Food Effect study and drug supply scale-up for PTI-125

项目总结/摘要 PTI-125（sumifilam）是一种新型小分子阿尔茨海默病（AD）治疗剂 具有新靶点和作用机制的候选物。PTI-125结合并逆转 改变骨架蛋白细丝蛋白A（FLNA）的构象，以阻止A β 42的紧密结合， 通过α 7-烟碱乙酰胆碱受体（α 7nAChR）结合和毒性信号传导， 以及A β 42对Toll样受体4（TLR4）的异常激活。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减少了tau蛋白的表达， 过度磷酸化和神经炎症。下游影响包括减少 神经系统病变和淀粉样蛋白沉积，提示疾病改变， 改善α 7 nAChR、NMDAR和胰岛素受体的突触可塑性和功能， 提示症状改善。根据美国IND，首次人体临床试验 未显示药物相关的不良反应和剂量比例药代动力学。我们 在轻度至中度AD患者中进行的首次患者临床试验显示，20 - 34% 确定的CSF生物标志物P-tau181、总tau、神经颗粒蛋白和 神经丝轻链，以及5 - 15%的神经炎性标志物减少。 在62名患者中进行的为期1个月的安慰剂对照临床试验中重复了这些结果， 与安慰剂相比，50 mg和100 mg剂量显著改善了7种CSF生物标志物， 包括CSF A β 42的预期增加。在一项对发作性的认知评估中， 记忆，50和100 mg剂量分别产生37%和23%的效应量， 对比安慰剂。这一主要认知终点的改善与 生物标志物的改进。有了这些非常令人鼓舞的临床结果，PTI-125 准备进行大型2/3期临床试验和合作。我们在这里提出一个阶段 3、准备工作范围。我们将进行一项临床研究， 根据FDA的要求，伴随食物对PTI-125吸收的影响。我们还将扩大 III期（商业）PTI-125口服片剂的生产和分析方法 标准和生产药物供应，以启动大型2/3期试验。最后我们将 选择临床试验中心、患者招募方法和电子临床结局 评估（eCOA）平台。

Project Summary/Abstract PTI-125 (sumifilam) is a novel small molecule Alzheimer’s disease (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). 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. Under a US IND, the first-in-human clinical trial showed no drug-related adverse effects and dose proportional pharmacokinetics. Our first-in-patient clinical trial in mild-to-moderate AD patients demonstrated 20-34% reductions in established CSF biomarkers P-tau181, total tau, neurogranin and neurofilament light chain, as well as 5-15% reductions neuroinflammatory markers. Replicating these results in a 1-month placebo-controlled clinical trial in 62 patients, both 50 mg and 100 mg doses significantly improved 7 CSF biomarkers compared to placebo, including the desired increase in CSF Aβ42. In a cognitive assessment of episodic memory, the 50 and 100 mg doses produced 37% and 23% effect sizes, respectively, versus placebo. Improvement on this primary cognitive endpoint correlated with improvements in biomarkers. With these highly encouraging clinical results, PTI-125 is ready for a large Phase 2/3 clinical trial and partnering efforts. We propose here a Phase 3 readiness scope of work. We will conduct a clinical study to determine the effect of concomitant food on absorption of PTI-125, as required by FDA. We will also scale-up manufacturing and analytical methods of PTI-125 oral tablets to Phase 3 (commercial) standards and manufacture drug supply to initiate a large Phase 2/3 trial. Finally, we will select clinical trial sites, patient recruitment methods and an electronic clinical outcome assessment (eCOA) platform.