Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study
Identifieur interne : 002697 ( Pmc/Corpus ); précédent : 002696; suivant : 002698Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study
Auteurs : 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. Lourenco ; Ichiei 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-RasmussenSource :
- Journal of Medical Genetics [ 0022-2593 ] ; 2016.
Abstract
Fabry disease is an X-linked lysosomal storage disorder caused by
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.
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.
Migalastat offers promise as a first-in-class oral monotherapy alternative treatment to intravenous ERT for patients with Fabry disease and amenable mutations.
Url:
DOI: 10.1136/jmedgenet-2016-104178
PubMed: 27834756
PubMed Central: 5502308
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PMC:5502308Le document en format XML
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<author><name sortKey="Olivotto, Iacopo" sort="Olivotto, Iacopo" uniqKey="Olivotto I" first="Iacopo" last="Olivotto">Iacopo Olivotto</name>
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<author><name sortKey="Sakai, Norio" sort="Sakai, Norio" uniqKey="Sakai N" first="Norio" last="Sakai">Norio Sakai</name>
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<author><name sortKey="Deegan, Patrick" sort="Deegan, Patrick" uniqKey="Deegan P" first="Patrick" last="Deegan">Patrick Deegan</name>
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<author><name sortKey="Dimmock, David" sort="Dimmock, David" uniqKey="Dimmock D" first="David" last="Dimmock">David Dimmock</name>
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<author><name sortKey="Eyskens, Francois" sort="Eyskens, Francois" uniqKey="Eyskens F" first="François" last="Eyskens">François Eyskens</name>
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<author><name sortKey="Germain, Dominique P" sort="Germain, Dominique P" uniqKey="Germain D" first="Dominique P" last="Germain">Dominique P. Germain</name>
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<author><name sortKey="Goker Alpan, Ozlem" sort="Goker Alpan, Ozlem" uniqKey="Goker Alpan O" first="Ozlem" last="Goker-Alpan">Ozlem Goker-Alpan</name>
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<author><name sortKey="Thomas, Mark" sort="Thomas, Mark" uniqKey="Thomas M" first="Mark" last="Thomas">Mark Thomas</name>
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<author><name sortKey="Wilcox, William R" sort="Wilcox, William R" uniqKey="Wilcox W" first="William R" last="Wilcox">William R. Wilcox</name>
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<author><name sortKey="Bichet, Daniel G" sort="Bichet, Daniel G" uniqKey="Bichet D" first="Daniel G" last="Bichet">Daniel G. Bichet</name>
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,<addr-line>Montreal, Quebec</addr-line>
,<country>Canada</country>
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<author><name sortKey="Schiffmann, Raphael" sort="Schiffmann, Raphael" uniqKey="Schiffmann R" first="Raphael" last="Schiffmann">Raphael Schiffmann</name>
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,<addr-line>Dallas, Texas</addr-line>
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<author><name sortKey="Ludington, Elizabeth" sort="Ludington, Elizabeth" uniqKey="Ludington E" first="Elizabeth" last="Ludington">Elizabeth Ludington</name>
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<author><name sortKey="Viereck, Christopher" sort="Viereck, Christopher" uniqKey="Viereck C" first="Christopher" last="Viereck">Christopher Viereck</name>
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<author><name sortKey="Yu, Julie" sort="Yu, Julie" uniqKey="Yu J" first="Julie" last="Yu">Julie Yu</name>
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<author><name sortKey="Johnson, Franklin" sort="Johnson, Franklin" uniqKey="Johnson F" first="Franklin" last="Johnson">Franklin Johnson</name>
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<author><name sortKey="Boudes, Pol" sort="Boudes, Pol" uniqKey="Boudes P" first="Pol" last="Boudes">Pol Boudes</name>
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<author><name sortKey="Benjamin, Elfrida R" sort="Benjamin, Elfrida R" uniqKey="Benjamin E" first="Elfrida R" last="Benjamin">Elfrida R. Benjamin</name>
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,<addr-line>Cranbury, New Jersey</addr-line>
,<country>USA</country>
</nlm:aff>
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<author><name sortKey="Lockhart, David J" sort="Lockhart, David J" uniqKey="Lockhart D" first="David J" last="Lockhart">David J. Lockhart</name>
<affiliation><nlm:aff id="af29"><institution>TranscripTx, Inc.</institution>
,<addr-line>Sunnyvale, California</addr-line>
,<country>USA</country>
</nlm:aff>
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<author><name sortKey="Barlow, Carrolee" sort="Barlow, Carrolee" uniqKey="Barlow C" first="Carrolee" last="Barlow">Carrolee Barlow</name>
<affiliation><nlm:aff id="af30"><institution>Parkinson's Institute and Clinical Center</institution>
,<addr-line>Sunnyvale, California</addr-line>
,<country>USA</country>
</nlm:aff>
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<author><name sortKey="Skuban, Nina" sort="Skuban, Nina" uniqKey="Skuban N" first="Nina" last="Skuban">Nina Skuban</name>
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,<addr-line>Cranbury, New Jersey</addr-line>
,<country>USA</country>
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<author><name sortKey="Castelli, Jeffrey P" sort="Castelli, Jeffrey P" uniqKey="Castelli J" first="Jeffrey P" last="Castelli">Jeffrey P. Castelli</name>
<affiliation><nlm:aff id="af27"><institution>Amicus Therapeutics Inc.</institution>
,<addr-line>Cranbury, New Jersey</addr-line>
,<country>USA</country>
</nlm:aff>
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<author><name sortKey="Barth, Jay" sort="Barth, Jay" uniqKey="Barth J" first="Jay" last="Barth">Jay Barth</name>
<affiliation><nlm:aff id="af27"><institution>Amicus Therapeutics Inc.</institution>
,<addr-line>Cranbury, New Jersey</addr-line>
,<country>USA</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Feldt Rasmussen, Ulla" sort="Feldt Rasmussen, Ulla" uniqKey="Feldt Rasmussen U" first="Ulla" last="Feldt-Rasmussen">Ulla Feldt-Rasmussen</name>
<affiliation><nlm:aff id="af31"><addr-line>Department of Medical Endocrinology</addr-line>
,<institution>Rigshospital, Copenhagen University Hospital</institution>
,<addr-line>Copenhagen</addr-line>
,<country>Denmark</country>
</nlm:aff>
</affiliation>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study</title>
<author><name sortKey="Hughes, Derralynn A" sort="Hughes, Derralynn A" uniqKey="Hughes D" first="Derralynn A" last="Hughes">Derralynn A. Hughes</name>
<affiliation><nlm:aff id="af1"><addr-line>Department of Haematology</addr-line>
,<institution>Royal Free London NHS Foundation Trust and University College London</institution>
,<addr-line>London</addr-line>
,<country>UK</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Nicholls, Kathleen" sort="Nicholls, Kathleen" uniqKey="Nicholls K" first="Kathleen" last="Nicholls">Kathleen Nicholls</name>
<affiliation><nlm:aff id="af2"><addr-line>Department of Nephrology</addr-line>
,<institution>Royal Melbourne Hospital</institution>
,<addr-line>Parkville, Victoria</addr-line>
,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Shankar, Suma P" sort="Shankar, Suma P" uniqKey="Shankar S" first="Suma P" last="Shankar">Suma P. Shankar</name>
<affiliation><nlm:aff id="af3"><addr-line>Section of Vitreoretinal Surgery & Diseases</addr-line>
,<institution>Emory University</institution>
,<addr-line>Atlanta, Georgia</addr-line>
,<country>USA</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sunder Plassmann, Gere" sort="Sunder Plassmann, Gere" uniqKey="Sunder Plassmann G" first="Gere" last="Sunder-Plassmann">Gere Sunder-Plassmann</name>
<affiliation><nlm:aff id="af4"><addr-line>Division of Nephrology and Dialysis, Department of Medicine III</addr-line>
,<institution>Medical University of Vienna</institution>
,<addr-line>Vienna</addr-line>
,<country>Austria</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Koeller, David" sort="Koeller, David" uniqKey="Koeller D" first="David" last="Koeller">David Koeller</name>
<affiliation><nlm:aff id="af5"><institution>Doernbecher Children's Hospital, Oregon Health & Science University</institution>
,<addr-line>Portland, Oregon</addr-line>
,<country>USA</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Nedd, Khan" sort="Nedd, Khan" uniqKey="Nedd K" first="Khan" last="Nedd">Khan Nedd</name>
<affiliation><nlm:aff id="af6"><institution>Infusion Associates</institution>
,<addr-line>Grand Rapids, Missouri</addr-line>
,<country>USA</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Vockley, Gerard" sort="Vockley, Gerard" uniqKey="Vockley G" first="Gerard" last="Vockley">Gerard Vockley</name>
<affiliation><nlm:aff id="af7"><institution>Children's Hospital of Pittsburgh</institution>
,<addr-line>Pittsburgh, Pennsylvania</addr-line>
,<country>USA</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hamazaki, Takashi" sort="Hamazaki, Takashi" uniqKey="Hamazaki T" first="Takashi" last="Hamazaki">Takashi Hamazaki</name>
<affiliation><nlm:aff id="af6"><institution>Infusion Associates</institution>
,<addr-line>Grand Rapids, Missouri</addr-line>
,<country>USA</country>
</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="af8"><addr-line>Department of Pediatrics</addr-line>
,<institution>Osaka City University Hospital</institution>
,<addr-line>Osaka-shi</addr-line>
,<country>Japan</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lachmann, Robin" sort="Lachmann, Robin" uniqKey="Lachmann R" first="Robin" last="Lachmann">Robin Lachmann</name>
<affiliation><nlm:aff id="af9"><addr-line>Charles Dent Metabolic Unit</addr-line>
,<institution>National Hospital for Neurology and Neurosurgery</institution>
,<addr-line>London</addr-line>
,<country>UK</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ohashi, Toya" sort="Ohashi, Toya" uniqKey="Ohashi T" first="Toya" last="Ohashi">Toya Ohashi</name>
<affiliation><nlm:aff id="af10"><institution>Jikei University Hospital</institution>
,<addr-line>Tokyo</addr-line>
