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
- enzyme replacement therapy
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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.