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

7.项目概要/摘要 PTI-125是一种具有新靶点的新型化合物，设计用于治疗和减缓 阿尔茨海默病（AD）。PTI-125以飞摩尔亲和力结合细丝蛋白A上的特定位点 （FLNA），我们最近证明的支架蛋白对β淀粉样蛋白的毒性至关重要。Beta 淀粉样蛋白1 -42（Aβ42）通过劫持α7-烟碱乙酰胆碱受体发挥其毒性作用 （α 7 nAChR）和通过该受体的信号传导使tau过度磷酸化。除了扰乱 α 7 nAChR和tau的正常功能，这种毒性信号传导导致信号缠结， AD患者大脑中发现的斑块。我们已经证明，Aβ42的这种毒性信号需要 FLNA募集至α 7 nAChR。募集的FLNA稳定Aβ42-α 7 nAChR复合物 （促进飞摩尔相互作用），使进一步的Aβ42堆积和毒性信号，导致 最终导致神经退化PTI-125与FLNA的结合阻止或逆转FLNA -125的表达。 α 7 nAChR结合和Aβ42的紧密结合以及随后的毒性作用。Aβ42也会损害 另外两种受体对神经元的存活、认知和记忆起着关键作用， 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。PTI-125也破坏了FLNA与Toll样受体-4的类似结合 TLR-4是一种负责释放炎性细胞因子的受体。因此，PTI-125具有 第二个功能是阻断AD脑中的炎症。临床前疗效为 在急性ICV Aβ42输注小鼠模型、正常老年小鼠和大多数 重要的是，在人类死后AD脑组织中。死后有效浓度 人类大脑的浓度低至1 pM。PTI-125已完成并批准了所有IND使能研究， 正在进行GMP生产和一期临床用药供应。28天毒性研究 证实NOAEL（无可观察到的不良事件水平）之间的50倍安全性界限 在大鼠和犬中，与有效剂量相比，两种小鼠有效性的安全范围均为15倍 问题研究PTI-125被快速吸收和消除，口服生物利用度接近100%，剂量 成比例PK，无蓄积。代谢分析显示， 物种在本快速通道提案的第一阶段，我们将提交IND。 提交后，我们将启动II期：在健康志愿者中进行的单次剂量递增（SAD）研究， 随后在两个物种中进行了为期3个月的毒性研究。除此之外的其他工作包括： AD患者中的SAD临床研究，将确定多次给药PK的给药频率 和安全性研究。3个月毒性研究将支持3个月临床试验 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NDA。

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.