New compound shows promise in reversing dangerous fentanyl effects

Few days go by without a new headline about the devastation wrought by drugs like fentanyl. And those are just the ones that make the news: More than 71,000 people overdosed on the synthetic opioid in 2021, a 20% increase over 2020, according to provisional data from the Centers for Disease Control and Prevention.  

As U.S. policymakers, patient advocates, healthcare providers and law enforcement agencies grapple with how to address the problem, a lab at the University of Maryland has developed a new drug that shows early promise in reversing the effects not only of fentanyl, but methamphetamine as well—and potentially a whole host of other substances, too. The researchers described their findings in a study published Dec. 15 in Chem.

“It works through a completely different mechanism than naloxone [the first line drug for treating opioid overdose], which is really the incredibly exciting part,” Lyle Isaacs, Ph.D., lead author, told Fierce Biotech Research.

The drug, Pillar[6]MaxQ—or P6AS—is a molecular container compound, a rigid, hollow ring structure that’s capable of confining another molecule inside. It works similarly to the Merck drug sugammadex (trade name Bridion), which reverses anesthesia-induced neuromuscular blockade by binding to the agents that cause it and excretes them in urine. P6AS binds to compounds that contain water-resistant, positively charged ammonium ions, which includes several commonly abused drugs. 

Isaacs’ lab wasn’t aiming to develop treatment to counteract drug effects when it synthesized the molecule back in 2020. As supermolecular chemists, his team studies the way container molecules bind to smaller molecules, or “guest” molecules. They later realized that P6AS would likely bind with the ammonium ions on commonly abused drugs and decided to conduct some experiments.

“We thought it was a natural fit to see whether they would also bind strongly to opioids and non-opioid drugs of abuse,” Isaacs said. As they expected, in vitro studies showed that the compound bound to multiple drugs of abuse. They decided to take a closer look at whether it could reverse the effects of fentanyl and methamphetamine.

After working with University of Maryland cell biology Professor Volker Briken, Ph.D., to carry out some toxicity assays to see what doses of the compound were safe for animals, the researchers teamed up with the psychology lab of Matthew Roesch, Ph.D., to conduct some behavioral studies in rodents.

Groups of eight to 10 mice were given high doses of either methamphetamine or fentanyl followed by P6AS at different time intervals. The scientists found that they could reverse the drugs’ effects if P6AS was administered up to five minutes after the mice were given methamphetamine, while they had up to 15 minutes to treat those who’d received fentanyl.

The researchers could tell P6AS was working by monitoring their behavior. Normally, when mice are given fentanyl or methamphetamine, they begin rapidly running around their boxes in what scientists describe as “hyperlocomotion.”

“If we give them our compound, we can see that those locomotion levels return towards baseline,” Isaacs said.

The scientists also tested how well P6AS stood up to naloxone. They dosed mice with fentanyl, then on different testing days gave them either P6AS or naloxone 15 minutes later. Their locomotion levels went back to baseline at the same rate with both drugs.

The next steps will involve eliciting more safety information along with learning more about how P6AS works. While the scientists believe the compound is being excreted through the kidneys—like other drugs that work similarly—they’ll need to do more tests to confirm this. There’s also some concern that P6AS could be interacting with neurotransmitters that are present elsewhere in the body, though Isaacs feels the work done so far shows the risk is likely low in the context it's meant to be used.

“We have done in vivo work, and it looks like at least for these acute applications—where either the animal is going to potentially have an overdose—those issues of what else it can do are perhaps somewhat secondary,” he said.

Isaacs and a former postdoc in his lab, Weijian Xue, have filed a patent application for the molecule, and the University of Maryland is interested in talking to potential investors or partners to develop it further. Isaacs is also hoping to receive a grant from the National Institutes of Health’s CounterACT program, which partners with researchers to develop new therapeutics for toxic compounds, to continue his team’s work.

While progress on new ways to prevent overdoses is invariably a good thing, the National Harm Reduction Coalition—a group that advocates on behalf of individuals struggling with addiction or who have been harmed by racist drug policies—told Fierce Biotech Research it believes the bigger problem is lack of access to tools that already exist.

“We’re excited about any opportunities to reduce overdoses,” Mary Sylla, director of overdose prevention policy and strategy at the National Harm Reduction Coalition, said. “However, naloxone is available and it reverses overdose for opioids and fentanyl. What’s more important is that we get naloxone to people who need it.”

Naloxone is currently out of reach for many individuals because it’s not yet available over the counter—though the FDA may change that in the coming months—forcing them to rely on health officials or safety programs to get it. A prescription for generic naloxone costs about $68 on average for the uninsured, according to 2018 figures from a study published earlier this year in JAMA.

It’s too soon to say how much any drug built around P6AS would cost or whether it could be made somehow more accessible to at-risk individuals than naloxone. These are factors that should be considered as development moves forward, Sylla added.

“If we can reduce the cost of the agents we have, we can do a lot more for the overdose crisis,” she said.