Novel Therapeutic Agents to Reverse Opioid Overdose

Project Summary/Abstract The abuse of opioids is a serious national crisis that affects public health as well as social and economic welfare. A 2018 report from the Centers for Disease Control and Prevention (CDC) shows that every day, 128 people in the United States die from opioid overdose. Synthetic opioids (e.g. fentanyl) have become the leading cause of drug-related deaths in recent years. The current standard of care for opioid overdose, naloxone, is not sufficient in treating intoxication caused by synthetic opioids since its serum half-life is much shorter than that for synthetic opioids. Renarcotization is known to occur after an initial dose of naloxone. Patients treated for fentanyl overdose often remain hospitalized for extended periods of time, receiving multiple rounds of naloxone via infusion. It is reported that high doses or repeated doses of naloxone can cause cardiovascular complications and sudden withdrawal symptoms. A more effective therapeutic agent is needed to treat patients with overdoses caused by synthetic opioids. We have previously identified a small molecule drug candidate with a demonstrated safety and efficacy in reversing fentanyl-induced respiratory depression in a rat model. Our drug candidate addresses the drawbacks of naloxone including renarcotization and sudden withdrawal symptoms via a different mechanism of action – sequestration and removal of opioids in the bloodstream as an effective means of reversing intoxication (similar to an antibody). Our drug candidate binds opioid in the blood and facilitates its removal from the body. We propose to conduct a small pilot preclinical study to evaluate the efficacy of our drug candidate in a standard non-human primate model. The results from this study will allow us to enter an IND-enabling preclinical study on the candidate molecule.Project Narrative The goal of this program is to develop a new therapeutic agent to treat intoxication caused by opioids and especially synthetic opioids. We have identified a lead candidate which reverses fentanyl-induced respiratory depression and dysfunction of the central nerve system without the drawbacks of naloxone. We propose to further develop this compound into an effective therapeutic agent.