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

项目总结 Kappa阿片受体(KOR)在大脑中控制奖赏、动机和焦虑的区域表达。 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 恐惧和焦虑等状态促使人们逃离。此外，在阿片类药物戒断和戒断后， 异常调节的Dyn/KOR信号可导致厌恶的身体和情感状态，这是导致 旧病复发。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 戒烟。目前减轻阿片类药物戒断身体症状的护理标准是 α2a肾上腺素能受体激动剂洛非西定。尽管洛非西定已获批准，但在以下情况下仅有一定疗效 戒断症状严重程度减轻，并可能有显著的不良副作用，如低血压， 急性站立和晕厥、QT延长以及服用时中枢神经系统抑制作用的增强 服用镇静剂。Cerevel Treateutics正在开发一种短效、 选择性的KOR对抗者。这种名为CVL-354的化合物减弱了急性戒断症状 啮齿动物的阿片类药物戒断模型，我们已经完成了一项全面的非临床安全方案，将 支持在人类身上服用长达90天的剂量。如果获得这些基金，我们将准备好运营单一和多个 评估健康志愿者安全性和耐受性的递增剂量研究(UG3部分)。在UH3部分 我们将进行正电子发射计算机断层扫描研究，以进一步探索受体在人类中的占有率，并结合其他 非临床安全性和制造工作，将支持旨在提供更多 有效的治疗选择，以缓解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.