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

Abstract

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.

• Authors: C M Eng, M Banikazemi, R E Gordon, M Goldman, R Phelps, L Kim, A Gass, J Winston, S Dikman, J T Fallon, S Brodie, C B Stacy, D Mehta, R Parsons, K Norton, M O'Callaghan, R J Desnick
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 68 Issue 3 Pg. 711-22 (Mar 2001) ISSN: 0002-9297 [Print] United States
• PMID: 11179018 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Recombinant Proteins
• alpha-Galactosidase

Topics

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