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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; Lourenco, 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.
Afiliación
  • Germain DP; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Hughes DA; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Nicholls K; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Bichet DG; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Giugliani R; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Wilcox WR; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Feliciani C; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Shankar SP; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Ezgu F; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Amartino H; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Bratkovic D; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Feldt-Rasmussen U; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Nedd K; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Sharaf El Din U; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Lourenco CM; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Banikazemi M; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Charrow J; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Dasouki M; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Finegold D; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Giraldo P; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Goker-Alpan O; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Longo N; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Scott CR; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Torra R; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Tuffaha A; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Jovanovic A; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Waldek S; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Packman S; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Ludington E; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Viereck C; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Kirk J; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Yu J; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Benjamin ER; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Johnson F; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Lockhart DJ; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Skuban N; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Castelli J; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Barth J; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Barlow C; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
  • Schiffmann R; From the Division of Medical Genetics, University of Versailles, Paris-Saclay University, Versailles, and Assistance Publique-Hôpitaux de Paris, Paris - both in France (D.P.G.); the Department of Academic Haematology, Royal Free and University College Medical School, London (D.A.H.), Salford Royal N
N Engl J Med ; 375(6): 545-55, 2016 Aug 11.
Article en En | MEDLINE | ID: mdl-27509102
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 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].).
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Trihexosilceramidas / Enfermedad de Fabry / 1-Desoxinojirimicina / Alfa-Galactosidasa / Riñón Tipo de estudio: Clinical_trials / Diagnostic_studies / Etiology_studies Límite: Adolescent / Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: N Engl J Med Año: 2016 Tipo del documento: Article
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Trihexosilceramidas / Enfermedad de Fabry / 1-Desoxinojirimicina / Alfa-Galactosidasa / Riñón Tipo de estudio: Clinical_trials / Diagnostic_studies / Etiology_studies Límite: Adolescent / Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: N Engl J Med Año: 2016 Tipo del documento: Article