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，延迟和治疗阿尔茨海默氏病（AD）的治疗学尚待实现。目前，超过500万美国人被诊断出患有AD，除非取得治疗性进步，否则预计该人数将在二十年内增加到1,1600万。本文提出的是一种再生医学，即系统生物学方法，它针对大脑的再生系统，同时激活系统以减少AD病理。 Allopregnanolone（Allo）是一种多效性再生治疗，可促进神经发生并恢复临床前AD模型和野生型老年小鼠的认知功能，并在临床前AD模型中降低病理学。进一步的Allo促进了人类神经干细胞的再生。 Allo是低分子量和血脑屏障渗透物的神经固醇，具有动物和人类的现有安全数据。它的神经干细胞增殖的机制和认知功能的恢复是很好的特征，并且与大脑中描述的神经源性机制一致。 Allo通过上游到Abeta生成的良好途径来减少AD病理，以防止ABETA产生，同时减少炎症并增加髓磷脂产生。 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.为了实现这一目标，提出了两个具体目标。 AIM 1旨在在因AD和早期AD而被诊断为MCI的参与者中进行Allo的1阶段多升剂量试验。主要安全目标是确定：1​​）最大耐受剂量； 2）治疗新出现不良事件的发病率和严重程度； 3）指定的医疗活动； 4）安全评估的临床重要变化，包括淀粉样蛋白相关的成像异常（ARIA）。 AIM 2旨在进行探索性安全和可行性分析，以分析每周一次暴露12周的影响，以4剂对认知功能和基于MRI的生物标志物的影响。次要目标是：1）评估剂量对AD认知和MRI指标的潜在短期影响； 2）以基于MRI的再生功效生物标志物为随后的第2阶段概念验证验证。具有Allo Systems生物学专业知识的研究人员的多学科团队，对AD Therapeutics的转化研究和临床试验致力于该项目。试验结果将提供：1）估计的Allo的安全且耐受良好的剂量； 2）认知功效的参数估计值，以提高Allo的概念概念验证验证； 3）基于MRI的生物标志物的参数估计值。该建议符合RFA-AG-13-016的目标。