Clinical Trial

. 2017 Apr;54(4):288-296.

doi: 10.1136/jmedgenet-2016-104178. Epub 2016 Nov 10.

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

Derralynn A Hughes¹, Kathleen Nicholls², Suma P Shankar³, Gere Sunder-Plassmann⁴, David Koeller⁵, Khan Nedd⁶, Gerard Vockley⁷, Takashi Hamazaki^{6

8}, Robin Lachmann⁹, Toya Ohashi¹⁰, Iacopo Olivotto¹¹, Norio Sakai¹², Patrick Deegan¹³, David Dimmock¹⁴, François Eyskens¹⁵, Dominique P Germain¹⁶, Ozlem Goker-Alpan¹⁷, Eric Hachulla¹⁸, Ana Jovanovic¹⁹, Charles M Lourenco²⁰, Ichiei Narita²¹, Mark Thomas²², William R Wilcox²³, Daniel G Bichet²⁴, Raphael Schiffmann²⁵, Elizabeth Ludington²⁶, Christopher Viereck²⁷, John Kirk²⁷, Julie Yu²⁷, Franklin Johnson²⁷, Pol Boudes²⁸, Elfrida R Benjamin²⁷, David J Lockhart²⁹, Carrolee Barlow³⁰, Nina Skuban²⁷, Jeffrey P Castelli²⁷, Jay Barth²⁷, Ulla Feldt-Rasmussen³¹

Affiliations

¹ Department of Haematology, Royal Free London NHS Foundation Trust and University College London, London, UK.
² Department of Nephrology, Royal Melbourne Hospital, Parkville, Victoria, Australia.
³ Section of Vitreoretinal Surgery & Diseases, Emory University, Atlanta, Georgia, USA.
⁴ Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
⁵ Doernbecher Children's Hospital, Oregon Health & Science University, Portland, Oregon, USA.
⁶ Infusion Associates, Grand Rapids, Missouri, USA.
⁷ Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁸ Department of Pediatrics, Osaka City University Hospital, Osaka-shi, Japan.
⁹ Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK.
¹⁰ Jikei University Hospital, Tokyo, Japan.
¹¹ Departmento Cuore e vasi, A.O.U. Careggi Firenze, Firenze, Italy.
¹² Osaka City University Hospital, Osaka-shi, Japan.
¹³ Lysosmal Disorders Unit, Department of Medicine, Addenbrooke's Hospital, Cambridge, UK.
¹⁴ Genetics Center MS716, Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA.
¹⁵ Univeritair Ziekenhaus Anterpen, Edegem, Belgium.
¹⁶ Division of Medical Genetics, University of Versailles, Paris-Saclay University and Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁷ O & O Alpan LLC, Springfield, Virginia, USA.
¹⁸ Service de Médecine, Hôpital Claude Huriez-CHRU Lille, Lille, France.
¹⁹ Department of Endocrinology and Metabolic Medicine, Salford Royal NHS Foundation Trust, Salford, UK.
²⁰ Hospital das Clínicas FMUSP-Ribeirão Preto, São Paulo, Ribeirão Preto, Brazil.
²¹ Niigata University Graduate School of Medicine and Dental Sciences, Niigata, Japan.
²² Royal Perth Hospital, Perth, New South Wales, Australia.
²³ Department of Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
²⁴ Clinical Research Division, Hôpital du Sacré-Coeur de Montreal, University of Montreal, Montreal, Quebec, Canada.
²⁵ Institute of Metabolic Disease, Baylor Research Institute, Dallas, Texas, USA.
²⁶ Agility Clinical Inc., Carlsbad, California, USA.
²⁷ Amicus Therapeutics Inc., Cranbury, New Jersey, USA.
²⁸ CymaBay Therapeutics, Inc., Newark, California, USA.
²⁹ TranscripTx, Inc., Sunnyvale, California, USA.
³⁰ Parkinson's Institute and Clinical Center, Sunnyvale, California, USA.
³¹ Department of Medical Endocrinology, Rigshospital, Copenhagen University Hospital, Copenhagen, Denmark.

PMID: 27834756
PMCID: PMC5502308
DOI: 10.1136/jmedgenet-2016-104178

Clinical Trial

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 et al. J Med Genet. 2017 Apr.

. 2017 Apr;54(4):288-296.

doi: 10.1136/jmedgenet-2016-104178. Epub 2016 Nov 10.

