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Tytuł:
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Safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of the novel enzyme replacement therapy avalglucosidase alfa (neoGAA) in treatment-naïve and alglucosidase alfa-treated patients with late-onset Pompe disease: A phase 1, open-label, multicenter, multinational, ascending dose study.
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Autorzy:
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Pena LDM; Duke University Medical Center, Durham, NC, USA. Electronic address: .
Barohn RJ; University of Kansas Medical Center, Kansas City, KS, USA.
Byrne BJ; University of Florida, Gainesville, FL, USA.
Desnuelle C; University Hospital of Nice, Côte d'Azur University, Nice, France.
Goker-Alpan O; O and O Alpan LLC, Fairfax, VA, USA.
Ladha S; Barrow Neurological Institute, Phoenix, AZ, USA.
Laforêt P; Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France Service de Neurologie, Hôpital Raymond-Poincaré, Garches, AP-HP and INSERM U1179, Université Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, France.
Mengel KE; Villa Metabolica, Centre for Pediatric and Adolescent Medicine, University Medical Center, Mainz, Germany.
Pestronk A; Washington University School of Medicine, St Louis, MO, USA.
Pouget J; CHU Timone APHM, Marseille, France.
Schoser B; Friedrich-Baur-Institut, Department of Neurology Klinikum München, München, Germany.
Straub V; Newcastle University John Walton Muscular Dystrophy Research Centre, Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK.
Trivedi J; University of Texas Southwestern Medical Center, Dallas, TX, USA.
Van Damme P; KU Leuven (Catholic University of Leuven), Department of Neurosciences, VIB - Center for Brain & Disease Research, and University Hospitals Leuven, Department of Neurology, Leuven, Belgium.
Vissing J; Copenhagen Neuromuscular Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Young P; Department of Sleep Medicine and Neuromuscular Disorders, Universitätsklinikum Münster, Münster, Germany.
Kacena K; Sanofi Genzyme, Cambridge, MA, USA.
Shafi R; Sanofi Genzyme, Cambridge, MA, USA.
Thurberg BL; Sanofi Genzyme, Cambridge, MA, USA.
Culm-Merdek K; Sanofi Genzyme, Cambridge, MA, USA.
van der Ploeg AT; Erasmus Medical Center, Pompe Center, Rotterdam, The Netherlands.
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Corporate Authors:
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NEO1 Investigator Group
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Źródło:
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Neuromuscular disorders : NMD [Neuromuscul Disord] 2019 Mar; Vol. 29 (3), pp. 167-186. Date of Electronic Publication: 2018 Dec 17.
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Typ publikacji:
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Clinical Trial, Phase I; Journal Article; Multicenter Study; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Original Publication: Oxford ; New York : Pergamon Press, c1991-
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MeSH Terms:
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Enzyme Replacement Therapy*/adverse effects
Glucan 1,4-alpha-Glucosidase/*metabolism
Glycogen Storage Disease Type II/*drug therapy
alpha-Glucosidases/*pharmacology
Adult ; Female ; Glucan 1,4-alpha-Glucosidase/pharmacology ; Glycogen/metabolism ; Glycogen Storage Disease Type II/physiopathology ; Humans ; Male ; Middle Aged ; Treatment Outcome ; alpha-Glucosidases/adverse effects ; alpha-Glucosidases/drug effects ; alpha-Glucosidases/pharmacokinetics
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Contributed Indexing:
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Keywords: Alglucosidase alfa; Avalglucosidase alfa (neoGAA); Enzyme replacement therapy; Glycogen storage disease type II; Late-onset Pompe disease (LOPD); Lysosomal acid α-glucosidase (GAA) deficiency
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Substance Nomenclature:
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9005-79-2 (Glycogen)
EC 3.2.1.20 (GAA protein, human)
EC 3.2.1.20 (alpha-Glucosidases)
EC 3.2.1.3 (Glucan 1,4-alpha-Glucosidase)
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Entry Date(s):
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Date Created: 20190217 Date Completed: 20200601 Latest Revision: 20200601
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Update Code:
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20240105
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DOI:
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10.1016/j.nmd.2018.12.004
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PMID:
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30770310
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This multicenter/multinational, open-label, ascending-dose study (NCT01898364) evaluated safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of repeat-dose avalglucosidase alfa (neoGAA), a second-generation, recombinant acid α-glucosidase replacement therapy, in late-onset Pompe disease (LOPD). Patients ≥18 years, alglucosidase alfa naïve (Naïve) or previously receiving alglucosidase alfa for ≥9 months (Switch), with baseline FVC ≥50% predicted and independently ambulatory, received every-other-week avalglucosidase alfa 5, 10, or 20 mg/kg over 24 weeks. 9/10 Naïve and 12/14 Switch patients completed the study. Avalglucosidase alfa was well-tolerated; no deaths/life-threatening serious adverse events (SAEs). One Naïve patient withdrew for study drug-related SAEs (respiratory distress/chest discomfort). Infusion-associated reactions (IARs) affected 8 patients. Most treatment-emergent AEs/IARs were non-serious with mild-to-moderate intensity. At screening, 5 Switch patients tested positive for anti-avalglucosidase alfa antibodies; on-treatment, 2 Switch and 9 Naïve patients seroconverted. Post-infusion, avalglucosidase alfa plasma concentrations declined monoexponentially (t 1/2z ∼1.0 h). AUC was 5-6 × higher in the 20 vs 5 mg/kg group. Pharmacokinetics were similar between Switch and Naïve groups and over time. Baseline quadriceps muscle glycogen was low (∼6%) in most patients, generally remaining unchanged thereafter. Exploratory efficacy parameters (pulmonary function/functional capacity) generally remained stable or improved. Avalglucosidase alfa's well-tolerated safety profile and exploratory efficacy results support further avalglucosidase alfa development.
(Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)
