文摘
摘要目的:DNL343正在调查作为一个潜在的治疗肌萎缩性脊髓侧索硬化症(ALS)的代理。
背景:ALS是一种致命的神经退行性疾病与TDP-43包含病理学在95%的病人。慢性激活的综合压力反应(ISR)可能导致ALS通过阻断翻译,改变RNA和endosomal贩卖,并增加TDP-43-containing压力颗粒的形成。DNL343是一种小分子,激活一个关键ISR监管者,eIF2B,抑制ISR应力形成颗粒细胞模型和促进神经保护在动物模型。
设计/方法:安全,药物动力学(PK)和药效学(PD) DNL343在第一阶段评估随机、安慰剂对照试验(RCT)在健康志愿者(NCT04268784在ALS)和28天期1 b个随机对照试验参与者(NCT05006352),进行18个月的开放标签扩展(OLE)。ISR抑制被测量评估CHAC1基因表达和ATF4蛋白质刺激外周血单核细胞(PBMCs)。
结果:在第一阶段的研究中,九十五名健康受试者随机(n = 48悲伤,n = 47疯了)。DNL343一般安全耐受良好,没有严重不良事件(节约)或中止与研究药物有关。DNL343等离子体浓度存在剂量依赖的相关性,血浆半衰期38-46小时和CSF-to-unbound血浆浓度0.66 - -0.92的比例。DNL343减两个ISR生物标记在剂量期和槽后24小时最后剂量(CHAC1(66 - 94%)和ATF4(50 - 73%))在所有疯狂的人群。安全、药物动力学和药效学ISR ALS 28天1 b期研究的参与者将会呈现。
结论:DNL343通常是安全的,同时在剂量演示ISR的健壮的抑制CHAC1和ATF4抑制。支持一次每日口服剂量和药动学特征有广泛的CSF分布。高压和ALS患者的这些早期的研究数据支持进一步发展DNL343作为一个潜在的治疗治疗肌萎缩性侧索硬化症。
披露:孙博士已经收到个人赔偿作为一个员工的德纳里峰的疗法。孙博士在德纳里峰疗法有股票。蔡博士已经收到个人赔偿作为一个员工的德纳里峰的疗法。蔡博士股票德纳里治疗。Yulyaningsih博士已经收到个人赔偿作为一个员工的德纳里峰的疗法。Yulyaningsih博士股票德纳里治疗。Yulyaningsih博士23 &我的股票。Yulyaningsih博士在Ardelyx股票。Yulyaningsih博士在Amylyx股票。Fanok博士已经收到个人赔偿作为一个员工的德纳里峰的疗法。 An immediate family member of Dr. Fanok has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for Cincor Pharma. Dr. Fanok has stock in Denali Therapeutics. Mr. Vissers has received personal compensation for serving as an employee of Centre for Human Drug Research. Dr. Heuberger has received personal compensation for serving as an employee of Centre for Human Drug Research. Dr. Flores has nothing to disclose. Fen Huang has nothing to disclose. Dr. Kane has received personal compensation for serving as an employee of Denali Therapeutics. Dr. Kane has stock in Denali Therapeutics. Dr. Cohen has received personal compensation for serving as an employee of Denali. Dr. Cohen has stock in Denali. Dr. Dhuria has received personal compensation for serving as an employee of Denali Therapeutics. Dr. Dhuria has stock in Denali Thereapeutics. Dr. Fang has received personal compensation for serving as an employee of Denali Therapeutics. Dr. Fang has stock in Denali therapeutics. Dr. Estrada has stock in Denali Therapeutics . Dr. Osipov has received personal compensation for serving as an employee of Denali Therapeutics. Dr. Osipov has stock in Denali Therapeutics. Dr. Osipov has received intellectual property interests from a discovery or technology relating to health care. Mr. Willman-Yoswa has received personal compensation for serving as an employee of Denali Therapeutics. Mr. Maciuca has received personal compensation for serving as an employee of Denali Therapeutics. Mr. Maciuca has received stock or an ownership interest from Denali Therapeutics. Ms. Dobbins has received personal compensation for serving as an employee of Denali Therapeutics. Ms. Dobbins has stock in Denali Therapeutics. Miss Chau has received personal compensation for serving as an employee of Denali Therapeutics. Miss Chau has stock in Denali Therapeutics. Timothy Earr has received personal compensation for serving as an employee of Denali Therapeutics. Timothy Earr has stock in Denali Therapeutics. Ms. Nguyen has received personal compensation for serving as an employee of DENALI THERAPEUTICS. Ms. Nguyen has stock in Denali Therapeutics. Mrs. Lopez has nothing to disclose. Kimberly Scearce-Levie has received personal compensation for serving as an employee of Denali Therapeutics. Kimberly Scearce-Levie has stock in Denali Therapeutics. Mr. Bunte has nothing to disclose. Dr. Van den Berg has nothing to disclose. Carole Ho has nothing to disclose. Geert-Jan Groeneveld has nothing to disclose. Dr. Troyer has received personal compensation for serving as an employee of Denali Therapeutics Inc. Dr. Troyer has stock in Denali Therapeutics Inc. Dr. Troyer has stock in Merck & Co., Inc. Dr. Troyer has stock in Eli Lilly.
