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

Am J Hum Genet. 2001 Mar;68(3):711-22. doi: 10.1086/318809. Epub 2001 Feb 1.


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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Fabry Disease / blood
  • Fabry Disease / drug therapy*
  • Fabry Disease / pathology
  • Humans
  • Kidney / metabolism
  • Kidney / pathology
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Metabolic Clearance Rate
  • Mice
  • Mice, Knockout
  • Myocardium / metabolism
  • Myocardium / pathology
  • Recombinant Proteins / adverse effects
  • Recombinant Proteins / pharmacokinetics
  • Recombinant Proteins / therapeutic use
  • Skin / pathology
  • Tissue Distribution
  • alpha-Galactosidase / adverse effects
  • alpha-Galactosidase / pharmacokinetics*
  • alpha-Galactosidase / therapeutic use*


  • Recombinant Proteins
  • alpha-Galactosidase