset Pompe disease
title A study on the safety and efficacy of reveglucosidase alfa in patients with late-onset Pompe disease
title_full A study on the safety and efficacy of reveglucosidase alfa in patients with late-onset Pompe disease
title_fullStr A study on the safety and efficacy of reveglucosidase alfa in patients with late-onset Pompe disease
title_full_unstemmed A study on the safety and efficacy of reveglucosidase alfa in patients with late-onset Pompe disease
title_short A study on the safety and efficacy of reveglucosidase alfa in patients with late-onset Pompe disease
title_sort study on the safety and efficacy of reveglucosidase alfa in patients with late-onset pompe disease
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571484/
https://www.ncbi.nlm.nih.gov/pubmed/28838325
http://dx.doi.org/10.1186/s13023-017-0693-2
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