Safety and pharmacodynamic effects of a pharmacological chaperone on alpha-galactosidase A activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies

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  • Germain, Dominique P
    • Other Affiliation: Division of Medical Genetics, Hôpital Raymond Poincaré (AP-HP), University of Versailles – St Quentin en Yvelines (UVSQ), Garches, 92380, France
  • Giugliani, Roberto
    • Other Affiliation: Medical Genetics Service, HCPA/UFRGS, Porto Alegre, Brazil
  • Hughes, Derralynn A
    • Other Affiliation: Royal Free Campus, University College London, London, UK
  • Mehta, Atul
    • Other Affiliation: Royal Free Campus, University College London, London, UK
  • Nicholls, Kathy
    • Other Affiliation: Royal Melbourne Hospital, Parkville, VIC, Australia
  • Barisoni, Laura
    • Other Affiliation: New York University School of Medicine, New York, NY, USA
  • Jennette, Charles
  • Bragat, Alexander
    • Other Affiliation: Amicus Therapeutics, Cranbury, NJ, USA
  • Castelli, Jeff
    • Other Affiliation: Amicus Therapeutics, Cranbury, NJ, USA
  • Sitaraman, Sheela
    • Other Affiliation: Amicus Therapeutics, Cranbury, NJ, USA
  • Lockhart, David J
    • Other Affiliation: Amicus Therapeutics, Cranbury, NJ, USA
  • Boudes, Pol F
    • Other Affiliation: Amicus Therapeutics, Cranbury, NJ, USA
Abstract
  • 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. Trial registration Clinicaltrial.gov: NCT00283959 and NCT00283933
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  • Article
Rights statement
  • In Copyright
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  • Dominique P Germain et al.; licensee BioMed Central Ltd.
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Journal title
  • Orphanet Journal of Rare Diseases
Journal volume
  • 7
Journal issue
  • 1
Page start
  • 91
Language
  • English
Is the article or chapter peer-reviewed?
  • Yes
ISSN
  • 1750-1172
Bibliographic citation
  • Orphanet Journal of Rare Diseases. 2012 Nov 24;7(1):91
Publisher
  • BioMed Central Ltd
Access right
  • Open Access
Date uploaded
  • December 21, 2012

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