Development of a Novel Chemokine Receptor Antagonist as a Treatment for Opioid Use Disorder

7.项目摘要 超过210万美国人患有阿片类药物使用障碍（OUD），每年导致47，000人死亡。个人 寻求治疗必须处理有限的获得合格的医疗保健专业人员，以及障碍， 药物辅助治疗（MAT）。使用丁丙诺啡的常见MAT治疗通常需要 患者在MAT开始前几天出现戒断症状。此外，OUD的耻辱 如果病人接受门诊护理，治疗可能会减少，这是获得治疗的另一个障碍。 和治疗。这些人和治疗他们的医务人员几乎没有选择， 由于美沙酮、丁丙诺啡和纳洛酮等标准治疗往往不能成功地实现 治疗目标。新的证据表明大脑趋化因子受体控制多巴胺奖励 途径和影响药物滥用的行为效应，可通过趋化因子受体减弱 对手。CBP建议用RAP-103（一种口服稳定的小趋化因子）扩展OUD的MAT能力 受体拮抗肽，阻断阿片类药物的获得、维持和戒断。我们的证据表明 RAP-103作为MAT使用的非阿片类药物具有显著的安全性和有效性优势， 在固定比例试验中给药，显示阿片样物质消耗总量和渐进比例减少 实验表明，维持阿片类药物使用的动机大大降低。此外，RAP-103减轻了 在吗啡依赖的啮齿动物模型中，纳洛酮诱导的阿片类戒断。在这个项目中，我们的目标 进一步证明RAP-103作为MAT剂的可行性，并进行人体试验。我们打算 通过优化RAP-103减轻进行性- 雄性和雌性大鼠的比例实验。鉴于RAP-103通过趋化因子发挥作用的独特机制， 受体拮抗，我们将确定趋化因子和细胞因子的变化，在中脑边缘（VTA和核 大脑奖励区域，以提供RAP-103如何减轻 阿片类药物和其他滥用药物。CBP一直在进行临床前药代动力学和毒代动力学安全性研究 测试以满足申请IND和进行首次人体安全性测试的要求。CBP已 组建了一个经验丰富的MAT临床医生/研究人员团队，以规划OUD的临床开发计划 使用.我们建议进行额外的临床前安全性试验，以支持OUD的IND申请 在计划结束时使用RAP-103治疗。CBP将推进RAP-103的临床开发， MAT for OUD的目标是提供更安全的治疗，无滥用风险，改善患者访问，依从性， 宽容和对待。上级安全性（无呼吸抑制和滥用或转移潜力）， 减少维持阿片类药物使用的动机，缓解戒断症状和口服生物利用度， 每日剂量将使RAP-103成为OUD MAT工具箱的一个非常有价值的补充，最初是作为一种替代品， 治疗，可以帮助克服MAT访问和使用的利用不足。

7. Project Summary Over 2.1 million Americans suffer from opioid use disorder (OUD) resulting in 47,000 deaths annually. Individuals seeking treatment must deal with limited access to qualified healthcare professionals, as well as barriers to getting medication assisted treatment (MAT). Common MAT treatments utilizing buprenorphine often require patients to experience withdrawal symptoms for several days prior to MAT initiation. Further, the stigma of OUD treatment, which could be reduced if patients received ambulatory care, acts as an additional hindrance to access and treatment. There is a paucity of options available for these individuals and the medical staff who treat them, as methadone, buprenorphine and naloxone, the standards of care, are often not successful in achieving treatment goals. Emerging evidence demonstrates that brain chemokine receptors control dopamine reward pathways and influence behavioral effects of drug abuse which can be blunted by chemokine receptor antagonists. CBP proposes to expand MAT capabilities for OUD with RAP-103, a small orally stable chemokine receptor antagonist peptide that block’s opioid acquisition, maintenance, and withdrawal. Our evidence indicates that RAP-103 has significant safety and efficacy advantages as a non-opioid for MAT use that blocks opioid self- administration in fixed-ratio tests that show reduction in total opioid consumed and in progressive-ratio experiments that show greatly reduced motivation to maintain opioid use. Additionally RAP-103 mitigates signs of naloxone induced opioid withdrawal in a rodent model of morphine dependence. In this project, our objective is to further demonstrate the feasibility of RAP-103 as a MAT agent and to progress to human testing. We intend to do this by optimizing the lowest dose at which RAP-103 mitigates opioid self-administration in progressive- ratio experiments in male and female rats. In view of the unique mechanism of RAP-103 action via chemokine receptor antagonism we will identify chemokine and cytokine changes in mesolimbic (VTA and nucleus accumbens) brain reward areas to provide a mechanism for how RAP-103 may mitigate the rewarding effects of opioids and other drugs of abuse. CBP has been conducting pre-clinical pharmacokinetic and toxicokinetic safety testing toward fulfilling requirements for filing an IND and conducting first-in-human safety testing. CBP has assembled a team of experienced MAT clinician/researchers to plan a clinical development program for an OUD use. We propose to conduct the additional pre-clinical safety tests that would support filing of an IND for an OUD treatment use of RAP-103 at the end of the program. CBP will advance clinical development of RAP-103 as a MAT for OUD with goals to provide safer treatment with no abuse risk, improve patient access, adherence, tolerance and treatment. The superior safety profile (no respiratory depression and abuse or diversion potential), reduced motivation to maintain opioid use, mitigation of withdrawal symptoms and oral bioavailability by once daily dosing would make RAP-103 a highly valuable addition to the OUD MAT toolbox, initially as an adjunctive therapy that can help overcome the underutilization of MAT access and use.