CN-105 Safe and Feasible for Decreasing Postoperative Delirium in Older Patients: Study
USA: Researchers have found in a phase 2 randomized clinical trial involving older surgical patients that CN-105 was found to be safe and feasible, with no increase in adverse events compared to placebo. These findings support the need for a phase 3 trial to further assess its effectiveness in reducing postoperative complications, particularly its impact on the incidence and severity of postoperative delirium.
The MARBLE trial, published in JAMA Network Open and led by Noah J. Timko from Duke University, assessed whether CN-105—an apolipoprotein E mimetic peptide—could reduce neuroinflammation and postoperative delirium in older surgical patients, a complication associated with poor outcomes and delayed recovery.
In the triple-blind randomized clinical trial conducted between April 2019 and December 2022, 186 patients aged 60 years or older undergoing noncardiac, nonintracranial surgeries were enrolled. Participants were randomized in a 3:1 ratio to receive either intravenous CN-105 or placebo, administered within one hour before surgery and then every six hours until discharge or up to 13 doses.
The primary outcome was safety, measured by postoperative adverse events, while secondary outcomes included feasibility of administration, incidence and severity of delirium, and changes in cerebrospinal fluid inflammatory markers.
The trial findings were as follows:
- CN-105 was found to be well-tolerated among older surgical patients.
- The proportion of patients experiencing moderate to severe adverse events was slightly lower in the CN-105 group compared to placebo, but the difference was not statistically significant.
- Patients receiving CN-105 had fewer adverse events per individual, indicating a potential clinical benefit.
- More than 90% of doses in both groups were administered within the predefined time window, demonstrating good feasibility in the perioperative setting.
- The incidence of postoperative delirium was lower in the CN-105 group compared to placebo (19.3% vs 26.5%), though the difference was not statistically significant.
- No significant differences were observed between the groups in terms of delirium severity.
- Postoperative inflammatory biomarkers, including interleukins and other cytokines, did not differ significantly between the CN-105 and placebo groups.
The researchers noted several limitations, including the single-center design, relatively small sample size, and variability in surgical procedures, which may have influenced the findings. The trial was also not powered to determine the most effective dosing strategy.
Despite these limitations, the study provides encouraging early evidence supporting the safety and practicality of CN-105 in older surgical patients. The authors highlighted that the drug’s ability to cross the blood-brain barrier and its favorable pharmacokinetic profile make it a promising candidate for further investigation.
Overall, the findings pave the way for larger, well-powered phase 3 trials to determine whether CN-105 can meaningfully reduce postoperative delirium and improve outcomes in the growing population of older surgical patients.
Reference:
Timko NJ, Cooter Wright M, Smith MR, et al. Apolipoprotein E Mimetic Peptide CN-105 and Postoperative Delirium in Older Patients: The Phase 2 MARBLE Randomized Clinical Trial. JAMA Netw Open. 2026;9(4):e262289. doi:10.1001/jamanetworkopen.2026.2289
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