A novel therapeutic to ameliorate chronic pain and reduce opiate use

一种缓解慢性疼痛和减少阿片类药物使用的新型疗法

• 批准号: 10449288
• 负责人: Boris Tabakoff
• 金额: $ 328.38万
• 依托单位: LOHOCLA RESEARCH CORPORATION
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449288
• 关键词: Acute; Address; Adult; Affect; Animal Model; Animals; Applications Grants; Biological Assay; Blood; Body Weight; Budgets; Carboxylic Acids; Cardiovascular system; Centers for Disease Control and Prevention (U.S.); Chemicals; Chronology; Clinical; Clinical Chemistry; Clinical Research; Coagulation Process; Complex; Computer Models; Country; Cyclic GMP; Data; Development; Dose; Double-Blind Method; Drug Design; Drug Formulations; Drug Kinetics; Drug Modelings; Drug Prescriptions; Drug Targeting; Equilibrium; Evaluation; Excretory function; Female; Fertility; Formulation; Funding; Glycine; Goals; Hematology; Hip Osteoarthritis; Histopathology; Human; Hyperalgesia; In Vitro; Institutional Review Boards; Ion Channel; Kilogram; Knee Osteoarthritis; Licensing; Metabolism; Miniature Swine; Molecular; Monitor; Morphine; N-Methyl-D-Aspartate Receptors; Names; Opiate Addiction; Opioid; Oral; Oral Administration; Oryctolagus cuniculus; Overdose; Pain; Pain management; Pathology; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase Ia Trial; Phenotype; Phototoxicity; Placebo Control; Plasma; Population; Postoperative Period; Procedures; Process; Production; Randomized; Rattus; Recovery; Request for Applications; Research; Safety; Site; Sodium Channel; Solid; Syndrome; System; Testing; Tissues; Toxic effect; Toxicokinetics; Toxicology; addiction; antagonist; chronic pain; chronic pain management; cohort; design; drug distribution; efficacy study; experimental study; first-in-human; food consumption; genotoxicity; in vivo; inhibitor; male; meetings; method development; non-opioid analgesic; novel therapeutics; opioid abuse; opioid epidemic; opioid overdose; opioid sparing; opioid use; osteoarthritis pain; overdose death; pain signal; pharmacophore; placebo controlled study; postnatal development; pre-clinical; preclinical study; prescription opioid; prevent; quinoline; receptor; reproductive; respiratory; response; safety study; scale up; sensory system; synthetic opioid; tissue injury

Over 100 million adults in the U.S. suffer from intermittent or constant chronic pain, and chronic pain affects at least 10% of the world’s population. The primary pharmaceuticals for treatment of chronic pain have been natural or synthetic opioids and the use of opioids for pain treatment has resulted in what has been called an “epidemic” of opioid abuse, addiction and lethal overdoses. We have, through a process of rational drug design, generated a new chemical entity (NCE) and have given it the name Kindolor. Kindolor is a non-opiate, non-addicting molecule that was developed specifically to simultaneously control the aberrant activity of three targets on the peripheral sensory system that are integral in the development and propagation of chronic pain. Kindolor acts as an inhibitor of the pain propagating Nav1.7 and Nav1.8 sodium channels and as an inhibitor of NMDA receptors that act to magnify pain signals (Fig A). We have generated a process to synthesize Kindolor at 99% purity. In our pre-clinical studies we have demonstrated the efficacy of Kindolor to reduce or eliminate chronic pain generated in five animal models at doses compatible with use of Kindolor in humans. We have generated evidence that this broad range of efficacy is a result of the multi-target engagement by Kindolor. We have generated the initial evidence for the safety (high TI) of Kindolor and its uneventful metabolism. Additional attractive features of Kindolor are that it can prevent the development of chronic pain if given soon after tissue injury. And if combined with low doses of opiates, Kindolor produces a substantial “opiate sparing” effect through synergistic actions with the opiates. To bring Kindolor to the public, we are proposing to complete the pre-clinical studies necessary for an IND application to the FDA and, if the IND is approved, the completion of a Phase 1a and 1b, first in human, study of the safety of our compound, and then a Phase 2a study of efficacy on pain of osteoarthritis. To start, we will have Kindolor synthesized using cGMP procedures. This will include development of methods for scaling up production quantities. We will produce a formulation for oral drug administration to humans and will use this formulation for GLP studies of pharmacokinetics and toxicokinetics in two species of animals (rat and minipig). We will complete GLP studies of safety of the formulation in the two species, including escalating dose experiments and sub-chronic dosing for 28 days with low, moderate, and high doses of the drug product. These studies will include a 14 day recovery period to assess delayed toxicity. Genotoxicity studies will also be completed, as will specific assessments of cardiovascular and respiratory toxicity prior to a pre-IND meeting with the FDA. The satisfactory completion of the pre-IND meeting will allow for expedient completion of the IND application. Given approval of the IND application, we propose to complete the Phase Ia and 1b study and the Phase 2a study. In all, our goal is to bring our compound to a full Phase 2 ready stage for licensing or partnering with a Pharma company willing and able to bring the medication to the chronic pain sufferer.

