Comparison of integrated white blood cell alpha-galactosidase a activity exposure between every-other-day orally administered migalastat and biweekly infusions of agalsidase beta or agalsidase alfa

Fabry disease is an x-linked α-galactosidase (α-Gal A) deficiency. It involves progressive globotriaosylcerimide (GL-3) accumulation, which affects multiple organs and organ systems including the kidney and heart. Currently approved treatments include once-every-other-week infusions with enzyme replacement therapies 1 mg/kg agalsidase beta or 0.2 mg/kg agalsidase alfa. Misfolded or unstable α-Gal A is degraded in the endoplasmic reticulum. Migalastat HCl is a low molecular weight iminosugar and is an analogue of the terminal galactose of GL-3 that binds to the active site of α-Gal A. Pre-clinical in vitro and in vivo studies have demonstrated that migalastat acts as a pharmacological chaperone for α-Gal A, selectively and reversibly binding, with high affinity, to the active site of both wild-type and specific mutant forms of α-Gal A, the genotypes of which are referred to as amenable mutations.a In in vitro and in vivo models bound migalastat stabilizes α-Gal A, slowing its denaturation at neutral pH and body temperature.b Migalastat binding stabilizes these mutant forms of α-Gal A in the endoplasmic reticulum facilitating their proper trafficking to lysosomes where dissociation of migalastat allows α-Gal A to reduce GL-3 storage material. In contrast, misfolded and/or unstable α-Gal A is recognized by the endoplasmic reticulum quality control system as aberrant and targeted for degradation, never reaching the lysosome.c The PK of migalastat has been well-characterized. Migalastat is dose proportional from 50 to 1250 mg, well absorbed in 3 hours, and has a terminal half-life of approximately 4 hours.d