Low-dose agalsidase beta treatment in male pediatric patients with Fabry disease: A 5-year randomized controlled trial

Uma Ramaswami, Daniel G. Bichet, Lorne A. Clarke, Gabriela Dostalova, Alejandro Fainboim, Andreas Fellgiebel, Cassiano M. Forcelini, Kristina An Haack, Robert J. Hopkin, Michael Mauer, Behzad Najafian, C. Ronald Scott, Suma Shankar, Beth L. Thurberg, Camilla Tøndel, Anna Tylki-Szymanska, Bernard Bénichou, Frits A. Wijburg

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


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.

Original languageEnglish (US)
JournalMolecular Genetics and Metabolism
StatePublished - Jan 1 2019
Externally publishedYes


  • Agalsidase beta
  • Biopsy
  • Classic phenotype
  • Clinical outcomes
  • Enzyme replacement therapy
  • Fabry disease
  • Globotriaosylceramide
  • Pediatric
  • Podocytes
  • Superficial skin capillary endothelium
  • Symptoms

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology


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