Low-dose agalsidase beta treatment in male pediatric patients with Fabry disease: A 5-year randomized controlled trial.
Mol Genet Metab
; 127(1): 86-94, 2019 05.
Article
em En
| MEDLINE
| ID: mdl-30987917
ABSTRACT
BACKGROUND:
Fabry disease is a rare, X-linked, lifelong progressive lysosomal storage disorder. Severely deficient α-galactosidase A activity in males is associated with the classic phenotype with early-onset, multisystem manifestations evolving to vital organ complications during adulthood. We assessed the ability of 2 low-dose agalsidase beta regimens to lower skin, plasma, and urine globotriaosylceramide (GL-3) levels, and influence clinical manifestations in male pediatric Fabry patients.METHODS:
In this multicenter, open-label, parallel-group, phase 3b study, male patients aged 5-18â¯years were randomized to receive agalsidase beta at 0.5â¯mg/kg 2-weekly (nâ¯=â¯16) or 1.0â¯mg/kg 4-weekly (nâ¯=â¯15) for 5â¯years. All had plasma/urine GL-3 accumulation but no clinically evident organ involvement. The primary outcome was GL-3 accumulation in superficial skin capillary endothelium (SSCE).RESULTS:
The mean age was 11.6 (range 5-18) years and all but one of the 31 patients had classic GLA mutations. In the overall cohort, shifts from non-0 to 0-scores for SSCE GL-3 were significant at years 1, 3, and 5, but results were variable. Plasma GL-3 normalized and urine GL-3 reduced substantially. Higher anti-agalsidase beta antibody titers were associated with less robust SSCE GL-3 clearance and higher urine GL-3 levels. Renal function remained stable and normal. Most Fabry signs and symptoms tended to stabilize; abdominal pain was significantly reduced (-26.3%; Pâ¯=â¯.0215). No new clinical major organ complications were observed. GL-3 accumulation and cellular and vascular injury were present in baseline kidney biopsies (nâ¯=â¯7). Treatment effects on podocyte GL-3 content and foot process width were highly variable. Fabry arteriopathy overall increased in severity. Two patients withdrew and 2 had their agalsidase beta dose increased.CONCLUSIONS:
Our findings increase the limited amount of available data on long-term effects of enzyme replacement therapy in pediatric, classic Fabry patients. The low-dose regimens studied here over a period of 5â¯years did not demonstrate a consistent benefit among the patients in terms of controlling symptomatology, urine GL-3 levels, and pathological histology. The current available evidence supports treatment of pediatric, classic male Fabry patients at the approved agalsidase beta dose of 1.0â¯mg/kg 2-weekly if these patients are considered for enzyme replacement therapy with agalsidase beta.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doença de Fabry
/
Alfa-Galactosidase
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Terapia de Reposição de Enzimas
/
Isoenzimas
Tipo de estudo:
Clinical_trials
Limite:
Adolescent
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Child
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Child, preschool
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Humans
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Male
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article