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。项目摘要/摘要 该SBIR应用程序是针对RFA-DA-19-019的RFA-DA-019提出的 阻止阿片类药物危机。 Creative Biopeptides，Inc。致力于提供有效且安全的非阿片类药物 每天遭受痛苦的5000万美国人的治疗，以及与阿片类药物依赖相处的200万人 或成瘾。当前数十年历史的成瘾治疗（如Metagadone）并未达到这一规模 问题，他们自己有虐待责任的问题。趋化因子（免疫系统的激素 介导先天免疫仪式）缓解疼痛，减轻Oioid镇痛并促进寻求毒品 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中发挥着核心作用。所以， 阻止趋化因子（即，而不是阿片类药物受体）为您提供了令人兴奋且未经测试的治疗机会 疼痛和阿片类药物使用障碍（OUD）。我们的趋化因子拮抗剂（阻滞剂）胡椒R103停止神经疗法 疼痛并增强吗啡可缓解急性疼痛的效力。最近的研究表明R103也可以 成为OUD的有效待遇。其他药物，阻止了相同的趋化因子受体 R103，降低了滥用药物的奖励和增强作用。使用模拟的大鼠行为研究 人类吸毒，我们和其他人报告说CXCR4拮抗剂AMD3100（Plerixafor），CCR5 拮抗剂maraviroc（selzentry）和CCR2拮抗剂减少了药物的奖励和运动作用 虐待。但是，只有两种批准的治疗方法只有一个受体靶标，并且具有显着的 安全问题（需要注射，过敏风险和/或肝毒性）。 R103是一种首选治疗 阻断多个趋化因子受体（CCR2/CCR5/CXCR4），是更重要的，我们先前的临床类似物（非常 类似的肽）在人类中没有安全问题。我们建议在动物自我管理模型中评估 这种模仿人类吸毒，无论R103是否会减少吗啡的摄入量。成功将定义为> 50％ 降低断点差异评分，这是吸毒动机的度量。身体依赖 慢性阿片类药物暴露期间的发展和终止阿片类药物摄入后，作为戒断 引发阿片类中继的综合征。我们将进一步评估R103是否会预防或钝化纳洛酮的沉积 依赖吗啡依赖大鼠的戒断迹象并停止退休。成功将降低> 50％ 与车辆相比，R103的“戒断症状评分”。我们还将评估R103的安全性 确定最大耐受剂量。该程序的成功执行将创建新的实质性 财产，II期开发中R103的脱危性研究，并将以预先指示达到顶峰 与FDA会面，为我们随后的人类效率研究制定监管批准计划 Oud。 Creative Bio肽，Inc已获得了R103的两项已发行的专利，即物质的组成 （US10,071,153）以及治疗神经性疼痛的用途（US10,130,674）。我们有十个未决申请， 包括使用R103减少吗啡在疼痛中的使用，以及作为成瘾的治疗方法。