Allopregnanolone Regenerative Therapeutic for MCI/AD: Dose Finding Phase I

描述：预防，延迟和治疗阿尔茨海默病（AD）的治疗方法仍有待实现。目前，超过500万美国人被诊断患有AD，除非治疗取得进展，否则预计这一数字将在二十年内增加到1100万至1600万。本文提出了一种再生医学、系统生物学方法，其靶向脑的再生系统，同时激活系统以减少AD病理。别孕烯醇酮（Allo）是一种多效性再生治疗剂，其在临床前AD模型和野生型老年小鼠中促进神经发生并恢复认知功能，并在临床前AD模型中减少病理学。此外，Allo促进人类神经干细胞的再生。Allo是一种低分子量的脑内源性神经甾体，具有血脑屏障渗透性，在动物和人体中已有丰富的安全性数据。它的神经干细胞增殖和恢复认知功能的机制是很好的特点，并与脑中的神经发生机制的描述一致。Allo通过Abeta生成上游的成熟途径减少AD病理学，以防止Abeta的生成，同时还减少炎症和增加髓鞘生成。基于临床前发现（ADDF）、转化研究（NIA U 01）、NIA USC ADRC临床开发和FDA评估的基础，我们提出了一项1期多剂量递增临床试验，以每周一次的再生方案给予4种Allo剂量，持续12周，以确定进入2期疗效试验所需的安全和耐受剂量。为实现这一目标，提出了两个具体目标。目的1是在诊断为AD和早期AD所致MCI的受试者中进行Allo的I期多次递增剂量试验。主要安全性目的是确定：1）最大耐受剂量; 2）治疗后出现的不良事件的发生率和严重程度; 3）指定的医学事件; 4）安全性评估中具有临床意义的变化，包括淀粉样蛋白相关成像异常（ARIA）。目的2旨在进行探索性安全性和可行性分析，分析每周一次暴露于4种剂量的Allo 12周对认知功能和基于MRI的生物标志物的影响。次要目的是：1）评估Allo给药对AD的认知和MRI指标的潜在短期影响; 2）为后续的II期概念验证试验提供信息，该试验使用基于MRI的再生功效生物标志物。一个多学科的研究人员团队，具有Allo系统生物学和AD治疗的转化研究和临床试验的专业知识，致力于该项目。试验结果将提供：1）估计的Allo的安全和良好耐受剂量; 2）用于认知功效的参数估计，以推进到Allo的概念试验的2期验证;和3）用于基于MRI的生物标志物的参数估计。本提案符合RFA-AG-13-016的目标。

DESCRIPTION: Therapeutics to prevent, delay and treat Alzheimer's disease (AD) remains to be achieved. Currently, over 5 million Americans are diagnosed with AD and the number is projected to increase to 11-16 million within two decades unless therapeutic advances are made. Proposed herein is a regenerative medicine, systems biology approach that targets the regenerative system of the brain while simultaneously activating systems to reduce AD pathology. Allopregnanolone (Allo) is a pleiotropic regenerative therapeutic that promotes neurogenesis and restores cognitive function in both a preclinical AD model and wild type aged mice and reduces pathology in a preclinical AD model. Further Allo promotes regeneration of human neural stem cells. Allo is a neurosteroid endogenous to the brain of low molecular weight and blood brain barrier penetrant with abundant existing safety data in animals and humans. Its mechanisms of neural stem cell proliferation and restoration of cognitive function are well characterized and consistent with well-described neurogenic mechanisms in brain. Allo reduces AD pathology via well-established pathways upstream to Abeta generation to prevent the generation of Abeta while also decreasing inflammation and increasing myelin generation. Based on a foundation of preclinical discovery (ADDF), translational research (NIA U01), clinical development with NIA USC ADRC and FDA assessment, we propose a Phase 1 multiple ascending dose clinical trial of four Allo doses administered in a regenerative regimen of once-per-week for twelve weeks to establish a safe and tolerated dose of Allo necessary to advance to a Phase 2 efficacy trial. To achieve this goal, two specific aims are proposed. Aim 1 is designed to conduct a Phase 1 multiple ascending dose trial of Allo in participants diagnosed with MCI due to AD and early AD. Primary safety objectives are to determine: 1) maximally tolerated dose; 2) incidence and severity of treatment emergent adverse events; 3) designated medical events; 4) clinically important changes in safety assessments including amyloid related imaging abnormalities (ARIA). Aim 2 is designed to conduct exploratory safety and feasibility analyses regarding the effect of once- per-week-exposure for 12 weeks to Allo at 4 doses on cognitive function and MRI-based biomarkers. Secondary objectives are to: 1) assess potential short-term effects of Allo dosing on cognition and MRI indicators of AD; 2) inform subsequent phase 2 proof of concept trial with MRI-based biomarkers of regenerative efficacy. A multidisciplinary team of investigators with expertise in Allo systems biology and translational research and clinical trials for AD therapeutics are committed to the project. Trial outcomes will provide: 1) an estimated safe and well-tolerated dose of Allo; 2) parameter estimates for cognitive efficacy to advance to a Phase 2 proof of concept trial of Allo; and 3) parameter estimates for MRI-based biomarkers. This proposal meets the objectives of RFA-AG-13-016.