Development of a novel drug for treating opioid use disorder

项目总结 阿片类药物使用障碍(OUD)、过量用药和死亡的持续流行是前所未有的。可用 治疗阿片使用障碍(Moud)的药物未能阻止这一趋势，受到依从性差和 保留，与复发和治疗失败相关的主要因素。超过80%的人拥有 都没有得到治疗。需要更多的治疗选择。这项提议寻求开发一种乌德药理 比目前可用的治疗方法更好的选择。美沙酮和美沙酮的激动剂/部分激动剂治疗 丁丙诺啡目前在治疗OUD的药物治疗中占据主导地位。然而，拮抗疗法可能更多 适用于重要的亚人群：年轻人、新近上瘾的人和患者，他们的就业、信仰、 或者，偏好会促使人们节欲。每月一次注射缓释纳曲酮(XR-NTX) FDA于2010年批准了OUD。由于与每日口服一次相比，患者的依从性和保留率有所提高 纳曲酮，XR-NTX正在获得更广泛的接受。2019年，美国处方数量增长了约11%。尽管如此，早期患者 大约一半的患者在服用XR-NTX仅1个月后就停止服用，导致复发和治疗。 失败了。我们的目标是通过持续至少两个月的单次注射来维持有效的阿片类药物拮抗作用， 潜在4-6个月，极大地改善了遵从性、保留率和后勤负担。我们发明了 FDA批准的阿片类拮抗剂的专利前药类似物NRS-033。我们已经建立了PK/PD 动物之间的相关性，很可能是可以翻译成人类的。我们的计划使用的是FDA简化的505(B)2 审批路径，降低开发风险和时间。NRS-033，显示在体内计算的大鼠~31天的T1/2 和~在犬体内的活性代谢物。PK模型表明，人类也有类似的PK。NRS-033‘S 大鼠34天时IS活性代谢物的平均血浆浓度为3.7 ng/ml，而XR-NTX的纳曲酮在34天时的平均浓度为3.7 ng/ml ~1.7 ng/ml，可能对合成阿片类药物有更强的拮抗作用。对于怀孕和怀孕的妇女 在生育潜力方面，我们预计NRS-033在怀孕期间的安全性比所有其他批准的药物都要好 穆德。我们完成的UG3目标包括销售线索确认和选择、cGMP原料药制造、预调试 与FDA会面，并进行药效学研究。即将完成的目标包括支持IND的毒理学 研究、cGMP填充剂制造和IND提交。中期毒理学发现似乎很有希望。后来 UH3的目标包括第一阶段研究和第二阶段临床试验。目标是紧急推进到第三阶段试验 以及FDA的批准。我们假设我们可以开发出一种具有超强粘附性和保留性的新型疗法， 在有生育潜力的妇女中表现得更好，阿片类药物的阻断更强。这一及时的进展应该 对公众健康有重大影响，减少复发、过量用药和死亡。 机密

PROJECT SUMMARY The ongoing epidemic of opioid use disorder (OUD), overdose, and death is unprecedented. Available medications for opioid use disorder (MOUD) have failed to stem the tide, plagued by poor adherence and retention, the principal factors associated with relapse and treatment failure. Over 80% of individuals with OUD are untreated. More treatment options are needed. This proposal seeks to develop an OUD pharmacologic option superior to currently available therapies. Agonist/ partial agonist treatments with methadone and buprenorphine currently dominate pharmacologic therapies for OUD. However, antagonist therapy may be more appropriate for important sub-populations: the young, newly addicted, and patients whose employment, beliefs, or preferences motivate abstinence. Once-monthly injectable extended-release naltrexone (XR-NTX) received FDA approval in 2010 for OUD. Due to improved patient adherence and retention relative to oral once-daily naltrexone, XR-NTX is gaining wider acceptance. US prescription volume grew ~11% in 2019. Still, early patient discontinuation after just 1 month on XR-NTX occurs in about half of patients, leading to relapse and treatment failure. We aim to maintain effective opioid antagonism with a single injection lasting at least two months, potentially 4-6 months, dramatically improving adherence, retention, and logistical burdens. We invented patented NRS-033 prodrug analogue of an FDA approved opioid antagonist. We have established PK/PD correlations in animals, likely translatable into humans. Our program is utilizing FDA’s abbreviated 505(b)2 approval path, reducing development risk and time. NRS-033, shows in vivo calculated T1/2 of ~31 days in rats and ~64 days in dogs for the active metabolite. PK modelling suggests a similar PK in humans. NRS-033’s mean plasma concentration in rats of is active metabolite at 34 days is 3.7 ng/ml vs. XR-NTX’s naltrexone at ~1.7 ng/ml, likely allowing stronger antagonism vs. potent synthetic opioids. For women who are pregnant and of child-bearing potential, we expect more favorable safety in pregnancy for NRS-033 than all other approved MOUD. Our UG3 completed aims include lead confirmation and selection, cGMP API manufacturing, pre-IND meeting with FDA, and pharmacodynamic study. Aims being completed soon include IND-enabling toxicology studies, cGMP fill-finish manufacturing, and IND submission. Interim toxicology findings appear promising. Later UH3 aims include phase 1 studies and phase 2 clinical trials. The goal is to urgently advance to phase 3 trials and FDA approval. We hypothesize we can develop a novel therapeutic with superior adherence and retention, better indicated in women of child-bearing potential, with stronger opioid blockade. This timely advance should have a significant public health impact, reducing relapse, overdose, and death. Confidential