title: Long-term safety and efficacy of enzyme replacement therapy for Fabry disease.
abstract: Elsewhere, we reported the safety and efficacy results of a multicenter phase 3 trial of recombinant human alpha -galactosidase A (rh-alpha GalA) replacement in patients with Fabry disease. All 58 patients who were enrolled in the 20-wk phase 3 double-blind, randomized, and placebo-controlled study received subsequently 1 mg/kg of rh-alpha GalA (agalsidase beta, Fabrazyme, Genzyme Corporation) biweekly in an ongoing open-label extension study. Evidence of long-term efficacy, even in patients who developed IgG antibodies against rh- alpha GalA, included the continuously normal mean plasma globotriaosylceramide (GL-3) levels during 30 mo of the extension study and the sustained capillary endothelial GL-3 clearance in 98% (39/40) of patients who had a skin biopsy taken after treatment for 30 mo (original placebo group) or 36 mo (original enzyme-treated group). The mean serum creatinine level and estimated glomerular filtration rate also remained stable after 30-36 mo of treatment. Infusion-associated reactions decreased over time, as did anti-rh- alpha GalA IgG antibody titers. Among seroconverted patients, after 30-36 mo of treatment, seven patients tolerized (no detectable IgG antibody), and 59% had > or =4-fold reductions in antibody titers. As of 30 mo into the extension trial, three patients were withdrawn from the study because of positive serum IgE or skin tests; however, all have been rechallenged successfully at the time of this report. Thus, enzyme replacement therapy for 30-36 mo with agalsidase beta resulted in continuously decreased plasma GL-3 levels, sustained endothelial GL-3 clearance, stable kidney function, and a favorable safety profile.
authors.affiliation: Cedars-Sinai Burns and Allen Research Institute and UCLA School of Medicine, Los Angeles, CA, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Wilcox
authors.forename: Maryam
authors.initials: M
authors.lastname: Banikazemi
authors.forename: Nathalie
authors.initials: N
authors.lastname: Guffon
authors.forename: Stephen
authors.initials: S
authors.lastname: Waldek
authors.forename: Philip
authors.initials: P
authors.lastname: Lee
authors.forename: Gabor E
authors.initials: GE
authors.lastname: Linthorst
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
authors.forename: Dominique P
authors.initials: DP
authors.lastname: Germain
mesh_terms: D000328:Adult; D001706:Biopsy; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D000795:Fabry Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D007527:Isoenzymes / Q000627:therapeutic use*; D007668:Kidney / Q000098:blood supply / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D008657:Metabolic Clearance Rate; D010919:Placebos; D011994:Recombinant Proteins / Q000627:therapeutic use; D012867:Skin / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D014281:Trihexosylceramides / Q000032:analysis / Q000097:blood / Q000378:metabolism*; D000519:alpha-Galactosidase / Q000627:therapeutic use*
chemical_list: D007527:Isoenzymes; D010919:Placebos; D011994:Recombinant Proteins; D014281:Trihexosylceramides; D007073:Immunoglobulin E; C018549:globotriaosylceramide; D000519:alpha-Galactosidase; C459420:agalsidase beta