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)及其后果是一个重大的公共卫生问题， 最近被宣布为国家公共卫生紧急状态。尽管有药物可用， 为了治疗OUD，需要改进的治疗方式，包括其他机制 行动。目前的药物治疗选择都是针对u-阿片受体，或者作为完整的 激动剂(美沙酮)、部分激动剂(丁丙诺啡)或拮抗剂(纳曲酮)。而这些 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 激动剂有滥用的责任，并且有很大程度的滥用、滥用和转移 在美国和国际上观察到(Lofwall 2014；Yokell 2012)。这导致了 由于缺乏获得豁免的处方者和患者对以下方面的处方限制而限制了访问 丁丙诺啡和通过联邦监管的阿片类药物治疗计划分配需要 每日观察丁丙诺啡。此外，还有对美沙酮过量的担忧。 纳曲酮要求在开始治疗之前戒除阿片类药物，这是治疗的障碍 治疗了很多病人。在美国210万患有自闭症的人中，只有20% 似乎接受了任何形式的治疗，许多接受这些药物治疗的人 不能实现阿片类药物使用的戒断，也不能实现康复(塞隆纳，2015)。因此， 需要有更多的药物治疗选择，特别是对于没有 滥用责任，并且不要求在治疗前完成阿片类药物的戒断。 非临床研究支持食欲素系统在药物寻找中的作用，如 选择性阻断食欲素-1受体(OX1R)上的信号减少对多种药物的寻求 虐待(詹姆斯2017)。C4X3256，一种非阿片类药物，高度选择性的OX1R拮抗剂 显示在OX1R有较长的停留时间，也减少了静脉注射自身 给药和线索诱导的尼古丁成瘾动物模型的恢复，提示 这可能是一种治疗一系列与成瘾有关的行为的方法。建议的研究 应用程序将使C4X3256从临床前开发进入第一阶段测试，包括 健康志愿者最多服药7天，而患有黑色素瘤的受试者最多服药28天。这个 目前的毒理学研究将支持C4X3256人体志愿者服用4周 几周。建议进行额外的毒理学研究，以延长分阶段给药时间。 第二阶段和有生育潜力的妇女参加第二阶段门诊试验。因此， 拟议的临床、临床前和支持性药物开发研究将使 C4X3256将进入第二阶段研究。

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.