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 OUD的药物治疗未能阻止这一趋势，受到粘附性和保留性差的困扰， 与复发和治疗失败相关的主要因素。超过80%的OUD患者未经治疗。 需要更多的治疗选择。该提案旨在开发一种上级的OUD药理学选择， 目前可用的疗法。目前使用美沙酮和丁丙诺啡的激动剂/部分激动剂治疗 OUD的主要药物治疗。然而，拮抗剂治疗可能更适合于 重要的亚人群：年轻人，新成瘾者，军人，选择刑事司法客户，以及 职业、信仰或偏好是禁欲的动机。每月一次注射用缓释纳洛酮 (XRN)2010年获得FDA批准用于治疗OUD。由于患者依从性和保持力得到改善 相对于每日一次口服纳曲酮，XRN正在获得更广泛的接受。美国处方量增长约37% 2017年尽管如此，与其他OUD治疗一样，XRN的早期患者停药是普遍的，通常在 1个月，通常导致早期复发和治疗失败。我们的目标是维持有效的阿片拮抗作用 单次注射持续至少两个月，最多4个月或更长时间，改善了依从性， 保留和可比疗法的治疗负担。我们已经合成了一系列新颖的和专有的 FDA批准的阿片类拮抗剂的小分子酯型前药，具有确定的PK/PD相关性 和动物-人类的可译性。这些候选产品旨在满足FDA的简化505（B）2批准 路径，降低开发和监管风险。已提交广泛的临时专利保护。我们的头号候选人， NRS-033显示活性代谢产物在大鼠体内的T1/2计算值约为33天。PK模型表明， 3个月或更长时间的剂量可能在人类中。NRS-033活性代谢物的平均血浆浓度， 28天为2.15 ng/ml，剂量能力高出>50%，而XRN约为1.7 ng/ml，可能允许更强的 对强效合成阿片类药物的拮抗作用。对于怀孕和有生育能力的女性，我们 预期NRS-033的妊娠类别B比所有其他MAT的妊娠类别C更有利。我们的UG 3目标 包括：1）先导化合物确认研究、先导化合物选择、FDA快速通道备案和毒理学批次生产; 2)IND启动研究、GMP生产和IND提交; UH 3的目标是，3）1期研究， 致癌性研究、2期临床试验启动和FDA突破性治疗备案。目标是 紧急推进到第三阶段试验和FDA的批准。我们假设我们可以开发一种新的治疗方法， 上级粘附性和保持力，可能更适合许多女性，并且比合成材料更强 阿片类药物。尽管开发风险较低，但这一及时的进展应具有重大的公共健康 通过降低复发率，过量和死亡率来影响。 机密

PROJECT SUMMARY The ongoing epidemic of opioid use disorder (OUD), overdose, and death is unprecedented. Available pharmacologic therapies for OUD 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, military, select criminal justice clients, and patients whose employment, beliefs, or preferences motivate abstinence. Once-monthly injectable extended-release naltrexone (XRN) received FDA approval in 2010 for treating OUD. Due to improved patient adherence and retention relative to oral once-daily naltrexone, XRN is gaining wider acceptance. US prescription volume has grown ~37% in 2017. Still, early patient discontinuation with XRN is pervasive, as with other OUD treatments, often after just 1 month, usually leading to early relapse and treatment failure. We aim to maintain effective opioid antagonism with a single injection lasting at least two months, and up to 4 months or more, improving upon the adherence, retention, and treatment burden of comparable therapies. We have synthesized a series of novel and proprietary small molecule ester-type prodrugs of FDA approved opioid antagonists, with established PK/PD correlations and animal-human translatability. These candidates are designed to meet FDA’s abbreviated 505(b)2 approval path, reducing development and regulatory risk. Broad provisional patent protection is filed. Our lead candidate, NRS-033, shows in vivo calculated T1/2 of ~33 days in rats for the active metabolite. PK modelling suggest every 3 months or longer dosing is likely in humans. NRS-033’s mean plasma concentration of active metabolite at 28 days is 2.15 ng/ml, with ability to dose >50% higher, vs. XRN ~1.7 ng/ml, possibly allowing stronger antagonism against potent synthetic opioids. For women who are pregnant and of child-bearing potential, we expect more favorable pregnancy category B for NRS-033, rather than C as for all other MAT. Our UG3 aims include: 1) lead confirmation studies, lead selection, FDA Fast Track Filing, and toxicology batch manufacturing; 2) IND-enabling studies, GMP manufacturing, and IND submission; UH3 aims are, 3) Phase 1 studies, carcinogenicity studies, phase 2 clinical trial initiation, and FDA Breakthrough Therapy filing. 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, that may be better indicated in many women and stronger vs. synthetic opioids. Despite atypically lower development risk, this timely advance should have a significant public health impact by reducing rates of relapse, overdose, and death. Confidential