Evaluation of the Safety and Efficacy of a New Oral Small Molecule GABA-B Receptor Positive Allosteric Modulator (PAM) as an Add-on Maintenance Therapy for Opioid Use Disorder (OUD)

新型口服小分子 GABA-B 受体正变构调节剂 (PAM) 作为阿片类药物使用障碍 (OUD) 附加维持疗法的安全性和有效性评估

• 批准号: 10026953
• 负责人: Jay Erdman
• 金额: $ 600万
• 依托单位: ASTELLAS PHARMA GLOBAL DEVELOPMENT, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10026953
• 关键词: Address; Adverse event; Agonist; Alcohols; American; Americas; Applications Grants; Area; Award; Baclofen; Blood; Brain; Buprenorphine; Butyric Acids; Cardiac; Clinical; Clinical Research; Clinical Trials; Cocaine; Corpus striatum structure; Data; Development; Digit structure; Dopamine; Dose; Double-Blind Method; Drowsiness; Drug Kinetics; Drug Receptors; Drug user; Electrocardiogram; Ethanol; Evaluation; FDA approved; Fentanyl; Funding; Future; GABA-B Receptor; GTP-Binding Protein alpha Subunits, Gs; Grant; Human; Incidence; Investments; Laboratories; Liver Function Tests; Measures; Mediating; Medical; Methadone; Modality; Modeling; Monitor; Monkeys; Morphine; Naloxone; Naltrexone; National Institute of Drug Abuse; Nature; Neuraxis; Nicotine; Opioid; Opioid replacement therapy; Oral; Overdose; Oxygen; Patient Self-Report; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase; Physiological; Placebos; Population; Prefrontal Cortex; Publications; Pulse Oximetry; Randomized; Rat-1; Rattus; Recreational Drugs; Research; Safety; Sampling; Scourge; Sedation procedure; Self Administration; Self Stimulation; Serious Adverse Event; Severities; Ships; Signal Transduction; Societies; Source; Study Subject; Suboxone; Substance of Abuse; Testing; Therapeutic; United States; Urine; Ventilatory Depression; Ventral Tegmental Area; Vertigo; Withdrawal; Withdrawal Symptom; base; craving; drug seeking behavior; gamma-Aminobutyric Acid; medication-assisted treatment; meetings; neurotransmission; novel therapeutics; opioid epidemic; opioid overdose; opioid use; opioid use disorder; phase 1 study; phase 2 study; positive allosteric modulator; preservation; primary endpoint; psychologic; receptor; respiratory; secondary endpoint; side effect; small molecule; spatiotemporal; standard of care; success; treatment program

The opioid crisis in America is real and increasing. In 2017, over 47,600 American lives were lost due to an overdose of an opioid. The recent rise in illegally manufactured fentanyl shipped to the United States from sources around the globe have only increased the opioid epidemic and further accelerated a critical need to find and develop new therapies to address this scourge. This UG3/UH3 grant seeks funding to test a γ-aminobutyric acid subtype B positive allosteric modulator (GABAB PAM) compound, ASP8062, in 3 separate clinical studies. This target is one of the prioritized research approaches for NIDA to evaluate in trying to address the opioid crisis. This grant application will include two phase 1 studies to evaluate the impact of ASP8062 on side effects including respiratory depression when administered in combination with a) buprenorphine/naloxone and b) morphine. The third clinical study included in the grant is a phase 2 study in opioid use disorder (OUD) subjects testing ASP8062 or placebo in addition to an ongoing medication assisted treatment (MAT) program that includes buprenorphine-based therapy as cornerstone treatment. Studies have shown that the GABAB receptor is involved with reducing self-administration and drug-seeking behavior across several substances of abuse (i.e., opioids, alcohol, cocaine, nicotine) by suppressing dopamine release from key areas of the brain, including the prefrontal cortex, ventral tegmental area and the striatum. Baclofen, a GABAB receptor agonist, has yielded positive findings in nonclinical studies such as suppression of opioid, ethanol, cocaine or nicotine self-administration in rats. However, activation of GABAB receptors by direct-acting agonists induces side effects including sedation or somnolence, excessive weakness, vertigo and psychological disturbances. Centrally penetrant GABAB PAMs amplify the signaling of endogenous GABA to its receptor within the central nervous system and preserve the spatiotemporal nature of GABA neurotransmission, thus resulting in a lower incidence of undesirable side effects compared to orthosteric GABAB agonist drugs and optimizing compliance and prolonged, tolerable craving suppression. The sponsor will conduct these studies under a company IND. A pre-IND meeting with FDA is planned for Q4 2019 to confirm adequacy of the current nonclinical pharmacology and toxicology data package, clinical study subject populations, endpoints and safety monitoring. Upon execution of the studies included in this grant application, the sponsor will evaluate the data together with input from NIDA, and make a go/no-go decision for further internal investment for future development of ASP8062 in the management of OUD.

美国的阿片类药物危机是真实的，而且还在增加。2017年，超过47，600名美国人因战争而丧生。 阿片类药物过量最近，从美国运往美国的非法制造芬太尼的数量有所增加， 地球仪的使用只会增加阿片类药物的流行，并进一步加速寻找 并开发新的疗法来解决这一问题。此UG 3/UH 3赠款寻求资金来测试γ-氨基丁酸 在3项单独的临床研究中，使用酸性B亚型阳性变构调节剂（GABAB PAM）化合物ASP 8062。 这一目标是NIDA在试图解决阿片类药物问题时评估的优先研究方法之一 危机该资助申请将包括两项1期研究，以评估ASP 8062对副作用的影响 包括与a）丁丙诺啡/纳洛酮和B） 吗啡第三项临床研究是阿片类药物使用障碍（OUD）的2期研究 除正在进行的药物辅助治疗（MAT）计划外，还检测了ASP 8062或安慰剂的受试者 包括丁丙诺啡为基础的治疗。 研究表明，GABAB受体参与减少自我给药和药物寻求 几种滥用物质的行为（即，阿片类药物，酒精，可卡因，尼古丁）通过抑制多巴胺 从大脑的关键区域释放，包括前额叶皮质、腹侧被盖区和纹状体。 巴氯芬是一种GABAB受体激动剂，在非临床研究中获得了积极的发现，如抑制 阿片样物质、乙醇、可卡因或尼古丁自我给药。然而，GABAB受体的激活， 直接作用激动剂引起副作用，包括镇静或嗜睡、过度虚弱、眩晕和 心理障碍中枢渗透性GABAB PAM放大内源性GABA信号传导至其受体， 在中枢神经系统内的受体，并保持GABA的时空性质 神经传递，因此与正构剂相比，导致不良副作用的发生率较低。 GABAB激动剂药物和优化的依从性和长期的，可耐受的渴望抑制。 申办者将在公司IND下开展这些研究。计划于第4季度与FDA召开IND前会议 2019年确认当前非临床药理学和毒理学数据包、临床研究的充分性 受试者人群、终点和安全性监测。在执行本补助金所包括的研究后， 申请人将评估数据以及NIDA的输入，并做出通过/不通过的决定 为未来在OUD管理中开发ASP 8062进行进一步的内部投资。