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

基本信息

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
项目类别：
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

项目摘要

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.

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合格医疗保健专业人员的机会，以及获得药物辅助治疗（MAT）。使用丁丙诺啡的常见垫子治疗通常需要在MAT计划前几天，患者会经历戒断症状。此外，Oud的污名如果患者获得门诊护理，可以减少治疗，这是额外的障碍和治疗。这些个人和对待他们的医务人员都有很少的选择，作为Metagadone，丁丙诺啡和纳洛酮（护理标准）通常无法成功实现治疗目标。新兴证据表明，脑趋化因子接收器控制多巴胺奖励途径和影响药物滥用的行为影响，这可能会被趋化因子接收器钝化对手。 CBP提案提出了用RAP-103扩展OUD的MAT功能的提议，RAP-103（一种小口服趋化因子）受体拮抗剂肽阻断了阿片类药物的获取，维护和戒断。我们的证据表明 RAP-103具有可阻止阿片类药物自我的非阿片类药物的非阿片类药物具有显着的安全性和有效的优势在固定比率测试中给药，显示总阿片类药物消耗和进行性比率减少表明维持阿片类药物使用的动力大大减少的实验。此外，RAP-103减轻标志纳洛酮在吗啡依赖性的啮齿动物模型中诱导阿片类药物戒断。在这个项目中，我们的目标是为了进一步证明RAP-103作为MAT剂的可行性并进行人类测试。我们打算通过优化最低剂量来做到这一点，RAP-103减轻渐进的oid自我给药。男性和雌性大鼠的比率实验。鉴于RAP-103作用的独特机制通过趋化因子受体拮抗剂我们将鉴定中左右的趋化因子和细胞因子变化（VTA和Nucleus） a伏and）大脑奖励领域，以提供RAP-103如何减轻奖励影响的机制 opioid和其他滥用药物。 CBP一直在进行临床前药代动力学和有毒动力学安全性测试满足提交IND和进行首次人类安全测试的要求。 CBP有组建了一支经验丰富的MAT临床/研究人员的团队，以计划OUD的临床开发计划使用。我们建议进行额外的临床前安全测试，以支持为Oud提交IND RAP-103在程序结束时使用RAP-103。 CBP将推进RAP-103的临床开发垫子的目标有目标，以提供更安全的治疗，没有虐待风险，改善患者的访问，依从性，耐受性和治疗。优越的安全性（无呼吸抑郁，滥用或转移潜力），减少维持阿片类药物使用，减轻戒断症状和口服生物利用度的动机每日剂量将使RAP-103成为Oud Mat Toolbox的高度宝贵补充，最初是辅助手段可以帮助克服垫子访问和使用的基础的治疗。