Safety of switching to Migalastat from enzyme replacement therapy in Fabry disease: Experience from the Phase 3 ATTRACT study

Lysosomal Storage Disorders Unit, Royal Free NHS Foundation Trust and University College London, London, United Kingdom Department of Nephrology, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria The Mark Holland Metabolic Unit, Salford Royal Hospital and NHS Foundation Trust, Salford, United Kingdom Department of Medical Endocrinology and Metabolism, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Metabolic Disease, Baylor Research Institute, Dallas, Texas Medical Genetics Service, HCPA, and Department of Genetics, UFRGS, Porto Alegre, Rio Grande do Sul, Brazil Amicus Therapeutics, Inc., Cranbury, New Jersey Departments of Medicine and Physiology, Hôpital du Sacré-Coeur, University of Montreal, Montreal, Quebec, Canada Correspondence 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 Funding information Amicus Therapeutics, Inc.


Correspondence
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

Funding information
Amicus Therapeutics, Inc. To the editor: Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the GLA gene that result in functional deficiency of alphagalactosidase A (α-Gal A); the accumulation of lysosomal α-Gal A substrates can lead to multisystem disease and early death Mehta et al., 2010;Waldek, Patel, Banikazemi, Lemay, & Lee, 2009).
Migalastat is a first-in-class, small-molecule pharmacological chaperone that binds to and stabilizes amenable mutant forms of α-Gal A in the endoplasmic reticulum, facilitating proper trafficking to lysosomes, where dissociation of migalastat allows α-galactosidase to catabolize accumulated substrates (Benjamin et al., 2009;Germain et al., 2016;Germain & Fan, 2009;Ishii et al., 2007;Khanna et al., 2010;Yam, Zuber, & Roth, 2005). It is estimated that 35-50% of patients with Fabry disease have migalastat-amenable mutations (Hughes et al., 2017). As of July 23, 2018, the total exposure to migalastat in the Phase 2 and 3 clinical programs was 660 patient-years, with 128 patients exposed ≥1 year (Data on file. Amicus Therapeutics Inc., 2018). The efficacy and safety of migalastat in patients with Fabry disease who have amenable GLA mutations have been established in both placebo and activecontrolled clinical trials and long-term open-label extension studies (Germain et al., 2016;Germain et al., 2018;Hughes et al., 2017;Nicholls et al., 2018). Oral migalastat has been approved in the European Union, Switzerland, Australia, Israel, Republic of Korea, and Japan for long-term treatment of adults and adolescents aged 16 years and older with a confirmed diagnosis of Fabry disease (α-Gal A deficiency) who have a migalastat-amenable GLA mutation (Amicus Therapeutics Inc., 2018).
Migalastat is also approved in the United States and Canada for adults (aged 18 years and older; Amicus Therapeutics U.S., Inc., 2018; Amicus Therapeutics UK Ltd., 2017).
We previously reported on Part 1 of the Phase 3 ATTRACT study (AT1001-012; NCT01218659), an 18-month randomized treatment † Deceased December 19, 2017. Table 1). Prior ERT characteristics were similar between male and female patients. In patients for whom the data were available, migalastat was started 4 to 19 days after their last ERT infusion. The most common treatment-emergent adverse events (AEs) in Cohort 1 (occurring in ≥20% of patients) during the first 18 months were nasopharyngitis (33%) and headache (25%; Table 2), and during the full 30 months were nasopharyngitis (42%), headache (36%), and influenza (27%; Table 2). AEs were generally mild or moderate; no patient discontinued due to an AE. There were no clinically meaningful changes in mean values from baseline for hematology, serum chemistry, urinalysis analysis, and vital signs (Supporting Information Table S1). Thirty-four (94%) Cohort 1 patients started a new medication during months 0-30. The most common new concomitant mediations were amoxicillin (22%), ibuprofen (19%), paracetamol (19%), amoxicillin with clavulanic acid (11%), and temazepam (11%). Only two (6%) patients started a new angiotensinconverting enzyme inhibitor, angiotensin II receptor blocker, or renin inhibitor. Overall, based on a review of AEs, laboratory measures, and concomitant medications in Cohort 1, migalastat was well tolerated after patients switched from ERT.
In patients for whom the data were available, migalastat was started 2 to 14 days after their last ERT infusion. The most common AEs during 12 months of migalastat treatment in Part 2 were nasopharyngitis (33%), diarrhea (27%), vomiting (27%), influenza (20%), and headache (20%; Table 3). Although the percentages of patients experiencing diarrhea or vomiting increased after the switch to migalastat, these reflect changes in only 1-2 patients and the small patient numbers limit interpretation.
There were no clinically meaningful changes in mean values from hematology, serum chemistry, urinalysis analysis, and vital signs following the switch from ERT to migalastat (Supporting Information Table S2).
Twelve (80%) Cohort 2 patients started a new medication during months 18-30. The most common new concomitant medications were general    Thirty patients completed treatment through 30 months (Part 2). Reasons for discontinuation during Part 2 include withdrawal by participant (n = 1), pregnancy (n = 1), and lack of efficacy (n = 1). d Any adverse events that started after first study drug administration and before OLE first dose date.
female patients to become pregnant. Patients' preference and hypersen-