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

Jonas Müntze, Daniel Gensler, Octavian Maniuc, Dan Liu, Tereza Cairns, Daniel Oder, Kai Hu, Kristina Lorenz, Stefan Frantz, Christoph Wanner, Peter Nordbeck, Jonas Müntze, Daniel Gensler, Octavian Maniuc, Dan Liu, Tereza Cairns, Daniel Oder, Kai Hu, Kristina Lorenz, Stefan Frantz, Christoph Wanner, Peter Nordbeck

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/m2 ; 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 m2 ; 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.

Conflict of interest statement

J.M., D.G., T.C., D.O., P.N., and C.W. are members of the FAZiT of the University Hospital Würzburg. J.M. received travel assistance from Amicus Therapeutics, Sanofi Genzyme, and Shire. D.O. received travel assistance and speaker honoraria from Sanofi Genzyme and Shire. C.W. received speaker honoraria from Actelion, Protalix, Sanofi Genzyme, and Shire. P.N. received speaker honoraria and research grants from Amicus Therapeutics, Idorsia, Sanofi Genzyme, and Shire.

© 2018 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Changes in α‐galactosidase A activity in individual patients (n = 14) during 1 year of migalastat therapy. (Left) Absolute changes from baseline; (right) percentage changes from baseline.
Figure 2
Figure 2
Changes in plasma globotriaosylsphingosine levels in individual patients during 1 year of migalastat therapy. (a,b) All patients who received migalastat (total group; n = 14); (c,d) patients who did not receive Fabry‐specific therapy before migalastat (therapy‐naive group; n = 8). (e,f) Patients who switched from enzyme replacement therapy to migalastat (previous enzyme replacement therapy group; n = 6). (Left panels) Absolute changes from baseline; (right panels) percentage changes from baseline.
Figure 3
Figure 3
Changes of myocardial mass index in individual patients (n = 14) during 1 year of migalastat therapy. (Left) Patients with moderately severe or severe myocardial hypertrophy; (right) patients with mildly abnormal or normal myocardial hypertrophy.44

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