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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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是一种新型的小分子阿尔茨海默氏病（AD）治疗候选者新颖的目标和作用机理。 PTI-125绑定并逆转了变化脚手架蛋白丝A（FLNA）的构象，以防止Aβ42的紧密结合通过α7-NICOTINIC乙酰胆碱受体（α7NACHR）以及Aβ42的毒性信号传导 Toll样受体4（TLR4）的异常激活。因此，通过恢复FLNA的本地形状 PTI-125阻止了这两个有毒的级联反应，降低了两种tau高磷酸化和神经炎症。下游效应包括降低的神经纤维病变和淀粉样蛋白沉积物，提示疾病修饰，并改善突触可塑性和 α7NACHR，NMDAR和胰岛素受体的功能，表明有症状改进。我们将寻求症状改善的标签声明，而不是对疾病的修改更加困难，因此将在轻度至中度广告。在美国印第安纳州，第一个人类临床试验显示没有药物相关的不良反应（AES）和剂量比例药代动力学（PK）。我们的第一个轻度至中度AD患者的患者临床试验显示，降低了20-34％ CSF P-TAU，T-TAU，神经植物和神经丝轻链以及5-15％的降低神经炎症标记。我们刚刚开始了1个月的盲目临床试验用两种剂量复制这些引人注目的生物标志物效应，并将它们与探索性认知测量值。该临床试验已从36例增加到60例当前的提案要求与此增加的试验规模相关的资金。和复制生物标志物数据，并有可能在认知度量中效应大小，PTI-125 对于第三阶段临床试验和合作努力，将既可以很好地定位。