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: 9889937
• 负责人: Boris Tabakoff
• 金额: $ 327.05万
• 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 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889937
• 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; Placebos; 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; chronic pain; cohort; design; drug distribution; efficacy study; experimental study; first-in-human; food consumption; genotoxicity; in vivo; inhibitor/antagonist; 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.

美国有超过 1 亿成年人患有间歇性或持续性慢性疼痛，慢性疼痛影响了 世界人口的至少10%。治疗慢性疼痛的主要药物是天然药物 或合成阿片类药物以及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、成瘾和致命过量。我们通过合理的药物设计过程，产生了 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，不会成瘾 专门开发用于同时控制三个靶标的异常活动的分子 外周感觉系统在慢性疼痛的发展和传播中不可或缺。善良的行为 作为疼痛传播 Nav1.7 和 Nav1.8 钠通道的抑制剂以及 NMDA 受体的抑制剂 其作用是放大疼痛信号（图 A）。我们已经开发出了一种合成纯度为 99% 的 Kindolor 的工艺。在 我们的临床前研究已经证明了 Kindolor 可以减轻或消除慢性疼痛的功效 在五种动物模型中产生的剂量与 Kindolor 在人类中的使用相容。我们已经生成了 有证据表明，这种广泛的功效是 Kindolor 多目标参与的结果。我们有 产生了 Kindolor 的安全性（高 TI）及其平稳代谢的初步证据。额外的 Kindolor 的吸引人的特点是，如果在组织后立即服用，它可以预防慢性疼痛的发展 受伤。如果与低剂量的阿片类药物结合使用，Kindolor 会通过以下方式产生显着的“阿片类药物节约”效果： 与阿片类药物有协同作用。为了将 Kindolor 推向公众，我们建议完成临床前研究 向 FDA 提交 IND 申请所需的研究，如果 IND 获得批准，则完成 1a 阶段 1b，首先在人体中研究我们的化合物的安全性，然后进行 2a 期研究，研究其对疼痛的功效 骨关节炎。首先，我们将使用 cGMP 程序合成 Kindolor。这将包括开发 扩大生产数量的方法。我们将生产口服药物制剂 人类，并将使用该制剂进行两个物种的药代动力学和毒代动力学的 GLP 研究 动物（大鼠和小型猪）。我们将完成两个物种制剂安全性的 GLP 研究，包括 剂量递增实验和亚慢性给药 28 天，低、中、高剂量药物 产品。这些研究将包括 14 天的恢复期以评估延迟毒性。遗传毒性研究将 也将完成，以及在预 IND 之前对心血管和呼吸系统毒性的具体评估 与 FDA 会面。 IND 前会议的圆满完成将有助于加快完成 IND 申请。鉴于 IND 申请获得批准，我们建议完成 Ia 和 1b 期研究 和 2a 期研究。总而言之，我们的目标是使我们的化合物进入全面的第二阶段准备阶段，以获得许可或 与一家愿意并且能够为慢性疼痛患者提供药物的制药公司合作。