Email updates

Keep up to date with the latest news and content from Orphanet Journal of Rare Diseases and BioMed Central.

Open Access Highly Accessed Research

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

For all author emails, please log on.

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

Published: 24 November 2012

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

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