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

Allopregnanolone 作为阿尔茨海默病再生疗法：2 期临床试验

• 批准号: 9991710
• 负责人: ROBERTA EILEEN BRINTON
• 金额: $ 737.08万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9991710
• 关键词: Activities of Daily Living; Address; Advanced Development; Adverse event; Age; Aging; Algorithms; Allopregnanolone; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease therapeutic; Animals; Biological Markers; Blood; Blood - brain barrier anatomy; Brain; Brain imaging; CD34 gene; Cells; Chronic; Clinical; Clinical Research; Clinical Trials; Cognitive; Communities; Data; Diagnosis; Disease; Documentation; Dose; Double-Blind Method; Fiber; Foundations; Guidelines; Hippocampus (Brain); Human; In Vitro; Intravenous; Intravenous infusion procedures; Laboratories; Magnetic Resonance Imaging; Measures; Mitochondria; Molecular Weight; National Institute on Aging; Natural regeneration; Nature; Nerve Regeneration; Neurons; Outcome; Outcome Measure; Participant; Pathway interactions; Peripheral Blood Mononuclear Cell; Persons; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phase III Clinical Trials; Placebos; Population; Randomized; Regenerative Medicine; Respiration; Risk; S Phase; Safety; Structure; Surrogate Markers; System; Systems Biology; Testing; Therapeutic; Toxicology; Translational Research; Treatment Protocols; Woman; adverse outcome; aged; base; biomarker validation; blood-based biomarker; candidate marker; clinical development; clinical efficacy; cognitive function; cognitive testing; cohort; design; functional outcomes; good laboratory practice; gray matter; induced pluripotent stem cell; men; myelination; nerve stem cell; neurogenesis; neurosteroids; novel; open label; placebo group; pre-clinical; pre-clinical research; predictive marker; prevent; primary outcome; quality assurance; rate of change; regenerative; regenerative therapy; regenerative treatment; repaired; responders and non-responders; restoration; secondary analysis; stem cell self renewal; therapeutic target; white matter

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.

项目概要/摘要 本文提出的预防、延迟和治疗阿尔茨海默氏病（AD）的疗法仍然是一个未满足的需求。 再生医学，针对大脑再生系统的系统生物学方法，同时 同时激活系统以减轻 AD 病理负担。Allopregnanolone (Allo) 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 Allo 促进神经干细胞再生的机制。 认知功能的恢复和恢复通常具有较大的安全边际。 Allo 是一种低分子量神经类固醇，可在体外促进人类神经干细胞的再生。 大脑内源性，具有血脑屏障渗透性，现有丰富的动物安全性数据 已完成国家衰老研究所 (NIA) 对诊断为 MCI 的人进行的 Allo 1 期临床试验。 因AD或轻度AD，表明每周一次静脉注射再生治疗方案 输注耐受性良好，没有出现与再生相关的 MRI 脑成像不良事件的迹象。 替代标记和认知测试在这个早期 AD 队列中具有良好的耐受性和可行性。 女性和男性的耐受性研究结果与 IND 支持的慢性毒理学结果一致： 每周一次的 Allo 暴露剂量超过 24 周后表明没有不良后果的物种 基于发现和临床前机制的基础，将在人体中进行 10 倍测试。 研究、IND 启用研究和女性和男性的 1 期临床开发，我们建议延迟 开始以再生治疗方案进行为期 18 个月的 Allo 2 期临床试验，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。 临床开发，提出了三个具体目标，目标 1 旨在进行 2 期、随机、 安慰剂对照、延迟启动组、APOEe4 阳性参与者中 Allo 的概念验证临床试验 诊断为轻度 AD 的主要结果指标是 12 年后 ADAS-cog14 评分的变化率。 次要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 体积结果以及 CANTAB 确定的认知功能进行评估 AD 电池、MMSE 和 CDR-SB 探索性分析将评估临床认知和功能。 延迟开始期间（12-18 个月）的结果是探索性的，旨在发展。 目标 3 是基于 MRI 的海马再生和连接性替代生物标志物。 旨在建立再生反应者和无反应者的基于血液的预测生物标志物。 有待探索的是 Allo 诱导 iPSC 衍生的神经干细胞和线粒体再生 次要目标是确定具有最高预测准确性的细胞群。 使用衍生的 iPSC/神经干细胞、外周血单核细胞和 CD34+ 参与者细胞。