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.

项目概要/摘要 PTI-125（sumifilam）是一种新型小分子阿尔茨海默病（AD）治疗药物 具有新颖目标和作用机制的候选者。 PTI-125 结合并逆转 改变支架蛋白丝蛋白 A (FLNA) 的构象以防止 Aβ42 紧密结合 通过 α7-烟碱乙酰胆碱受体 (α7nAChR) 结合并发出毒性信号 以及 Aβ42 对 Toll 样受体 4 (TLR4) 的异常激活。通过恢复 FLNA 的本机 PTI-125 塑造并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。下游影响包括减少 神经原纤维病变和淀粉样蛋白沉积，提示疾病改变，以及 改善 α7nAChR、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 的首次人体临床试验 没有显示与药物相关的不良反应和剂量比例的药代动力学。我们的 首次针对轻度至中度 AD 患者的临床试验表明，20-34% 已确定的脑脊液生物标志物 P-tau181、总 tau、神经粒蛋白和 神经丝轻链，以及神经炎症标记物减少 5-15%。 在一项针对 62 名患者的为期 1 个月的安慰剂对照临床试验中复制了这些结果， 与安慰剂相比，50 毫克和 100 毫克剂量显着改善了 7 种脑脊液生物标志物， 包括 CSF Aβ42 的预期增加。在情景认知评估中 记忆力方面，50 毫克和 100 毫克剂量分别产生 37% 和 23% 的效应量， 与安慰剂相比。这一主要认知终点的改善与 生物标志物的改进。凭借这些非常令人鼓舞的临床结果，PTI-125 为大型 2/3 期临床试验和合作努力做好准备。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来确定其效果 根据 FDA 的要求，伴随食物吸收 PTI-125。我们还将扩大规模 PTI-125口服片剂的生产和分析方法进入第3阶段（商业） 标准和生产药品供应以启动大型 2/3 期试验。最后，我们将 选择临床试验地点、患者招募方法和电子临床结果 评估（eCOA）平台。