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Sustained, Long-Term Renal Stabilization After 54 Months of Agalsidase Therapy in Patients with Fabry Disease

Dominique P. Germain^*, Stephen Waldek, Maryam Banikazemi, David A. Bushinsky, Joel Charrow^||, Robert J. Desnick, Philip Lee^¶, Thomas Loew^**, Anouk C. Vedder, Rekha Abichandani, William R. Wilcox and Nathalie Guffon^||||

^* Assistance Publique–Hôpitaux de Paris, Paris, France; Department of Renal Medicine, Salford Royal NHS Foundation Trust, Salford, United Kingdom; Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York; Nephrology Division, Department of Medicine, University of Rochester School of Medicine, Rochester, New York; ^|| Division of Genetics, Birth Defects, and Metabolism, Department of Pediatrics, Children's Memorial Hospital, Chicago, Illinois; ^¶ Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, United Kingdom; ^** Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Iowa Hospital & Clinics, Iowa City, Iowa; Department of Internal Medicine, Endocrinology and Metabolism, Academisch Medisch Centrum, Amsterdam, Netherlands; Genzyme Corp., Cambridge, Massachusetts; Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California; and ^|||| Hôpital Edouard Herriot, Lyon, France

Address correspondence to: Dr. Dominique P. Germain, Centre de Référence de la Maladie de Fabry et des Maladies Héréditaires du Tissu Conjonctif, Assistance Publique–Hôpitaux de Paris, Paris, France. Phone: +33-1-56-09-23-06; Fax: +33-1-56-09-24-80; E-mail: dominique.germain{at}egp.aphp.fr

Received for publication August 2, 2006. Accepted for publication February 21, 2007.

Fabry disease, an inherited deficiency of the lysosomal enzyme -galactosidase A, causes progressive intralysosomal accumulation of globotriaosylceramide (GL-3) and premature death from renal, cardiac, and cerebrovascular manifestations. To determine the long-term safety and efficacy of recombinant human -galactosidase A, an open-label, phase III extension study was conducted, involving 58 patients who had classic Fabry disease and completed a 20-wk, double-blind, randomized, placebo-controlled, phase III study of agalsidase and were transitioned to an extension trial to receive biweekly 1 mg/kg agalsidase for up to an additional 54 mo. GL-3 accumulation was evaluated in the capillary endothelia of the skin, kidney, and heart. Renal function was assessed. By month 54, all patients with optional kidney biopsies (n = 8) maintained complete GL-3 clearance in renal capillary endothelial cells and multiple cell types. Continued, complete clearance of skin (31 of 36) and heart (six of eight) capillary endothelium was demonstrated. Mean plasma GL-3 levels remained decreased in the normal range. Median serum creatinine and estimated GFR remained stable (normal) in patients with renal data at month 54 (n = 41). Six patients had renal disease progression; most (four of six) were older than 40 yr and had significant proteinuria at baseline and evidence of sclerotic glomeruli pretreatment. Adverse events were generally mild and unrelated to treatment. The most common treatment-related adverse events were infusion-associated reactions, which decreased over time. Long-term agalsidase therapy stabilizes renal function in patients without renal involvement at baseline, maintains reduction of plasma GL-3, and sustains GL-3 clearance in capillary endothelial cells and multiple renal cell types.

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