Duvoglustat HCl Increases Systemic and Tissue Exposure of Active Acid alpha-Glucosidase in Pompe Patients Co-administered with Alglucosidase alpha

作者：Kishnani Priya; Tarnopolsky Mark; Roberts Mark; Sivakumar Kumarswamy; Dasouki Majed; Dimachkie Mazen M; Finanger Erika; Goker Alpan Ozlem; Guter Karl A; Mozaffar Tahseen; Pervaiz Muhammad Ali; Laforet Pascal; Levine Todd; Adera Matthews; Lazauskas Richard; Sitaraman Sheela; Khanna Richie; Benjamin Elfrida; Feng Jessie; Flanagan John J; Barth Jay; Barlow Carrolee; Lockhart David J; Valenzano Kenneth J; Boudes Pol; Johnson Franklin K^*; Byrne Barry

来源：Molecular Therapy, 2017, 25(5): 1199-1208.

DOI：10.1016/j.ymthe.2017.02.017

Duvoglustat HCl (AT2220, 1-deoxynojirimycin) is an investigational pharmacological chaperone for the treatment of acid alpha-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.

• 出版日期2017-5-3