TY - JOUR
T1 - A phase 1/2 clinical trial of enzyme replacement in Fabry disease
T2 - Pharmacokinetic, substrate clearance, and safety studies
AU - Eng, C. M.
AU - Banikazemi, M.
AU - Gordon, R. E.
AU - Goldman, M.
AU - Phelps, R.
AU - Kim, L.
AU - Gass, A.
AU - Winston, J.
AU - Dikman, S.
AU - Fallon, J. T.
AU - Brodie, S.
AU - Stacy, C. B.
AU - Mehta, D.
AU - Parsons, R.
AU - Norton, K.
AU - O'Callaghan, M.
AU - Desnick, R. J.
N1 - Funding Information:
The authors express their appreciation to the patients who participated in this trial, to our study coordinators (Melissa Nunn, B.A., and Athena Palearis, R.N.); to our medical fellows (Patricia Ashton-Prolla, M.D., and Kamal Topaloglu, M.D.); to our physician consultants (Mark W. Babyatsky, M.D., Meir Shinnar, M.D., and Swan N. Thung, M.D.); to the nursing and support staff of the General Clinical Research Center at the Mount Sinai School of Medicine, New York; and to our collaborators at the Genzyme Corporation (Richard Moscicki, M.D.; Susan Richards, Ph.D.; P. K. Tandon, Ph.D.; and their respective staffs). This work was supported in part by grants from the National Institutes of Health, including a Merit Award (5 R37 DK34045), a grant (5 M01 RR00071) for the Mount Sinai General Clinical Research Center, a grant (5 P30 HD28822) for the Mount Sinai Child Health Research Center, and a research grant from the Genzyme Corporation.
PY - 2001
Y1 - 2001
N2 - Fabry disease results from deficient α-galactosidase A (α-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 α-Gal A (r-hαGalA) 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-hαGalA treatment in 15 patients, each of whom received five infusions at one of five dose regimens. Intravenously administered r-hαGalA 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-hαGalA; 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.
AB - Fabry disease results from deficient α-galactosidase A (α-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 α-Gal A (r-hαGalA) 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-hαGalA treatment in 15 patients, each of whom received five infusions at one of five dose regimens. Intravenously administered r-hαGalA 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-hαGalA; 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.
UR - http://www.scopus.com/inward/record.url?scp=0035097499&partnerID=8YFLogxK
U2 - 10.1086/318809
DO - 10.1086/318809
M3 - Article
C2 - 11179018
AN - SCOPUS:0035097499
SN - 0002-9297
VL - 68
SP - 711
EP - 722
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 3
ER -