Abstract | BACKGROUND: 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.
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Authors | 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 |
Journal | Orphanet journal of rare diseases
(Orphanet J Rare Dis)
Vol. 7
Pg. 91
(Nov 24 2012)
ISSN: 1750-1172 [Electronic] England |
PMID | 23176611
(Publication Type: Clinical Trial, Phase II, Journal Article)
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Chemical References |
- Molecular Chaperones
- Trihexosylceramides
- globotriaosylceramide
- alpha-Galactosidase
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Topics |
- Fabry Disease
(drug therapy, enzymology, metabolism, pathology)
- Humans
- Male
- Molecular Chaperones
(adverse effects, therapeutic use)
- Trihexosylceramides
(metabolism)
- alpha-Galactosidase
(metabolism)
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