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

Sudaxine 的开发用于治疗医院围手术期阿片类药物引起的呼吸抑制 (OIRD)

• 批准号: 10706602
• 负责人: JAMES N BATES
• 金额: $ 92.85万
• 依托单位: ATELERIX LIFE SCIENCES INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10706602
• 关键词: Absence of pain sensation; Address; Adult; Analgesics; Anesthesia procedures; Animals; Biological Assay; Biological Sciences; CYP1A2 gene; CYP2B6 gene; CYP3A4 gene; Canis familiaris; Caring; Clinical; Clinical Trials; Collaborations; Complication; Cyclic GMP; Cystine; Cytochrome P450; Data; Development; Dose; Drug Interactions; Equilibrium; Esters; Formulation; Foundations; Future; General Anesthesia; Goals; Grant; Health Personnel; Healthcare Systems; Hepatocyte; Hospitals; Human; In Vitro; Intubation; Isoenzymes; Lead; Life; Liver Microsomes; Metabolism; Methods; Molecular; Monitor; Morbidity - disease rate; Mus; Naloxone; National Heart, Lung, and Blood Institute; Operative Surgical Procedures; Opioid; Opioid Analgesics; Opioid Antagonist; Opioid Receptor; Outcome; Pain management; Patient Monitoring; Patients; Perioperative; Perioperative Care; Pharmaceutical Preparations; Pharmacology; Phase; Phase I Clinical Trials; Preclinical Testing; Process; Qualifying; Rattus; Readiness; Regimen; Reporting; Respiratory Stimulants; Safety; Sedation procedure; Signal Pathway; Testing; Therapeutic; Time; Titrations; Toxic effect; Toxicokinetics; Toxicology; Ventilatory Depression; Work; analytical method; cost; design; drug development; drug discovery; efficacy testing; experience; first-in-human; genotoxicity; in vivo; manufacture; mortality; novel; novel therapeutics; operation; opioid epidemic; pain relief; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical development; preclinical study; preservation; programs; respiratory; safety testing; scale up; small molecule; small molecule therapeutics; standard of care

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.

项目摘要 阿片类药物诱导的呼吸抑制（OIRD）是阿片类药物治疗的潜在致命并发症。在 在围手术期，阿片类药物广泛用于在全身麻醉期间提供镇痛和补充镇静。 麻醉或监测麻醉护理。然而，超过46%的接受阿片类药物的手术患者将 经历OIRD，从有问题到危及生命。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受到限制，因为它也逆转了OIRD。 阿片类药物提供的疼痛缓解。因此，仍然迫切需要开发一种可以逆转肿瘤生长的治疗剂。 OIRD，同时保持经典阿片类镇痛药的镇痛疗效。 Atelerix Life Sciences在围手术期护理环境中针对OIRD的解决方案是Sudaxine，一种新型小分子 选择性靶向激活的阿片受体下游的信号传导途径以减轻 OIRD不逆转镇痛。我们已经通过早期临床前研究取得了Sudaxine的进展 包括体内功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Sudaxine是安全的（没有不良的心肺或体温调节作用）， 靶向方法导致OIRD逆转而不减弱镇痛。因此，Sudaxine有可能 破坏了OIRD在围手术期环境中的当前护理标准。 在这个直接进入II期项目中，Atelerix将专注于额外的临床前测试和制造步骤 促进IND提交和未来临床试验。这将通过执行 四个目标。在目标1中，我们将通过进行非GLP单次给药毒性评价苏达辛的毒性， 犬的毒代动力学研究。在目标2中，我们将进行药物相互作用筛选。在目标3中，我们将 IND使能GLP遗传毒性、安全药理学和毒理学研究。Aim 4将专注于制造业 GMP级Sudaxine原料药。该项目的成功结果将导致一个破坏性的， 在围手术期医院环境中治疗OIRD所需的治疗解决方案。拟议工作 这将为开发其他新型呼吸兴奋剂奠定基础， 在围手术期护理之外的应用，并最终释放Sudaxine的更大潜力， 与阿片类药物危机相关的需求。