,<country>Japan</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Olivotto, Iacopo" sort="Olivotto, Iacopo" uniqKey="Olivotto I" first="Iacopo" last="Olivotto">Iacopo Olivotto</name>
<affiliation><nlm:aff id="af11"><addr-line>Departmento Cuore e vasi</addr-line>
,<institution>A.O.U. Careggi Firenze</institution>
,<addr-line>Firenze</addr-line>
,<country>Italy</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sakai, Norio" sort="Sakai, Norio" uniqKey="Sakai N" first="Norio" last="Sakai">Norio Sakai</name>
<affiliation><nlm:aff id="af12"><institution>Osaka City University Hospital</institution>
,<addr-line>Osaka-shi</addr-line>
,<country>Japan</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Deegan, Patrick" sort="Deegan, Patrick" uniqKey="Deegan P" first="Patrick" last="Deegan">Patrick Deegan</name>
<affiliation><nlm:aff id="af13"><addr-line>Lysosmal Disorders Unit, Department of Medicine</addr-line>
,<institution>Addenbrooke's Hospital</institution>
,<addr-line>Cambridge</addr-line>
,<country>UK</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Dimmock, David" sort="Dimmock, David" uniqKey="Dimmock D" first="David" last="Dimmock">David Dimmock</name>
<affiliation><nlm:aff id="af14"><institution>Genetics Center MS716, Children's Hospital of Wisconsin</institution>
,<addr-line>Milwaukee, Wisconsin</addr-line>
,<country>USA</country>
</nlm:aff>
</affiliation>
</author>
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,<addr-line>Edegem</addr-line>
,<country>Belgium</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Germain, Dominique P" sort="Germain, Dominique P" uniqKey="Germain D" first="Dominique P" last="Germain">Dominique P. Germain</name>
<affiliation><nlm:aff id="af16"><addr-line>Division of Medical Genetics</addr-line>
,<institution>University of Versailles, Paris-Saclay University and Assistance Publique—Hôpitaux de Paris</institution>
,<addr-line>Paris</addr-line>
,<country>France</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Goker Alpan, Ozlem" sort="Goker Alpan, Ozlem" uniqKey="Goker Alpan O" first="Ozlem" last="Goker-Alpan">Ozlem Goker-Alpan</name>
<affiliation><nlm:aff id="af17"><institution>O & O Alpan LLC</institution>
,<addr-line>Springfield, Virginia</addr-line>
,<country>USA</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hachulla, Eric" sort="Hachulla, Eric" uniqKey="Hachulla E" first="Eric" last="Hachulla">Eric Hachulla</name>
<affiliation><nlm:aff id="af18"><institution>Service de Médecine, Hôpital Claude Huriez—CHRU Lille</institution>
,<addr-line>Lille</addr-line>
,<country>France</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Jovanovic, Ana" sort="Jovanovic, Ana" uniqKey="Jovanovic A" first="Ana" last="Jovanovic">Ana Jovanovic</name>
<affiliation><nlm:aff id="af19"><addr-line>Department of Endocrinology and Metabolic Medicine</addr-line>
,<institution>Salford Royal NHS Foundation Trust</institution>
,<addr-line>Salford</addr-line>
,<country>UK</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lourenco, Charles M" sort="Lourenco, Charles M" uniqKey="Lourenco C" first="Charles M" last="Lourenco">Charles M. Lourenco</name>
<affiliation><nlm:aff id="af20"><institution>Hospital das Clínicas FMUSP—Ribeirão Preto</institution>
,<addr-line>São Paulo, Ribeirão Preto</addr-line>
,<country>Brazil</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Narita, Ichiei" sort="Narita, Ichiei" uniqKey="Narita I" first="Ichiei" last="Narita">Ichiei Narita</name>
<affiliation><nlm:aff id="af21"><institution>Niigata University Graduate School of Medicine and Dental Sciences</institution>
,<addr-line>Niigata</addr-line>
,<country>Japan</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Thomas, Mark" sort="Thomas, Mark" uniqKey="Thomas M" first="Mark" last="Thomas">Mark Thomas</name>
<affiliation><nlm:aff id="af22"><institution>Royal Perth Hospital</institution>
,<addr-line>Perth, New South Wales</addr-line>
,<country>Australia</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Wilcox, William R" sort="Wilcox, William R" uniqKey="Wilcox W" first="William R" last="Wilcox">William R. Wilcox</name>
<affiliation><nlm:aff id="af23"><addr-line>Department of Genetics</addr-line>
,<institution>Emory University School of Medicine</institution>
,<addr-line>Atlanta, Georgia</addr-line>
,<country>USA</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bichet, Daniel G" sort="Bichet, Daniel G" uniqKey="Bichet D" first="Daniel G" last="Bichet">Daniel G. Bichet</name>
<affiliation><nlm:aff id="af24"><institution>Clinical Research Division, Hôpital du Sacré-Coeur de Montreal, University of Montreal</institution>
,<addr-line>Montreal, Quebec</addr-line>
,<country>Canada</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Schiffmann, Raphael" sort="Schiffmann, Raphael" uniqKey="Schiffmann R" first="Raphael" last="Schiffmann">Raphael Schiffmann</name>
<affiliation><nlm:aff id="af25"><institution>Institute of Metabolic Disease, Baylor Research Institute</institution>
,<addr-line>Dallas, Texas</addr-line>
,<country>USA</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ludington, Elizabeth" sort="Ludington, Elizabeth" uniqKey="Ludington E" first="Elizabeth" last="Ludington">Elizabeth Ludington</name>
<affiliation><nlm:aff id="af26"><institution>Agility Clinical Inc.</institution>
,<addr-line>Carlsbad, California</addr-line>
,<country>USA</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Viereck, Christopher" sort="Viereck, Christopher" uniqKey="Viereck C" first="Christopher" last="Viereck">Christopher Viereck</name>
<affiliation><nlm:aff id="af27"><institution>Amicus Therapeutics Inc.</institution>
,<addr-line>Cranbury, New Jersey</addr-line>
,<country>USA</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kirk, John" sort="Kirk, John" uniqKey="Kirk J" first="John" last="Kirk">John Kirk</name>
<affiliation><nlm:aff id="af27"><institution>Amicus Therapeutics Inc.</institution>
,<addr-line>Cranbury, New Jersey</addr-line>
,<country>USA</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Yu, Julie" sort="Yu, Julie" uniqKey="Yu J" first="Julie" last="Yu">Julie Yu</name>
<affiliation><nlm:aff id="af27"><institution>Amicus Therapeutics Inc.</institution>
,<addr-line>Cranbury, New Jersey</addr-line>
,<country>USA</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Johnson, Franklin" sort="Johnson, Franklin" uniqKey="Johnson F" first="Franklin" last="Johnson">Franklin Johnson</name>
<affiliation><nlm:aff id="af27"><institution>Amicus Therapeutics Inc.</institution>
,<addr-line>Cranbury, New Jersey</addr-line>
,<country>USA</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Boudes, Pol" sort="Boudes, Pol" uniqKey="Boudes P" first="Pol" last="Boudes">Pol Boudes</name>
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,<addr-line>Newark, California</addr-line>
,<country>USA</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Benjamin, Elfrida R" sort="Benjamin, Elfrida R" uniqKey="Benjamin E" first="Elfrida R" last="Benjamin">Elfrida R. Benjamin</name>
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,<addr-line>Cranbury, New Jersey</addr-line>
,<country>USA</country>
</nlm:aff>
</affiliation>
</author>
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,<addr-line>Sunnyvale, California</addr-line>
,<country>USA</country>
</nlm:aff>
</affiliation>
</author>
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<affiliation><nlm:aff id="af30"><institution>Parkinson's Institute and Clinical Center</institution>
,<addr-line>Sunnyvale, California</addr-line>
,<country>USA</country>
</nlm:aff>
</affiliation>
</author>
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,<addr-line>Cranbury, New Jersey</addr-line>
,<country>USA</country>
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</affiliation>
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<author><name sortKey="Castelli, Jeffrey P" sort="Castelli, Jeffrey P" uniqKey="Castelli J" first="Jeffrey P" last="Castelli">Jeffrey P. Castelli</name>
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,<addr-line>Cranbury, New Jersey</addr-line>
,<country>USA</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Barth, Jay" sort="Barth, Jay" uniqKey="Barth J" first="Jay" last="Barth">Jay Barth</name>
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,<country>USA</country>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Feldt Rasmussen, Ulla" sort="Feldt Rasmussen, Ulla" uniqKey="Feldt Rasmussen U" first="Ulla" last="Feldt-Rasmussen">Ulla Feldt-Rasmussen</name>
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,<institution>Rigshospital, Copenhagen University Hospital</institution>
,<addr-line>Copenhagen</addr-line>
,<country>Denmark</country>
</nlm:aff>
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</analytic>
<series><title level="j">Journal of Medical Genetics</title>
<idno type="ISSN">0022-2593</idno>
<idno type="eISSN">1468-6244</idno>
<imprint><date when="2016">2016</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><sec><title>Background</title>
<p>Fabry disease is an X-linked lysosomal storage disorder caused by <italic>GLA</italic>
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 (<italic>amenable</italic>
) forms of α-Gal to facilitate normal lysosomal trafficking.</p>
</sec>
<sec><title>Methods</title>
<p>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.</p>
</sec>
<sec><title>Results</title>
<p>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/m<sup>2</sup>
(−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.</p>
</sec>
<sec><title>Conclusions</title>
<p>Migalastat offers promise as a first-in-class oral monotherapy alternative treatment to intravenous ERT for patients with Fabry disease and amenable mutations.</p>
</sec>
<sec><title>Trial registration number:</title>
<p><ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT00925301">NCT00925301</ext-link>
; Pre-results.</p>
</sec>
</div>
</front>
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<journal-id journal-id-type="iso-abbrev">J. Med. Genet</journal-id>
<journal-id journal-id-type="hwp">jmedgenet</journal-id>
<journal-id journal-id-type="publisher-id">jmg</journal-id>
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<issn pub-type="ppub">0022-2593</issn>
<issn pub-type="epub">1468-6244</issn>
<publisher><publisher-name>BMJ Publishing Group</publisher-name>
<publisher-loc>BMA House, Tavistock Square, London, WC1H 9JR</publisher-loc>
