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

摘要 阿尔茨海默病(AD)和相关痴呆是一种异质性的多因素疾病，其中许多 发病机制涉及，最终导致神经元死亡和认知功能丧失。 许多人试图阻止这种疾病，或通过直接针对其靶向来减缓其进展 主要特征-淀粉样变性、病理性神经纤维缠结和局部神经炎；没有 到目前为止，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的、范式转换的方法是利用 身体自身的维护和修复机制。在这些常见的途径中，有一种是系统免疫。 反应，已被证明对大脑维护、可塑性和修复具有支持作用。 由以色列魏兹曼科学研究所米哈尔·施瓦茨教授的实验室发起的研究 在其他人的支持下，二十多年来，阐明了我们对错综复杂的关系的理解 在大脑和外周免疫系统之间，并已证明了潜在的好处 利用脑免疫关系治疗阿尔茨海默病和神经变性。 免疫脑检查点(IBC)正在提议在AD中进行一项首次人类(FIH)研究，使用其新的 一过性阻断抑制物靶向外周免疫系统的免疫治疗途径 免疫检查点，程序性死亡配体1(PD-L1)。临床前药理研究 各种阿尔茨海默病和痴呆的小鼠模型表明，单一抗体注射足以 引发一系列事件，导致大脑病理减少和认知能力的恢复/维持 超能力。这些研究表明，抗PD-L1抗体具有治疗疾病的作用 给药需要间歇重复注射短命抗体，间隔时间较长 连续注射。这些观察为IBC独特的工程抗体IBC-Ab002奠定了基础，并 用于拟议的FIH临床研究设计。 IBC建议进行一项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性计划中的研究将是一项 递增多次静脉注射的随机、双盲、安慰剂对照研究，结合单次和 多个上升剂量组分。这项研究将采用适应性设计，并将在2年内进行 零件。A部分将包括单次递增剂量(SAD)研究，B部分将继续A部分的剂量 受试者为多次递增剂量(SAD)研究，两次给药间隔12周。数据 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，最重要的是设定任何未来的剂量、剂量间隔和生物标记物收集策略 第二阶段研究。

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.