A Novel Chemokine Receptor Antagonist to Block Opioid Reinforcement, Relapse and Physical Dependence

一种新型趋化因子受体拮抗剂，可阻止阿片类药物强化、复发和身体依赖性

• 批准号: 9908597
• 负责人: Michael R Ruff
• 金额: $ 32.18万
• 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 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9908597
• 关键词: AMD3100; Acute Pain; Adverse effects; Allergic; American; Analgesics; Anaphylaxis; Animal Model; Animals; Behavior; Binding; Biological Assay; Buprenorphine; CCR5 gene; CXCR4 gene; Chronic; Clinical; Cocaine; Data; Dependence; Development; Dose; Gold; Health; Hepatotoxicity; Hormones; Human; Immune; Immune system; Individual; Inflammation; Injections; Intake; Intellectual Property; Legal patent; Maximum Tolerated Dose; Measures; Mediating; Methadone; Modeling; Morphine; Morphine Dependence; Motivation; NOEL; Naloxone; Neurobiology; Opiate Addiction; Opioid; Opioid Analgesics; Opioid Receptor; Oral; Pain; Pain management; Peptides; Persons; Pharmaceutical Preparations; Phase; Physical Dependence; Placebo Control; Plasma; Population; Psychological reinforcement; Rattus; Recovery; Regimen; Relapse; Reporting; Rewards; Risk; Role; Safety; Self Administration; Sex Differences; Small Business Innovation Research Grant; Substance Withdrawal Syndrome; Sum; System; Technology; Testing; Therapeutic; Therapeutic Effect; Withdrawal; Withdrawal Symptom; addiction; analog; behavioral study; chemokine; chemokine receptor; chronic pain; clinical development; daily pain; desensitization; design; drug of abuse; drug reinforcement; drug seeking behavior; effective therapy; efficacy study; experience; human model; innovation; meetings; neuroinflammation; non-opioid analgesic; novel; off-patent; opioid epidemic; opioid exposure; opioid overdose; opioid use; opioid use disorder; painful neuropathy; phase 1 study; pre-clinical; preference; prevent; programs; receptor; receptor function; response; safety study; sex; success; treatment duration

7. Project Summary/Abstract This SBIR application is proposed in response to RFA-DA-19-019, the HEAL Initiative on building technologies to stop the opioid crisis. Creative Bio-Peptides, Inc. is committed to providing effective and safe non-opioid treatments for the 50 million Americans suffering daily pain and the 2 million who live with opioid dependency or addiction. Current decades-old addiction treatments like methadone are not up to the magnitude of this problem, and themselves have abuse liability concerns. Chemokines (hormones of the immune system that mediate innate immune inflammation) enhance pain, reduce opioid analgesia, and promote drug-seeking behavior and addiction – giving them a central role at the crossroads of chronic pain and the opioid crisis. So, blocking chemokines (rather than opioid receptors) provides an exciting and untested treatment opportunity for pain and opioid use disorders (OUD). Our chemokine antagonist (blocker) peptide R103 stops neuropathic pain and enhances the potency of morphine to relieve acute pain. Recent studies suggest that R103 could also become an effective treatment for OUD. Other drugs, that block the same chemokine receptors targeted by R103, lower the rewarding and reinforcing effects of drugs of abuse. Using rat behavioral studies that model human drug-taking, we and others have reported that a CXCR4 antagonist AMD3100 (Plerixafor), a CCR5 antagonist Maraviroc (Selzentry), and a CCR2 antagonist reduce the rewarding and locomotor effects of drugs of abuse. However, the only two approved treatments each block only one receptor target and have significant safety concerns (need to be injected, allergic risks and/or liver toxicity). R103 is a preferred treatment, as it blocks multiple chemokine receptors (CCR2/CCR5/CXCR4), is more potent and our prior clinical analog (very similar peptide) had no safety issues in humans. We propose to assess, in animal self-administration models that mimic human drug-taking, whether R103 reduces morphine intake. Success will be defined as a >50% reduction in the breakpoint difference score, a measure of motivation for drug-taking. Physical dependence develops during chronic opioid exposure and upon discontinuation of opioid intake, presents as a withdrawal syndrome that triggers opioid relapse. We will further assess if R103 will prevent or blunt naloxone-precipitated withdrawal signs in morphine-dependent rats and stop relapse. Success will be a >50% reduction in the “Withdrawal Symptom Score” of R103 compared to vehicle. We will also evaluate the safety of R103 by determining a maximum tolerated dose. Successful execution of this program will create new intellectual property, de-risk IND-enabling studies of R103 in Phase II development, and will culminate with a pre-IND meeting with the FDA to establish a regulatory approval plan for our subsequent human efficacy studies in OUD. Creative Bio-Peptides, Inc has obtained two issued patents for R103, the composition of matter (US10,071,153) and the use in treating neuropathic pain (US10,130,674). We have ten pending applications, including uses of R103 to reduce morphine use in pain, and as a treatment for addictions.

