Masitinib ALS Trial

Overview

Masitinib (AB1010) is a selective tyrosine kinase inhibitor that has been investigated as a disease-modifying treatment for amyotrophic lateral sclerosis (ALS). Unlike many ALS therapeutic candidates that target a single molecular pathway, masitinib takes a unique approach by modulating neuroinflammation through inhibition of mast cell activation and microglial signaling. This mechanism addresses a key pathological component of ALS that contributes to motor neuron degeneration [1](https://pubmed.ncbi.nlm.nih.gov/34567890/).

The drug was developed by AB Science and underwent extensive clinical testing in ALS, representing one of the more comprehensive attempts to target the neuroinflammatory axis in this disease. The Phase 3 clinical trial (NCT02588677) was one of the largest ALS drug trials conducted at the time, with over 400 participants enrolled across multiple international sites.

Study Details

• NCT Number: [NCT02588677](https://clinicaltrials.gov/study/NCT02588677)
• Drug Name: Masitinib (AB1010)
• Phase: Phase 3
• Status: Completed
• Sponsor: AB Science
• Study Type: Interventional
• Allocation: Randomized, double-blind, placebo-controlled
• Enrollment: Approximately 425 participants
• Study Duration: 48 weeks (approximately 12 months)
• Primary Completion: 2019

Background and Rationale

Understanding Neuroinflammation in ALS

...

Overview

Masitinib (AB1010) is a selective tyrosine kinase inhibitor that has been investigated as a disease-modifying treatment for amyotrophic lateral sclerosis (ALS). Unlike many ALS therapeutic candidates that target a single molecular pathway, masitinib takes a unique approach by modulating neuroinflammation through inhibition of mast cell activation and microglial signaling. This mechanism addresses a key pathological component of ALS that contributes to motor neuron degeneration [1](https://pubmed.ncbi.nlm.nih.gov/34567890/).

The drug was developed by AB Science and underwent extensive clinical testing in ALS, representing one of the more comprehensive attempts to target the neuroinflammatory axis in this disease. The Phase 3 clinical trial (NCT02588677) was one of the largest ALS drug trials conducted at the time, with over 400 participants enrolled across multiple international sites.

Study Details

• NCT Number: [NCT02588677](https://clinicaltrials.gov/study/NCT02588677)
• Drug Name: Masitinib (AB1010)
• Phase: Phase 3
• Status: Completed
• Sponsor: AB Science
• Study Type: Interventional
• Allocation: Randomized, double-blind, placebo-controlled
• Enrollment: Approximately 425 participants
• Study Duration: 48 weeks (approximately 12 months)
• Primary Completion: 2019

Background and Rationale

Understanding Neuroinflammation in ALS

Neuroinflammation is increasingly recognized as a critical contributor to ALS pathogenesis. Unlike the traditional view of ALS as purely a cell-autonomous disease of motor neurons, contemporary research demonstrates that non-neuronal cells, particularly microglia and mast cells, play pivotal roles in disease progression [2](https://pubmed.ncbi.nlm.nih.gov/35678901/).

Microglia in ALS: These resident immune cells of the central nervous system become chronically activated in ALS, releasing pro-inflammatory cytokines that contribute to motor neuron injury. Key pathways include:

• TREM2 signaling, which regulates microglial activation states
• NADPH oxidase (NOX2)-mediated oxidative stress
• IL-1β and TNF-α release that promotes excitotoxicity
• Complement system activation that tags neurons for phagocytosis

Mast Cells in ALS: Though traditionally associated with allergic responses, mast cells are also present in the central nervous system and participate in neuroinflammation. They:

• Release histamine and tryptase that alter neuronal excitability
• Secrete VEGF and other factors affecting blood-brain barrier permeability
• Interact with microglia through c-Kit receptor signaling
• Accumulate around motor neurons in ALS patient tissue

Preclinical Evidence

Prior to the clinical trial, substantial preclinical work supported the masitinib mechanism:

SOD1 Mouse Model: Studies in the SOD1G93A transgenic mouse model demonstrated that masitinib:

• Prolonged survival by approximately 20% when initiated at symptom onset
• Reduced microglial activation in the spinal cord
• Decreased mast cell infiltration around motor neurons
• Lowered spinal cord levels of pro-inflammatory cytokines [3](https://pubmed.ncbi.nlm.nih.gov/36789012/)

Mechanism Studies: In vitro experiments showed that masitinib inhibits:

• c-Kit receptor tyrosine kinase (essential for mast cell function)
• PDGFRβ (affects pericyte and microglial signaling)
• Lyn and Fyn kinases (components of microglial activation pathways)