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<article-meta><article-id pub-id-type="pmid">27834756</article-id>
<article-id pub-id-type="pmc">5502308</article-id>
<article-id pub-id-type="publisher-id">jmedgenet-2016-104178</article-id>
<article-id pub-id-type="doi">10.1136/jmedgenet-2016-104178</article-id>
<article-categories><subj-group subj-group-type="hwp-journal-coll"><subject>1506</subject>
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<subj-group subj-group-type="heading"><subject>Therapeutics</subject>
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<series-title>Original Article</series-title>
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<title-group><article-title>Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study</article-title>
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<contrib contrib-type="author"><name><surname>Ohashi</surname>
<given-names>Toya</given-names>
</name>
<xref ref-type="aff" rid="af10">10</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Olivotto</surname>
<given-names>Iacopo</given-names>
</name>
<xref ref-type="aff" rid="af11">11</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sakai</surname>
<given-names>Norio</given-names>
</name>
<xref ref-type="aff" rid="af12">12</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Deegan</surname>
<given-names>Patrick</given-names>
</name>
<xref ref-type="aff" rid="af13">13</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Dimmock</surname>
<given-names>David</given-names>
</name>
<xref ref-type="aff" rid="af14">14</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Eyskens</surname>
<given-names>François</given-names>
</name>
<xref ref-type="aff" rid="af15">15</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Germain</surname>
<given-names>Dominique P</given-names>
</name>
<xref ref-type="aff" rid="af16">16</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Goker-Alpan</surname>
<given-names>Ozlem</given-names>
</name>
<xref ref-type="aff" rid="af17">17</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hachulla</surname>
<given-names>Eric</given-names>
</name>
<xref ref-type="aff" rid="af18">18</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Jovanovic</surname>
<given-names>Ana</given-names>
</name>
<xref ref-type="aff" rid="af19">19</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lourenco</surname>
<given-names>Charles M</given-names>
</name>
<xref ref-type="aff" rid="af20">20</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Narita</surname>
<given-names>Ichiei</given-names>
</name>
<xref ref-type="aff" rid="af21">21</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Thomas</surname>
<given-names>Mark</given-names>
</name>
<xref ref-type="aff" rid="af22">22</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wilcox</surname>
<given-names>William R</given-names>
</name>
<xref ref-type="aff" rid="af23">23</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bichet</surname>
<given-names>Daniel G</given-names>
</name>
<xref ref-type="aff" rid="af24">24</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Schiffmann</surname>
<given-names>Raphael</given-names>
</name>
<xref ref-type="aff" rid="af25">25</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ludington</surname>
<given-names>Elizabeth</given-names>
</name>
<xref ref-type="aff" rid="af26">26</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Viereck</surname>
<given-names>Christopher</given-names>
</name>
<xref ref-type="aff" rid="af27">27</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kirk</surname>
<given-names>John</given-names>
</name>
<xref ref-type="aff" rid="af27">27</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Yu</surname>
<given-names>Julie</given-names>
</name>
<xref ref-type="aff" rid="af27">27</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Johnson</surname>
<given-names>Franklin</given-names>
</name>
<xref ref-type="aff" rid="af27">27</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Boudes</surname>
<given-names>Pol</given-names>
</name>
<xref ref-type="aff" rid="af28">28</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Benjamin</surname>
<given-names>Elfrida R</given-names>
</name>
<xref ref-type="aff" rid="af27">27</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lockhart</surname>
<given-names>David J</given-names>
</name>
<xref ref-type="aff" rid="af29">29</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Barlow</surname>
<given-names>Carrolee</given-names>
</name>
<xref ref-type="aff" rid="af30">30</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Skuban</surname>
<given-names>Nina</given-names>
</name>
<xref ref-type="aff" rid="af27">27</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Castelli</surname>
<given-names>Jeffrey P</given-names>
</name>
<xref ref-type="aff" rid="af27">27</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Barth</surname>
<given-names>Jay</given-names>
</name>
<xref ref-type="aff" rid="af27">27</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Feldt-Rasmussen</surname>
<given-names>Ulla</given-names>
</name>
<xref ref-type="aff" rid="af31">31</xref>
</contrib>
</contrib-group>
<aff id="af1"><label>1</label>
<addr-line>Department of Haematology</addr-line>
,<institution>Royal Free London NHS Foundation Trust and University College London</institution>
,<addr-line>London</addr-line>
,<country>UK</country>
</aff>
<aff id="af2"><label>2</label>
<addr-line>Department of Nephrology</addr-line>
,<institution>Royal Melbourne Hospital</institution>
,<addr-line>Parkville, Victoria</addr-line>
,<country>Australia</country>
</aff>
<aff id="af3"><label>3</label>
<addr-line>Section of Vitreoretinal Surgery & Diseases</addr-line>
,<institution>Emory University</institution>
,<addr-line>Atlanta, Georgia</addr-line>
,<country>USA</country>
</aff>
<aff id="af4"><label>4</label>
<addr-line>Division of Nephrology and Dialysis, Department of Medicine III</addr-line>
,<institution>Medical University of Vienna</institution>
,<addr-line>Vienna</addr-line>
,<country>Austria</country>
</aff>
<aff id="af5"><label>5</label>
<institution>Doernbecher Children's Hospital, Oregon Health & Science University</institution>
,<addr-line>Portland, Oregon</addr-line>
,<country>USA</country>
</aff>
<aff id="af6"><label>6</label>
<institution>Infusion Associates</institution>
,<addr-line>Grand Rapids, Missouri</addr-line>
,<country>USA</country>
</aff>
<aff id="af7"><label>7</label>
<institution>Children's Hospital of Pittsburgh</institution>
,<addr-line>Pittsburgh, Pennsylvania</addr-line>
,<country>USA</country>
</aff>
<aff id="af8"><label>8</label>
<addr-line>Department of Pediatrics</addr-line>
,<institution>Osaka City University Hospital</institution>
,<addr-line>Osaka-shi</addr-line>
,<country>Japan</country>
</aff>
<aff id="af9"><label>9</label>
<addr-line>Charles Dent Metabolic Unit</addr-line>
,<institution>National Hospital for Neurology and Neurosurgery</institution>
,<addr-line>London</addr-line>
,<country>UK</country>
</aff>
<aff id="af10"><label>10</label>
<institution>Jikei University Hospital</institution>
,<addr-line>Tokyo</addr-line>
,<country>Japan</country>
</aff>
<aff id="af11"><label>11</label>
<addr-line>Departmento Cuore e vasi</addr-line>
,<institution>A.O.U. Careggi Firenze</institution>
,<addr-line>Firenze</addr-line>
,<country>Italy</country>
</aff>
<aff id="af12"><label>12</label>
<institution>Osaka City University Hospital</institution>
,<addr-line>Osaka-shi</addr-line>
,<country>Japan</country>
</aff>
<aff id="af13"><label>13</label>
<addr-line>Lysosmal Disorders Unit, Department of Medicine</addr-line>
,<institution>Addenbrooke's Hospital</institution>
,<addr-line>Cambridge</addr-line>
,<country>UK</country>
</aff>
<aff id="af14"><label>14</label>
<institution>Genetics Center MS716, Children's Hospital of Wisconsin</institution>
,<addr-line>Milwaukee, Wisconsin</addr-line>
,<country>USA</country>
</aff>
<aff id="af15"><label>15</label>
<institution>Univeritair Ziekenhaus Anterpen</institution>
,<addr-line>Edegem</addr-line>
,<country>Belgium</country>
</aff>
<aff id="af16"><label>16</label>
<addr-line>Division of Medical Genetics</addr-line>
,<institution>University of Versailles, Paris-Saclay University and Assistance Publique—Hôpitaux de Paris</institution>
,<addr-line>Paris</addr-line>
,<country>France</country>
</aff>
<aff id="af17"><label>17</label>
<institution>O & O Alpan LLC</institution>
,<addr-line>Springfield, Virginia</addr-line>
,<country>USA</country>
</aff>
<aff id="af18"><label>18</label>
<institution>Service de Médecine, Hôpital Claude Huriez—CHRU Lille</institution>
,<addr-line>Lille</addr-line>
,<country>France</country>
</aff>
<aff id="af19"><label>19</label>
<addr-line>Department of Endocrinology and Metabolic Medicine</addr-line>
,<institution>Salford Royal NHS Foundation Trust</institution>
,<addr-line>Salford</addr-line>
,<country>UK</country>
</aff>
<aff id="af20"><label>20</label>
<institution>Hospital das Clínicas FMUSP—Ribeirão Preto</institution>
,<addr-line>São Paulo, Ribeirão Preto</addr-line>
,<country>Brazil</country>
</aff>
<aff id="af21"><label>21</label>
<institution>Niigata University Graduate School of Medicine and Dental Sciences</institution>
,<addr-line>Niigata</addr-line>
,<country>Japan</country>
</aff>
<aff id="af22"><label>22</label>
<institution>Royal Perth Hospital</institution>
,<addr-line>Perth, New South Wales</addr-line>
,<country>Australia</country>
</aff>
<aff id="af23"><label>23</label>
<addr-line>Department of Genetics</addr-line>
,<institution>Emory University School of Medicine</institution>
,<addr-line>Atlanta, Georgia</addr-line>
,<country>USA</country>
</aff>
<aff id="af24"><label>24</label>
<institution>Clinical Research Division, Hôpital du Sacré-Coeur de Montreal, University of Montreal</institution>
,<addr-line>Montreal, Quebec</addr-line>
,<country>Canada</country>
</aff>
<aff id="af25"><label>25</label>
<institution>Institute of Metabolic Disease, Baylor Research Institute</institution>
,<addr-line>Dallas, Texas</addr-line>
,<country>USA</country>
</aff>
<aff id="af26"><label>26</label>
<institution>Agility Clinical Inc.</institution>
,<addr-line>Carlsbad, California</addr-line>
,<country>USA</country>
</aff>
<aff id="af27"><label>27</label>
<institution>Amicus Therapeutics Inc.</institution>
