Byrne, BJ;
Geberhiwot, T;
Barshop, BA;
Barohn, R;
Hughes, D;
Bratkovic, D;
Desnuelle, C;
... Walsh, L; + view all
(2017)
A study on the safety and efficacy of reveglucosidase alfa in patients with late-onset Pompe disease.
Orphanet Journal of Rare Diseases
, 12
, Article 144. 10.1186/s13023-017-0693-2.
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Abstract
BACKGROUND: Late-onset Pompe disease is a rare genetic neuromuscular disorder caused by lysosomal acid alphaglucosidase (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.
| Type: | Article |
|---|---|
| Title: | A study on the safety and efficacy of reveglucosidase alfa in patients with late-onset Pompe disease |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1186/s13023-017-0693-2 |
| Publisher version: | http://dx.doi.org/10.1186/s13023-017-0693-2 |
| Language: | English |
| Additional information: | © The Author(s). 2017 Open Access This 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. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, Medicine, Research & Experimental, Research & Experimental Medicine, Reveglucosidase alfa, Late-onset Pompe disease, Enzyme replacement therapy, Pharmacokinetics, Safety, Efficacy, Respiratory, Pulmonary, ENZYME REPLACEMENT THERAPY, MANNOSE 6-PHOSPHATE RECEPTOR, FORCED VITAL CAPACITY, ALGLUCOSIDASE ALPHA, NONINVASIVE VENTILATION, INSPIRATORY PRESSURE, RESPIRATORY-FAILURE, GLUCOSIDASE, STORAGE, ADULTS |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1573183 |
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