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

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 阿尔茨海默病（AD）是美国和美国神经病学领域最大的未满足的医疗需求。 由于社会老龄化，该疾病在全球范围内已达到流行程度，但尚无有效的治疗方法。 一种能够有效缓解症状、减缓病情进展并恢复细胞功能的疗法， 需要一种系统性方法来修复受损细胞、重建突触并恢复大脑的稳态。 神经营养因子活性的调节提出了一种对抗神经退行性变和解决问题的新策略 病理学的多个方面，有可能改善症状和改变病程 NDX-1017 是 Athira Pharma, Inc. 开发的主要临床候选药物，可增强进展。 肝细胞生长因子（HGF）系统的活性，这是一种有效的体外神经营养和再生系统。 研究表明，NDX-1017 已被证明可以激活目标 HGF 系统并诱导下游效应 促进棘发生和突触发生，增强长时程增强，并保护神经元免受氧化 在动物研究中，NDX-1017 已被证明可以恢复突触损失、再生神经元并逆转压力。 认知和功能障碍，在神经变性的 6-OHDA 模型中，以及东莨菪碱和老年人 此外，NDX-1017 还可诱导急性和持续的伽玛能量诱导。 通过野生型和 APP/PS1 小鼠的定量脑电图 (qEEG) 测量，表明 CNS NDX-1017 的持续 qEEG 效应表明潜在的疾病。 通过大脑结构变化进行修改 从第一阶段开始，随机、双盲、安慰剂对照。 研究 (NCT03298672)，NDX-1017 已被证明在一系列治疗中是安全的且耐受性良好 相关剂量（2-90 mg）的药代动力学（PK）曲线在动物中表现出良好的一致性。 重要的是，qEEG 观察到的功能影响，即急性和人类。 伽玛能量的持续诱导，已在类似 PK 暴露的人体中得到复制。 对于患者，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 将共同作为转化生物标志物，指导早期临床的剂量优化 拟议的 2 期研究旨在评估 26 周 NDX-1017 的临床疗效和安全性。 此外，该研究旨在证明对轻度至中度 AD 痴呆患者的治疗。 ERP 生物标志物的翻译及其在认知结果中的预测潜力，为认知贡献知识 科学界正在寻找替代终点以加速 AD 的临床开发。最后是治疗。 将测量神经退行性变和 AD 病理对 CSF 和血浆生物标志物的影响 NDX-1017 改变疾病病理学的潜力该研究将提供临床关键信息。 NDX-1017 的功效、安全性、PK、药效学和药理学。