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

PTI-125 的食物效应研究和药物供应规模扩大

• 批准号: 10216906
• 负责人: Lindsay H Burns
• 金额: $ 271.02万
• 依托单位: CASSAVA SCIENCES, INC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216906
• 关键词: Adverse drug effect; Affinity; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-42; Binding; Bioavailable; Biological Availability; Biological Markers; Blinded; Brain; CD14 gene; Chemicals; Clinical; Clinical Research; Clinical Trials; Cognitive; Conduct Clinical Trials; Controlled Clinical Trials; Cross-Over Studies; Deposition; Disease; Dose; Drug Kinetics; Elderly; Enrollment; Episodic memory; Evaluation; Fasting; Fatty acid glycerol esters; Female; Food; Impairment; Inflammatory; Instruction; Insulin Receptor; Interleukin-6; Knowledge; Light; Link; Mediating; Methods; Modification; Molecular Conformation; Nerve Degeneration; Neurofibrillary Tangles; Oral; Paired-Associate Learning; Patient Recruitments; Patients; Pharmaceutical Preparations; Phase; Phase II/III Clinical Trial; Phase II/III Trial; Phosphotransferases; Placebos; Procedures; Readiness; Scaffolding Protein; Shapes; Signal Pathway; Signal Transduction; Site; Synaptic plasticity; TLR4 gene; Tablets; Testing; Toll-like receptors; Work; absorption; alpha-bungarotoxin receptor; analytical method; career preparation; clinical outcome assessment; clinical research site; cognitive testing; cytokine; data integrity; drug candidate; filamin; first-in-human; healthy volunteer; hyperphosphorylated tau; improved; interest; male; manufacturing process; manufacturing scale-up; neurofilament; neurogranin; neuroinflammation; novel; open label; placebo controlled trial; prevent; receptor; recruit; scale up; small molecule; symptomatic improvement; synaptic function; tau Proteins; therapeutic candidate

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.

项目摘要/摘要 PTI-125（Sumifilam）是一种新型的小分子阿尔茨海默氏病（AD）治疗 具有新颖的目标和作用机理的候选人。 PTI-125绑定并逆转 脚手架蛋白丝蛋白A（FLNA）的构象改变以防止Aβ42的紧密 通过α7-NICOTINIC乙酰胆碱受体（α7NACHR）与有毒信号结合和有毒信号传导AS 以及Aβ42的异常激活类Toll样受体4（TLR4）。通过恢复FLNA的本地 PTI-125塑造并阻止这两个有毒的级联 高磷酸化和神经炎症。下游效果包括减少 神经原纤维病变和淀粉样蛋白沉积物，表明疾病改变，并 改善了α7NACHR，NMDAR和胰岛素受体的突触可塑性和功能， 暗示有症状的改善。在美国印第安纳州的第一个人类临床试验下 没有显示与药物有关的不良反应和剂量比例药代动力学。我们的 轻度至中度AD患者的初次临床试验显示20-34％ 减少已建立的CSF生物标志物P-Tau181，Total Tau，Neurogranin和 神经丝轻链以及5-15％的降低神经炎症标记。 复制这些结果在1个月的安慰剂对照临床试验中，对62例患者，均为 与安慰剂相比 包括CSFAβ42所需的增加。在情节的认知评估中 记忆，50和100 mg剂量分别产生37％和23％的效应大小 与安慰剂。此主要认知终点的改进与 生物标志物的改进。通过这些极为令人鼓舞的临床结果，PTI-125是 准备进行大型2/3期临床试验和合作工作。我们在这里提出了一个阶段 3准备工作范围。我们将进行一项临床研究，以确定 根据FDA的要求，伴随着滥用PTI-125的食物。我们还将扩大规模 PTI-125口服片剂的制造和分析方法（商业） 标准和制造药物供应启动大型2/3期试验。最后，我们会的 选择临床试验地点，患者招聘方法和电子临床结果 评估（ECOA）平台。