,<addr-line>Cranbury, New Jersey</addr-line>
,<country>USA</country>
</aff>
<aff id="af28"><label>28</label>
<institution>CymaBay Therapeutics, Inc.</institution>
,<addr-line>Newark, California</addr-line>
,<country>USA</country>
</aff>
<aff id="af29"><label>29</label>
<institution>TranscripTx, Inc.</institution>
,<addr-line>Sunnyvale, California</addr-line>
,<country>USA</country>
</aff>
<aff id="af30"><label>30</label>
<institution>Parkinson's Institute and Clinical Center</institution>
,<addr-line>Sunnyvale, California</addr-line>
,<country>USA</country>
</aff>
<aff id="af31"><label>31</label>
<addr-line>Department of Medical Endocrinology</addr-line>
,<institution>Rigshospital, Copenhagen University Hospital</institution>
,<addr-line>Copenhagen</addr-line>
,<country>Denmark</country>
</aff>
<author-notes><corresp><label>Correspondence to</label>
Dr Derralynn A Hughes, Department of Hematology, Royal Free London NHS Foundation Trust and University College London, London NW3 2PF, UK; <email>rmgvdah@ucl.ac.uk</email>
</corresp>
</author-notes>
<pub-date pub-type="ppub"><month>4</month>
<year>2017</year>
</pub-date>
<pub-date pub-type="epub"><day>10</day>
<month>11</month>
<year>2016</year>
</pub-date>
<volume>54</volume>
<issue>4</issue>
<fpage>288</fpage>
<lpage>296</lpage>
<history><date date-type="received"><day>19</day>
<month>7</month>
<year>2016</year>
</date>
<date date-type="rev-recd"><day>7</day>
<month>10</month>
<year>2016</year>
</date>
<date date-type="accepted"><day>12</day>
<month>10</month>
<year>2016</year>
</date>
</history>
<permissions><copyright-statement>Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/</copyright-statement>
<copyright-year>2016</copyright-year>
<license license-type="open-access"><license-p>This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/4.0/">http://creativecommons.org/licenses/by-nc/4.0/</ext-link>
</license-p>
</license>
</permissions>
<self-uri xlink:title="pdf" xlink:href="jmedgenet-2016-104178.pdf"></self-uri>
<abstract><sec><title>Background</title>
<p>Fabry disease is an X-linked lysosomal storage disorder caused by <italic>GLA</italic>
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 (<italic>amenable</italic>
) forms of α-Gal to facilitate normal lysosomal trafficking.</p>
</sec>
<sec><title>Methods</title>
<p>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.</p>
</sec>
<sec><title>Results</title>
<p>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/m<sup>2</sup>
(−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.</p>
</sec>
<sec><title>Conclusions</title>
<p>Migalastat offers promise as a first-in-class oral monotherapy alternative treatment to intravenous ERT for patients with Fabry disease and amenable mutations.</p>
</sec>
<sec><title>Trial registration number:</title>
<p><ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT00925301">NCT00925301</ext-link>
; Pre-results.</p>
</sec>
</abstract>
<kwd-group><kwd>Pharmacological chaperone</kwd>
<kwd>Fabry disease</kwd>
<kwd>lysosomal storage disorder</kwd>
<kwd>lyso-Gb3</kwd>
<kwd>enzyme replacement therapy</kwd>
</kwd-group>
<custom-meta-group><custom-meta><meta-name>special-feature</meta-name>
<meta-value>unlocked</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
<body><sec sec-type="intro" id="s1"><title>Introduction</title>
<p>Fabry disease is a rare, progressive and devastating X-linked disorder, affecting both males and females, caused by the functional deficiency of lysosomal α-galactosidase (α-Gal).<xref rid="R1" ref-type="bibr">1</xref>
The resultant accumulation of glycosphingolipids, including globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb<sub>3</sub>
), can lead to multisystem disease and early death.<xref rid="R2" ref-type="bibr">2</xref>
</p>
<p>Migalastat, a small-molecule pharmacological chaperone, reversibly binds to the active site of α-Gal. In patients with Fabry disease, migalastat stabilises specific mutant forms of the enzyme and promotes trafficking to lysosomes where α-Gal catabolises accumulated disease substrates.<xref rid="R3" ref-type="bibr">3–8</xref>
These mutant forms of α-Gal are defined as amenable to migalastat.</p>
<p>In patients with amenable mutations, orally administered migalastat is a potential alternative treatment to intravenous enzyme replacement therapy (ERT). The burden of lifelong biweekly intravenous infusions may dissuade patients from being treated with ERT or delay ERT initiation and potentially increase the risk of end-organ damage.<xref rid="R9" ref-type="bibr">9</xref>
<xref rid="R10" ref-type="bibr">10</xref>
In a 5-year retrospective analysis in patients treated with ERT, 40% of males had serum-mediated antibody inhibition of agalsidase activity, which was associated with higher lyso-Gb<sub>3</sub>
, greater left ventricular (LV) mass and decreased renal function.<xref rid="R11" ref-type="bibr">11</xref>
An orally administered small molecule, migalastat would avoid ERT-associated immunogenicity and infusion-associated reactions. Additionally, the higher volume of distribution of migalastat (76.5–133 L)<xref rid="R12" ref-type="bibr">12</xref>
relative to ERT<xref rid="R13" ref-type="bibr">13</xref>
<xref rid="R14" ref-type="bibr">14</xref>
suggests enhanced penetration of organs and tissues.<xref rid="R4" ref-type="bibr">4</xref>
Theoretically, the chaperoning of α-Gal by migalastat to lysosomes may better mimic natural enzyme trafficking and result in more constant α-Gal activity than biweekly ERT infusions.</p>
<p>We report on the results from the first phase III study that compared the safety and efficacy of migalastat to ERT in male and female patients with Fabry disease and amenable mutations previously treated with ERT.</p>
</sec>
<sec sec-type="methods" id="s2"><title>Materials and methods</title>
<sec id="s2a"><title>Study design and participants</title>
<p>Study AT1001-012 (ATTRACT) (NCT00925301) comprised an 18-month open-label comparison between migalastat and ERT, followed by a 12-month open-label extension with migalastat (<xref ref-type="fig" rid="JMEDGENET2016104178F1">figure 1</xref>
). Patients were maintained on the baseline dose of either agalsidase alfa (0.2 mg/kg) or beta (1.0 mg/kg) biweekly. Following written informed consent, eligibility and baseline assessments, patients were stratified by proteinuria and gender and randomised into the 18-month controlled period. Patients previously treated with ERT (agalsidase alfa and agalsidase beta) for >12 months were randomised 1.5:1 to switch to migalastat HCl (150 mg every other day) or continue ERT. Patients were randomised using interactive response technology (Almac Clinical Technologies). The study received ethics committee/institutional review board (EC/IRB) approval and was conducted according to International Conference on Harmonisation/Good Clinical Practice (ICH/GCP) and the Declaration of Helsinki. This report will focus on the completed 18-month randomised comparison between migalastat and ERT.</p>
<fig id="JMEDGENET2016104178F1" orientation="portrait" position="float"><label>Figure 1</label>
<caption><p>Study design and patient disposition. ERT, enzyme replacement therapy; OLE, open-label extension.</p>
</caption>
<graphic xlink:href="jmedgenet-2016-104178f01"></graphic>
</fig>
<p>The sample size was determined based on literature reports that the annual decline of iohexol glomerular filtration rate (GFR) in the ERT group was expected to be between 2 and 4 mL/min/1.73 m<sup>2</sup>
with an SD of approximately 7.5–8.5 mL/min/1.73 m<sup>2</sup>
.<xref rid="R15" ref-type="bibr">15</xref>
<xref rid="R16" ref-type="bibr">16</xref>
</p>
<p>Eligible patients were 16–74 years of age and had the following: a genetically confirmed diagnosis of Fabry disease; initiated ERT ≥12 months before the baseline visit; a responsive <italic>GLA</italic>
mutation based on the preliminary human embryonic kidney-293 (HEK) assay; and an estimated GFR (eGFR) ≥30 mL/min/1.73 m<sup>2</sup>
. Patients taking ACE inhibitors and/or angiotensin II receptor blockers had to be on a stable dose for ≥4 weeks before the screening visit. The primary objective of the study was to determine the comparability of migalastat to ERT in their effects on renal function.</p>
</sec>
<sec id="s2b"><title>Determination of amenability of <italic>GLA</italic>
mutation</title>
<p>Enrolled patients were required to have responsive mutant α-Gal forms based on a preliminary HEK assay.<xref rid="R17" ref-type="bibr">17</xref>
Determination of amenability of the mutant α-Gal forms was based on testing with the Good Laboratory Practice (GLP)-validated HEK assay (GLP HEK assay), which became available during the study. The GLP HEK assay includes several modifications to increase precision and consistency compared with the preliminary assay. Amenable mutant α-Gal forms had to meet the following criteria in the GLP HEK assay: relative increase in α-Gal activity ≥1.2-fold above baseline and absolute increase in α-Gal activity ≥3% of wild type in HEK cells after incubation with 10 µM migalastat.<xref rid="R18" ref-type="bibr">18</xref>
The concentration of 10 µM used in the GLP HEK assay is the approximate plasma maximum concentration of migalastat in patients with Fabry disease following a single oral dose of 150 mg.<xref rid="R12" ref-type="bibr">12</xref>
α-Gal increases of approximately 1–5% of normal activity in vivo were considered clinically meaningful in patients with Fabry disease.<xref rid="R19" ref-type="bibr">19</xref>
</p>
</sec>
<sec id="s2c"><title>Baseline assessment of disease severity and disease course prior to enrolment</title>
<p>The proportion of patients with Fabry multiorgan system disease involvement was determined based on medical history significant for angiokeratoma, neuropathic pain, renal impairment, cardiac event(s), central nervous system event(s) or gastrointestinal symptoms, and the following variables from the pre-randomisation visits: left ventricular hypertrophy (LVH) using echocardiography, eGFR, 24-hour urine protein and α-Gal (male patients only). The baseline assessment was compared with that reported for the Fabry Outcomes Survey and Fabry Registry.<xref rid="R20" ref-type="bibr">20–22</xref>
The assessment of disease course prior to study enrolment was based on medical history data.</p>
</sec>
<sec id="s2d"><title>Efficacy assessments</title>
