Xylazine and opioid overdose mitigation therapy using decoy receptor biomimetic nanoparticles, NarcoBond platform

The number of opioid deaths has exploded in the last two years. This eruption of overdose deaths is being wrought by a deadly cocktail of fentanyl and xylazine. Xylazine, also known as “Tranq” or “zombie drug”, is a powerful veterinary sedative that is incredibly dangerous to people on its own. Xylazine extends the high or euphoria of opioids, affording greater profits for traffickers. Xylazine elicits these effects by agonism of a2A adrenergic receptor (a2A) in the spinal cord and brain. Since xylazine is not an opioid, its effects are not reversed by naloxone (Narcan), the only approved opioid overdose rescue treatment. Narcan’s lifesaving effects stem from reversal of respiratory depression. Xylazine-fentanyl cocktails have a high potential for fatal overdose since both substances depress respiratory function and this may account for the surge in deaths. As xylazine antidotes, existing a2A antagonist are inadequate, suffering from a lack of specificity. A major obstacle to developing a2A antagonist as xylazine antidotes is extensive functional interplay between the 3 adrenergic receptor a2 subtypes, causing concern over unexpected side effects. As a result, no approved antidote for xylazine exists. Further, an agent reversing both opioid and xylazine overdose is an unmet clinical need. Our Solution: NarcoBondα2/µO - a “nanosponge” containing decoy receptors for fentanyl (mu opioid receptor) and xylazine (α2A-adrenergic receptor -α2A) will safely corral the drugs in the peripheral blood. As a result, the drugs are trapped away the central nervous system, thus sparing the patient from the high CNS concentrations that depress respiration and cause death. This mechanism is distinct from that of countermeasures such as antagonists like naloxone, which displace and release drug from receptors back into circulation. Further, NarcoBond’s sequestration mechanism does not trigger unwanted pharmacological antagonism, like that of an α2A antagonist. A beneficial outgrowth of this mechanism is a broad capability to mitigate against all opioids & all alpha2 agonists (e.g., Xylazine or its future illicit successors). Given the likelihood that other known alpha2 agonists may soon appear in illicit drug supplies (as has multiple opiates), this principle is critical. We envision that first responders will administer naloxone, as is current practice. If clinicians at the hospital observe xylazine toxicity, they will administer NarcoBond (intravenously) to trap opioids and/or xylazine, fully remedying life-threatening toxicity. We have already laid part of the groundwork for this approach. Previously, we showed life-saving effects in rodents with NarcoBondµO, a nanosponge that sequestered opioids in the peripheral blood from where the opioids were safely cleared. In Aim 1 of this Phase I we will focus on a nanosponge with xylazine decoy receptors (NarcoBondα2). In Aim2, antagonism of the pharmacological effects xylazine in rodents by intravenous NarcoBondα2 will provide proof-of-principle (POC). Successful POC will justify a Phase II study to develop NarcoBondα2/µO, the combination nanosponge with both xylazine and opioid decoy receptors. Subsequent, clinical development of NarcoBondα2/µO will deliver a paradigm shifting treatment for drug overdose.