title: Long-term therapy with agalsidase alfa for Fabry disease: safety and effects on renal function in a home infusion setting.
abstract: BACKGROUND
  Fabry disease is an X-linked disorder of glycosphingolipid catabolism that is the result of an intracellular deficiency in the lysosomal enzyme alpha-galactosidase A (alpha-Gal A). This enzymatic defect results in the accumulation of globotriaosylceramide (Gb(3)) within cells and causes progressive neurological, cardiovascular and renal dysfunction. Our objective is to describe the safety and renal effects of long-term enzyme replacement therapy.
  
  
  METHODS
  This was a single centre, prospective open-label treatment trial in 25 adult male Fabry patients who had completed a 6-month randomized placebo-controlled study and subsequently enrolled in an open-label extension study. Patients were treated every other week with agalsidase alfa (0.2 mg/kg) infused intravenously over 40 min. The main outcome measures were safety, antibody response and renal glomerular filtration rate (GFR).
  
  
  RESULTS
  During the 4-4.5 years of enzyme replacement therapy, all eligible subjects were able to transition to home therapy. Eight patients developed persistent IgG antibodies to agalsidase alfa, but IgE antibodies were not detected in any patient. The development of IgG antibodies appeared not to affect any clinical end points. Estimated GFR remained stable in subgroups of patients with Stage I (GFR >90 ml/min) or Stage II (GFR 60-89 ml/min) chronic kidney disease at baseline. In contrast, in the subgroup of patients with Stage III chronic kidney disease (GFR 30-59 ml/min), the slope of the decline in GFR was reduced compared with comparable historical controls, suggesting that enzyme replacement therapy was slowing the decline of renal function in this susceptible population.
  
  
  CONCLUSIONS
  Long-term enzyme replacement therapy with agalsidase alfa is safe and may slow the progressive decline in renal function that was commonly observed in adult males with Fabry disease.
authors.affiliation: Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke National Institutes of Health, Bethesda, MD 20892-1260, USA. rs4e@nih.gov
authors.forename: Raphael
authors.initials: R
authors.lastname: Schiffmann
authors.forename: Markus
authors.initials: M
authors.lastname: Ries
authors.forename: Margaret
authors.initials: M
authors.lastname: Timmons
authors.forename: John T
authors.initials: JT
authors.lastname: Flaherty
authors.forename: Roscoe O
authors.initials: RO
authors.lastname: Brady
mesh_terms: D000328:Adult; D000795:Fabry Disease / Q000188:drug therapy*; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006699:Home Care Services; D006801:Humans; D007262:Infusions, Intravenous; D007527:Isoenzymes / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D011446:Prospective Studies; D011994:Recombinant Proteins; D012449:Safety; D013997:Time Factors; D000519:alpha-Galactosidase / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D007527:Isoenzymes; D011994:Recombinant Proteins; C000627036:agalsidase alfa; D000519:alpha-Galactosidase