7. 项目总结/摘要 此 SBIR 应用是为了响应 RFA-DA-19-019（建筑技术 HEAL 倡议）而提出的 阻止阿片类药物危机。 Creative Bio-Peptides, Inc. 致力于提供有效且安全的非阿片类药物。 为 5000 万每天遭受疼痛的美国人和 200 万阿片类药物依赖患者提供治疗 目前已有数十年历史的成瘾治疗方法，如美沙酮，还达不到这种程度。 问题，并且他们自己也有滥用趋化因子（免疫系统的激素）的担忧。 介导先天免疫炎症）增强疼痛，减少阿片类镇痛，促进药物寻求 行为和成瘾——使他们在慢性疼痛和阿片类药物危机的十字路口发挥核心作用。 阻断趋化因子（而不是阿片受体）为以下疾病提供了令人兴奋且未经测试的治疗机会 我们的趋化因子拮抗剂（阻滞剂）肽 R103 可阻止神经病理性疼痛和阿片类药物使用障碍。 最近的研究表明，R103 还可以增强吗啡缓解急性疼痛的功效。 成为 OUD 的有效治疗药物，可阻断与 OUD 相同的趋化因子受体。 R103，使用大鼠行为模型研究降低滥用药物的奖励和强化作用。 人类吸毒，我们和其他人报道了 CXCR4 拮抗剂 AMD3100 (Plerixafor)、CCR5 拮抗剂 Maraviroc (Selzentry) 和 CCR2 拮抗剂可降低药物的奖赏和运动效应 然而，仅有的两种批准的治疗方法仅阻断一种受体靶标，并且具有显着的滥用效果。 安全问题（需要注射、过敏风险和/或肝脏毒性），R103 是首选治疗方法，因为它。 阻断多种趋化因子受体（CCR2/CCR5/CXCR4），更有效，我们之前的临床类似物（非常 我们建议在动物自我给药模型中进行评估。 模拟人类吸毒，R103 是否减少吗啡摄入量将被定义为 >50%。 断点差异分数的减少，这是衡量吸毒动机的指标。 在慢性阿片类药物暴露期间和停止阿片类药物摄入后发生，表现为戒断 我们将进一步评估 R103 是否会预防或减弱纳洛酮沉淀。 吗啡依赖大鼠出现戒断症状并停止复发，则成功率将降低 50% 以上。 R103与车辆的“戒断症状评分”我们还将通过以下方式评估R103的安全性。 确定最大耐受剂量 该计划的成功执行将创造新的知识。 财产，降低 R103 II 期开发中 IND 启用研究的风险，并将以预 IND 达到顶峰 与 FDA 会面，为我们后续的人体功效研究制定监管批准计划 OUD Creative Bio-Peptides, Inc 已获得两项 R103（物质成分）专利。 （US10,071,153）和用于治疗神经性疼痛（US10,130,674）我们有十个待决申请， 包括使用 R103 来减少吗啡在疼痛中的使用，以及作为成瘾的治疗方法。