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：
10705245
负责人：
Nikej Shah
金额：
$ 305.29万
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/10705245
关键词：
Abbreviations Abstinence Acceleration Adherence Agonist Animals Belief Benign Binding Buprenorphine Canis familiaris Categories Cessation of life Client Clinical Clinical Trials Collaborations Consultations Contracts Criminal Justice Development Dose Drug Kinetics Employment Esters FDA approved Fentanyl Formulation Goals Half-Life Head Human In Vitro Individual Injectable Injections Intramuscular Investigation Investigational Drugs Lead Learning Legal patent Measures Methadone Military Personnel Modeling Naltrexone Opioid Opioid Antagonist Oral Outcome Overdose 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 Toxic effect Toxicology Translating Treatment Failure Woman Work adherence rate analytical method antagonist base carcinogenicity child bearing compliance behavior design drug development experience fighting healthy volunteer improved in vitro Assay in vitro testing in vivo lead candidate lipophilicity manufacture manufacturing organization mu opioid receptors nalmefene novel novel therapeutics opioid abuse opioid epidemic opioid therapy opioid use disorder patient retention pharmacokinetics and pharmacodynamics pharmacologic 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 timeline 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