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)

美国的阿片类药物危机是真实存在的，而且还在不断增加。2017年，超过47600名美国人因一场 过量服用阿片类药物。最近非法制造的芬太尼从美国运往美国的数量上升 全球各地的来源只会增加阿片类药物的流行，并进一步加速寻找 并开发新的疗法来应对这一祸害。这项UG3/UH3赠款寻求资金来测试γ-氨基丁酸 酸性B亚型阳性变构调节剂(GABAB PAM)化合物，ASP8062，在3个单独的临床研究中。 这一目标是NIDA在努力解决阿片类药物问题时要评估的优先研究方法之一 危机。这项赠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)联合使用时的呼吸抑制 吗啡。赠款中包括的第三项临床研究是阿片类药物使用障碍(Oud)的第二阶段研究。 受试者在正在进行的药物辅助治疗(MAT)计划之外测试ASP8062或安慰剂 这包括以丁丙诺啡为基础的治疗作为基石治疗。 研究表明，GABAB受体与减少自我给药和药物寻找有关 通过抑制多巴胺对几种滥用物质(如类阿片、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，在非临床研究中取得了积极的结果，例如抑制 阿片类药物、乙醇、可卡因或尼古丁在大鼠体内的自我给药。然而，GABAB受体的激活通过 直接作用激动剂会引起副作用，包括镇静或嗜睡、极度虚弱、眩晕和 心理障碍。中心穿透性GABAB PAM放大内源性GABA对ITS的信号传导 中枢神经系统内的受体和维持GABA的时空性质 神经传递，因此与正畸相比，不良副作用的发生率较低 GABAB激动剂药物和优化依从性和长期、耐受的渴望抑制。 赞助商将在一家公司IND下进行这些研究。计划在第四季度与FDA举行IND前会议 2019年确认当前非临床药理学和毒理学数据包的充分性，临床研究 受试者群体、终点和安全监测。在执行这项赠款中包括的研究之后 申请时，赞助商将与NIDA的输入一起评估数据，并做出通过/不通过的决定 为未来ASP8062在OUD管理方面的发展提供进一步的内部投资。

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.