CN-105 · program

CN-105 for Postoperative delirium

Phase 2CompletedAegisCN LLC

Indications for CN-105: Intracerebral hemorrhage · Phase 2 Postoperative delirium · Phase 2

MARBLE (NCT03802396) was an investigator-initiated Phase 2 at Duke led by anesthesiologist Miles Berger — not AegisCN-sponsored, though AegisCN supplied the drug and nonfinancial support. It was a triple-blind, escalating-dose, placebo-controlled trial in 186 randomized patients aged 60 and over undergoing major non-cardiac, non-intracranial surgery, giving IV CN-105 (0.1, 0.5 or 1 mg/kg) starting under an hour preoperatively and then every 6 hours for up to 13 doses. It met its safety and feasibility aims — Grade 2+ adverse events in 76.6% versus 87.8% on placebo (RR 0.87, 95% CI 0.76-1.00), serious adverse events 8% versus 22.4% (p=0.007), no deaths — but missed on efficacy: delirium occurred in 19.3% versus 26.5% (OR 0.66, 95% CI 0.31-1.42, p=0.29), with no significant effect on delirium severity, on the co-registered postoperative cognitive dysfunction endpoint, or on CSF cytokines and Alzheimer biomarkers. The CSF cytokine null matters beyond this indication: it is a failure to demonstrate CN-105's proposed anti-neuroinflammatory mechanism in humans. Enrolment ended 2022-12-28 and the results published only in April 2026. Duke and the authors call for a larger Phase 3 study; none is registered, and no CN-105 trial is ongoing anywhere as of July 2026.

Data current as of

Development timeline

Phase 2Jul 2018 – Apr 2026
  1. Published in JAMA Network Open more than three years after completion: safe and feasible, but the reduction in postoperative delirium was not statistically significant (19.3% vs 26.5%, OR 0.66, p=0.29) and no CSF cytokine endpoint moved. The authors argue a Phase 3 is warranted; none has been registered.↗
  2. missedMARBLE: CN-105 was safe and feasible but did not significantly reduce postoperative delirium (19.3% vs 26.5%, OR 0.66, p=0.29) or CSF cytokines in 186 randomized older surgical patients.↗
  3. metMARBLE tabular results posted to ClinicalTrials.gov: median Grade II+ adverse events per patient 1 (CN-105, n=137) versus 2 (placebo, n=49), p=0.025.
  4. MARBLE completes enrolment and follow-up; 203 enrolled, 186 randomized 3:1 to CN-105 versus placebo.
  5. MARBLE opens at Duke (NCT03802396). ClinicalTrials.gov study start 2018-07-15; the first patient was randomized 2019-04-17 per the publication.

Readouts

  • 2026-04-01ReportedFull resultsmissedNCT03802396

    MARBLE: CN-105 was safe and feasible but did not significantly reduce postoperative delirium (19.3% vs 26.5%, OR 0.66, p=0.29) or CSF cytokines in 186 randomized older surgical patients. ↗

  • 2024-09-04ReportedRegistry resultsmetNCT03802396

    MARBLE tabular results posted to ClinicalTrials.gov: median Grade II+ adverse events per patient 1 (CN-105, n=137) versus 2 (placebo, n=49), p=0.025.

Clinical trials in Postoperative delirium

NCT03802396MARBLEPhase 2Completedn=203

Modulating ApoE Signalling to Reduce Brain Inflammation, deLirium and postopErative Cognitive Dysfunction (MARBLE): A Phase 2 Trial to Evaluate the Efficacy and Feasibility of CN-105 in Preventing Postoperative Cognitive Dysfunction and Delirium — sponsor: Duke University (sponsor-investigator Miles Berger)

Started Jul 2018· Primary completion Dec 2022

missedsecondaryPeak delirium severity — median severity score 1 vs 2 (0.19)

No significant difference in peak delirium severity between CN-105 and placebo.

missedsecondaryDelirium incidence (CAM-3D / CAM-ICU) through postoperative day 5 — 19.3% vs 26.5%; OR 0.66 (95% CI 0.31-1.42) (0.29)

Delirium occurred in 19.3% of CN-105 patients versus 26.5% on placebo — not statistically significant. This is the trial's central efficacy question and it was negative.

metprimaryFeasibility: proportion of doses administered within the protocol time window — 94.6% (CN-105) vs 93.8% (placebo) of doses within window

