An experimental drug designed to reduce brain inflammation appears safe for older adults undergoing surgery and may lower the risk of postoperative delirium, according to a phase 2 clinical trial published in JAMA Network Open.
The drug, CN-105, is a lab-made peptide developed at Duke University School of Medicine to mimic the protective effects of apolipoprotein E (APOE), a protein linked to brain health.
The primary goal of the trial, known as MARBLE, was safety. On that front, CN-105 performed well, marking an early step toward what could become the first medication to treat postoperative delirium.
“Delirium remains one of the most common, costly and under addressed complications of surgery in older adults,” said the study’s lead author Miles Berger, MD, PhD, an anesthesiologist and perioperative care researcher at Stanford Medicine. “There is a critical need for new approaches that target its underlying biology.”
Roughly one in four older patients develop confusion and altered awareness in the hours and days after surgery. The condition — postoperative delirium — costs the U.S. health care system an estimated $80 billion a year.
In the trial, 186 patients ages 60 and older were randomly assigned to receive either CN-105 or a placebo. Patients who received CN-105 before surgery had fewer complications overall, with a median of one moderate or serious complication, such as infection, digestive or blood-related issues, compared to two in those who did not.
Although the study was not designed to measure effectiveness, researchers observed encouraging trends.
Postoperative delirium affected 19.3% of patients who received CN-105, compared with 26.5% of those in the non-treatment group.
The approximate 25% relative risk reduction favored the drug, but did not reach statistical significance, likely a result of the modest sample size, said first study author Noah Timko, MPH, a clinical research coordinator in the Duke Department of Anesthesiology.
The results set the stage for a larger clinical study to determine whether the drug truly reduces postoperative delirium.
“Even a modest reduction could translate into shorter hospital stays, lower costs, and a better quality of life,” Berger said.
Scientists increasingly believe inflammation is a key cause of postoperative delirium. One risk factor is the APOE ε4 gene variant, which is tied to Alzheimer’s disease and heightened inflammation in the brain.
That connection points to what happens next: Surgery triggers inflammation across the body. In more vulnerable brains, that surge can briefly scramble thinking and awareness.
“The idea is that postoperative delirium may be an acute, short-term version of the type of inflammatory processes that drive longer-term neurodegenerative diseases,” Berger said.
To target those processes, Duke scientists reverse engineered APOE’s neuroprotective effects into a drug refined enough to cross the blood-brain barrier and tamp down harmful inflammation.
It’s a discovery process that began more than 30 years ago in the lab of Daniel Laskowitz, MD, a Duke neurologist and co-inventor of CN-105. Laskowitz and colleagues hold multiple patents and, with Duke University, launched the startup, Aegis CN, to help develop the drug further.
“Because it helps block brain inflammation and prevents nerve cell death, it may be effective across a wide range of conditions – from acute brain injuries like stroke and intracranial hemorrhage to post-operative delirium and chronic neurogenerative diseases, such as Alzheimer’s,” Laskowitz said.
The study was funded by the Alzheimer’s Drug Discovery Foundation and the National Institutes on Aging.