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.

摘要：合成阿片类药物的滥用是一个迅速加剧的公共卫生问题，有超过 70,000 人滥用合成阿片类药物。据报道，美国将于 2022 年因服药过量死亡。目前可用于逆转阿片类药物中毒的药物包括阿片类拮抗剂纳洛酮的鼻内制剂，通常称为纳洛酮，而这种药物可以。虽然它可以挽救生命，但它有许多缺点，包括对更有效的芬太尼类似物的功效降低、短期作用持续时间，以及包括加速阿片类药物戒断在内的副作用。公共卫生问题，我们最近开发了一种新的候选药物来阻止有害影响称为 CSX-1004 的合成阿片类药物，一种单克隆抗体 (mAb)，具有高结合亲和力和特异性从机制上讲，CSX-1004 直接隔离芬太尼和相关类似物。外周血可减轻阿片类药物在大脑中的作用，而不与目标μ阿片受体相互作用。临床前研究中，我们发现静脉注射（IV）CSX-1004可以有效逆转和预防（>10倍）芬太尼引起的啮齿动物和非人灵长类动物（NHP）呼吸抑制持久功效持续超过3周此外，CSX-1004已通过关键的GLP毒理学和GMP。制造里程碑，使研究性新药 (IND) 能够满足预防的目标适应症通过 IV mAb 给药芬太尼类似物过量的结果支持了 CSX-1004 的观点。鉴于目前的药物治疗，这种疗法也可以在治疗芬太尼相关的 OUD 方面发挥重要的临床作用。 OUD（例如丁丙诺啡、美沙酮、纳曲酮）的治疗保留率和复发率不理想率，显然需要针对 OUD 的新药物策略，这是 NIDA 使命的主要重点。为了回应 PAR-22-200，我们建议首先进行概念验证研究来评估其效力， IV CSX-1004 阻断芬太尼服用和恢复芬太尼引发的功效和作用持续时间 NHP 中药物寻求与食物选择自我管理程序（目标 1）建立 IV CSX- 后。 1004 在猴子中的有效性（目标 1），我们将进一步开发和优化 CSX-1004 作为皮下注射剂 (SC) 目标 2 中芬太尼相关的 OUD 药物，与传统药物相比，这将允许其在更广泛的临床环境中使用目标 2 活动所需的住院环境将包括重新配制、生产、成功实现 UG3 阶段后，进行 NHP 自我给药测试和啮齿动物毒理学研究。里程碑，UH3 阶段研究将启动 a) 记录 CSX-1004 如何阻止芬太尼进入使用 PET/fMRI 来预防 NHP 中与虐待相关的神经活动失调；b) 评估是否 CSX-1004 在芬太尼依赖的猴子中诱导纳洛酮样戒断（目标 3）。支持 SC CSX-1004 的 IND 备案所需的 GLP 毒理学和 GMP 生产活动 OUD 指示（目标 4），我们预计 NHP 的系统研究计划将产生必要的成果。将支持与 CSX-1004 相关的 IND 活动和未来生物制品许可证申请 (BLA) 的信息。