Antibody-based therapy for fentanyl-related opioid use disorder

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， 2022年美国报告的过量死亡人数。目前可用的逆转阿片类药物中毒的药物包括 阿片样物质拮抗剂纳洛酮（通常称为Narcan）的鼻内制剂。虽然这种药物可以 虽然可以挽救生命，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， 作用持续时间，以及包括阿片类药物戒断的副作用。为了解决这个可怕的 公共卫生问题，我们最近开发了一种新的候选药物，用于阻断 称为CSX-1004的合成阿片类药物，其是一种单克隆抗体（mAb），具有高结合亲和力和特异性， 芬太尼和相关类似物。在机制上，CSX-1004直接螯合芬太尼和相关类似物， 外周血，以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。在 在临床前研究中，我们发现静脉内（IV）施用CSX-1004可以有效地逆转和 预防（>10倍）芬太尼诱导的啮齿动物和非人灵长类动物（NHP）呼吸抑制， 持续3周以上的持久疗效。此外，CSX-1004已通过关键GLP毒理学和GMP 制造里程碑，使研究性新药（IND）能够用于预防 通过IV mAb给药的芬太尼类似物过量。这些发现鼓励了CSX-1004 治疗在治疗芬太尼相关OUD中也可发挥重要的临床作用。鉴于目前的药物 对于OUD（例如，丁丙诺啡、美沙酮、纳洛酮）显示出不令人满意的治疗保持和复发 率，有一个明确的需要，为OUD，这是NIDA的使命的主要重点新的药物治疗策略。在 针对PAR-22-200，我们建议首先进行概念验证研究，以评估效力， 静脉注射CSX-1004阻断芬太尼摄入和恢复芬太尼预充的有效性和作用持续时间 NHP中药物与食物选择自我给药程序中的药物寻求（目标1）。在建立第四CSX- 鉴于CSX-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作为皮下给药方案。 (SC)目标2中的芬太尼相关OUD药物，这将允许其在更广泛的临床环境中使用， IV mAb治疗所需的住院患者环境。目标2活动将包括重新配制、制造、 NHP自我给药测试和啮齿动物毒理学研究。在成功完成UG 3阶段后， 里程碑，将启动UH 3期研究，以a）记录CSX-1004如何阻止芬太尼进入 使用PET/fMRI来预防NHP中滥用相关神经活动的失调;和B）评估是否 CSX-1004在芬太尼依赖性猴中诱导纳洛酮样戒断（目的3）。最后，我们将完成 支持SC CSX-1004 IND备案所需的GLP毒理学和GMP生产活动， OUD指示（目标4）。总之，我们期待我们在NHP研究的系统计划，以产生必要的 支持IND活动和未来与CSX-1004相关的生物制剂许可申请（BLA）的信息。

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.