Duvoglustat HCl Increases Systemic and Tissue Exposure of Active Acid α-Glucosidase in Pompe Patients Co-administered with Alglucosidase α.
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.
Duke University Medical Center, Durham, NC 27710, USA.
Priya
P
Kishnani
McMaster University Medical Center, Hamilton, ON L8N 3Z5, Canada.
Mark
M
Tarnopolsky
Salford Royal Hope HNS Trust Hope Hospital, Salford M6 8HD, UK.
Mark
M
Roberts
Neuromuscular Research Center, Scottsdale, AZ 85028, USA.
Kumarswamy
K
Sivakumar
University of Kansas Medical Center, Kansas City, KS 66160, USA.
Majed
M
Dasouki
University of Kansas Medical Center, Kansas City, KS 66160, USA.
Mazen M
MM
Dimachkie
Oregon Health and Science University, Portland, OR 97239, USA.
Erika
E
Finanger
LSD Research and Treatment Unit, O&O Alpan, LLC, Fairfax, VA 22030, USA.
Ozlem
O
Goker-Alpan
Great Falls Clinic, Great Falls, MT 59405, USA.
Karl A
KA
Guter
University of California, Irvine, Irvine, CA 92697, USA.
Tahseen
T
Mozaffar
Emory University, Decatur, GA 30030, USA.
Muhammad Ali
MA
Pervaiz
Hopital la Salpetriere Institut de Myologie, 75013 Paris, France.
Pascal
P
Laforet
Phoenix Neurological Associates, Phoenix, AZ 85018, USA.
Todd
T
Levine
Insys Therapeutics, Chandler, AZ 85224, USA.
Matthews
M
Adera
Amicus Therapeutics, Cranbury, NJ 08512, USA.
Richard
R
Lazauskas
Amicus Therapeutics, Cranbury, NJ 08512, USA.
Sheela
S
Sitaraman
Amicus Therapeutics, Cranbury, NJ 08512, USA.
Richie
R
Khanna
Amicus Therapeutics, Cranbury, NJ 08512, USA.
Elfrida
E
Benjamin
Amicus Therapeutics, Cranbury, NJ 08512, USA.
Jessie
J
Feng
Arvinas, Inc., New Haven, CT 06511, USA.
John J
JJ
Flanagan
Amicus Therapeutics, Cranbury, NJ 08512, USA.
Jay
J
Barth
The Parkinson's Institute and Clinical Center, Sunnyvale, CA 94085, USA.
Carrolee
C
Barlow
TranscripTx, Inc., Sunnyvale, CA 94085, USA.
David J
DJ
Lockhart
Amicus Therapeutics, Cranbury, NJ 08512, USA.
Kenneth J
KJ
Valenzano
Cymabay Therapeutics, Newark, CA 94560, USA.
Pol
P
Boudes
Amicus Therapeutics, Cranbury, NJ 08512, USA. Electronic address: fjohnson@amicusrx.com.
Franklin K
FK
Johnson
University of Florida, Gainesville, FL 32611, USA.
Barry
B
Byrne
D017485:1-Deoxynojirimycin / Q000627:therapeutic use*; D000284:Administration, Oral; D000328:Adult; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D056947:Enzyme Replacement Therapy / Q000379:methods; D005260:Female; D006009:Glycogen Storage Disease Type II / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007262:Infusions, Intravenous; D008247:Lysosomes / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D061214:Patient Safety; D016896:Treatment Outcome; D000520:alpha-Glucosidases / Q000097:blood / Q000493:pharmacokinetics*
D017485:1-Deoxynojirimycin; C509951:GAA protein, human; D000520:alpha-Glucosidases
Pompe disease; enzyme replacement therapy; pharmacokinetics; pharmacological chaperone