Oral Migalastat HCl Leads to Greater Systemic Exposure and Tissue Levels of Active α-Galactosidase A in Fabry Patients when Co-Administered with Infused Agalsidase

• Type of Material: Article
• Authors: David G. Warnock, University of Alabama; Daniel G. Bichet, University of Montreal; Myrl Holida, University of Iowa; Ozlem Goker-Alpan, O&O Alpan LLC; Kathy Nicholls, University of Melbourne; Mark Thomas, University of Western Australia; Francois Eyskens, Universitair Ziekenhuis Antwerpen; Suma Shankar, Emory University; Mathews Adera, Amicus Therapeutics; Sheela Sitaraman, Amicus Therapeutics; Richie Khanna, Amicus Therapeutics; John J. Flanagan, Arvinas Inc; Brandon A. Wustman, Institute and Clinical Center; Jay Barth, Amicus Therapeutics; Carrolee Barlow, Amicus Therapeutics; Kenneth J. Valenzano, Amicus Therapeutics; David J. Lockhart, Institute and Clinical Center; Pol Boudes, Cymabay Therapeutics; Franklin K. Johnson, Amicus Therapeutics
• Language: English
• Date: 2015-08-07
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2015 Warnock et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0134341
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 10
• Issue: 8
• Start Page: e0134341
• End Page: e0134341
• Grant/Funding Information: This clinical trial, AT1001-013, its design, execution, data analysis, report writing, and manuscript preparation was funded by Amicus Therapeutics and GSK.
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Pharmacology

Abstract

Migalastat HCl (AT1001, 1-Deoxygalactonojirimycin) is an investigational pharmacological chaperone for the treatment of α-galactosidase A (α-Gal A) deficiency, which leads to Fabry disease, an X-linked, lysosomal storage disorder. The currently approved, biologics-based therapy for Fabry disease is enzyme replacement therapy (ERT) with either agalsidase alfa (Replagal) or agalsidase beta (Fabrazyme). Based on preclinical data, migalastat HCl in combination with agalsidase is expected to result in the pharmacokinetic (PK) enhancement of agalsidase in plasma by increasing the systemic exposure of active agalsidase, thereby leading to increased cellular levels in disease-relevant tissues. This Phase 2a study design consisted of an open-label, fixed-treatment sequence that evaluated the effects of single oral doses of 150 mg or 450 mg migalastat HCl on the PK and tissue levels of intravenously infused agalsidase (0.2, 0.5, or 1.0 mg/kg) in male Fabry patients. As expected, intravenous administration of agalsidase alone resulted in increased α-Gal A activity in plasma, skin, and peripheral blood mononuclear cells (PBMCs) compared to baseline. Following co-administration of migalastat HCl and agalsidase, α-Gal A activity in plasma was further significantly increased 1.2- to 5.1-fold compared to agalsidase administration alone, in 22 of 23 patients (95.6%). Importantly, similar increases in skin and PBMC α-Gal A activity were seen following co-administration of migalastat HCl and agalsidase. The effects were not related to the administered migalastat HCl dose, as the 150 mg dose of migalastat HCl increased α-Gal A activity to the same extent as the 450 mg dose. Conversely, agalsidase had no effect on the plasma PK of migalastat. No migalastat HCl-related adverse events or drug-related tolerability issues were identified.