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。

基本信息

批准号：
10469590
负责人：
Ian Gurrell
金额：
$ 223.28万
依托单位：
ASTRAZENECA PHARMACEUTICALS, LP
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10469590
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 Persons 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 antagonist 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

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 Persons 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 antagonist 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

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项目摘要

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。当前的治疗表现出有限的功效，无法预防试图戒酒和药物过多的药物中使用药物的复发都太频繁了。与 eolas Therapeutics和NIH蓝图神经疗法网络，阿斯利康发展了有效的选择性OX1受体拮抗剂（AZD4041/BPN-19302）具有有利的药物样理化学特性。 AZD4041的选择性OX1受体拮抗作用减少了啮齿动物和成瘾的行为灵长类动物与阿片类药物使用障碍患者通常发现的灵长类动物有关。具体而言，AZD4041降低了消费阿片类药物（或尼古丁）的动机，并减弱实验室中的复发式毒品寻求行为动物的同时避免使用OX2受体相关的作用，这可能会限制其作为新型处理的潜力（例如，促进睡眠效果）。 AZD4041在啮齿动物或灵长类动物中没有任何非特异性行为影响。 AZD4041在大鼠和狗中显示出有利的药物样安全性和药代动力学（PK）剖面。基于这些调查结果是，我们在健康志愿者（HV）（IND144437）中启动了1期单一升剂剂量安全研究。到在此试验中，AZD4041在人类志愿者中表现出了有利的PK和安全性。涵盖那些预计在OUD患者中具有功效的人。在此提案中，在UG3阶段，我们将进行测试OUD中所需的多重升剂剂量和呼吸安全评估患者。取决于成功完成UG3里程碑，其中包括有利的安全性，PK 和呼吸抑郁症状，我们将晋升为UH3阶段，在此期间概念证明研究将对患有OUD的患者进行。成功完成UH3阶段将提供选择性的OX1受体拮抗剂，准备前进到大规模第2期和3期关键疗效研究，基于阿斯利康将使这种有希望的和非常有益的治疗可广泛使用 Oud患者。