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J Med Genet. 2017 Apr;54(4):288-296. doi: 10.1136/jmedgenet-2016-104178. Epub 2016 Nov 10.

Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study.

Author information

1
Department of Haematology, Royal Free London NHS Foundation Trust and University College London, London, UK.
2
Department of Nephrology, Royal Melbourne Hospital, Parkville, Victoria, Australia.
3
Section of Vitreoretinal Surgery & Diseases, Emory University, Atlanta, Georgia, USA.
4
Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
5
Doernbecher Children's Hospital, Oregon Health & Science University, Portland, Oregon, USA.
6
Infusion Associates, Grand Rapids, Missouri, USA.
7
Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
8
Department of Pediatrics, Osaka City University Hospital, Osaka-shi, Japan.
9
Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK.
10
Jikei University Hospital, Tokyo, Japan.
11
Departmento Cuore e vasi, A.O.U. Careggi Firenze, Firenze, Italy.
12
Osaka City University Hospital, Osaka-shi, Japan.
13
Lysosmal Disorders Unit, Department of Medicine, Addenbrooke's Hospital, Cambridge, UK.
14
Genetics Center MS716, Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA.
15
Univeritair Ziekenhaus Anterpen, Edegem, Belgium.
16
Division of Medical Genetics, University of Versailles, Paris-Saclay University and Assistance Publique-Hôpitaux de Paris, Paris, France.
17
O & O Alpan LLC, Springfield, Virginia, USA.
18
Service de Médecine, Hôpital Claude Huriez-CHRU Lille, Lille, France.
19
Department of Endocrinology and Metabolic Medicine, Salford Royal NHS Foundation Trust, Salford, UK.
20
Hospital das Clínicas FMUSP-Ribeirão Preto, São Paulo, Ribeirão Preto, Brazil.
21
Niigata University Graduate School of Medicine and Dental Sciences, Niigata, Japan.
22
Royal Perth Hospital, Perth, New South Wales, Australia.
23
Department of Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
24
Clinical Research Division, Hôpital du Sacré-Coeur de Montreal, University of Montreal, Montreal, Quebec, Canada.
25
Institute of Metabolic Disease, Baylor Research Institute, Dallas, Texas, USA.
26
Agility Clinical Inc., Carlsbad, California, USA.
27
Amicus Therapeutics Inc., Cranbury, New Jersey, USA.
28
CymaBay Therapeutics, Inc., Newark, California, USA.
29
TranscripTx, Inc., Sunnyvale, California, USA.
30
Parkinson's Institute and Clinical Center, Sunnyvale, California, USA.
31
Department of Medical Endocrinology, Rigshospital, Copenhagen University Hospital, Copenhagen, Denmark.

Abstract

BACKGROUND:

Fabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, 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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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

TRIAL REGISTRATION NUMBER:

NCT00925301; Pre-results.

KEYWORDS:

Fabry disease; Pharmacological chaperone; enzyme replacement therapy; lyso-Gb3; lysosomal storage disorder

PMID:
27834756
PMCID:
PMC5502308
DOI:
10.1136/jmedgenet-2016-104178
[Indexed for MEDLINE]
Free PMC Article

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