TY - JOUR
T1 - Duvoglustat HCl Increases Systemic and Tissue Exposure of Active Acid α-Glucosidase in Pompe Patients Co-administered with Alglucosidase α
AU - Kishnani, Priya
AU - Tarnopolsky, Mark
AU - Roberts, Mark
AU - Sivakumar, Kumarswamy
AU - Dasouki, Majed
AU - Dimachkie, Mazen M.
AU - Finanger, Erika
AU - Goker-Alpan, Ozlem
AU - Guter, Karl A.
AU - Mozaffar, Tahseen
AU - Pervaiz, Muhammad Ali
AU - Laforet, Pascal
AU - Levine, Todd
AU - Adera, Matthews
AU - Lazauskas, Richard
AU - Sitaraman, Sheela
AU - Khanna, Richie
AU - Benjamin, Elfrida
AU - Feng, Jessie
AU - Flanagan, John J.
AU - Barth, Jay
AU - Barlow, Carrolee
AU - Lockhart, David J.
AU - Valenzano, Kenneth J.
AU - Boudes, Pol
AU - Johnson, Franklin K.
AU - Byrne, Barry
N1 - Publisher Copyright:
© 2017 The Author(s)
PY - 2017/5/3
Y1 - 2017/5/3
N2 - Duvoglustat HCl (AT2220, 1-deoxynojirimycin) is an investigational pharmacological chaperone for the treatment of acid α-glucosidase (GAA) deficiency, which leads to the lysosomal storage disorder Pompe disease, which is characterized by progressive accumulation of lysosomal glycogen primarily in heart and skeletal muscles. The current standard of care is enzyme replacement therapy with recombinant human GAA (alglucosidase alfa [AA], Genzyme). Based on preclinical data, oral co-administration of duvoglustat HCl with AA increases exposure of active levels in plasma and skeletal muscles, leading to greater substrate reduction in muscle. This phase 2a study consisted of an open-label, fixed-treatment sequence that evaluated the effect of single oral doses of 50 mg, 100 mg, 250 mg, or 600 mg duvoglustat HCl on the pharmacokinetics and tissue levels of intravenously infused AA (20 mg/kg) in Pompe patients. AA alone resulted in increases in total GAA activity and protein in plasma compared to baseline. Following co-administration with duvoglustat HCl, total GAA activity and protein in plasma were further increased 1.2- to 2.8-fold compared to AA alone in all 25 Pompe patients; importantly, muscle GAA activity was increased for all co-administration treatments from day 3 biopsy specimens. No duvoglustat-related adverse events or drug-related tolerability issues were identified.
AB - Duvoglustat HCl (AT2220, 1-deoxynojirimycin) is an investigational pharmacological chaperone for the treatment of acid α-glucosidase (GAA) deficiency, which leads to the lysosomal storage disorder Pompe disease, which is characterized by progressive accumulation of lysosomal glycogen primarily in heart and skeletal muscles. The current standard of care is enzyme replacement therapy with recombinant human GAA (alglucosidase alfa [AA], Genzyme). Based on preclinical data, oral co-administration of duvoglustat HCl with AA increases exposure of active levels in plasma and skeletal muscles, leading to greater substrate reduction in muscle. This phase 2a study consisted of an open-label, fixed-treatment sequence that evaluated the effect of single oral doses of 50 mg, 100 mg, 250 mg, or 600 mg duvoglustat HCl on the pharmacokinetics and tissue levels of intravenously infused AA (20 mg/kg) in Pompe patients. AA alone resulted in increases in total GAA activity and protein in plasma compared to baseline. Following co-administration with duvoglustat HCl, total GAA activity and protein in plasma were further increased 1.2- to 2.8-fold compared to AA alone in all 25 Pompe patients; importantly, muscle GAA activity was increased for all co-administration treatments from day 3 biopsy specimens. No duvoglustat-related adverse events or drug-related tolerability issues were identified.
KW - Pompe disease
KW - enzyme replacement therapy
KW - pharmacokinetics
KW - pharmacological chaperone
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U2 - 10.1016/j.ymthe.2017.02.017
DO - 10.1016/j.ymthe.2017.02.017
M3 - Article
C2 - 28341561
AN - SCOPUS:85018788525
SN - 1525-0016
VL - 25
SP - 1199
EP - 1208
JO - Molecular Therapy
JF - Molecular Therapy
IS - 5
ER -