T.P.44 The pharmacological chaperone AT2220 increases the stability of recombinant human acid α-glucosidase and leads to greater tissue uptake and glycogen reduction in a mouse model of Pompe disease

Abstract

Pompe disease is a lysosomal storage disease caused by deficiency of acid α-glucosidase (GAA) activity, and is characterized by impaired lysosomal glycogen catabolism, progressive skeletal muscle weakness, reduced cardiac function, and respiratory insufficiency. Recombinant human GAA (rhGAA, Genzyme) is the only approved enzyme replacement therapy (ERT) for Pompe, and is administered biweekly via intravenous infusion. While rhGAA does provide clinical benefit, it suffers from low stability at neutral pH/body temperature, shows modest tissue uptake and glycogen reduction, and can elicit immune responses that affect tolerability and efficacy. AT2220 (1-deoxynojirimycin HCl, duvoglustat hydrochloride) is a small molecule pharmacological chaperone that binds and stabilizes endogenous GAA in cells and tissues, resulting in increased lysosomal GAA activity. We hypothesized that AT2220 might also improve the pharmacological properties of exogenous rhGAA. In human plasma, AT2220 co-incubation increased the stability and prevented denaturation of rhGAA at neutral pH/ 37°C for up to 24h. In rats, a single oral administration of AT2220 followed 30min later by intravenous bolus administration of rhGAA resulted in a dose-dependent increase of up to 2-fold in the circulating half-life of rhGAA. A similar effect was seen on the circulating half-life of rhGAA when administered via intravenous infusion. In mice lacking endogenous GAA, oral administration of AT2220 resulted in up to 2.5-fold greater rhGAA uptake and glycogen reduction compared to administration of rhGAA alone in disease-relevant tissues. Collectively, these data indicate that AT2220 increases the stability of rhGAA, and that greater enzyme activity and substrate turnover can be achieved in muscle when co-administered with rhGAA. Based on these findings, a Phase 2 study exploring AT2220 co-administration with rhGAA has been initiated.