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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 Germain1*, Roberto Giugliani2, Derralynn A Hughes3, Atul Mehta3, Kathy Nicholls4, Laura Barisoni5, Charles J Jennette6, Alexander Bragat7, Jeff Castelli7, Sheela Sitaraman7, David J Lockhart7 and Pol F Boudes7

Author Affiliations

1 Division of Medical Genetics, Hôpital Raymond Poincaré (AP-HP), University of Versailles – St Quentin en Yvelines (UVSQ), Garches, 92380, France

2 Medical Genetics Service, HCPA/UFRGS, Porto Alegre, Brazil

3 Royal Free Campus, University College London, London, UK

4 Royal Melbourne Hospital, Parkville, VIC, Australia

5 New York University School of Medicine, New York, NY, USA

6 University of North Carolina, Chapel Hill, NC, USA

7 Amicus Therapeutics, Cranbury, NJ, USA

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Orphanet Journal of Rare Diseases 2012, 7:91  doi:10.1186/1750-1172-7-91

Published: 24 November 2012



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.


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.


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.


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 NCT00283959 and NCT00283933

Pharmacological chaperone; Conformational diseases; Protein-misfolding; Fabry disease; Lysosomal storage disorder