Development of a novel analgesic for mixed inflammatory and neuropathic pain states

摘要 根据疾病控制中心的数据，2017年，超过4.7万美国人死于阿片类药物过量 和预防，导致国家紧急状态。相当数量的过量用药是由于滥用 处方类阿片。2500多万美国人遭受慢性疼痛的折磨，这是一种复杂而极具衰弱的疾病 缺乏有效或安全的治疗方法的医疗状况。慢性疼痛对 现有药物疗法的证据是：50%的患者对目前的药物如 如阿片类、加巴喷丁、普瑞巴林、三环类抗抑郁药和。因此，存在着严重的未得到满足的需求 创新的药理学解决方案，为疼痛开发替代治疗方案，将提供更好的 药效与成瘾和滥用的风险。 AnaBios公司开发了ANB-504，这是一种专门针对两个钠通道的铅小分子双重抑制剂 在感觉神经元中表达，并与多种形式的慢性疼痛有关。ANB-504显示出强大的剂量- 所有病理性疼痛状态下人类感觉神经元动作电位的依赖性抑制 到目前为止。通过观察ANB-504对啮齿动物疼痛模型的镇痛作用，证实了上述结果。ANB- 504具有类似药物的特性，没有细胞毒性或遗传毒性标志，具有良好的代谢稳定性 物种，干净的脱离靶标的药理特性，没有DDI倾向，良好的生物利用度，低清除量和 没有中枢神经系统或心血管毒性的证据。目前的提案旨在进行FDA授权的所有 支持IND应用的研究，该应用将允许在第一阶段临床研究中启动人类剂量。这个 提案包括制造足够数量的ANB-504进行非临床体外试验和 活体研究。该计划的早期里程碑之一将是开发和验证分析 能够在体外和体内研究期间对药物进行量化的方法，并将允许建立 后续临床批次的成分和纯度的等效性。接下来，该计划将解决 药物在动物模型中的吸收、分布、代谢和排泄的测定 药代动力学特性。此时，我们还将研究特定的代谢途径和代谢 ANB-504给药后产生的产品和药物参与的倾向 药物之间的相互作用。该药物的毒性和安全性将在两个模式物种中进行评估 单次给药方案以及延长的多次给药方案。这些研究将检验安全性和毒性。 多个器官系统的结果，将为人类选择第一个器官系统提供关键信息 给药。拟议方案的最后一步将是将所有研究汇编成一个全面的 符合监管规定的数据包，提交给FDA。

ABSTRACT In 2017, more than 47,000 Americans died from an opioid overdose, according to the Centers for Disease Control and Prevention, causing a National Emergency. A significant number of overdose cases were due to abuse of prescription opioids. More than 25 million Americans suffer from chronic pain, a complex and highly debilitating medical condition for which effective or safe treatments are still lacking. Chronic pain does not respond well to existing pharmacotherapy as evidenced by the fact that >50% patients are refractory to current medications such as opioids, gabapentin, pregabalin, tricyclic antidepressants and. Thus, there is a critical unmet need for innovative pharmacological solutions to develop alternative treatment options for pain that would provide better efficacy with the risk for addiction and abuse. AnaBios has developed ANB-504, a lead small molecule dual inhibitor of two sodium channels specifically expressed in sensory neurons and implicated in numerous forms of chronic pain. ANB-504 shows potent dose- dependent inhibition of action potentials in human sensory neurons, across all pathological pain states studied to date. These results were confirmed by observing ANB-504-induced analgesia in a rodent model of pain. ANB- 504 exhibits drug-like properties, shows no cytotoxicity or genotoxicity flags, has good metabolic stability across species, a clean off-target pharmacology profile, no propensity for DDI, good bioavailability, low clearance and no evidence of CNS or cardiovascular toxicities. The current proposal aims at conducting all the FDA-mandated studies to support an IND application which would allow initiating human dosing in a Phase 1 clinical study. The proposal includes the manufacturing of ANB-504 in an amount sufficient for conducting non-clinical in vitro and in vivo studies. One of the early milestones in the program will be the development and validation of analytical methods which will enable quantification of the drug during in vitro and in vivo studies and will allow establishing equivalency of composition and purity for subsequent clinical batches. Next, the program will address the determination of the absorption, distribution, metabolism and excretion of the drug in animal models and the pharmacokinetics properties. At this time, we will also investigate the specific metabolic pathways and metabolic products generated following the administration of ANB-504 and the propensity of the drug to be involved in drug-drug interactions. The toxicity and safety of the drug will then be assessed in two model species in both single dosing regimen as well a prolonged multi-dosing regimen. These studies will examine safety and toxicity outcomes for multiple organ systems and will provide critical information for the selection of the first in human dosing. The last step in the proposed program will be the compilation of all the studies into a comprehensive regulatory-compliant data package for submission to the FDA.