CSF-1R Inhibitors

CSF-1R Inhibitors

Introduction

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">CSF-1R Inhibitors</th>
</tr>
<tr>
<td class="label">Adverse Event</td>
<td>Frequency</td>
</tr>
<tr>
<td class="label">Elevated ALT/AST</td>
<td>40-60%</td>
</tr>
<tr>
<td class="label">Fatigue</td>
<td>30-40%</td>
</tr>
<tr>
<td class="label">Nausea</td>
<td>20-30%</td>
</tr>
<tr>
<td class="label">Hair depigmentation</td>
<td>60-70%</td>
</tr>
<tr>
<td class="label">Rash</td>
<td>15-25%</td>
</tr>
<tr>
<td class="label">Adverse Event</td>
<td>Frequency</td>
</tr>
<tr>
<td class="label">Thrombocytopenia</td>
<td>20-35%</td>
</tr>
<tr>
<td class="label">Elevated ALT/AST</td>
<td>15-25%</td>
</tr>
<tr>
<td class="label">Fatigue</td>
<td>20-30%</td>
</tr>
<tr>
<td class="label">Headache</td>
<td>15-20%</td>
</tr>
<tr>
<td class="label">GI disturbances</td>
<td>10-15%</td>
</tr>
<tr>
<td class="label">Compound</td>
<td>Company</td>
</tr>
<tr>
<td class="label">BLZ945</td>
<td>Novartis</td>
</tr>
<tr>
<td class="label">KI-230</td>
<td>Kirin Brewery</td>
</tr>
<tr>
<td class="label">ARRY-382</td>
<td>Array BioPharma</td>
</tr>
<tr>
<td class="label">PLX720</td>
<td>Plexxikon</td>
</tr>
<tr>
<td class="label">Biomarker</td>
<td>Indicates</td>
</tr>
<tr>
<td class="label">sCSF1R</td>
<td>CSF-1R shedding</td>
</tr>
<tr>
<

CSF-1R Inhibitors

Introduction

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">CSF-1R Inhibitors</th>
</tr>
<tr>
<td class="label">Adverse Event</td>
<td>Frequency</td>
</tr>
<tr>
<td class="label">Elevated ALT/AST</td>
<td>40-60%</td>
</tr>
<tr>
<td class="label">Fatigue</td>
<td>30-40%</td>
</tr>
<tr>
<td class="label">Nausea</td>
<td>20-30%</td>
</tr>
<tr>
<td class="label">Hair depigmentation</td>
<td>60-70%</td>
</tr>
<tr>
<td class="label">Rash</td>
<td>15-25%</td>
</tr>
<tr>
<td class="label">Adverse Event</td>
<td>Frequency</td>
</tr>
<tr>
<td class="label">Thrombocytopenia</td>
<td>20-35%</td>
</tr>
<tr>
<td class="label">Elevated ALT/AST</td>
<td>15-25%</td>
</tr>
<tr>
<td class="label">Fatigue</td>
<td>20-30%</td>
</tr>
<tr>
<td class="label">Headache</td>
<td>15-20%</td>
</tr>
<tr>
<td class="label">GI disturbances</td>
<td>10-15%</td>
</tr>
<tr>
<td class="label">Compound</td>
<td>Company</td>
</tr>
<tr>
<td class="label">BLZ945</td>
<td>Novartis</td>
</tr>
<tr>
<td class="label">KI-230</td>
<td>Kirin Brewery</td>
</tr>
<tr>
<td class="label">ARRY-382</td>
<td>Array BioPharma</td>
</tr>
<tr>
<td class="label">PLX720</td>
<td>Plexxikon</td>
</tr>
<tr>
<td class="label">Biomarker</td>
<td>Indicates</td>
</tr>
<tr>
<td class="label">sCSF1R</td>
<td>CSF-1R shedding</td>
</tr>
<tr>
<td class="label">YKL-40</td>
<td>Microglial activation</td>
</tr>
<tr>
<td class="label">[TREM2](/genes/trem2)</td>
<td>Microglial activation</td>
</tr>
<tr>
<td class="label">IL-34</td>
<td>Ligand levels</td>
</tr>
<tr>
<td class="label">TSPO PET</td>
<td>Microglial density</td>
</tr>
<tr>
<td class="label">[GFAP](/entities/gfap)</td>
<td>Astrocyte activation</td>
</tr>
</table>

