A phase 1/2 clinical trial of enzyme replacement in Fabry disease: Pharmacokinetic, substrate clearance, and safety studies

被引:316
作者
Eng, CM
Banikazemi, M
Gordon, RE
Goldman, M
Phelps, R
Kim, L
Gass, A
Winston, J
Dikman, S
Fallon, JT
Brodie, S
Stacy, CB
Mehta, D
Parsons, R
Norton, K
O'Callaghan, M
Desnick, RJ
机构
[1] CUNY Mt Sinai Sch Med, Dept Human Genet, New York, NY 10029 USA
[2] CUNY Mt Sinai Sch Med, Dept Pathol, New York, NY 10029 USA
[3] CUNY Mt Sinai Sch Med, Dept Med, New York, NY 10029 USA
[4] CUNY Mt Sinai Sch Med, Dept Dermatol, New York, NY 10029 USA
[5] CUNY Mt Sinai Sch Med, Dept Ophthalmol, New York, NY 10029 USA
[6] CUNY Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA
[7] CUNY Mt Sinai Sch Med, Dept Radiol, New York, NY 10029 USA
[8] Genzyme Corp, Cambridge, MA USA
关键词
D O I
10.1086/318809
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Fabry disease results from deficient alpha -galactosidase A (alpha -Gal A) activity and the pathologic accumulation of the globotriaosylceramide (GL-3) and related glycosphingolipids, primarily in vascular endothelial lysosomes. Treatment is currently palliative, and affected patients generally die in their 40s or 50s. Preclinical studies of recombinant human alpha -Gal A (r-h alpha GalA) infusions in knockout mice demonstrated reduction of GL-3 in tissues and plasma, providing rationale for a phase 1/2 clinical trial. Here, we report a single-center, open-label, dose-ranging study of r-h alpha GalA treatment in 15 patients, each of whom received five infusions at one of five dose regimens. Intravenously administered r-h alpha GalA was cleared from the circulation in a dose-dependent manner, via both saturable and non-saturable pathways. Rapid and marked reductions in plasma and tissue GL-3 were observed biochemically, histologically, and/or ultrastructurally. Clearance of plasma GL-3 was dose-dependent. In patients with pre- and posttreatment biopsies, mean GL-3 content decreased 84% in liver (n = 13), was markedly reduced in kidney in four of five patients, and after five doses was modestly lowered in the endomyocardium of four of seven patients. GL-3 deposits were cleared to near normal or were markedly reduced in the vascular endothelium of liver, skin, heart, and kidney, on the basis of light- and electron-microscopic evaluation. In addition, patients reported less pain, increased ability to sweat, and improved quality-of-life measures. Infusions were well tolerated; four patients experienced mild-to-moderate reactions, suggestive of hypersensitivity, that were managed conservatively. Of 15 patients, 8 (53%) developed IgG antibodies to r-h alpha GalA; however, the antibodies were not neutralizing, as indicated by unchanged pharmacokinetic values for infusions 1 and 5. This study provides the basis for a phase 3 trial of enzyme-replacement therapy for Fabry disease.
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页码:711 / 722
页数:12
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