Perioperative every-6-hours dosing proved feasible in a real surgical workflow.

missedsecondaryCSF cytokine change (IL-6, IL-8, MCP-1, G-CSF) from preoperative baseline to 24 h postoperatively

No significant between-group differences for any of IL-6, G-CSF, IL-8 or MCP-1 — the proposed anti-neuroinflammatory mechanism was not demonstrated in human CSF. This null is the most consequential result in the CN-105 dataset, because it bears on the mechanism underpinning every indication the compound is being developed for.

metprimaryPrimary: number of Grade II or higher adverse events per patient (safety), CN-105 versus placebo through 6-week follow-up — Grade 2+ AEs 76.6% vs 87.8% (RR 0.87, 95% CI 0.76-1.00); median events per patient 1 (IQR 1-3) vs 2 (IQR 1-5) (0.03 (events per patient, publication; 0.025 in the posted registry results); 0.10 for the proportion with any Grade 2+ AE)

203 enrolled, 186 randomized (137 to CN-105 across 0.1 / 0.5 / 1 mg/kg escalating doses, 49 to placebo). CN-105 did not increase adverse events; serious adverse events were 8% versus 22.4% on placebo (p=0.007) and there were no deaths.

Formulations

FormulationRouteRegimenPharmacokinetics
CN-105 intravenous solution
30-minute IV infusion. Phase 1 covered 0.01-1.0 mg/kg as single escalating and repeated doses. The clinical dose carried forward is 1.0 mg/kg IV every 6 hours: in acute intracerebral hemorrhage (CATCH, S-CATCH) started within 12 hours of symptom onset and continued up to 72 hours; in the MARBLE postoperative-delirium Phase 2, escalating cohorts of 0.1 / 0.5 / 1.0 mg/kg IV every 6 hours from 1 hour before surgery through postoperative day 3 or discharge (maximum 13 doses). The China Phase 2 (NCT06255977) tested 0.1, 0.3 and 1.0 mg/kg against placebo.
IntravenousOthert½ 3.6 h · Tmax 0.5 h · F 100%

Mechanism of action (compound-wide)

CN-105 is an apolipoprotein E-mimetic pentapeptide that reproduces the polar, receptor-binding face of the apoE alpha-helical domain (apoE residues ~130-149) in a five-residue linear sequence small enough to cross the blood-brain barrier, which intact apoE does not. In the injured brain it binds LDL-receptor-family receptors on microglia, astrocytes and neurons — LRP1 (low-density lipoprotein receptor-related protein 1) is the receptor most consistently implicated — and initiates signalling that downregulates the activated, pro-inflammatory glial phenotype. In translational models this produces markedly reduced microglial activation, smaller lesion and infarct volumes, less neuronal degeneration and improved functional and survival outcomes across intracerebral hemorrhage, subarachnoid hemorrhage, ischemic stroke and traumatic brain injury. Because the mechanism is immunomodulatory rather than hemostatic or thrombolytic, CN-105 is positioned as a secondary-brain-injury therapeutic, and the same rationale underlies its Phase 2 evaluation in postoperative delirium. No quantitative binding affinity for CN-105 at LRP1 has been published in open sources, so receptor engagement is characterised qualitatively; notably, the MARBLE trial found no significant effect on CSF IL-6, IL-8, MCP-1 or G-CSF, so target engagement in humans remains undemonstrated.

TargetActionAffinity
LRP1primaryLRP1Agonist—ⓘ

← Full CN-105 compound page (identity, identifiers, all indications)

Sources

  1. Apolipoprotein E Mimetic Peptide CN-105 and Postoperative Delirium in Older Patients: The Phase 2 MARBLE Randomized Clinical Trial — JAMA Network Open 2026;9(4):e262289, doi:10.1001/jamanetworkopen.2026.2289
  2. Apolipoprotein E mimetic peptide CN-105 improves outcome in a murine model of subarachnoid hemorrhage — Scientific Reports / PubMed Central
  3. MARBLE (NCT03802396) — posted study results — ClinicalTrials.gov
  4. Modulating ApoE Signalling to Reduce Brain Inflammation, deLirium and postopErative Cognitive Dysfunction (MARBLE) — ClinicalTrials.gov
  5. Tolerability and Pharmacokinetics of Single Escalating and Repeated Doses of CN-105 in Healthy Participants — Clinical Therapeutics 2022;44(5):744-754, doi:10.1016/j.clinthera.2022.03.006