Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat

Dominique P Germain; Derralynn A Hughes; Kathleen Nicholls; Daniel G Bichet; Roberto Giugliani; William R Wilcox; Claudio Feliciani; Suma P Shankar; Fatih Ezgu; Hernan Amartino; Drago Bratkovic; Ulla Feldt-Rasmussen; Khan Nedd; Usama Sharaf El Din; Charles M Lourenço; Maryam Banikazemi; Joel Charrow; Majed Dasouki; David Finegold; Pilar Giraldo; Ozlem Goker-Alpan; Nicola Longo; C Ronald Scott; Roser Torra; Ahmad Tuffaha; Ana Jovanovic; Stephen Waldek; Seymour Packman; Elizabeth Ludington; Christopher Viereck; John Kirk; Julie Yu; Elfrida R Benjamin; Franklin Johnson; David J Lockhart; Nina Skuban; Jeff Castelli; Jay Barth; Carrolee Barlow; Raphael Schiffmann

doi:10.1056/nejmoa1510198

Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat

Dominique P Germain, Derralynn A Hughes, Kathleen Nicholls, Daniel G Bichet, Roberto Giugliani, William R Wilcox, Claudio Feliciani, Suma P Shankar, Fatih Ezgu, Hernan Amartino, Drago Bratkovic, Ulla Feldt-Rasmussen, Khan Nedd, Usama Sharaf El Din, Charles M Lourenço, Maryam Banikazemi, Joel Charrow, Majed Dasouki, David Finegold, Pilar GiraldoOzlem Goker-Alpan, Nicola Longo, C Ronald Scott, Roser Torra, Ahmad Tuffaha, Ana Jovanovic, Stephen Waldek, Seymour Packman, Elizabeth Ludington, Christopher Viereck, John Kirk, Julie Yu, Elfrida R Benjamin, Franklin Johnson, David J Lockhart, Nina Skuban, Jeff Castelli, Jay Barth, Carrolee Barlow, Raphael Schiffmann

Department of Clinical Medicine

195 Citations (Scopus)

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 language	English
Journal	New England Journal of Medicine
Volume	375
Issue number	6
Pages (from-to)	545-555
Number of pages	11
ISSN	0028-4793
DOIs	https://doi.org/10.1056/nejmoa1510198
Publication status	Published - 11 Aug 2016

Keywords

1-Deoxynojirimycin
Adolescent
Adult
Aged
Diarrhea
Double-Blind Method
Fabry Disease
Female
Glomerular Filtration Rate
Heart Ventricles
Humans
Hypertrophy, Left Ventricular
Kidney
Male
Middle Aged
Mutation
Trihexosylceramides
Ultrasonography
Young Adult
alpha-Galactosidase
Clinical Trial, Phase III
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1056/nejmoa1510198

untitled.pdfFinal published version, 408 KB

Cite this

Germain, D. P., Hughes, D. A., Nicholls, K., Bichet, D. G., Giugliani, R., Wilcox, W. R., Feliciani, C., Shankar, S. P., Ezgu, F., Amartino, H., Bratkovic, D., Feldt-Rasmussen, U., Nedd, K., Sharaf El Din, U., Lourenço, 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

Germain, DP, Hughes, DA, Nicholls, K, Bichet, DG, Giugliani, R, Wilcox, WR, Feliciani, C, Shankar, SP, Ezgu, F, Amartino, H, Bratkovic, D, Feldt-Rasmussen, U, Nedd, K, Sharaf El Din, U, Lourenço, CM, Banikazemi, M, Charrow, J, Dasouki, M, Finegold, D, Giraldo, P, Goker-Alpan, O, Longo, N, Scott, CR, Torra, R, Tuffaha, A, Jovanovic, A, Waldek, S, Packman, S, Ludington, E, Viereck, C, Kirk, J, Yu, J, Benjamin, ER, Johnson, F, Lockhart, DJ, Skuban, N, Castelli, J, Barth, J, Barlow, C & Schiffmann, R 2016, 'Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat', New England Journal of Medicine, vol. 375, no. 6, pp. 545-555. https://doi.org/10.1056/nejmoa1510198

@article{ccb7f38823d64f4d89bc0dc7a4e164f8,

title = "Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat",

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.",

keywords = "1-Deoxynojirimycin, Adolescent, Adult, Aged, Diarrhea, Double-Blind Method, Fabry Disease, Female, Glomerular Filtration Rate, Heart Ventricles, Humans, Hypertrophy, Left Ventricular, Kidney, Male, Middle Aged, Mutation, Trihexosylceramides, Ultrasonography, Young Adult, alpha-Galactosidase, Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't",

author = "Germain, {Dominique P} and Hughes, {Derralynn A} and Kathleen Nicholls and Bichet, {Daniel G} and Roberto Giugliani and Wilcox, {William R} and Claudio Feliciani and Shankar, {Suma P} and Fatih Ezgu and Hernan Amartino and Drago Bratkovic and Ulla Feldt-Rasmussen and Khan Nedd and {Sharaf El Din}, Usama and Louren{\c c}o, {Charles M} and Maryam Banikazemi and Joel Charrow and Majed Dasouki and David Finegold and Pilar Giraldo and Ozlem Goker-Alpan and Nicola Longo and Scott, {C Ronald} and Roser Torra and Ahmad Tuffaha and Ana Jovanovic and Stephen Waldek and Seymour Packman and Elizabeth Ludington and Christopher Viereck and John Kirk and Julie Yu and Benjamin, {Elfrida R} and Franklin Johnson and Lockhart, {David J} and Nina Skuban and Jeff Castelli and Jay Barth and Carrolee Barlow and Raphael Schiffmann",

year = "2016",

month = aug,

day = "11",

doi = "10.1056/nejmoa1510198",

language = "English",

volume = "375",

pages = "545--555",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachusetts Medical Society",

number = "6",

}

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 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.

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 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.

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

SN - 0028-4793

VL - 375

SP - 545

EP - 555

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 6

ER -

Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this