First-in-Human (Phase 1) Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of IBC-Ab002 in Persons with Early Alzheimer's Disease (AD)

评估 IBC-Ab002 在早期阿尔茨海默病 (AD) 患者中的安全性、耐受性和药代动力学的首次人体（第一阶段）研究

• 批准号: 10696232
• 负责人: Eti Yoles
• 金额: $ 128.04万
• 依托单位: IMMUNOBRAIN CHECKPOINT INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10696232
• 关键词: Adverse effects; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid; Amyloidosis; Antibodies; Autoimmune; Behavior assessment; Biological; Biological Markers; Blood; Brain; Brain Pathology; Cells; Central Nervous System; Circulation; Clinical; Clinical Research; Clinical Trials; Cognitive; Collection; Data; Dementia; Disease; Dose; Double-Blind Method; Drug Kinetics; Electroencephalography; Equipment and supply inventories; Etiology; Event; Future; Homeostasis; Immune; Immune response; Immune system; Immunotherapy; Impaired cognition; Inflammation; Injections; Israel; Laboratories; Lead; Lymphocyte; Macrophage; Magnetic Resonance Imaging; Maintenance; Measures; Microglia; Modification; Monoclonal Antibodies; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Persons; Pharmaceutical Preparations; Pharmacology Study; Phase; Physiological; Physiology; Randomized; Regimen; Research; Research Design; Role; Safety; Science; Serum; Structure; System; Tauopathies; Therapeutic; antibody engineering; cancer immunotherapy; cancer therapy; clinical development; clinical outcome measures; cognitive ability; cognitive function; design; disease heterogeneity; dosage; first-in-human; human study; immune checkpoint; immune system function; improved; inflammatory milieu; monocyte; mouse model; neuroinflammation; neuron loss; neuropsychiatry; novel; novel therapeutic intervention; novel therapeutics; pharmacodynamic model; pharmacokinetics and pharmacodynamics; phase 2 study; placebo controlled study; potential biomarker; pre-clinical; programmed cell death ligand 1; programmed cell death protein 1; repaired; restoration; risk mitigation; safety assessment; scavenger receptor; study population; tau Proteins; trafficking

ABSTRACT Alzheimer’s disease (AD) and related dementias are heterogeneous multifactorial diseases, in which many etiopathogenic mechanisms are involved, eventually leading to neuronal death and loss of cognitive function. Numerous attempts are made to arrest the disease, or to slow down its progression by directly targeting its major hallmarks - amyloidosis, pathological neurofibrillary tangles, and local neuroinflammation; none have shown major clinical improvement to date. A novel, paradigm-shifting approach for treating AD and other neurodegenerative disorders is to harness the body’s own mechanisms of maintenance and repair. Among such common pathways is the systemic immune response, which has been shown to display supportive effects on brain maintenance, plasticity and repair. Studies initiated by the laboratory of Prof. Michal Schwartz at the Weizmann Institute of Science in Israel and supported by others, over two decades, have illuminated our understanding of the intricate relationships between the brain and the peripheral immune system, and have demonstrated the potential for benefit of leveraging the brain-immune relationship for the treatment of AD and neurodegeneration. ImmunoBrain Checkpoint (IBC) is proposing to conduct a first-in-human (FIH) study in AD using its novel immunotherapy approach of targeting the peripheral immune system by transient blockade of the inhibitory immune checkpoint, Programmed death-ligand 1 (PD-L1). The pre-clinical pharmacological studies with various mouse models for AD and dementia revealed that single antibody administration was sufficient to evoke a cascade of events leading to a reduction in brain pathology and restoration/maintenance of cognitive abilities. These studies indicated that the therapeutic disease-modifying effect of anti-PD-L1 antibody administration requires intermittent repeated injections of a short-lived antibody with long intervals between successive injections. These observations set the basis for IBC’s uniquely engineered antibody, IBC-Ab002, and for the proposed FIH clinical study design. IBC is proposing to conduct a FIH study to evaluate the safety, tolerability and pharmacokinetics and preliminary exploratory activity of IBC-Ab002 in persons with Early AD. The planned study will be a randomized, double-blind, placebo-controlled study of escalating multiple IV doses, combining Single- and Multiple- Ascending Dose components. The study will have an adaptive design and will be carried out in 2 parts. Parts A will comprise a Single-Ascending-Dose (SAD) study and Part B will continue dosing of Part A subjects as a Multiple-Ascending Dose (SAD) study, with 12 weeks interval between administrations. Data emerging from this study will be used to support decisions regarding further clinical development of IBC- Ab002, most importantly the setting of dose, dose interval and biomarker collection strategy for any future Phase 2 studies.

抽象的 阿尔茨海默病 (AD) 和相关痴呆是异质性多因素疾病，其中许多因素 涉及致病机制，最终导致神经元死亡和认知功能丧失。 人们做出了许多尝试来阻止这种疾病，或者通过直接针对其疾病来减缓其进展。 主要特征 - 淀粉样变性、病理性神经原纤维缠结和局部神经炎症； 迄今为止显示出重大的临床改善。 治疗 AD 和其他神经退行性疾病的一种新颖的、范式转变的方法是利用 人体自身的维护和修复机制就是系统免疫系统。 反应，已被证明对大脑维护、可塑性和修复具有支持作用。 以色列魏茨曼科学研究所 Michal Schwartz 教授实验室发起的研究 二十多年来，在其他人的支持下，阐明了我们对错综复杂关系的理解 大脑和周围免疫系统之间的联系，并已证明了潜在的益处 利用大脑-免疫关系来治疗 AD 和神经退行性疾病。 免疫脑检查点 (IBC) 提议利用其新颖的药物进行 AD 的首次人体 (FIH) 研究 通过暂时阻断抑制作用来靶向外周免疫系统的免疫治疗方法 免疫检查点，程序性死亡配体1（PD-L1）的临床前药理学研究。 各种 AD 和痴呆症小鼠模型表明，施用单一抗体就足以 引发一系列事件，导致大脑病理减少和认知恢复/维持 这些研究表明抗 PD-L1 抗体具有缓解疾病的治疗作用。 给药需要间歇性重复注射短效抗体，注射间隔很长 这些观察结果为 IBC 独特的工程抗体 IBC-Ab002 和 用于拟议的 FIH 临床研究设计。 IBC 提议进行 FIH 研究，以评估安全性、耐受性和药代动力学， IBC-Ab002 在早期 AD 患者中的初步探索活动 计划的研究将是一项。 随机、双盲、安慰剂对照研究，增加多次静脉注射剂量，结合单次和 多剂量递增部分该研究将采用适应性设计，并将分 2 小时进行。 A 部分将包括单次递增剂量 (SAD) 研究，B 部分将继续服用 A 部分。 受试者作为多剂量递增 (SAD) 研究，给药间隔 12 周。 这项研究的结果将用于支持有关 IBC 进一步临床开发的决策 Ab002，最重要的是任何未来的剂量、剂量间隔和生物标志物收集策略的设定 第二阶段研究。