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
Duke University Medical Center, Durham, NC 27710, USA.
McMaster University Medical Center, Hamilton, ON L8N 3Z5, Canada.
Mol Ther. 2017 May 3;25(5):1199-1208. doi: 10.1016/j.ymthe.2017.02.017. Epub 2017 Mar 22.
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.
盐酸度伏格司他（AT2220，1-脱氧野尻霉素）是一种用于治疗酸性α-葡萄糖苷酶（GAA）缺乏症的研究性药理伴侣分子，GAA缺乏会导致溶酶体贮积症庞贝病，其特征是溶酶体糖原主要在心脏和骨骼肌中进行性蓄积。当前的标准治疗方法是使用重组人GAA（阿糖苷酶α[AA]，健赞公司生产）进行酶替代疗法。基于临床前数据，盐酸度伏格司他与AA联合口服可增加血浆和骨骼肌中活性水平的暴露量，从而使肌肉中的底物减少更多。这项2a期研究采用开放标签、固定治疗顺序，评估了单剂量口服50毫克、100毫克、250毫克或600毫克盐酸度伏格司他对庞贝病患者静脉输注AA（20毫克/千克）的药代动力学和组织水平的影响。单独使用AA会使血浆中的总GAA活性和蛋白质水平相对于基线有所增加。在与盐酸度伏格司他联合给药后，所有25名庞贝病患者的血浆中总GAA活性和蛋白质水平相对于单独使用AA时进一步提高了1.2至2.8倍；重要的是，从第3天活检标本来看，所有联合给药治疗的肌肉GAA活性均有所增加。未发现与度伏格司他相关的不良事件或药物相关的耐受性问题。
