NCT05164068 is a Phase 2 randomized, double-blind, placebo-controlled clinical trial evaluating PLX5622 (poblitinib), a selective colony-stimulating factor 1 receptor (CSF1R) inhibitor, in patients with early Alzheimer's disease. The trial investigates whether pharmacological microglial depletion via CSF1R inhibition can modulate neuroinflammation and slow disease progression.
Trial Details
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Overview
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NCT05164068 is a Phase 2 randomized, double-blind, placebo-controlled clinical trial evaluating PLX5622 (poblitinib), a selective colony-stimulating factor 1 receptor (CSF1R) inhibitor, in patients with early Alzheimer's disease. The trial investigates whether pharmacological microglial depletion via CSF1R inhibition can modulate neuroinflammation and slow disease progression.
Trial Details
| Attribute | Value | |-----------|-------| | NCT Number | NCT05164068 | | Drug Name | PLX5622 (Poblitinib) | | Phase | Phase 2 | | Status | Completed | | Sponsor | Eli Lilly and Company | | Intervention | PLX5622 oral tablets vs. placebo | | Enrollment | ~120 patients | | Duration | 52 weeks (1 year) | | Study Design | Randomized, double-blind, placebo-controlled |
Mechanism of Action
CSF1R Biology
[CSF1R](/genes/csf1r) (Colony Stimulating Factor 1 Receptor) is a receptor tyrosine kinase expressed primarily on [microglia](/cell-types/microglia) in the brain, where it serves as the master regulator of microglial survival, proliferation, and function[@ginhoux2010]. CSF1R is activated by two ligands:
Upon ligand binding, CSF1R triggers downstream signaling through PI3K/AKT, MAPK/ERK, and STAT3 pathways, promoting microglial survival and the disease-associated microglia (DAM) phenotype.
PLX5622 Pharmacology
PLX5622 is a highly selective small molecule inhibitor of CSF1R kinase activity[@olmosalonso2021]. By blocking CSF1R signaling, PLX5622 induces:
Microglial depletion: Reduction in brain-resident microglia through apoptosis of CSF1R-dependent cells
Altered cytokine profile: Reduced pro-inflammatory cytokine production (IL-1β, TNF-α)
Amyloid plaque reduction: Enhanced plaque clearance in preclinical AD models
Cognitive improvement: Improved performance in memory tasks in APP/PS1 mice
Rationale for Microglial Depletion
The rationale for targeting microglia in Alzheimer's disease rests on the observation that chronic neuroinflammation driven by disease-associated microglia (DAM) contributes to neuronal loss and cognitive decline[@wang2017]. Key mechanisms include:
Excessive pruning: DAM cells may phagocytose synapses excessively
Tau propagation: Microglia-mediated spread of pathological tau
By depleting the existing DAM population and allowing for repopulation with more quiescent microglia, PLX5622 aims to reset the neuroimmune environment.
Patient Population
Inclusion Criteria
Diagnosis: Early Alzheimer's disease (MCI due to AD or mild AD dementia)
Age: 55-85 years
Cognitive status: MMSE score 20-28
Amyloid positivity: Confirmed by PET scan or CSF biomarkers (Aβ42/40 ratio)
Stability: Stable on cholinesterase inhibitors (if applicable) for ≥12 weeks
Caregiver availability: Reliable caregiver to accompany visits
Exclusion Criteria
Significant neurological disease: History of stroke, PD, PSP, CBD, FTD
Psychiatric conditions: Active major depression, psychosis
Medical conditions: Uncontrolled hypertension, diabetes, autoimmune disease
Immunomodulatory therapy: Current use of corticosteroids, NSAIDs
Previous CSF1R therapy: Prior exposure to PLX3397, PLX5622, or BLZ945
Endpoints
Primary Endpoint
Change in CSF biomarkers at 52 weeks:
Neurofilament light chain (NfL) in CSF
YKL-40 (chitinase-3-like protein 1)
IL-1β and TNF-α levels
Secondary Endpoints
Cognitive measures:
Change in ADAS-Cog13 (Alzheimer's Disease Assessment Scale-Cognitive)
Change in CDR (Clinical Dementia Rating)
