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CVL-354, a kappa opioid receptor antagonist for treatment of opioid use disorder, withdrawal and relapse

CVL-354，一种 kappa 阿片受体拮抗剂，用于治疗阿片类药物使用障碍、戒断和复发

基本信息

批准号：
10321502
负责人：
Philip Iredale
金额：
$ 540万
依托单位：
CEREVEL THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10321502
关键词：
Abstinence Acute Address Adrenergic Agonists Adult Affective Affinity Agonist Animals Anxiety Area Attenuated Award Brain Central Nervous System Depressants Chemistry Chemosensitization Chronic Clinic Clinical Clinical Research Data Development Dopamine Dose Drug Kinetics Drug abuse Dynorphins Electrocardiogram Formulation Fright Funding Funding Opportunities Future Grant Human Hypotension Laboratories Laboratory Finding Measures Mediating Mental Depression Modeling Motivation Mus Opioid Opioid Antagonist Opioid agonist Oral Orthostasis Output Oxycodone Pathologic Pharmaceutical Preparations Pharmacologic Substance Phase Phase II Clinical Trials Physiological Positioning Attribute Positron-Emission Tomography Pre-Clinical Model Property Receptor Signaling Regimen Relapse Research Rewards Rodent Running Safety Serious Adverse Event Severities Stress Syncope Therapeutic Up-Regulation Withdrawal Withdrawal Symptom Woman Work analytical method carfentanil child bearing clinically significant design developmental toxicity drug abstinence drug withdrawal effective therapy first-in-human healthy volunteer human data kappa opioid receptors lofexidine manufacturing process mu opioid receptors novel opioid use disorder opioid withdrawal patient population phase 2 study physical symptom pre-clinical preclinical safety receptor reproductive toxicity safety assessment safety study side effect spiradoline standard of care

项目摘要

PROJECT SUMMARY Kappa opioid receptors (KOR) are expressed in brain areas that control reward, motivation, and anxiety. Dynorphin (DYN), an endogenous KOR agonist controls KOR activity to promote physiological acute aversive states such as fear and anxiety to promote escape. Furthermore, upon opioid drug withdrawal and abstinence, dysregulated DYN/KOR signaling can result in aversive physical and affective states that are a major driver of relapse. Preclinically, KOR antagonists have demonstrated efficacy in reducing the physical signs of acute opioid withdrawal. The current standard of care administered to reduce the physical symptoms of opioid withdrawal is the alpha 2a adrenergic receptor agonist, lofexidine. Although approved, lofexidine is only modestly effective at withdrawal symptom severity reduction and can have significant unwanted side effects such as hypotension, acute orthostasis and syncope, QT prolongation, and the potentiation of CNS depressant effects when taken with sedating drugs. Cerevel Therapeutics is addressing this unmet need with the development of a short-acting, selective KOR antagonist. This compound, CVL-354, attenuated the physical signs of withdrawal in an acute opioid withdrawal model in rodents and we have completed a comprehensive nonclinical safety package that will support dosing up to 90 days in humans. If awarded these funds, we are poised to run single and multiple ascending dose studies to assess safety and tolerability in healthy volunteers (UG3 portion). In the UH3 portion we will execute PET studies to further explore receptor occupancy in human, in combination with additional nonclinical safety and manufacturing work that will support a Phase 2 clinical trial aimed at providing a more effective treatment option to mitigate the physical symptoms of opioid withdrawal.

项目摘要 Kappa阿片受体（KOR）在控制奖励，动机和焦虑的大脑区域中表达。强啡肽（Dynorphin，DYN）是一种内源性KOR激动剂，通过调节KOR活性，促进生理性急性厌恶反应恐惧和焦虑等状态，以促进逃避。此外，在阿片类药物戒断和禁欲后， DYN/KOR信号转导失调可导致令人厌恶的身体和情感状态，这些状态是DYN/KOR信号转导的主要驱动力。复发临床前，KOR拮抗剂已证明在减少急性阿片类药物的体征方面有效戒断目前为减少阿片类药物戒断的身体症状而实施的护理标准是 α 2a肾上腺素能受体激动剂洛非西定。虽然获得批准，但洛非西定仅在以下方面适度有效：戒断症状严重程度降低并可能具有显著的不希望的副作用如低血压，急性直立性和晕厥，QT间期延长，以及服用时CNS抑制作用增强注射了镇静剂Cerevel Therapeutics正在开发一种短效，选择性KOR拮抗剂。这种化合物CVL-354在急性戒断反应中减弱了戒断的体征。我们已经完成了一个全面的非临床安全性包，支持人体给药长达90天。如果获得这些资金，我们准备运行单一和多个在健康志愿者中评估安全性和耐受性的剂量递增研究（UG 3部分）。在UH 3部分我们将进行PET研究，以进一步探索人类的受体占有率，并结合其他研究非临床安全性和生产工作，将支持旨在提供更多有效的治疗选择，以减轻阿片类药物戒断的身体症状。