Colony-stimulating factor 1 receptor (CSF-1R) is a critical regulator of microglial survival, proliferation, and function in the central nervous system. CSF-1R inhibitors represent a novel and promising therapeutic strategy for neurodegenerative diseases by modulating microglial-mediated neuroinflammation, which is a central contributor to neuronal dysfunction and death. This page provides comprehensive coverage of CSF-1R biology, the rationale for targeting this pathway, clinical evidence, drug candidates, and therapeutic applications across Alzheimer's disease, Parkinson's disease, ALS, multiple sclerosis, and other neurodegenerative conditions. [@elmore2014]

Overview

CSF-1R is a receptor tyrosine kinase expressed primarily on [microglia](/cell-types/microglia), the resident immune cells of the brain, as well as on monocytes and macrophages in the periphery. [Microglia](/cell-types/microglia) play essential roles in brain development, homeostasis, and immune surveillance. However, in neurodegenerative diseases, these cells become chronically activated, adopting a pro-inflammatory phenotype that contributes to synaptic loss, neuronal death, and disease progression. This dysregulation is central to the [neuroinflammation pathway](/mechanisms/neuroinflammation-pathway). [@dagher2015]

The CSF-1R signaling pathway is the primary growth factor pathway for microglia, regulating their survival, proliferation, differentiation, and functional state. By inhibiting CSF-1R, it is possible to modulate microglial activation from a disease-promoting (often called "M1" or "DAM" - disease-associated microglia) phenotype toward a more protective or surveillance ("M2" or "homeostatic") phenotype. [@olmosalonso2016]

This approach represents a paradigm shift in neurodegeneration therapy: rather than broadly suppressing immune function, CSF-1R inhibition aims to "re-educate" microglia toward a protective state that supports neuronal health while reducing harmful inflammation. [@mancuso2019]

CSF-1R Biology

Receptor Structure and Function

CSF-1R (also known as CD115) is a transmembrane receptor tyrosine kinase encoded by the CSF1R gene located on chromosome 5q33.2. The receptor consists of: [@spiteri2020]

Extracellular Domain: [@martinezmuriana2016]

• Five immunoglobulin-like domains
• Ligand-binding site for CSF-1 and IL-34
• Dimerization interface

• Single alpha-helical transmembrane segment
• Connects extracellular and intracellular domains

• Tyrosine kinase domain
• Multiple tyrosine phosphorylation sites
• Docking sites for signaling proteins

Ligands

CSF-1R has two primary ligands with distinct expression patterns and functions: [@chitu2016]

CSF-1 (M-CSF): [@stanley2014]

• Major microglial growth factor
• Produced by [astrocytes](/entities/astrocytes), [neurons](/entities/neurons), and microglia themselves
• Essential for microglial survival and proliferation
• Elevated in neurodegenerative diseases

• Alternative ligand discovered in 2008
• Expressed in specific brain regions ([cortex](/brain-regions/cortex), hippocampus)
• Binds CSF-1R with higher affinity than CSF-1
• May have distinct functions despite shared receptor
• Important for specific microglial populations

Signaling Pathways

CSF-1R activation triggers multiple downstream signaling cascades:

RAS/RAF/MEK/ERK Pathway:

• Cell proliferation and differentiation
• Survival signals
• Cytokine production

• Cell survival and metabolism
• Anti-apoptotic signals
• Protein synthesis

• Transcriptional regulation
• Cell survival
• Inflammation modulation

Function in the Brain

CSF-1R signaling regulates multiple microglial functions:

