I. Project title
German observational multicenter study of patients with Fabry disease under chaperone therapy with Migalastat-HCl
II. Principle investigators
Malte Lendersa, Peter Nordbeckb, Christine Kurschatc, Maria Eveslaged; Nesrin Karabule, Jessica Kaufeldf, Julia B. Hennermanng, Monica Pattenh, Markus Cybullai, Jonas Müntzeb, Nurcan Üçeylerj, Dan Liub, Anibh M. Dask, Claudia Sommerj, Christian Pogodal, Stefanie Reiermanna, Thomas Duningm, Jens Gaedeken, Katharina von Cosselo, Daniela Blaschkep, Stefan-Martin Brandq, W. Alexander Manne, Christoph Kampmanng, Nicole Muscholo, Sima Canaan-Kühln, Eva Branda
aDepartment of Internal Medicine D, and Interdisciplinary Fabry Center (IFAZ), University Hospital Münster, Münster, bDepartment of Internal Medicine I, Comprehensive Heart Failure Center, and Fabry Center for Interdisciplinary Therapy (FAZIT), University of Würzburg, Würzburg, cDepartment II of Internal Medicine, Center for Molecular Medicine Cologne and Center for Rare Diseases, University of Cologne, Cologne, dInstitute of Biostatistics and Clinical Research (IBKF), University of Münster, Münster, eEndokrinologikum Frankfurt, Center of Hormonal and Metabolic Diseases, Rheumatology, Osteology and Neurology, Frankfurt, fDepartment of Nephrology and Hypertension, Hannover Medical School, Hannover, gVilla Metabolica, Department for Pediatric and Adolescent Medicine, University Medical Center Mainz, Mainz, hDepartment of general and interventional Cardiology, University Heart Center Hamburg, Hamburg, iFGM, Center of Internal Medicine, Department of Nephrology and Rheumatology, Mühlheim, jDepartment of Neurology, University of Würzburg, Würzburg, kDepartment of Paediatrics, Hannover Medical School, Hannover, lDepartment of Cardiology I – Coronary and Peripheral Vascular Disease, Heart Failure, and Interdisciplinary Fabry Center (IFAZ), University Hospital Münster, Münster, mDepartment of Neurology, and Interdisciplinary Fabry Center (IFAZ), University Hospital Münster, Münster, nMedizinische Klinik mit Schwerpunkt Nephrologie und Internistische Intensivmedizin, Fabry Zentrum, Zentrum für seltene Nierenerkrankungen (CeRKiD), Campus Charité Mitte, Charité - Universitätsmedizin Berlin, oDepartment of Pediatrics, University Medical Center Hamburg, Eppendorf, Hamburg, pDepartment of Medicine, Division of Cardiology, Charité, Campus Virchow-Klinikum, Berlin, qInstitute of Sports Medicine, Molecular Genetics of Cardiovascular Disease, and Interdisciplinary Fabry Center (IFAZ), University Hospital Münster, Münster, Germany
Fabry disease (FD; OMIM #301500) is an X-linked (Xq22.1) inborn error of glycosphingolipid catabolism resulting from deficient alpha-galactosidase A activity (GLA/AGAL; 300644) leading to a progressive lysosomal accumulation of glycosphingolipids (mainly globotriaosylceramide [Gb3]) within the vascular endothelium, as well as renal, cardiac, and neuronal cells. These accumulations result in a multisystemic disease with early myocardial failure and stroke, end-stage renal disease and severely decreased life expectancy. The enzymatic deficiency is based on GLA gene mutations (n>900) (http://www.hgmd.cf.ac.uk/ac/gene.php?gene=GLA). Identified mutations can be classified in nonsense and missense mutations. While nonsense mutations mostly result in a complete loss of function, missense mutations might result only in a partial loss of enzymatic activity due to single amino acid substitutions. Enzyme replacement therapy (ERT) is based on infusions of biotechnologically produced AGAL enzyme (Agalsidase-alfa, Replagal, 0.2 mg/kg BW every other week, Takeda/Shire, and Agalsidase-beta, Fabrazyme, 1 mg/kg BW every other week, Sanofi Genzyme), to compensate for the loss of endogenous enzyme. In contrast, the orally administered pharmacological chaperone Migalastat-HCl (Galafold, 1 capsule [123 mg] every other day, Amicus Therapeutics) enables the correct folding of the endogenous AGAL enzyme in patients with amenable GLA mutations. Several GLA missense mutations code for AGAL enzyme variants that are delivered to the proteasome for degeneration due to folding mistakes and failed quality control within the endoplasmic reticulum (ER). Many of these