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

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， 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。

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.