Allopregnanolone as Regenerative Therapeutic for Alzheimer's: Phase 2 Clinical Trial

项目摘要/摘要 预防、延迟和治疗阿尔茨海默病(AD)的治疗方法仍然是一个未得到满足的需求。在此建议的是一个 再生医学，系统生物学方法，目标是大脑的再生系统，而 同时激活系统，减轻AD病理负担。别孕酮是一种多效性药物 神经类固醇在AD和衰老的临床前发现模型中促进神经发生，恢复认知 功能，减轻AD病理负担。Allo促进神经干细胞再生的机制 而认知功能的恢复具有广泛的安全边际。重要的是，Allo 在体外促进人类神经干细胞的再生。Allo是一种低分子质量的神经类固醇 内源性脑，即血脑屏障穿透剂，具有丰富的现有动物安全性数据和 人类。国家老龄研究所(NIA)完成的Allo在被诊断为MCI的人中的第一阶段临床试验 由于AD或轻度AD，提示再生治疗方案为每周静脉注射一次 输液耐受性良好，没有出现与异体反应相关的不良反应。磁共振脑成像在再生方面的应用 代用标记物和认知测试在这个早期AD队列中具有很好的耐受性和可行性。安全和 女性和男性的耐受性结果与两名患者的IND慢性毒理学结果一致 表明每周一次的剂量超过24周的Allo暴露后没有不良后果的物种 那些将在人体上进行测试的药物是原来的10倍。基于发现的基础和临床前的机械论 在女性和男性的研究、启用IND的研究和第一阶段临床开发中，我们建议推迟 以再生治疗方案开始ALLO的第二阶段临床试验，为期18个月，包括 安慰剂控制期为12个月，随后是6个月的延迟开始(开放标签)期。晋级 在临床发展方面，提出了三个具体目标。AIM 1旨在进行阶段2，随机， 安慰剂对照、延迟开始组、概念验证Allo在APOEe4阳性参与者中的临床试验 被诊断为轻度阿尔茨海默病。主要的结果衡量标准是12岁以后ADAS-cog14评分的变化率 月份。二次分析将评估日常生活活动从基线到12个月的变化 通过ADCS-IADL、MRI容量结果和CANAB确定的认知功能进行评估 AD电池、MMSE和CDR-SB。目标1探索性分析将评估认知、临床和功能 延迟启动期间(12-18个月)的结果。目标2是探索性的，旨在开发 基于替代核磁共振的海马区再生和连接的生物标志物。目标3是探索性的，是 旨在建立再生反应者和无反应者的基于血液的预测性生物标记物。 有待探索的是Allo诱导的iPSC来源的神经干细胞和线粒体的再生 呼吸。次要目标是以最高的预测精度确定细胞数量 使用参与者来源的IPSCs/神经干细胞、外周血单个核细胞和CD34+细胞。

PROJECT SUMMARY/ABSTRACT Therapeutics to prevent, delay and treat Alzheimer’s disease (AD) remain an unmet need. Proposed herein is a regenerative medicine, systems biology approach that targets the regenerative system of the brain while simultaneously activating systems to reduce burden of AD pathology. Allopregnanolone (Allo) is a pleiotropic neurosteroid that in preclinical discovery models of AD and aging promotes neurogenesis, restores cognitive function and reduces burden of AD pathology. Mechanisms by which Allo promotes neural stem cell regeneration and restoration of cognitive function are extensively characterized with a large margin of safety. Importantly, Allo promotes regeneration of human neural stem cells in vitro. Allo is a low molecular weight neurosteroid endogenous to the brain that is blood brain barrier penetrant with abundant existing safety data in animals and humans. Completed National Institute on Aging (NIA) Phase 1 clinical trial of Allo in persons diagnosed with MCI due to AD or mild AD, indicates that the regenerative treatment regimen of once per week via intravenous infusion is well tolerated with no indications of Allo-related adverse events. MRI brain imaging for regenerative surrogate markers and cognitive testing were well tolerated and feasible in this early AD cohort. Safety and tolerability findings in women and men are consistent with outcomes of IND-enabling chronic toxicology in two species indicating no adverse outcomes following 24 weeks of once per week Allo exposure at doses exceeding those to be tested in humans by 10-fold. Based on a foundation of discovery and mechanistic preclinical research, IND-enabling studies and Phase 1 clinical development in women and men, we propose a delayed start Phase 2 clinical trial of Allo administered in a regenerative treatment regimen for 18 months, which includes a placebo-controlled period of 12 months followed by a delayed-start (open label) period of 6 months. To advance clinical development, three specific aims are proposed. Aim 1 is designed to conduct a Phase 2, randomized, placebo-controlled, delayed start group, proof of concept clinical trial of Allo in APOEe4 positive participants diagnosed with mild AD. The primary outcome measure will be rate of change in ADAS-cog14 score after 12 months. Secondary analyses will assess change from baseline to 12 months on activities of daily living assessed by ADCS-iADL, MRI volumetric outcomes, and on cognitive function as determined by CANTAB AD battery, MMSE, and CDR-SB. Aim 1 exploratory analyses will assess cognitive clinical and functional outcomes during the delayed-start period (12-18 months). Aim 2 is exploratory and designed to develop surrogate MRI-based biomarkers of hippocampal regeneration and connectivity. Aim 3 is exploratory and is designed to establish a blood-based predictive biomarker of regenerative responders and non-responders. To be explored are Allo-induced regeneration of iPSC-derived neural stem cells and mitochondrial respiration. Secondary objective is to determine the cellular population with greatest predictive accuracy using participant derived iPSCs / neural stem cells, peripheral blood mononuclear cells and CD34+ cells.