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.

2nd Department of Internal Medicine and Department of Cardiovascular Medicine Charles University Prague General University Hospital Prague Prague Czech Republic

Child and Family Research Institute University of British Columbia Vancouver BC Canada

Department of Pathology University of Washington Seattle WA USA

Department of Pediatric Metabolic Diseases Emma Children's Hospital and Amsterdam Lysosome Center Sphinx Academic Medical Center University Hospital of Amsterdam Amsterdam the Netherlands

Department of Pediatric Nutrition and Metabolic Diseases The Children's Memorial Health Institute Warsaw Poland

Department of Psychiatry and Psychotherapy University Medical Center Mainz Mainz Germany

Departments of Human Genetics and Ophthalmology Emory University School of Medicine Decatur GA USA

Departments of Pediatrics and Clinical Medicine Haukeland University Hospital Bergen Norway

Departments of Pediatrics and Medicine University of Minnesota Minneapolis MN USA

Division of Genetic Medicine Department of Pediatrics University of Washington School of Medicine Seattle WA USA

Division of Human Genetics Cincinnati Children's Hospital Medical Center University of Cincinnati College Medicine Cincinnati OH USA

Faculty of Medicine Universidade de Passo Fundo and Hospital São Vicente de Paulo Passo Fundo RS Brazil

Formerly Sanofi Genzyme Saint Germain en Laye Cedex France

Hospital de Niños Ricardo Gutierrez Hospital de Dia Polivalente Ciudad Autónoma de Buenos Aires Buenos Aires Argentina

Lysosomal Disorders Unit Institute of Immunity and Transplantation Royal Free London NHS Foundation Trust University College of London London United Kingdom

Nephrology Service Research Center Hôpital du Sacré Coeur de Montréal and University of Montreal Montreal QC Canada

Sanofi Genzyme Chilly Mazarin France

Sanofi Genzyme Framingham MA USA

References provided by Crossref.org

Early indicators of disease progression in Fabry disease that may indicate the need for disease-specific treatment initiation: findings from the opinion-based PREDICT-FD modified Delphi consensus initiative