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 -