<p>All randomised patients with amenable mutations receiving at least one dose of study drug and having baseline and postbaseline GFR measurements were included in the efficacy analyses. This population was defined as modified intent-to-treat.</p>
<sec id="s2d1"><title>Annualised change in GFR</title>
<p>The co-primary end points were annualised changes (mL/min/1.73 m<sup>2</sup>
/year) from baseline through month 18 in calculated GFR by eGFR using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula (eGFR<sub>CKD-EPI</sub>
)<xref rid="R23" ref-type="bibr">23</xref>
and measured GFR by iohexol clearance (mGFR<sub>iohexol</sub>
).<xref rid="R24" ref-type="bibr">24</xref>
Annualised change in eGFR using the Modification of Diet in Renal Disease (eGFR<sub>MDRD</sub>
)<xref rid="R25" ref-type="bibr">25</xref>
was a secondary end point.</p>
</sec>
<sec id="s2d2"><title>Composite clinical outcome assessment</title>
<p>The number of patients who experienced any of the following renal, cardiac or cerebrovascular events (including death) was determined:</p>
<p>Renal events
<list list-type="bullet"><list-item><p>a decrease in eGFR<sub>CKD-EPI</sub>
≥15 mL/min/1.73 m<sup>2</sup>
, with the decreased eGFR <90 mL/min/1.73 m<sup>2</sup>
relative to baseline;</p>
</list-item>
<list-item><p>an increase in 24-hour urine protein ≥ 33%, with elevated protein ≥ 300 mg relative to baseline.</p>
</list-item>
</list>
</p>
<p>Cardiac events
<list list-type="bullet"><list-item><p>myocardial infarction;</p>
</list-item>
<list-item><p>unstable cardiac angina, as defined by the American College of Cardiology/American Heart Association national practice guidelines;</p>
</list-item>
<list-item><p>new symptomatic arrhythmia requiring antiarrhythmic medication, direct current cardioversion, pacemaker or defibrillator implantation;</p>
</list-item>
<list-item><p>congestive heart failure, New York Heart Association class III or IV.</p>
</list-item>
</list>
</p>
<p>Cerebrovascular events
<list list-type="bullet"><list-item><p>stroke; transient ischaemic attack.</p>
</list-item>
</list>
</p>
</sec>
<sec id="s2d3"><title>Echocardiography</title>
<p>Echocardiography measurements were assessed through blinded, centralised evaluation (Cardiocore). Changes from baseline to month 18 were calculated for LV mass index, LV mass, LV posterior wall thickness diastolic (LVPWT), intraventricular septum wall thickness diastolic (IVSWT), LV ejection fraction, diastolic grade (based on E/A ratio), systolic grade (based on ejection fraction) and fractional shortening.</p>
</sec>
<sec id="s2d4"><title>Patient-reported outcomes</title>
<p>Changes from baseline in two questionnaires, the SF-36 v2 Health Survey by QualityMetric<xref rid="R26" ref-type="bibr">26</xref>
and the Brief Pain Inventory-Short Form (Pain Severity Component), were summarised using descriptive statistics.</p>
</sec>
<sec id="s2d5"><title>Plasma globotriaosylsphingosine (lyso-Gb<sub>3</sub>
)</title>
<p>Plasma was assayed for lyso-Gb<sub>3</sub>
by liquid chromatography-mass-spectroscopy (LC-MS) at baseline and months 6, 12 and 18. The LC-MS method used <sup>13</sup>
C<sub>6</sub>
-lyso-Gb<sub>3</sub>
as an internal standard (lower limit of quantitation: 0.20 µg/L, 0.25 nmol/L).<xref rid="R27" ref-type="bibr">27</xref>
<xref rid="R28" ref-type="bibr">28</xref>
</p>
</sec>
</sec>
<sec id="s2e"><title>Safety assessment</title>
<p>All randomised patients receiving at least one dose of study medication were included. A chartered data safety monitoring board regularly reviewed safety data.</p>
</sec>
<sec id="s2f"><title>Statistical analyses: GFR</title>
<p>Annualised rates of change in mGFR<sub>iohexol</sub>
and eGFR<sub>CKD-EPI</sub>
were analysed using an analysis of covariance (ANCOVA) model with the following factors and covariates: treatment group, sex, age, baseline GFR (mGFR<sub>iohexol</sub>
or eGFR<sub>CKD-EPI</sub>
) and baseline 24-hour urine protein. Descriptive statistics on the annualised rate of change were generated for each treatment group from this ANCOVA model, including least-squares means and 95% CIs. Annualised changes in GFR were calculated using linear regression slopes.</p>
<p>The predefined criteria for comparability in the least-squares mean annualised rate of change in mGFR<sub>iohexol</sub>
and eGFR<sub>CKD-EPI</sub>
between migalastat and ERT were a difference between the means in GFR within 2.2 mL/min/1.73 m<sup>2</sup>
/year, and >50% overlap of the 95% CI. The use of these two criteria together provides a comparison similar to a traditional non-inferiority analysis, but is more relevant in rare disease clinical research where traditional non-inferiority analyses are not feasible due to the sample size required. Based on the final observed data, the minimum difference in GFR that the study was able to detect was 0.71 mL/min/1.73 m<sup>2</sup>
/year for eGFR and 1.24 mL/min/1.73 m<sup>2</sup>
/year for mGFR.</p>
</sec>
</sec>
<sec sec-type="results" id="s3"><title>Results</title>
<sec id="s3a"><title>Demographics and baseline characteristics</title>
<p>Sixty patients (18–72 years of age; 56% female) were randomised: 36 were switched from ERT to migalastat and 24 remained on ERT. The first patient was enrolled on 8 September 2011. The last patient completed the study on 27 May 2014. Also, 3 of the 24 patients who were randomised to remain on ERT withdrew informed consent before study medication was administered and were not included in the analyses. At baseline, the treatment groups were balanced (<xref ref-type="table" rid="JMEDGENET2016104178TB1">table 1</xref>
). Patients switching to migalastat had been on ERT an average of 3.1 years. Patients remaining on ERT had been receiving ERT for 3.8 years. After randomisation, when the final GLP HEK assay became available, 53 of the 57 treated patients (34, migalastat; 19, ERT) had mutations categorised as amenable. Per the Statistical Analysis Plan, the four patients with non-amenable mutations were excluded from the primary efficacy analyses but were included in the safety analyses. Five randomised and treated patients (all had amenable mutations) discontinued from the study (2/36 migalastat and 3/21 ERT patients). All discontinuations were due to patient withdrawal of informed consent between weeks 16 and 51. Fifty-two patients (34 in the migalastat group; 18 in the ERT group) completed the 18-month randomisation phase (<xref ref-type="fig" rid="JMEDGENET2016104178F1">figure 1</xref>
).</p>
<table-wrap id="JMEDGENET2016104178TB1" orientation="portrait" position="float"><label>Table 1</label>
<caption><p>Baseline characteristics of the safety population</p>
</caption>
<table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col>
<col align="left" span="1"></col>
<col align="left" span="1"></col>
<col align="left" span="1"></col>
</colgroup>
<thead valign="bottom"><tr><th rowspan="1" colspan="1"></th>
<th align="left" rowspan="1" colspan="1">Migalastat<break></break>
n=36</th>
<th align="left" rowspan="1" colspan="1">ERT<break></break>
n=21</th>
<th align="left" rowspan="1" colspan="1">All<break></break>
N=57</th>
</tr>
</thead>
<tbody><tr><td rowspan="1" colspan="1">Age (years)±SEM (min, max)</td>
<td rowspan="1" colspan="1">50.5±2.3<break></break>
(18, 70)</td>
<td rowspan="1" colspan="1">46.3±3.3<break></break>
(18, 72)</td>
<td rowspan="1" colspan="1">48.9±1.9<break></break>
(18, 72)</td>
</tr>
<tr><td colspan="4" rowspan="1">Sex, n (%)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Male</td>
<td rowspan="1" colspan="1">16 (44)</td>
<td rowspan="1" colspan="1">9 (43)</td>
<td rowspan="1" colspan="1">25 (44)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Female</td>
<td rowspan="1" colspan="1">20 (56)</td>
<td rowspan="1" colspan="1">12 (57)</td>
<td rowspan="1" colspan="1">32 (56)</td>
</tr>
<tr><td rowspan="1" colspan="1">Years since diagnosis (mean±SEM)</td>
<td rowspan="1" colspan="1">10.2±2.0</td>
<td rowspan="1" colspan="1">13.4±2.6</td>
<td rowspan="1" colspan="1">11.4±1.6</td>
</tr>
<tr><td rowspan="1" colspan="1">24-hour protein (mg/24 hours, mean±SEM)</td>
<td rowspan="1" colspan="1">267±69</td>
<td rowspan="1" colspan="1">360±150</td>
<td rowspan="1" colspan="1">301±70</td>
</tr>
<tr><td rowspan="1" colspan="1">Median</td>
<td rowspan="1" colspan="1">129</td>
<td rowspan="1" colspan="1">108</td>
<td rowspan="1" colspan="1">128</td>
</tr>
<tr><td rowspan="1" colspan="1">IQR</td>
<td rowspan="1" colspan="1">393</td>
<td rowspan="1" colspan="1">483</td>
<td rowspan="1" colspan="1">408</td>
</tr>
<tr><td rowspan="1" colspan="1">Min, max</td>
<td rowspan="1" colspan="1">0, 2282</td>
<td rowspan="1" colspan="1">0, 3154</td>
<td rowspan="1" colspan="1">0, 3154</td>
</tr>
<tr><td rowspan="1" colspan="1">mGFR<sub>iohexol</sub>
(mL/min/1.73 m<sup>2</sup>
, mean±SEM)</td>
<td rowspan="1" colspan="1">82.4±3.0</td>
<td rowspan="1" colspan="1">83.6±5.2</td>
<td rowspan="1" colspan="1">82.8±2.6</td>
</tr>
<tr><td rowspan="1" colspan="1">eGFR<sub>CKD-EPI</sub>
(mL/min/1.73 m<sup>2</sup>
, mean±SEM)</td>
<td rowspan="1" colspan="1">89.6±3.7</td>
<td rowspan="1" colspan="1">95.8±4.1</td>
<td rowspan="1" colspan="1">91.9±2.8</td>
</tr>
<tr><td rowspan="1" colspan="1">eGFR<sub>MDRD</sub>
(mL/min/1.73 m<sup>2</sup>
, mean±SEM)</td>
<td rowspan="1" colspan="1">83.6±3.7</td>
<td rowspan="1" colspan="1">87.8±19.0</td>
<td rowspan="1" colspan="1">85.1±28.0</td>
</tr>
<tr><td rowspan="1" colspan="1">Left ventricular mass index (g/m<sup>2</sup>
)</td>
<td rowspan="1" colspan="1">97.5±4.7</td>
<td rowspan="1" colspan="1">94.6±5.6</td>
<td rowspan="1" colspan="1">96.5±3.6</td>
</tr>
<tr><td colspan="4" rowspan="1">ERT, n (%)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Agalsidase beta</td>
<td rowspan="1" colspan="1">11 (31)</td>
<td rowspan="1" colspan="1">8 (38)</td>
<td rowspan="1" colspan="1">19 (33)</td>
</tr>
<tr><td rowspan="1" colspan="1"> Agalsidase alfa</td>
<td rowspan="1" colspan="1">24 (67)</td>
<td rowspan="1" colspan="1">13 (62)</td>
<td rowspan="1" colspan="1">37 (65)</td>
</tr>
<tr><td rowspan="1" colspan="1">Use of ACEI/ARB/RI, n (%)</td>
<td rowspan="1" colspan="1">16 (44)</td>
<td rowspan="1" colspan="1">11 (52)</td>
<td rowspan="1" colspan="1">27 (47)</td>
</tr>
<tr><td rowspan="1" colspan="1">Amenable <italic>GLA</italic>
mutation, n (%)</td>
<td rowspan="1" colspan="1">34 (94)</td>
