Antibody-based therapy for fentanyl-related opioid use disorder

基于抗体的芬太尼相关阿片类药物使用障碍治疗

基本信息

批准号：
10831206
负责人：
Paul T Bremer
金额：
$ 420.26万
依托单位：
MCLEAN HOSPITAL
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：
2023-09-30 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10831206
关键词：
Abstinence Accounting Address Affinity Ambulatory Care Facilities American Animal Model Antibody Therapy Applications Grants Behavior Behavioral Binding Biological Products Books Brain Brain region Buffers Buprenorphine Clinical Clonidine Cocaine Data Development Diprenorphine Dose Effectiveness Excipients Fentanyl Food Formulation Functional Magnetic Resonance Imaging Future Injectable Inpatients Intravenous Intravenous infusion procedures Investigational Drugs Isotonic Exercise Licensing Life Measures Methadone Mission Monkeys Monoclonal Antibodies Mus Naloxone Naltrexone National Institute of Drug Abuse Opiate Addiction Opioid Opioid Antagonist Opioid Receptor Overdose Oxycodone Pharmaceutical Preparations Pharmacology Pharmacotherapy Phase Play Positron-Emission Tomography Pre-Clinical Model Prevention Procedures Production Public Health Rattus Recommendation Relapse Reporting Rodent Role Running Safety Self Administration Severities Sodium Chloride Specific qualifier value Specificity Testing Therapeutic Therapeutic Monoclonal Antibodies Time Toxicology United States Ventilatory Depression Withdrawal Work abuse liability analog antagonist antinociception drug candidate drug development effective therapy fentanyl abuse fentanyl analog fentanyl overdose human monoclonal antibodies in vivo intravenous administration manufacture manufacturing run medication for opioid use disorder neural neural circuit non-opioid analgesic nonhuman primate novel opioid epidemic opioid mortality opioid overdose opioid use disorder opioid withdrawal overdose death peripheral blood pharmacologic preclinical study prevent programs receptor respiratory response screening side effect stability testing subcutaneous synthetic opioid

项目摘要

Abstract. Abuse of synthetic opioids is a rapidly intensifying public health problem with more than 70,000 reported US overdose deaths in 2022. Currently available medications to reverse opioid intoxication include an intranasal formulation of the opioid antagonist naloxone, commonly known as Narcan. While this medication can be lifesaving, it has many drawbacks including decreased efficacy against more potent fentanyl analogs, a short duration of action, and a side-effect profile that includes precipitated opioid withdrawal. To address this direst public health problem, we recently developed a novel candidate medication for blocking the harmful effects of synthetic opioids known as CSX-1004, a monoclonal antibody (mAb) with high binding affinity and specificity to fentanyl and related analogs. Mechanistically, CSX-1004 directly sequesters fentanyl and related analogs in peripheral blood to mitigate opioid effects in the brain without interacting with the target µ-opioid receptors. In preclinical studies, we found that intravenous (IV) administration of CSX-1004 can effectively reverse and prevent (>10-fold) fentanyl-induced respiratory depression in rodents and non-human primates (NHP) with durable efficacy that lasts over 3 weeks. Moreover, CSX-1004 has passed key GLP toxicology and GMP manufacturing milestones, enabling an investigational new drug (IND) filling for the target indication of preventing fentanyl analog overdose via IV mAb administration. These findings have encouraged the idea that CSX-1004 therapy could also play a clinically important role in treating fentanyl-related OUD. Given that current medications for OUD (e.g., buprenorphine, methadone, naltrexone) show unsatisfactory treatment retention and relapse rates, there is a clear need for new medication strategies for OUD, which is a major focus of NIDA’s mission. In response to PAR-22-200, we propose to first conduct proof-of-concept studies that will evaluate the potency, efficacy, and duration of action of IV CSX-1004 in blocking fentanyl-taking and reinstatement of fentanyl-primed drug-seeking in drug vs food choice self-administration procedures in NHP (Aim 1). After establishing IV CSX- 1004's effectiveness in monkeys (Aim 1), we will further develop and optimize CSX-1004 as a subcutaneous (SC) fentanyl-related OUD medication in Aim 2, which will permit its use in a wider clinical setting compared to the required in-patient setting for IV mAb treatment. Aim 2 activities will include reformulation, manufacturing, testing in NHP self-administration, and rodent toxicology studies. After successfully achieving the UG3 phase milestones, UH3 phase studies will be initiated to a) document how CSX-1004 precludes fentanyl from entering the brain to prevent dysregulation of abuse-related neural activity in NHP using PET/fMRI; and b) evaluate if CSX-1004 induces naloxone-like withdrawal in fentanyl-dependent monkeys (Aim 3). Lastly, we will complete the GLP toxicology and GMP manufacturing activities necessary to support IND filing of SC CSX-1004 for the OUD indication (Aim 4). Together, we anticipate our systematic program of studies in NHPs to generate essential information that will support IND activities and future biologics license applications (BLA) related to CSX-1004.

