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

开发一种用于混合炎症和神经病理性疼痛状态的新型镇痛药

• 批准号: 10082913
• 负责人: Andrea Ghetti
• 金额: $ 173.44万
• 依托单位: ANABIOS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10082913
• 关键词: ABCB1 gene; ADME Study; Absence of pain sensation; Action Potentials; Address; Advanced Development; Adverse effects; Afferent Neurons; American; Ames Assay; Analgesics; Animal Model; Behavioral; Biological Assay; Biological Availability; Biological Markers; Caco-2 Cells; Cardiac; Cardiovascular system; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chromosome abnormality; Clinical; Clinical Pathology; Clinical Research; Complex; Data; Development; Dose; Dose-Limiting; Drug Interactions; Drug Kinetics; Emergency Situation; Enzyme Inhibition; Epidemic; Evaluation; Excipients; Excretory function; Exhibits; Feedback; Flavoring; Formulation; Future; Goals; Hepatocyte; Human; In Vitro; Inflammation; Ion Channel; Kidney; Lead; Link; Liquid substance; Masks; Maximum Tolerated Dose; Medical; Metabolic; Metabolic Pathway; Metabolism; Minor; Modeling; Morbidity - disease rate; Neurons; Neuropathy; No-Observed-Adverse-Effect Level; Opioid; Oral; Organ; Outcome; Overdose; Pain; Pathologic; Pathology; Patients; Permeability; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Pharmacology and Toxicology; Pharmacotherapy; Phase; Population; Property; Publishing; Refractory; Regimen; Respiratory distress; Risk; Rodent; Rodent Model; Route; Safety; Sodium Channel; Suspensions; Taste Perception; Time; Toxic effect; Toxicogenetics; Toxicology; Tricyclic Antidepressive Agents; Validation; Work; absorption; addiction; alternative treatment; analytical method; appropriate dose; base; body system; chronic pain; chronic pain patient; chronic painful condition; clinical development; cytotoxicity; design; drug efficacy; first-in-human; gabapentin; genotoxicity; immunoreaction; in vivo; inflammatory pain; inhibitor/antagonist; innovation; medication safety; meetings; method development; micronucleus; mortality; novel; novel therapeutics; opioid abuse; opioid epidemic; opioid overdose; pain model; painful neuropathy; pregabalin; prescription opioid abuse; programs; respiratory; response; scale up; small molecule; uptake

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.

抽象的 根据疾病控制中心的数据，2017 年，超过 47,000 名美国人死于阿片类药物过量 和预防，造成国家紧急状态。大量吸毒过量病例是由于滥用 处方阿片类药物。超过 2500 万美国人患有慢性疼痛，这是一种复杂且高度衰弱的疾病 仍缺乏有效或安全治疗的医疗状况。慢性疼痛反应不佳 现有的药物疗法有以下事实证明：>50% 的患者对现有药物（如 如阿片类药物、加巴喷丁、普瑞巴林、三环类抗抑郁药等。因此，存在一个未满足的关键需求 创新的药理学解决方案，开发疼痛的替代治疗方案，提供更好的效果 功效与成瘾和滥用的风险。 AnaBios 开发了 ANB-504，这是一种专门针对两个钠通道的先导小分子双重抑制剂 在感觉神经元中表达并与多种形式的慢性疼痛有关。 ANB-504 显示出有效的剂量- 在研究的所有病理疼痛状态下，人类感觉神经元动作电位的依赖性抑制 迄今为止。这些结果通过在啮齿动物疼痛模型中观察 ANB-504 诱导的镇痛作用得到证实。 ANB- 504 表现出类似药物的特性，没有显示出细胞毒性或基因毒性标志，具有良好的代谢稳定性 物种，干净的脱靶药理学特征，无 DDI 倾向，良好的生物利用度，低清除率和 没有中枢神经系统或心血管毒性的证据。当前的提案旨在执行 FDA 授权的所有 支持 IND 申请的研究，该申请将允许在 1 期临床研究中启动人体给药。这 提案包括生产足以进行非临床体外试验的 ANB-504 体内研究。该计划的早期里程碑之一将是分析的开发和验证 能够在体外和体内研究期间对药物进行定量的方法，并允许建立 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、代谢和排泄的测定以及 药代动力学特性。这个时候我们也会去研究一下具体的代谢途径和代谢情况 使用 ANB-504 后产生的产物以及药物参与的倾向 药物与药物的相互作用。然后将在两个模型物种中评估药物的毒性和安全性 单次给药方案以及长期多次给药方案。这些研究将检查安全性和毒性 多个器官系统的结果，将为人类第一个器官系统的选择提供关键信息 剂量。拟议计划的最后一步是将所有研究汇编成综合报告 符合法规的数据包，用于提交给 FDA。