NCT05606341 is a Phase 1 clinical trial evaluating the safety and tolerability of CpG1018, a Toll-like Receptor 9 (TLR9) agonist, in patients with mild cognitive impairment (MCI) due to Alzheimer's Disease or mild Alzheimer's dementia. This trial represents a novel immunomodulatory approach targeting neuroinflammation, a key contributor to neurodegenerative pathology.
| Attribute |
Value |
| Status |
Recruiting |
| Phase |
Phase 1 |
| Sponsor |
NYU Langone Health |
| Collaborator |
Alzheimer's Association |
| Enrollment |
18 participants (estimated) |
| Start Date |
March 13, 2023 |
| Primary Completion |
November 2026 |
| Location |
New York, NY, USA |
| Principal Investigator |
Arjun Masurkar, MD |
CpG1018 is a synthetic oligodeoxynucleotide that acts as a TLR9 agonist. TLR9 is expressed primarily in plasmacytoid dendritic cells and B cells, where it recognizes unmethylated CpG DNA motifs common in bacterial and viral DNA. The therapeutic hypothesis rests on innate immune stimulation to modulate the neuroinflammatory environment in AD:
- Systemic immune activation: CpG1018 stimulates TLR9 to produce anti-inflammatory cytokines and modulate microglial phenotype
- Immune tolerance modulation: May shift from a pro-inflammatory (M1) to an anti-inflammatory (M2) microglial state
- Amyloid clearance: Enhanced innate immune activity may promote clearance of amyloid-beta plaques
- Neuroprotection: Reduced neuroinflammation may slow neurodegeneration
This approach differs from previous anti-amyloid and anti-tau therapies by targeting the immune microenvironment rather than directly removing pathological proteins.
CpG1018 was originally developed by Dynavax Technologies Inc. as a vaccine adjuvant. Its safety profile has been established in previous human studies, making it suitable for repurposing in neurodegenerative disease.
- Allocation: Randomized
- Intervention Model: Sequential
- Masking: Double-blind (Participant and Investigator)
- Purpose: Treatment
- Type: Interventional
The trial uses a sequential dose-escalation design with three dose cohorts:
| Cohort |
Dose |
Administration |
| 1 |
0.1 mg/kg |
Subcutaneous injection at Day 1, Week 4, Week 8 |
| 2 |
0.25 mg/kg |
Subcutaneous injection at Day 1, Week 4, Week 8 |
| 3 |
0.5 mg/kg |
Subcutaneous injection at Day 1, Week 4, Week 8 |
A placebo control (sterile saline) is included in each cohort.
- Number of patient-reported adverse events — Time frame: Up to Week 18
- Percentage with Rheumatoid Factor (RF) confirmed autoimmunity — Time frame: Up to Week 18
- Percentage with Antinuclear Antibody (ANA) confirmed autoimmunity — Time frame: Up to Week 18
- Percentage with Antineutrophil Cytoplasmic Antibody (ANCA) confirmed — Time frame: Up to Week 18
- Percentage with ARIA-H (Amyloid-Related Imaging Abnormalities-Haemosiderin) — Time frame: Up to Week 14
- Percentage with ARIA-E (Amyloid-Related Imaging Abnormalities-Edema) — Time frame: Up to Week 14
- Change in AD Assessment Scale Cognitive Subscale (ADAS-Cog-13) — Baseline to Week 18
- Change in ADCS-ADL-MCI (Activities of Daily Living) — Baseline to Week 18
- Change in Columbia-Suicide Severity Rating Scale (C-SSRS) — Baseline to Week 18
- Change in Clinical Dementia Rating (CDR-Global) — Baseline to Week 18
- Change in Montreal Cognitive Assessment (MoCA) — Baseline to Week 18
- Change in Plasma Amyloid Biomarker Concentration — Baseline to Week 18
- Change in CSF Amyloid Biomarker Concentration — Baseline to Week 18
- Change in Plasma Tau Biomarker Concentration — Baseline to Week 18
- Change in CSF Tau Biomarker Concentration — Baseline to Week 18
- Age 65-85 years
- MCI due to AD or mild AD dementia per NIA-AA 2018 criteria
- MoCA score ≥17
- Positive Florbetaben PET amyloid scan (within 1 year)
- Able to provide consent/assent
- Willing to participate in all study procedures
- Have a reliable study partner
- History of psychiatric illness interfering with study procedures
- History of autoimmune disorders, severe asthma, or serious systemic illness
- Corticosteroid or immunosuppressive drug use within 30 days
- History of splenectomy
- Renal impairment
- Chloroquine use within 8 weeks
- Inability to undergo MRI
- TIA, stroke, or seizures within 12 months
- Neurological condition other than AD contributing to cognitive impairment
- Current participation in other AD investigational trials
- Current anti-coagulant use
- Current use of CYP1A2 substrates
- Recent COVID-19 infection/symptoms within 14 days
¶ Significance and Challenges
- Novel mechanism: First-in-human TLR9 agonist for AD
- Immunomodulatory approach: Targets neuroinflammation rather than amyloid/tau directly
- Biomarker-rich: Comprehensive CSF and plasma biomarker collection
- Early intervention: Targets early-stage patients