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

ABSTRACT: Fabry disease (FD) is a genetic disorder resulting from deficiency of the lysosomal enzyme ?-galactosidase A (?-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.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, ?-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.Compared to baseline, increased ?-Gal A activity of at least 50% was demonstrated in blood, skin and kidney in 6 of 9 patients. Patients' increased ?-Gal A activities paralleled the ?-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 ?-Gal A activity also had GL-3 reduction in skin, urine and/or kidney, and had ?-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 ?-Gal A mutations that did not respond to migalastat HCl in transfected cells. Migalastat HCl was well tolerated.Migalastat HCl is a candidate pharmacological chaperone that provides a novel genotype-specific treatment for FD. It enhanced ?-Gal A activity and resulted in GL-3 substrate decrease in patients with responsive GLA mutations. Phase 3 studies are ongoing.

SUBMITTER: Germain DP 

PROVIDER: S-EPMC3527132 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature