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应用程序是为了响应RFA-DA-19-019（关于建筑技术的HEAL倡议）而提出的 来阻止阿片类药物危机Creative Bio-Peptides，Inc.致力于提供有效和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者提供治疗 或者上瘾目前几十年的成瘾治疗，如美沙酮，还没有达到这个程度 问题，他们有滥用责任的担忧。趋化因子（免疫系统的激素， 介导先天免疫炎症）增强疼痛，减少阿片类镇痛，并促进药物寻求 行为和成瘾-让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。所以， 阻断趋化因子（而不是阿片受体）提供了一个令人兴奋的和未经测试的治疗机会， 阿片类药物使用障碍（OUD）我们的趋化因子拮抗剂（阻断剂）肽R103阻止神经病理性 疼痛和增强吗啡的效力，以减轻急性疼痛。最近的研究表明，R103也可以 成为治疗OUD的有效方法。其他药物，阻断相同的趋化因子受体， R103，降低滥用药物的奖励和强化作用。利用大鼠行为研究， 我们和其他人已经报道了CXCR 4拮抗剂AMD 3100（Plerixafor）、CCR 5 拮抗剂马拉韦罗（Selzentry）和CCR 2拮抗剂降低药物的奖励和运动效应 虐待然而，仅有的两种批准的治疗方法每种仅阻断一种受体靶点，并且具有显著的 安全性问题（需要注射、过敏风险和/或肝毒性）。R103是优选的治疗，因为它 阻断多种趋化因子受体（CCR 2/CCR 5/CXCR 4），是更有效的和我们以前的临床类似物（非常 类似肽）在人类中没有安全性问题。我们建议在动物自我给药模型中评估 R103是否能减少吗啡的摄入。成功将被定义为>50% 减少断点差异分数，衡量吸毒动机。身体依赖性 在慢性阿片类药物暴露期间和阿片类药物摄入停止时发生，表现为戒断 引发阿片类药物复吸的综合征我们将进一步评估R103是否会预防或减弱纳洛酮沉淀 吗啡依赖大鼠的戒断症状并停止复发。成功将是减少>50%， R103与媒介物相比的“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。该计划的成功实施将创造新的知识分子 在第二阶段开发中对R103进行财产、去风险IND支持研究，并将以IND前达到高潮 与FDA会面，为我们随后的人体疗效研究制定监管批准计划， OUD。Creative Bio-Peptides，Inc已获得两项关于R103的专利， (US10 071，153）和在治疗神经性疼痛中的用途（US 10，130，674）。我们有10份申请， 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。