Abstract
BackgroundFabry 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.MethodsTwo 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.ResultsCompared 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.ConclusionsMigalastat 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.Trial registrationClinicaltrial.gov: NCT00283959 and NCT00283933
Highlights
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 two phase 2 studies exploring the safety and pharmacodynamic responses to migalastat HCl in male patients with FD
All patients carried a missense mutant α-Gal A that was considered to be responsive in the initial lymphocyte assay
Summary
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. Fabry disease (FD, OMIM 301500) is a rare, X-linked, multi-system genetic disorder [1]. Absent or deficient activity of lysosomal exoglycohydrolase α-galactosidase A (α-D-galactoside galactohydrolase, EC 3.2.1.22; α-Gal A) results in progressive accumulation of globotriaosylceramide (Gb3 or GL-3) and related glycosphingolipids within lysosomes in a variety of cell types, including capillary endothelial cells, and renal (podocytes, tubular cells, glomerular endothelial, mesangial and intersticial cells), and nerve cells [1]. Due to concerns regarding convenience, cost and incomplete effects on disease progression, unmet medical needs remain and other treatments are under investigation [1,4]
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