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

基本信息

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
项目类别：
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

项目摘要

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

项目概要阿片类药物使用障碍（OUD）、药物过量和死亡的持续流行是前所未有的。 OUD 的药物治疗未能阻止这种趋势，因为依从性和保留率较差，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优于 OUD 的药理学选择。目前可用的疗法为美沙酮和丁丙诺啡的激动剂/部分激动剂治疗。 OUD 的药物治疗占主导地位，但拮抗剂治疗可能更适合。重要的亚人群：年轻人、新近成瘾的人、军人、特定的刑事司法当事人以及患有此类疾病的患者就业、信仰或偏好促使每月一次注射缓释纳曲酮。由于改善了患者的依从性和保留率，XRN 于 2010 年获得 FDA 批准用于治疗 OUD。相对于每日一次口服纳曲酮，XRN 正在获得更广泛的接受，美国处方量增长了约 37%。 2017 年。尽管如此，与其他 OUD 治疗一样，患者早期停止使用 XRN 的现象仍然普遍存在，通常是在治疗结束后不久 1个月，通常会导致早期复发和治疗失败，我们的目标是维持有效的阿片类药物拮抗作用。单次注射持续至少两个月，最多 4 个月或更长时间，改善依从性，我们合成了一系列新颖且新颖的疗法。 FDA 批准的阿片拮抗剂的小分子酯型前药，具有已确定的 PK/PD 相关性这些候选药物旨在满足 FDA 的缩写 505(b)2 批准。路径，减少开发和监管风险已申请广泛的临时专利保护。 NRS-033 显示，活性代谢物 PK 模型在大鼠体内计算出的 T1/2 约为 33 天。 NRS-033 的活性代谢物平均血浆浓度可能为 3 个月或更长时间。 28 天为 2.15 ng/ml，剂量可高出 >50%，而 XRN 约为 1.7 ng/ml，可能允许更强的剂量对于怀孕和育龄妇女，我们对强效合成阿片类药物有拮抗作用。预计 NRS-033 的妊娠类别 B 比我们所有其他 MAT 的 C 更有利。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量生产； 2) 支持 IND 的研究、GMP 生产和 IND 提交；3) 第一阶段研究，致癌性研究、2 期临床试验启动以及 FDA 突破性疗法备案。紧急推进到 3 期试验并获得 FDA 批准，我们勇敢地说我们可以开发一种新的治疗方法。优异的依从性和保留性，这在许多女性中可能更好，并且比合成材料更强尽管阿片类药物的开发风险非常低，但这一及时的进展应该会对公共健康产生重大影响。通过降低复发率、用药过量和死亡率来产生影响。机密的