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

7.项目总结 超过210万美国人患有阿片使用障碍(OUD)，每年导致4.7万人死亡。个人 寻求治疗必须解决获得合格医疗专业人员的有限机会，以及 接受药物辅助治疗(MAT)。使用丁丙诺啡的常见垫类治疗通常需要 患者在开始服用地塞米松前会有几天的戒断症状。此外，OUD的耻辱 如果患者接受门诊护理，治疗可能会减少，这是获得治疗的额外障碍 和治疗。对于这些个人和治疗他们的医务人员来说，可用的选择很少， 作为美沙酮、丁丙诺啡和纳洛酮的治疗标准，往往达不到 治疗目标。新的证据表明，大脑趋化因子受体控制多巴胺奖赏 趋化因子受体可钝化药物滥用行为效应的途径和影响 对抗者。CBP建议使用RAP-103扩大OUD的MAT功能，RAP-103是一种口服稳定的小分子趋化因子 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作为一种非阿片类药物，具有显著安全性和有效性优势，可阻断阿片类药物的自我作用 在显示阿片类药物总消耗量和累进比率减少的固定比例试验中给药 实验表明，维持阿片类药物使用的动机大大降低。此外，RAP-103还能缓解体征 纳洛酮诱导吗啡依赖啮齿动物阿片类药物戒断。在这个项目中，我们的目标是 目的是进一步证明RAP-103作为垫剂的可行性，并进行人体试验。我们打算 要做到这一点，优化RAP-103在渐进性-阿片类药物自我给药中减轻阿片类药物自我给药的最低剂量 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中脑边缘(VTA)和核内趋化因子和细胞因子的变化 伏隔区)，以提供一种机制，说明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 测试以满足提交IND和进行首个人类安全测试的要求。CBP有 组建经验丰富的MAT临床医生/研究人员团队，为OUD制定临床开发计划 使用。我们建议进行额外的临床前安全性测试，以支持向OUD提交IND 在节目结束时使用RAP-103进行治疗。CBP将推动RAP-103作为一种 我们的目标是提供更安全的治疗而没有滥用风险，改善患者的接触，依从性， 耐受性和治疗。卓越的安全性(没有呼吸抑制、滥用或转移的可能性)， 一次减少维持阿片类药物使用、缓解戒断症状和口服生物利用度的动力 每天服用RAP-103将使RAP-103成为oud mat工具箱的一个非常有价值的补充，最初是作为一种辅助工具 可帮助克服垫子接触和使用不足的治疗方法。

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.