Could monthly treatment prevent fentanyl overdoses? Scientists are working on it

Scientists have developed a promising antibody treatment to block the potentially deadly effects of fentanyl for nearly a month, raising hopes for a new tool to combat overdoses.

Animal tests showed the treatment could effectively block the effects of fentanyl, laying the groundwork for evaluating whether the drug will prove effective in humans, according to a study published in the journal Natural communications.

The antibodies are too large to cross the blood-brain barrier. So when they bind to fentanyl in the bloodstream, they block the powerful opioid from reaching receptors in the brain, the researchers explained. The experimental treatment, called CSX-1004, was administered to the animals by intravenous infusion.

Andrew Barrett, chief scientific officer of Cessation Therapeutics, the company that developed the treatment, compared the way it works to “Pac-Man” capturing fentanyl in the bloodstream, which “blocks fentanyl from reaching the brain where it produces its effects. “, both pleasant and dangerous.

Among its possible uses: The infusion could be given as a preventative measure to patients undergoing an inpatient detoxification program “to try to prevent death in the event of a relapse,” Barrett said.

Finding such a tool is particularly urgent as the number of American lives lost to drug overdoses has climbed to more than 100,000 a year, according to federal data. The bulk of these deaths are linked to synthetic opioids such as fentanyl, a powerful drug that has also been found in counterfeit pills and is often mixed with other drugs such as methamphetamine.

Scientists at Cessation Therapeutics in San Diego, in collaboration with researchers at Harvard Medical School and McLean Hospital in Massachusetts, conducted a series of tests on rodents and squirrel monkeys to evaluate the effects of CSX-1004 and found that a single infusion protected primates from fentanyl for more than three weeks.

One series of experiments included eight monkeys that were given fentanyl multiple times over 28 days. The animals were first given a placebo to see how they reacted to the opioid without treatment. Later, they received a low or high dose of CSX-1004 at the start of the cycle and received fentanyl six times.

Respiratory measurements showed that the drug was most protective during the first week and declined steadily thereafter, with the highest dose showing significant effects for up to 28 days.

The experimental treatment reversed slowed or shallow breathing, a symptom of overdose that can lead to death, the researchers reported. And it worked on other dangerous fentanyl analogs like carfentanil — a synthetic opioid intended to sedate large animals — without affecting oxycodone or other opioids prescribed by doctors to manage pain, the authors found. the study.

Cessation Therapeutics has begun evaluating the treatment’s safety in human volunteers and plans to next evaluate its effects in people addicted to opioids, Barrett said. If CSX-1004 proves effective in clinical trials, researchers said, it could protect people at high risk of overdose and become a bridge to other treatments that treat craving and withdrawal symptoms, they said. write the researchers.

“We are in a crisis situation where we need all hands on deck to help prevent people from dying,” said Kelly E. Dunn, professor of psychiatry and behavioral sciences at the University of Texas School of Medicine. Johns Hopkins University, which advised the company on the issue. designed human trials of the drug, but was not involved in collecting data for the new study.

“These transformative approaches are exactly what we need,” because with existing tools, “we’re just not making the progress we hoped for.”

Arming people with antibodies has long been explored by researchers as a potential way to protect people against a range of addictive drugs.

As fentanyl-related deaths have risen sharply since the start of the COVID-19 pandemic, research into antibody treatments “really opens the door to a tool that will help us respond to very high-risk populations,” he said. said Dr. Nora Volkow, director of the National Institute on Drug Abuse. Among them are people coming out of jail or prison, who face an alarming risk of overdose in the weeks after their release, she said.

Volkow added that treatment could help protect people who use cocaine or methamphetamine, who are at risk of overdose when their drugs are contaminated with fentanyl. For these people, she said, “you will significantly reduce the risk of dying.”

Antibodies may have advantages over extended-release naltrexone, a drug that blocks the effects of opioids, Barrett said. Monthly naltrexone injections require people to abstain from taking opioids for a period of time before starting treatment.

“Your tolerance goes down very quickly” during this time, said Dr. Melissa B. Weimer, an associate professor of medicine and public health at Yale, who was not involved in the study. When experiencing withdrawal, “most people with serious opioid use disorder will be very uncomfortable during this period. This puts them at risk of not starting treatment,” leaving them unprotected and at higher risk of opioid overdose.

Additionally, people taking naltrexone cannot use other common medications to reduce opioid cravings, such as methadone. And because naltrexone blocks all opioids, it can make pain management more difficult in an emergency. Based on results so far, CSX-1004 does not have these drawbacks, Barrett said.

The research team is still studying whether CSX-1004 causes “precipitated withdrawal” – an abrupt, sickening experience people have had with some opioid use disorder treatments. “We don’t know the answer yet, but we don’t think it’s going to be a deep withdrawal” because of the way it works, Barrett said.

Weimer said another important question is what happens if people use more fentanyl to try to reverse the effects of the drug. Doctors will need to know whether people are at greater risk of overdose as the drug’s effects wear off, she said.

And then there’s the practical question of “what proportion of individuals would opt for this treatment,” said Dr. Larissa Mooney, an addiction psychiatrist at UCLA. “Individuals who choose this treatment option should be motivated to receive treatment that would reduce the effects of fentanyl.”

Scientists have also attempted to develop vaccines that trigger the body to produce antibodies that can protect against fentanyl and other illicit drugs. Dr. Thomas Kosten, a psychiatrist at Baylor College of Medicine who has worked on a fentanyl vaccine, said antibody therapies could have some practical drawbacks.

The cost of making monoclonal antibodies like CSX-1004 is “pretty high,” Kosten said, and “you can’t just store a monoclonal in your cupboard, you have to refrigerate it.” practical solution to what is a huge problem. » He also questioned whether health insurers would cover the costs of infusion treatment for substance use disorders.

Volkow said that if a treatment like CSX-1004 proves effective in humans, “there’s a lot of room for innovation” to solve practical problems. “It would make sense to make this innovation if it seems to work.”

Cessation Therapeutics said it was already developing an injectable version of the antibody treatment that could be more practical. In the new paper, the authors wrote that the price of monoclonal antibodies could be about the same as some existing treatments for opioid use disorder.

Dunn of Johns Hopkins University called for more investment in new drugs and approaches to thwarting overdoses. There is “very little mainstream investment in this area,” she said, despite the alarming number of lives lost. “We need this investment to be able to actually make big changes.”

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