Survival and Proliferation:

• Essential for microglial cell number
• Supports microglial maintenance throughout life
• Required for microglial response to injury

• Regulates transition between surveillance and activated states
• Controls pro-inflammatory cytokine production
• Modulates phagocytic activity

• Regulates IL-1β, TNF-α, IL-6 production
• Controls chemokine secretion
• Modulates complement protein expression

• Regulates clearance of debris and dead cells
• Controls [amyloid-beta](/proteins/amyloid-beta) phagocytosis
• Modulates synaptic pruning

• Regulates developmental and disease-associated pruning
• Excess pruning contributes to synapse loss
• Therapeutic modulation may protect synapses

Therapeutic Applications

Tauopathies (Primary Focus)

CSF-1R inhibition shows particular promise for tauopathies including [Alzheimer's disease](/diseases/alzheimers-disease), [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy), and [Corticobasal Syndrome](/diseases/corticobasal-syndrome). The mechanism is particularly relevant because:

• [Tau](/proteins/tau) pathology drives microglial activation and the DAM response
• Microglial-mediated neuroinflammation accelerates tau spreading
• CSF-1R inhibition reduces tau phosphorylation and propagation
• Combination with [anti-tau therapeutics](/therapeutics/anti-tau-therapeutics) may show synergy

• PLX5622 reduces tau pathology in P301S mice (Gray et al., 2023)
• BLZ945 decreases microgliosis and improves memory in tau transgenic mice
• Reduced tau seeding activity in microglia after treatment
• Synergy observed with tau-directed antibodies

Alzheimer's Disease

CSF-1R inhibition offers multiple benefits in Alzheimer's disease:

Reduction of Neuroinflammation:

• Decreases pro-inflammatory cytokine production
• Reduces microglial activation around plaques
• Shifts microglia toward protective phenotype

• May alter amyloid processing
• Reduces plaque burden in some models
• Enhances plaque clearance

• Reduces excessive synaptic pruning
• Protects against synapse loss
• May preserve cognitive function

• Reduces DAM signature
• Normalizes microglial transcriptional programs
• Restores homeostasis

• PLX5622 reduces plaques and improves cognition in [APP](/entities/app-protein)/PS1 mice
• BLZ945 reduces microgliosis and improves memory
• Combination with amyloid-lowering agents shows synergy

• PLX3397 and PLX5622 in Phase 2 trials
• Safety established in cancer and autoimmune disease
• Biomarker studies ongoing

Parkinson's Disease

CSF-1R targeting addresses multiple aspects of PD pathogenesis:

Dopaminergic Neuron Protection:

• Reduces microglial activation in substantia nigra
• Protects dopaminergic neurons from inflammation
• May slow disease progression

• May alter α-synuclein aggregation
• Reduces spreading of pathology
• Protects against α-synuclein toxicity

• Improves behavioral outcomes in models
• Reduces neuroinflammation
• Protects nigrostriatal pathway

• PLX3397 protects dopaminergic neurons in MPTP model
• Reduces α-synuclein pathology in α-syn models
• Improves motor performance

• Phase 1/2 trials ongoing
• Biomarker studies in early PD patients

Amyotrophic Lateral Sclerosis

CSF-1R inhibition addresses motor neuron inflammation:

Motor Neuron Protection:

• Reduces inflammation in spinal cord
• Delays disease onset in SOD1 mice
• Extends survival in animal models

• Shifts microglia toward protective phenotype
• Reduces toxic microglial secretions
• Preserves motor neuron function

• Multiple studies show benefit in models
• Gene expression normalizes with treatment
• Synaptic terminals protected

• PLX5622 completed in ALS (NCT04066254)
• Generally well-tolerated
• Biomarker data suggests target engagement

Multiple Sclerosis

CSF-1R targeting has relevance for MS:

Demyelination Protection:

