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Principal Investigator: Nikej Shah
Organization: NIRSUM LABORATORIES, INC.
Fiscal Year: 2024
Award: $3,051,459
Funding agency: National Institute on Drug Abuse
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
Terms: <Abbreviations><Abstinence><Acceleration><Actiq><Adanon><Adherence><Agonist><Althose><Animals><Armed Forces Personnel><Belief><Benign><Binding><Blood Plasma><Buprenorphine><Canine Species><Canis familiaris><Categories><Cessation of life><Client><Clinical><Clinical Trials><Collaborations><Common Rat Strains><Consultations><Contracting Opportunities><Contracts><Criminal Justice><Death><Development><Dogs><Dogs Mammals><Dolophine><Dose><Drug Kinetics><Drug Precursors><Drugs><Duragesic><Employment><Esters><FDA approved><Fentanest><Fentanyl><Fentyl><Formulation><Gestation><Goals><Half-Life><Head><Human><In Vitro><Individual><Injectable><Injections><Intramuscular><Investigation><Investigational Drugs><Investigational New Drugs><Investigators><Lead><Learning><Legal patent><Measures><Medication><Methadone><Methadose><Military><Military Personnel><Modeling><Modern Man><Molecular Interaction><Nalorex><Naltrexone><Nemexin><Opiate Antagonist><Opiate receptor antagonist><Opiates><Opioid><Opioid Antagonist><Opioid receptor antagonist><Oral><Outcome><Overdose><PK/PD><Patents><Patient Compliance><Patients><Pb element><Pharmaceutical Preparations><Pharmacodynamics><Pharmacokinetics><Pharmacology><Phase><Phase 2 Clinical Trials><Phase I Study><Phase II Clinical Trials><Phentanyl><Plasma><Plasma Serum><Pregnancy><Pro-Drugs><Prodrugs><Public Health><Qualifying><Rat><Rats Mammals><Rattus><ReVia><Regulatory Pathway><Relapse><Research><Research Contracts><Research Personnel><Researchers><Reticuloendothelial System, Serum, Plasma><Risk><Rodent><Rodentia><Rodents Mammals><Safety><Series><Severities><Sterility><Testing><Therapeutic><Therapeutic Agents><Therapeutic Index><Toxic effect><Toxicities><Toxicology><Translating><Treatment Failure><Vivitrol><Woman><Work><adherence rate><analytical method><antagonism><antagonist><base><bases><bear children><bearing children><canine><carcinogenicity><child bearing><childbearing><consultation><design><designing><developmental><domestic dog><drug development><drug/agent><experience><fighting><healthy volunteer><heavy metal Pb><heavy metal lead><improved><in vitro Assay><in vitro testing><in vivo><lead candidate><lipophilicity><manufacture><manufacturing organization><military population><mu opioid receptors><nalmefene><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><opiate abuse><opiate crisis><opiate drug abuse><opiate therapy><opiate use disorder><opioid abuse><opioid crisis><opioid drug abuse><opioid epidemic><opioid therapy><opioid use disorder><patient adherence><patient cooperation><patient retention><pharmacokinetics and pharmacodynamics><pharmacologic><phase 1 study><phase 2 designs><phase 2 study><phase 2 trial><phase 3 trial><phase II designs><phase II protocol><phase II study><phase II trial><phase III trial><preference><pregnant><retention rate><retention strategy><scale up><simulation><small molecule><stem><sterile><synthetic opiate><synthetic opioid><therapy failure><timeline><weapons><μ opioid receptors><μ-OR><μOR>