Development of a Potent and Highly Selective NaV1.7 Inhibitor for the Treatment of Acute Pain with the Goal of Reducing Opioid Use and Preventing Opioid Use Disorders

项目摘要/摘要 2015年，超过63%的药物过量死亡涉及阿片类药物，其中近一半涉及处方阿片类药物。 虽然大多数阿片类药物的死亡和过量可能是由于非法制造的芬太尼，但处方阿片类药物的使用 对于急性疼痛的治疗似乎是阿片类药物使用障碍发展的门户 或分别在患者或非患者中转用。具体地说，在接受治疗的7000万名患者中 在美国，每年约有6%的处方阿片类药物用于治疗小手术或大手术后的急性疼痛 坚持使用阿片类药物。2016年，报告非医疗用途的12岁及以上个人中有53% 大多数处方类阿片类药物是从家人或朋友那里获得滥用/转移药物的。因此，发展 治疗急性术后疼痛的非阿片类止痛药应减少或取代阿片类药物 处方，从而防止阿片类药物使用障碍。 电压门控钠离子通道Nav1.7在外周、躯体和内脏优先表达 背根神经节内的感觉神经元，包括伤害性感受器、嗅觉感觉神经元和 交感神经节神经元。在小鼠中，Nav1.7的全局敲除导致了对疼痛触觉的不敏感， 热刺激和化学刺激以及嗅觉障碍。在患有先天性心脏病的人中也观察到类似的表型。 对疼痛不敏感的患者，Nav1.7功能丧失突变导致无法体验大多数类型的 疼痛，但除嗅觉丧失外，其他神经功能正常。相比之下，主要是遗传收益- 在红斑性肢痛症和发作性极端患者中发现Nav1.7功能错义突变 疼痛障碍，报告由温和的温暖或排便引起的潮红和严重的阵发性疼痛。基座 根据这些数据，以及Nav1.7在中枢神经系统中的低表达，Nav1.7抑制剂有可能减少 急性疼痛强度，无阿片类成瘾倾向。 至少有五种Nav1.7抑制剂已经在临床试验中进行了评估，但没有一种超过第二阶段。 虽然这可能被解释为抑制Nav1.7不够止痛的证据，但达到 临床上有意义的通道阻断程度是具有挑战性的。对于依赖国家的国家来说，情况尤其如此 NAV1.7(PF-05089771，GDC-0276，GDC-0310)的抑制剂，高蛋白结合药物(PF-05089771)，以及 对Nav1.7(Xen-402，CNV-1014802)具有低到中等选择性的药物，其靶外相互作用受限 临床上可以安全使用的剂量。 ST-2427是一种新型的、一流的、状态独立的Nav1.7抑制剂，非临床数据表明其 安全性和可接受的药代动力学特性，以及其疗效优于阿片类药物的潜力。这项建议 目标是完成启用IND的研究，并使用ST-2427进行第一阶段和第二阶段临床试验 急性手术后疼痛的治疗，以及对显著减少和/或 消除阿片类药物消费。

Project Summary/Abstract In 2015, over 63% of drug overdose deaths involved an opioid of which nearly half involved a prescription opioid. While most opioid deaths and overdoses are likely due to illicitly-manufactured fentanyl, prescription opioid use for treatment of acute pain appears to be a gateway for development of opioid use disorders through prescribed or diverted use in patients or non-patients, respectively. Specifically, of the >70 million patients who receive prescription opioids for acute pain following minor or major surgery every year in the US, an estimated 6% go on to use opioids persistently. In 2016, 53% of individuals aged 12 years or older who reported non-medical use of prescription opioids obtained the misused/diverted medications from family or friends. Therefore, developing a non-opioid analgesic medication to manage acute, post-operative pain should reduce or replace opioid prescriptions and thereby prevent opioid use disorders. The voltage-gated sodium ion channel NaV1.7 is preferentially expressed in peripheral somatic and visceral sensory neurons within the dorsal root ganglion, including nociceptors, olfactory sensory neurons and sympathetic ganglion neurons. Global knockout of NaV1.7 in mice resulted in insensitivity to painful tactile, thermal and chemical stimuli and anosmia. A similar phenotype is observed in humans with congenital insensitivity to pain in whom loss-of-function mutations in NaV1.7 lead to an inability to experience most types of pain but have otherwise normal neuronal function except for loss of smell. In contrast, dominantly inherited gain- of function missense mutations of NaV1.7 are found in patients with erythromelalgia and paroxysmal extreme pain disorder, who report flushing and severe, episodic pain triggered by mild warmth or bowel movement. Based on these data, and the very low expression of NaV1.7 in the CNS, NaV1.7 inhibitors have the potential to decrease acute pain intensity without opioid-like addiction liability. At least five NaV1.7 inhibitors have been assessed in clinical trials, yet none has advanced beyond Phase 2. While this might be interpreted as evidence that inhibiting NaV1.7 is not sufficiently analgesic, attainment of clinically-meaningful levels of channel blockade is challenging. This is especially true with state-dependent inhibitors of NaV1.7 (PF-05089771, GDC-0276, GDC-0310), highly protein-bound drugs (PF-05089771), and drugs with low-to-moderate selectivity for NaV1.7 (XEN-402, CNV-1014802) where off-target interactions limit the dose that can be safely administered in clinic. ST-2427 is a novel, first-in-class, state-independent inhibitor of NaV1.7 with nonclinical data demonstrating its safety and acceptable pharmacokinetic properties, and its potential for superior efficacy to opioids. This proposal aims to complete IND-enabling research and conduct Phase 1 and Phase 2 clinical trials with ST-2427 for treatment of acute, post-operative pain, and an assessment of the potential to significantly reduce and/or eliminate opioid consumption.