抽象的。滥用合成阿片类药物是一个迅速加剧的公共卫生问题，超过70,000 报道了我们在2022年过量用药过量。目前可用的药物逆转阿片类药物包括阿片类药物拮抗剂纳洛酮的鼻内配方，通常称为Narcan。虽然这种药物可以为了挽救救生，它具有许多缺点，包括效率降低，对更有效的芬太尼类似物，很短作用持续时间和包括沉淀阿片类药物戒断的副作用曲线。解决这个目的地公共卫生问题，我们最近开发了一种新颖的候选药物，以阻止合成阿片类药物称为CSX-1004，一种具有高结合亲和力和特异性的单克隆抗体（MAB）芬太尼和相关类似物。从机械上讲，CSX-1004直接隔离芬太尼和相关的类似物外周血可减轻大脑中阿片类药物的作用，而无需与靶µ-阿片受体相互作用。在临床前研究，我们发现CSX-1004的静脉内（IV）给药可以有效地逆转和防止芬太尼诱导的（10倍）啮齿动物和非人类素数（NHP）的（NHP）持续3周的耐用效率。此外，CSX-1004通过了关键GLP毒理学和GMP 制造里程碑，实现研究性新药（IND），以防止目标指示芬太尼类似物过量通过静脉内施用。这些发现鼓励了CSX-1004的想法治疗在治疗与芬太尼相关的OUD方面也可能发挥临床重要作用。考虑到当前的药物对于OUD（例如丁丙诺啡，Metagadone，Naltrexone）显示出不满意的治疗保留和退休价格，很明显需要为Oud提供新的药物策略，这是NIDA使命的重点。对PAR 22-200的反应，我们建议首先进行概念验证研究，以评估效力， IV CSX-1004在阻断芬太尼摄入和恢复芬太尼化的官方的功效和作用持续时间 NHP中的药物与食物选择自我管理程序的寻求药物（AIM 1）。建立IV CSX- 1004在猴子中的有效性（AIM 1），我们将进一步发展并优化CSX-1004作为皮下（SC）AIM 2中与芬太尼相关的OUD药物，这将允许在广泛的临床环境中使用 IV MAB治疗所需的住院设置。 AIM 2活动将包括重新制定，制造， NHP自我管理和啮齿动物毒理学研究中的测试。成功实现UG3阶段之后里程碑，UH3阶段研究将启动到）a）记录CSX-1004如何排除芬太尼进入通过PET/fMRI，大脑可防止NHP中与滥用相关的神经活动的失调； b）评估是否 CSX-1004在依赖芬太尼依赖性猴子中诱导纳洛酮样的戒断（AIM 3）。最后，我们将完成 GLP毒理学和GMP制造活动，以支持SC CSX-1004的IND提交 OUD指示（AIM 4）。我们预计我们在NHP中的系统研究计划将产生必需品将支持与CSX-1004相关的IND活动和未来生物制品许可应用程序（BLA）的信息。