Development of Sudaxine for the Treatment of Opioid Induced Respiratory Depression (OIRD) in the Peri-operative Hospital Setting

项目总结 阿片类药物引起的呼吸抑制(OIRD)是阿片类药物治疗的一种潜在的致命并发症。在 围手术期，阿片类药物被广泛用于提供止痛和补充镇静 麻醉或监护麻醉护理。然而，超过46%的接受阿片类药物的外科患者将 经历从有问题到危及生命的OIRD。阿片受体纳洛酮的使用 有效逆转OIRD的拮抗剂在围手术期环境中是有限的，因为它还逆转 由阿片类药物提供的止痛作用。因此，仍然迫切需要开发一种可以逆转 OIRD，同时保持经典阿片类镇痛剂的止痛效果。 Atelerix生命科学公司在围手术期护理环境中解决OIRD的方案是一种新型小分子苏达辛 选择性靶向激活的阿片受体下游的信号通路以缓解 OIRD不逆转止痛。我们已经通过早期临床前研究取得了舒达辛的进展 包括体内疗效和安全性测试，以及药效学和药代动力学测试。我们的结果 已经证明舒达辛是安全的(没有不良的心肺或体温调节作用)，而且这 靶向治疗可逆转OIRD，但不会削弱其止痛作用。因此，舒达辛有可能 扰乱目前OIRD围手术期的护理标准。 在这个直接到第二阶段的项目中，Atelerix将专注于更多的临床前测试和制造步骤 为促进IND提交和未来的临床试验所需。这将通过执行 四个目标。在目标1中，我们将通过进行非GLP单剂量毒性和 犬体内毒代动力学研究。在目标2中，我们将进行药物-药物相互作用筛查。在目标3中，我们将进行 IND-Enabling GLP基因毒性、安全药理学和毒理学研究。目标4将专注于制造业 GMP级苏他辛药材。一个成功的项目结果将导致一个破坏性的和极大的 在围手术期医院环境中治疗OIRD所需的治疗方案。拟议中的工作 将为开发更多的新型呼吸兴奋剂奠定基础，这些兴奋剂可以有更广泛的 在围手术期护理之外的应用，并最终释放舒达辛针对未满足的目标的更大潜力 与阿片类药物危机相关的需求。

PROJECT SUMMARY Opioid-induced respiratory depression (OIRD) is a potentially fatal complication of treatment with opioids. In the peri-operative setting, opioids are widely used to provide analgesia and supplement sedation during general anesthesia or monitored anesthesia care. However, over 46% of surgical patients receiving opioids will experience OIRD ranging from problematic to life-threatening. The use of naloxone, an opioid receptor antagonist that is effective at reversing OIRD, is limited in the peri-operative setting because it also reverses the pain relief provided by the opioid. Thus, there remains a critical need to develop a therapeutic that can reverse OIRD while maintaining the analgesic efficacy of classical opioid analgesics. Atelerix Life Sciences’ solution to OIRD in the peri-operative care setting is Sudaxine, a novel small molecule therapeutic that selectively targets signaling pathways downstream of activated opioid receptors to alleviate OIRD without reversing analgesia. We have already progressed Sudaxine through early preclinical studies including in vivo efficacy and safety testing, and pharmacodynamic and pharmacokinetic testing. Our results have demonstrated that Sudaxine is safe (no adverse cardiorespiratory or thermoregulatory effects) and that this targeted approach leads to reversal of OIRD without blunting analgesia. Thus, Sudaxine has the potential to disrupt the current standard of care for OIRD in the peri-operative setting. In this Direct to Phase II project, Atelerix will focus on additional preclinical testing and manufacturing steps required to facilitate IND-submission and future clinical trials. This will be accomplished through the execution of four Aims. In Aim 1, we will evaluate the toxicity of Sudaxine by conducting a non-GLP single dose toxicity and toxicokinetic study in dogs. In Aim 2, we will conduct a drug-drug interaction screen. In Aim 3, we will conduct IND-enabling GLP genotoxicity, safety pharmacology, and toxicology studies. Aim 4 will focus on manufacturing GMP-grade Sudaxine drug substance. A successful outcome of the project will lead to a disruptive and greatly needed therapeutic solution for the treatment of OIRD in the peri-operative hospital setting. The proposed work will lay the foundation for the development of additional novel respiratory stimulants that can have broader applications beyond peri-operative care and ultimately unleash the greater potential of Sudaxine to target unmet needs associated with the opioid crisis.