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, S. P. 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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

209 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

ASJC Scopus subject areas

  • Medicine(all)

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