Supplement to: Medication Development for the Treatment of Alcohol Use Disorder - U01AA028957

美国有近1500万人，全球约有1亿人患有AUD。超过5%的医疗 发病率都有与酒精相关的风险。虽然有三种FDA批准的药物治疗AUD， 其他几种是标签外使用，药物治疗仅显示出适度的成功（约20%的患者 治疗）。因此，在DSM-V中迫切需要新的药物治疗剂 AUD频谱。我们在U 01 AA 028957中的方法是一个简单的医疗化学计划，IND使能 首先是人体安全测试。要求提供补充，以应付意外的直接 原目标1和2的费用，但对目标3-4有利。[原目标：1：发展 生产标准; 2：完成临床前IND使能研究; 3：I期临床试验;单- 递增剂量; 4：I期临床试验;多次递增剂量。]具体而言，根据 Charles Rivers实验室和我们的顾问，我们预计需要1公斤的化合物来完成 目的2的动物研究因此，我们开发的纯化方法就足够了。然而，在这方面， 我们现在需要大幅度提高产量。Curia Global是一家生产公吨 二甲胺四环素，并有竞争力的投标，以完成GMP药物的需要，这一赠款。但我们需要 他们消除了纯化步骤，如果成功的话，将大大降低未来的成本。 更高的需要。鉴于他们使用四环素的经验，并在与他们的进一步讨论中，他们 相信他们可以在技术转移过程中消除有问题的色谱纯化步骤。的 目标3和4的红利是，相应的成本将为16，000美元，而不是60，000美元。 kg.这些费用没有包括在最初的提案中。补充的目标是：改善 效率和增加产量从1至约15公斤丁醚米诺环素，以支持这两个 IND前和I期活动。

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. Our approach in U01AA028957 was a straightforward medchem plan, IND-enabling studies followed by first in human safety tests. A supplement is requested to meet unexpected direct expenses for Original Aim 1 and 2 with benefit to aims 3-4. [Original Aims: 1: Development of manufacturing standards; 2: Completion of pre-clinical IND enabling studies; 3: Phase I clinical trial; single- ascending dose; 4: Phase I clinical trial; multiple-ascending dose.] Specifically, based on estimations from Charles Rivers Lab and our consultants, we had anticipated needing 1 kg of compound to complete the animal studies of aim 2. As such, the purification method we developed would have sufficed. However, we now need to significantly upscale production. Curia Global is a company that produces metric tons of minocycline and has competitively bid to complete the GMP drug needs for this grant. However, we need them to eliminate a purification step, which, if successful, will dramatically reduce the future costs of the higher need. Given their experience with tetracycline and in further discussions with them, they are confident they can remove the problematic chromatographic purification step during tech transfer. The dividend for Aims 3 and 4 will be that the commensurate costs will be ~$16,000 rather than ~$60,000 per kg. These costs were not covered in the original proposal. The goal of the supplement is: To improve efficiency and increase output from 1 to approximately 15 kg butylether minocycline in support of both pre-IND and phase 1 activities.