Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783259347971735552 |
---|---|
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. |
format | Online Article Text |
id | pubmed-5571484 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT byrnebarryj astudyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT geberhiwottarekegn astudyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT barshopbrucea astudyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT barohnrichard astudyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT hughesderralynn astudyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT bratkovicdrago astudyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT desnuelleclaude astudyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT laforetpascal astudyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT mengeleugen astudyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT robertsmark astudyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT haroldsenpeter astudyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT reilleykristin astudyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT jayaramkala astudyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT yangke astudyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT walshliron astudyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT astudyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT byrnebarryj studyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT geberhiwottarekegn studyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT barshopbrucea studyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT barohnrichard studyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT hughesderralynn studyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT bratkovicdrago studyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT desnuelleclaude studyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT laforetpascal studyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT mengeleugen studyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT robertsmark studyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT haroldsenpeter studyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT reilleykristin studyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT jayaramkala studyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT yangke studyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT walshliron studyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease AT studyonthesafetyandefficacyofreveglucosidasealfainpatientswithlateonsetpompedisease |