Select Late-Stage CMC, Non-clinical Studies, and Quality Programs to Accelerate NRS-033 Towards Pivotal Studies and Registration in Opioid Use Disorder - PROJECT SUMMARY The epidemic of opioid use disorder (OUD) is the greatest public health crisis the United States has faced in a generation. Yet essentially the same three Food and Drug Administration (FDA) approved medications for OUD (MOUD), in various formulations, have been available since the crisis began decades ago: opioid agonist methadone, partial agonist buprenorphine and antagonist naltrexone. These few legacy defenses against the staggering tide of addiction have proven feeble, primarily due to short treatment retention and lack of access. These MOUD are poorly accepted, offered to <20% of indicated patients. In the significant sub-population of OUD patients seeking opioid abstinence, only one MOUD, monthly injectable extended-release naltrexone (XR-NTX) is indicated. However, the median treatment duration on XR-NTX is just ~30 days (i.e., a single initial injection). Further, given its highly variable pharmacokinetics (PK), XR-NTX appears to lose efficacy in a substantial group of patients in the fourth week prior to repeat dosing, with abrupt loss of all opioid blockade in most patients within a week after a missed dose, leaving opioid intolerant patients completely unprotected. XR- NTX’s refrigeration, time-consuming 30-minute thawing, and cumbersome reconstitution requirements create workflow friction and storage challenges in many addiction practice settings, hindering availability. As a result, even after successful medical withdrawal (i.e., opioid detoxification), an estimated ~95% of abstinence-seeking patients are discharged un-initiated onto XR-NTX, resulting in relapse rates of up to 90% within a year. NRS- 033 is a patented novel chemical composition ultra long-acting opioid antagonist with successful preliminary Phase 1 clinical data. These data suggest NRS-033 will be longer duration, stronger acting, more consistently efficacious, and more forgivingly dosed than XR-NTX. NRS-033’s human Phase 1 PK data suggests >400% longer duration of action than XR-NTX, corresponding to dramatically improved treatment retention. Given its gradual decline and high trough levels of plasma nalmefene, NRS-033 should provide stronger and more consistent opioid blockade, as well as a more forgiving dosing schedule than XR-NTX. Such upgrades are critical for socially complex patients in today’s illicit market dominated by potent synthetic opioids, different from that decades ago. Also, NRS-033 is a room temperature stable ready-to-use prefilled syringe, much easier to use and clinically accessible than XR-NTX. Our proposed Aims seek to expedite NRS-033 into Phase 3 trials and FDA registration, hence include: late stage (registration batch) chemistry, manufacturing, and controls (CMC) for API and drug product, registration enabling non-clinical studies, quality systems, and regulatory engagement with FDA. Despite significantly de-risked development, the timely advance of NRS-033 will have a profound public health impact once available, reducing relapse and overdose risk for abstinence-seeking OUD patients, helping defeat the prevailing stigma that opioid dependence is inescapable.