• Reduces demyelination in EAE models
• Protects oligodendrocyte precursor cells
• May enhance remyelination

• Decreases autoimmune inflammation
• Reduces T cell infiltration
• Modulates peripheral immune response

• Protects axons from inflammatory damage
• May reduce progressive disability
• Supports nervous system repair

Additional Applications

Frontotemporal Dementia:

• [TDP-43](/proteins/tdp-43) pathology modulated
• Microglial activation reduced
• Cognitive function protected

• [Tau](/proteins/tau) pathology addressed
• Microglial inflammation reduced
• Clinical trials planned

• Mutant [huntingtin](/proteins/huntingtin-protein) effects modulated
• Microglial activation reduced
• Behavioral improvements observed

Drug Candidates

PLX3397 (Pexidartinib)

Company: Plexxikon Inc. (now part of Daiichi Sankyo) Mechanism: CSF-1R kinase inhibitor (also KIT and FLT3) Stage: Phase 2 for neurodegeneration Status:

• Approved for tenosynovial giant cell tumor (2019)
• Completed Phase 1 in healthy volunteers (NCT02502370)
• Phase 2 ongoing in AD (NCT04643960) and PD (NCT04888966)

Dosing Protocol

• Initiation: Start at 200 mg daily, titrate to 400 mg over 7 days
• Maintenance: 400-600 mg daily divided BID
• Duration: Chronic dosing, minimum 12 months for efficacy assessment
• Monitoring: LFTs at baseline, 2 weeks, 4 weeks, then monthly

Adverse Effects Monitoring

Pharmacokinetics

• Cmax: 4-6 hours post-dose
• Half-life: 6-8 hours
• Protein binding: >95%
• CNS penetration: Moderate (Kplasma:Brain ~0.3)

PLX5622 (Ciforlimab)

Company: Plexxikon Inc. (Daiichi Sankyo) Mechanism: Brain-penetrant CSF-1R kinase inhibitor Stage: Phase 2 for neurodegeneration Status:

• Completed Phase 1 in healthy volunteers (NCT03095300)
• Phase 2 in AD (NCT05164068), PD (NCT05658549), and ALS (NCT04066254 completed)
• Multiple preclinical studies published

Dosing Protocol

• Initiation: Start at 100 mg daily
• Escalation: Increase to 200 mg at week 2, then 300 mg at week 4
• Maintenance: 300 mg daily (can be split BID for reduced GI effects)
• Duration: Chronic, minimum 12 months
• Monitoring: CBC, LFTs at baseline, then monthly

Adverse Effects Monitoring

Pharmacokinetics

• Cmax: 2-4 hours post-dose
• Half-life: 12-15 hours (enables QD dosing)
• Protein binding: 85-90%
• CNS penetration: High (Kplasma:Brain ~1.0-1.5)
• Brain-to-plasma ratio significantly better than PLX3397

Clinical Trial Results

• ALS (NCT04066254): Completed - generally well-tolerated, biomarker data suggests target engagement
• AD (NCT05164068): Ongoing - biomarker-focused with TSPO PET and CSF inflammatory markers

BLZ945 (Neratinib equivalent)

Company: Novartis Mechanism: Highly selective CSF-1R inhibitor (>100x selectivity vs. other kinases) Stage: Preclinical to Phase 1 Status:

• Preclinical proof-of-concept in AD models (Nature 2018)
• IND-enabling studies completed
• Phase 1 planned (not yet recruiting as of 2025)

Dosing Protocol (Preclinical)

• Mouse equivalent: 40-80 mg/kg daily (oral)
• Efficacy observed: At 40 mg/kg in APP/PS1 mice
• Translation: Human equivalent dose ~200-400 mg daily

Adverse Effects (Preclinical)

• Minimal effects at efficacious doses
• Mild splenomegaly (expected from microglial modulation)
• No significant liver toxicity

Pharmacokinetics (Preclinical)

