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

开发新型趋化因子受体拮抗剂治疗阿片类药物使用障碍

• 批准号: 10385311
• 负责人: Michael R Ruff
• 金额: $ 115.13万
• 依托单位: CREATIVE BIO-PEPTIDES, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10385311
• 关键词: Adherence; Affect; Ambulatory Care; American; Animal Model; Animals; Area; Behavior; Behavioral; Biological Assay; Biological Availability; Biological Markers; Brain; Buprenorphine; Cardiovascular system; Caring; Cessation of life; Clinical; Data; Data Analytics; Dependence; Development; Dopamine; Dose; Drug Kinetics; Drug Stability; Drug abuse; Economic Burden; Female; Goals; Gold; Health Professional; Health Services Accessibility; Helping to End Addiction Long-term; Heroin; Human; Immune signaling; Individual; Maintenance; Measures; Medical Staff; Metabolic; Methadone; Modeling; Morphine Dependence; Motivation; Naloxone; Neurobiology; Nucleus Accumbens; Opioid; Oral; Outcome; Oxycodone; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phase; Plasma; Program Development; Psychological reinforcement; Rattus; Recovery; Regimen; Reporting; Research Personnel; Resistance; Rewards; Risk; Rodent; Rodent Model; Safety; Self Administration; Sex Differences; Small Business Innovation Research Grant; Suboxone; Substance Use Disorder; Substance abuse problem; Sucrose; Testing; Toxicokinetics; Ventilatory Depression; Withdrawal; Withdrawal Symptom; Work; addiction; adherence rate; animal safety; base; behavior influence; behavioral study; chemokine; chemokine receptor; clinical development; craving; cytokine; design; drug of abuse; experience; experimental study; first-in-human; human model; improved; innovation; male; manufacturing scale-up; medication-assisted treatment; mu opioid receptors; non-opioid analgesic; novel; novel strategies; opioid agonist therapy; opioid overdose; opioid use; opioid use disorder; opioid withdrawal; personalized care; pre-clinical; preclinical safety; prescription opioid; programs; receptor; reinforcer; respiratory; response; safety study; safety testing; sex; side effect; social stigma; stability testing; substance use treatment; treatment duration

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.

七、项目概要 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。 寻求治疗必须解决获得合格医疗保健专业人员的机会有限以及接受治疗的障碍 接受药物辅助治疗 (MAT) 通常需要使用丁丙诺啡进行常见 MAT 治疗。 患者在 MAT 开始前几天会出现戒断症状。 此外，OUD 的耻辱。 如果患者接受门诊护理，治疗量可能会减少，但这是获得治疗的额外障碍 这些人和治疗他们的医务人员可供选择的选择很少， 由于美沙酮、丁丙诺啡和纳洛酮等护理标准往往无法成功实现 新的证据表明大脑趋化因子受体控制多巴胺奖励。 药物滥用的途径和影响行为效应，可被趋化因子受体减弱 CBP 提议使用 RAP-103（一种小型口服稳定趋化因子）扩展 OUD 的 MAT 功能。 我们的证据表明，受体拮抗剂肽可阻止阿片类药物的获取、维持和戒断。 RAP-103 作为一种用于 MAT 的非阿片类药物，具有显着的安全性和有效性优势，可阻止阿片类药物自身 固定比例测试中的给药显示阿片类药物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，RAP-103 还可以减轻症状。 纳洛酮在吗啡依赖的啮齿动物模型中诱导阿片类药物戒断的研究在这个项目中，我们的目标是。 我们打算进一步证明 RAP-103 作为 MAT 制剂的可行性并进行人体测试。 通过优化 RAP-103 减轻渐进性阿片类药物自我给药的最低剂量来做到这一点 鉴于 RAP-103 通过趋化因子发挥作用的独特机制，在雄性和雌性大鼠中进行了比例实验。 受体拮抗作用我们将识别中脑边缘（VTA 和核）中趋化因子和细胞因子的变化 伏隔核）大脑奖励区域，以提供 RAP-103 如何减轻奖励效应的机制 CBP 一直在开展阿片类药物和其他滥用药物的临床前药代动力学和毒代动力学安全性研究。 美国海关和边境保护局 (CBP) 已向提交 IND 和进行首次人体安全测试的要求转变。 组建了一支由经验丰富的 MAT 临床医生/研究人员组成的团队，为 OUD 规划临床开发计划 我们建议进行额外的临床前安全测试，以支持 OUD 的 IND 申请。 计划结束时 RAP-103 的治疗使用将推动 RAP-103 作为一种药物的临床开发。 MAT for OUD 的目标是提供更安全的治疗，没有滥用风险，改善患者的可及性、依从性、 耐受性和治疗优越的安全性（无呼吸抑制和滥用或转移的可能性）， 维持阿片类药物使用的动机降低，戒断症状和口服生物利用度减轻一次 每日剂量将使 RAP-103 成为 OUD MAT 工具箱中非常有价值的补充，最初是作为辅助剂 有助于克服 MAT 获取和使用未充分利用的问题的疗法。