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: 10673373
• 负责人: Nikej Shah
• 金额: $ 305.65万
• 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 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673373
• 关键词: Abstinence; Adherence; Agonist; Animals; Belief; Benign; Binding; Buprenorphine; Canis familiaris; Categories; Client; Clinical; Clinical Trials; Collaborations; Consultations; Contractor; Contracts; Criminal Justice; Development; Dose; Drug Kinetics; Employment; Esters; FDA approved; Fentanyl; Formulation; Goals; Half-Life; Head; Human; In Vitro; Individual; Injectable; Injections; Intramuscular; Investigational Drugs; Investigational New Drug Application; Lead; Learning; Legal patent; Measures; Methadone; Military Personnel; Modeling; Naltrexone; Opioid Antagonist; Oral; Outcome; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phase II Clinical Trials; Plasma; Pregnancy; Prodrugs; Public Health; Qualifying; Rattus; Regulatory Pathway; Relapse; Research; Research Contracts; Research Personnel; Risk; Rodent; Safety; Series; Severities; Sterility; Testing; Therapeutic; Therapeutic Agents; Therapeutic Index; Time; TimeLine; Toxic effect; Toxicology; Translating; Treatment Failure; Woman; Work; adherence rate; analytical method; antagonist; base; carcinogenicity; child bearing; compliance behavior; design; drug development; experience; fight against; healthy volunteer; improved; in vitro Assay; in vitro testing; in vivo; lead candidate; lipophilicity; 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 2 designs; phase 2 study; phase II trial; phase III trial; preference; pregnant; retention rate; scale up; simulation; small molecule; stem; synthetic opioid; weapons

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

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 OUD的药理学疗法未能阻止潮汐，依从性和保留性差，困扰 与救济和治疗失败有关的主要因素。超过80％的OUD患者未经治疗。 需要更多的治疗选择。该建议旨在开发出优于优于的Oud药理选择 目前可用的疗法。当前使用Metagadone和丁丙诺啡治疗激动剂/部分激动剂治疗 OUD的主导药物疗法。但是，拮抗剂治疗可能更适合 重要的子人群：年轻，新增的军事，选择刑事司法客户和患者 就业，信念或偏好动机禁欲。一个月一次可注射的扩展释放纳曲酮 （XRN）2010年因治疗Oud而获得了FDA批准。由于改善患者的依从性和保留率 相对于每天一次的口服Naltrexone，XRN正在获得更广泛的接受。美国处方量增长了〜37％ 在2017年。尽管如 1个月，通常导致早期退休和治疗失败。我们旨在保持有效的阿片类药物拮抗作用 单个注射持续至少两个月，最多4个月或更长时间，可提高依从性， 保留和可比较疗法的治疗燃烧。我们已经合成了一系列新颖和专有的 FDA批准的阿片类拮抗剂的小分子酯型前药，具有已建立的PK/PD相关性 和动物人类的翻译性。这些候选人旨在满足FDA的缩写505（b）2批准 路径，降低发展和监管风险。提出了广泛的临时专利保护。我们的主要候选人， NRS-033，在体内显示了活性代谢物的大鼠的T1/2的〜33天。 PK建模建议每一个 人类可能有3个月或更长时间的给药。 NRS-033的平均血浆活性代谢产物的平均血浆浓度 28天为2.15 ng/ml，能力高于50％，而XRN〜1.7 ng/ml，可能会使更强大 对潜在合成阿片类药物的拮抗作用。对于怀孕和育儿潜力的女性，我们 对于NRS-033，预计B类更有利的怀孕类别，而不是所有其他垫子。我们的UG3目标 包括：1）铅确认研究，铅选择，FDA快速档案归档和毒理学批次制造； 2）辅助研究，GMP制造和IND提交； UH3的目标是，3）第1阶段研究， 致癌性研究，第2阶段临床试验计划和FDA突破性疗法。目标是 急切地晋升为第三阶段试验和FDA批准。我们假设我们可以通过 卓越的依从性和保留率，在许多女性中可能会更好地指出，而强度与合成 阿片类药物。尽管开发风险显着降低，但这种及时的进步应该具有重大的公共卫生 降低救济率，用药过量和死亡的影响。 机密的