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 阿尔茨海默氏病（AD）和相关痴呆是异质性多因素疾病，其中许多疾病是遗传性的。 涉及致病机制，最终导致神经元死亡和认知功能丧失。 人们进行了许多尝试来阻止疾病，或通过直接靶向其代谢产物来减缓其进展。 主要特征-淀粉样变性、病理性神经纤维缠结和局部神经炎症; 到目前为止，临床症状有了很大改善。 治疗AD和其他神经退行性疾病的一种新的范式转变方法是利用 身体自身的维护和修复机制。在这些共同的途径是系统性免疫 反应，已被证明对大脑的维护，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， 大脑和外周免疫系统之间的联系，并已证明 利用脑免疫关系治疗AD和神经变性。 ImmunoBrain Checkpoint（IBC）建议使用其新的免疫抑制剂在AD中进行首次人体（FIH）研究。 通过瞬时阻断抑制性免疫应答而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）。临床前药理学研究， AD和痴呆的各种小鼠模型揭示了单一抗体给药足以 诱发一连串事件，导致脑病理学减轻和认知功能恢复/维持， 能力.这些研究表明，抗PD-L1抗体的治疗性疾病改善作用 施用需要间歇性重复注射短寿命抗体， 连续注射。这些观察结果为IBC独特的工程抗体IBC-Ab 002奠定了基础， 用于拟定的FIH临床研究设计。 IBC建议进行FIH研究，以评估安全性、耐受性和药代动力学， IBC-Ab 002在早期AD患者中的初步探索活性。计划中的研究将是一项 一项随机、双盲、安慰剂对照研究，研究了多次IV给药递增，单次给药和 多个-递增剂量组件。该研究将采用适应性设计，并将在2 零件. A部分将包括单次给药递增（SAD）研究，B部分将继续A部分给药 受试者作为多次递增剂量（SAD）研究，给药间隔为12周。数据 本研究中出现的结果将用于支持有关IBC进一步临床开发的决策- Ab 002，最重要的是剂量的设定，剂量间隔和生物标志物收集策略，用于任何未来 II期研究。

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.