IND- and NDA-enabling toxicology studies for PTI-125, a novel small molecule for Alzheimer's disease

 描述（由申请人提供）：PTI-125是一种具有新靶点的新型化合物，旨在治疗和减缓阿尔茨海默病（AD）的进展。PTI-125通过与细丝蛋白A（FLNA）上的一个特定位点紧密结合而起作用，我们最近证明这种蛋白质对β淀粉样蛋白的毒性至关重要。β淀粉样蛋白1 -42（A β 42）通过结合和劫持α 7-烟碱乙酰胆碱受体（α 7 nAChR），破坏其正常功能并引起AD患者脑中发现的特征性缠结和斑块来发挥其毒性作用。我们最近表明，这种由A β 42发出的毒性信号需要FLNA的帮助，当A β 42结合该受体时，FLNA被招募与α 7 nAChR相互作用。A β 42通过α 7 nAChR的毒性信号传导还损害了对认知、记忆和神经元存活起关键作用的另外两种受体（NMDA受体和胰岛素受体）的功能。通过破坏FLNA -α 7 nAChR的结合，PTI-125防止A β 42的毒性作用并恢复这三种受体的正常功能。PTI-125还破坏了FLNA与toll样受体-4（TLR-4）（一种负责释放炎性细胞因子的受体）的类似关联;因此，PTI-125具有阻断AD脑中注意到的炎症的第二功能。PTI-125已分别通过致突变性和心脏毒性的艾姆斯和hERG试验（非GLP）。它很容易通过血脑屏障，估计有75%的口服生物利用度，并具有合理的候选药物半衰期。小鼠口服2个月是安全的。通过脑片培养实验，我们知道了脑内的有效浓度。PTI- 125准备开始拟议的IND使能研究，以确保临床试验前的安全性。在本提案中，我们的I期工作将包括非GLP剂量选择研究、更正式的PK/ADME工作、遗传毒性研究以及先前开发的分析和生物分析方法的GLP验证。除非在接近预期治疗剂量的剂量范围内出现非预期毒性，否则我们将继续进行II期工作范围：GLP安全性药理学以及支持首次人体研究和临床试验的4周和长期GLP毒理学研究 AD和NDA。

 DESCRIPTION (provided by applicant): PTI-125 is a novel compound with a novel target, designed to treat and slow the progression of Alzheimer's disease (AD). PTI-125 works by binding extremely tightly to a particular site on filamin A (FLNA), a protein we recently demonstrated to be critical to beta amyloid's toxicity. Beta amyloid1-42 (Aß42) exerts its toxic effects by binding and hijacking the a7-nicotinic acetylcholine receptor (a7nAChR), disrupting its normal function and causing the signature tangles and plaques found in brains of AD patients. We recently showed that this toxic signaling by Aß42 requires the help of FLNA, which is recruited to interact with a7nAChR when Aß42 binds this receptor. Aß42's toxic signaling via a7nAChR also impairs the function of two other receptors key to cognition, memory and neuronal survival, the NMDA receptor and the insulin receptor. By disrupting the FLNA - a7nAChR association, PTI-125 prevents Aß42's toxic effects and restores normal function of these three receptors. PTI-125 also disrupts a similar association of FLNA with toll-like receptor-4 (TLR-4), a receptor responsible for releasing inflammatory cytokines; hence, PTI-125 has a second function of blocking the inflammation noted in AD brain. PTI-125 has passed the Ames and hERG tests (non-GLP) for mutagenicity and cardiac toxicity, respectively. It easily passes the blood brain barrier, has an estimated 75% oral bioavailability and has a reasonable half-life for a drug candidate. It was safe given orally for two months in mice. We know the effective concentrations in brain from brain slice culture experiments. PTI- 125 is ready to start the proposed IND-enabling studies to ensure safety prior to a clinical trial. In this proposal, our Phase I work will include the non-GLP dose selection studies, more formal PK/ADME work, genotoxicity studies and the GLP validation of previously developed analytical and bioanalytical methods. Barring unexpected toxicity in a dose range close to the anticipated therapeutic dose, we will proceed to the Phase II scope of work: GLP safety pharmacology and both 4-week and chronic GLP toxicology studies that would support a first-in-human study as well as clinical trials in AD and an NDA.