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

Abstract

Purpose: Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene. Migalastat, a pharmacological chaperone, binds to specific mutant forms of α-galactosidase A to restore lysosomal activity.

Methods: A pharmacogenetic assay was used to identify the α-galactosidase A mutant forms amenable to migalastat. Six hundred Fabry disease-causing mutations were expressed in HEK-293 (HEK) cells; increases in α-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 α-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.Genet Med 19 4, 430-438.

Trial registration: ClinicalTrials.gov NCT00214500 NCT00283959 NCT00283933 NCT00304512 NCT00925301 NCT01218659.

Figure 1

Substrate changes following migalastat treatment by amenability category. (a) (top): Kidney interstitial capillary GL-3 absolute change after 6 months of treatment with migalastat grouped by amenability category. Study 011 combines male and female patients receiving 6 months of migalastat (baseline to month 6 for patients randomized to migalastat at baseline, plus month 6 to month 12 for male patients receiving placebo from baseline to month 6). IC GL-3: mean number of GL-3 inclusions per interstitial capillary. Baseline refers to the kidney IC GL-3 value during the study 011 baseline visit (visit 1) for patients treated with migalastat during stages 1 and 2; it refers to the kidney IC GL-3 value at month 6 for patients treated with placebo during stage 1 and migalastat during stage 2. The mean (minimum, maximum) baseline IC GL-3 values for patients with amenable and nonamenable mutations were 0.646 (0.013, 5.692; n = 42) and 1.350 (0.117, 5.248; n = 14), respectively. After 6 months of treatment, the mean changes (95% confidence interval) from baseline for patients with amenable and nonamenable mutations were −0.282 (−0.455, −0.109; n = 42) and 0.324 (−0.105, 0.752; n = 14), respectively. The mean difference (95% confidence interval) in the change from baseline after 6 months (amenable minus nonamenable) was −0.606 (−1.059, −0.153). (b) (bottom): Plasma lyso-Gb₃ absolute change after 6 months of treatment with migalastat grouped by amenability category. Study 011 combines male and female patients receiving 6 months of migalastat (baseline to month 6 for patients randomized to migalastat at baseline, plus month 6 to month 12 for patients receiving placebo from baseline to month 6). Baseline refers to the plasma lyso-Gb₃ value during the study 011 baseline visit (visit 1) for patients treated with migalastat during stage 1 and stage 2; it refers to the kidney IC GL-3 value at month 6 in patients treated with placebo during stage 1 and migalastat during stage 2. The mean (minimum, maximum) baseline plasma lyso-Gb₃ values for patients with amenable and nonamenable mutations were 45.236 (1.187, 218.333; n = 31) and 74.396 (9.720, 249.333; n = 13), respectively. After 6 months of treatment, the mean changes (95% confidence interval) from baseline for patients with amenable and nonamenable mutations were −13.011 (−20.642, −5.380; n = 31) and 9.801 (−1.6478, 21.2498; n = 13), respectively. The mean difference (95% confidence interval) in the change from baseline after 6 months (amenable minus nonamenable) was −22.812 (−36.100, −9.524).

Figure 2

Plasma lyso-Gb₃ absolute change from baseline after treatment with migalastat grouped by GLA mutation category. Study 012 changes from baseline in patients with amenable and nonamenable GLA mutations. Blue dotted lines represent zero change from baseline. Left: Data points represent the mean, error bars represent the standard deviation, and values in parentheses represent the number (n) of patients with amenable mutations. At month 18, in patients with amenable mutations, the mean changes (95% confidence interval) from baseline for migalastat and ERT were 1.728 (−0.301, 3.758) and −1.926 (−4.632, 0.781), respectively. Right: Data points are from individual patients with nonamenable mutations. Lines represent the mean, values in parentheses represent the number (n) of patients with nonamenable mutations. Due to small sample sizes, no statistical comparisons were made for patients with nonamenable mutations. Data are based on patients with available samples for this analysis.