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

• Main Authors: Germain Dominique P, Giugliani Roberto, Hughes Derralynn A, Mehta Atul, Nicholls Kathy, Barisoni Laura, Jennette Charles J, Bragat Alexander, Castelli Jeff, Sitaraman Sheela, Lockhart David J, Boudes Pol F
• Format: Article
• Language: English
• Published: BMC 2012-11-01
• Series: Orphanet Journal of Rare Diseases
• Subjects: Pharmacological chaperone; Conformational diseases; Protein-misfolding; Fabry disease; Lysosomal storage disorder
• Online Access: http://www.ojrd.com/content/7/1/91

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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 <it>in vitro</it> 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 <it>in vivo</it> had α-Gal A mutations that did not respond to migalastat HCl in transfected cells. Migalastat HCl was well tolerated.</p> <p>Conclusions</p> <p>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 <it>GLA</it> mutations. Phase 3 studies are ongoing.</p> <p>Trial registration</p> <p>Clinicaltrial.gov: NCT00283959 and NCT00283933</p>