Xylazine Reversal Research

The emergence of xylazine, an α2 adrenergic receptor agonist (α2 agonist), as an adulterant in the illicit drug supply, especially fentanyl, has led to a rapid increase in overdoses complicating the worst drug epidemic in U.S. history. Concerningly, recent reports have also implicated even stronger α2 agonists utilized as opioid adulterants, including medetomidine and dexmedetomidine. Currently, there are no human-approved antidotes for xylazine or other α2 agonists. While the education, detection, and prevention efforts to combat xylazine usage are underway, further work toward developing xylazine overdose and blocking treatments is warranted. Rapid reversal of α2 agonists using α2 antagonists have been used widely in the veterinary field, but currently are only approved for animal use.
 

 Age-adjusted rate of drug overdose deaths involving xylazine, by sex: United States, 2018-2021  
¹Increasing trend from 2018 through 2021 (p < 0.05).
NOTES: Drug overdose deaths are identified using International Classification of Diseases, 10th Revision underlying cause-of-death codes X40-X44, X60-X64, X85, and Y10-Y14. Deaths may involve other drugs in addition to the referent (listed) drug. Age-adjusted death rates were calculated using the direct method and adjusted to the 2000 U.S. standard population. When comparing rates across years, note that trends may be influenced by improvements in drug reporting. The reporting of at least one specific drug or drug class in the literal text, as identified by multiple cause-of-death codes T36-T50.8, improved from 92.0% of drug overdose deaths in 2018 to 95.2% in 2021. SOURCE: National Center for Health Statistics, death certificate literal text from the National Vital Statistics System as of May 24, 2023.

Due to this alarming trend, Akina, Inc. is concurrently developing two formulations, a short-acting nasal formulation for rapid reversal of xylazine, and a long-acting injectable microparticle formulation for continual blocking of xylazine effects for up to 1 month. One goal of this project is to develop, characterize, cGMP manufacture, and clinically evaluate a short-acting nasal formulation for reversal of α2 agonist overdose. Concurrently, a second goal is to develop, characterize, cGMP manufacture, and prepare for clinical testing a long-acting injectable formulation to block α2 agonist effects. Development of both short-acting nasal and long-acting injectable formulations will be completed using Akina’s technology and expertise.
 

The innovation in this technology is to adapt an α2 antagonist into a short-acting nasal formulation for the treatment of xylazine overdose as well as develop a long-acting formulation by loading an α2 antagonist into PLGA microparticles with release kinetics sufficient for one-month α2 agonist blocking. We will use our GMP manufacturing capacity to rapidly translate research into a clinical product. The significance of this product development program will provide two new, practical solutions to combat the emergence of xylazine and other α2 agonists as adulterants in the illicit drug supply.