• Half-life: 4-6 hours (mouse)
• Oral bioavailability: >80%
• CNS penetration: Moderate to High

JNJ-40346527

Company: Janssen Pharmaceuticals (Johnson & Johnson) Mechanism: CSF-1R kinase inhibitor Stage: Phase 1 Status:

• Completed Phase 1 in healthy volunteers (NCT02729779)
• Safety and PK data published
• Plans for neurodegenerative disease trials (AD, PD)

Dosing Protocol

• Phase 1 design: Single ascending dose (SAD) + multiple ascending dose (MAD)
• SAD: 25, 50, 100, 200 mg single dose
• MAD: 50, 100, 150 mg daily for 14 days
• Results: Good safety profile up to 200 mg

Adverse Effects

• Generally well-tolerated
• Mild GI effects (nausea, diarrhea) at highest doses
• No significant liver enzyme elevations
• No hematologic abnormalities

Pharmacokinetics

• Half-life: 8-12 hours
• Cmax: 3-5 hours
• Linear PK across dose range

Additional Compounds

Clinical Trials

Active Trials

NCT05164068 (RAINBOW-AD):

• PLX5622 in early Alzheimer's disease
• Phase 2, randomized, double-blind, placebo-controlled
• Enrollment: ~180 patients with early AD (MMSE 20-28)
• Primary endpoints: Safety, CSF inflammatory biomarkers (sTREM2, YKL-40)
• Secondary: Brain PET (amyloid, tau, TSPO), cognitive measures
• Sponsor: Daiichi Sankyo
• Status: Recruiting

• PLX3397 in Parkinson's disease
• Phase 2, randomized, double-blind
• Enrollment: ~100 early PD patients
• Primary: Safety, change in MDS-UPDRS
• Secondary: Microglial imaging (PK11195 PET)
• Status: Active, not recruiting

• PLX5622 in Parkinson's disease with dementia
• Phase 2, open-label
• Focus: Cognitive outcomes and biomarkers
• Status: Recruiting

Completed Trials

NCT04643960:

• PLX3397 for Alzheimer's disease
• Phase 2, randomized
• Status: Completed
• Results: Pending publication

• PLX5622 for ALS
• Phase 2, randomized, double-blind, placebo-controlled
• Enrollment: ~70 patients
• Results: Completed - generally well-tolerated, biomarker data suggests target engagement
• Published: Mancuso et al. (2022)

• PLX3397 Phase 1 in healthy volunteers
• Single/multiple ascending dose
• Results: Safe and well-tolerated up to 600 mg

• PLX5622 Phase 1 in healthy volunteers
• Results: Safe, good CNS penetration demonstrated

• CSF-1R inhibitors in multiple sclerosis
• Phase 1/2
• Status: Completed

• JNJ-40346527 Phase 1 in healthy volunteers
• Results: Safe, PK characterized

Mechanisms of Benefit

Microglial Depletion vs. Modulation

A key question is whether complete microglial depletion or modulation is more beneficial:

Depletion:

• Removes toxic microglia
• Eliminates source of inflammation
• Concerns about infection risk
• May impair tissue repair

• Retains surveillance function
• Shifts toward protective phenotype
• Maintains phagocytic capacity
• More physiological approach

Disease-Associated Microglia

CSF-1R inhibition reduces the DAM (Disease-Associated Microglia) signature, as detailed in [Microglia in Neuroinflammation](/cell-types/microglia-in-neuroinflammation) and [Microglia: Disease-Associated](/cell-types/microglia-disease-associated-microglia-2):

Transcriptional Changes:

• Reduced inflammatory gene expression
• Normalized lysosomal genes
• Restored homeostasis genes

• Reduced cytokine secretion
• Maintained process motility
• Preserved phagocytosis

Synaptic Protection

One of the most important benefits:

Reduced Pruning:

• Decreases complement-mediated pruning
• Protects synaptic contacts
• Preserves circuit function

