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 OUD的药物治疗未能阻止这股潮流，受到粘附性和保持性差的困扰， 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优于 目前可用的治疗方法。目前美沙酮和丁丙诺啡的激动剂/部分激动剂治疗 主宰了OUD的药物治疗。然而，拮抗疗法可能更适合于 重要的亚人群：年轻人、新近上瘾的军人、精选的刑事司法客户，以及 就业、信仰或喜好会刺激节欲。每月一次注射用缓释纳曲酮 (XRN)于2010年获得FDA批准，用于治疗OUD。由于改善了患者的依从性和保留率 相对于每天口服一次的纳曲酮，XRN正在获得更广泛的接受。美国处方数量增长了约37% 2017年。尽管如此，早期患者停用XRN的情况很普遍，就像其他OUD治疗一样，通常是在 1个月，通常会导致早期复发和治疗失败。我们的目标是保持有效的阿片类拮抗作用 单次注射至少持续两个月，最多持续4个月或更长时间，在粘附性基础上改善， 类似疗法的保留率和治疗负担。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类前药，建立了PK/PD相关性 以及动物与人类之间的可译性。这些候选人的设计符合FDA简化的505(B)2批准 路径，降低发展和监管风险。申请了广泛的临时专利保护。我们的领先候选人， NRS-033，显示体内计算的t1/2为大鼠~33天的活性代谢物。PK建模建议每 人类可能会服用3个月或更长时间的药物。S活性代谢物平均血药浓度 28天为2.15 ng/ml，与XRN~1.7 ng/ml相比，剂量提高50%，可能允许更强 对抗强效合成阿片类药物。对于怀孕和有生育潜力的妇女，我们 预计NRS-033的B类怀孕会更有利，而不是所有其他垫子的C类怀孕。我们的UG3目标是 包括：1)铅确认研究、铅选择、FDA快速通道归档和毒理学批量生产； 2)支持IND的研究、GMP制造和IND提交；UH3的目标是，3)第一阶段研究， 致癌性研究、第二阶段临床试验启动和FDA突破性治疗申请。我们的目标是 紧急推进到第三阶段试验并获得FDA批准。我们假设我们可以开发出一种新的治疗方法 更好的粘附性和保持性，这在许多女性身上可能表现得更好，比合成材料更强 阿片类药物。尽管发展风险异常低，但这种及时的进展应该会对公众健康产生重大影响 通过降低复发率、服药过量和死亡率来产生影响。 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