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。可用的 因依从性差而困扰的杀菌障碍药物（MOUD）未能阻止潮汐 保留，与救济和治疗失败有关的主要因素。超过80％的OUD个人 未经治疗。需要更多的治疗选择。该建议旨在开发OUD药理学 选项优于当前可用的疗法。用方法加成酮的激动剂/部分激动剂治疗 目前，丁丙诺啡目前主导了OUD的药物学疗法。但是，拮抗剂治疗可能更多 适合重要的子人群：年轻，新增的年轻人以及就业的患者，认为， 或偏好节制。每月一次注射的扩展释放纳曲酮（XR-NTX）收到 FDA在2010年获得Oud的批准。由于改善患者的依从性和相对于口服一次的保留率 naltrexone，XR-NTX正在获得更广泛的接受。美国处方量在2019年增长〜11％。 在XR-NTX上仅1个月后停用，大约一半的患者发生，导致救济和治疗 失败。我们旨在保持有效的阿片类药物拮抗作用，以持续至少两个月的单个注射 可能有4-6个月的时间大大提高了依从性，保留率和后勤伯良。我们发明了 FDA批准的阿片类药物拮抗剂的专利NRS-033前药类似物。我们已经建立了PK/PD 动物的相关性，可能可以翻译成人类。我们的计划使用FDA的缩写505（b）2 批准路径，减少发展风险和时间。 NRS-033，在体内显示大鼠的T1/2的T1/2 〜31天 狗的活性代谢产物约64天。 PK建模表明在人类中也有类似的PK。 NRS-033 在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naltrexone在 〜1.7 ng/mL，可能允许更强的拮抗作用与潜在的合成阿片类药物。对于怀孕的女性 具有育儿潜力，我们希望NRS-033的怀孕安全性更高 穆德。我们的UG3完成的目标包括铅确认和选择，CGMP API制造，预先启动 与FDA和药效学研究会面。目标很快完成包括毒理学 研究，CGMP填充填充制造和IND提交。临时毒理学发现似乎很有希望。之后 UH3的目的包括1阶段研究和2阶段临床试验。目标是紧急前进3阶段试验 和FDA批准。我们假设我们可以开发一种具有优越的依从性和保留率的新型治疗性， 在具有育儿潜力的女性中更好地指出，阿片类药物封锁强烈。这个及时的进步应该 对公共卫生产生重大影响，减少继电器，用药过量和死亡。 机密的