Clinical Evaluation of C4X3256, a Non-Opioid, Highly-Selective Orexin-1 Receptor Antagonist for the Treatment of Opioid Use Disorder

阿片类药物使用障碍（OUD）及其后果是一个主要的公共卫生问题， 最近被宣布为国家突发公共卫生事件。尽管有可用的药物 为了治疗OUD，需要改进的治疗方式，其涉及OUD的其他机制。 行动上目前的药理学治疗选择都靶向μ-阿片受体，无论是作为一个完整的 激动剂（美沙酮）、部分激动剂（丁丙诺啡）或拮抗剂（纳洛酮）。虽然这些 药物已经证明了有效性和安全性，但它们也有局限性。全部和部分 激动剂具有滥用倾向，并且已经发生了显著水平的误用、滥用和转移。 在美国和国际上观察到（Lofwall 2014; Yokell 2012）。这导致 由于缺乏豁免处方者和患者对处方的限制， 丁丙诺啡和通过联邦监管的阿片类药物治疗计划配药， 每日观察丁丙诺啡。此外，人们还担心美沙酮过量。 纳洛酮需要在开始治疗前戒断阿片类药物，这是一个障碍， 为许多患者治疗。在美国210万OUD患者中，只有20% 似乎接受任何形式的治疗，许多接受这些药物治疗的人 未实现戒断阿片类药物使用，且未能实现康复（Saloner 2015）。因此，在本发明中， 需要额外的药理学治疗选择，特别是对于没有 滥用责任，并且不需要在治疗前完成阿片类药物戒断。 非临床研究支持食欲素系统在药物寻找中的作用，因为化合物 选择性阻断食欲素-1受体（OX 1 R）的信号传导， 滥用（James 2017）。C4 X3256，一种非阿片类药物，高选择性OX 1 R拮抗剂， 显示在OX 1 R处具有长的停留时间，并且还减少静脉内的自身免疫。 在尼古丁成瘾的动物模型中， 它可以治疗一系列与成瘾有关的行为。建议的研究 申请将C4 X3256从临床前开发阶段转移到I期测试阶段，包括 健康志愿者给药长达7天，OUD受试者给药长达28天。的 目前的毒理学研究将支持对人类志愿者给予C4 X3256 4 周拟定了额外的毒理学研究，以延长阶段给药持续时间 II期和有生育能力的女性参与II期门诊试验。因此 拟定的临床、临床前和支持性药物开发研究将允许 C4 X3256进入II期研究。

Opioid use disorder (OUD) and its consequences are a major public health concern and have recently been declared a national public health emergency. Despite the availability of medications to treat OUD, there is a need for improved treatment modalities that involve other mechanisms of action. Current pharmacologic treatment options all target the mu-opioid receptor, either as a full agonist (methadone), partial agonist (buprenorphine), or antagonist (naltrexone). While these medications have demonstrated efficacy and safety, they also have limitations. Full and partial agonists have abuse liability, and significant levels of misuse, abuse, and diversion have been observed in the US and internationally (Lofwall 2014; Yokell 2012). This has resulted in restrictions on access due to a lack of waivered prescribers and patient limits on prescribing for buprenorphine and dispensing through federally regulated opioid treatment programs requiring daily observed buprenorphine. In addition, there are concerns about methadone overdose. Naltrexone requires abstinence from opioids prior to initiation of treatment, which is a barrier to treatment for many patients. Of the 2.1 million people suffering from OUD in the US, only 20% seem to receive any form of treatment and many of those who are treated with these medications do not achieve abstinence from opioid use and fail to achieve recovery (Saloner 2015). Thus, there is a need for additional pharmacologic treatment options, particularly for medications without abuse liability and that do not require completion of withdrawal from opioids prior to treatment. Nonclinical studies support a role for the orexin system in drug seeking, as compounds that selectively block signaling at the orexin-1 receptor (OX1R) reduce seeking of multiple drugs of abuse (James 2017). C4X3256, a Non-Opioid, Highly-Selective OX1R Antagonist has been shown to have a long residence time at the OX1R, and also reduce intravenous self- administration and cue-induced reinstatement in animal models of nicotine addiction, suggesting it could be a treatment for a range of addiction related behaviors. Studies proposed in the application will move C4X3256 from preclinical development through Phase I testing, including up to 7 days dosing in healthy volunteers and up to 28 days dosing in subjects with OUD. The current toxicology studies will support the administration of C4X3256 to human volunteers for 4 weeks. Additional toxicology studies are proposed to allow for extended dosing duration in phase II and for women of childbearing potential to participate in Phase II outpatient trials. Thus, the clinical, preclinical and supporting pharmaceutical development studies proposed will allow C4X3256 to move to Phase II studies.