MCLENA-1: A Clinical Trial for the Assessment of Lenalidomide in Amnestic MCI Patients

MCLENA-1：评估来那度胺在遗忘性 MCI 患者中的临床试验

• 批准号: 10630526
• 负责人: Boris Decourt
• 金额: $ 66.39万
• 依托单位: ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10630526
• 关键词: Active Immunization; Adverse event; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; Amyloid beta-42; Amyloid beta-Protein; Anti-Inflammatory Agents; Antineoplastic Agents; Back; Blood; Brain; Chronic; Clinical; Clinical Research; Clinical Trials; Cognition; Data; Dose; Enzyme-Linked Immunosorbent Assay; FDA approved; Hematopoietic Neoplasms; Human; IL8 gene; Immunomodulators; Impaired cognition; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-10; Interleukin-2; Interleukin-6; Interleukins; Measures; Methods; Monitor; NF-kappa B; Neuraxis; Neutropenia; Passive Immunization; Patients; Penetration; Peripheral; Pharmaceutical Preparations; Phase; Placebo Control; Placebos; Plasma; Play; Reader; Recommendation; Reporting; Research; Role; Safety; Spectrophotometry; Study Subject; TNF gene; Testing; Thalidomide; Therapeutic Intervention; Thrombocytopenia; Visit; adaptive immune response; analog; animal data; beta-site APP cleaving enzyme 1; cancer therapy; chemokine; cognitive performance; cytokine; design; disorder risk; experience; gamma secretase; improved; inflammatory marker; inhibitor; interest; lenalidomide; mild cognitive impairment; mortality; nervous system disorder; neuroinflammation; neuropathology; novel; novel therapeutic intervention; prevent; tau Proteins; tau-1

ABSTRACT The vast majority of therapeutic interventions targeting Alzheimer's disease (AD) until now have focused on monotherapies to alter a single neuropathology. Unfortunately, all these approaches have failed to meet the clinical endpoint of significantly slowing or reversing cognitive decline in AD subjects. This emphasizes the urgent need for novel therapeutic interventions to reduce several AD neuropathologies simultaneously. Inflammation is pervasive to many neurological disorders, yet no clinical trial has demonstrated the efficacy of anti-inflammatory agents for AD. Our research group is particularly interested in drugs that lower both systemic and central inflammation aiming at preventing or slowing down the clinical progression of AD. Our most promising compound is the immunomodulator, anti-cancer agent lenalidomide, which is one of the very few pleiotropic agents that both lowers the expression of pro-inflammatory (e.g. TNFα, IL-6, IL-8), and increases the expression of anti-inflammatory cytokines (e.g. IL-10), to modulate both innate and adaptive immune responses. Capitalizing on our experience from a previous clinical trial with an analog and our animal data, in the current project we aim to test the central hypothesis that lenalidomide reduces AD-associated neuroinflammation and neuropathologies, which might result in improved cognitive performances. For this, we designed a Phase Ib-IIa, proof-of-mechanism, placebo-controlled clinical study on single and multiple domain amnestic MCI subjects administered 10 mg/day lenalidomide for 12 months. Because lenalidomide has never been tested in the context of AD, we will monitor carefully the safety and tolerability in MCI patients. To demonstrate the engagement of lenalidomide in study subjects, we will measure inflammatory markers in the periphery every 3 months. We will measure cognitive performance via MCI-sensitive tests. In addition, we will assess target engagement (CSF markers) at the completion of dosing. This is highly significant because, if successful, lenalidomide will become one of the very few compounds capable of lowering several neuropathological features associated with AD. Furthermore, the major advantage of lenalidomide is that the drug I already FDA-approved for cancer treatment, thus it could rapidly be repurposed in a Phase IIb study.

抽象的 到目前为止，针对阿尔茨海默氏病（AD）的绝大多数治疗干预措施一直集中在 改变单一神经病理学的单层。不幸的是，所有这些方法都无法满足 AD受试者认知能力下降的临床终点显着放缓或逆转。这强调了 迫切需要新的热干预措施，以简单地减少几种AD神经病理学。 炎症普遍于许多神经系统疾病，但没有临床试验证明效率 AD的抗炎剂。我们的研究小组对降低两者的药物特别感兴趣 旨在防止或减缓AD临床进展的系统性和中枢炎症。我们的 最有前途的化合物是免疫调节剂，抗癌剂莱纳程胺，这是一种 很少有降低促炎性表达（例如TNFα，IL-6，IL-8）和 增加抗炎细胞因子的表达（例如IL-10），以调节先天和适应性 免疫反应。 利用我们以前的临床试验的经验，具有模拟和动物数据， 当前的项目我们旨在测试中心假设，即列纳莱度胺会减少与广告相关的 神经炎症和神经病理学，这可能会改善认知性能。为此，我们 设计了IB-IIA期，机械验证，安慰剂对照的单个领域和多个领域的临床研究 Amnestic MCI受试者施用了10 mg/天的列纳奈度胺12个月。因为那纳利度胺从来没有 我们在AD的背景下进行了测试，我们将仔细监测MCI患者的安全性和耐受性。到 证明了Lenalidomide在研究对象中的参与，我们将测量 每3个月外围一次。我们将通过对MCI敏感的测试来测量认知性能。此外，我们将 剂量完成时评估目标参与（CSF标记）。这是非常重要的，因为如果 成功的，列纳莱度胺将成为少数能够降低几种的化合物之一 与AD相关的神经病理学特征。此外，Lenalidomide的主要优势是 药物I已经接受了FDA批准用于癌症治疗，因此可以在IIB期研究中迅速重新使用。