Safety and pharmacodynamic effects of a pharmacological chaperone on α-galactosidase A activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies.

Published online

Journal Article

BACKGROUND: Fabry disease (FD) is a genetic disorder resulting from deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A), which leads to globotriaosylceramide (GL-3) accumulation in multiple tissues. We report on the safety and pharmacodynamics of migalastat hydrochloride, an investigational pharmacological chaperone given orally at 150 mg every-other-day. METHODS: Two open-label uncontrolled phase 2 studies of 12 and 24 weeks (NCT00283959 and NCT00283933) in 9 males with FD were combined. At multiple time points, α-Gal A activity and GL-3 levels were quantified in blood cells, kidney and skin. GL-3 levels were also evaluated through skin and renal histology. RESULTS: Compared to baseline, increased α-Gal A activity of at least 50% was demonstrated in blood, skin and kidney in 6 of 9 patients. Patients' increased α-Gal A activities paralleled the α-Gal A increases observed in vitro in HEK-293 cells transfected with the corresponding mutant form of the enzyme. The same 6 patients who demonstrated increases of α-Gal A activity also had GL-3 reduction in skin, urine and/or kidney, and had α-Gal A mutations that responded in transfected cells incubated with the drug. The 3 patients who did not show a consistent response in vivo had α-Gal A mutations that did not respond to migalastat HCl in transfected cells. Migalastat HCl was well tolerated. CONCLUSIONS: Migalastat HCl is a candidate pharmacological chaperone that provides a novel genotype-specific treatment for FD. It enhanced α-Gal A activity and resulted in GL-3 substrate decrease in patients with responsive GLA mutations. Phase 3 studies are ongoing.

Full Text

Duke Authors

Cited Authors

  • Germain, DP; Giugliani, R; Hughes, DA; Mehta, A; Nicholls, K; Barisoni, L; Jennette, CJ; Bragat, A; Castelli, J; Sitaraman, S; Lockhart, DJ; Boudes, PF

Published Date

  • November 24, 2012

Published In

Volume / Issue

  • 7 /

Start / End Page

  • 91 -

PubMed ID

  • 23176611

Pubmed Central ID

  • 23176611

Electronic International Standard Serial Number (EISSN)

  • 1750-1172

Digital Object Identifier (DOI)

  • 10.1186/1750-1172-7-91

Language

  • eng

Conference Location

  • England