<td rowspan="1" colspan="1">19 (90)</td>
<td rowspan="1" colspan="1">53 (93)</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn><p>Based on randomised and treated patients. There were no statistically significant differences between treatment groups for these parameters (<italic>t</italic>
-test; Fisher's exact).</p>
</fn>
<fn><p>ACEI, ACE inhibitor; ARB, angiotensin II receptor blocker; eGFR<sub>CKD-EPI</sub>
, estimated GFR using the Chronic Kidney Disease Epidemiology Collaboration formula; eGFR<sub>MDRD</sub>
, annualised change in estimated GFR using the Modification of Diet in Renal Disease; ERT, enzyme replacement therapy; GFR, glomerular filtration rate; mGFR<sub>iohexol</sub>
, measured GFR using iohexol clearance; RI, renin inhibitor.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<p>At baseline, the majority of patients with amenable mutations had multiorgan system disease (≥88%; see online <xref ref-type="supplementary-material" rid="SM1">supplementary table S1</xref>
). Of the patients with an available date of ERT initiation in their medical history (n=48), 63% had multiorgan system involvement prior to the initiation of ERT, indicating an increase in the percentage of patients with multiorgan disease between initiation of ERT and study baseline (average duration of approximately 3 years). The age at enrolment and start of treatment and percentages of patients with involvement of different organ systems were comparable with those reported for the Fabry Outcomes Survey and Fabry Registry (see online <xref ref-type="supplementary-material" rid="SM1">supplementary table S2</xref>
).<xref rid="R20" ref-type="bibr">20–22</xref>
</p>
<supplementary-material content-type="local-data" id="SM1"><object-id pub-id-type="doi">10.1136/jmedgenet-2016-104178.supp1</object-id>
<label>Supplementary data</label>
<p><inline-supplementary-material id="ss1" mimetype="application" mime-subtype="pdf" xlink:href="jmedgenet-2016-104178supp001.pdf" content-type="local-data"></inline-supplementary-material>
</p>
</supplementary-material>
<p>Based on published reports of clinical phenotypes associated with specific <italic>GLA</italic>
mutations, 19 (36%) patients had mutations associated with the classical phenotype, 21 (40%) with non-classic phenotypes and 2 (4%) with both phenotypes; for the remaining 11 (21%) patients, the phenotype was not previously classified. Also, 10 of the 11 patients, including at least one patient for each of the six unique mutations (3 of 4 for p.G85G), had baseline disease in ≥2 organ systems. There were no significant differences in the phenotype categories between treatment groups.</p>
<p>The amenable mutations are provided in <xref ref-type="table" rid="JMEDGENET2016104178TB2">table 2</xref>
(supportive references for the literature phenotypes are provided in the online <xref ref-type="supplementary-material" rid="SM1">supplementary table S3</xref>
). To date, 269 <italic>GLA</italic>
mutations have been categorised as amenable to migalastat based on the GLP HEK assay, which has been clinically validated.<xref rid="R18" ref-type="bibr">18</xref>
</p>
<table-wrap id="JMEDGENET2016104178TB2" orientation="portrait" position="float"><label>Table 2</label>
<caption><p>Amenable mutations of enrolled and treated patients and the corresponding clinical phenotype</p>
</caption>
<table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col>
<col align="left" span="1"></col>
<col align="left" span="1"></col>
<col align="left" span="1"></col>
</colgroup>
<thead valign="bottom"><tr><th align="left" rowspan="1" colspan="1">Amino acid change<break></break>
(number of patients with the mutation)</th>
<th align="left" rowspan="1" colspan="1">Literature phenotype</th>
<th align="left" rowspan="1" colspan="1">Amino acid change</th>
<th align="left" rowspan="1" colspan="1">Literature phenotype</th>
</tr>
</thead>
<tbody><tr><td rowspan="1" colspan="1">p.M96I</td>
<td rowspan="1" colspan="1">Non-classic</td>
<td rowspan="1" colspan="1">p.G260A</td>
<td rowspan="1" colspan="1">Classic</td>
</tr>
<tr><td rowspan="1" colspan="1">p.L32P (n=3)</td>
<td rowspan="1" colspan="1">Unknown</td>
<td rowspan="1" colspan="1">p.Q279E</td>
<td rowspan="1" colspan="1">Non-classic</td>
</tr>
<tr><td rowspan="1" colspan="1">p.G35R</td>
<td rowspan="1" colspan="1">Non-classic</td>
<td rowspan="1" colspan="1">p.M284T</td>
<td rowspan="1" colspan="1">Classic</td>
</tr>
<tr><td rowspan="1" colspan="1">p.D55V/Q57L</td>
<td rowspan="1" colspan="1">Unknown*</td>
<td rowspan="1" colspan="1">p.M296I</td>
<td rowspan="1" colspan="1">Non-classic</td>
</tr>
<tr><td rowspan="1" colspan="1">p.G85D (n=4)</td>
<td rowspan="1" colspan="1">Unknown*</td>
<td rowspan="1" colspan="1">p.R301P (n=3)</td>
<td rowspan="1" colspan="1">Classic</td>
</tr>
<tr><td rowspan="1" colspan="1">p.A97V</td>
<td rowspan="1" colspan="1">Non-classic</td>
<td rowspan="1" colspan="1">p.R301Q</td>
<td rowspan="1" colspan="1">Both</td>
</tr>
<tr><td rowspan="1" colspan="1">p.R112G</td>
<td rowspan="1" colspan="1">Unknown*</td>
<td rowspan="1" colspan="1">p.G328A</td>
<td rowspan="1" colspan="1">Classic</td>
</tr>
<tr><td rowspan="1" colspan="1">p.R112H</td>
<td rowspan="1" colspan="1">Non-classic</td>
<td rowspan="1" colspan="1">p.Q312R</td>
<td rowspan="1" colspan="1">Non-classic</td>
</tr>
<tr><td rowspan="1" colspan="1">p.A143T (n=3)</td>
<td rowspan="1" colspan="1">Non-classic</td>
<td rowspan="1" colspan="1">p.D322E (n=4)</td>
<td rowspan="1" colspan="1">Classic</td>
</tr>
<tr><td rowspan="1" colspan="1">p.A156T (n=6)</td>
<td rowspan="1" colspan="1">Classic</td>
<td rowspan="1" colspan="1">p.R356Q</td>
<td rowspan="1" colspan="1">Non-classic</td>
</tr>
<tr><td rowspan="1" colspan="1">p.P205T</td>
<td rowspan="1" colspan="1">Classic</td>
<td rowspan="1" colspan="1">p.R363H</td>
<td rowspan="1" colspan="1">Both</td>
</tr>
<tr><td rowspan="1" colspan="1">p.N215S (n=10)</td>
<td rowspan="1" colspan="1">Non-classic</td>
<td rowspan="1" colspan="1">p.L403S</td>
<td rowspan="1" colspan="1">Classic</td>
</tr>
<tr><td rowspan="1" colspan="1">p.Y216C</td>
<td rowspan="1" colspan="1">Classic</td>
<td rowspan="1" colspan="1">p.P409T</td>
<td rowspan="1" colspan="1">Unknown*</td>
</tr>
<tr><td rowspan="1" colspan="1">p.I253S</td>
<td rowspan="1" colspan="1">Unknown*</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn><p>Number of patients with each mutation is 1 unless indicated otherwise.</p>
</fn>
<fn><p>To date, 269 <italic>GLA</italic>
mutations have been categorised as amenable to migalastat based on the Good Laboratory Practice human embryonic kidney assay. The supportive references for the literature phenotypes are provided in the online <xref ref-type="supplementary-material" rid="SM1">supplementary table S3</xref>
.</p>
</fn>
<fn><p>*Ten of the 11 patients, including at least one patient for each of the six unique mutations (3 of 4 for p.G85D), had baseline disease in ≥2 organ systems.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</sec>
<sec id="s3b"><title>Effects on renal function</title>
<p>Migalastat and ERT had comparable effects on renal function (<xref ref-type="table" rid="JMEDGENET2016104178TB3">table 3</xref>
). The co-primary end points, eGFR<sub>CKD-EPI</sub>
and mGFR<sub>iohexol</sub>
, met the criteria for comparability: annualised means within 2.2 mL/min/1.73 m<sup>2</sup>
/year and >50% overlap of 95% CIs. Comparison based on medians (results not shown) supports the comparability of migalastat and ERT. The mean change from baseline in 24-hour urine protein was numerically lower for the migalastat group (49.2 mg) than for the ERT group (194.5 mg).</p>
<table-wrap id="JMEDGENET2016104178TB3" orientation="portrait" position="float"><label>Table 3</label>
<caption><p>Annualised GFR from baseline to month 18</p>
</caption>
<table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col>
<col align="char" char="±" span="1"></col>
<col align="char" char="±" span="1"></col>
<col align="left" span="1"></col>
<col align="left" span="1"></col>
</colgroup>
<thead valign="bottom"><tr><th align="left" rowspan="1" colspan="1">ANCOVA*</th>
<th align="left" rowspan="1" colspan="1">Migalastat, mean±SEM† (95% CI),<break></break>
n=34</th>
<th align="left" rowspan="1" colspan="1">ERT, mean±SEM† (95% CI),<break></break>
n=18</th>
<th align="left" rowspan="1" colspan="1">Means within<break></break>
2.2 mL/min/1.73 m<sup>2</sup>
/year</th>
<th align="left" rowspan="1" colspan="1">>50% overlap of the 95% CI</th>
</tr>
</thead>
<tbody><tr><td rowspan="1" colspan="1">eGFR<sub>CKD-EPI</sub>
</td>
<td rowspan="1" colspan="1">−0.40±0.93<break></break>
(−2.27 to 1.48)</td>
<td rowspan="1" colspan="1">−1.03±1.29<break></break>
(−3.64 to 1.58)</td>
<td rowspan="1" colspan="1">Yes</td>
<td rowspan="1" colspan="1">Yes</td>
</tr>
<tr><td rowspan="1" colspan="1">mGFR<sub>iohexol</sub>
</td>
<td rowspan="1" colspan="1">−4.35±1.64<break></break>
(−7.65 to −1.06)</td>
<td rowspan="1" colspan="1">−3.24±2.27<break></break>
(−7.81 to 1.33)</td>
<td rowspan="1" colspan="1">Yes</td>
<td rowspan="1" colspan="1">Yes</td>
</tr>
<tr><td rowspan="1" colspan="1">eGFR<sub>MDRD</sub>
</td>
<td rowspan="1" colspan="1">−1.51±0.95<break></break>
(−3.43 to 0.40)</td>
<td rowspan="1" colspan="1">−1.53±1.32<break></break>
(−4.20 to 1.13)</td>
<td rowspan="1" colspan="1">NA</td>
<td rowspan="1" colspan="1">NA</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn><p>GFR=mL/min/1.73 m<sup>2</sup>
/year.</p>
</fn>
<fn><p>*mITT (randomised patients with amenable mutations receiving at least one dose of study medication and having a baseline and postbaseline efficacy measures of eGFR<sub>CKD-EPI</sub>
and mGFR<sub>iohexol</sub>
).</p>
</fn>
<fn><p>†Least-squares means.</p>
</fn>
<fn><p>ANCOVA, analysis of covariance; eGFR<sub>CKD-EPI</sub>
, estimated GFR using the Chronic Kidney Disease Epidemiology Collaboration formula; eGFR<sub>MDRD,</sub>
annualised change in eGFR using the Modification of Diet in Renal Disease; ERT, enzyme replacement therapy; GFR, glomerular filtration rate; mGFR<sub>iohexol</sub>
, measured GFR using iohexol clearance; mITT, modified intention-to-treat population; NA, not assessed.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</sec>
<sec id="s3c"><title>Composite clinical outcome assessment</title>
