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Clinical Trial
. 2017 May 3;25(5):1199-1208.
doi: 10.1016/j.ymthe.2017.02.017. Epub 2017 Mar 22.

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

Priya Kishnani  1 , Mark Tarnopolsky  2 , Mark Roberts  3 , Kumarswamy Sivakumar  4 , Majed Dasouki  5 , Mazen M Dimachkie  5 , Erika Finanger  6 , Ozlem Goker-Alpan  7 , Karl A Guter  8 , Tahseen Mozaffar  9 , Muhammad Ali Pervaiz  10 , Pascal Laforet  11 , Todd Levine  12 , Matthews Adera  13 , Richard Lazauskas  14 , Sheela Sitaraman  14 , Richie Khanna  14 , Elfrida Benjamin  14 , Jessie Feng  14 , John J Flanagan  15 , Jay Barth  14 , Carrolee Barlow  16 , David J Lockhart  17 , Kenneth J Valenzano  14 , Pol Boudes  18 , Franklin K Johnson  19 , Barry Byrne  20
Affiliations
Clinical Trial

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

Priya Kishnani et al. Mol Ther. .

Abstract

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.

Keywords: Pompe disease; enzyme replacement therapy; pharmacokinetics; pharmacological chaperone.

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Figures

Figure 1
Figure 1
Mean and SD Total Plasma GAA Activity-Time Profiles for All Treatments
Figure 2
Figure 2
Two-by-Two Panel of Total Plasma GAA Activity AUC Stick Plots for AA Alone and Co-administered with Duvoglustat HCl
Figure 3
Figure 3
Mean and SD Plasma Duvoglustat Concentration-Time Profiles following Co-administration of AA with 50 mg, 100 mg, 250 mg, or 600 mg Duvoglustat HCl
Figure 4
Figure 4
Flow Diagram of Patient Disposition Period 1 patients received AA alone on day 1. In period 2, the same patients received AA co-administered with 50 mg, 100 mg, 250 mg, or 600 mg duvoglustat HCl on day 1. All 25 patients completed the study, and all 25 had plasma total GAA activity and protein and plasma duvoglustat analyzed.
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