在美国，超过1亿的成年人患有间歇性或持续性慢性疼痛，慢性疼痛的影响范围为 占世界人口的10%。治疗慢性疼痛的主要药物是天然的 或合成阿片类药物和使用阿片类药物治疗疼痛导致了所谓的“流行病”， 阿片类药物滥用成瘾和过量致死我们通过合理的药物设计， 一种新的化学实体（NCE），并将其命名为Kindolor。Kindolor是一种非阿片类药物， 这种分子是专门开发的，可以同时控制细胞上三种靶点的异常活性。 外周感觉系统是慢性疼痛的发展和传播中不可或缺的。金多洛行为 作为疼痛传播Nav1.7和Nav1.8钠通道的抑制剂和作为NMDA受体的抑制剂 放大疼痛信号（图A）。我们已经产生了一种合成Kindolor的方法，纯度为99%。在 我们的临床前研究已经证明了Kindolor减轻或消除慢性疼痛的功效 在五种动物模型中以与人类使用Kindolor相容的剂量产生。我们已经生成 有证据表明，这种广泛的疗效是Kindolor多靶点参与的结果。我们有 产生了Kindolor安全性（高TI）及其平稳代谢的初步证据。额外 Kindolor的吸引人的特点是，它可以防止慢性疼痛的发展，如果给予组织后不久， 损伤如果与低剂量的阿片类药物结合使用，Kindolor会产生实质性的“阿片类药物节省”效果， 与阿片类药物的协同作用。为了将Kindolor推向公众，我们建议完成临床前 向FDA提交IND申请所需的研究，如果IND获得批准，则完成1a期研究 和1b，首先是在人类中，研究我们的化合物的安全性，然后是2a期研究对疼痛的疗效， 骨关节炎首先，我们将使用cGMP程序合成Kindolor。这将包括发展 扩大产量的方法。我们将生产一种口服药物制剂， 并将使用该制剂进行两种动物的药代动力学和毒代动力学GLP研究， 动物（大鼠和小型猪）。我们将在两个物种中完成制剂安全性的GLP研究，包括 递增剂量实验和亚慢性给药28天，低、中、高剂量给药 产品这些研究将包括14天恢复期，以评估迟发毒性。遗传毒性研究将 也将在IND前完成心血管和呼吸系统毒性的特定评估 与FDA会面。IND前会议的圆满完成将允许快速完成 IND申请。鉴于IND申请获得批准，我们建议完成Ia期和Ib期研究 和2a期研究。总之，我们的目标是使我们的化合物进入完整的第二阶段准备阶段， 与一家愿意并能够将药物带给慢性疼痛患者的制药公司合作。