Increasing size of Phase 2b clinical trial to 60 patients

2b 期临床试验规模扩大至 60 名患者

• 批准号: 10018305
• 负责人: Lindsay H Burns
• 金额: $ 37.45万
• 依托单位: CASSAVA SCIENCES, INC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018305
• 关键词: Address; Adverse effects; Affinity; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Alzheimer’s disease biomarker; Amyloid; Binding; Bioavailable; Biological Markers; Blinded; Brain; CD14 gene; Clinical; Clinical Research; Clinical Trials; Cognition; Cognitive; Data; Deposition; Disease; Disease Progression; Dose; Drug Kinetics; Funding; Goals; Human Resources; Inflammatory; Insulin Receptor; Label; Light; Link; Measures; Mediating; Modification; Molecular Conformation; Monitoring Clinical Trials; Nature; Nerve Degeneration; Neurofibrillary Tangles; Oral; Outcome Measure; Participant; Patients; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Phosphotransferases; Placebos; Plasma; Positioning Attribute; Request for Proposals; Scaffolding Protein; Shapes; Signal Pathway; Signal Transduction; Synaptic plasticity; TLR4 gene; Toll-like receptors; Work; alpha-bungarotoxin receptor; clinical research site; cytokine; design; filamin; first-in-human; hyperphosphorylated tau; improved; member; neurofilament; neurogranin; neuroinflammation; novel; open label; power analysis; prevent; randomized placebo controlled trial; receptor; response; safety study; small molecule; small molecule therapeutics; symptomatic improvement; synaptic function; tau Proteins; tau-1; therapeutic candidate

Project Summary/Abstract PTI-125 is a novel small molecule Alzheimer’s disease (AD) therapeutic candidate with a novel target and mechanism of action. PTI-125 binds and reverses an altered conformation of the scaffolding protein filamin A (FLNA) to prevent Aβ42’s tight binding to and toxic signaling via the α7-nicotinic acetylcholine receptor (α7nAChR) as well as Aβ42’s aberrant activation of toll-like receptor 4 (TLR4). Hence, by restoring FLNA’s native shape and blocking these two toxic cascades, PTI-125 reduces both tau hyperphosphorylation and neuroinflammation. Downstream effects include reduced neurofibrillary lesions and amyloid deposits, suggesting disease modification, and improved synaptic plasticity and function of α7nAChR, NMDAR and insulin receptors, suggesting symptomatic improvement. We will pursue a label claim of symptomatic improvement instead of the more difficult claim of disease modification and will therefore conduct clinical studies in mild-to-moderate AD. Under a US IND, the first-in-human clinical trial showed no drug- related adverse effects (AEs) and dose proportional pharmacokinetics (PK). Our first-in- patient clinical trial in mild-to-moderate AD patients demonstrated 20-34% reductions in CSF P-tau, T-tau, neurogranin and neurofilament light chain, as well as 5-15% reductions neuroinflammatory markers. We have just initiated a 1-month blinded clinical trial to replicate these striking biomarker effects with two doses and correlate them with exploratory cognitive measures. This clinical trial has increased from 36 to 60 patients, and the current proposal requests funds associated with this increased trial size. With biomarker data replicated and potentially an effect size in cognitive measures, PTI-125 will be well positioned both for Phase 3 clinical trials and partnering efforts.

项目总结/摘要 PTI-125是一种新的小分子阿尔茨海默病（AD）治疗候选药物， 新的靶点和作用机制。PTI-125结合并逆转改变的 支架蛋白细丝蛋白A（FLNA）的构象，以防止Aβ42与 以及通过α7-烟碱乙酰胆碱受体（α 7 nAChR）和Aβ42的毒性信号 Toll样受体4（TLR 4）的异常激活。因此，通过恢复FLNA的原始形状， 阻断这两个毒性级联反应，PTI-125可以降低tau蛋白的过度磷酸化， 和神经炎症。下游效应包括减少神经系统病变， 淀粉样蛋白沉积，提示疾病修饰，改善突触可塑性， α 7 nAChR、NMDAR和胰岛素受体的功能，提示有症状 改进.我们将追求症状改善的标签声明，而不是 更难的疾病改变的索赔，因此将进行临床研究， 轻度至中度AD。根据美国IND，首次人体临床试验显示没有药物- 相关不良反应（AE）和剂量比例药代动力学（PK）。我们的第一个- 在轻度至中度AD患者中进行的患者临床试验显示， CSF P-tau、T-tau、神经颗粒蛋白和神经丝轻链，以及5-15%降低 神经炎症标记物。我们刚刚启动了一项为期一个月的盲法临床试验， 用两种剂量复制这些惊人的生物标志物效应，并将它们与 探索性认知测量。这项临床试验从36名患者增加到60名， 目前的提案要求提供与扩大审判规模有关的资金。与 生物标志物数据重复，可能是认知测量的效应量，PTI-125 将为3期临床试验和合作努力做好准备。