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

David G. Warnock, Daniel G. Bichet, Myrl Holida, Ozlem Goker-Alpan, Kathy Nicholls, Mark Thomas, Francois Eyskens, Suma Shankar, Mathews Adera, Sheela Sitaraman, Richie Khanna, John J. Flanagan, Brandon A. Wustman, Jay Barth, Carrolee Barlow, Kenneth J. Valenzano, David J. Lockhart, Pol Boudes, Franklin K. Johnson

Research output: Contribution to journalArticle

32 Citations (Scopus)

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, biologicsbased 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.

Original languageEnglish (US)
Article numbere0134341
JournalPLoS One
Volume10
Issue number8
DOIs
StatePublished - Aug 7 2015
Externally publishedYes

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Galactosidases
galactosidases
mouth
Tissue
pharmacokinetics
mononuclear leukocytes
dosage
skin (animal)
Pharmacokinetics
therapeutics
Fabry Disease
Plasmas
intravenous injection
experimental design
Blood Cells
Skin
Blood
drugs
tissues
migalastat

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

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. / Warnock, David G.; Bichet, Daniel G.; Holida, Myrl; Goker-Alpan, Ozlem; Nicholls, Kathy; Thomas, Mark; Eyskens, Francois; Shankar, Suma; Adera, Mathews; Sitaraman, Sheela; Khanna, Richie; Flanagan, John J.; Wustman, Brandon A.; Barth, Jay; Barlow, Carrolee; Valenzano, Kenneth J.; Lockhart, David J.; Boudes, Pol; Johnson, Franklin K.

In: PLoS One, Vol. 10, No. 8, e0134341, 07.08.2015.

Research output: Contribution to journalArticle

Warnock, DG, Bichet, DG, Holida, M, Goker-Alpan, O, Nicholls, K, Thomas, M, Eyskens, F, Shankar, S, Adera, M, Sitaraman, S, Khanna, R, Flanagan, JJ, Wustman, BA, Barth, J, Barlow, C, Valenzano, KJ, Lockhart, DJ, Boudes, P & Johnson, FK 2015, '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', PLoS One, vol. 10, no. 8, e0134341. https://doi.org/10.1371/journal.pone.0134341
Warnock, David G. ; Bichet, Daniel G. ; Holida, Myrl ; Goker-Alpan, Ozlem ; Nicholls, Kathy ; Thomas, Mark ; Eyskens, Francois ; Shankar, Suma ; Adera, Mathews ; Sitaraman, Sheela ; Khanna, Richie ; Flanagan, John J. ; Wustman, Brandon A. ; Barth, Jay ; Barlow, Carrolee ; Valenzano, Kenneth J. ; Lockhart, David J. ; Boudes, Pol ; Johnson, Franklin K. / 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. In: PLoS One. 2015 ; Vol. 10, No. 8.
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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, biologicsbased 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.",
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AU - Warnock, David G.

AU - Bichet, Daniel G.

AU - Holida, Myrl

AU - Goker-Alpan, Ozlem

AU - Nicholls, Kathy

AU - Thomas, Mark

AU - Eyskens, Francois

AU - Shankar, Suma

AU - Adera, Mathews

AU - Sitaraman, Sheela

AU - Khanna, Richie

AU - Flanagan, John J.

AU - Wustman, Brandon A.

AU - Barth, Jay

AU - Barlow, Carrolee

AU - Valenzano, Kenneth J.

AU - Lockhart, David J.

AU - Boudes, Pol

AU - Johnson, Franklin K.

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N2 - 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, biologicsbased 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.

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