A randomized, placebo-controlled, double-blind study to evaluate safety and efficacy of NDX-1017 treatment in Alzheimer's dementia patients

摘要 阿尔茨海默病（AD）是神经病学中最大的未满足的医疗需求。美国的患者人群， 由于社会老龄化，艾滋病在全球范围内已达到流行病的程度，但没有有效的治疗方法。找到 提供有意义的症状缓解、减缓进展和恢复细胞功能的疗法， 需要系统的方法来修复受损的细胞，重建突触，并恢复大脑的稳态。 神经营养因子活性的调节提供了一种对抗神经变性和解决 病理学的多个方面，具有改善症状和改变疾病进程的潜力 进展NDX-1017是Athira Pharma，Inc.开发的主要临床候选药物，这增强了 肝细胞生长因子（HGF）系统的活性，一种有效的神经营养和再生系统。体外 研究表明，NDX-1017可激活目标HGF系统并诱导下游效应， 促进脊髓和突触发生，增强长时程增强，保护神经元免受氧化损伤， 应力在动物研究中，NDX-1017已被证明可以恢复突触丢失，再生神经元，并逆转 认知和功能障碍，在6-OHDA模型的神经变性，以及东莨菪碱和老年 痴呆的动物模型。此外，NDX-1017在伽马功率下诱导急性和持续诱导 在野生型和APP/PS1小鼠中通过定量脑电图（qEEG）测量，表明CNS 穿透和目标接合。NDX-1017的持续qEEG效应提示潜在疾病 通过大脑结构的改变来改变。来自I期随机、双盲、安慰剂对照研究 研究（NCT 03298672）显示，NDX-1017在一系列治疗剂量下安全且耐受良好。 相关剂量（2-90 mg）。药代动力学（PK）特征在动物间具有良好的一致性 物种（即，大鼠、狗、小鼠）和人类。重要的是，通过qEEG观察到的功能效应，即急性和 在人体中以相当的PK暴露量复制了伽马功率持续诱导。AD中 NDX-1017已被证明可以减少通过事件相关电位（ERP）测量的P300潜伏期。 qEEG和ERP将共同作为翻译生物标志物，指导早期临床剂量优化 审判拟定的II期研究旨在评价26周NDX-1017的临床疗效和安全性 治疗轻度至中度AD痴呆患者。此外，该研究旨在证明 ERP生物标志物的翻译及其在认知结果中的预测潜力， 科学界正在寻找替代终点，以加速AD的临床开发。最后，治疗 将测量对神经变性和AD病理学的CSF和血浆生物标志物的影响， 了解NDX-1017改变疾病病理的潜力。该研究将提供有关临床的关键信息， NDX-1017的疗效、安全性、PK、药效学和药理学。

Abstract Alzheimer’s disease (AD) is the largest unmet medical need in neurology. The patient population in the US and globally is reaching epidemic proportions due to aging societies, yet no effective treatment is available. To find a therapy that provides meaningful symptomatic relief, slows progression, and restores cellular functions, a systemic approach is needed to repair damaged cells, rebuild synapses, and restore homeostasis in the brain. Modulation of neurotrophic factor activity presents a novel strategy to counteract neurodegeneration and address multiple aspects of pathology, with the potential to improve symptoms and alter the course of disease progression. NDX-1017 is the lead clinical candidate developed by Athira Pharma, Inc., which enhances the activity of the hepatocyte growth factor (HGF) system, a potent neurotrophic and regenerative system. In in vitro studies, NDX-1017 has been shown to activate the target HGF system and induce downstream effects to promote spinogenesis and synaptogenesis, enhance long-term potentiation, and protect neurons from oxidative stress. In animal studies, NDX-1017 has been shown to restore synaptic loss, regenerate neurons, and reverse cognitive and functional impairment, in 6-OHDA model of neurodegeneration, as well as scopolamine and aged animal models of dementia. Additionally, NDX-1017 induces both acute and sustained induction in gamma power measured by quantitative electroencephalogram (qEEG) in wild-type and APP/PS1 mice, indicating CNS penetration and target engagement. The sustained qEEG effect of NDX-1017 suggests potential disease modification via structural changes in the brain. From the Phase 1 randomized, double-blind, placebo-controlled study (NCT03298672), NDX-1017 has been shown to be safe and well-tolerated at a range of therapeutically relevant doses (2-90 mg). The pharmacokinetics (PK) profile has demonstrated good consistency across animal species (i.e., rat, dog, mouse) and humans. Importantly, the functional effects observed by qEEG, i.e. acute and sustained induction in gamma power, have been replicated in humans at comparable PK exposure. In AD patients, NDX-1017 has been shown to reduce P300 latency measured by event-related potential (ERP). Together, qEEG and ERP will serve as translational biomarkers to guide dose optimization in early stage clinical trials. The proposed Phase 2 study is designed to evaluate the clinical efficacy and safety of 26-week NDX-1017 treatment in mild-to-moderate AD dementia patients. Additionally, the study is designed to demonstrate the translation of ERP biomarker and its predictive potential in cognitive outcomes, contributing knowledge to the scientific community in search of surrogate endpoints to accelerate clinical development in AD. Finally, treatment effects on CSF and plasma biomarkers of neurodegeneration and AD pathologies will be measured to understand NDX-1017’s potential to alter disease pathology. The study will provide critical information on clinical efficacy, safety, PK, pharmacodynamics, and pharmacology of NDX-1017.