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，目前已有7万多人 据报道，美国在2022年死于服药过量。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腔制剂，俗称纳尔康。虽然这种药物可以 为了挽救生命，它有许多缺点，包括对更有效的芬太尼类似物的疗效降低，短期的 行动的持续时间和副作用情况，包括阿片类药物的催促戒断。为了解决这一最可怕的问题 公共健康问题，我们最近开发了一种新的候选药物来阻断 被称为CSX-1004的合成阿片类药物是一种具有高结合亲和力和特异性的单抗 芬太尼及相关类似物。从机理上讲，CSX-1004直接隔离芬太尼及其类似物 可在不与靶阿片受体相互作用的情况下减轻脑内阿片类药物的影响。在……里面 临床前研究，我们发现静脉注射CSX-1004可以有效地逆转和 预防(&gt；10倍)芬太尼引起的啮齿动物和非人灵长类(NHP)呼吸抑制 持久的药效，持续3周以上。此外，CSX-1004还通过了关键的GLP毒理学和GMP 制造里程碑，使研究新药(IND)能够填补预防的目标适应症 静脉注射芬太尼类似物过量。这些发现鼓励了这样的想法：CSX-1004 在治疗芬太尼相关的尿路感染方面，治疗也可能发挥重要的临床作用。鉴于目前的药物 对于OUD(如丁丙诺啡、美沙酮、纳曲酮)显示治疗保留和复发不满意 尽管目前的药物使用效率不高，但显然有必要为OUD制定新的用药策略，这是NIDA使命的一个主要重点。在……里面 为了响应PAR-22-200，我们建议首先进行概念验证研究，以评估其效力， 静脉注射CSX-1004阻断芬太尼服用和恢复芬太尼的疗效和作用时间 国家卫生计划药物与食物选择自我给药程序中的药物寻觅(目标1)。在建立了IV CSX之后- 1004‘S在猴体内的有效性(目标1)，我们将进一步开发和优化CSX-1004作为皮下药物 (SC)AIM 2中芬太尼相关的OUD药物，与AIM 2相比，这将允许其在更广泛的临床环境中使用 静脉注射单抗治疗所需的住院环境。目标2的活动将包括改装配方、制造、 在NHP自我管理和啮齿动物毒理学研究中进行测试。在成功实现UG3阶段后 里程碑，将启动UH3阶段研究，以a)记录CSX-1004如何阻止芬太尼进入 使用PET/fMRI对NHP患者的大脑进行评估，以防止滥用相关神经活动的失调；以及b)评估是否 CSX-1004诱导芬太尼依赖猴子纳洛酮样戒断(目标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备案 OUD指征(目标4)。总之，我们期待着我们在NHP中的系统研究计划能够产生必要的 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。

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.