Development of a novel drug for treating opioid use disorder

开发治疗阿片类药物使用障碍的新药

• 批准号: 10331501
• 负责人: Nikej Shah
• 金额: $ 16.41万
• 依托单位: NIRSUM LABORATORIES, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10331501
• 关键词: Abstinence; Adherence; Adoption; Agonist; Animals; Award; Belief; Benign; Buprenorphine; Canis familiaris; Cleaved cell; Client; Cold Chains; Contractor; Contracts; Criminal Justice; Cyclic GMP; Development; Dose; Employment; Engineering; Esters; FDA approved; Fentanyl; Friction; Goals; Half-Life; Human; Individual; Injectable; Injections; Intramuscular; Language; Lead; Legal patent; Logistics; Methadone; Military Personnel; Modeling; Naltrexone; Opioid; Opioid Antagonist; Oral; Outcome; Patients; Pharmacodynamics; Pharmacology; Phase; Phase II Clinical Trials; Plasma; Pregnancy; Prodrugs; Production; Public Health; Rattus; Relapse; Research; Research Contracts; Research Personnel; Risk; Safety; Severities; Syringes; Temperature; Therapeutic; Therapeutic Agents; Therapeutic Index; Time; Toxicology; Treatment Failure; Woman; Work; adherence rate; analog; base; child bearing; compliance behavior; design; drug development; improved; in vivo; lipophilicity; meetings; mu opioid receptors; nalmefene; novel; novel therapeutics; opioid abuse; opioid epidemic; opioid therapy; opioid use disorder; overdose death; pharmacokinetics and pharmacodynamics; phase 1 study; phase III trial; preference; pregnant; prescription opioid; programs; retention rate; stem; synthetic opioid

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

项目概要 阿片类药物使用障碍 (OUD)、用药过量和死亡的持续流行是前所未有的。可用的 治疗阿片类药物使用障碍 (MOUD) 的药物未能阻止这种趋势，原因是依从性差和 保留，是与复发和治疗失败相关的主要因素。超过 80% 的人患有 OUD 未经治疗。需要更多的治疗选择。该提案旨在开发 OUD 药理学 优于目前可用疗法的选择。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，拮抗剂治疗可能更有效 适合重要的亚人群：年轻人、新成瘾者以及其就业、信仰、 或偏好促使禁欲。收到每月一次注射缓释纳曲酮 (XR-NTX) OUD 于 2010 年获得 FDA 批准。由于相对于每日口服一次，患者的依从性和保留率有所提高 纳曲酮、XR-NTX 正在获得更广泛的认可。 2019 年美国处方量增长约 11%。但早期患者 大约一半的患者在使用 XR-NTX 仅仅 1 个月后就停药，导致复发和治疗 失败。我们的目标是通过单次注射维持有效的阿片类药物拮抗作用，持续至少两个月， 可能需要 4-6 个月，显着改善依从性、保留率和后勤负担。我们发明了 FDA 批准的阿片拮抗剂的专利 NRS-033 前药类似物。我们建立了PK/PD 动物中的相关性可能也适用于人类。我们的计划正在利用 FDA 的缩写 505(b)2 审批路径，减少开发风险和时间。 NRS-033，显示大鼠体内计算的 T1/2 约为 31 天 狗体内的活性代谢物约为 64 天。 PK 模型表明人类也有类似的 PK。 NRS-033的 与 XR-NTX 纳曲酮 34 天时的大鼠平均血浆浓度相比，活性代谢物的平均血浆浓度为 3.7 ng/ml ~1.7 ng/ml，可能比强效合成阿片类药物具有更强的拮抗作用。对于怀孕和怀孕的女性 考虑到生育潜力，我们预计 NRS-033 比所有其他已批准的药物在怀孕期间的安全性更高 模型。我们的 UG3 完成的目标包括先导化合物确认和选择、cGMP API 制造、IND 前 与 FDA 会面，以及药效学研究。即将完成的目标包括支持 IND 的毒理学 研究、cGMP 灌装生产和 IND 提交。中期毒理学研究结果似乎很有希望。之后 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 批准。我们假设我们可以开发出一种具有优异依从性和保留率的新型治疗方法， 具有更强的阿片类药物阻断作用的育龄妇女的适应症更好。这一及时的进展应该 对公共健康产生重大影响，减少复发、用药过量和死亡。 机密的