Development of a novel drug for treating opioid use disorder

项目总结

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