RT Journal Article
SR Electronic
T1 Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP jmedgenet-2016-104178
DO 10.1136/jmedgenet-2016-104178
A1 Derralynn A Hughes
A1 Kathleen Nicholls
A1 Suma P Shankar
A1 Gere Sunder-Plassmann
A1 David Koeller
A1 Khan Nedd
A1 Gerard Vockley
A1 Takashi Hamazaki
A1 Robin Lachmann
A1 Toya Ohashi
A1 Iacopo Olivotto
A1 Norio Sakai
A1 Patrick Deegan
A1 David Dimmock
A1 François Eyskens
A1 Dominique P Germain
A1 Ozlem Goker-Alpan
A1 Eric Hachulla
A1 Ana Jovanovic
A1 Charles M Lourenco
A1 Ichiei Narita
A1 Mark Thomas
A1 William R Wilcox
A1 Daniel G Bichet
A1 Raphael Schiffmann
A1 Elizabeth Ludington
A1 Christopher Viereck
A1 John Kirk
A1 Julie Yu
A1 Franklin Johnson
A1 Pol Boudes
A1 Elfrida R Benjamin
A1 David J Lockhart
A1 Carrolee Barlow
A1 Nina Skuban
A1 Jeffrey P Castelli
A1 Jay Barth
A1 Ulla Feldt-Rasmussen
YR 2016
UL http://jmg.bmj.com/content/early/2016/11/10/jmedgenet-2016-104178.abstract
AB 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.