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

项目总结/摘要 预防、延迟和治疗阿尔茨海默病（AD）的治疗剂仍然是未满足的需求。本文提出的是一个 再生医学是一种针对大脑再生系统的系统生物学方法， 同时激活系统以减轻AD病理学的负担。别孕烯醇酮（Allo）是一种多效性 在AD和衰老的临床前发现模型中促进神经发生、恢复认知能力的神经类固醇 功能和减轻AD病理负担。Allo促进神经干细胞再生的机制 和认知功能的恢复具有广泛的特征，具有大的安全裕度。重要的是，Allo 促进体外人神经干细胞的再生。Allo是一种低分子量神经甾体 脑内源性，是血脑屏障渗透剂，在动物中有丰富的现有安全性数据， 人类已完成国家老龄化研究所（NIA）在诊断为MCI的患者中进行的Allo 1期临床试验 由于AD或轻度AD，表明每周一次通过静脉注射的再生治疗方案 输注耐受性良好，无同种异体相关不良事件的迹象。MRI脑成像用于再生 在该早期AD队列中，替代标记物和认知测试耐受良好且可行。安全和 女性和男性的耐受性研究结果与两项IND启用慢性毒理学研究的结果一致。 表明每周一次Allo暴露24周后， 在人类身上测试的人增加了10倍基于发现和临床前机制的基础 研究，IND使能研究和1期临床开发的妇女和男子，我们提出了一个延迟 开始在再生治疗方案中施用Allo的2期临床试验，为期18个月，其中包括 12个月的安慰剂对照期，随后是6个月的延迟开始（开放标签）期。推进 临床发展，提出了三个具体目标。目的1旨在进行一项II期、随机、 安慰剂对照、延迟开始组、Allo在APOEe 4阳性受试者中的概念验证临床试验 诊断为轻度AD。主要结局指标为12个月后ADAS-cog 14评分的变化率。 个月次要分析将评估日常生活活动从基线至12个月的变化 通过ADCS-iADL、MRI体积结局和CANTAB确定的认知功能进行评估 AD成套测验、MMSE和CDR-SB。目的1探索性分析将评估认知临床和功能 延迟开始期（12-18个月）的结果。目标2是探索性的，旨在开发 海马再生和连接的替代性基于MRI的生物标志物。目标3是探索性的， 旨在建立再生应答者和无应答者的基于血液的预测性生物标志物。 待探索的是同种异体诱导的iPSC衍生的神经干细胞和线粒体的再生。 呼吸次要目的是确定具有最大预测准确性的细胞群 使用来自参与者的iPSC/神经干细胞、外周血单核细胞和CD 34+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.