IND, FIH study and 3-month tox for PTI-125, a novel therapeutic for Alzheimer's disease

PTI-125（一种阿尔茨海默病的新型疗法）的 IND、FIH 研究和 3 个月毒性

• 批准号: 9337906
• 负责人: Lindsay H Burns
• 金额: $ 22.5万
• 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: 2017-06-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9337906
• 关键词: Acute; Adverse event; Affinity; Age; Alzheimer' s Disease; Amyloid; Autopsy; Binding; Biodistribution; Biological Availability; Blood; Blood Pressure; Brain; Brain Diseases; Canis familiaris; Chemistry; Chronic; Clinical; Clinical Research; Clinical Trials; Cognition; Complex; Data; Disease; Documentation; Dose; Double-Blind Method; Drug or chemical Tissue Distribution; Electrocardiogram; Employee; Enrollment; Female; Frequencies; Functional disorder; Goals; Heart Rate; Hematology; Hepatocyte; Human; Human Resources; Impairment; Inflammation; Inflammatory; Infusion procedures; Insulin Receptor; Memory; Metabolism; Mus; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Neurofibrillary Tangles; Nicotinic Receptors; Oral; Pathologic; Patients; Pharmaceutical Preparations; Pharmacology Study; Phase; Phase I Clinical Trials; Phenotype; Placebos; Rattus; Receptor Signaling; Recovery; Recruitment Activity; Reporting; Safety; Scaffolding Protein; Signal Transduction; Site; Small Business Innovation Research Grant; Synaptic plasticity; TLR4 gene; Testing; Therapeutic; Time; Toxic effect; Toxicology; Urinalysis; Urine; Work; abeta toxicity; aged; alpha-bungarotoxin receptor; base; brain tissue; clinical development; clinical lot; cytokine; design; efficacy study; exposed human population; filamin; healthy volunteer; hyperphosphorylated tau; male; metabolic profile; mouse model; neuroinflammation; neuronal survival; novel; novel strategies; novel therapeutics; preclinical efficacy; preclinical study; prevent; receptor; respiratory; safety study; small molecule; tau Proteins; volunteer

7. Project Summary/Abstract PTI-125 is a novel compound with a novel target, designed to treat and slow the progression of Alzheimer's disease (AD). PTI-125 binds with femtomolar affinity to a particular site on filamin A (FLNA), a scaffolding protein we recently demonstrated is critical to beta amyloid's toxicity. Beta amyloid1-42 (Aβ42) exerts its toxic effects by hijacking the α7-nicotinic acetylcholine receptor (α7nAChR) and signaling via this receptor to hyperphosphorylate tau. In addition to disrupting normal function of α7nAChR and tau, this toxic signaling leads to the signature tangles and plaques found in brains of AD patients. We have shown that this toxic signaling of Aβ42 requires FLNA recruitment to α7nAChR. The recruited FLNA stabilizes Aβ42-α7nAChR complexes (promoting a femtomolar interaction) to enable further Aβ42 piling and the toxic signaling that leads to eventual neurodegeneration. PTI-125 binding to FLNA prevents or reverses the FLNA – α7nAChR association and Aβ42's tight binding and subsequent toxic effects. Aβ42 also impairs the function of two other receptors that are pivotal to neuronal survival, cognition and memory, the NMDA receptor and the insulin receptor. By binding to FLNA, PTI-125 restores normal function of all three receptors. PTI-125 also disrupts a similar association of FLNA with toll-like receptor-4 (TLR-4), a receptor responsible for releasing inflammatory cytokines. Hence, PTI-125 has a second function of blocking the inflammation noted in AD brain. Preclinical efficacy was demonstrated in an acute ICV Aβ42 infusion mouse model, in normal aged mice, and most importantly, in human postmortem AD brain tissue. The effective concentration in postmortem human brain is as low as 1 pM. PTI-125 has completed and cleared all IND-enabling studies, and the GMP manufacture and Phase I clinical drug supply is underway. The 28-day toxicity studies demonstrated a 50-fold safety margin between the NOAEL (no observable adverse event level) in rat and a 15-fold safety margin in dog compared to the efficacious doses in both mouse efficacy studies. PTI-125 is rapidly absorbed and eliminated with nearly 100% oral bioavailability, dose proportional PK and no accumulation. Metabolic profiling showed minimal metabolism across species. In Phase I of this Fast-track proposal, we will file an IND. With a successful IND submission, we will initiate Phase II: a single ascending dose (SAD) study in healthy volunteers, followed by 3-month toxicity studies in two species. Further work outside this proposal included a SAD clinical study in AD patients, which will determine the dosing frequency for a multi-dose PK and safety study in AD patients. The 3-month toxicity studies will support clinical trials of 3-month duration but are also needed to determine doses for the chronic toxicity studies needed to support clinical trials of any duration as well as an NDA.

7。项目摘要/摘要 PTI-125是一种具有新靶标的新颖化合物，旨在治疗和减慢 阿尔茨海默氏病（AD）。 PTI-125与Femtomall亲和力与丝蛋白A上的特定位点结合 （FLNA），我们最近证明的一种脚手架蛋白对于β-淀粉样蛋白的毒性至关重要。 淀粉样蛋白1-42（Aβ42）通过劫持α7-NICOTINIC乙酰胆碱受体发挥其毒性作用 （α7NACHR）和通过该受体的信号传导到过度磷酸化tau。除了破坏 α7nAChr和tau的正常功能，这种有毒的信号导致标志性缠结和 在AD患者的大脑中发现的斑块。我们已经表明，Aβ42的这种有毒信号需要 FLNA募集到α7NACHR。招募的FLNA稳定Aβ42-α7NACHR复合物 （促进替代摩尔相互作用）以实现进一步的Aβ42堆积和导致的有毒信号传导 最终的神经变性。 PTI-125与FLNA结合可防止或逆转FLNA - α7NACHR关联和Aβ42的紧密结合和随后的毒性作用。 Aβ42也损害了 对神经元生存，认知和记忆至关重要的其他两个受体的功能， NMDA受体和胰岛素受体。通过与FLNA结合，PTI-125恢复了正常功能 在所有三个受体中。 PTI-125还破坏了类似的FLNA与Toll样受体-4的关联 （TLR-4），负责释放炎症细胞因子的接收器。因此，PTI-125具有 阻断AD大脑中指出的炎症的第二个功能。临床前效率是 在正常老年小鼠中，在急性ICVAβ42输注小鼠模型中证明，大多数 重要的是，在人类尸体后脑组织中。验尸的有效浓度 人脑低至下午1点。 PTI-125已完成并清除了所有指定研究，并 GMP制造和I期临床药物供应正在进行中。 28天的毒性研究 在Noael之间证明了50倍的安全保证金（没有可观察到的广告级别） 与两种小鼠效率的有效剂量相比 研究。 PTI-125迅速吸收并消除了几乎100％的口服生物利用度，剂量 比例PK，无积累。代谢分析表明，整个代谢很少 物种。在此快速提案的第一阶段，我们将提交一个IND。成功的印度 提交，我们将启动II期：健康志愿者的单一升剂剂量（SAD）研究， 然后在两个物种中进行3个月的毒性研究。此提案之外的进一步工作包括 AD患者的SAD临床研究将确定多剂量PK的给药频率 和AD患者的安全研究。 3个月的毒性研究将支持3个月的临床试验 持续时间，但还需要确定支持慢性毒性研究的剂量 任何持续时间和NDA的临床试验。