Development of a novel drug for treating opioid use disorder

项目摘要 阿片类药物使用障碍（OUD），过量和死亡的持续流行是前所未有的。可用 阿片类药物使用障碍（MOUD）的药物未能阻止这一趋势，受到依从性差的困扰， 保留，复发和治疗失败的主要因素。超过80%的OUD患者 都没有得到治疗需要更多的治疗选择。该提案旨在开发一种OUD药理学 比目前可用的治疗方法更好的上级选择。美沙酮激动剂/部分激动剂治疗， 丁丙诺啡目前在OUD的药物治疗中占主导地位。然而，拮抗剂治疗可能更多 适用于重要的亚人群：年轻人，新成瘾者，以及其就业，信仰， 或者偏好会促使禁欲接受每月一次注射缓释纳洛酮（XR-NTX） 2010年FDA批准OUD。由于相对于每日一次口服给药，患者依从性和保留性得到改善 纳洛酮，XR-NTX正在获得更广泛的接受。2019年美国处方量增长约11%。早期病人 大约一半的患者在XR-NTX治疗仅1个月后就停止治疗，导致复发和治疗 失败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拮抗作用， 可能需要4 - 6个月，显著改善依从性、保留率和后勤负担。我们发明 FDA批准的阿片类拮抗剂的专利NRS-033前药类似物。我们已经建立了PK/PD 在动物中的相关性，很可能可以转化为人类。我们的项目利用FDA的缩写505（B）2 审批路径，降低开发风险和时间。NRS-033显示大鼠体内计算的T1/2约为31天 犬中活性代谢产物约为64天。PK建模表明人体中的PK相似。NRS-033的 在34天时，活性代谢物在大鼠中的平均血浆浓度为3.7 ng/ml，而XR-NTX的纳洛酮在 ~1.7 ng/ml，可能与强效合成阿片类药物相比具有更强的拮抗作用。对于孕妇和 我们预计NRS-033的妊娠安全性比所有其他已批准的 MOUD。我们的UG3完成的目标包括先导化合物确认和选择、cGMP API生产、pre-IND 与FDA会面，以及药效学研究。即将完成的目标包括IND使能毒理学 研究、cGMP灌装-成品生产和IND提交。中期毒理学结果似乎很有希望。后来 UH3的目标包括1期研究和2期临床试验。目标是紧急推进到3期试验 和FDA的批准。我们假设我们可以开发一种新的治疗方法，具有上级粘附性和保留性， 更好地适用于有生育能力的女性，具有更强的阿片类药物阻滞作用。这一及时的进展应 对公共卫生有重大影响，减少复发、过量和死亡。 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