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

补充：治疗酒精使用障碍的药物开发 - U01AA028957

• 批准号: 10840525
• 负责人: SUSAN E. BERGESON
• 金额: $ 15.3万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2024-05-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10840525
• 关键词: Address; Animals; Chromatography; Clinical Treatment; Collaborations; Competitive Bidding; Complex; DSM-V; Dangerousness; Development; Disease; Dose; Ethanol; Ethers; FDA approved; Future; Goals; Grant; Innate Immune System; Lead; Medical; Methods; Minocycline; Morbidity - disease rate; National Institute on Alcohol Abuse and Alcoholism; Output; Patients; Persons; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Physical Dependence; Production; Risk; Rivers; Tetracyclines; Withdrawal Symptom; alcohol use disorder; cost; experience; first-in-human; high risk drinking; improved; manufacture; off-label use; pre-clinical; public health relevance; safety testing; success; therapy development

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.

美国有近1500万人患有澳元，全球约有1亿人。超过5%的医疗费用 与酒精有关的疾病也有风险。尽管FDA批准了三种治疗AUD的药物，以及 其他几种药物在标签外使用，药物仅显示出适度的成功(在约20%的患者中 已治疗)。因此，在整个DSM-V中迫切需要新的药物疗法 AUD光谱。我们在U01AA028957中的方法是一个简单的MEDCHEM计划，支持IND 研究紧随其后的是人体安全测试。需要补充以满足意外的直接要求 原目标1和2的费用，惠及目标3-4。[最初目标：1：发展 制造标准；2：完成临床前IND使能研究；3：I期临床试验； 递增剂量；4：I期临床试验；多次递增剂量。]具体地说，基于来自 Charles Rivers Lab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的动物实验。因此，我们开发的纯化方法就足够了。然而， 我们现在需要大幅提高产量。Curia Global是一家生产公吨天然气的公司 米诺环素，并已竞争性地竞标，以完成GMP药物需求的这一赠款。然而，我们需要 如果成功，将极大地降低未来的成本 更高的需求。鉴于他们使用四环素的经验以及在与他们的进一步讨论中，他们是 有信心他们可以在技术转让过程中删除有问题的层析纯化步骤。这个 AIMS 3和AIMS 4的红利将是相应的成本为约16,000美元，而不是约60,000美元 千克。这些费用没有包括在最初的提案中。增刊的目的是：改进 效率和产量从1公斤丁醚米诺环素增加到大约15公斤，以支持这两种 前期IND和第一阶段活动。