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

项目摘要 迟发性或散发性阿尔茨海默病（AD）占所有AD的95%，APOE 4是主要的 遗传风险因素虽然有三种主要的APOE等位基因变体（APOE 2、APOE 3和APOE 4），但APOE 4 携带者患AD的风险增加，高达66%的AD型痴呆患者 64%的轻度认知障碍患者也携带APOE 4等位基因。目前没有治疗方法 APOE 4驱动的AD或其他痴呆。Artery Therapeutics，Inc.（动脉; ATI）开发了一种新的化学物质， 用于治疗APOE 4驱动的痴呆，包括AD的实体。CS6253是第二代选择性ATP- 结合盒A1（ABCA 1）转运蛋白激动剂肽，来源于apoE的C-末端。CS6253是一种 安全、有效且可药用的ABCA 1激动剂。ATI在细胞系统和两种不同apoE 4中的临床前数据 转基因小鼠模型已经证明CS6253将ABCA 1作为靶点， 脂质化，预防海马淀粉样蛋白-β（Aβ）病理生理学，并改善认知。在IND启用中 研究显示了极好的安全性和药代动力学特性，证明在灵长类动物中， CS6253治疗9天后，脑脊液（CSF）中的剂量反应显著降低 Aβ42、Aβ40和APP以及其他标志物的浓度。这些数据有力地支持和扩展了我们的 在小鼠药理学模型中产生功效，并预测在人体中的功效。因此，有了这个SBIR 根据该提案，我们将推进CS6253进入早期临床试验。在目标1中，ATI将为以下各项建立资格鉴定方法 GMP制剂和在-20 ℃下的稳定性，用于1期临床试验材料。GMP原料 产品将完成CMC部分（已生产GMP原料药），该部分将添加到 IND的临床和非临床部分，用于提交IND。目标1里程碑是打开IND， 即接受FDA的支持，以启动CS6253 I期试验。我们有信心成功的IND基于 2020年8月与FDA举行的IND前会议，会议就 项目包括CMC、非临床和初始临床试验。在目标2中，我们将执行随机双 在50-70岁健康人群中进行的盲法安慰剂对照单次剂量递增试验男性和女性（n=8/队列，6 活性药物组：2例安慰剂组，总计n=32），将对其进行APOE亚型表征但不分层。参与者将 接受CS6253单次静脉（iv）给药，剂量递增4次。我们的目标2里程碑 是确定人体安全性和药代动力学（血浆和CSF）以及安全的起始剂量， 多次递增剂量（MAD）研究。我们还将通过以下方法探索对脂质和AD生物标志物的短暂影响： CS6253包括载脂蛋白和AD标志物的时间血浆- CSF动力学。 本项目将确定CS6253的药代动力学（血浆和CSF）和单次给药安全性，并准备 对于1期MAD研究，最长30天。总体而言，CS6253是一种非常有前途的ABCA 1靶向新药。 有可能解决APOE 4相关痴呆症（包括AD）的治疗。

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.