Solid oral dosage form and chronic tox for PTI-125

项目总结/摘要 PTI-125是一种具有新靶点的新型小分子AD治疗候选药物， 作用机制。PTI-125结合并逆转改变的构象， 支架蛋白细丝蛋白A（FLNA）阻止Aβ42与毒性信号的紧密结合 通过α7-烟碱乙酰胆碱受体（α 7 nAChR）以及Aβ42的异常 Toll样受体4（TLR 4）的活化。因此，通过恢复FLNA的原始形状， 阻断这两个毒性级联，PTI-125减少tau蛋白过度磷酸化， 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.我们将首先追求症状改善的标签声明， 更困难的疾病修改索赔，因此将进行临床 轻度至中度AD的研究。在美国IND下进行，这是首次人体临床试验 试验显示无药物相关不良反应（AE）， 口服溶液的药代动力学（PK）。在这个更新建议中，我们将选择一个坚实的 基于加速3个月稳定性研究（强制降解下）的口服剂型 目前正在开发的三种候选制剂。与 成功的选择一个稳定的配方，我们将生产临床试验用品， 多次给药临床试验（未纳入本建议书的临床试验）。我们将同时 优化原料药的结晶工艺，以尽量减少甲醇含量， 在进一步GMP生产原料药之前需要进行研究。我们还将 进行转运蛋白研究，以检查PTI-125是否是P- 糖蛋白（Pgp）和其他外排和摄取转运蛋白，如FDA在前 IND指导。最后，我们将进行PTI-125的慢性重复剂量口服毒性研究 在大鼠和狗中。慢性毒性研究将支持疗效的临床试验， 最终保密协议沿着我们计划进行的多剂量I期临床试验 另外，本文提出的工作将推进PTI-125的临床开发， 使PTI-125对潜在的商业化合作伙伴更具吸引力。

Project Summary/Abstract 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 initially 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. Conducted under a US IND, the first-in-human clinical trial showed no drug-related adverse effects (AEs) and dose proportional pharmacokinetics (PK) of the oral solution. In this renewal proposal, we will select a solid oral dosage form based on an accelerated 3-month stability study (under stress conditions) of three candidate formulations currently being developed. With the successful selection of a stable formulation, we will manufacture clinical trial supplies for multi-dose clinical trials (clinical trials not included in this proposal). We will concurrently optimize the crystallization process for Drug Substance to minimize methanol content, a study needed prior to further GMP manufacturing of Drug Substance. We will also conduct a transporter study to examine whether PTI-125 is a substrate or inhibitor of P- glycoprotein (Pgp) and other efflux and uptake transporters, as requested by FDA in pre- IND guidance. Finally, we will conduct chronic repeat dose oral toxicity studies of PTI-125 in rat and dog. Chronic tox studies will support clinical trials for efficacy as well as an eventual NDA. Along with a multi-dose Phase I clinical trial that we plan to conduct separately, the work proposed here will progress the clinical development of PTI-125 and make PTI-125 more attractive to potential commercialization partners.