Methocinnamox (MCAM): A novel opioid receptor antagonist

Methocinnamox (MCAM)：一种新型阿片受体拮抗剂

基本信息

批准号：
10844948
负责人：
CHARLES P FRANCE
金额：
$ 15.5万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10844948
关键词：
Administrative Supplement Adverse effects Affect Agonist Award Biological Availability Blood Pressure Body Temperature Buprenorphine Canis familiaris Chemistry Clinical Clinical Trials Cognition Development Dose FDA approved Fentanyl Food Funding Goals Grant Heart Rate Heroin Hour In Vitro Intravenous Laboratories Legal patent Light Maleates Mediating Memory Methadone Methocinnamox Naloxone Naltrexone Opioid Opioid Antagonist Opioid agonist Oral Overdose Parents Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology Study Pharmacology and Toxicology Plasma Process Property Public Health Rattus Relapse Reporting Request for Applications Research Contracts Route Safety Schedule Self Administration Therapeutic Toxic effect Toxicology U-Series Cooperative Agreements United States National Institutes of Health analog cocaine self-administration cost effective therapy first-in-human good laboratory practice in vivo manufacture medication for opioid use disorder mu opioid receptors nonhuman primate novel opioid epidemic opioid misuse opioid overdose opioid use opioid use disorder overdose death pharmacologic pre-Investigational New Drug meeting prescription opioid misuse programs relapse prevention response

项目摘要

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.

摘要/总结本申请请求对家长合作协议 UH3DA048387 进行补充，并回应 PA-20-272 现有 NIH 拨款和合作协议的行政补充（家长管理尽管有 FDA 批准的药物可供使用，但阿片类药物危机仍在继续。用于治疗阿片类药物使用障碍（美沙酮、丁丙诺啡和纳曲酮）和阿片类药物过量（纳洛酮）。虽然这些药物对许多患者有效，但每种药物的药理学特性都限制了它们的作用临床实用性 Methocinnamox (MCAM) 是一种新型阿片受体拮抗剂，其药理学特性如下：可以使其特别适用于治疗阿片类药物使用障碍（即预防复发）和过量。 MCAM 剂量可在大鼠和非人类灵长类动物体内阻断阿片类药物滥用相关的毒性作用数周。 MCAM 计划目前正在各个合同研究组织 (CRO) 中开展，并得到以下机构的支持 UH3DA048387包括以下内容：1）体内（大鼠和狗）和体外良好实验室规范（GLP）毒理学和安全药理学研究；2）化学、制造和控制（CMC）；非 GMP MCAM 马来酸盐，用于支持完成 IND 的非临床研究；4) 稳定性研究； 5) 制定临床计划。 IND 申请将于 2023 年夏季与 FDA 举行。将提交，目标是在 2024 年进行首次人体研究。获得了 MCAM 的一项美国专利另外三项正在审查 IND 启用研究的成本以及准备和研究的成本。向 FDA 提交 IND 申请的数量显着增加，并且远高于预算由于与 CRO 的研究成本意外增加。 IND 申请，当前奖励中没有足够的资金来完成所有必要的 IND 支持该补充材料需要额外的资金来完成非 GMP MCAM 马来酸盐的合成。 Veranova 将用于完成 Charles 的非临床毒理学和安全药理学研究 River 实验室。该计划有可能对公众健康产生重大影响。作用持续时间特别长，口服生物利用度高，可以经济地大规模合成，并且在 3000 倍的剂量范围内没有任何已知的副作用——它有可能拯救生命。