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.

项目摘要/摘要 PTI-125是一种新的小分子阿尔茨海默病(AD)候选治疗药物，具有 新颖的作用靶点和作用机制。PTI-125结合并逆转改变的 阻止β42‘与S紧密结合的支架蛋白丝蛋白A的构象 以及通过α7-烟碱型乙酰胆碱受体(α7nAChR)和Aβ42‘S传递的毒性信号 Toll样受体4(TLR4)的异常激活。因此，通过恢复FLNA的原生形状 通过阻断这两个毒性级联反应，PTI-125可减少两种tau蛋白的过度磷酸化 和神经炎。下游影响包括减少神经原纤维损伤和 淀粉样蛋白沉积，提示疾病改变，并改善突触可塑性和 α7nAChR、NMDAR和胰岛素受体的功能提示有症状 进步。我们将寻求症状改善的标签声明，而不是 更难声称疾病修改，因此将在#年进行临床研究 轻至中度AD。在美国的IND下，第一次人类临床试验显示没有药物- 相关不良反应(AEs)和剂量比例药代动力学(PK)。我们的第一个- 对轻至中度AD患者的患者临床试验显示， 脑脊液中的P-tau、T-tau、神经颗粒素和神经丝轻链，以及5-15%的减少 神经炎性标志物。我们刚刚启动了一项为期1个月的盲法临床试验 用两次剂量复制这些显著的生物标记物效应，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名患者， 目前的提案要求提供与扩大试验规模相关的资金。使用 生物标记物数据复制，在认知测量中潜在的影响大小，PTI-125 将在第三阶段临床试验和合作努力中处于有利地位。