Authors

Affiliations

¹ Department of Haematology, Royal Free London NHS Foundation Trust and University College London, London, UK.
² Department of Nephrology, Royal Melbourne Hospital, Parkville, Victoria, Australia.
³ Section of Vitreoretinal Surgery & Diseases, Emory University, Atlanta, Georgia, USA.
⁴ Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
⁵ Doernbecher Children's Hospital, Oregon Health & Science University, Portland, Oregon, USA.
⁶ Infusion Associates, Grand Rapids, Missouri, USA.
⁷ Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁸ Department of Pediatrics, Osaka City University Hospital, Osaka-shi, Japan.
⁹ Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK.
¹⁰ Jikei University Hospital, Tokyo, Japan.
¹¹ Departmento Cuore e vasi, A.O.U. Careggi Firenze, Firenze, Italy.
¹² Osaka City University Hospital, Osaka-shi, Japan.
¹³ Lysosmal Disorders Unit, Department of Medicine, Addenbrooke's Hospital, Cambridge, UK.
¹⁴ Genetics Center MS716, Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA.
¹⁵ Univeritair Ziekenhaus Anterpen, Edegem, Belgium.
¹⁶ Division of Medical Genetics, University of Versailles, Paris-Saclay University and Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁷ O & O Alpan LLC, Springfield, Virginia, USA.
¹⁸ Service de Médecine, Hôpital Claude Huriez-CHRU Lille, Lille, France.
¹⁹ Department of Endocrinology and Metabolic Medicine, Salford Royal NHS Foundation Trust, Salford, UK.
²⁰ Hospital das Clínicas FMUSP-Ribeirão Preto, São Paulo, Ribeirão Preto, Brazil.
²¹ Niigata University Graduate School of Medicine and Dental Sciences, Niigata, Japan.
²² Royal Perth Hospital, Perth, New South Wales, Australia.
²³ Department of Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
²⁴ Clinical Research Division, Hôpital du Sacré-Coeur de Montreal, University of Montreal, Montreal, Quebec, Canada.
²⁵ Institute of Metabolic Disease, Baylor Research Institute, Dallas, Texas, USA.
²⁶ Agility Clinical Inc., Carlsbad, California, USA.
²⁷ Amicus Therapeutics Inc., Cranbury, New Jersey, USA.
²⁸ CymaBay Therapeutics, Inc., Newark, California, USA.
²⁹ TranscripTx, Inc., Sunnyvale, California, USA.
³⁰ Parkinson's Institute and Clinical Center, Sunnyvale, California, USA.
³¹ Department of Medical Endocrinology, Rigshospital, Copenhagen University Hospital, Copenhagen, Denmark.

PMID: 27834756
PMCID: PMC5502308
DOI: 10.1136/jmedgenet-2016-104178

Erratum in

Correction: Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study.
[No authors listed] [No authors listed] J Med Genet. 2018 Jun;55(6):422-429. doi: 10.1136/jmedgenet-2016-104178corr1. Epub 2018 Apr 16. J Med Genet. 2018. PMID: 29661968 Free PMC article. No abstract available.

Abstract

Background: Fabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in α-galactosidase (α-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy (ERT), stabilises specific mutant (amenable) forms of α-Gal to facilitate normal lysosomal trafficking.

Methods: The main objective of the 18-month, randomised, active-controlled ATTRACT study was to assess the effects of migalastat on renal function in patients with Fabry disease previously treated with ERT. Effects on heart, disease substrate, patient-reported outcomes (PROs) and safety were also assessed.

Results: Fifty-seven adults (56% female) receiving ERT (88% had multiorgan disease) were randomised (1.5:1), based on a preliminary cell-based assay of responsiveness to migalastat, to receive 18 months open-label migalastat or remain on ERT. Four patients had non-amenable mutant forms of α-Gal based on the validated cell-based assay conducted after treatment initiation and were excluded from primary efficacy analyses only. Migalastat and ERT had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment (-6.6 g/m² (-11.0 to -2.2)); there was no significant change with ERT. Predefined renal, cardiac or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following the switch from ERT to migalastat. PROs were comparable between groups. Migalastat was generally safe and well tolerated.

Conclusions: Migalastat offers promise as a first-in-class oral monotherapy alternative treatment to intravenous ERT for patients with Fabry disease and amenable mutations.

Trial registration number: NCT00925301; Pre-results.

Trial registration: ClinicalTrials.gov NCT01218659.

Keywords: Fabry disease; Pharmacological chaperone; enzyme replacement therapy; lyso-Gb3; lysosomal storage disorder.

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/.

PubMed Disclaimer

Conflict of interest statement

Competing interests: 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.

Figures

**Figure 1**
Study design and patient disposition. ERT, enzyme replacement therapy; OLE, open-label extension.

See this image and copyright information in PMC

References

1. Brady RO, Gal AE, Bradley RM, Martensson E, Warshaw AL, Laster L. Enzymatic defect in Fabry's disease. Ceramidetrihexosidase deficiency. N Engl J Med 1967;276:1163–7. 10.1056/NEJM196705252762101 - DOI - PubMed
1. Germain DP. Fabry disease. Orphanet J Rare Dis 2010;5:30 10.1186/1750-1172-5-30 - DOI - PMC - PubMed
1. Fan JQ, Ishii S, Asano N, Suzuki Y. Accelerated transport and maturation of lysosomal a-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor. Nat Med 1999;5:112–15. 10.1038/4801 - DOI - PubMed
1. Khanna R, Soska R, Lun Y, Feng J, Frascella M, Young B, Brignol N, Pellegrino L, Sitaraman SA, Desnick RJ, Benjamin ER, Lockhart DJ, Valenzano KJ. The pharmacological chaperone 1-deoxygalactonojirimycin reduces tissue globotriaosylceramide levels in a mouse model of Fabry disease. Mol Ther 2010;18:23–33. 10.1038/mt.2009.220 - DOI - PMC - PubMed
1. Benjamin ER, Flanagan JJ, Schilling A, Chang HH, Agarwal L, Katz E, Wu X, Pine C, Wustman B, Desnick RJ, Lockhart DJ, Valenzano KJ. The pharmacological chaperone 1-deoxygalactonojirimycin increases alpha-galactosidase A levels in Fabry patient cell lines. J Inherit Metab Dis 2009;32:424–40. 10.1007/s10545-009-1077-0 - DOI - PubMed

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

Affiliations

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

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

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