Repurposing Siponimod for Alzheimer's Disease

重新利用西波尼莫德治疗阿尔茨海默病

• 批准号: 10274977
• 负责人: Boris Decourt
• 金额: $ 73.19万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2021-10-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10274977
• 关键词: Adverse event; Agonist; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' 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; 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; Heart; Heart Rate; Hepatic; Human; Immune; Immunomodulators; Impaired cognition; Individual; Inflammation; Inflammatory; Intervention; Literature; Magnetic Resonance Imaging; 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; 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; base; brain cell; cerebral atrophy; cohort; design; drug efficacy; drug withdrawal; genetic variant; immunoregulation; in vivo; innovation; lenalidomide; medication safety; mild cognitive impairment; multidisciplinary; multiple sclerosis patient; neuroinflammation; neuropathology; novel; pleiotropism; receptor; tau Proteins; tau-1

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.

总结/摘要 辛波莫德治疗阿尔茨海默病的新用途 阿尔茨海默病（AD）是一种神经退行性疾病，具有几种复杂的神经病理学， 随着症状进展为痴呆症，这些症状会依次出现，但会随着时间的推移而重叠。为了有效，未来 干预策略可能需要联合治疗或多效性药物来解决几种AD 分子致病途径。十多年来，我们的团队一直在探索 免疫调节剂的再利用。最近与多发性硬化症专业合作者的讨论 表明鞘氨醇-1-磷酸受体（S1 PR）调节剂是在AD中再利用的强有力的候选者。 实际上，S1 PR调节剂是血脑屏障（BBB）渗透剂，并显示多效性作用，包括 免疫调节和神经保护特性。S1 P是一种多功能的内源性分子， 通过与五种G蛋白偶联受体结合，几种信号传导途径，这些受体在体内高水平表达， 心脏血管免疫和脑细胞S1 PR的广泛本地化是 诺华制药公司将开发用于多发性硬化症（MS）的S1 PR调节剂口服制剂， 这证明是成功的，并产生了两种市售化合物。在本项目中，我们打算 与诺华公司合作，使用最新FDA批准的S1 PR调节剂辛波莫德。基于MS和 根据动物实验文献，我们推测辛波莫德可以降低AD的脑萎缩率 科目在这项II期、概念验证、严格的转化临床研究中，轻度AD受试者将 以2：1的比例随机分组，接受辛波莫德缓慢上调方案，直至1 mg/天（N=70）或安慰剂（N=35） 持续12个月，然后是6个月的洗脱期。主要目的是AD患者的药物安全性和耐受性 在整个给药期间通过定期临床试验评估受试者。严重，最终治疗后出现 毒性将驱动我们的进行/不进行决定过程以继续或停止给药。次要目的是 通过比较治疗前和治疗后，确定药物对两组相对年脑萎缩率的影响。 暴露体积MRI数据。三级目标是AD的认知和CSF标志物（淀粉样蛋白、tau、p-tau） 和炎症。作为探索性目的，我们还将研究血细胞计数和血液 生物标志物可用作药物功效的动态替代标志物。因为辛波莫德已经证明 在MS中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，这种药物具有改变AD病理学和疾病轨迹标志物的强大潜力。