A phase 1/2 clinical trial of enzyme replacement in fabry disease: pharmacokinetic, substrate clearance, and safety studies.

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-halphaGalA) 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-halphaGalA treatment in 15 patients, each of whom received five infusions at one of five dose regimens. Intravenously administered r-halphaGalA 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-halphaGalA; 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.

[1]  J. Ware.  SF-36 health survey: Manual and interpretation guide , 2003 .

[2]  R. Desnick,et al.  Fabry disease: preclinical studies demonstrate the effectiveness of alpha-galactosidase A replacement in enzyme-deficient mice. , 2001, American journal of human genetics.

[3]  R. Desnick.  α-Galactosidase A deficiency. Fabry disease , 2001 .

[4]  R. Schiffmann,et al.  Infusion of α-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease , 2000 .

[5]  R. Desnick,et al.  Quantitative determination of globotriaosylceramide by immunodetection of glycolipid-bound recombinant verotoxin B subunit. , 1999, Analytical biochemistry.

[6]  Y. Matsuzawa,et al.  Reduced plasma transforming growth factor-beta1 levels in patients with chronic hepatitis C after interferon-alpha therapy: association with regression of hepatic fibrosis. , 1999, Journal of hepatology.

[7]  P. Mistry.  Gaucher's disease: a model for modern management of a genetic disease. , 1999, Journal of hepatology.

[8]  N. Leslie,et al.  Enzyme therapy for Gaucher disease: the first 5 years. , 1998, Blood reviews.

[9]  R. Desnick,et al.  Human α-galactosidase A: characterization of the N-linked oligosaccharides on the intracellular and secreted glycoforms overexpressed by Chinese hamster ovary cells , 1998 .

[10]  C. Eng,et al.  Nature and frequency of mutations in the alpha-galactosidase A gene that cause Fabry disease. , 1993, American journal of human genetics.

[11]  R. Desnick,et al.  Overexpression of human alpha-galactosidase A results in its intracellular aggregation, crystallization in lysosomes, and selective secretion , 1992, The Journal of cell biology.

[12]  C. Eng,et al.  An atypical variant of Fabry's disease with manifestations confined to the myocardium. , 1991, The New England journal of medicine.

[13]  Ronald Melzack,et al.  The short-form McGill pain questionnaire , 1987, Pain.

[14]  R. Desnick,et al.  Human alpha-galactosidase A: nucleotide sequence of a cDNA clone encoding the mature enzyme. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[15]  K. J. Dean,et al.  Enzyme therapy XVII: metabolic and immunologic evaluation of alpha- galactosidase A replacement in Fabry disease. , 1980, Birth defects original article series.

[16]  K. J. Dean,et al.  Enzyme therapy in Fabry disease: differential in vivo plasma clearance and metabolic effectiveness of plasma and splenic alpha-galactosidase A isozymes. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[17]  S. Stubb,et al.  [Angiokeratoma corporis diffusum (Fabry's disease)]. , 1976, Duodecim; laaketieteellinen aikakauskirja.

[18]  R. Brady,et al.  Replacement therapy for inherited enzyme deficiency. Use of purified ceramidetrihexosidase in Fabry's disease. , 1973, The New England journal of medicine.

[19]  R. Desnick,et al.  Fabry's disease: enzymatic diagnosis of hemizygotes and heterozygotes. Alpha-galactosidase activities in plasma, serum, urine, and leukocytes. , 1973, The Journal of laboratory and clinical medicine.

[20]  R. Desnick,et al.  Enzyme Replacement in Fabry's Disease, an Inborn Error of Metabolism , 1970, Science.