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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：
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
项目类别：
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

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1亿的成年人患有间歇性或持续性的慢性疼痛，慢性疼痛影响到每个人