Additional bioanalytical, dose analysis and DSMB costs for PTI-125 development

PTI-125 开发的额外生物分析、剂量分析和 DSMB 成本

基本信息

批准号：
9524402
负责人：
Lindsay H Burns
金额：
$ 14.17万
依托单位：
CASSAVA SCIENCES, INC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9524402
关键词：
Administrative Supplement Affinity Age Alzheimer&apos s Disease Amyloid Autopsy Binding Biodistribution Biological Availability Blood Blood Pressure Canis familiaris Chemistry Chronic Clinical Clinical Trials Clinical Trials Data Monitoring Committees Data Deposition Development Disease Documentation Dose Drug or chemical Tissue Distribution Electrocardiogram Employee Enrollment Female Frequencies Functional disorder Goals Grant Heart Rate Hematology Hepatocyte Human Human Resources Impairment Inflammation Inflammatory Insulin Receptor Label Methods Modification Molecular Conformation Mus Neurofibrillary Tangles Nicotinic Receptors No-Observed-Adverse-Effect Level Oral Pathologic Patients Pharmaceutical Preparations Pharmacology Study Phase Phenotype Placebos Plasma Rattus Recovery Recruitment Activity Regulation Reporting Safety Sampling Scaffolding Protein Shapes Signal Transduction Site Small Business Innovation Research Grant Synaptic plasticity TLR4 gene Testing Therapeutic Time Toxic effect Toxicology Urinalysis Urine Validation Work alpha-bungarotoxin receptor base brain tissue clinical development clinical lot cognitive function cost cytokine efficacy study exposed human population filamin healthy volunteer improved male metabolic profile mouse model neuroinflammation novel novel strategies preclinical study prevent receptor respiratory safety study small molecule symptomatic improvement synaptic function tau Proteins therapeutic candidate volunteer

项目摘要

PTI-125 is a novel small molecule 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. An IND has been filed and the first-inhuman trial will start August 9, 2017. The current administrative supplement proposal includes additional development work related to this first-in-human clinical trial and the ongoing interim 3-month oral toxicity study in dog. These activities include 1) the Data and Safety Monitoring Board, 2) the bioanalytical method adaptation and validation for use in human plasma, 3) the bioanalysis of plasma samples from the 3-month dog study, 4) the dose analysis for the dosing solutions used in the 3-month dog study, required by GLP regulations, and 5) the cost of the recently completed independent audit of the previous SBIR grant that closed Dec. 31, 2016. All these activities are necessary for the continued development of this novel AD therapeutic candidate.

PTI-125是一种新型的小分子AD治疗候选者，具有新的靶标和作用机理。 PTI-125结合并逆转了变化的构象脚手架蛋白丝蛋白A（FLNA），以防止Aβ42与有毒信号的紧密结合通过α7-NICOTINIC乙酰胆碱受体（α7NACHR）以及Aβ42的异常 Toll样受体4（TLR4）的激活。因此，通过恢复Flna的原生形状和阻止这两个有毒的级联反应，PTI-125均降低了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，而不是疾病改变更加困难。已经提交了印第安人审判将于2017年8月9日开始。当前的行政补充提案包括其他开发工作与该人类的第一个临床试验和正在进行的临时3个月有关研究狗。这些活动包括1）数据和安全监控委员会，2）生物分析方法适应和验证用于人血浆，3） 3个月狗研究中血浆样品的生物分析，4） 3个月研究中使用的剂量溶液，GLP法规要求，5）最近完成的对先前SBIR赠款的独立审计的成本 2016年12月31日。所有这些活动对于继续发展都是必要的新颖的广告治疗候选人。