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.

项目概要 Kappa 阿片受体 (KOR) 在控制奖赏、动机和焦虑的大脑区域表达。强啡肽 (DYN) 是一种内源性 KOR 激动剂，控制 KOR 活性以促进生理性急性厌恶恐惧和焦虑等状态会促进逃避。此外，在阿片类药物戒断和戒断后， DYN/KOR 信号失调可能导致令人厌恶的身体和情感状态，这是复发。临床前，KOR 拮抗剂已证明可有效减少急性阿片类药物的体征撤回。目前用于减轻阿片类药物戒断症状的护理标准是 α2a 肾上腺素受体激动剂洛非西定。尽管已获得批准，但洛非西定仅在以下方面有效：戒断症状严重程度减轻，并可能产生显着的不良副作用，例如低血压、服用后出现急性直立性停滞和晕厥、QT 间期延长以及中枢神经系统抑制作用增强与镇静药物。 Cerevel Therapeutics 正在通过开发一种短效、选择性 KOR 拮抗剂。这种化合物 CVL-354 可减轻急性戒断症状啮齿类动物的阿片类药物戒断模型，我们已经完成了一个全面的非临床安全包，将支持在人体中给药长达 90 天。如果获得这些资金，我们准备运行单一和多个剂量递增研究，以评估健康志愿者的安全性和耐受性（UG3 部分）。在UH3部分我们将进行 PET 研究，结合其他技术进一步探索人类受体占据情况非临床安全和制造工作将支持第二阶段临床试验，旨在提供更多减轻阿片类药物戒断引起的身体症状的有效治疗选择。