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Enzyme replacement therapy (ERT) with GAA is currently the sole treatment option for patients with Pompe disease. ERT burdens patients with frequent intravenous infusions while insufficiently halting disease progression due to incomplete ERT skeletal muscle distribution. Glycogen synthase 1 (GYS1) has been proposed as a substrate reduction therapy (SRT) target for Pompe disease. Here, we report results from the first\u2010in\u2010human study of the orally available GYS1 inhibitor MZE001 in healthy subjects. In 88 participants, MZE001 was well\u2010tolerated up to a single dose of 480\u2009mg BID and multiple doses of 720\u2009mg BID for 10\u2009days. Noncompartmental analysis determined that the half\u2010life and <jats:italic>C<\/jats:italic><jats:sub>trough<\/jats:sub> concentrations of MZE001 could provide efficacious exposures with once or twice daily oral dosing. Change from baseline of peripheral blood mononuclear cell (PBMC) glycogen, which correlated with muscle glycogen levels in preclinical models, was significantly reduced dose\u2010dependently following 10\u2009days of MZE001 treatment in healthy subjects. A muscle biopsy sub\u2010study demonstrated that 10\u2009days of MZE001 (480\u2009mg BID) dosing safely and substantially lowered muscle glycogen stores in healthy adults. This correlated with the PBMC exposure response and supports the use of PBMC glycogen reduction as a surrogate for muscle response, and MZE001 potential for development as the first oral substrate reduction therapy for patients with Pompe disease.<\/jats:p>","DOI":"10.1002\/cpt.3470","type":"journal-article","created":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T05:44:41Z","timestamp":1729662281000},"page":"1580-1592","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["First\u2010in\u2010Human Evaluation of Safety, Pharmacokinetics and Muscle Glycogen Lowering of a Novel Glycogen Synthase 1 Inhibitor for the Treatment of Pompe Disease"],"prefix":"10.1002","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1325-0650","authenticated-orcid":false,"given":"Julie C.","family":"Ullman","sequence":"first","affiliation":[{"name":"Maze Therapeutics  South San Francisco California 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