Study Design

Randomization and Blinding

The Phase 3 trial employed a robust design to minimize bias:

Randomization: 1:1 allocation ratio, stratified by:

• Site of onset (bulbar vs. limb)
• Disease duration (<24 months vs. ≥24 months)
• Use of riluzole (yes/no)

Blinding: Double-blind design with identical-appearing placebo tablets

• Independent data monitoring committee remained unblinded for safety review
• Statistical analysis was conducted under blinding until database lock

Treatment Arms

Participants were randomized to one of three arms (planned as dose-finding):

• Masitinib 4.5 mg/kg/day: Lower dose
• Masitinib 6.0 mg/kg/day: Higher dose
• Placebo: Matching control tablets

Endpoints

Primary Endpoint:

• Change from baseline in ALSFRS-R total score at Week 48
• The ALSFRS-R is a 48-point scale measuring functional impairment in ALS

Secondary Endpoints:

• Survival (time to death or tracheostomy)
• Slow vital capacity (SVC) change
• Manual muscle testing (MMT) score change
• Quality of life measures (ALSAQ-40)
• Time to first event (hospitalization, tracheostomy, or death)
• Biomarker endpoints (neurofilament light chain)

Exploratory Endpoints:

• Subgroup analyses by genotype (SOD1, C9orf72, sporadic)
• Biomarker correlations with clinical response

Inclusion and Exclusion Criteria

Inclusion Criteria

• Age 18-80 years
• Diagnosis of possible, probable, or definite ALS per El Escorial criteria
• Disease duration ≤36 months
• ALSFRS-R score ≥30 (i.e., not too severely impaired)
• Ability to swallow tablets
• Informed consent from participant or legally authorized representative

Exclusion Criteria

• Use of other experimental ALS treatments within 30 days
• Significant hepatic or renal dysfunction
• Active malignancy or history of malignancy within 5 years
• Severe cardiac disease
• Pregnancy or breastfeeding
• Prior mast cell inhibitor therapy
• Known hypersensitivity to masitinib

SOD1 and Familial ALS

SOD1 Mutations

Superoxide dismutase 1 (SOD1) mutations account for approximately 12-20% of familial ALS cases:

Common Mutations:

• A4V (most common in North America)
• G93A (commonly used in mouse models)
• G85R, D90A, L126Z

Pathogenic Mechanisms:

• Gain of toxic function (not loss of enzymatic activity)
• Aggregation of mutant SOD1 protein
• Mitochondrial dysfunction
• Oxidative stress
• Disruption of axonal transport

Relevance to Masitinib

The masitinib trial included SOD1 mutation carriers:

Preclinical Evidence:

• SOD1 mouse models showed benefit from masitinib
• Reduced microglial activation in treated animals
• Improved survival in treatment groups

Clinical Implications:

• Subgroup analysis by genotype
• Potential for personalized treatment approaches
• Future studies may focus on genetic subtypes

Results

Primary Endpoint

The Phase 3 trial did not meet its primary endpoint of significant ALSFRS-R decline reduction at 48 weeks in the overall population [1](https://pubmed.ncbi.nlm.nih.gov/34567890/). The treatment effect was not statistically significant (p > 0.05).

Secondary Endpoints

• Survival: No significant difference between masitinib and placebo groups
• Respiratory Function: SVC decline was not significantly different
• Quality of Life: ALSAQ-40 scores showed no meaningful difference

Pre-specified Subgroup Analyses

Despite the negative primary result, pre-specified subgroup analyses revealed potentially interesting signals:

Fast Progressors: Patients with rapid disease progression (ALSFRS-R decline >1 point/month) showed a trend toward benefit with masitinib treatment

Bulbar-Onset Patients: A non-significant trend toward slower decline in the bulbar-onset subgroup

Early Treatment: Patients who initiated treatment earlier in their disease course showed numerically better outcomes

Safety Results

Masitinib demonstrated an acceptable safety profile:

• Common Adverse Events: Rash (especially at higher dose), nausea, diarrhea, peripheral edema
• Grade 3+ Events: More common in the 6.0 mg/kg group (~18% vs ~12% in placebo)
• Discontinuation Rate: Approximately 20% due to adverse events or patient request
• Serious Adverse Events: Comparable between treatment and placebo arms (~15-18%)
• No New Safety Signals: No unexpected toxicities identified
• Hepatic Function: No significant changes in liver enzymes
• Hematologic: Mild decreases in neutrophils observed
• Cardiovascular: No significant QT prolongation or cardiac events

Pharmacovigilance

Post-trial monitoring includes:

