BACKGROUND: Pompe disease is a rare glycogen storage disorder characterized by progressive muscle and respiratory insufficiency due to acid alpha glucosidase (GAA) deficiency. Patients treated with current standard of care, an enzyme replacement therapy (ERT) administered intravenously, ultimately succumb to progressive muscle and respiratory disability due to incomplete skeletal muscle distribution of ERT and buildup of muscle glycogen. We previously reported the discovery of an oral small molecule inhibitor of glycogen synthase 1 (GYS1), MZE001, as a potential substrate reduction therapy for patients with Pompe disease. In healthy adults treated for ten days, MZE001 was safe and well-tolerated at doses up to 720 mg BID and lowered glycogen levels in peripheral blood mononuclear cells. Plasma exposures of MZE001 reached levels that reduced muscle glycogen accumulation in healthy rodents and canines, and in mouse models of Pompe disease.
METHODS: In this study, eight healthy adults received MZE001 480 mg BID or placebo for ten days. At baseline and Day 10, we administered an oral solution containing 13C6-glucose and performed needle biopsy in quadriceps muscle. We evaluated the dose-exposure relationship for MZE001 in muscle, the change in total muscle glycogen, and muscle glycogen synthesis by 13C6-glucose incorporation. We also assessed the change in glucose and insulin response to oral glucose challenge.
RESULTS: MZE001 inhibited acute synthesis of muscle glycogen by 64% (+/-9%) and reduced total muscle glycogen by 41% (+/-12%) compared to placebo in quadriceps muscle on Day 10. The dose-exposure relationship for MZE001 in muscle was consistent with MZE001 in plasma. Plasma time-concentration profiles and areas under the curve for both glucose and insulin were unchanged with MZE001 administration compared to placebo.
CONCLUSIONS: MZE001 safely and substantially lowered muscle glycogen stores in healthy adults, supporting its potential for development as the first oral substrate reduction therapy for patients with Pompe disease.