title: A Phase 2 study of migalastat hydrochloride in females with Fabry disease: selection of population, safety and pharmacodynamic effects.
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 every other day (QOD) to females with FD.
  
  
  METHODS
  This was an open-label, uncontrolled, Phase 2 study of 12 weeks with extension to 48 weeks in nine females with FD. Doses of 50mg, 150 mg and 250 mg were given QOD. 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. Each individual GLA mutation was retrospectively categorized as being amenable or not to migalastat HCl based on an in vitro α-Gal A transfection assay developed in human embryonic kidney (HEK)-293 cells.
  
  
  RESULTS
  Migalastat HCl was generally well tolerated. Patients with amenable mutations seem to demonstrate greater pharmacodynamic response to migalastat HCl compared to patients with non-amenable mutations. The greatest declines in urine GL-3 were observed in the three patients with amenable GLA mutations that were treated with 150 or 250 mg migalastat HCl QOD. Additionally, these three patients all demonstrated decreases in GL-3 inclusions in kidney peri-tubular capillaries.
  
  
  CONCLUSIONS
  Migalastat HCl is a candidate oral pharmacological chaperone that provides a potential novel genotype-specific treatment for FD. Treatment resulted in GL-3 substrate decrease in female patients with amenable GLA mutations. Phase 3 studies are ongoing.
authors.affiliation: Medical Genetics Service, HCPA and Department of Genetics, UFRGS, Rua Ramiro Barcelos 2350, Porto Alegre 90035-903, RS, Brazil. rgiugliani@hcpa.ufrgs.br
authors.forename: R
authors.initials: R
authors.lastname: Giugliani
authors.forename: S
authors.initials: S
authors.lastname: Waldek
authors.forename: D P
authors.initials: DP
authors.lastname: Germain
authors.forename: K
authors.initials: K
authors.lastname: Nicholls
authors.forename: D G
authors.initials: DG
authors.lastname: Bichet
authors.forename: J K
authors.initials: JK
authors.lastname: Simosky
authors.forename: A C
authors.initials: AC
authors.lastname: Bragat
authors.forename: J P
authors.initials: JP
authors.lastname: Castelli
authors.forename: E R
authors.initials: ER
authors.lastname: Benjamin
authors.forename: P F
authors.initials: PF
authors.lastname: Boudes
mesh_terms: D017485:1-Deoxynojirimycin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000328:Adult; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D000795:Fabry Disease / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008875:Middle Aged; D009154:Mutation; D012867:Skin / Q000187:drug effects / Q000201:enzymology; D014162:Transfection; D000519:alpha-Galactosidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D017485:1-Deoxynojirimycin; C090092:migalastat; D000519:alpha-Galactosidase