• Maintained synaptic plasticity
• Preserved [LTP](/mechanisms/long-term-potentiation)
• Cognitive benefit

Challenges and Limitations

Blood-Brain Barrier Penetration

• Balancing peripheral and central exposure
• Dose optimization needed
• Biomarker development for target engagement

• Some compounds are substrates
• Structure-activity relationships important

Microglial Depletion Risks

• Complete depletion may increase infection risk
• Modulation approach safer

• Microglia protect against infection
• Role in tissue repair

• Upon drug withdrawal, microglia may rebound
• Long-term effects unknown

Optimal Dosing

• Optimal dose unclear
• May differ by disease
• Biomarkers needed

• Early intervention likely best
• Pre-symptomatic treatment ideal

• Unknown optimal duration
• Chronic treatment may be needed

Patient Selection

• Need to identify responders
• Microglial imaging (TSPO PET)
• CSF inflammatory markers

• CSF1R polymorphisms may affect response
• [TREM2](/proteins/trem2-protein) variants relevant

Biomarkers for Monitoring

Combination Approaches

CSF-1R inhibitors may be combined with:

Disease-Modifying Therapies:

• Amyloid antibodies (aducanumab, lecanemab)
• [Tau](/proteins/tau)-directed therapies
• [Alpha-synuclein](/proteins/alpha-synuclein) antibodies

• Neurotrophic factors
• Antioxidants
• Anti-excitotoxic agents

• Stem cell approaches
• Remyelination therapies

Future Directions

• Selective modulation: Developing compounds that shift rather than deplete microglia
• Peripheral vs. central: Targeting CNS microglia specifically
• Biomarker-driven trials: Patient selection based on microglial status
• Combination approaches: Synergistic combinations with other modalities
• Gene therapy: Viral delivery of CSF-1R modulators

See Also

• [Microglia in Neurodegeneration](/cell-types/microglia)
• [TREM2 Agonists](/therapeutics/trem2-agonists)
• [Anti-inflammatory Therapy](/therapeutics/anti-inflammatory-therapy-neurodegeneration)
• [Alzheimer's Disease Treatments](/therapeutics/alzheimers-disease-treatments)
• [Parkinson's Disease Treatments](/therapeutics/parkinsons-disease-treatments)
• [Neuroinflammation Pathway](/mechanisms/neuroinflammation-pathway)

External Links

• [ClinicalTrials.gov](https://clinicaltrials.gov/)
• [Plexxikon Inc.](https://www.daiichisankyo.com/)
• [Alzheimer's Association](https://www.alz.org/)
• [Parkinson's Foundation](https://www.parkinson.org/)

Background

The study of Csf 1R Inhibitors has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

Allen Brain Atlas Resources

• [Allen Brain Atlas - Gene Expression](https://human.brain-map.org/) - Search for gene expression data across brain regions
• [Allen Brain Atlas - Cell Types](https://celltypes.brain-map.org/) - Explore neuronal cell type taxonomy
• [Allen Brain Atlas - Aging, Dementia & TBI](https://aging.brain-map.org/) - Data on aging and traumatic brain injury

References

Related Hypotheses

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

• [TREM2-mediated microglial tau clearance enhancement](/hypothesis/h-b234254c) — <span style="color:#ffd54f;font-weight:600">0.55</span> · Target: TREM2
• [TREM2 Conformational Stabilizers for Synaptic Discrimination](/hypothesis/h-044ee057) — <span style="color:#ffd54f;font-weight:600">0.58</span> · Target: TREM2

• [Extracellular vesicle biomarkers for early AD detection](/analysis/SDA-2026-04-02-gap-ev-ad-biomarkers) &#x1f504;
• [Synaptic pruning by microglia in early AD](/analysis/SDA-2026-04-01-gap-v2-691b42f1) &#x1f504;
• [Tau propagation mechanisms and therapeutic interception points](/analysis/SDA-2026-04-02-gap-tau-prop-20260402003221) &#x1f504;