TY - JOUR

T1 - Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat

AU - Germain, Dominique P

AU - Hughes, Derralynn A

AU - Nicholls, Kathleen

AU - Bichet, Daniel G

AU - Giugliani, Roberto

AU - Wilcox, William R

AU - Feliciani, Claudio

AU - Shankar, Suma P

AU - Ezgu, Fatih

AU - Amartino, Hernan

AU - Bratkovic, Drago

AU - Feldt-Rasmussen, Ulla

AU - Nedd, Khan

AU - Sharaf El Din, Usama

AU - Lourenço, Charles M

AU - Banikazemi, Maryam

AU - Charrow, Joel

AU - Dasouki, Majed

AU - Finegold, David

AU - Giraldo, Pilar

AU - Goker-Alpan, Ozlem

AU - Longo, Nicola

AU - Scott, C Ronald

AU - Torra, Roser

AU - Tuffaha, Ahmad

AU - Jovanovic, Ana

AU - Waldek, Stephen

AU - Packman, Seymour

AU - Ludington, Elizabeth

AU - Viereck, Christopher

AU - Kirk, John

AU - Yu, Julie

AU - Benjamin, Elfrida R

AU - Johnson, Franklin

AU - Lockhart, David J

AU - Skuban, Nina

AU - Castelli, Jeff

AU - Barth, Jay

AU - Barlow, Carrolee

AU - Schiffmann, Raphael

PY - 2016/8/11

Y1 - 2016/8/11

N2 - 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 m(2) 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. (Funded by Amicus Therapeutics; ClinicalTrials.gov numbers, NCT00925301 [study AT1001-011] and NCT01458119 [study AT1001-041].).

AB - 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 m(2) 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. (Funded by Amicus Therapeutics; ClinicalTrials.gov numbers, NCT00925301 [study AT1001-011] and NCT01458119 [study AT1001-041].).

KW - 1-Deoxynojirimycin

KW - Adolescent

KW - Adult

KW - Aged

KW - Diarrhea

KW - Double-Blind Method

KW - Fabry Disease

KW - Female

KW - Glomerular Filtration Rate

KW - Heart Ventricles

KW - Humans

KW - Hypertrophy, Left Ventricular

KW - Kidney

KW - Male

KW - Middle Aged

KW - Mutation

KW - Trihexosylceramides

KW - Ultrasonography

KW - Young Adult

KW - alpha-Galactosidase

KW - Clinical Trial, Phase III

KW - Journal Article

KW - Randomized Controlled Trial

KW - Research Support, Non-U.S. Gov't

U2 - 10.1056/NEJMoa1510198

DO - 10.1056/NEJMoa1510198

M3 - Journal article

C2 - 27509102

VL - 375

SP - 545

EP - 555

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 6

ER -