A randomized double-blind placebo controlled Phase 1 SAD study in male and female healthy volunteers to assess safety, pharmacokinetics, and transient biomarker changes by the ABCA1 agonist CS6253

在男性和女性健康志愿者中进行的一项随机双盲安慰剂对照 1 期 SAD 研究，旨在评估 ABCA1 激动剂 CS6253 的安全性、药代动力学和短暂生物标志物变化

• 批准号: 10734158
• 负责人: Jan Johansson
• 金额: $ 248.22万
• 依托单位: ARTERY THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10734158
• 关键词: randomized; double; blind; placebo; controlled

PROJECT SUMMARY Late-onset or sporadic Alzheimer's disease (AD) constitute 95 percent of all AD and APOE4 is the dominating genetic risk factor. While there are three major APOE allelic variants (APOE2, APOE3, and APOE4), APOE4 carriers have an increased risk of developing AD, and up to 66% of individuals with AD-type dementia cases and 64% with mild cognitive impairment, also carry the APOE4 allele. There are currently no treatments for APOE4 driven AD or other dementias. Artery Therapeutics, Inc. (Artery; ATI) has developed a novel chemical entity for the treatment of APOE4 driven dementias, including AD. CS6253 is a 2nd-generation selective ATP- Binding-Cassette A1 (ABCA1) transporter agonist peptide derived from the C-terminal of apoE. CS6253 is a safe, potent, and druggable ABCA1 agonist. ATI's preclinical data in cell systems and two different apoE4 transgenic mice models have demonstrated that CS6253 engages ABCA1 as a target, improves apoE lipidation, prevents hippocampal amyloid-β (Aβ) pathophysiology, and improves cognition. In IND-enabling studies, which showed excellent safety and pharmacokinetics properties, it was demonstrated that in primates, CS6253 treatment over 9 days showed pronounced dose-response reductions in cerebrospinal fluid (CSF) concentrations of Aβ42, Aβ40, and APP, and other markers. These data strongly support and extend our efficacy results in mice pharmacology models and are predictive of efficacy in humans. Thus, with this SBIR proposal, we will advance CS6253 into early clinical trials. In Aim 1, ATI will establish qualifying methods for GMP drug product and stability at -20C for CofA and release for Phase 1 Clinical Trial Material. GMP drug product will complete the CMC section (GMP drug substance is already produced) which will be added to the clinical and nonclinical sections of the IND, for submitting the IND. The aim 1 milestone is to open the IND, i.e. receive FDA buy-in for initiating the CS6253 Phase 1 trial. We are confident of a successful IND based on the August 2020 pre-IND meeting with FDA where consensus was reached regarding key aspects of the program including CMC, nonclinical and the initial clinical trials. In Aim 2, we will perform a randomized double blind placebo controlled single ascending dose trial in healthy 50-70 y.o. men and women (n=8/cohort, 6 active: 2 placebo, total n=32) who will be characterized but not stratified for APOE isoform. Participants will receive a single intravenous (iv) administration of CS6253 at 4 single ascending doses. Our Aim 2 milestone is to establish safety and pharmacokinetics (plasma and CSF) in humans and a safe starting dose for the multiple ascending dose (MAD) study. We will also explore transient effects on lipids and AD biomarkers by CS6253 including temporal plasma – CSF dynamics of apolipoproteins and AD markers. This project will determine CS6253's pharmacokinetics (plasma and CSF) and single dose safety, and prepare for Phase 1 MAD studies of up to 30 days. Overall, CS6253 is an extremely promising ABCA1 targeting novel therapy with potential to address APOE4 associated dementia including AD.

项目摘要 晚期或零星的阿尔茨海默氏病（AD）占所有AD和APOE4的95％是主要的 遗传危险因素。虽然有三个主要的APOE等位基因变体（APOE2，APOE3和APOE4），APOE4 运营商的风险增加了AD的风险，多达66％的AD型痴呆症患者的风险增加 64％的认知障碍也带有APOE4等位基因。目前尚无治疗方法 APOE4驱动的广告或其他痴呆症。 Artery Therapeutics，Inc。（动脉； ATI）开发了一种新型化学物质 治疗APOE4驱动痴呆症的实体，包括AD。 CS6253是第二代选择性ATP- 源自APOE的C末端的结合式A1（ABCA1）转运蛋白激动剂肽。 CS6253是a 安全，潜力和可吸毒的ABCA1激动剂。 ATI在细胞系统中的临床前数据和两个不同的APOE4 转基因小鼠模型已证明CS6253将ABCA1与ABCA1接合，可改善APOE 脂化，防止海马淀粉样β（Aβ）病理生理学，并改善认知。在索引中 研究表明安全性和药代动力学特性的研究表明，在私人中， CS6253在9天内的治疗表明脑脊液（CSF）的明显剂量反应减少 Aβ42，Aβ40和APP以及其他标记的浓度。这些数据强烈支持并扩展了我们的 疗效导致小鼠药理学模型，并预测人类功效。那，有这个sbir 提案，我们将把CS6253推进到早期临床试验中。在AIM 1中，ATI将建立合格方法 GMP药物和-20C的稳定性可用于COFA，并释放1期临床试验材料。 GMP药物 产品将完成CMC部分（已经生产GMP药物），将添加到 IND的临床和非临床部分，用于提交IND。目标1的里程碑是打开IND， 即，通过启动CS6253第1阶段试验而获得FDA买入。我们对成功的IND充满信心 2020年8月与FDA的预定会议，就关键方面达成共识 包括CMC，非临床和初始临床试验的程序。在AIM 2中，我们将执行一个随机双重 在健康50-70 Y.O.男性和女人（n = 8/队列，6 活跃：2安慰剂，总n = 32），他们将被表征但不为APOE同工型分层。参与者会 以4个单次升级剂量接受单次静脉内（IV）给药CS6253。我们的目标2里程碑 是在人类中建立安全性和药代动力学（等离子体和CSF），并为此剂量建立安全的起始剂量 多重升剂（MAD）研究。我们还将通过通过 CS6253包括临时等离子体 - 载脂蛋白和AD标记的CSF动力学。 该项目将确定CS6253的药代动力学（等离子体和CSF）和单剂量安全，并准备 对于第1阶段的疯狂研究，最多30天。总体而言，CS6253是一个非常有希望的ABCA1针对小说 有可能解决APOE4相关痴呆在内的治疗。