Medication Development for the Treatment of Alcohol Use Disorder

治疗酒精使用障碍的药物开发

• 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
• 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

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.

项目摘要 我们的应用是响应RFA-AA-20-007 [饮酒治疗的药物开发 障碍（AUD）]。支持过度饮酒LED的神经免疫性假设的初步证据 我们在奖励和依赖模型中测试四环素。显示出饮酒和急性的减少 提取，我们使用结构功能数据设计新的化学修饰米诺环素（CMM）化合物 为了丧失抗生素特性，但保留已知的先天免疫作用。与NIAAA合作 药物开发的划分，我们创建并测试了16个CMM类似物，以潜在的处理 奥德几个既显示抗菌作用的损失，又显示了对米诺环素的改善，以减少 在高饮酒的动物模型中喝酒。按照口头管理测试，我们现在有 确定了铅（最佳选择）和备用化合物，并正在完成临床前 药理学和毒理学筛选。在美国，近1500万人，全世界约有1亿人受苦 来自aud。超过5％的医疗病患者具有与乙醇相关的风险。虽然有三个FDA 经过批准的药物治疗AUD，其他几个药物都在标签外使用，药物仅显示适中 成功（在接受治疗的患者中约有20％）。结果，迫切需要新的药物治疗药 跨DSM-V AUD频谱。实际上，改进的药物可以减少两种奖励的高酒精消耗 - 或寻求救济的患者是最理想的。目前，加巴喷丁被使用了。它减少了 饮酒和与依赖相关的症状，但其适度的有效性和明显的侧面 效果留出了相当大的改进的机会。根据FDA的要求，我们的CMM的初步数据 显示了两种哺乳动物物种的饮酒量显着降低。我们有专利覆盖 100个用于神经炎症性疾病的四环素修饰，包括AUD。德州理工大学 系统拥有专利权。他们已获得授权到南平原生物技术公司，AUD细分， LLC，部分由与该项目相关的研究人员拥有。结果， 下面的目标是迈向潜在商业化的积极步骤。我们将完成四个目标 讲话：目标1：制造标准的制定；目标2：完成前临床启用 研究； AIM 3：I期临床试验；单级剂量； AIM 4：I期临床试验；多重 剂量。未来的第二阶段计划包括对奖励和救济的AUD患者进行测试，首先是在一次小型试验中与 我们的临床研究所，然后与NIAAA临床研究小组合作。影响： 没有成瘾潜力的药物的开发，可以成功治疗奖励和救济驱动 迫切需要aud。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。