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存在的，而且还在加剧。2017 年，超过 47,600 名美国人因阿片类药物而丧生。 最近运往美国的非法制造的芬太尼数量有所增加。 全球各地的来源只会加剧阿片类药物的流行，并进一步加速寻找阿片类药物的迫切需要 并开发新疗法来解决这一祸害。 UG3/UH3 拨款寻求资金来测试 γ-氨基丁酸。 酸性 B 亚型正变构调节剂 (GABAB PAM) 化合物 ASP8062，在 3 项独立的临床研究中。 该目标是 NIDA 在尝试解决阿片类药物问题时评估的优先研究方法之一 该拨款申请将包括两项第一阶段研究，以评估 ASP8062 对副作用的影响。 包括与 a) 丁丙诺啡/纳洛酮和 b) 联合给药时的呼吸抑制 拨款中包含的第三项临床研究是阿片类药物使用障碍 (OUD) 的 2 期研究。 除了正在进行的药物辅助治疗 (MAT) 计划外，受试者还测试 ASP8062 或安慰剂 其中包括以丁丙诺啡为基础的治疗作为基础治疗。 研究表明，GABAB 受体与减少自我给药和寻求药物有关 通过抑制多巴胺来抑制多种滥用药物（即阿片类药物、酒精、可卡因、尼古丁）的行为 从大脑的关键区域释放，包括前额皮质、腹侧被盖区和纹状体。 巴氯芬是一种 GABAB 受体激动剂，在非临床研究中取得了积极的成果，例如抑制 大鼠自行给予阿片类药物、乙醇、可卡因或尼古丁，但会激活 GABAB 受体。 直接作用激动剂会引起副作用，包括镇静或嗜睡、过度虚弱、眩晕和 中枢渗透性 GABAB PAM 会放大内源性 GABA 对其的信号传导。 中枢神经系统内的受体并保留 GABA 的时空性质 神经传递，因此与正位相比，不良副作用的发生率较低 GABAB 激动剂药物并优化依从性和长期、可耐受的渴望抑制。 申办者将在公司 IND 下进行这些研究，计划于第四季度与 FDA 举行预 IND 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、终点和安全监测在执行本拨款中包含的研究时。 申请后，申办者将评估数据以及 NIDA 的输入，并做出继续/不继续的决定 为 OUD 管理中 ASP8062 的未来发展提供进一步的内部投资。