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

Abstract

Long‐term effects of migalastat therapy in clinical practice are currently unknown. We evaluated migalastat efficacy and biomarker changes in a prospective, single‐center study on 14 patients with Fabry disease (55 ± 14 years; 11 men). After 1 year of open‐label migalastat therapy, patients showed significant changes in alpha‐galactosidase‐A activity (0.06–0.2 nmol/minute/mg protein; P = 0.001), left ventricular myocardial mass index (137–130 g/m 2 ; P = 0.037), and serum creatinine (0.94–1.0 mg/ dL ; P = 0.021), accounting for deterioration in estimated glomerular filtration rate (87–78 mL/minute/1.73 m 2 ; P = 0.012). The enzymatic increase correlated with myocardial mass reduction ( r = −0.546; P = 0.044) but not with renal function ( r = −0.086; P = 0.770). Plasma globotriaosylsphingosine was reduced in therapy‐naive patients (10.9–6.0 ng/mL; P = 0.021) and stable (9.6–12.1 ng/mL; P = 0.607) in patients switched from prior enzyme‐replacement therapy. These first real‐world data show that migalastat substantially increases alpha‐galactosidase‐A activity, stabilizes related serum biomarkers, and improves cardiac integrity in male and female patients with amenable Fabry disease mutations.

Fabry disease genotype, phenotype, and migalastat amenability: Insights from a national cohort

“…However, the actual proportion of patients who can be considered for migalastat therapy is important: in contrast to a mutation database, a community of Fabry patients consists of families rather than of single mutations, and the cohort composition depends on the diagnostic approaches within a country, such as national screening programs and programs increasing physicians' awareness of the disease. In a study of the Fabry center in Würzburg (Germany), Muntze et al mentioned that 37% of their FD patients had amenable mutations, which is less than in the present Swiss Fabry cohort.…”

“…In patients on ERT, it is not surprising that the change in endogenous enzyme activity does not correlate with change in lyso‐Gb3, as they were treated with exogenous enzyme. An increasing level of lyso‐Gb3 after switch to migalastat has already been observed in a recent article by Muntze et al These findings suggest that migalastat cannot stabilize important biomarkers in all patients; the clinical impact of this result needs to be further studied.…”

Response to “Oral Chaperone Therapy Migalastat for the Treatment of Fabry Disease: Potentials and Pitfalls of Real‐World Data”

“…To the Editor: We thank Dr Körver and colleagues for their interest in our work. 1 We absolutely agree that validity of current amenability criteria arguably might still be subject to discussion. From the clinical viewpoint, the cutoff values of 1.2fold relative and 3% absolute increase in alpha galactosidase activity chosen in the recent multicenter trials might be questionable particularly in patients with polymorphism-like genotypes, such as the benign variant D313Y, presenting with near-normal wild-type enzyme activity but currently still categorized as amenable.…”

Strong increase of leukocyte apha‐galactosidase A activity in two male patients with Fabry disease following oral chaperone therapy

“…A recent study showed a significant increase of leukocyte α‐Gal A activity, but not a complete normalization, in 14 FD patients (three females) after 1 year of migalastat, increasing from 0.06 (IQR 0.04–0.12) to 0.2 nmol min −1 mg −1 protein (IQR 0.06–0.26; reference values reported in the publication: 0.4–1.0 nmol min −1 mg −1 protein) (Müntze et al, ). In this study, the subgroup of p.N215S carriers ( n = 8), had an increase of α‐Gal A activity from 0.06 (0.05–0.07) to 0.2 nmol min −1 mg −1 protein (0.1–0.25) (Müntze et al, ). Although blood leukocytes are not the main therapeutic target in FD, intracellular leukocyte α‐Gal A activity reflects the amount of enzyme that could reach the lysosome via intracellular trafficking.…”