N Engl J Med 2016 Aug;375(6):545-55
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 NHS Foundation Trust, Salford (A.J.), and University of Sunderland, Sunderland (S.W.) - all in the United Kingdom; the Department of Nephrology, Royal Melbourne Hospital, Parkville, VIC (K. Nicholls), and the Metabolic Clinic, Women's and Children's Hospital, Adelaide, SA (D.B.) - both in Australia; the Clinical Research Division, Hôpital du Sacré-Coeur, Montreal (D.G.B.); Medical Genetics Service, Clinic Hospital of Porto Alegre, Porto Alegre (R.G.), and Hospital das Clínicas Faculdade de Medicina da Universidade de São Paulo-Ribeirão Preto, Ribeirão Preto (C.M.L.) - both in Brazil; the Departments of Human Genetics (W.R.W., S.P.S.) and Ophthalmology (S.P.S.), Emory University School of Medicine, Atlanta; the Dermatology Unit, University of Parma, Parma, Italy (C.F.); the Faculty of Medicine, Department and Laboratory of Pediatric Metabolic Disorders, Gazi University, Ankara, Turkey (F.E.); the Department of Pediatrics, Hospital Alemán, Buenos Aires (H.A.); the Department of Medical Endocrinology, Rigshospital, Copenhagen University Hospital, Copenhagen (U.F.-R.); Infusion Associates, Grand Rapids, MI (K. Nedd); the Faculty of Medicine, Kasr El Ainy Hospital, Cairo (U.S.E.D.); New York Presbyterian Hospital, New York (M.B.); the Division of Genetics, Ann & Robert H. Lurie Children's Hospital of Chicago, and Northwestern University Feinberg School of Medicine, Chicago (J. Charrow); the Department of Urology, University of Kansas Medical Center, Kansas City (M.D., A.T.); Children's Hospital of Pittsburgh, Pittsburgh (D.F.); Hospital Miguel Servet, Zaragoza (P.G.), and Fundacio Puigvert, Universidad Autónoma de Barcelona, Barcelona (R.T.) - both in Spain; O & O Alpa
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].).