PracticeUpdate Conference Series_WORLDSymposium 2019

Long-TermMigalastat Therapy Benefits Renal Function and Cardiac Mass in Patients With Fabry Disease Subanalysis of the ATTRACT trial points to better outcomes with the therapy.

L ong-term therapy with migalastat has been shown to benefit renal function and cardiac mass in patients with Fabry disease, outcome of a subanalysis of the phase III, randomized, enzyme replacement therapy-controlled ATTRACT trial shows. Nina Skuban, MD, of Amicus Therapeutics in Cranbury, New Jersey, and colleagues set out to evaluate the long-term effects of migalastat on α-galactosidase A activity and clinical outcomes in enzyme replacement therapy-experienced patients enrolled in ATTRACT. The analysis focused on 5 patients (3 females, 2 males) whose GLA variants, when tested with the in vitro migalastat amenability assay, resulted in a relatively low response of α-galactosidase A activity (an increase of ≥3% to <6% of wild type) but still met amenable criteria (≥1.2-fold relative increase over baseline and ≥3% absolute increase of wild-type activity). These 5 patients, after an average of 2.2 years of migalastat treatment, achieved stabilization in renal function and a reduction in cardiac mass. Their glo- botriaosylsphingosine levels also remained stable, consistent with the overall population. White blood cell α-galactosidase A activity (assessed in 2 males only) was very low at baseline in this subset and achieved sustained increases during migalastat treatment, maintaining absolute

increases of 4.6% (1.7-fold) and 7.2% (16.9-fold) of normal at last assessment, respectively. Every-other-day dosing resulted in consistent lev- els of migalastat exposure in these patients. Dr. Skuban explained that Fabry disease is a rare, X-linked disorder of α-galactosidase A deficiency caused by mutations in the GLA gene. The def- ciency results in substrate accumulation and multiorgan deterioration. Migalastat is a first-in-class, oral, small-molecule pharmacological chaperone that binds to and sta- bilizes endogenous α-galactosidase A, leading to increased lysosomal activity and reduced substrates in patients with amenable GLA variants, as deter- mined by an in vitro migalastat amenability assay. Dr. Skuban concluded that in patients with amenable GLA variants with low α-galactosidase A responses in the in vitro migalastat amenability assay, long- term migalastat therapy benefits renal function and cardiac mass in patients with Fabry disease.

" …given the uncertainty in the origin of plasma globotriasosylceramide and differences in the biodistribution and mechanism of action among the current treatment options, plasma globotriasosylceramide should not be interpreted as a stand-alone biomarker. " PRACTICEUPDATE CONFERENCE SERIES • WORLDSymposium 2019 8