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

Derralynn A. Hughes, Kathleen Nicholls, Suma P. Shankar, Gere Sunder-Plassmann, David Koeller, Khan Nedd, Gerard Vockley, Takashi Hamazaki, Robin Lachmann, Toya Ohashi, Iacopo Olivotto, Norio Sakai, Patrick Deegan, David Dimmock, François Eyskens, Dominique P. Germain, Ozlem Goker-Alpan, Eric Hachulla, Ana Jovanovic, Charles M. LourencoIchiei Narita, Mark Thomas, William R. Wilcox, Daniel G. Bichet, Raphael Schiffmann, Elizabeth Ludington, Christopher Viereck, John Kirk, Julie Yu, Franklin Johnson, Pol Boudes, Elfrida R. Benjamin, David J. Lockhart, Carrolee Barlow, Nina Skuban, Jeffrey P. Castelli, Jay Barth, Ulla Feldt-Rasmussen

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Abstract

Background Fabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in a-galactosidase (a-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 a-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 a-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; Preresults.

Original languageEnglish (US)
JournalJournal of Medical Genetics
DOIs
StateAccepted/In press - Nov 10 2016

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Enzyme Replacement Therapy
Fabry Disease
Pharmacology
Galactosidases
Kidney
migalastat
Mutation
Heart Diseases
Therapeutics

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease : 18-month results from the randomised phase III ATTRACT study. / Hughes, Derralynn A.; Nicholls, Kathleen; Shankar, Suma P.; Sunder-Plassmann, Gere; Koeller, David; Nedd, Khan; Vockley, Gerard; Hamazaki, Takashi; Lachmann, Robin; Ohashi, Toya; Olivotto, Iacopo; Sakai, Norio; Deegan, Patrick; Dimmock, David; Eyskens, François; Germain, Dominique P.; Goker-Alpan, Ozlem; Hachulla, Eric; Jovanovic, Ana; Lourenco, Charles M.; Narita, Ichiei; Thomas, Mark; Wilcox, William R.; Bichet, Daniel G.; Schiffmann, Raphael; Ludington, Elizabeth; Viereck, Christopher; Kirk, John; Yu, Julie; Johnson, Franklin; Boudes, Pol; Benjamin, Elfrida R.; Lockhart, David J.; Barlow, Carrolee; Skuban, Nina; Castelli, Jeffrey P.; Barth, Jay; Feldt-Rasmussen, Ulla.

In: Journal of Medical Genetics, 10.11.2016.

Research output: Contribution to journalArticle

Hughes, DA, Nicholls, K, Shankar, SP, Sunder-Plassmann, G, Koeller, D, Nedd, K, Vockley, G, Hamazaki, T, Lachmann, R, Ohashi, T, Olivotto, I, Sakai, N, Deegan, P, Dimmock, D, Eyskens, F, Germain, DP, Goker-Alpan, O, Hachulla, E, Jovanovic, A, Lourenco, CM, Narita, I, Thomas, M, Wilcox, WR, Bichet, DG, Schiffmann, R, Ludington, E, Viereck, C, Kirk, J, Yu, J, Johnson, F, Boudes, P, Benjamin, ER, Lockhart, DJ, Barlow, C, Skuban, N, Castelli, JP, Barth, J & Feldt-Rasmussen, U 2016, 'Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study', Journal of Medical Genetics. https://doi.org/10.1136/jmedgenet-2016-104178
Hughes, Derralynn A. ; Nicholls, Kathleen ; Shankar, Suma P. ; Sunder-Plassmann, Gere ; Koeller, David ; Nedd, Khan ; Vockley, Gerard ; Hamazaki, Takashi ; Lachmann, Robin ; Ohashi, Toya ; Olivotto, Iacopo ; Sakai, Norio ; Deegan, Patrick ; Dimmock, David ; Eyskens, François ; Germain, Dominique P. ; Goker-Alpan, Ozlem ; Hachulla, Eric ; Jovanovic, Ana ; Lourenco, Charles M. ; Narita, Ichiei ; Thomas, Mark ; Wilcox, William R. ; Bichet, Daniel G. ; Schiffmann, Raphael ; Ludington, Elizabeth ; Viereck, Christopher ; Kirk, John ; Yu, Julie ; Johnson, Franklin ; Boudes, Pol ; Benjamin, Elfrida R. ; Lockhart, David J. ; Barlow, Carrolee ; Skuban, Nina ; Castelli, Jeffrey P. ; Barth, Jay ; Feldt-Rasmussen, Ulla. / Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease : 18-month results from the randomised phase III ATTRACT study. In: Journal of Medical Genetics. 2016.
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abstract = "Background Fabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in a-galactosidase (a-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 a-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 a-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; Preresults.",
author = "Hughes, {Derralynn A.} and Kathleen Nicholls and Shankar, {Suma P.} and Gere Sunder-Plassmann and David Koeller and Khan Nedd and Gerard Vockley and Takashi Hamazaki and Robin Lachmann and Toya Ohashi and Iacopo Olivotto and Norio Sakai and Patrick Deegan and David Dimmock and Fran{\cc}ois Eyskens and Germain, {Dominique P.} and Ozlem Goker-Alpan and Eric Hachulla and Ana Jovanovic and Lourenco, {Charles M.} and Ichiei Narita and Mark Thomas and Wilcox, {William R.} and Bichet, {Daniel G.} and Raphael Schiffmann and Elizabeth Ludington and Christopher Viereck and John Kirk and Julie Yu and Franklin Johnson and Pol Boudes and Benjamin, {Elfrida R.} and Lockhart, {David J.} and Carrolee Barlow and Nina Skuban and Castelli, {Jeffrey P.} and Jay Barth and Ulla Feldt-Rasmussen",
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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 - 2016/11/10

Y1 - 2016/11/10

N2 - Background Fabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in a-galactosidase (a-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 a-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 a-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; Preresults.

AB - Background Fabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in a-galactosidase (a-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 a-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 a-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; Preresults.

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U2 - 10.1136/jmedgenet-2016-104178

DO - 10.1136/jmedgenet-2016-104178

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