Repurposing Siponimod for Alzheimer's Disease

重新利用西波尼莫德治疗阿尔茨海默病

基本信息

批准号：
10671526
负责人：
Boris Decourt
金额：
$ 68.73万
依托单位：
ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10671526
关键词：
Adverse event Agonist Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer’s disease biomarker Amyloid Amyloid beta-Protein Amyotrophic Lateral Sclerosis Animal Experimentation Animal Experiments Anti-Inflammatory Agents Antioxidants Arrhythmia Attenuated Binding Biological Markers Blood Blood - brain barrier anatomy Blood Cell Count Blood Vessels Bradycardia Brain CYP2C9 gene Cardiac Cardiotoxicity Cells Clinical Clinical Research Clinical Trials Cognition Cognitive Collaborations Combined Modality Therapy Complex Custom Cytochrome P450 Data Dementia Disease Dose Drug Labeling Elderly Electrocardiogram Encephalitis Enzyme Inhibitor Drugs Enzyme-Linked Immunosorbent Assay Enzymes Evaluation Excision Exposure to FDA approved Formulation Future G-Protein-Coupled Receptors Genes Heart Heart Rate Hepatic Human Immune Immunomodulators Impaired cognition Individual Inflammation Inflammatory Intervention Literature Magnetic Resonance Imaging Marketing Measures Metabolism Modeling Molecular Disease Monitor Multiple Sclerosis Mus Nerve Degeneration Neurodegenerative Disorders Oral Pathogenicity Pathology Pathway interactions Patients Peripheral Pharmaceutical Preparations Pharmacologic Substance Phase Phase III Clinical Trials Physicians Placebos Population Positron-Emission Tomography Process Property Protocols documentation Proxy Randomized Recommendation Regimen Research Risk Safety Schedule Serious Adverse Event Signal Pathway Specialist Sphingosine-1-Phosphate Receptor Study Subject Surrogate Markers Symptoms Synapses TNF gene Testing Thalidomide Time Tissues Titrations Toxic effect Tracer Traumatic Brain Injury Urine Visit analog anti-cancer brain cell cerebral atrophy clinical translation cohort design drug efficacy drug withdrawal genetic variant immunoregulation in vivo innovation lenalidomide medication safety mild cognitive impairment multidisciplinary multiple sclerosis patient neuroinflammation neuropathology neuroprotection novel pleiotropism receptor tau Proteins tau-1

项目摘要

SUMMARY/ABSTRACT Repurposing Siponimod for Alzheimer’s Disease Alzheimer’s disease (AD) is a neurodegenerative disorder with several complex neuropathologies suspected to develop sequentially but that overlap over time as symptoms progress to dementia. Thus, to be effective, future intervention strategies will likely require combination therapies or pleiotropic agents to tackle several AD molecular pathogenic pathways simultaneously. For more than a decade, our group has been exploring the repurposing of immunomodulators for AD. Recent discussions with collaborators specialized in multiple sclerosis suggest that sphingosine-1-phosphate receptor (S1PR) modulators are strong candidates for repurposing in AD. Indeed, S1PR modulators are blood brain barrier (BBB) penetrant and display pleiotropic actions, including immunomodulation and neuroprotective properties. S1P is a versatile endogenous molecule that regulates several signaling pathways by binding to five G-protein-coupled receptors, which are expressed in high levels in cardiac, vascular, immune, and brain cells. This widespread localization of S1PR was the historical basis for Novartis Pharmaceuticals, Inc, to develop oral formulations of S1PR modulators for multiple sclerosis (MS), which proved successful and resulted in two marketed compounds. In the present project, we intend to collaborate with Novartis to use the most recently FDA-approved S1PR modulator siponimod. Based on MS and animal experimentation literature, we hypothesize that siponimod could lower the rate of brain atrophy in AD subjects. In this Phase II, proof-of-concept, rigorous translational clinical study, mild AD subjects will be randomized 2:1 and receive a slow up-titration regimen of siponimod up to 1 mg/day (N=70) or placebo (N=35) for 12 months, followed by a 6-month washout period. Primary objectives are drug safety and tolerability in AD subjects assessed via regular clinical tests throughout the dosing period. Critically, eventual treatment-emergent toxicities will drive our go/no-go decision process to pursue or stop dosing. The secondary objective is to determine drug effect on relative annual brain atrophy rates in the two groups by comparing pre- and post- exposure volumetric MRI data. Tertiary objectives are cognition and CSF markers of AD (amyloid, tau, p-tau) and inflammation. As an exploratory objective, we will also investigate whether blood cell counts and blood biomarkers can be used as dynamic surrogate markers of drug efficacy. Because siponimod has demonstrated positive immunomodulatory and neuroprotective actions in MS, and because its toxicity profile is favorable for use in older individuals, this drug has a strong potential to alter markers of AD pathology and disease trajectory.

摘要/摘要重新利用阿尔茨海默氏病的siponimod 阿尔茨海默氏病（AD）是一种神经退行性疾病，怀疑有几种复杂的神经病理学依次发展，但随着时间的流逝，随着症状发展为痴呆，这会随着时间的流逝而重叠。这是有效的未来干预策略可能需要组合疗法或多效剂来解决几个广告分子致病途径。十多年来，我们的小组一直在探索对AD的免疫调节剂的重新利用。与专门从事多发性硬化症的合作者的最新讨论表明鞘氨醇1-磷酸受体（S1PR）调节剂是在AD中重新利用的强大候选者。实际上，S1PR调节剂是血脑屏障（BBB）渗透物，并显示多效性动作，包括免疫调节和神经保护特性。 S1P是一种多功能的内源分子，可调节通过与五个G蛋白偶联受体结合，几种信号通路，它们在高水平中以高水平表示心脏，血管，免疫和脑细胞。 S1PR的这种宽度定位是历史基础诺华制药公司（Novartis Pharmaceuticals，Inc）开发用于多发性硬化症（MS）的S1PR调节剂的口服配方事实证明，这是成功的，并产生了两种销售的化合物。在本项目中，我们打算与诺华合作，使用了最近FDA批准的S1PR调制器Siponimod。基于MS和动物实验文献，我们假设siponimod可以降低AD的脑萎缩率主题。在这第二阶段，概念验证，严格翻译的临床研究，轻度AD受试者将是随机2：1，并接受siponimod的慢速上递次方案，最多1 mg/天（n = 70）或安慰剂（n = 35）在12个月内，然后进行了6个月的冲洗期。主要目标是药物安全和AD的耐受性在整个给药期间，通过常规临床测试评估受试者。至关重要的是，最终的治疗效果毒性将推动我们进行/不进行决策过程，以追求或停止给药。第二个目标是通过比较前后，确定两组对相对年度脑萎缩率的影响暴露体积MRI数据。三级目标是AD的认知和CSF标记（淀粉样蛋白，TAU，P-TAU）和炎症。作为探索性目标，我们还将研究血细胞计数和血液是否计数生物标志物可以用作药物效率的动态替代标记。因为Siponimod已证明 MS中的阳性免疫调节和神经保护作用，并且因为其毒性特征有利于在老年人中，这种药物具有改变AD病理和疾病轨迹标记的强大潜力。