title: 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.affiliation: Department of Human Genetics, Mount Sinai School of Medicine, Fifth Avenue and 100th Street, New York, NY, 10029, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Eng
authors.forename: M
authors.initials: M
authors.lastname: Banikazemi
authors.forename: R E
authors.initials: RE
authors.lastname: Gordon
authors.forename: M
authors.initials: M
authors.lastname: Goldman
authors.forename: R
authors.initials: R
authors.lastname: Phelps
authors.forename: L
authors.initials: L
authors.lastname: Kim
authors.forename: A
authors.initials: A
authors.lastname: Gass
authors.forename: J
authors.initials: J
authors.lastname: Winston
authors.forename: S
authors.initials: S
authors.lastname: Dikman
authors.forename: J T
authors.initials: JT
authors.lastname: Fallon
authors.forename: S
authors.initials: S
authors.lastname: Brodie
authors.forename: C B
authors.initials: CB
authors.lastname: Stacy
authors.forename: D
authors.initials: D
authors.lastname: Mehta
authors.forename: R
authors.initials: R
authors.lastname: Parsons
authors.forename: K
authors.initials: K
authors.lastname: Norton
authors.forename: M
authors.initials: M
authors.lastname: O'Callaghan
authors.forename: R J
authors.initials: RJ
authors.lastname: Desnick
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000795:Fabry Disease / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011994:Recombinant Proteins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D012867:Skin / Q000473:pathology; D014018:Tissue Distribution; D000519:alpha-Galactosidase / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D011994:Recombinant Proteins; D000519:alpha-Galactosidase