Medication Development for the Treatment of Alcohol Use Disorder

治疗酒精使用障碍的药物开发

基本信息

批准号：
10482357
负责人：
SUSAN E. BERGESON
金额：
$ 146.29万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-20 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10482357
关键词：
Acute Address Advisory Committees Alcohol consumption Alcohol dependence Animal Model Animals Antibiotic Resistance Antibiotics Biological Biotechnology Chemicals Clinical Clinical Research Clinical Treatment Collaborations Complex Consult Consultations DSM-V Dangerousness Data Dependence Development Disease Dose Effectiveness Ethanol Excision FDA approved Female Future Goals Heavy Drinking High Pressure Liquid Chromatography Human Immune Innate Immune System Investigational Drugs Laboratories Lead Legal patent Medical Minocycline Modeling Modification Morbidity - disease rate National Institute on Alcohol Abuse and Alcoholism Neuroimmune Oral Administration Ownership Patients Persons Pharmaceutical Preparations Pharmacology and Toxicology Phase Phase I Clinical Trials Physical Dependence Physiology Process Property Recording of previous events Relapse Research Research Institute Research Personnel Rewards Rights Risk Structure Symptoms System Testing Tetracyclines Texas Therapeutic Toxicology Universities Withdrawal Withdrawal Symptom Work addiction liability alcohol abuse therapy alcohol seeking behavior alcohol use disorder analog antimicrobial clinical investigation clinical toxicology commercialization comorbidity cost design drinking experience gabapentin high risk drinking improved male neuroinflammation novel off-label drug off-label use pre-clinical pre-clinical research public health relevance response side effect stability testing success therapy development

项目摘要

PROJECT SUMMARY Our application is in response to RFA-AA-20-007 [Medications Development for the Treatment of Alcohol Use Disorder (AUD)]. Initial evidence supporting a neuroimmune hypothesis for excessive alcohol consumption led us to test tetracyclines in reward- and dependence-models. Having shown reductions in drinking and acute withdrawal, we used structure-functional data to design new chemically modified minocycline (CMM) compounds for loss of antibiotic properties, but retention of known innate immune action. In collaboration with the NIAAA Division of Medications Development, we have created and tested 16 CMM analogs for potential treatment of AUD. Several have shown both a loss of antimicrobial action and improvement over minocycline to reduce drinking in animal models of high alcohol consumption. Following oral administration tests, we have now identified a lead (best choice) and a backup compound and are in the process of completing preclinical pharmacology and toxicology screens. Nearly 15 million people in the US and ~100 million worldwide suffer from AUD. Over 5% of all medical morbidities share an ethanol-related risk. Although there are three FDA approved drugs to treat AUD, and several others are used off-label, medications have shown only modest success (in ~20% of patients treated). As a consequence, there is an urgent need for new pharmacotherapeutics across the DSM-V AUD spectrum. In fact, improved drugs that reduce high alcohol consumption in either reward- or relief-seeking patients would be most desirable. Currently, gabapentin is used off label as such; it reduces alcohol consumption and dependence-related symptoms, but its modest effectiveness and significant side- effects leave opportunity for considerable improvement. As required by the FDA, preliminary data for our CMMs show a significant reduction of alcohol consumption in two mammalian species. We have patents covering over 100 tetracycline modifications for use in neuroinflammatory diseases, including AUD. Texas Tech University System holds the patent rights. They have been licensed to South Plains Biotechnology, Inc., AUD subdivision, LLC, which is owned, in part, by researchers associated with this project. As a consequence, the success of the below aims represent a positive step toward potential commercialization. We will complete four aims addressing: Aim 1: Development of manufacturing standards; Aim 2: Completion of pre-clinical IND enabling studies; Aim 3: Phase I clinical trial; single-ascending dose; Aim 4: Phase I clinical trial; multiple-ascending dose. Future Phase II plans include testing in reward- and relief-seeking AUD patients, first in a small trial with our Clinical Research Institute and then in cooperation with the NIAAA Clinical Investigations Group. Impact: The development of a drug without addiction potential that successfully treats reward- and relief-driven AUD is critically needed. Our NIAAA collaboration, TTUHSC team, scientific advisers (Drs. Adron Harris and Bob Messing) and FastTrack (FDA consulting firm) represent unique expertise to complete the proposed work.

项目概要我们的申请是为了响应 RFA-AA-20-007 [治疗酒精使用的药物开发混乱（澳元）]。支持过量饮酒的神经免疫假说的初步证据导致我们在奖励模型和依赖性模型中测试四环素。饮酒和急性发作的减少撤回后，我们使用结构功能数据来设计新的化学修饰米诺环素（CMM）化合物失去抗生素特性，但保留已知的先天免疫作用。与 NIAAA 合作药物开发部门，我们创建并测试了 16 种 CMM 类似物，用于潜在的治疗澳元。一些药物显示出抗菌作用的丧失，但比米诺环素有所改善，以减少在高饮酒量的动物模型中饮酒。经过口服给药测试，我们现在有确定了一种先导化合物（最佳选择）和一种备用化合物，并且正在完成临床前工作药理学和毒理学筛选。美国有近 1500 万人，全球约有 1 亿人受苦来自澳元。超过 5% 的疾病都与乙醇相关。虽然FDA有3个批准用于治疗 AUD 的药物，以及其他几种药物在适应症外使用，药物效果有限成功（约 20% 的治疗患者）。因此，迫切需要新的药物治疗涵盖 DSM-V 澳元范围。事实上，改进的药物可以减少大量饮酒，无论是奖励还是或寻求缓解的患者将是最理想的。目前，加巴喷丁是在标签外使用的；它减少了饮酒和依赖相关症状，但其效果有限且副作用显着效果为相当大的改进留下了机会。根据 FDA 的要求，我们的 CMM 的初步数据显示两种哺乳动物的酒精消耗量显着减少。我们拥有的专利涵盖 100 种四环素修饰，用于治疗神经炎症疾病，包括 AUD。德克萨斯理工大学系统拥有专利权。他们已获得 South Plains Biotechnology, Inc. 澳大利亚分部的许可， LLC，部分由与该项目相关的研究人员拥有。结果，该项目的成功以下目标代表了朝着潜在商业化迈出的积极一步。我们将完成四个目标解决：目标 1：制定制造标准；目标 2：完成临床前 IND 启用研究；目标3：I期临床试验；单次递增剂量；目标4：I期临床试验；多重升序剂量。未来的第二阶段计划包括在寻求奖励和缓解的 AUD 患者中进行测试，首先是一项小型试验我们的临床研究所，然后与 NIAAA 临床研究小组合作。影响：开发一种无成瘾潜力的药物，可成功治疗奖励和缓解驱动的疾病澳元是迫切需要的。我们的 NIAAA 合作、TTUHSC 团队、科学顾问（Adron Harris 博士和 Bob Messing）和 FastTrack（FDA 咨询公司）代表了完成拟议工作的独特专业知识。