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

Allopregnanolone 再生治疗 MCI/AD：剂量探索 I 期

• 批准号: 8605469
• 负责人: ROBERTA EILEEN BRINTON
• 金额: $ 242.96万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8605469
• 关键词: Address; Adverse event; Allopregnanolone; Alzheimer' s Disease; Alzheimer' s disease model; Amendment; American; Amyloid; Amyloid beta-Protein; Animals; Biological Markers; Blood - brain barrier anatomy; Brain; Cell Proliferation; Cholesterol Homeostasis; Chronic; Clinical; Clinical Research; Clinical Trials; Clinical trial protocol document; Cognition; Cognitive; Collaborations; Commit; Data; Development; Diagnosis; Disease; Disease Progression; Dose; Drug Containers; Drug Formulations; Drug Kinetics; Event; FDA approved; Foundations; Future; Generations; Goals; Hemorrhage; Hippocampus (Brain); Human; Image; Incidence; Inflammation; Inflammatory Response; Intervention; Investigational Drugs; Investigational New Drug Application; Letters; Magnetic Resonance Imaging; Maximum Tolerated Dose; Medical; Methods; Molecular Weight; Mus; Myelin; Natural regeneration; Nature; Neurology; Neurons; Outcome; Participant; Pathology; Pathway interactions; Phase; Placebos; Regenerative Medicine; Regimen; Research Personnel; Rest; Risk; Safety; Severities; Suggestion; Symptoms; System; Systems Biology; Therapeutic; Translational Research; Traumatic Brain Injury; Treatment Efficacy; aged; base; cognitive function; design; efficacy trial; meetings; multidisciplinary; nerve stem cell; neurogenesis; neurosteroids; phase 2 study; pre-clinical; prevent; public health relevance; regenerative; relating to nervous system; restoration; small molecule; stem; therapeutic target; trafficking; white matter

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.

描述：预防、延缓和治疗阿尔茨海默病 (AD) 的疗法仍有待实现。目前，超过 500 万美国人被诊断患有 AD，如果治疗方法不取得进展，预计这一数字将在 20 年内增加到 11-1600 万。本文提出了一种再生医学、系统生物学方法，其目标是大脑的再生系统，同时激活系统以减少 AD 病理。 Allopregnanolone (Allo) 是一种多效性再生治疗药物，可促进临床前 AD 模型和野生型老年小鼠的神经发生并恢复认知功能，并减少临床前 AD 模型中的病理。此外，Allo 还能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类固醇，具有血脑屏障渗透性，在动物和人类中已有丰富的安全性数据。其神经干细胞增殖和认知功能恢复的机制已得到很好的表征，并且与大脑中已明确描述的神经发生机制一致。 Allo 通过 Abeta 生成上游的成熟途径减少 AD 病理，防止 Abeta 的生成，同时减少炎症并增加髓鞘质的生成。基于临床前发现 (ADDF)、转化研究 (NIA U01)、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，以一次再生方案施用四剂 Allo 剂量。每周持续 12 周，以确定进入 2 期疗效试验所需的安全且耐受的 Allo 剂量。为了实现这一目标，提出了两个具体目标。目标 1 旨在对因 AD 和早期 AD 诊断为 MCI 的参与者进行 Allo 的 1 期多剂量递增试验。主要安全目标是确定： 1) 最大耐受剂量； 2) 治疗中出现的不良事件的发生率和严重程度； 3）指定医疗事件； 4）安全性评估的临床重要变化，包括淀粉样蛋白相关的影像学异常（ARIA）。目标 2 旨在针对每周一次、连续 12 周暴露​​于 4 剂 Allo 对认知功能和基于 MRI 的生物标志物的影响进行探索性安全性和可行性分析。次要目标是：1）评估 Allo 给药对 AD 认知和 MRI 指标的潜在短期影响； 2) 使用基于 MRI 的再生功效生物标志物为后续第二阶段概念验证试验提供信息。一个由在 Allo 系统生物学、转化研究和 AD 疗法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 Allo 安全且耐受性良好的剂量； 2) 认知功效的参数估计，以推进 Allo 的第二阶段概念验证试验； 3) 基于 MRI 的生物标志物的参数估计。该提案符合 RFA-AG-13-016 的目标。