title: 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.
abstract: 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.
authors.affiliation: Division of Medical Genetics, Hôpital Raymond Poincaré (AP-HP), University of Versailles - St Quentin en Yvelines (UVSQ), Garches, 92380, France. dominique.germain@rpc.aphp.fr
authors.forename: Dominique P
authors.initials: DP
authors.lastname: Germain
authors.forename: Roberto
authors.initials: R
authors.lastname: Giugliani
authors.forename: Derralynn A
authors.initials: DA
authors.lastname: Hughes
authors.forename: Atul
authors.initials: A
authors.lastname: Mehta
authors.forename: Kathy
authors.initials: K
authors.lastname: Nicholls
authors.forename: Laura
authors.initials: L
authors.lastname: Barisoni
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Jennette
authors.forename: Alexander
authors.initials: A
authors.lastname: Bragat
authors.forename: Jeff
authors.initials: J
authors.lastname: Castelli
authors.forename: Sheela
authors.initials: S
authors.lastname: Sitaraman
authors.forename: David J
authors.initials: DJ
authors.lastname: Lockhart
authors.forename: Pol F
authors.initials: PF
authors.lastname: Boudes
mesh_terms: D000795:Fabry Disease / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D018832:Molecular Chaperones / Q000009:adverse effects / Q000627:therapeutic use*; D014281:Trihexosylceramides / Q000378:metabolism*; D000519:alpha-Galactosidase / Q000378:metabolism*
chemical_list: D018832:Molecular Chaperones; D014281:Trihexosylceramides; C018549:globotriaosylceramide; D000519:alpha-Galactosidase