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.

项目摘要 阿片类药物使用障碍（OUD）是一种公共卫生危机。目前的治疗效果有限， 在试图戒断期间重新吸毒和吸毒过量的情况十分常见。协同 Eolas Therapeutics和NIH Blueprint Neurotherapeutics Network，阿斯利康开发了一种有效的， 选择性OX 1受体拮抗剂（AZD 4041/BPN-19302），具有良好的类药理化性质。 AZD 4041的选择性OX 1受体拮抗作用可减少啮齿类动物的成瘾相关行为， 与阿片类药物使用障碍患者中常见的灵长类动物相关。具体而言，AZD 4041降低了 在实验室中消耗阿片类药物（或尼古丁）的动机和减弱的复发样药物寻求行为 同时避免OX 2受体相关效应，这可能限制其作为OUD新治疗方法的潜力 (e.g.,促进睡眠的作用）。AZD 4041在啮齿类动物或灵长类动物中没有任何非特异性行为影响。 AZD 4041在大鼠和犬中显示出良好的药物样安全性和药代动力学（PK）特征。基于这些 根据这些发现，我们在健康志愿者（HV）中启动了一项I期单次给药剂量递增安全性研究（IND 144437）。到 在本试验的日期，AZD 4041在人类志愿者中显示出有利的PK和安全性特征， 包括预测在OUD患者中具有疗效的那些。在本提案中，在UG 3阶段，我们将 进行多次递增剂量和呼吸安全性评估，以检测OUD中的化合物 患者取决于UG 3里程碑的成功完成，包括有利的安全性、PK 和呼吸抑制特征，我们将进入UH 3阶段，在此期间， 研究将在OUD患者中进行。UH 3阶段的成功完成将提供一个 选择性OX 1受体拮抗剂，准备推进大规模II期和III期关键疗效研究， 基于此，阿斯利康将使这种有前途的和非常有益的治疗广泛提供， OUD患者。