Abstract:
N-methyl-D-aspartate receptor (NMDAR)-positive allosteric modulators (PAMs) represent a potential therapeutic strategy for cognitive impairment in disorders associated with NMDAR hypofunction, including Huntington\'s disease (HD) and Alzheimer\'s disease. Dalzanemdor (SAGE-718) is a novel, investigational NMDAR PAM being evaluated for the potential treatment of cognitive impairment in these disorders. We report first-in-human, phase I, double-blind, dose-finding studies to assess the safety, tolerability, and clinical pharmacology of dalzanemdor. A single-ascending dose study (dalzanemdor 0.35, 0.75, 1.5, or 3.0 mg vs. placebo) was conducted in healthy participants and included food effects. A multiple-ascending dose study (14 days) was conducted in healthy participants (dalzanemdor 0.5 or 1.0 mg vs. placebo) and HD participants (open-label dalzanemdor 1.0 mg) 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-daily dosing. Following single and multiple doses in healthy participants, median terminal half-life was 8-118 h, and the median time to reach maximum plasma concentration was 4-7 h. Exposures were dose-proportional after single dose (6-46 ng/mL) and more than dose-proportional after multiple doses (6-41 ng/mL). With multiple dosing, a steady state was achieved after 11 days in healthy participants and 13 days 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.
摘要:
N-甲基-D-天冬氨酸受体(NMDAR)-正变构调节剂(PAMs)代表了与NMDAR功能减退相关的认知障碍的潜在治疗策略,包括亨廷顿病(HD)和阿尔茨海默病。Dalzanemdor(SAGE-718)是一部小说,正在评估研究性NMDARPAM对这些疾病中认知障碍的潜在治疗方法。我们报告的是人类第一,第一阶段,双盲,剂量发现研究以评估安全性,耐受性,和dalzanemdor的临床药理学。单次递增剂量研究(dalzanemdor0.35、0.75、1.5或3.0mg与安慰剂)在健康参与者中进行,并包括食物效应。在健康参与者中进行了多次递增剂量研究(14天)(dalzanemdor0.5或1.0mg与安慰剂)和HD参与者(开放标签dalzanemdor1.0mg),并包括对认知表现的探索性药效学。Dalzanemdor通常具有良好的耐受性,没有导致停药的不良事件。Dalzanemdor表现出适合每日一次给药的药代动力学参数。在健康参与者中单次和多次剂量后,中位终末半衰期为8-118小时,达到最大血浆浓度的中位时间为4-7小时。单剂量(6-46ng/mL)后暴露量与剂量成正比,多剂量(6-41ng/mL)后暴露量与剂量成正比。多次给药,健康参与者在11天后达到稳定状态,HD参与者在13天后达到稳定状态.Dalzanemdor暴露量随食物的增加而略有减少。在HD参与者中,结果表明,dalzanemdor可以改善执行功能测试的认知表现。这些结果支持dalzanemdor的持续临床开发,用于治疗NMDAR功能减退的认知障碍。