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

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.

Trial registration: ClinicalTrials.gov NCT01196871.

Conflict of interest statement

Competing Interests: F. K. Johnson, M. Adera, S. Sitaraman, R. Khanna, K. J. Valenzano, and J. Barth are employed by Amicus Therapeutics and are shareholders in the company. J. J. Flanagan, B. A. Wustman, and D. J. Lockhart were formerly employed by Amicus Therapeutics and were shareholders in the company. C. Barlow was a paid consultant of Amicus Therapeutics. Amicus Therapeutics and GlaxoSmithKline (GSK) funded the research and any publication fees. D. G. Warnock, D. G. Bichet, M. Holida, O. Goker-Alpan, K. Nicholls, M. Thomas, F. Eyskens, and S. Shankar are independent clinical research investigators, and are not shareholders in either company. The two forms of enzyme replacement used in this study (Fabrazyme and Replagal) are products of Genzyme and Shire, respectively. There are no further patents, products in development, or marketed products to declare. This does not alter the authors' adherence to all of the PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Flow diagram of subject disposition.

Stage 1 was comprised of 3 periods. Period 1 patients received ERT alone on Day 1, Period 2 patients received ERT co-administered with 150 mg migalastat HCl on Day 1, and Period 3 patients received migalastat HCl alone on Day 7 (i.e., 7 days after the previous ERT infusion). A new cohort of patients was recruited for Stage 2. Stage 2 was comprised of 2 periods. Period 1 patients received ERT alone on Day 1 and Period 2 patients received ERT co-administered with 450 mg migalastat HCl on Day 1.

Fig 2. Two-by-two panel of total plasma α-Gal A activity AUC stick plots for agalsidase alone and co-administered with migalastat HCl.

Upper left and right plots show individual patient changes between agalsidase beta alone and when co-administered with 150 mg migalastat HCl (upper left) or 450 mg migalastat (upper right) for plasma α-Gal activity AUC0-∞. Lower left and right plots show individual patient changes between agalsidase alfa alone and when co-administered with 150 mg migalastat HCl (lower left) or 450 mg migalastat HCl (lower right) for plasma α-Gal activity AUC0-∞. Patients’ actual ID number is blinded with the following code: Treatment and Dose (AB = agalsidase beta, 0.5 = 0.5 mg/kg dose or 1.0 = 1.0 mg/kg dose; AA = agalsidase alfa, 0.2 = 0.2 mg/kg dose)–migalastat HCl dose (150 = 150 mg, 450 = 450 mg)–arbitrary sequential number (1 through 23). Increases in plasma α-Gal activity AUC0-∞ are observed for all patients with the exception of AB1.0-450-14 shown in the upper left plot.

Fig 3. Mean (SD) total plasma α-Gal A activity-time profile panel for all treatments.

Mean α-Gal A activity increased at all post-dose time points for all treatments after co-administration with migalastat HCl. Increases after co-administration do not appear to be related to migalastat dose.

Fig 4. Mean (CV%) change from baseline on Days 2 and 7 for 1.0 mg/kg, 0.5 mg/kg, and 0.2 mg/kg agalsidase alone and agalsidase co-administered with 150 mg or 450 mg migalastat HCl.

Fig 5. Mean (SD) plasma migalastat concentration-time profiles following co-administration of agalsidase with 450 mg or 150 mg migalastat HCl, and 150 mg migalastat HCl alone.

Whether co-administered with agalsidase (Stage 1/Period 2) or administered alone (Stage 1/Period 3), plasma migalastat concentrations were similar at all post-dose time points. Mean concentration-time profiles following administration of 450 mg migalastat HCl (Stage 2/Period 2) were approximately dose proportional to 150 mg (Stage 1).