Solid oral dosage form and chronic tox for PTI-125

PTI-125的固体口服剂型和慢性毒性

• 批准号: 9624887
• 负责人: Lindsay H Burns
• 金额: $ 289.63万
• 依托单位: CASSAVA SCIENCES, INC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9624887
• 关键词: ABCG2 gene; Adverse effects; Adverse event; Affinity; Alzheimer' s Disease; Amyloid; Autopsy; Binding; Bioavailable; Blood Chemical Analysis; Body Surface Area; Body Weight; Brain; Brain Diseases; CD14 gene; Caco-2 Cells; Canis familiaris; Cells; Chemistry; Chronic; Clinical; Clinical Pathology; Clinical Research; Clinical Trials; Cognitive; Crystallization; Cyclic GMP; Deposition; Development; Disease; Disease Progression; Dosage Forms; Dose; Drug Kinetics; Evaluation; Exposure to; Formulation; Functional disorder; Human Resources; Impairment; In Vitro; Inflammation; Inflammatory; Insulin Receptor; Label; Measures; Mediating; Methanol; Microscopic; Modification; Molecular Conformation; Mus; Neurofibrillary Tangles; No-Observed-Adverse-Effect Level; Oral; Organ Weight; P-Glycoprotein; Pathologic; Pharmaceutical Preparations; Phase I Clinical Trials; Phase II Clinical Trials; Phosphotransferases; Placebos; Plasma; Powder dose form; Process; Rattus; Safety; Scaffolding Protein; Shapes; Signal Transduction; Solid; Stress; Synaptic plasticity; TLR4 gene; Therapeutic; Tissues; Toxic effect; Toxicology; Work; alpha-bungarotoxin receptor; base; brain tissue; cGMP production; capsule; clinical development; cognitive function; commercialization; cytokine; efficacy trial; filamin; first-in-human; food consumption; healthy volunteer; hyperphosphorylated tau; improved; inhibitor/antagonist; mortality; mouse model; neuroinflammation; novel; prevent; receptor; small molecule; small molecule therapeutics; stability testing; symptomatic improvement; synaptic function; tau Proteins; therapeutic candidate; uptake

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.

项目概要/摘要 PTI-125是一种新型小分子AD候选治疗药物，具有新的靶点和 作用机制。 PTI-125 结合并逆转改变的构象 支架蛋白细丝蛋白 A (FLNA) 可防止 Aβ42 与 Aβ42 紧密结合并产生毒性信号传导 通过 α7-烟碱乙酰胆碱受体 (α7nAChR) 以及 Aβ42 的异常 Toll 样受体 4 (TLR4) 的激活。因此，通过恢复 FLNA 的原始形状和 PTI-125 阻断这两种毒性级联反应，同时减少 tau 蛋白过度磷酸化和 神经炎症。下游效应包括减少神经原纤维损伤和 淀粉样蛋白沉积，表明疾病改变，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 改进。我们最初将寻求症状改善的标签声明 疾病改变的更困难的主张，因此将进行临床 轻度至中度 AD 的研究。根据美国 IND 进行的首次人体临床试验 试验显示没有药物相关的不良反应 (AE) 与剂量成正比 口服溶液的药代动力学（PK）。在这个更新提案中，我们将选择一个可靠的 基于 3 个月加速稳定性研究（压力下）的口服剂型 目前正在开发的三种候选制剂的条件）。随着 成功选择稳定的配方，我们将为您生产临床试验用品 多剂量临床试验（本提案不包括临床试验）。我们将同时 优化原料药的结晶工艺，最大限度地减少甲醇含量， 在进一步按照 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-的底物或抑制剂 糖蛋白 (Pgp) 和其他外排和摄取转运蛋白，按照 FDA 的要求 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 在老鼠和狗中。慢性毒性研究将支持临床试验的功效以及 最终的保密协议。随着我们计划进行的多剂量 I 期临床试验 单独地，这里提出的工作将推进 PTI-125 和 使 PTI-125 对潜在商业化合作伙伴更具吸引力。