Most participants in the agalsidase beta phase 3 clinical trial in patients with classic Fabry disease experienced no severe clinical events during a 10-year follow-up period. D. P. Germain1, J. Charrow2, R. J. Desnick3, J. T. Ebels4, N. Guffon5, J. Kempf4, R. H. Lachmann6, R. Lemay4, G. E. Linthorst7, S. Packman8, C. R. Scott9, S. Waldek10, D. G. Warnock11, N. J. Weinreb12, W. R. Wilcox13 1) Division of Medical Genetics, University of Versailles - St Quentin en Yvelines, Versailles, France; Assistance Publique - Hôpitaux de Paris, Garches, France; 2) Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; 3) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 4) Genzyme, a Sanofi company, Cambridge, MA, USA; 5) Centre de Référence des Maladies Héréditaires du Métabolisme, Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Bron, France; 6) Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, United Kingdom; 7) Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, Netherlands; 8) Division of Medical Genetics, Department of Pediatrics, University of California San Francisco, CA, USA; 9) Department of Pediatrics, University of Washington, Seattle, WA, USA; 10) Salford Royal NHS Foundation Trust (retired Oct. 2011); 11) Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL, USA; 12) University Research Foundation for Lysosomal Storage Diseases, Coral Springs, FL, USA; 13) Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.

   Fabry disease (OMIM 301500) is an X-linked disorder caused by deficiency of the lysosomal enzyme -galactosidase A that results in accumulation of globotriaosylceramide (GL-3) and other glycosphingolipids in cells throughout the body. Signs and symptoms can begin in early childhood and lead to progressive life-threatening renal, cardiac, and cerebrovascular complications. In this study, the outcomes of 52 of 58 classic Fabry disease patients enrolled in the 1999 randomized, placebo-controlled, double-blind phase 3 agalsidase beta clinical trial were analyzed. Data from the phase 3 clinical trial, the phase 3 extension study (NCT00074971), and the Fabry Registry (NCT00196742), all sponsored by Genzyme, a Sanofi company, were used. During a median of 10 years of treatment, 81% of patients (42/52) did not experience any severe clinical event and 94% (49/52) were alive. Severe clinical events were defined as dialysis, kidney transplant, atrial fibrillation, congestive heart failure, myocardial infarction, major cardiac procedures, stroke, and death. Patients with a urine protein-to-creatinine ratio (UPCR) 0.5 g/g and 50% sclerotic glomeruli at baseline were classified as low renal involvement (LRI, n=32); patients with UPCR 0.5 g/g or 50% sclerotic glomeruli at baseline were classified as high renal involvement (HRI, n=20). The mean slope for estimated glomerular filtration rate (eGFR) for LRI was -1.88 ml/min/1.73 m2/year; the mean slope for eGFR for HRI was -6.82 ml/min/1.73 m2/year. In addition, the mean slopes for eGFR for patients who either maintained (n=20) or did not maintain UPCR values 0.5 g/g (n=12) within the LRI group throughout the treatment period were -1.48 and -2.6 mL/min/1.73m2/year, respectively. There were no significant changes in mean inter-ventricular septum thickness and left posterior wall thickness slopes. Patients classified as LRI started therapy a mean of 13 years younger than HRI (25 vs. 38 years of age). Mean plasma GL-3 levels decreased to normal levels within 6 months of treatment and remained normal. This 10-year study documents the effectiveness of treatment with agalsidase beta (1 mg/kg/two weeks) in patients with classic Fabry disease. Most patients remained event-free (81%) and alive (94%) during the 10-year follow-up period of the phase 3 study. Patients who initiated treatment at a younger age and with less severe kidney involvement benefited the most from agalsidase beta therapy.

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