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

开发一种有效且高选择性的 NaV1.7 抑制剂，用于治疗急性疼痛，目标是减少阿片类药物的使用和预防阿片类药物使用障碍

• 批准号: 10025176
• 负责人: John Cureton Hunter
• 金额: $ 244.01万
• 依托单位: SITEONE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10025176
• 关键词: 12 year old; Absence of pain sensation; Acute; Acute Pain; Acute pain management; Adult; Afferent Neurons; Analgesics; Anesthesia and Analgesia; Animal Genetics; Animals; Anosmia; Award; Binding; Binding Proteins; Biological Assay; Buprenorphine; Chemicals; Clinic; Clinical; Clinical Trials; Collaborations; Congenital Pain Insensitivity; Data; Defecation; Development; Dose; Drug Kinetics; Drug Targeting; Drug usage; Erythromelalgia; Evaluation; Exhibits; Family; Female; Fentanyl; Flushing; Friends; Funding; Goals; Hernia; Hospitals; Human; Human Genetics; In Vitro; Individual; Inherited; Intravenous; Investigational Drugs; Investigational New Drug Application; Ions; Knock-out; Lead; Macaca fascicularis; Mammalian Cell; Metabolism; Methods; Minor; Missense Mutation; Monkeys; Morphine; Mus; Neurons; Nociceptors; Operative Surgical Procedures; Opioid; Pain; Pain Disorder; Pain Measurement; Pain intensity; Paroxysmal extreme pain disorder; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Pharmacology Study; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phenotype; Postoperative Pain; Primates; Process; Program Development; Property; Protein Isoforms; Rattus; Reporting; Research; Safety; Series; Small Business Innovation Research Grant; Smell Perception; Sodium Channel; Soft Tissue Injuries; Spinal Ganglia; Stimulus; Structure; Sympathetic Ganglia; Tactile; Therapeutic; Toxic effect; Toxin; Validation; Variant; Visceral; Weight; Writing; absorption; acute care; addiction; base; behavior observation; clinical development; design; drug candidate; efficacy study; experience; gain of function; gain of function mutation; good laboratory practice; guanidinium; human subject; hydrophilicity; in vivo; inhibitor/antagonist; intravenous administration; loss of function mutation; male; nanomolar; non-opioid analgesic; nonhuman primate; novel; olfactory sensory neurons; opioid mortality; opioid overdose; opioid sparing; opioid use; opioid use disorder; overdose death; pain model; pain reduction; phase II trial; prescription opioid; prescription opioid misuse; prevent; programs; repaired; small molecule inhibitor; soft tissue; voltage; volunteer

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.

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死亡和过量药物可能是由于芬太尼非法制造的，但处方阿片类药物使用 为了治疗急性疼痛，似乎是通过规定开发阿片类药物使用障碍的门户 或分别用于患者或非患者的使用。具体而言，在接受的7,000万患者中 在美国，每年进行小手术或大型手术后的急性疼痛处方阿片类药物，估计有6％ 持续使用阿片类药物。 2016年，有53％的12岁以上的人报告了非医学使用 处方阿片类药物从家人或朋友那里获得了滥用/转移的药物。因此，发展 一种非阿片类镇痛药来治疗急性，术后疼痛应减轻或替代阿片类药物 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优先表达在外周体和内脏 背根神经节内的感觉神经元，包括伤害感受器，嗅觉感觉神经元和 交感神经神经元。全球对老鼠的NAV1.7的敲除导致对痛苦的触觉不敏感， 热和化学刺激和厌食。先天性的人类观察到类似的表型 对疼痛的不敏感性，在NAV1.7中，功能丧失突变导致无法体验大多数类型的疼痛 疼痛，但除了闻气味的流失外，具有正常的神经元功能。相反，主要继承的收益 - NAV1.7的功能错义突变是在红细胞毛和阵发性极端的患者中发现的 疼痛障碍，报告潮红和严重的情节性疼痛，是由轻度温暖或肠运动触发的。基于 在这些数据上，以及CNS中NAV1.7的非常低的表达，NAV1.7抑制剂具有减少的潜力 急性疼痛强度，无阿片类成瘾责任。 在临床试验中已经评估了至少五个NAV1.7抑制剂，但没有一个超过第2阶段的抑制剂。 虽然这可能被解释为抑制NAV1.7的证据不足以镇痛 临床上的通道封锁水平是具有挑战性的。与国家有关的尤其如此 NAV1.7（PF-05089771，GDC-0276，GDC-0310）的抑制剂，高度蛋白质结合的药物（PF-05089771）和 NAV1.7（XEN-402，CNV-1014802）的低到中度选择性的药物，其中靶向相互作用限制 可以在诊所安全施用的剂量。 ST-2427是一种新型，一类新型的，国家独立于NAV1.7的抑制剂，具有非临床数据证明其 安全性和可接受的药代动力学特性及其对阿片类药物有效性的潜力。这个建议 旨在完成使用ST-2427的第1阶段和第2阶段临床试验的核对研究和进行 治疗急性，术后疼痛以及对显着减少和/或显着减少和/或的潜力的评估 消除阿片类药物的消耗。