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Original Article
Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study
  1. Derralynn A Hughes1,
  2. Kathleen Nicholls2,
  3. Suma P Shankar3,
  4. Gere Sunder-Plassmann4,
  5. David Koeller5,
  6. Khan Nedd6,
  7. Gerard Vockley7,
  8. Takashi Hamazaki6,8,
  9. Robin Lachmann9,
  10. Toya Ohashi10,
  11. Iacopo Olivotto11,
  12. Norio Sakai12,
  13. Patrick Deegan13,
  14. David Dimmock14,
  15. François Eyskens15,
  16. Dominique P Germain16,
  17. Ozlem Goker-Alpan17,
  18. Eric Hachulla18,
  19. Ana Jovanovic19,
  20. Charles M Lourenco20,
  21. Ichiei Narita21,
  22. Mark Thomas22,
  23. William R Wilcox23,
  24. Daniel G Bichet24,
  25. Raphael Schiffmann25,
  26. Elizabeth Ludington26,
  27. Christopher Viereck27,
  28. John Kirk27,
  29. Julie Yu27,
  30. Franklin Johnson27,
  31. Pol Boudes28,
  32. Elfrida R Benjamin27,
  33. David J Lockhart29,
  34. Carrolee Barlow30,
  35. Nina Skuban27,
  36. Jeffrey P Castelli27,
  37. Jay Barth27,
  38. Ulla Feldt-Rasmussen31
  1. 1Department of Haematology, Royal Free London NHS Foundation Trust and University College London, London, UK
  2. 2Department of Nephrology, Royal Melbourne Hospital, Parkville, Victoria, Australia
  3. 3Section of Vitreoretinal Surgery & Diseases, Emory University, Atlanta, Georgia, USA
  4. 4Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
  5. 5Doernbecher Children's Hospital, Oregon Health & Science University, Portland, Oregon, USA
  6. 6Infusion Associates, Grand Rapids, Missouri, USA
  7. 7Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
  8. 8Department of Pediatrics, Osaka City University Hospital, Osaka-shi, Japan
  9. 9Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK
  10. 10Jikei University Hospital, Tokyo, Japan
  11. 11Departmento Cuore e vasi, A.O.U. Careggi Firenze, Firenze, Italy
  12. 12Osaka City University Hospital, Osaka-shi, Japan
  13. 13Lysosmal Disorders Unit, Department of Medicine, Addenbrooke's Hospital, Cambridge, UK
  14. 14Genetics Center MS716, Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA
  15. 15Univeritair Ziekenhaus Anterpen, Edegem, Belgium
  16. 16Division of Medical Genetics, University of Versailles, Paris-Saclay University and Assistance Publique—Hôpitaux de Paris, Paris, France
  17. 17O & O Alpan LLC, Springfield, Virginia, USA
  18. 18Service de Médecine, Hôpital Claude Huriez—CHRU Lille, Lille, France
  19. 19Department of Endocrinology and Metabolic Medicine, Salford Royal NHS Foundation Trust, Salford, UK
  20. 20Hospital das Clínicas FMUSP—Ribeirão Preto, São Paulo, Ribeirão Preto, Brazil
  21. 21Niigata University Graduate School of Medicine and Dental Sciences, Niigata, Japan
  22. 22Royal Perth Hospital, Perth, New South Wales, Australia
  23. 23Department of Genetics, Emory University School of Medicine, Atlanta, Georgia, USA
  24. 24Clinical Research Division, Hôpital du Sacré-Coeur de Montreal, University of Montreal, Montreal, Quebec, Canada
  25. 25Institute of Metabolic Disease, Baylor Research Institute, Dallas, Texas, USA
  26. 26Agility Clinical Inc., Carlsbad, California, USA
  27. 27Amicus Therapeutics Inc., Cranbury, New Jersey, USA
  28. 28CymaBay Therapeutics, Inc., Newark, California, USA
  29. 29TranscripTx, Inc., Sunnyvale, California, USA
  30. 30Parkinson's Institute and Clinical Center, Sunnyvale, California, USA
  31. 31Department of Medical Endocrinology, Rigshospital, Copenhagen University Hospital, Copenhagen, Denmark
  1. Correspondence to Dr Derralynn A Hughes, Department of Hematology, Royal Free London NHS Foundation Trust and University College London, London NW3 2PF, UK; rmgvdah{at}ucl.ac.uk

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.

  • Pharmacological chaperone
  • Fabry disease
  • lysosomal storage disorder
  • lyso-Gb3
  • enzyme replacement therapy

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Footnotes

  • Contributors 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.

  • Funding Amicus Therapeutics, Cranbury, NJ, USA.

  • 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.

  • Patient consent Obtained.

  • Ethics approval Several IRBs approved this study. The institutions were those in which the principal investigators undertook this clinical trial.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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