P.17.8 The co-formulation of pharmacological chaperone AT2220 with recombinant human acid alpha-glucosidase improves enzyme uptake and glycogen reduction in a mouse model of Pompe disease

Pompe disease is an inherited lysosomal storage disease that results from deficiency in acid alpha-glucosidase (GAA) activity, and is characterized by progressive accumulation of lysosomal glycogen in heart and skeletal muscles. Enzyme replacement therapy using recombinant human GAA (rhGAA) is the only approved treatment available for Pompe disease. While rhGAA provides some clinical benefits, the infused enzyme tends to be unstable at neutral pH/body temperature, shows insufficient uptake in key tissues, and can elicit immune responses that affect tolerability and efficacy. We have shown previously that oral pre-administration of the pharmacological chaperone AT2220 (1-deoxynojirimycin HCl, duvoglustat HCl) improves the pharmacological properties of rhGAA via binding and stabilization, leading to increased enzyme uptake and glycogen reduction in GAA knock-out (KO) mice. In this study we tested the effects of intravenous (IV) and subcutaneous (SQ) administration of co-formulated AT2220 and rhGAA (AT2220 + rhGAA) as an alternative to giving AT2220 orally prior to rhGAA IV. In rats, IV or SQ administration of co-formulated AT2220 + rhGAA increased the circulating half-life of rhGAA up to twofold, though the maximal rhGAA plasma levels achieved via the SQ route were significantly lower than those seen following IV administration. In GAA KO mice, four IV administrations of co-formulated AT2220 + rhGAA resulted in up to 2.5-fold greater enzyme uptake and glycogen reduction in disease-relevant tissues compared to rhGAA alone; histological staining confirmed reduced skeletal muscle glycogen. Interestingly, four SQ administrations of co-formulated AT2220 + rhGAA increased rhGAA uptake in GAA KO mice, which was not significantly different from those seen following four IV administrations of rhGAA alone. Collectively, these data highlight the potential effects of co-formulated AT2220 + rhGAA using IV or SQ administration, thus warranting further preclinical investigation.