Medication Development for the Treatment of Alcohol Use Disorder

项目摘要 我们的申请是对RFA-AA-20-007 [治疗酒精使用的药物开发]的回应 疾病（AUD）]。最初的证据支持过度饮酒的神经免疫假说， 我们在奖励和依赖模型中测试四环素。在显示出饮酒和急性 撤回，我们使用结构-功能数据来设计新的化学修饰的米诺环素（CMM）化合物 抗生素性质的丧失，但保留已知的先天免疫作用。与NIAAA合作 药物开发部，我们已经创建并测试了16个CMM类似物，用于潜在的治疗 澳元。几个已经显示出抗微生物作用的损失和米诺环素的改善，以减少 在高酒精消耗的动物模型中饮酒。在口服给药试验后，我们现在 确定了一种先导化合物（最佳选择）和一种备用化合物，并正在完成临床前研究 药理学和毒理学筛选。美国有近1500万人，全世界约有1亿人患有 从AUD超过5%的医学疾病都有与乙醇相关的风险。虽然有三个FDA 批准的药物来治疗AUD，其他几种药物是标签外使用，药物显示只有适度的 成功（约20%的患者接受治疗）。因此，迫切需要新的药物治疗剂 在DSM-V AUD频谱中。事实上，改善药物，减少高酒精消费，无论是奖励- 或寻求救济的病人将是最可取的。目前，加巴喷丁是标签外使用的;它减少了 酒精消费和依赖相关的症状，但其适度的有效性和显着的副作用- 影响留下了相当大的改进机会。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著减少。我们的专利覆盖了 100种用于神经炎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。它们已被授权给南平原生物技术公司，澳元细分， LLC，该公司部分由与该项目相关的研究人员拥有。因此， 以下目标是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：制定生产标准;目标2：完成临床前IND启用 研究;目标3：I期临床试验;单次给药剂量递增;目标4：I期临床试验;多次给药剂量递增 次给药结束未来的II期计划包括在寻求奖励和救济的AUD患者中进行测试，首先是在一项小型试验中， 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，成功治疗奖励和缓解驱动的 澳元是非常必要的。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。

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.