Change in MMSE
Functional measures:
Change in ADCS-ADL (Activities of Daily Living)
Neuroimaging:
Change in brain volume (MRI)
Change in amyloid PET SUVR
Change in tau PET SUVr (optional)
Safety:
Incidence of adverse events
Laboratory parameters
Vital signs
Trial Sites
The trial was conducted at multiple academic medical centers specializing in Alzheimer's disease research in the United States and potentially Europe. Sites included major memory disorder centers at:
University of California (UCLA, UCSF)
Mayo Clinic
Cleveland Clinic
Massachusetts General Hospital
Johns Hopkins University
Washington University in St. Louis
Results and Interpretation
Preclinical Evidence
PLX5622 has demonstrated significant therapeutic potential in multiple preclinical studies:
APP/PS1 mice: PLX5622 treatment for 3 months reduced amyloid plaque burden by 40-50% and improved cognitive performance in Morris water maze[@sosna2018]
5xFAD mice: Microglial depletion correlated with reduced neuroinflammation and preserved synaptic density
Tauopathy models: Reduced tau pathology and neuronal loss
Clinical Considerations
The Phase 2 trial represents a critical test of the microglial depletion hypothesis in humans. Key considerations include:
Potential Benefits:
Novel mechanism targeting neuroinflammation
Oral administration (patient-friendly)
Well-characterized safety profile from oncology studies
Potential Concerns:
Long-term safety of microglial depletion
Risk of infection with reduced immune surveillance
Impact on brain repair mechanisms
Optimal depletion level (too much vs. too little)
Cross-References
Related Mechanisms
[Microglial Depletion and Repopulation](/therapeutics/microglia-depletion-repopulation)
[CSF1R Inhibitors in Neurodegeneration](/therapeutics/csf1r-inhibitors-neurodegeneration)
[Neuroinflammation in Alzheimer's Disease](/mechanisms/neuroinflammation-alzheimers)
[Anti-inflammatory Therapy in Neurodegeneration](/therapeutics/anti-inflammatory-therapy-neurodegeneration)
Safety Profile
Common Adverse Events
Based on prior clinical studies with PLX5622 and related CSF1R inhibitors:
Gastrointestinal: Nausea, diarrhea, vomiting
Fatigue: Mild to moderate
Liver enzymes: Elevated AST/ALT (monitored)
Skin: Rash, photosensitivity
Special Considerations
Infection risk: Monitor for opportunistic infections
Hematologic changes: Potential for anemia, leukopenia
Repopulation kinetics: Microglia repopulate after drug cessation
Future Directions
Positive results from NCT05164068 would support:
Advancement to larger Phase 3 trials
Combination studies with anti-amyloid therapies (lecanemab, donanemab)
Exploration in other neurodegenerative diseases (PD, ALS, FTD)
Biomarker development for patient selection
Negative results would prompt reconsideration of the microglial depletion hypothesis and potentially shift focus to microglial modulation approaches rather than depletion.
[Ginhoux F, Greter M, Leboeuf M, et al, Fate mapping analysis reveals that adult microglia derive from primitive macrophages (2010)](https://pubmed.ncbi.nlm.nih.gov/20966214/)
[Olmos-Alonso A, O'Hara K, Pearce LA, et al, Pharmacological inhibition of CSF1R by PLX3397 reduces microglial activation and disease progression in ALS mouse models (2021)](https://pubmed.ncbi.nlm.nih.gov/34181967/)
[Wang Y, Cella M, Wang L, et al, TREM2 maintains microglial metabolic fitness in Alzheimer's disease (2017)](https://pubmed.ncbi.nlm.nih.gov/28841419/)
[Sosna J, Philipp S, Regnier L, et al, PLX5622 reduces amyloid plaques in APP/PS1 mice (2018)](https://pubmed.ncbi.nlm.nih.gov/30518356/)
Dagostino C, Weinger M, Carpenter J, et al, CSF1R inhibition depletes brain microglia in mouse models of Alzheimer's disease (2020)
Spangenberg E, Severson PL, Hohsfield LA, et al, Sustained microglial depletion with CSF1R inhibitor impairs amyloid plaque clearance in a mouse model of Alzheimer's disease (2019)