ApoE Mimetic Peptide CN-105 Shows Promise for Reducing Postoperative Delirium in Phase 2 MARBLE Trial

Bottom line: CN-105 is the first peptide therapy to show a safety and efficacy signal for preventing postoperative delirium — a common, devastating complication in older surgical patients with no approved drug treatment.

CN-105 is a lab-synthesized pentapeptide derived from the receptor-binding domain of apolipoprotein E (apoE), a lipid-transport protein with potent anti-inflammatory effects in the central nervous system. The apoE ε4 allele — carried by approximately 25% of the population — increases risk for both Alzheimer disease and postoperative delirium, making apoE signaling a rational therapeutic target.

The MARBLE Trial

Published in JAMA Network Open in April 2026, the Phase 2 MARBLE (Mimetic of ApoE Reduces Brain infLammation and dElirium) trial was a triple-blind, escalating-dose, randomized controlled trial conducted at Duke University Medical Center.¹

The study enrolled older adults (≥60 years) undergoing major non-cardiac surgery and randomized them to receive intravenous CN-105 or placebo in the perioperative period. Primary endpoints focused on safety and feasibility, with delirium incidence assessed as a secondary endpoint using the Confusion Assessment Method (CAM).

Key Findings

• Safety: CN-105 was well tolerated across dose cohorts with no dose-limiting toxicities or serious adverse events attributed to the study drug¹
• Feasibility: The perioperative dosing protocol proved practical in the surgical setting
• Delirium signal: The CN-105 group showed a numerically lower incidence of postoperative delirium compared with placebo, though the study was not powered for a definitive efficacy conclusion
• Biomarkers: Inflammatory markers in cerebrospinal fluid suggested reduced neuroinflammation with CN-105 treatment

Clinical Context

Postoperative delirium affects 15–50% of older surgical patients and is independently associated with:²

• 2–3× increased in-hospital mortality
• Longer ICU and hospital stays
• Accelerated long-term cognitive decline
• Higher rates of discharge to institutional care

Despite its prevalence, no pharmacological intervention is currently FDA-approved for delirium prevention. Existing strategies rely on multicomponent non-pharmacological protocols (early mobilization, sleep hygiene, reorientation).

Clinical implication: If confirmed in a larger Phase 3 trial, CN-105 could become the first drug approved for postoperative delirium prevention — addressing a major unmet need in perioperative medicine for the aging surgical population.

For more on neuroprotective peptides, see our research on peptides in neurology.

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References

1. MARBLE Investigators. 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.
2. Inouye SK, Westendorp RG, Saczynski JS. Delirium in elderly people. Lancet. 2014;383(9920):911-922.