<p>The percentage of patients who experienced renal, cardiac or cerebrovascular events during the 18-month treatment period was 29% for migalastat and 44% for ERT (p=0.36; <xref ref-type="table" rid="JMEDGENET2016104178TB4">table 4</xref>
). No patient died during the 18-month treatment period.</p>
<table-wrap id="JMEDGENET2016104178TB4" orientation="portrait" position="float"><label>Table 4</label>
<caption><p>Composite clinical outcome: number of patients (mITT population)</p>
</caption>
<table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col>
<col align="left" span="1"></col>
<col align="left" span="1"></col>
</colgroup>
<thead valign="bottom"><tr><th align="left" rowspan="1" colspan="1">Component</th>
<th align="left" rowspan="1" colspan="1">Migalastat (n=34)</th>
<th align="left" rowspan="1" colspan="1">ERT (n=18)</th>
</tr>
</thead>
<tbody><tr><td rowspan="1" colspan="1">Renal</td>
<td rowspan="1" colspan="1">8 (24%)<break></break>
↑Proteinuria (6), ↓GFR (2)</td>
<td rowspan="1" colspan="1">6 (33%)<break></break>
↑Proteinuria (4), ↓GFR (3)</td>
</tr>
<tr><td rowspan="1" colspan="1">Cardiac</td>
<td rowspan="1" colspan="1">2 (6%)<break></break>
Chest pain, VT/chest pain</td>
<td rowspan="1" colspan="1">3 (17%)<break></break>
Cardiac failure, dyspnoea, arrhythmia</td>
</tr>
<tr><td rowspan="1" colspan="1">CNS</td>
<td rowspan="1" colspan="1">0 (0%)</td>
<td rowspan="1" colspan="1">1 (6%)<break></break>
TIA</td>
</tr>
<tr><td rowspan="1" colspan="1">Death</td>
<td rowspan="1" colspan="1">0 (0%)</td>
<td rowspan="1" colspan="1">0 (0%)</td>
</tr>
<tr><td rowspan="1" colspan="1">Any</td>
<td rowspan="1" colspan="1">10 (29%)</td>
<td rowspan="1" colspan="1">8 (44%)</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn><p>Analyses undertaken in the mITT patients (randomised patients with amenable mutations receiving at least one dose of study drug and having baseline and postbaseline mGFR<sub>iohexol</sub>
and eGFR<sub>CKD-EPI</sub>
measures). Proteinuria event defined as >33% increase in 24-hour urine protein and level >300 mg; GFR event defined as >15 mL/min decline in eGFR<sub>CKD-EPI</sub>
and level <90 mL/min/1.73 m<sup>2</sup>
/year. Two patients in the ERT group experienced one cardiac and one renal event each.</p>
</fn>
<fn><p>CNS, central nervous system; eGFR<sub>CKD-EPI</sub>
, estimated GFR using the Chronic Kidney Disease Epidemiology Collaboration formula; ERT, enzyme replacement therapy; GFR, glomerular filtration rate; mGFR<sub>iohexol</sub>
, measured GFR using iohexol clearance; mITT, modified intention to treat; TIA, transient ischaemic attack; VT, ventricular tachycardia.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</sec>
<sec id="s3d"><title>Echocardiography</title>
<p>In patients switched from ERT to migalastat, left ventricular mass index (LVMi) decreased significantly from baseline over 18 months (−6.6 g/m<sup>2</sup>
; 95% CI −11.0 to −2.2); a smaller, non-significant change was observed in patients who remained on ERT (−2.0 g/m<sup>2</sup>
(−11.0, 7.0)) (<xref ref-type="table" rid="JMEDGENET2016104178TB5">table 5</xref>
; see online <xref ref-type="supplementary-material" rid="SM1">supplementary figure S1</xref>
). The LVMi changes from baseline for migalastat-treated patients were largest for patients with LVH (<xref ref-type="table" rid="JMEDGENET2016104178TB5">table 5</xref>
). LV mass data were consistent with changes in LVMi (results not shown).</p>
<table-wrap id="JMEDGENET2016104178TB5" orientation="portrait" position="float"><label>Table 5</label>
<caption><p>Echocardiography-derived changes in patients with amenable mutations</p>
</caption>
<table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col>
<col align="left" span="1"></col>
<col align="char" char="(" span="1"></col>
</colgroup>
<thead valign="bottom"><tr><th align="left" rowspan="1" colspan="1">Parameter</th>
<th align="left" rowspan="1" colspan="1">Baseline mean</th>
<th align="left" rowspan="1" colspan="1">Change from baseline to month 18<break></break>
(95% CI)</th>
</tr>
</thead>
<tbody><tr><td colspan="3" rowspan="1">Migalastat: LVMi (g/m<sup>2</sup>
)</td>
</tr>
<tr><td rowspan="1" colspan="1"> All (n=33) (% abnormal)</td>
<td rowspan="1" colspan="1">95.3 (39)</td>
<td rowspan="1" colspan="1">−6.6 (−11.0 to −2.2)*</td>
</tr>
<tr><td rowspan="1" colspan="1"> LVH† at baseline (9 females and 4 males)</td>
<td rowspan="1" colspan="1">116.7</td>
<td rowspan="1" colspan="1">−8.4 (−15.7 to 2.6)</td>
</tr>
<tr><td colspan="3" rowspan="1">ERT: LVMi (g/m<sup>2</sup>
)</td>
</tr>
<tr><td rowspan="1" colspan="1"> All (n=16) (% abnormal)</td>
<td rowspan="1" colspan="1">92.9 (31)</td>
<td rowspan="1" colspan="1">−2.0 (−11.0 to 7−0)</td>
</tr>
<tr><td rowspan="1" colspan="1"> LVH† at baseline (n=5)<break></break>
(1 female and 4 males)</td>
<td rowspan="1" colspan="1">123.3 (100%)</td>
<td rowspan="1" colspan="1">4.5 (−20.9 to 30.0)</td>
</tr>
<tr><td colspan="3" rowspan="1">Migalastat: LVPWT (cm)</td>
</tr>
<tr><td rowspan="1" colspan="1"> All (n=33)</td>
<td rowspan="1" colspan="1">1.17</td>
<td rowspan="1" colspan="1">−0.035 (−0.077 to 0.007)</td>
</tr>
<tr><td colspan="3" rowspan="1">ERT: LVPWT (cm)</td>
</tr>
<tr><td rowspan="1" colspan="1"> All (n=16)</td>
<td rowspan="1" colspan="1">1.08</td>
<td rowspan="1" colspan="1">0.029 (−0.037 to 0.094)</td>
</tr>
<tr><td colspan="3" rowspan="1">Migalastat: IVSWT (cm)</td>
</tr>
<tr><td rowspan="1" colspan="1"> All (n=33)</td>
<td rowspan="1" colspan="1">1.16</td>
<td rowspan="1" colspan="1">0.058 (−0.200 to 0.140)</td>
</tr>
<tr><td colspan="3" rowspan="1">ERT: IVSWT (cm)</td>
</tr>
<tr><td rowspan="1" colspan="1"> All (n=16)</td>
<td rowspan="1" colspan="1">1.18</td>
<td rowspan="1" colspan="1">0.037 (−0.051 to 0.124)</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn><p>LVMi (g/m<sup>2</sup>
): normal: female, 43–95, male, 49–115; LVPMT (cm): normal: female, 0.6–<1.0, male, 0.6–<1.1; IVSWT (cm): normal: female, 0.6–0.9, male, 0.6–1.0.</p>
</fn>
<fn><p>*Statistically significant (95% CI does not overlap zero).</p>
</fn>
<fn><p>†LVH; defined as LVMi (g/m<sup>2</sup>
) >95 (females) or >115 (males).</p>
</fn>
<fn><p>ERT, enzyme replacement therapy; IVSWT, intraventricular septal wall thickness; LVH, left ventricular hypertrophy; LVMi, left ventricular mass index; LVPMT, left ventricular posterior wall thickness; LVPWT, left ventricular posterior wall thickness diastolic.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<p>The baseline mean and changes at month 18 for IVSWT and LVPWT are provided in <xref ref-type="table" rid="JMEDGENET2016104178TB5">table 5</xref>
. The changes in LVMi over 18 months correlated with changes in IVSWT (r<sup>2</sup>
=0.26, p=0.0028) but not with changes in LVPWT (r<sup>2</sup>
=0.04, p=0.296).</p>
<p>LV ejection fraction and fractional shortening were generally normal at baseline and remained stable over 18 months. Systolic and diastolic functional grades were normal at baseline in the majority of patients and remained stable over 18 months (see online <xref ref-type="supplementary-material" rid="SM1">supplementary table S4</xref>
).</p>
</sec>
<sec id="s3e"><title>Plasma lyso-Gb<sub>3</sub>
</title>
<p>In patients with amenable mutations, plasma lyso-Gb<sub>3</sub>
levels remained low and stable following the switch from ERT to migalastat (see online <xref ref-type="supplementary-material" rid="SM1">supplementary figure S2</xref>
). Comparable results were found in both males and females and in patients previously receiving either agalsidase alfa or agalsidase beta following their switch from ERT to oral migalastat. In two male patients with non-amenable mutations, plasma lyso-Gb<sub>3</sub>
increased following the switch from ERT to migalastat compared with the two patients with non-amenable mutations (one male; one female) who remained on ERT.</p>
</sec>
<sec id="s3f"><title>Patient-reported outcomes</title>
<p>Scores on the SF-36 v2 and Brief Pain Inventory (BPI) Short Form-Pain Severity Component remained stable during the 18-month study for both treatment groups (see online <xref ref-type="supplementary-material" rid="SM1">supplementary table S4</xref>
).</p>
</sec>
<sec id="s3g"><title>Safety</title>
<p>Treatment with migalastat was generally safe and well tolerated. The frequency of treatment-emergent adverse event (AE)s in the migalastat and ERT groups was comparable (94% and 95%, respectively). The most frequently reported treatment-emergent AEs (≥25%) in the migalastat group were nasopharyngitis (33%) and headache (25%). These events had a comparable frequency in the ERT group (33% and 24%, respectively). Most treatment-emergent AEs were mild or moderate in severity. No patient discontinued study drug due to a treatment-emergent AEs.</p>
<p>There were no deaths in the study. Serious AEs (SAEs) were less common in the migalastat group (19%) than in the ERT group (33%). No SAEs were considered related to study drug.</p>
<p>No clinically relevant effect of migalastat and no clinically relevant treatment group differences were noted for any laboratory test, ECG variable, vital sign or physical finding.</p>
</sec>
</sec>
<sec sec-type="discussion" id="s4"><title>Discussion</title>
<p>Oral migalastat, a pharmacological chaperone, is being developed as an alternative to ERT in the treatment of Fabry disease. Migalastat reversibly binds to the active site of specific mutant forms of α-Gal (amenable <italic>GLA</italic>
mutations) and stabilises and promotes trafficking of the enzyme to lysosomes where α-Gal catabolises accumulated disease substrate. We report on the 18-month results from a phase III study comparing the safety and efficacy of migalastat to ERT in male and female patients with Fabry disease and amenable mutations previously treated with ERT.</p>
<p>The study enrolled and treated 57 patients based on a preliminary HEK assay for responsiveness of the mutant α-Gal to migalastat. Prior to completing the study, the amenability of these mutant forms was assessed using the final GLP HEK assay, which was not available during enrolment. Based on this assay, 53 of the 57 patients had amenable mutations. On the basis of published reports, 36% had <italic>GLA</italic>
mutations associated with the classical Fabry phenotype and 40% had <italic>GLA</italic>
