TY - JOUR
T1 - Low-dose agalsidase beta treatment in male pediatric patients with Fabry disease
T2 - A 5-year randomized controlled trial
AU - Ramaswami, Uma
AU - Bichet, Daniel G.
AU - Clarke, Lorne A.
AU - Dostalova, Gabriela
AU - Fainboim, Alejandro
AU - Fellgiebel, Andreas
AU - Forcelini, Cassiano M.
AU - An Haack, Kristina
AU - Hopkin, Robert J.
AU - Mauer, Michael
AU - Najafian, Behzad
AU - Scott, C. Ronald
AU - Shankar, Suma P.
AU - Thurberg, Beth L.
AU - Tøndel, Camilla
AU - Tylki-Szymanska, Anna
AU - Bénichou, Bernard
AU - Wijburg, Frits A.
N1 - Publisher Copyright:
© 2019 The Authors
PY - 2019/5
Y1 - 2019/5
N2 - 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 5–18 years were randomized to receive agalsidase beta at 0.5 mg/kg 2-weekly (n = 16)or 1.0 mg/kg 4-weekly (n = 15)for 5 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%; P =.0215). No new clinical major organ complications were observed. GL-3 accumulation and cellular and vascular injury were present in baseline kidney biopsies (n = 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 5 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 1.0 mg/kg 2-weekly if these patients are considered for enzyme replacement therapy with agalsidase beta.
AB - 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 5–18 years were randomized to receive agalsidase beta at 0.5 mg/kg 2-weekly (n = 16)or 1.0 mg/kg 4-weekly (n = 15)for 5 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%; P =.0215). No new clinical major organ complications were observed. GL-3 accumulation and cellular and vascular injury were present in baseline kidney biopsies (n = 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 5 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 1.0 mg/kg 2-weekly if these patients are considered for enzyme replacement therapy with agalsidase beta.
KW - Agalsidase beta
KW - Biopsy
KW - Classic phenotype
KW - Clinical outcomes
KW - Enzyme replacement therapy
KW - Fabry disease
KW - Globotriaosylceramide
KW - Pediatric
KW - Podocytes
KW - Superficial skin capillary endothelium
KW - Symptoms
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U2 - 10.1016/j.ymgme.2019.03.010
DO - 10.1016/j.ymgme.2019.03.010
M3 - Article
C2 - 30987917
AN - SCOPUS:85064183980
SN - 1096-7192
VL - 127
SP - 86
EP - 94
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
IS - 1
ER -