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

项目总结

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.