Treatment of Fabry's disease with the pharmacologic chaperone migalastat

D. P. Germain, D. A. Hughes, K. Nicholls, D. G. Bichet, R. Giugliani, W. R. Wilcox, C. Feliciani, Suma Shankar, F. Ezgu, H. Amartino, D. Bratkovic, U. Feldt-Rasmussen, K. Nedd, U. Sharaf El Din, C. M. Lourenco, M. Banikazemi, J. Charrow, M. Dasouki, D. Finegold, P. GiraldoO. Goker-Alpan, N. Longo, C. R. Scott, R. Torra, A. Tuffaha, A. Jovanovic, S. Waldek, S. Packman, E. Ludington, C. Viereck, J. Kirk, J. Yu, E. R. Benjamin, F. Johnson, D. J. Lockhart, N. Skuban, J. Castelli, J. Barth, C. Barlow, R. Schiffmann

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143 Scopus citations

Abstract

BACKGROUND: Fabry's disease, an X-linked disorder of lysosomal α-galactosidase deficiency, leads to substrate accumulation in multiple organs. Migalastat, an oral pharmacologic chaperone, stabilizes specific mutant forms of α-galactosidase, increasing enzyme trafficking to lysosomes. METHODS: The initial assay of mutant α-galactosidase forms that we used to categorize 67 patients with Fabry's disease for randomization to 6 months of double-blind migalastat or placebo (stage 1), followed by open-label migalastat from 6 to 12 months (stage 2) plus an additional year, had certain limitations. Before unblinding, a new, validated assay showed that 50 of the 67 participants had mutant α-galactosidase forms suitable for targeting by migalastat. The primary end point was the percentage of patients who had a response (≥50% reduction in the number of globotriaosylceramide inclusions per kidney interstitial capillary) at 6 months. We assessed safety along with disease substrates and renal, cardiovascular, and patient-reported outcomes. RESULTS: The primary end-point analysis, involving patients with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy, did not show a significant treatment effect: 13 of 32 patients (41%) who received migalastat and 9 of 32 patients (28%) who received placebo had a response at 6 months (P=0.30). Among patients with suitable mutant α-galactosidase who received migalastat for up to 24 months, the annualized changes from baseline in the estimated glomerular filtration rate (GFR) and measured GFR were -0.30±0.66 and -1.51±1.33 ml per minute per 1.73 m2 of body-surface area, respectively. The left-ventricular-mass index decreased significantly from baseline (-7.7 g per square meter; 95% confidence interval [CI], -15.4 to -0.01), particularly when left ventricular hypertrophy was present (-18.6 g per square meter; 95% CI, -38.2 to 1.0). The severity of diarrhea, reflux, and indigestion decreased. CONCLUSIONS: Among all randomly assigned patients (with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy), the percentage of patients who had a response at 6 months did not differ significantly between the migalastat group and the placebo group.

Original languageEnglish (US)
Pages (from-to)545-555
Number of pages11
JournalNew England Journal of Medicine
Volume375
Issue number6
DOIs
StatePublished - Aug 11 2016
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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    Germain, D. P., Hughes, D. A., Nicholls, K., Bichet, D. G., Giugliani, R., Wilcox, W. R., Feliciani, C., Shankar, S., Ezgu, F., Amartino, H., Bratkovic, D., Feldt-Rasmussen, U., Nedd, K., Sharaf El Din, U., Lourenco, C. M., Banikazemi, M., Charrow, J., Dasouki, M., Finegold, D., ... Schiffmann, R. (2016). Treatment of Fabry's disease with the pharmacologic chaperone migalastat. New England Journal of Medicine, 375(6), 545-555. https://doi.org/10.1056/NEJMoa1510198