TY - JOUR
T1 - Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease
T2 - 18-month results from the randomised phase III ATTRACT study
AU - Hughes, Derralynn A.
AU - Nicholls, Kathleen
AU - Shankar, Suma P.
AU - Sunder-Plassmann, Gere
AU - Koeller, David
AU - Nedd, Khan
AU - Vockley, Gerard
AU - Hamazaki, Takashi
AU - Lachmann, Robin
AU - Ohashi, Toya
AU - Olivotto, Iacopo
AU - Sakai, Norio
AU - Deegan, Patrick
AU - Dimmock, David
AU - Eyskens, François
AU - Germain, Dominique P.
AU - Goker-Alpan, Ozlem
AU - Hachulla, Eric
AU - Jovanovic, Ana
AU - Lourenco, Charles M.
AU - Narita, Ichiei
AU - Thomas, Mark
AU - Wilcox, William R.
AU - Bichet, Daniel G.
AU - Schiffmann, Raphael
AU - Ludington, Elizabeth
AU - Viereck, Christopher
AU - Kirk, John
AU - Yu, Julie
AU - Johnson, Franklin
AU - Boudes, Pol
AU - Benjamin, Elfrida R.
AU - Lockhart, David J.
AU - Barlow, Carrolee
AU - Skuban, Nina
AU - Castelli, Jeffrey P.
AU - Barth, Jay
AU - Feldt-Rasmussen, Ulla
PY - 2017/4
Y1 - 2017/4
N2 - 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 nonamenable 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.
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 nonamenable 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.
U2 - 10.1136/jmedgenet-2016-104178
DO - 10.1136/jmedgenet-2016-104178
M3 - Journal article
C2 - 27834756
AN - SCOPUS:84995530518
VL - 54
SP - 288
EP - 296
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
SN - 0022-2593
IS - 4
ER -