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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

基本信息

批准号：
10653196
负责人：
Boris Tabakoff
金额：
$ 192.56万
依托单位：
LOHOCLA RESEARCH CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653196
关键词：
Acute Address Adult Affect Animal Model Animals Applications Grants Autopsy Biological Assay Blood Body Weight Budgets Carboxylic Acids Cardiovascular system 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 Embryonic and Fetal Development 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 Randomized Rattus Recovery Request for Applications Research Safety Site Sodium Channel Solid Syndrome System Testing Tissues Toxic effect Toxicokinetics Toxicology Writing 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 manufacturing scale-up method development new chemical entity 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-Investigational New Drug meeting pre-clinical preclinical study prenatal prescription opioid prevent quinoline receptor reproductive respiratory response safety study scale up sensory system synthetic opioid tissue injury

项目摘要

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1亿成年人患有间歇性或持续性慢性疼痛，慢性疼痛影响至少占世界人口的10%。治疗慢性疼痛的主要药物是天然的或合成阿片类药物，以及使用阿片类药物治疗疼痛，造成了所谓的“流行病”。阿片类药物滥用、成瘾和致命性过量。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是一种非鸦片类药物，不会上瘾一种分子，专门用来同时控制三个靶点的异常活性外周感觉系统在慢性疼痛的发展和传播中是不可或缺的。金多尔表演作为痛觉传播Nav1.7和Nav1.8钠通道的抑制剂和NMDA受体的抑制剂这种行为会放大疼痛信号(图A)。我们已经开发了一种合成Kindolor的工艺，纯度为99%。在……里面我们的临床前研究已经证明了Kindolor在减轻或消除慢性疼痛方面的有效性在五个动物模型中产生的剂量与在人类中使用Kindolor的剂量相一致。我们已经产生了有证据表明，这种广泛的效力范围是Kindolor多目标参与的结果。我们有为Kindolor的安全性(高TI)及其平稳的新陈代谢提供了初步证据。其他内容 Kindolor的吸引人的特点是，如果在组织后不久给药，它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联合使用，Kindolor可通过以下途径产生显著的“阿片类药物节约”效应与鸦片类药物的协同作用。为了将Kindolor推向公众，我们提议完成临床前向FDA申请IND所需的研究，如果IND获得批准，完成阶段1a 和1b，首先是在人体上研究我们的化合物的安全性，然后是2a阶段的疼痛疗效研究骨性关节炎。首先，我们将使用cGMP程序合成Kindolor。这将包括发展扩大生产数量的方法。我们将制定口服给药配方，以并将使用这种制剂进行GLP研究，研究两种药物的药物动力学和毒代动力学动物(大鼠和小型猪)。我们将完成对该制剂在两个物种中的安全性的GLP研究，包括递增剂量实验和亚慢性给药，低、中、高剂量各28天产品。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IND前对心血管和呼吸系统毒性的具体评估与食品和药物管理局会面。IND前会议的圆满完成将有助于顺利完成 Ind应用程序。如工业发展计划的申请获得批准，我们建议完成第Ia和1b阶段的研究以及2a期研究。总而言之，我们的目标是使我们的化合物进入完全的第二阶段准备阶段，以获得许可或与一家愿意并有能力将药物带给慢性疼痛患者的制药公司合作。