Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study.
Fabry disease is an X-linked lysosomal storage disorder caused byGLAmutations, resulting in α-galactosidase (α-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy (ERT), stabilises specific mutant (amenable) forms of α-Gal to facilitate normal lysosomal trafficking.



The main objective of the 18-month, randomised, active-controlled ATTRACT study was to assess the effects of migalastat on renal function in patients with Fabry disease previously treated with ERT. Effects on heart, disease substrate, patient-reported outcomes (PROs) and safety were also assessed.



Fifty-seven adults (56% female) receiving ERT (88% had multiorgan disease) were randomised (1.5:1), based on a preliminary cell-based assay of responsiveness to migalastat, to receive 18 months open-label migalastat or remain on ERT. Four patients had non-amenable mutant forms of α-Gal based on the validated cell-based assay conducted after treatment initiation and were excluded from primary efficacy analyses only. Migalastat and ERT had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment (-6.6 g/m2(-11.0 to -2.2)); there was no significant change with ERT. Predefined renal, cardiac or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following the switch from ERT to migalastat. PROs were comparable between groups. Migalastat was generally safe and well tolerated.



Migalastat offers promise as a first-in-class oral monotherapy alternative treatment to intravenous ERT for patients with Fabry disease and amenable mutations.



NCT00925301; Pre-results.
Department of Haematology, Royal Free London NHS Foundation Trust and University College London, London, UK.
Derralynn A
DA
Hughes
Department of Nephrology, Royal Melbourne Hospital, Parkville, Victoria, Australia.
Kathleen
K
Nicholls
Section of Vitreoretinal Surgery & Diseases, Emory University, Atlanta, Georgia, USA.
Suma P
SP
Shankar
Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
Gere
G
Sunder-Plassmann
Doernbecher Children's Hospital, Oregon Health & Science University, Portland, Oregon, USA.
David
D
Koeller
Infusion Associates, Grand Rapids, Missouri, USA.
Khan
K
Nedd
Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Gerard
G
Vockley
Infusion Associates, Grand Rapids, Missouri, USA.|Department of Pediatrics, Osaka City University Hospital, Osaka-shi, Japan.
Takashi
T
Hamazaki
Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK.
Robin
R
Lachmann
Jikei University Hospital, Tokyo, Japan.
Toya
T
Ohashi
Departmento Cuore e vasi, A.O.U. Careggi Firenze, Firenze, Italy.
Iacopo
I
Olivotto
Osaka City University Hospital, Osaka-shi, Japan.
Norio
N
Sakai
Lysosmal Disorders Unit, Department of Medicine, Addenbrooke's Hospital, Cambridge, UK.
Patrick
P
Deegan
Genetics Center MS716, Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA.
David
D
Dimmock
Univeritair Ziekenhaus Anterpen, Edegem, Belgium.
François
F
Eyskens
Division of Medical Genetics, University of Versailles, Paris-Saclay University and Assistance Publique-Hôpitaux de Paris, Paris, France.
Dominique P
DP
Germain
O & O Alpan LLC, Springfield, Virginia, USA.
Ozlem
O
Goker-Alpan
Service de Médecine, Hôpital Claude Huriez-CHRU Lille, Lille, France.
Eric
E
Hachulla
Department of Endocrinology and Metabolic Medicine, Salford Royal NHS Foundation Trust, Salford, UK.
Ana
A
Jovanovic
Hospital das Clínicas FMUSP-Ribeirão Preto, São Paulo, Ribeirão Preto, Brazil.
Charles M
CM
Lourenco
Niigata University Graduate School of Medicine and Dental Sciences, Niigata, Japan.
Ichiei
I
Narita
Royal Perth Hospital, Perth, New South Wales, Australia.
Mark
M
Thomas
Department of Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
William R
WR
Wilcox
Clinical Research Division, Hôpital du Sacré-Coeur de Montreal, University of Montreal, Montreal, Quebec, Canada.
Daniel G
DG
Bichet
Institute of Metabolic Disease, Baylor Research Institute, Dallas, Texas, USA.
Raphael
R
Schiffmann
Agility Clinical Inc., Carlsbad, California, USA.
Elizabeth
E
Ludington
Amicus Therapeutics Inc., Cranbury, New Jersey, USA.
Christopher
C
Viereck
Amicus Therapeutics Inc., Cranbury, New Jersey, USA.
John
J
Kirk
Amicus Therapeutics Inc., Cranbury, New Jersey, USA.
Julie
J
Yu
Amicus Therapeutics Inc., Cranbury, New Jersey, USA.
Franklin
F
Johnson
CymaBay Therapeutics, Inc., Newark, California, USA.
Pol
P
Boudes
Amicus Therapeutics Inc., Cranbury, New Jersey, USA.
Elfrida R
ER
Benjamin
TranscripTx, Inc., Sunnyvale, California, USA.
David J
DJ
Lockhart
Parkinson's Institute and Clinical Center, Sunnyvale, California, USA.
Carrolee
C
Barlow
Amicus Therapeutics Inc., Cranbury, New Jersey, USA.
Nina
N
Skuban
Amicus Therapeutics Inc., Cranbury, New Jersey, USA.
Jeffrey P
JP
Castelli
Amicus Therapeutics Inc., Cranbury, New Jersey, USA.
Jay
J
Barth
Department of Medical Endocrinology, Rigshospital, Copenhagen University Hospital, Copenhagen, Denmark.
Ulla
U
Feldt-Rasmussen
D017485:1-Deoxynojirimycin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D056947:Enzyme Replacement Therapy / Q000009:adverse effects; D000795:Fabry Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D000519:alpha-Galactosidase / Q000235:genetics*
D018832:Molecular Chaperones; D017485:1-Deoxynojirimycin; C090092:migalastat; D000519:alpha-Galactosidase
Fabry disease; Pharmacological chaperone; enzyme replacement therapy; lyso-Gb3; lysosomal storage disorder