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Dalzanemdor (SAGE\u2010718) is a novel, investigational NMDAR PAM being evaluated for the potential treatment of cognitive impairment in these disorders. We report first\u2010in\u2010human, phase I, double\u2010blind, dose\u2010finding studies to assess the safety, tolerability, and clinical pharmacology of dalzanemdor. A single\u2010ascending dose study (dalzanemdor 0.35, 0.75, 1.5, or 3.0\u2009mg vs. placebo) was conducted in healthy participants and included food effects. A multiple\u2010ascending dose study (14\u2009days) was conducted in healthy participants (dalzanemdor 0.5 or 1.0\u2009mg vs. placebo) and HD participants (open\u2010label dalzanemdor 1.0\u2009mg) and included exploratory pharmacodynamics on cognitive performance. Dalzanemdor was generally well tolerated with no adverse events leading to discontinuation. Dalzanemdor exhibited pharmacokinetic parameters appropriate for once\u2010daily dosing. Following single and multiple doses in healthy participants, median terminal half\u2010life was 8\u2013118\u2009h, and the median time to reach maximum plasma concentration was 4\u20137\u2009h. Exposures were dose\u2010proportional after single dose (6\u201346\u2009ng\/mL) and more than dose\u2010proportional after multiple doses (6\u201341\u2009ng\/mL). With multiple dosing, a steady state was achieved after 11\u2009days in healthy participants and 13\u2009days in HD participants. Dalzanemdor exposure decreased slightly with food. In HD participants, results suggest that dalzanemdor may improve cognitive performance on tests of executive function. These results support continued clinical development of dalzanemdor for the potential treatment of cognitive impairment in disorders of NMDAR hypofunction.<\/jats:p>","DOI":"10.1111\/cts.13852","type":"journal-article","created":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T05:40:44Z","timestamp":1720676444000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Dalzanemdor (SAGE\u2010718), a novel, investigational N\u2010methyl\u2010D\u2010aspartate receptor positive allosteric modulator: Safety, tolerability, and clinical pharmacology in randomized dose\u2010finding studies in healthy participants and an open\u2010label study in participants with Huntington's disease"],"prefix":"10.1111","volume":"17","author":[{"given":"Aaron","family":"Koenig","sequence":"first","affiliation":[{"name":"Sage Therapeutics, Inc  Cambridge Massachusetts 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