Repurposing Siponimod for Alzheimer's Disease

摘要/摘要 西波尼莫特治疗阿尔茨海默病的再利用 阿尔茨海默病(AD)是一种神经退行性疾病，有几种复杂的神经病理怀疑 疾病按顺序发展，但随着症状进展为痴呆症，这种情况会随着时间的推移而重叠。因此，要想卓有成效，未来 干预策略可能需要综合疗法或多效剂来应对几种AD 分子致病途径同时发生。十多年来，我们团队一直在探索 治疗阿尔茨海默病的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 提示鞘氨醇-1-磷酸受体(S1PR)调节剂在AD中有很强的再利用潜力。 事实上，S1PR调节剂是血脑屏障(BBB)的渗透者，并显示出多效性作用，包括 免疫调节和神经保护特性。S1P是一种多功能的内源性分子，调节 通过与五个G蛋白偶联受体结合的几个信号通路，这五个受体在 心脏细胞、血管细胞、免疫细胞和脑细胞。S1PR的这种广泛的本地化是 诺华制药公司开发治疗多发性硬化症(MS)的S1PR调节剂的口服配方， 这被证明是成功的，并产生了两种上市的化合物。在本项目中，我们打算 与诺华公司合作，使用FDA批准的最新S1PR调节剂siponimod。基于MS和 在动物实验文献中，我们假设西波利莫特可以降低AD患者的脑萎缩比率 研究对象。在这个第二阶段，概念验证，严格的翻译临床研究，轻度AD受试者将 随机2：1，接受西波莫特缓慢向上滴定方案，最高1毫克/天(N=70)或安慰剂(N=35)。 12个月，然后是6个月的洗涤期。AD的主要目标是药物安全性和耐受性 在给药期间，受试者通过定期的临床测试进行评估。关键的，最终的治疗-紧急 毒性将驱动我们决定是否继续或停止服药。次要目标是 比较治疗前后药物对两组相对年脑萎缩率的影响。 曝光体积磁共振数据。第三目标是AD的认知和脑脊液标志物(淀粉样蛋白、tau、p-tau) 和炎症。作为一项探索性目标，我们还将调查血细胞计数和血液 生物标志物可作为药物疗效的动态替代标志物。因为西波尼莫特已经证明 在MS中具有积极的免疫调节和神经保护作用，因为其毒性特征有利于 在老年人中使用，这种药物有很大的潜力改变AD病理和疾病轨迹的标志物。

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.