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

描述：预防、延缓和治疗阿尔茨海默病(AD)的治疗方法仍有待实现。目前，有500多万美国人被诊断为阿尔茨海默病，除非在治疗方面取得进展，否则这一数字预计将在20年内增加到1100-1600万。这里提出了一种再生医学，系统生物学方法，目标是大脑的再生系统，同时激活系统以减少AD病理。别孕酮(Allo)是一种多效性再生疗法，可促进临床前AD模型和野生型衰老小鼠的神经再生和认知功能恢复，并减少临床前AD模型的病理改变。此外，Allo还促进人类神经干细胞的再生。ALLO是一种低分子的脑内源性神经类固醇，具有血脑屏障穿透性，在动物和人类中已有大量的安全性数据。其神经干细胞增殖和认知功能恢复的机制被很好地描述，并与脑内已描述的神经发生机制相一致。Allo通过Abeta生成上游成熟的途径减少AD的病理，以防止Abeta的生成，同时还减少炎症和增加髓鞘生成。在临床前发现(ADDF)、转化研究(NIA U01)、NIA USC ADRC和FDA评估的临床开发的基础上，我们提议进行一期多剂量递增剂量临床试验，以每周一次的再生方案给予四种Allo剂量，持续12周，以建立进入第二阶段疗效试验所需的安全和耐受剂量的Allo。为了实现这一目标，提出了两个具体目标。AIM 1旨在对因AD和早期AD而被诊断为MCI的参与者进行Allo的第一阶段多剂量递增试验。主要安全目标是确定：1)最大耐受量；2)治疗紧急不良事件的发生率和严重性；3)指定的医疗事件；4)安全评估中的临床重要变化，包括淀粉样蛋白相关成像异常(ARIA)。AIM 2旨在进行探索性安全性和可行性分析，探讨每周一次、持续12周的4种剂量的Allo对认知功能和基于MRI的生物标记物的影响。次要目标是：1)评估Allo剂量对AD认知和MRI指标的潜在短期影响；2)向随后的第二阶段概念验证试验提供基于MRI的再生效果生物标记物的信息。一个在Allo系统生物学和AD治疗的转化研究和临床试验方面具有专业知识的多学科研究团队致力于该项目。试验结果将提供：1)估计的安全和耐受性良好的Allo剂量；2)认知功效的参数估计，以进入Allo的第二阶段概念验证试验；以及3)基于MRI的生物标记物的参数估计。该提案符合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.