Methocinnamox (MCAM): A novel opioid receptor antagonist

摘要/摘要 本申请请求补充母公司合作协议UH3DA048387，并回应 PA-20-272对现有NIH拨款和合作协议的行政补充(家长管理 补充临床试验(可选)。尽管有FDA批准的药物可用，阿片类药物危机仍在继续 用于治疗阿片使用障碍(美沙酮、丁丙诺啡和纳曲酮)和阿片过量(纳洛酮)。 虽然这些药物对许多患者都有效，但每种药物的药理特性都限制了他们的 临床应用。美托卡诺(MCAM)是一种新型阿片受体拮抗剂，具有以下药理特性 可使其在治疗阿片使用障碍(即防止复发)和过量用药方面特别有用。单人间 剂量的MCAM可在数周内阻断阿片类药物在大鼠和非人类灵长类动物中的滥用相关和毒性影响。 MCAM倡议目前在各合同研究组织(CRO)进行，并得到以下方面的支持 UH3DA048387包括：1)体内(大鼠和狗)和体外的良好实验室操作规范(GLP) 毒理学和安全性药理学研究；2)化学、制造和对照(CMC)；3)合成 非GMP MCAM马来酸酯，用于支持IND非临床研究的完成；4)稳定性研究；以及 5)制定临床计划。与FDA的IND前会议将于2023年夏天举行。IND应用程序 将提交，目标是在2024年进行第一次人体研究。为MCAM颁发了一项美国专利 另有三家公司正在接受审查。支持IND的研究的成本以及准备和 向FDA提交IND申请显著增加，远远超过#年的预算 原始应用程序。由于与CRO进行研究所需的费用意外增加 IND申请，当前奖励中没有足够的资金来完成所有必要的IND启用 学习。本补编要求额外拨款，以完成非GMP马来酸酯的合成，网址为 Veranova将用于完成Charles的非临床毒理学和安全性药理学研究 河水实验室。这一计划有可能对公众健康产生重大影响。MCAM有一个 超长的作用时间，高的口服生物利用度，可以经济地大规模合成，以及 在3000倍的剂量范围内没有任何已知的不良反应--它有可能拯救生命。

Abstract/Summary This application requests a supplement to parent cooperative agreement UH3DA048387 and is in response to PA-20-272 Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional). The opioid crisis continues despite the availability of FDA-approved medications for treating opioid use disorder (methadone, buprenorphine, and naltrexone) and opioid overdose (naloxone). While these medications are effective in many patients, each has pharmacological properties that limit their clinical utility. Methocinnamox (MCAM) is a novel opioid receptor antagonist with pharmacological properties that could make it especially useful for treating opioid use disorder (i.e., preventing relapse) and overdose. A single dose of MCAM blocks the abuse-related and toxic effects of opioids for weeks in rats and nonhuman primates. MCAM initiatives currently underway at various contract research organizations (CROs) and supported by UH3DA048387 include the following: 1) good laboratory practice (GLP) in vivo (rats and dogs) and in vitro toxicology and safety pharmacology studies; 2) chemistry, manufacturing, and controls (CMC); 3) synthesis of non-GMP MCAM maleate to support the completion of IND-enabling nonclinical studies; 4) stability studies; and 5) development of a clinical plan. A pre-IND meeting with the FDA will occur in Summer 2023. An IND application will be submitted with the goal of conducting first-in-human studies in 2024. One US patent for MCAM was issued and three more are under review. The cost of the IND-enabling studies as well as the cost of preparing and submitting an IND application to the FDA have increased significantly and are much greater than budgeted in the original application. Due to unanticipated increases in the cost of studies with CROs that are required for the IND application, there are not sufficient funds in the current award to complete all of the necessary IND-enabling studies. This supplement requests additional funding to complete synthesis of non-GMP MCAM maleate at Veranova that will be used to complete the nonclinical toxicology and safety pharmacology studies at Charles River Laboratories. This program has the potential to significantly impact public health. MCAM has an exceptionally long duration of action, high oral bioavailability, can be synthesized economically at scale, and does not have any known adverse effects over a 3000-fold dose range – it has the potential to save lives.