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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.

ABSTRACT: BACKGROUND:Fabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in ?-galactosidase (?-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 ?-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 ?-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.

SUBMITTER: Hughes DA

PROVIDER: S-EPMC5502308 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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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.

Hughes Derralynn A DA Nicholls Kathleen K Shankar Suma P SP Sunder-Plassmann Gere G Koeller David D Nedd Khan K Vockley Gerard G Hamazaki Takashi T Lachmann Robin R Ohashi Toya T Olivotto Iacopo I Sakai Norio N Deegan Patrick P Dimmock David D Eyskens François F Germain Dominique P DP Goker-Alpan Ozlem O Hachulla Eric E Jovanovic Ana A Lourenco Charles M CM Narita Ichiei I Thomas Mark M Wilcox William R WR Bichet Daniel G DG Schiffmann Raphael R Ludington Elizabeth E Viereck Christopher C Kirk John J Yu Julie J Johnson Franklin F Boudes Pol P Benjamin Elfrida R ER Lockhart David J DJ Barlow Carrolee C Skuban Nina N Castelli Jeffrey P JP Barth Jay J Feldt-Rasmussen Ulla U

Journal of medical genetics 20161110 4

<h4>Background</h4>Fabry disease is an X-linked lysosomal storage disorder caused by <i>GLA</i> 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 (<i>amenable</i>) forms of α-Gal to facilitate normal lysosomal trafficking.<h4>Methods</h4>The main objective of the 18-month, randomised, active- ...[more]

PMID: 27834756

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Project description:Fabry disease is one of the most common lysosomal storage disorders caused by mutations in the gene encoding lysosomal ?-galactosidase A (?-Gal A) and resultant accumulation of glycosphingolipids. The sugar mimetic 1-deoxygalactonojirimycin (DGJ), an orally available pharmacological chaperone, was clinically approved as an alternative to intravenous enzyme replacement therapy. The decision as to whether a patient should be treated with DGJ depends on the genetic variant within the ?-galactosidase A encoding gene (GLA). A good laboratory practice (GLP)-validated cell culture-based assay to investigate the biochemical responsiveness of the variants is currently the only source available to obtain pivotal information about susceptibility to treatment. Herein, variants were defined amenable when an absolute increase in enzyme activity of ?3% of wild type enzyme activity and a relative increase in enzyme activity of ?1.2-fold was achieved following DGJ treatment. Efficacy testing was carried out for over 1000 identified GLA variants in cell culture. Recent data suggest that about one-third of the variants comply with the amenability criteria. A recent study highlighted the impact of inter-assay variability on DGJ amenability, thereby reducing the power of the assay to predict eligible patients. This prompted us to compare our own ?-galactosidase A enzyme activity data in a very similar in-house developed assay with those from the GLP assay. In an essentially retrospective approach, we reviewed 148 GLA gene variants from our former studies for which enzyme data from the GLP study were available and added novel data for 30 variants. We also present data for 18 GLA gene variants for which no data from the GLP assay are currently available. We found that both differences in experimental biochemical data and the criteria for the classification of amenability cause inter-assay discrepancy. We conclude that low baseline activity, borderline biochemical responsiveness, and inter-assay discrepancy are alarm signals for misclassifying a variant that must not be ignored. Furthermore, there is no solid basis for setting a minimum response threshold on which a clinical indication with DGJ can be justified.

Dataset Information

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

Publications

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

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