Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Standard
Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat. / Germain, Dominique P; Hughes, Derralynn A; Nicholls, Kathleen; Bichet, Daniel G; Giugliani, Roberto; Wilcox, William R; Feliciani, Claudio; Shankar, Suma P; Ezgu, Fatih; Amartino, Hernan; Bratkovic, Drago; Feldt-Rasmussen, Ulla; Nedd, Khan; Sharaf El Din, Usama; Lourenço, Charles M; Banikazemi, Maryam; Charrow, Joel; Dasouki, Majed; Finegold, David; Giraldo, Pilar; Goker-Alpan, Ozlem; Longo, Nicola; Scott, C Ronald; Torra, Roser; Tuffaha, Ahmad; Jovanovic, Ana; Waldek, Stephen; Packman, Seymour; Ludington, Elizabeth; Viereck, Christopher; Kirk, John; Yu, Julie; Benjamin, Elfrida R; Johnson, Franklin; Lockhart, David J; Skuban, Nina; Castelli, Jeff; Barth, Jay; Barlow, Carrolee; Schiffmann, Raphael.
I: New England Journal of Medicine, Bind 375, Nr. 6, 11.08.2016, s. 545-555.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
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 -
ID: 179042871