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: 10184198
• 负责人: Eti Yoles
• 金额: $ 198.46万
• 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/10184198
• 关键词: Adverse effects; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid; Amyloidosis; Antibodies; Autoimmune; Behavior assessment; Biological; Biological Markers; Blood; Blood Circulation; Brain; Brain Pathology; Cells; Clinical; Clinical Research; Clinical Trials; Cognitive; Collection; Data; 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; Institutes; Israel; Laboratories; Lead; Life; Lymphocyte; Magnetic Resonance Imaging; Maintenance; Measures; Microglia; Modification; Monoclonal Antibodies; Nature; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurofibrillary Tangles; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Persons; Pharmaceutical Preparations; Pharmacology Study; Phase; Physiological; Physiology; Randomized; Regimen; Research; Research Design; Risk; Role; Safety; Science; Serum; Structure; System; Tauopathies; Therapeutic; antibody engineering; base; 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; macrophage; monocyte; mouse model; neuroinflammation; neuron loss; neuropsychiatry; novel; novel therapeutic intervention; novel therapeutics; pharmacodynamic model; pharmacokinetics and pharmacodynamics; phase 1 study; phase 2 study; placebo controlled study; potential biomarker; pre-clinical; programmed cell death ligand 1; programmed cell death protein 1; repaired; restoration; 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 阿尔茨海默氏病（AD）和相关痴呆症是异质的多因素疾病，其中许多疾病 涉及疗法机制，最终导致神经元死亡和认知功能的丧失。 进行了许多尝试以阻止该疾病的尝试，或通过直接针对的疾病来减慢其进展 主要标志 - 淀粉样变性，病理神经原纤维缠结和局部神经炎症；没有 显示迄今为止的主要临床改进。 一种用于治疗AD和其他神经退行性疾病的新颖的范式转移方法是利用 身体自己的维护和维修机制。这种常见的途径包括全身免疫 响应已显示出对脑维护，可塑性和修复的支持作用。 由以色列魏兹曼科学学院和 在二十年的时间里，他人的支持，已经阐明了我们对复杂关系的理解 在大脑和周围免疫系统之间，并证明了受益的潜力 利用脑免疫关系来治疗AD和神经变性。 Immunobrain检查点（IBC）提议使用其新颖 免疫疗法方法是通过抑制性瞬态阻断靶向周围免疫系统 免疫检查点，编程死亡配体1（PD-L1）。临床前药物研究 AD和痴呆症的各种小鼠模型表明，单抗体给药足以 唤起一系列事件，导致脑病理学和认知恢复/维持的减少 能力。这些研究表明，抗PD-L1抗体的治疗性疾病修饰作用 给药需要间歇性重复注射短寿命抗体，两次之间的间隔很长 连续注射。这些观察结果为IBC独特工程抗体IBC-AB002和 用于拟议的FIH临床研究设计。 IBC提议进行一项FIH研究，以评估安全性，耐受性和药代动力学以及 IBC-AB002在早期广告中的初步探索活动。计划的研究将是 随机，双盲的，安慰剂对照的研究，升级多种静脉注射剂量，结合了单一和 多升剂量成分。该研究将具有自适应设计，将在2中进行 部分。部分A将包括单次剂量（SAD）研究，B部分将继续给予A部分的剂量 受试者是一项多重剂量（SAD）研究，管理部门之间的间隔12周。数据 这项研究的出现将用于支持有关IBC-进一步临床发展的决策 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 第2阶段研究。