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

一项随机、安慰剂对照、双盲研究，旨在评估 NDX-1017 治疗阿尔茨海默氏痴呆患者的安全性和有效性

• 批准号: 10261435
• 负责人: Charles Bernick
• 金额: $ 448.97万
• 依托单位: ATHIRA PHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10261435
• 关键词: APP-PS1; Acute; Address; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-42; Animal Model; Animals; Behavior; Biological Markers; Brain; Canis familiaris; Caregiver Burden; Cell physiology; Clinical; Cognition; Cognitive; Communities; Data; Dementia; Development; Disease; Disease Progression; Dose; Double-Blind Method; Drug Kinetics; Elderly; Electroencephalogram; Epidemic; Equipment and supply inventories; Event-Related Potentials; HGF gene; Homeostasis; Human; Impaired cognition; In Vitro; Injections; Interview; Knowledge; Lead; Light; Liquid substance; Long-Term Potentiation; Measures; Medical; Modeling; Modification; Mus; Natural regeneration; Nerve Degeneration; Neurology; Neurons; Oral; Outcome; Oxidative Stress; Oxidopamine; P300 Event-Related Potentials; Pathology; Patients; Penetration; Pharmacodynamics; Pharmacology; Phase; Phase I Clinical Trials; Placebos; Plasma; Prediction of Response to Therapy; Prevalence; Randomized; Rattus; Resources; Safety; Scopolamine; Single-Blind Study; Societies; Structure; Subcutaneous Injections; Surrogate Endpoint; Synapses; System; Testing; Therapeutic; Toxicology; Translations; Word Association Tests; aged; base; cell injury; clinical candidate; clinical development; clinical efficacy; cooperative study; design; disability; effective therapy; functional disability; impression; mental state; neurofilament; neurogranin; neuroinflammation; neuropsychiatry; neurotrophic factor; novel strategies; patient population; pharmacodynamic biomarker; phase 1 study; phase 2 study; phase I trial; phase II trial; placebo controlled study; potential biomarker; regenerative; repaired; small molecule; subcutaneous; symptomatic improvement; synaptogenesis; targeted biomarker; tau Proteins; tau-1; treatment duration; treatment effect; APP-PS1; Acute; Address; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-42; Animal Model; Animals; Behavior; Biological Markers; Brain; Canis familiaris; Caregiver Burden; Cell physiology; Clinical; Cognition; Cognitive; Communities; Data; Dementia; Development; Disease; Disease Progression; Dose; Double-Blind Method; Drug Kinetics; Elderly; Electroencephalogram; Epidemic; Equipment and supply inventories; Event-Related Potentials; HGF gene; Homeostasis; Human; Impaired cognition; In Vitro; Injections; Interview; Knowledge; Lead; Light; Liquid substance; Long-Term Potentiation; Measures; Medical; Modeling; Modification; Mus; Natural regeneration; Nerve Degeneration; Neurology; Neurons; Oral; Outcome; Oxidative Stress; Oxidopamine; P300 Event-Related Potentials; Pathology; Patients; Penetration; Pharmacodynamics; Pharmacology; Phase; Phase I Clinical Trials; Placebos; Plasma; Prediction of Response to Therapy; Prevalence; Randomized; Rattus; Resources; Safety; Scopolamine; Single-Blind Study; Societies; Structure; Subcutaneous Injections; Surrogate Endpoint; Synapses; System; Testing; Therapeutic; Toxicology; Translations; Word Association Tests; aged; base; cell injury; clinical candidate; clinical development; clinical efficacy; cooperative study; design; disability; effective therapy; functional disability; impression; mental state; neurofilament; neurogranin; neuroinflammation; neuropsychiatry; neurotrophic factor; novel strategies; patient population; pharmacodynamic biomarker; phase 1 study; phase 2 study; phase I trial; phase II trial; placebo controlled study; potential biomarker; regenerative; repaired; small molecule; subcutaneous; symptomatic improvement; synaptogenesis; targeted biomarker; tau Proteins; tau-1; treatment duration; treatment effect

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.

抽象的 阿尔茨海默氏病（AD）是神经病学中最大的未满足医疗需求。美国的患者人数 由于社会的衰老，全球正在达到流行比例，但没有有效的治疗方法。找到 一种可提供有意义的症状缓解，减慢进展并恢复细胞功能的疗法 需要全身方法来修复受损的细胞，重建突触并恢复大脑中的体内平衡。 神经营养因子活性的调节提出了一种应对神经变性的新策略 病理的多个方面，有可能改善症状并改变疾病的病程 进展。 NDX-1017是由Athira Pharma，Inc。开发的主要临床候选者，可增强 肝细胞生长因子（HGF）系统的活性，这是一种潜在的神经营养和再生系统。在体外 研究，NDX-1017已被证明会激活目标HGF系统，并引起下游效应 促进旋转生成和突触发生，增强长期增强并保护神经元免受氧化的影响 压力。在动物研究中，NDX-1017已被证明可以恢复突触损失，再生神经元和反向 在6-OHDA神经退行性模型中以及骨pol碱和老化中的认知和功能障碍 痴呆的动物模型。此外，NDX-1017诱导伽马功率急性和持续诱导 通过野生型和APP/PS1小鼠的定量脑电图（QEEG）测量，表明CNS 穿透和目标参与。 NDX-1017的持续QEEG效应表明潜在疾病 通过大脑的结构变化进行修改。从第1阶段随机，双盲，安慰剂对照 研究（NCT03298672），NDX-1017已被证明在一系列治疗范围内安全且耐受性良好 相关剂量（2-90 mg）。药代动力学（PK）剖面表现出跨动物的良好一致性 物种（即老鼠，狗，老鼠）和人类。重要的是，QEEG观察到的功能效应，即急性和 在可比较的PK暴露时，人类在人类中的持续诱导持续诱导。在广告中 患者NDX-1017已显示可减少通过事件相关电位（ERP）测量的P300潜伏期。 QEEG和ERP一起将用作翻译的生物标志物，以指导早期临床的剂量优化 试验。拟议的2阶段研究旨在评估26周NDX-1017的临床效率和安全性 在轻度至中度的AD痴呆症患者中进行治疗。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，为知识贡献了知识 科学界寻找替代终点，以加速AD的临床发展。最后，治疗 对神经退行性和AD病理的CSF和血浆生物标志物的影响将被测量为 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的功效，安全性，PK，药效学和药理学。