T.P.45 An ongoing phase 2a study to investigate drug–drug interactions between escalating doses of AT2220 (duvoglustat hydrochloride) and acid alpha glucosidase in subjects with Pompe disease – Preliminary results

Abstract Pompe disease is an inherited lysosomal storage disease that results from a deficiency in acid alpha-glucosidase (GAA) activity, and is characterized by progressive accumulation of lysosomal glycogen primarily in heart and skeletal muscles. Recombinant human GAA (rhGAA, Genzyme) is the only approved enzyme replacement therapy for Pompe, and is administered biweekly via intravenous infusion. While rhGAA provides clinical benefit, drawbacks as low stability at neutral pH/body temperature, modest tissue uptake and glycogen reduction, and immune responses affect tolerability and efficacy. AT2220 (duvoglustat HCl) is a pharmacological chaperone which selectively and reversibly binds and stabilizes endogenous GAA, facilitating proper folding and trafficking to lysosomes. AT2220-010 is an open-label, single ascending dose, fixed-sequence, two-period, dose-finding study comprised of four cohorts of 4–6 subjects with Pompe disease. During the first period, subjects receive their regularly scheduled intravenous infusion of rhGAA 20 mg/kg alone. During the second period they receive a single oral dose of AT2220 with rhGAA. The objectives of the study are (1) evaluate the safety of single ascending doses of AT2220 (50 mg, 100 mg, 250 mg, and 600 mg) and (2) characterize the pharmacokinetic interaction of AT2220 on rhGAA. Preliminary plasma, peripheral blood mononuclear cells, and muscle GAA activity, total GAA protein, and AT2220 concentrations as well as safety data including urine Hex 4 concentrations are available for the first and second cohorts. Anti-GAA antibodies are also being evaluated.