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.
Trial Details
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CpG1018 TLR9 Agonist Phase 1 Trial in Early Alzheimer's Disease (NCT05606341)
Overview
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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.
Trial Details
| 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 |
Mechanism: TLR9 Agonism in Alzheimer's Disease
Rationale
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 Background
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.
Study Design
Allocation: Randomized
Intervention Model: Sequential
Masking: Double-blind (Participant and Investigator)
Purpose: Treatment
Type: Interventional
Dose Escalation
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.
Outcome Measures
Primary Endpoints (Safety)
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
Secondary Endpoints (Efficacy)
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
Eligibility Criteria
Inclusion Criteria
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
Exclusion Criteria
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
Potential Significance
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
Challenges
Small sample size: Only 18 participants limits statistical power
Short duration: 18-week follow-up may be insufficient to detect clinical benefit
Autoimmunity risk: TLR9 stimulation may trigger autoimmune responses (monitored as primary endpoints)