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.

Dominique P. Germain, Roberto Giugliani, Derralynn A. Hughes, Atul Mehta, Kathy Nicholls, Laura Barisoni, Charles J. Jennette, Alexander Bragat, Jeff Castelli, Sheela Sitaraman, David J. Lockhart, Pol F. Boudes

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

Abstract

Background: Fabry disease (FD) is a genetic disorder resulting from deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-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, alpha-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 alpha-Gal A activity of at least 50% was demonstrated in blood, skin and kidney in 6 of 9 patients. Patients' increased alpha-Gal A activities paralleled the alpha-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 alpha-Gal A activity also had GL-3 reduction in skin, urine and/or kidney, and had alpha-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 alpha-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 alpha-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.

Original languageEnglish (US)
JournalOrphanet journal of rare diseases
Volume7
DOIs
StatePublished - 2012
Externally publishedYes

ASJC Scopus subject areas

  • Genetics(clinical)
  • Pharmacology (medical)

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