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Principal Investigator: Michael V. Voronkov
Organization: SERODOPA THERAPEUTICS INC
Fiscal Year: 2024
Award: $1,539,426
Funding agency: National Institute on Drug Abuse
PROJECT SUMMARY
There has been a dramatic rise in synthetic opioid-related deaths, primarily due to high-potency opioids such as
fentanyl and its analogs. The cumulative burden of fatal and non-fatal fentanyl overdoses on public health is
unprecedented. An effective overdose reversal agent to rapidly relieve opioid-induced respiratory depression
(OIRD) caused by high-potency opioids is an unmet public health need. The gold standard of treatment for
reversing opioid overdose is to administer naloxone (Narcan®), a mu-opioid receptor (MOR) antagonist. Since
OIRD is due to direct activation of MORs in the brain, naloxone competes with the other opioids (i.e., fentanyl)
for the receptor. However, the anomalous pharmacology of fentanyl, including rapid onset of action and reduced
sensitivity to reversal by naloxone, has contributed to fentanyl's lethality. The rising death toll from fentanyl and
other high-potency opioids requires rapid delivery of naloxone at higher/repeated doses that push the limits of
its safety. Thus, there is a critical need to develop a reversal agent for fentanyl-induced overdose that is not only
more effective than naloxone, but also acts faster, is effective at lower doses, and has an improved side effect
and safety profile. Serodopa Therapeutics, Inc is developing a novel derivative of naloxone, designed to
overcome the naloxone-resistant pharmacology of high-potency opioids via improved brain exposure and faster
onset of action. We intend to develop an intranasal (IN) formulation of our novel derivative of naloxone as an
overdose reversal agent for OIRD. Critically, we have demonstrated efficacy in reversing fentanyl-induced OIRD
in rats and dogs. The therapeutic potential of our novel naloxone derivative has been established with preliminary
preclinical studies, including Eurofins Early Discovery Suite of Testing and work conducted by the National
Institute on Drug Abuse (NIDA)’s Addiction Treatment Discovery Program. We have demonstrated proof-of-
concept in two species (rat and dog), developed a chemical process for the drug substance, developed an
aqueous IN drug product prototype, and established an in vitro safety profile. The goals of this Direct-to-Phase
II SBIR project are to complete the formulation development and preclinical testing required to bring our novel
drug product to a point of readiness to file an IND. To accomplish this objective, we will select a lead formulation
(Aim 1) and establish the preclinical toxicology profile (Aim 2) and safety profile (Aim 3). Completing this project
will allow us to prepare and submit an IND package to the FDA, a key step toward initiating a Phase 1 clinical
trial.
Terms: <Acceleration><Acquired brain injury><Actiq><Blood><Blood Plasma><Blood Reticuloendothelial System><Brain><Brain Injuries><Brain Nervous System><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><Canine Species><Canis familiaris><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cessation of life><Chemicals><Clinical Research><Clinical Study><Clinical Trials><Common Rat Strains><Data><Death><Development><Dogs><Dogs Mammals><Dose><Drugs><Dryness><Duragesic><Early-Stage Clinical Trials><Encephalon><Fentanest><Fentanyl><Fentyl><Formulation><Goals><Heart Vascular><Hypoxia><Hypoxic><In Vitro><Injury><Intervention><Intervention Strategies><Lead><Life><Long term disability><Medication><NIDA><Naloxone><Narcan><Narcanti><National Institute of Drug Abuse><National Institute on Drug Abuse><Opiate Antagonist><Opiate receptor antagonist><Opiates><Opioid><Opioid Antagonist><Opioid receptor antagonist><Overdose><Overdose reversal><Oxygen Deficiency><Pb element><Pharmaceutical Preparations><Pharmacological Study><Pharmacology><Pharmacology Study><Phase><Phase 1 Clinical Trials><Phase I Clinical Trials><Phentanyl><Plasma><Plasma Serum><Population><Powder dose form><Powders><Preclinical Testing><Preparedness><Process><Property><Public Health><Rat><Rats Mammals><Rattus><Readiness><Receptor Protein><Regimen><Reporting><Resistance><Respiratory Depression><Reticuloendothelial System, Serum, Plasma><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SBIR><Safety><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Small Business Innovation Research><Small Business Innovation Research Grant><Survival Rate><Temperature><Testing><Therapeutic><Toxicology><United States><Ventilatory Depression><Work><addiction><addictive disorder><analog><aqueous><brain damage><brain-injured><canine><circulatory system><combat><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><depressed breathing><depression of breathing><design><designing><developmental><domestic dog><drug/agent><fentanyl overdose><first in man><first-in-human><heavy metal Pb><heavy metal lead><improved><injuries><innovate><innovation><innovative><interventional strategy><mu opioid receptors><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 crisis><opiate deaths><opiate mortality><opiate overdose><opiate related overdose><opioid crisis><opioid deaths><opioid drug overdose><opioid epidemic><opioid induced overdose><opioid intoxication><opioid medication overdose><opioid mortality><opioid overdose><opioid overdose death><opioid poisoning><opioid related death><opioid related overdose><opioid toxicity><overdose death><overdose fatalities><phase I protocol><pre-clinical><pre-clinical development><pre-clinical study><pre-clinical testing><preclinical><preclinical development><preclinical study><prevent><preventing><programs><prototype><receptor><resistant><respiratory><reverse overdose><safety assessment><scale up><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><side effect><standard care><standard treatment><synthetic opiate><synthetic opioid><μ opioid receptors><μ-OR><μOR>