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

PTI-125是一种具有新靶点的新型化合物，旨在治疗和减缓癌症的进展。 阿尔茨海默病(AD)。PTI-125与细丝蛋白A上的特定位点结合 我们最近证明了一种支架蛋白(FLNA)，它对β淀粉样蛋白的毒性至关重要。测试版 淀粉样蛋白1-42(Aβ42)通过劫持α7-烟碱型乙酰胆碱受体发挥毒性作用 (α7nAChR)，并通过该受体发出信号过度磷酸化tau。除了扰乱 α7nAChR和tau的正常功能，这种有毒的信号导致签名缠结和 阿尔茨海默病患者大脑中发现的斑块。我们已经证明，Aβ42的这种有毒信号需要 α7nAChR.募集的Flna稳定Aβ42-α7nAChR复合体 (促进毫微子分子相互作用)，以实现进一步的Aβ42堆积和导致 最终导致神经退化。PTI-125与Fla结合可阻止或逆转Flna- α7nAChR结合和Aβ42‘S紧密结合及随后的毒性效应。β42还会损害 对神经元存活、认知和记忆至关重要的另外两个受体的功能， NMDA受体和胰岛素受体。通过与FLNA结合，PTI-125恢复正常功能 所有三种受体的。PTI-125也破坏了FLNA与Toll样受体-4的类似联系 (TLR-4)，一种负责释放炎症细胞因子的受体。因此，PTI-125具有 阻断阿尔茨海默病脑内炎症的第二功能。临床前疗效是 在急性ICV Aβ42输注小鼠模型中显示，在正常老年小鼠和大多数 重要的是，在人类死后阿尔茨海默病的脑组织中。尸检中的有效浓度 人脑低至下午1点PTI-125已完成并通过了所有支持IND的研究，以及 GMP的生产和一期临床药物供应正在进行中。28天的毒性研究 NOAEL之间的安全裕度为50倍(没有可观察到的不良事件水平) 在大鼠身上和狗身上的安全边际是有效剂量的15倍 学习。PTI-125被迅速吸收和消除，几乎100%的口服生物利用度，剂量 成比例的PK和无积累。新陈代谢图谱显示 物种。在此快速通道提案的第一阶段，我们将提交IND。拥有成功的IND 提交，我们将启动第二阶段：健康志愿者的单次递增剂量(SAD)研究， 随后对两个物种进行了为期3个月的毒性研究。这项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的剂量频率 以及AD患者的安全性研究。为期3个月的毒性研究将支持为期3个月的临床试验。 持续时间，但也需要确定慢性毒性研究所需的剂量 任何持续时间的临床试验以及保密协议。

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.