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.

项目概要/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服用可能是由于非法制造的芬太尼，但处方阿片类药物的使用 治疗急性疼痛似乎是通过处方治疗阿片类药物使用障碍的一个途径 或分别用于患者或非患者。具体来说，在超过 7000 万接受治疗的患者中 在美国，每年有 6% 的人使用处方阿片类药物治疗小手术或大手术后的急性疼痛 持续使用阿片类药物。 2016 年，12 岁或以上的人中有 53% 报告有非医疗用途 的处方阿片类药物从家人或朋友那里获得了滥用/转用的药物。因此，开发 用于治疗术后急性疼痛的非阿片类镇痛药物应减少或替代阿片类药物 处方，从而预防阿片类药物使用障碍。 电压门控钠离子通道 NaV1.7 优先在外周体细胞和内脏中表达 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 交感神经节神经元。小鼠体内 NaV1.7 的整体敲除导致对疼痛的触觉不敏感， 热刺激和化学刺激以及嗅觉丧失。在患有先天性疾病的人类中观察到类似的表型 对疼痛不敏感，NaV1.7 的功能丧失突变导致无法经历大多数类型的疼痛 疼痛，但除嗅觉丧失外，神经元功能正常。相比之下，显性遗传增益 在红斑性肢痛症和阵发性极度疼痛患者中发现了 NaV1.7 的功能错义突变 疼痛障碍，患者报告由轻微发热或排便引发的潮红和严重的阵发性疼痛。基于 根据这些数据，NaV1.7 在 CNS 中的表达非常低，NaV1.7 抑制剂有可能降低 急性疼痛强度，无阿片类药物成瘾倾向。 至少有五种 NaV1.7 抑制剂已在临床试验中进行了评估，但没有一种已经进入第二阶段。 虽然这可能被解释为抑制 NaV1.7 不足以镇痛的证据，但达到 具有临床意义的通道阻断水平具有挑战性。对于依赖于国家的情况尤其如此 NaV1.7 抑制剂 (PF-05089771、GDC-0276、GDC-0310)、高度蛋白结合药物 (PF-05089771) 和 对 NaV1.7（XEN-402、CNV-1014802）具有低至中度选择性的药物，其中脱靶相互作用受到限制 临床上可以安全给药的剂量。 ST-2427 是一种新型、首创、状态独立的 NaV1.7 抑制剂，非临床数据证明其 安全性和可接受的药代动力学特性，及其优于阿片类药物的潜力。这个提议 旨在完成 IND 支持的研究，并使用 ST-2427 进行 1 期和 2 期临床试验 治疗急性术后疼痛，并评估显着减轻和/或 消除阿片类药物的消费。