A novel phase 2a study design to investigate drug-drug interactions between escalating doses of AT2220 (duvoglustat hydrochloride) and acid alpha-glucosidase in subjects with Pompe disease

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 (1-deoxynojirimycin; duvoglustat HCl) is a pharmacological chaperone that 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. Study objectives: (1) evaluate the safety of single ascending doses of AT2220 co-administered with rhGAA, and (2) characterize the pharmacokinetic interaction of AT2220 and rhGAA on activity and protein levels in plasma, muscle, and peripheral blood mononuclear cells, and on urine Hex four levels. Period 1, subjects receive rhGAA alone, then Period 2 they receive a single oral dose of AT2220 with rhGAA. Safety data from each completed dose cohort is reviewed by a Data Safety Monitoring Board. An innovative muscle biopsy technique, which requires specialized investigator training, is used to sample quadricep muscle either on Day 3 or 7 of each period. This unique crossover study design allows for meaningful evaluation of safety and pharmacokinetic data in the rare disease field by allowing each subject to serve as their own control and reducing variability as opposed to parallel designs requiring larger sample sizes for statistical comparisons.