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/摘要重新利用西波尼莫德治疗阿尔茨海默病阿尔茨海默病 (AD) 是一种神经退行性疾病，可能会导致多种复杂的神经病理学症状顺序发展，但随着时间的推移，随着症状发展为痴呆，这种重叠因此，为了有效，未来。干预策略可能需要联合疗法或多效药物来解决多种AD 十多年来，我们的团队一直在探索分子致病途径。最近与专门从事多发性硬化症的合作者进行了讨论。表明 1-磷酸鞘氨醇受体 (S1PR) 调节剂是 AD 中重新利用的有力候选者。事实上，S1PR 调节剂具有血脑屏障 (BBB) 渗透性并表现出多效性作用，包括 S1P 是一种多功能内源性分子，具有免疫调节和神经保护作用。通过与 5 个 G 蛋白偶联受体结合来调节多种信号通路，这些受体在 S1PR 的广泛定位是心脏、血管、免疫和脑细胞的历史基础。诺华制药公司将开发用于治疗多发性硬化症 (MS) 的 S1PR 调节剂口服制剂，事实证明是成功的，并产生了两种上市化合物。在目前的项目中，我们打算与诺华合作使用最新 FDA 批准的基于 MS 的 S1PR 调节剂 siponimod。动物实验文献中，我们认为辛波尼莫德可以降低 AD 脑萎缩的发生率在第二阶段，概念验证、严格的转化临床研究中，轻度 AD 受试者将被纳入其中。按 2:1 随机分配并接受辛波莫德缓慢加量方案至 1 mg/天 (N=70) 或安慰剂 (N=35) 12 个月，随后是 6 个月的清除期，主要目标是 AD 的药物安全性和耐受性。在整个给药期间通过定期临床测试对受试者进行评估，最终治疗紧急。毒性将推动我们继续或停止给药的决策过程。通过比较治疗前和治疗后，确定药物对两组相对年度脑萎缩率的影响暴露体积 MRI 数据的第三个目标是 AD 的认知和脑脊液标记（淀粉样蛋白、tau、p-tau）。作为探索性目标，我们还将研究血细胞计数和血液是否存在差异。生物标志物可以用作药物疗效的动态替代标志物，因为辛波尼莫德已被证明。对多发性硬化症具有积极的免疫调节和神经保护作用，并且由于其毒性特征有利于在老年人中使用，该药物具有改变 AD 病理学和疾病轨迹标志物的强大潜力。