title: 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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01196871.
authors.affiliation: University of Alabama at Birmingham School of Medicine Department of Medicine, Division of Nephrology, Birmingham, Alabama, United States of America.
authors.forename: David G
authors.initials: DG
authors.lastname: Warnock
authors.affiliation: University of Montreal, Quebec, Canada.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Bichet
authors.affiliation: University of Iowa Children's Hospital, Iowa City, Iowa, United States of America.
authors.forename: Myrl
authors.initials: M
authors.lastname: Holida
authors.affiliation: LSD Research and Treatment Unit, O&O Alpan LLC, Fairfax, Virginia, United States of America.
authors.forename: Ozlem
authors.initials: O
authors.lastname: Goker-Alpan
authors.affiliation: Department of Nephrology, Royal Melbourne Hospital, and University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Kathy
authors.initials: K
authors.lastname: Nicholls
authors.affiliation: Linear Clinical Research Ltd, Queen Elizabeth II Medical Centre, and University of Western Australia, Nedlands, Western Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Thomas
authors.affiliation: Universitair Ziekenhuis Antwerpen, Antwerpen, Belgium.
authors.forename: Francois
authors.initials: F
authors.lastname: Eyskens
authors.affiliation: Emory University School of Medicine, Emory Genetics Clinic, Athens, Georgia, United States of America.
authors.forename: Suma
authors.initials: S
authors.lastname: Shankar
authors.affiliation: Amicus Therapeutics, Cranbury, New Jersey, United States of America.
authors.forename: Mathews
authors.initials: M
authors.lastname: Adera
authors.affiliation: Amicus Therapeutics, Cranbury, New Jersey, United States of America.
authors.forename: Sheela
authors.initials: S
authors.lastname: Sitaraman
authors.affiliation: Amicus Therapeutics, Cranbury, New Jersey, United States of America.
authors.forename: Richie
authors.initials: R
authors.lastname: Khanna
authors.affiliation: Arvinas Inc, New Haven, Connecticut, United States of America.
authors.forename: John J
authors.initials: JJ
authors.lastname: Flanagan
authors.affiliation: Institute and Clinical Center, Sunnyvale, California, United States of America.
authors.forename: Brandon A
authors.initials: BA
authors.lastname: Wustman
authors.affiliation: Amicus Therapeutics, Cranbury, New Jersey, United States of America.
authors.forename: Jay
authors.initials: J
authors.lastname: Barth
authors.affiliation: Amicus Therapeutics, Cranbury, New Jersey, United States of America.
authors.forename: Carrolee
authors.initials: C
authors.lastname: Barlow
authors.affiliation: Amicus Therapeutics, Cranbury, New Jersey, United States of America.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Valenzano
authors.affiliation: Institute and Clinical Center, Sunnyvale, California, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Lockhart
authors.affiliation: Cymabay Therapeutics, Newark, California, United States of America.
authors.forename: Pol
authors.initials: P
authors.lastname: Boudes
authors.affiliation: Amicus Therapeutics, Cranbury, New Jersey, United States of America.
authors.forename: Franklin K
authors.initials: FK
authors.lastname: Johnson
mesh_terms: D017485:1-Deoxynojirimycin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D003710:Demography; D000795:Fabry Disease / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology*; D006801:Humans; D007260:Infusion Pumps; D007527:Isoenzymes / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins; D012867:Skin / Q000201:enzymology; D000519:alpha-Galactosidase / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000627:therapeutic use
chemical_list: D007527:Isoenzymes; D011994:Recombinant Proteins; D017485:1-Deoxynojirimycin; C000627036:agalsidase alfa; C090092:migalastat; D000519:alpha-Galactosidase; C459420:agalsidase beta