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

在美国，大约有1亿人遭受疼痛，约900万至1200万人患有慢性或持续性疼痛。由于阿片类药物仍然处于治疗的前沿，阿片类药物滥用和阿片类药物过量显然已成为重大和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人死于呼吸抑制导致的阿片类药物过量。尽管阿片类药物使用和滥用的增加无疑是多种因素造成的，但迫切需要一种有效的阿片类止痛剂，同时解决围绕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蛋白偶联受体信号转导相关药理学机制的了解的进展，我们已经了解到Mu阿片受体的激活 (MOR)同时调节治疗和不良反应，并通过药理上不同的信号转导实现 小路。与吗啡和其他MOR激动剂相关的不良反应已被追踪到通过β-arrestin途径发挥作用，而镇痛作用与G-蛋白途径有关。G蛋白特异性激动剂可避免激活β-arrestin信号及其相关的负面后果，为开发特定途径或“有偏向”的药物提供了新的策略，旨在选择性地产生止痛，同时消除包括呼吸抑制、滥用倾向和便秘在内的不良反应。 Mebias Discovery LLC已经开发了一种新的平台，并已经确定了高度“偏向”的MOR激动剂，这些药物是有效的止痛药，但没有阿片类药物引起的不良反应。Mebias的临床前研究将两种化合物MEB-1166和MEB-1170与Trevena的奥利塞定(TRV-130)和吗啡进行了比较。在需要达到相当于吗啡ED80的疗效的4倍剂量下，两种Mebias化合物都没有表现出呼吸抑制，而吗啡和奥利塞定显著降低了呼吸功能。与吗啡相反，MEB-1166和MEB-1170都不会产生条件性位置偏爱，这表明没有滥用责任。 本申请UG3部分概述的研究是基于迄今为止收集的这些令人鼓舞的结果，旨在提供对MEB-1166和MEB-1170的彻底评估，以表征它们的药学和药理学特征，以选择IND使能研究的候选者。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止痛活性。在完成本提案的UG3部分后，我们预计MEB-1166或MEB-1170将进入本申请的UH3部分，进行第一阶段研究，以检查健康志愿者的单次和多次递增剂量研究，并在“Connoisseur研究”中检查滥用倾向。

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’.