The validation of pharmacogenetics for the identification of Fabry patients to be treated with migalastat

Purpose: Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the a-galactosidase A gene. Migalastat, a pharmacological chaperone, binds to specific mutant forms of a-galactosidase A to restore lysosomal activity. Methods: A phannacogenetic assay was used to identify the a-galactosidase A mutant forms amenable to migalastat. Six hundred Fabry disease causing mutations were expressed in HEK-293 (HEK) cells; increases in a-galactosidase A activity were measured by a good laboratory practice (GLP)-validated assay (GLP HEK/Migalastat Amenability Assay). The predictive value of the assay was assessed based on pharmacodynamic responses to migalastat in phase II and III clinical studies. Results: Comparison of the GLP HEK assay results in in vivo white blood cell a-galactosidase A responses to migalastat in male patients showed high sensitivity, specificity, and positive and negative predictive values (>= 0.875). GLP HEK assay results were also predictive of decreases in kidney globotriaosylceramide in males and plasma globotriaosylsphingosine in males and females. The clinical study subset of amenable mutations (n = 51) was representative of all 268 amenable mutations identified by the GLP HEK assay. Conclusion: The GLP HEK assay is a clinically validated method of identifying male and female Fabry patients for treatment with migalastat.