Safety and efficacy of recombinant human alpha-galactosidase a replacementtherapy in Fabry's disease.

Background: Fabry's disease, lysosomal alpha- galactosidase A deficiency, r esults from the progressive accumulation of globotriaosylceramide and relat ed glycosphingolipids. Affected patients have microvascular disease of the kidneys, heart, and brain. Methods: We evaluated the safety and effectiveness of recombinant alpha -ga lactosidase A in a multicenter, randomized, placebo-controlled, double-blin d study of 58 patients who were treated every 2 weeks for 20 weeks. Thereaf ter, all patients received recombinant alpha- galactosidase A in an open-la bel extension study. The primary efficacy end point was the percentage of p atients in whom renal microvascular endothelial deposits of globotriaosylce ramide were cleared (reduced to normal or near-normal levels). We also eval uated the histologic clearance of microvascular endothelial deposits of glo botriaosylceramide in the endomyocardium and skin, as well as changes in th e level of pain and the quality of life. Results: In the double-blind study, 20 of the 29 patients in the recombinan t alpha -galactosidase A group (69 percent) had no microvascular endothelia l deposits of globotriaosylceramide after 20 weeks, as compared with none o f the 29 patients in the placebo group (P<0.001). Patients in the recombina nt <alpha>-galactosidase A group also had decreased microvascular endotheli al deposits of globotriaosylceramide in the skin (P<0.001) and heart (P<0.0 01). Plasma levels of globotriaosylceramide were directly correlated with c learance of the microvascular deposits. After six months of open-label ther apy, all patients in the former placebo group and 98 percent of patients in the former recombinant alpha -galactosidase A group who had biopsies had c learance of microvascular endothelial deposits of globotriaosylceramide. Mi ld-to-moderate infusion reactions (i.e., rigors and fever) were more common in the recombinant alpha -galactosidase A group than in the placebo group. Conclusions: Recombinant alpha -galactosidase A replacement therapy cleared microvascular endothelial deposits of globotriaosylceramide from the kidne ys, heart, and skin in patients with Fabry's disease, reversing the pathoge nesis of the chief clinical manifestations of this disease. (N Engl J Med 2 001;345:9-16.) Copyright (C) 2001 Massachusetts Medical Society.