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1亿成年人患有断断续续或持续的慢性疼痛，慢性疼痛会影响 至少有10％的世界人口。治疗慢性疼痛的主要药物很自然 或合成阿片类药物以及阿片类药物用于疼痛治疗的方法导致了所谓的“流行病” 阿片类药物滥用，成瘾和致命性过量。通过合理的药物设计，我们已经产生了 一个新的化学实体（NCE），并将其命名为Kindolor。 Kindolor是一个非专业的，非副作用的 专门为简单地控制三个目标的异常活动而开发的分子 周围感觉系统在慢性疼痛的发展和传播中不可或缺。 Kindolor行为 作为传播NAV1.7和NAV1.8钠通道的疼痛抑制剂，作为NMDA受体的抑制剂 该作用以放大疼痛信号（图A）。我们已经生成了一个以99％纯度合成Kindolor的过程。在 我们的临床前研究我们已经证明了Kindleor减轻或消除慢性疼痛的效率 在五个动物模型中以剂量与人类使用Kindolor兼容的剂量产生。我们已经生成了 这种广泛的效率的证据是金洛雷尔多目标参与的结果。我们有 生成了Kindolor及其平稳代谢的安全性（高TI）的初步证据。额外的 Kindolor的有吸引力的特征是，如果在组织后不久就可以防止慢性疼痛的发展 受伤。如果与低剂量的阿片类药物结合在一起，Kindle会通过 优化的协同作用。为了将Kindle带给公众，我们建议完成前临床前 IND应用于FDA所必需的研究，如果批准IND，则完成了1A期的完成 1B，首先是人类的研究，研究我们化合物的安全性，然后是对疼痛效率的2A期研究 骨关节炎。首先，我们将使用CGMP程序合成Kindle。这将包括开发 扩展生产量的方法。我们将生成口服药物管理的公式 人类并将使用此公式进行两种物种的药代动力学和有毒动力学的GLP研究 动物（大鼠和小型）。我们将完成有关两个物种中公式安全性的GLP研究，包括 剂量实验和低剂量高剂量的剂量实验和亚基剂量持续28天 产品。这些研究将包括14天的恢复期，以评估延迟的毒性。遗传毒性研究将 同样可以完成，在预先介绍之前对心血管和呼吸毒性的特定评估 与FDA会面。预定会议的满意厂完成将允许权宜地完成 IND申请。如果批准了IND应用程序，我们建议完成IA期和1B研究 和第2A期研究。总的来说，我们的目标是将我们的化合物带入许可或 与愿意并能够将药物带给慢性疼痛患者的制药公司合作。