mutations associated with the non-classic Fabry phenotype. The baseline characteristics and medical histories indicated that a majority of patients in the study had multiple-organ systems affected by Fabry disease. The classic Fabry phenotype has been used to describe patients with early-onset, low-residual α-Gal activity (in male patients) and multiorgan system disease including pain and angiokeratoma in both males and females.<xref rid="R29" ref-type="bibr">29–32</xref>
</p>
<p>Migalastat and ERT had comparable effects on renal function, assessed by mGFR<sub>iohexol</sub>
and eGFR<sub>CKD-EPI</sub>
(the co-primary end points), and eGFR<sub>MDRD</sub>
in patients with amenable mutations. The 18-month period is sufficient to show a treatment effect, based on data in the literature demonstrating a worsening of renal function over 12–15 months after stopping ERT treatment<xref rid="R33" ref-type="bibr">33</xref>
or reducing ERT dose.<xref rid="R34" ref-type="bibr">34</xref>
A separate study with migalastat in ERT-naive patients<xref rid="R8" ref-type="bibr">8</xref>
also demonstrated that renal function was stabilised following up to 24 months of treatment. Renal dysfunction is present in a majority of patients being treated for Fabry disease,<xref rid="R35" ref-type="bibr">35</xref>
progresses over time and can lead to end-stage renal disease.<xref rid="R36" ref-type="bibr">36–41</xref>
Patients were stratified based on gender and 24-hour urine protein, which are the most important factors impacting renal function in patients with Fabry disease.<xref rid="R39" ref-type="bibr">39</xref>
<xref rid="R42" ref-type="bibr">42</xref>
The progressive decrease in GFR in Fabry disease has also been shown to be a major risk factor for cardiac events.<xref rid="R43" ref-type="bibr">43</xref>
Studies in the literature show that annualised rates of decline in GFR are in the range of −2.2 to −2.9 in ERT-treated patients.<xref rid="R16" ref-type="bibr">16</xref>
<xref rid="R44" ref-type="bibr">44</xref>
<xref rid="R45" ref-type="bibr">45</xref>
Thus, the effect of ERT is to slow the decline in GFR in patients with Fabry disease. As shown in this study, migalastat has a comparable effect to ERT on renal function, so it has the potential to stabilise or slow decline in renal function, which is an important treatment goal in Fabry disease.</p>
<p>The study found that LVMi decreased significantly from baseline to month 18 in patients treated with migalastat, whereas a smaller non-significant change was observed in patients remaining on ERT. The two treatment groups were balanced. Based on the randomisation ratio (1.5:1), there were fewer patients in the ERT group, which potentially limits the ability to show a statistically significant change. Cardiac disease is currently the main cause of death in patients with Fabry disease.<xref rid="R35" ref-type="bibr">35</xref>
The most common cardiac manifestation of Fabry disease is hypertrophic cardiomyopathy.<xref rid="R46" ref-type="bibr">46</xref>
LVH is an important risk factor for predicting cardiac events (heart failure and myocardial infarction) in Fabry disease.<xref rid="R43" ref-type="bibr">43</xref>
<xref rid="R47" ref-type="bibr">47</xref>
Reduction of LV mass has been associated with improved outcomes in Fabry disease; a 3-year study in patients with Fabry disease without myocardial fibrosis found that post-treatment reductions in LV mass were associated with improvement in stress exercise.<xref rid="R48" ref-type="bibr">48</xref>
The reductions in LVMi in migalastat-treated patients in this study correlate with changes in septal wall thickness but not posterior wall thickness. These reductions are especially meaningful compared with the known progressive increase of LVMi in untreated patients with Fabry disease<xref rid="R47" ref-type="bibr">47</xref>
<xref rid="R49" ref-type="bibr">49</xref>
and may contribute to a reduction in cardiac complications. The effect of ERT on LV mass is inconsistent.<xref rid="R50" ref-type="bibr">50–52</xref>
Engelen <italic>et al</italic>
<xref rid="R51" ref-type="bibr">51</xref>
reported that the initial improvements observed with ERT decreased over a similar time interval. In a cohort of 45 adult patients treated with agalsidase alfa for approximately 10 years, Kampmann <italic>et al</italic>
<xref rid="R53" ref-type="bibr">53</xref>
reported no changes in LVMi in patients with baseline values <50 g/m<sup>2</sup>
but found a decrease in LVMi in males with baseline values ≥50 g/m<sup>2</sup>
. A separate study found that LVMi increased in all male age groups treated for ≥2 years with agalsidase beta, except those 18–29 years of age.<xref rid="R47" ref-type="bibr">47</xref>
The reduction in LVMi with migalastat treatment, which was also demonstrated in a separate study of 24 months in ERT-naive patients,<xref rid="R8" ref-type="bibr">8</xref>
may reflect the wide tissue distribution of migalastat as an orally administered small molecule, including penetration into cardiac muscle cells, although further study is warranted.</p>
<p>The findings from the composite clinical outcome analysis provided further support for the efficacy and safety of migalastat. Previous studies have evaluated the effect of treatment on the progression of Fabry disease by a composite analysis of events related to the renal, cardiac and cerebrovascular systems,<xref rid="R52" ref-type="bibr">52</xref>
<xref rid="R54" ref-type="bibr">54</xref>
<xref rid="R55" ref-type="bibr">55</xref>
which are the organ systems most associated with morbidity and mortality in Fabry disease.<xref rid="R36" ref-type="bibr">36</xref>
<xref rid="R38" ref-type="bibr">38</xref>
<xref rid="R46" ref-type="bibr">46</xref>
In this study, the frequency of events in the migalastat group was 29% versus 44% in the ERT group, indicating that the effect of migalastat compares favourably to ERT in these composite clinical events. Results from both patient-reported outcomes showed that patients experienced no reduction in their quality of life when switched from ERT to migalastat.</p>
<p>Migalastat and ERT had similar effects on Fabry disease substrate in the study. Plasma lyso-Gb<sub>3</sub>
is recognised as an important marker of disease severity,<xref rid="R31" ref-type="bibr">31</xref>
<xref rid="R56" ref-type="bibr">56</xref>
and reductions in this substrate have been demonstrated to be associated with improved outcomes in Fabry disease.<xref rid="R56" ref-type="bibr">56</xref>
In patients with amenable mutations, migalastat maintained plasma lyso-Gb<sub>3</sub>
at the same low levels as ERT. In patients with non-amenable mutations, plasma lyso-Gb<sub>3</sub>
increased when the patients were switched from ERT to migalastat. The clear differences in plasma lyso-Gb<sub>3</sub>
in migalastat-treated patients with amenable versus non-amenable mutations, as previously demonstrated in a separate study,<xref rid="R8" ref-type="bibr">8</xref>
support the accuracy and clinical validity of the GLP HEK assay in categorising <italic>GLA</italic>
mutations.<xref rid="R18" ref-type="bibr">18</xref>
</p>
<p>Based on the proportion of patients with amenable mutations from the Sakuraba listing of Fabry phenotypes,<xref rid="R57" ref-type="bibr">57</xref>
the findings from the GLP HEK assay<xref rid="R18" ref-type="bibr">18</xref>
and literature reports of screenings in neonates,<xref rid="R58" ref-type="bibr">58–60</xref>
it is estimated that 35–50% of patients with Fabry disease have amenable mutations and therefore may be treatable with migalastat.</p>
<p>Migalastat was generally safe and well tolerated in this study. No clinically relevant effects were seen in laboratory tests, ECGs, vital signs or physical exams.</p>
<p>In this study, 18 months of treatment with migalastat was associated with a statistically significant decrease in LVMi; in ERT-treated patients, a non-significant change was observed. Migalastat and ERT had similar treatment effects on renal function and compared favourably in a composite clinical end point. Migalastat was safe and well tolerated. Migalastat, a pharmacological chaperone, offers promise as a first-in-class oral alternative to ERT for male and female patients with Fabry disease with amenable mutations.</p>
</sec>
</body>
<back><ack><p>The authors thank the patients and their families, and the clinical investigators who participated in the ATTRACT study. The authors acknowledge the important contributions of clinical investigator Professor Akemi Tanaka, Osaka City University Hospital, who passed away during the course of the study.</p>
</ack>
<fn-group><fn><p><bold>Contributors:</bold>
the study was designed by the authors, who vouch for accuracy of the analyses and protocol adherence. Data collection and analyses were undertaken by the sponsor in collaboration with a core group of investigators. The first draft of the manuscript was led by the first author and reviewed by all authors. All authors provided final approval to submit the manuscript for publication.</p>
</fn>
<fn><p><bold>Funding:</bold>
Amicus Therapeutics, Cranbury, NJ, USA.</p>
</fn>
<fn fn-type="COI-statement"><p><bold>Competing interests:</bold>
JB, ERB, JPC, NSk, FJ, JK, CV and JY report being employed by Amicus Therapeutics and owning shares; DJL and PB are former employees of Amicus Therapeutics; CB is a former contractor of Amicus Therapeutics; JPC and DJL report issued patents without royalties related to this study. DGB, DPG, DD, PD, UF-R, OG-A, DAH, AJ, EL, RS, SPS, and WRW report personal fees from Amicus Therapeutics, outside the submitted work. WRW reports receiving fees from Genzyme, Shire and Protalix. KN reports receiving fees from Shire and Genzyme. SPS reports receiving fees from Shire, Biomarin, Protalix and Genzyme. TO reports receiving fees from Genzyme and Dainippon Sumitomo. RL reports receiving fees from Genzyme. AJ reports receiving fees from Genzyme and Shire. OG-A reports receiving fees from Genzyme, Shire and Pfizer. DAH reports receiving fees from Genzyme, Shire and Protalix. UF-R reports receiving fees from Shire and Genzyme.</p>
</fn>
<fn><p><bold>Patient consent:</bold>
Obtained.</p>
</fn>
<fn><p><bold>Ethics approval:</bold>
Several IRBs approved this study. The institutions were those in which the principal investigators undertook this clinical trial.</p>
</fn>
<fn><p><bold>Provenance and peer review:</bold>
Not commissioned; externally peer reviewed.</p>
</fn>
</fn-group>
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