Solid oral dosage form and chronic tox for PTI-125

项目摘要/摘要 PTI-125是一种新的小分子AD治疗候选药物，具有新的靶点和 作用机制。PTI-125结合并逆转改变的构象 支架蛋白丝蛋白A阻止A-β42‘-S紧密结合及毒性信号转导 通过α7-烟碱型乙酰胆碱受体(α7nAChR)和Aβ42‘S异常 Toll样受体4(TLR4)的激活。因此，通过恢复FLNA的原生形状和 阻断这两个有毒的级联反应，PTI-125既可以减少tau的过度磷酸化，也可以减少 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。相反，我们最初将寻求症状改善的标签声明 更难的疾病修改声明，因此将进行临床 轻至中度AD的研究。在美国IND下进行的，这是人类第一个临床 试验显示没有与药物相关的不良反应(AEs)和剂量比例 该口服液的药代动力学(PK)。在此续订建议书中，我们将选择一个坚实的 基于加速3个月稳定性研究的口服剂型(在压力下 目前正在开发的三种候选配方的条件)。与 成功选择稳定的配方，我们将为其生产临床试验用品 多剂量临床试验(临床试验不包括在本提案中)。我们将同时 优化药材结晶工艺将甲醇含量降至最低 在进一步生产药品GMP之前需要进行的研究。我们还将 进行转运体研究，以检查PTI-125是P-125的底物还是抑制物 糖蛋白(Pgp)和其他外排和摄取转运体，如FDA在Pre. 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 在老鼠和狗身上。慢性毒性研究将支持有效性的临床试验以及 最终的保密协议。以及我们计划进行的多剂量I期临床试验 另外，这里提出的工作将推进PTI-125和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.