Biased Mu-Opioid Receptor Analgesics to Prevent Overdose and Opioid Use Disorders

在美国，大约有1亿人患有疼痛，其中约900万至1200万人患有慢性或持续性疼痛。由于类阿片仍然处于治疗的最前沿，很明显，类阿片滥用和类阿片过量已成为重大而复杂的公共卫生挑战。阿片类药物过量是美国意外死亡的主要原因，估计每天有100人因呼吸抑制而死于阿片类药物过量。虽然多种因素无疑是阿片类药物使用和滥用增加的原因，但迫切需要一种有效的阿片类镇痛剂，同时解决阿片类药物滥用责任和过量死亡的重大问题。随着我们对G蛋白偶联受体信号传导相关药理学机制的理解的进展，我们已经认识到μ阿片受体的激活 (MOR)介导治疗和副作用，并通过不同的信号传导 途径。与吗啡和其他莫尔激动剂相关的副作用已被追踪到通过β-抑制蛋白途径的作用，而镇痛与G-蛋白途径有关。避免β-抑制蛋白信号传导激活及其相关负面后果的G-蛋白特异性激动剂为开发通路特异性或“偏向性”药物提供了新的策略，这些药物被设计为选择性地产生镇痛，同时消除不希望的不良反应，包括呼吸抑制、滥用倾向和便秘。 Mebias Discovery LLC开发了一种新的平台，并鉴定了高度“偏倚”的莫尔激动剂，这些激动剂是有效的镇痛剂，但没有阿片类药物诱导的不良反应。Mebias的临床前研究比较了两种化合物MEB-1166和MEB-1170与Trevena的Oliceridine（TRV-130）和吗啡。在达到相当于吗啡ED 80的疗效所需的4X剂量下，两种Mebias化合物均未显示呼吸抑制，而吗啡和奥利色定显著降低了呼吸功能。与吗啡相反，MEB-1166和MEB-1170都没有产生条件性位置偏爱，表明没有滥用倾向。 本申请的UG 3部分概述的研究基于迄今为止收集的这些令人鼓舞的结果，旨在对MEB-1166和MEB-1170进行全面评价，以表征其药物和药理学特征，从而选择IND使能研究的候选药物。我们还将进行滥用责任研究，并在更广泛的疼痛模型中检查镇痛活性。在完成本提案的UG 3部分后，我们预计MEB-1166或MEB-1170将进入本申请的UH 3部分，进行I期研究，以检查健康志愿者中的单次和多次递增剂量研究以及“鉴赏家研究”中的滥用倾向。

Approximately 100 million people in the United States suffer from pain with some 9 to 12 million individuals suffering from chronic or persistent pain. With opioids remaining at the forefront of treatment, it has become clear that opioid abuse and opioid overdose have emerged as significant and complicated public health challenges. Drug overdose from opioids is the leading cause of accidental death in the U.S. with an estimated 100 individuals a day dying from opioid overdose due to respiratory depression. Although multiple factors are unquestionably responsible for the increase in the use and abuse of opioids, there is a pressing need for an effective opioid analgesic that also addresses the significant issues surrounding opioid abuse liability and overdose fatalities. Advances in our understanding of the pharmacological mechanisms associated with signaling of G-protein coupled receptors have resulted in the knowledge that activation of the mu-opioid receptor (MOR) mediates both the therapeutic and adverse effects and does so through pharmacologically distinct signaling pathways. The adverse effects associated with morphine and other MOR agonists have been traced to action through the β-arrestin pathway, while analgesia is tied to the G-protein pathway. G-protein specific agonists that avoid activation of β-arrestin signaling and its associated negative consequences provide novel strategies for the development of pathway specific or ‘biased’ drugs designed to selectively produce analgesia while eliminating unwanted adverse effects that include respiratory depression, abuse liability, and constipation. Mebias Discovery LLC has developed a novel platform and has identified highly ‘biased’ MOR agonists that are effective analgesics but are devoid of opioid induced adverse effects. Mebias’ preclinical studies compared two compounds, MEB-1166 and MEB-1170, against Trevena’s Oliceridine (TRV-130) and morphine. At a dose 4X that required to reach the efficacy equivalent to ED80 of morphine, both Mebias compounds displayed no respiratory depression, while morphine and Oliceridine significantly reduced respiratory function. In contrast to morphine, neither MEB-1166 nor MEB-1170 produced conditioned place preference, suggesting an absence of abuse liability. The research outlined in the UG3 portion of this application is based on these encouraging results collected thus far and is designed to provide a thorough evaluation of MEB-1166 and MEB-1170 to characterize their pharmaceutical and pharmacological profiles to select a candidate for IND-enabling studies. We will also conduct abuse liability studies and examine analgesic activity in a wider range of pain models. Upon completion of the UG3 portion of this proposal, we anticipate that MEB-1166 or MEB-1170 will proceed into the UH3 portion of this application conducting Phase 1 studies to examine single and multiple ascending dose studies in healthy volunteers and abuse liability in a ‘Connoisseur study’.