Efficacy of the pharmacologic chaperone migalastat in a subset of male patients with the classic phenotype of Fabry disease and migalastat-amenable variants: data from the phase 3 randomized, multicenter, double-blind clinical trial and extension study

Abstract

Purpose: Outcomes in patients with Fabry disease receiving migalastat during the phase 3 FACETS trial (NCT00925301) were evaluated by phenotype.

Methods: Data were evaluated in two subgroups of patients with migalastat-amenable GLA variants: "classic phenotype" (n = 14; males with residual peripheral blood mononuclear cell α-galactosidase A <3% normal and multiorgan system involvement) and "other patients" (n = 36; males not meeting classic phenotype criteria and all females). Endpoints included estimated glomerular filtration rate (eGFR), left ventricular mass index (LVMi), Gastrointestinal Symptoms Rating Scale diarrhea subscale (GSRS-D), renal peritubular capillary (PTC) globotriaosylceramide (GL-3) inclusions, and plasma globotriaosylsphingosine (lyso-Gb3).

Results: Baseline measures in the classic phenotype patients suggested a more severe phenotype. At month 24, mean (SD) annualized change in eGFRCKD-EPI with migalastat was -0.3 (3.76) mL/min/1.73 m2 in the classic phenotype subgroup; changes in LVMi, GSRS-D, and lyso-Gb3 were -16.7 (18.64) g/m2, -0.9 (1.66), and -36.8 (35.78) nmol/L, respectively. At month 6, mean PTC GL-3 inclusions decreased with migalastat (-0.8) and increased with placebo (0.3); switching from placebo to migalastat, PTC inclusions decreased by -0.7. Numerically smaller changes in these endpoints were observed in the other patients.

Conclusion: Migalastat provided clinical benefit to patients with Fabry disease and amenable variants, regardless of disease severity.

Keywords: Fabry disease; classic; migalastat; pharmacogenetics; precision medicine.

Conflict of interest statement

D.P.G. has received honoraria and research grants from Amicus, Sanofi Genzyme, and Shire. K.N. has served as an advisor for Amicus, Shire, and Sanofi Genzyme, has received research support from Amicus and Shire, and has received travel support from Sanofi Genzyme. R.G. has received honoraria from Amicus, BioMarin, Sanofi Genzyme, and Shire. D.G.B. has received research funding, serves as a consultant, and is on the speaker’s bureau for Amicus and Sanofi Genzyme, and has received research funding from Shire. D.A.H. has served as a consultant for and received research funding and honoraria from Amicus, Shire, Sanofi Genzyme, Protalix, and Actelion. L.M.B. has served as a consultant for Protalix. R.B.C. has served as a consultant for Amicus and has received grants from the National Institutes of Health. N.S., J.P.C., E.B., and J.A.B. are employees of and hold stock in Amicus. At the time the work was done, C.V. was an employee and held stock in Amicus. J.C.J. declares no conflicts of interest.

Figures

Fig. 1

Measurements of disease severity and treatment effect in the classic phenotype and other patient subgroups. (a) Mean annualized rate of change in estimated glomerular filtration rate (eGFR) and measured glomerular filtration rate (mGFR) from baseline to month 24. (b) Mean change in LVMi from baseline to month 24. (c) Mean change in GSRS-D from baseline to month 24. (d) Mean change from baseline to month 12 in average number of GL-3 inclusions per peritubular capillary. Within each subgroup, patients are grouped according to treatment allocation (migalastat to migalastat or placebo to migalastat). (e) Mean change from baseline to month 24 in plasma lyso-Gb3. aGroup is comprised of patients who switched from placebo to migalastat at month 6. bData are mean (SD) number of GL-3 inclusions per peritubular capillary at month 6 (i.e., after 6 months of placebo treatment). The upper cutoff value for normal plasma lyso-Gb3 level is 2.4 nmol/L.eGFRCKD-EPI estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation, GL-3 globotriaosylceramide, GSRS-D Gastrointestinal Symptoms Rating Scale diarrhea subscale, LVMi left ventricular mass index, lyso-Gb3 plasma globotriaosylsphingosine, mGFRiohexol glomerular filtration rate measured using iohexol clearance.

Fig. 2. Comparisons of published data for male patients with Fabry disease.

Annualized changes in (a) renal function and (b) LVMi as reported in the literature for male patients who are either untreated or have been treated with migalastat or ERT. aChange from baseline calculated using the weighted average for end-stage renal disease subgroups (n = 128 males with non-end-stage renal disease and n = 17 males with end-stage renal disease). eGFR estimated glomerular filtration rate, ERT enzyme replacement therapy, LVMi left ventricular mass index.