A novel and highly selective orexin 1 receptor antagonist for the treatment of patients with opioid use disorder.

一种新型高选择性食欲素 1 受体拮抗剂，用于治疗阿片类药物使用障碍患者。

• 批准号: 10322644
• 负责人: Thor Ostenfeld
• 金额: $ 303.27万
• 依托单位: ASTRAZENECA PHARMACEUTICALS, LP
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322644
• 关键词: Abstinence; Adverse event; Animal Model; Anxiety; Arousal; Attenuated; Behavior; Behavioral; Biological Availability; Blood; Blood - brain barrier anatomy; Buprenorphine; Canis familiaris; Carbon Dioxide; Cerebrospinal Fluid; Cessation of life; Chemistry; Clinic; Clinical; Clinical Research; Collaborations; Dose; Double-Blind Method; Drug Addiction; Drug Kinetics; Drug usage; Economics; Electrocardiogram; Enzymes; Evaluation; FDA approved; Food; Hematology; Human Volunteers; Hypothalamic structure; Impairment; Incidence; Laboratory Animals; Lateral; Measurement; Measures; Metabolic; Metabolism; Morphine; Motivation; Neuropeptides; Nicotine; Opioid; Oral; Overdose; Oxygen; Patient Self-Report; Patients; Pharmaceutical Preparations; Phase; Placebos; Plasma; Population; Primates; Process; Property; Psychological reinforcement; Public Health; Randomized; Rattus; Relapse; Risk; Rodent; Safety; Sampling; Sedation procedure; Serious Adverse Event; Signal Transduction; Sleep; Stress; Testing; Therapeutic; Time; United States National Institutes of Health; Urine; Ventilatory Depression; Withdrawal Symptom; addiction; aged; base; circadian; clinically significant; cohort; craving; drug of abuse; drug seeking behavior; efficacy evaluation; efficacy study; efficacy testing; healthy volunteer; hypocretin; novel; novel therapeutics; opioid misuse; opioid use; opioid use disorder; opioid user; orexin 1 receptor; orexin A; orexin B; orexin B receptor; overdose death; overdose risk; pre-clinical; preclinical study; prevent; primary endpoint; programs; public health emergency; respiratory; safety assessment; safety study; secondary endpoint; tablet formulation; treatment group

PROJECT SUMMARY Opioid use disorder (OUD) is a public health crisis. Current treatments show limited efficacy and fail to prevent relapse to drug use during attempted abstinence and drug-overdose are all too frequent. In collaboration with Eolas Therapeutics and the NIH Blueprint Neurotherapeutics Network, AstraZeneca has developed a potent and selective OX1 receptor antagonist (AZD4041/BPN-19302) with favorable drug-like physiochemical properties. Selective OX1 receptor antagonism by AZD4041 reduces the addiction-relevant behaviors in rodents and primates relevant to those commonly found in opioid use disorder patients. Specifically, AZD4041 reduced the motivation to consume opioids (or nicotine) and attenuated relapse-like drug seeking behaviors in laboratory animals while avoiding OX2 receptor-associated effects that could limit its potential as a novel treatment for OUD (e.g., sleep-promoting effects). AZD4041 did not have any non-specific behavioral effects in rodents or primates. AZD4041 shows favorable drug-like safety and pharmacokinetic (PK) profiles in rats and dogs. Based on these findings, we initiated a Phase 1 single ascending dose safety study in healthy volunteers (HV) (IND144437). To date in this trial, AZD4041 has shown a favorable PK and safety profile in human volunteers at exposures that encompass those predicted to have efficacy in OUD patients. In this proposal, during the UG3 phase, we will conduct the multiple ascending dose and respiratory safety assessments required to test the compound in OUD patients. Contingent upon the successful completion of the UG3 milestones, which include favorable safety, PK and respiratory depression profiles, we will advance to the UH3 phase, during which a proof of concept efficacy study will be conducted in patients suffering from OUD. Successful completion of the UH3 phase will deliver a selective OX1 receptor antagonist that is ready to advance to large-scale Phase 2 and 3 pivotal efficacy studies, based upon which AstraZeneca will make this promising and highly beneficial therapeutic widely available to OUD patients.

项目总结 阿片使用障碍(OUD)是一种公共健康危机。目前的治疗方法显示出有限的疗效，并且无法预防 在尝试禁欲期间再次吸毒和吸毒过量的情况太频繁了。与 Eolas Treateutics和NIH蓝图神经治疗网络，阿斯利康已经开发出一种有效和 选择性氧合酶1受体拮抗剂(AZD4041/BPn-19302)，具有良好的类药物物理化学性质。 AZD4041选择性OX1受体拮抗剂减少啮齿动物成瘾相关行为 灵长类动物与阿片类药物使用障碍患者中常见的相关。具体来说，AZD4041降低了 实验室中阿片类药物(或尼古丁)的消费动机和减轻复发的类药物寻找行为 同时避免与OX2受体相关的效应，限制其作为治疗OUD的新方法的潜力 (例如，促进睡眠的效果)。AZD4041对啮齿动物和灵长类动物没有任何非特异性行为影响。 AZD4041在大鼠和狗身上显示出良好的类药物安全性和药代动力学(PK)特征。基于这些 结果，我们在健康志愿者(HV)中启动了一项第一阶段单次递增剂量安全性研究(IND144437)。至 在这项试验中，AZD4041在人体志愿者中显示出良好的PK和安全性 包括那些预测对OUD患者有效的药物。在这项提案中，在UG3阶段，我们将 进行多次递增剂量和呼吸安全评估，以在OUD中测试该化合物 病人。取决于UG3里程碑的成功完成，其中包括良好的安全性，PK 和呼吸抑制概况，我们将进入UH3阶段，在此期间验证疗效的概念 研究将在患有OUD的患者中进行。UH3阶段的成功完成将带来 准备进入大规模第二和第三阶段关键疗效研究的选择性OX1受体拮抗剂， 在此基础上，阿斯利康将使这种前景看好且非常有益的疗法广泛应用于 我们的病人。