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

Abstract

BackgroundFabry 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.MethodsThe 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.ResultsFifty-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.ConclusionsMigalastat 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.

Oral Chaperone Therapy Migalastat for Treating Fabry Disease: Enzymatic Response and Serum Biomarker Changes After 1 Year

“…The general trend of a decline we observed in lyso‐Gb3 levels was consistent with recent findings from the migalastat phase III ATTRACT study . In our study, lyso‐Gb3 levels significantly declined, followed by stabilization, but one patient who had switched from ERT to migalastat showed a rapid increase in lyso‐Gb3 from baseline (12.4–66.1 ng/mL at the second follow‐up).…”

“…30 Mehta et al 31 observed a mean yearly decline of 2.46−3.58 mL/minute/1.73 m 2 with ERT. Compared with those findings, and other studies that described first experiences with migalastat, 11,23 we detected an overall greater reduction in renal function (−9 mL/minute/1.73 m 2 ) in the total cohort after 1 year of migalastat therapy. However, in our study seven patients displayed a baseline estimated GFR > 80 mL/minute/1.73 m 2 in which the precision of GFR values remains suboptimal.…”

Lysosomes as a therapeutic target

“…Eliglustat, another GCS inhibitor that does not penetrate the CNS, was also approved for Gaucher disease in 2014. Other GCS inhibitors in clinical devel opment include lucerastat, a miglustat analogue with an improved safety profile that is currently in a phase III trial for Fabry disease (FD) 236,286 , and ibiglustat, which penetrates the CNS. The latter is in clinical development for FD (phase II), for Gaucher disease type 3 (phase II) and for patients with PD who carry a mutation in GBA (phase II).…”

Drug development in the era of precision medicine

“…Two recent phase III studies (the FACETS and ATTRACT studies, NCT00925301 and NCT01218659, respectively) evaluating the safety and efficacy of the chaperone drug migalastat, which targets certain GLA mutations that affect enzyme conformation, have demonstrated favourable clinical outcomes for patients carrying these mutations compared with placebo or enzyme replacement therapy 113,114 . Migalastat has since been approved for the treatment of Fabry disease by the European Medicines Agency, and a new drug application will be submitted to the FDA by the end of this year (see Further information).…”