Pharmacokinetics, pharmacodynamics, and safety of moss-aGalactosidase A in patients with Fabry disease.
J Inherit Metab Dis
; 42(3): 527-533, 2019 05.
Article
em En
| MEDLINE
| ID: mdl-30746723
ABSTRACT
Moss-aGalactosidase A (moss-aGal) is a moss-derived version of human α-galactosidase developed for enzyme replacement therapy in patients with Fabry disease. It exhibits a homogenous N-glycosylation profile with >90% mannose-terminated glycans. In contrast to mammalian cell produced α-galactosidase, moss-aGal does not rely on mannose-6-phosphate receptor mediated endocytosis but targets the mannose receptor for tissue uptake. We conducted a phase 1 clinical trial with moss-aGal in six patients with confirmed diagnosis of Fabry disease during a 28-day schedule. All patients received a single dose of 0.2 mg/kg moss-aGal by i.v.-infusion. Primary endpoints of the trial were safety and pharmacokinetics; secondary endpoints were pharmacodynamics by analyzing urine and plasma Gb3 and lyso-Gb3 concentrations. In all patients, the administered single dose was well tolerated. No safety issues were observed. Pharmacokinetic data revealed a stable nonlinear profile with a short plasma half-life of moss-aGal of 14 minutes. After one single dose of moss-aGal, urinary Gb3 concentrations decreased up to 23% 7 days and up to 60% 28 days post-dose. Plasma concentrations of lyso-Gb3 decreased by 3.8% and of Gb3 by 11% 28 days post-dose. These data reveal that a single dose of moss-aGal was safe, well tolerated, and led to a prolonged reduction of Gb3 excretion. As previously shown, moss-aGal is taken up via the mannose receptor, which is expressed on macrophages but also on endothelial and kidney cells. Thus, these data indicate that moss-aGal may target kidney cells. After these promising results, phase 2/3 clinical trials are in preparation.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Esfingolipídeos
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Glicolipídeos
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Doença de Fabry
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Alfa-Galactosidase
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Terapia de Reposição de Enzimas
Tipo de estudo:
Clinical_trials
Limite:
Adult
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Female
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Humans
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Male
/
Middle aged
País/Região como assunto:
Europa
Idioma:
En
Revista:
J Inherit Metab Dis
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Alemanha