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 遗传风险因素。 运营商有发展AD的风险，多达66％的患有ADPE痴呆症的个体 64％的认知障碍也有APOE4等位基因。 APOE4驱动的AD或其他痴呆症。 APOE4驱动痴呆症的实体，CS6253是第二代选择性ATP- 衍生自APOE的C末端的结合式A1（ABCA1）转运蛋白激动剂肽 安全，有效和可药的激动剂。 转基因小鼠模型已证明CS6253将ABCA1与ABCA1接合，可改善APOE 脂质可防止海马淀粉样蛋白β（Aβ）病理生理学，并改善认知 研究表现出了出色的安全性和药代动力学特性的研究，证明在灵长类动物中， CS6253在9天内的治疗表明明显的剂量反应减少了脑乳液（CSF）的减少。 Aβ42，Aβ40和APP的浓度以及其他标记。 疗效导致小鼠药理学模型，并预测了人类的功效。 提案，我们将在AIM 1中将CS6253提高到早期的临床试验。 GMP药物和-20C的稳定性可用于COFA，并释放1期临床试验材料。 产品将完成CMC部分（已经生产GMP药物），该药物将被划给 IND的临床和非临床部分，用于提交IND 1。 也就是说。 2020年8月与FDA的印度预科，达成共识达到了关键方面 包含CMC，非临床和初始临床试验的程序。 在健康50-70 Y.O.中，盲blood剂量剂量试验。 活跃：2个安慰剂，总n = 32），他们将被表征但不为APOE同工型 以4个单次允许的剂量接受单次静脉内（IV）给药。 是在人类中建立安全性和药代动力学（等离子体和CSF），并为其提供安全的起始剂量。 多次升级剂量（MAD）研究。 CS6253包括时间等离子体 - 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 对于最多30天的疯狂研究，CS6253是一个非常有前途的ABCA1。 有可能解决APOE4相关痴呆在内的治疗。