GLA variants might not only pass the quality control, but also meet up their function within the lysosomes, if a proper folding would be achieved. Since Migalastat-HCl serves as an AGAL folding template, the folding of mutated enzymes may be achieved and GLA enzyme function will be stabilized. By a proper tertiary protein structure, the AGAL enzyme passes the quality control within the ER and will be subsequently translocated to the Golgi apparatus and lysosomes. The pH shift (from neutral to acidic) within the lysosomes leads to a release of Migalastat-HCl and Gb3 as natural substrate can interact with the catalytic center of AGAL. The advantages of the pharmacological chaperone therapy over ERT are: 1) orally administered drug therapy, 2) encompassing the blood-brain barrier that cannot be encompassed by ERT (probably reduced effectiveness of ERT within the brain) and 3) no immunogenicity, which protects against an antibody-mediated ERT inhibition and loss of effectiveness in affected patients. The rationale of the current project is that disease progression of patients with FD with amenable GLA mutations for chaperones can be stabilized comparable to patients under ERT, leading to a validation of the clinical phase 3-studies and a transfer of these previous outcomes to a nationwide “real world” designed study in Germany. The published one year data on 60 patients with FD demonstrated that therapy with migalastat was generally safe and resulted in an amelioration of left ventricular mass (Lenders et al. 2020). In terms of impaired renal function, blood pressure control seems to be an unattended important goal.
The amendment of this study aimed to analyze treatment effects in patients with genetic variants of unknown significance (GVUS) within the GLA gene.
In detail, 15 (9 females) patients carrying p.A143T or p.D313Y were recruited and treated for 24 months with migalastat. 10 patients carried p.A143T (6 females) and 5 patients carried p.D313Y (3 females). Eight patients (4 females) were previously treated with ERT for a mean duration of 2.7±2.6 years. No differences for baseline characteristics between females and males were observed. Baseline characteristics demonstrated no FD-related renal or cardiac manifestations (including normal estimated glomerular filtration rate [eGFR], left ventricular septum thickness in diastole [lVSd] and left ventricular mass index [LVMi] values) independent of sex. However, females and males presented with relevant neurologic manifestations including the presence of FD-related pain and cerebrovascular events (transient ischemic attack [TIA]/stroke). Treatment with migalastat was well tolerated and safe and no adverse reactions were reported. During treatment, a total of 4 clinical events were assessed. In detail, one female suffered from 2 arrhythmia, one male suffered from one arrhythmia and one male from a TIA, resulting in an event rate of 133 events per 1,000 patient-years. Females and males demonstrated stable health conditions (including eGFR, lVSd and LVMi values) over 2 years.
15 patients carrying a GVUS within the GLA gene were treated for 24 months with migalastat. None of the treated individuals suffered from adverse reactions, demonstrating the safety and tolerability of this drug. Individuals presented with stable health conditions including normal renal function and cardiac parameters. Whether patients with GVUS (p.A143T, p.D313Y) and Fabry-like manifestations benefit from migalastat therapy is unclear because a comparison group of individuals without migalastat therapy is lacking. However, since individuals presented with stable health conditions over time, it can be concluded that migalastat was not harmful in this very cohort.
Lenders M, Nordbeck P, Kurschat C, Karabul N, Kaufeld J, Hennermann JB, Patten M, Cybulla M, Müntze J, Üçeyler N, Liu D, Das AM, Sommer C, Pogoda C, Reiermann S, Duning T, Gaedeke J, Stumpfe K, Blaschke D, Brand SM, Mann WA, Kampmann C, Muschol N, Canaan-Kühl S, Brand E. Treatment of Fabry's disease with migalastat: Outcome from a prospective observational multicenter study (FAMOUS). Clin Pharmacol Ther. 2020,108:326-337.
This project was funded by Amicus Therapeutics.