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.

PROJECT NARRATIVE The opioid crisis in the United States has been exacerbated by illicit fentanyl, resulting in a staggering increase in injuries and deaths. Currently available overdose reversal agents have a limited capacity to combat opioid- induced respiratory depression, and repeated, higher doses required to achieve the same effect push the intervention’s safety. Serodopa Therapeutics is developing a novel intranasal formulation of a naloxone derivative that will offer rapid and effective reversal of fentanyl-induced respiratory depression to vastly reduce injury and improve survival rates for opioid overdose.