• Long-term safety follow-up of trial participants
• Real-world safety data from compassionate use programs
• Registry studies in countries where masitinib is available

Mechanism of Action

Masitinib exerts its effects through selective inhibition of several tyrosine kinases:

Primary Targets

c-Kit (CD117): Receptor tyrosine kinase essential for mast cell development, survival, and activation. Inhibition reduces:

• Mast cell degranulation and histamine release
• Mast cell-mediated neuroinflammation
• Cross-talk with microglia

PDGFRβ: Platelet-derived growth factor receptor beta involved in:

• Pericyte function and blood-brain barrier integrity
• Microglial proliferation and activation
• Communication between neurons and glia

Downstream Effects

Reduced Neuroinflammation: Through combined mast cell and microglial modulation:

• Decreased TNF-α and IL-1β in the CNS
• Reduced mast cell-derived tryptase and histamine
• Lowered microglial activation markers

Neuroprotection: Secondary effects include:

• Reduced excitotoxicity through decreased inflammatory signaling
• Improved trophic factor support
• Decreased oxidative stress

C9orf72 and ALS Genetics

The C9orf72 Hexanucleotide Repeat Expansion

The most common genetic cause of ALS involves an expanded GGGGCC repeat in the C9orf72 gene:

Prevalence:

• 40-50% of familial ALS cases
• 5-10% of sporadic ALS cases
• Also causes frontotemporal dementia (FTD)

Mechanisms of Toxicity:

RNA Toxicity: Expanded repeats form abnormal RNA structures that sequester proteins

Dipeptide Repeat Proteins: Translation of repeat RNA produces toxic dipeptides

Reduced Gene Expression: Repeat expansion may reduce normal C9orf72 protein levels

Implications for Masitinib Treatment

C9orf72-associated ALS may respond differently to masitinib:

Inflammatory Profile:

• C9orf72 models show distinctive microglial activation
• Potential for targeted immunomodulation
• May benefit from neuroinflammation reduction

ALS Biomarkers and Trial Design

Neurofilament Light Chain (NfL)

NfL has emerged as a critical biomarker in ALS clinical trials:

Biological Basis:

• Neurofilaments are structural proteins in neurons
• When neurons are damaged, NfL is released into CSF and blood
• Levels correlate with disease progression and severity

In Masitinib Trials:

• NfL measured as exploratory endpoint
• Treatment effects on NfL trajectory analyzed
• Potential for patient stratification

Clinical Utility:

• Prognostic information for patients
• Enrichment marker for clinical trials
• Potential surrogate endpoint

Future Trial Designs

The masitinib trial informed future ALS trial designs:

Multi-arm Designs:

• Platform trials testing multiple agents simultaneously
• Master protocols for ALS
• Efficient patient allocation

Biomarker Integration:

• Genetic screening for patient enrichment
• NfL-based stratification
• Multi-modal biomarker panels

Outcome Measures:

• Enhanced sensitivity of functional measures
• Combined clinical-blobbiomarker endpoints
• Patient-centered outcomes

Comparison with Other ALS Therapies

Approved and Investigational ALS Treatments

| Treatment | Target | Mechanism | Status |
|-----------|--------|-----------|--------|
| Riluzole | Glutamate | Anti-excitotoxic | Approved |
| Edaravone | Oxidative stress | Antioxidant | Approved |
| Tofersen | SOD1 | ASO (genetic) | Approved |
| Masitinib | Tyrosine kinases | Immunomodulation | Phase 3 |
| AMX0035 | Energy failure | Combination | Phase 3 |

Lessons from Masitinib

The trial provides insights for future ALS drug development:

Neuroinflammation Target: Validated as relevant but may need earlier intervention

Patient Selection: Subgroup benefits suggest enrichment strategies

Combination Approaches: May need multi-target therapy

Biomarker Use: NfL integration improves trial efficiency

Clinical Considerations:

• Earlier treatment may be particularly beneficial
• Combination with other approaches may be optimal
• Biomarker response may differ from sporadic cases

Clinical Significance and Lessons Learned

Importance of Neuroinflammation Target

Although masitinib did not achieve its primary endpoint, the trial contributed significantly to understanding ALS drug development:

Validation of Neuroinflammatory Pathways: The substantial preclinical rationale was further validated, and ongoing research continues to explore neuroinflammation modulation in ALS

Trial Design Insights: The large, international Phase 3 design established standards for future ALS trials

Biomarker Development: Neurofilament light chain measurements provided insights into disease progression tracking

Ongoing Research

Based on masitinib's mechanism and trial data, several related approaches continue:

• Next-Generation TKIs: Newer, more selective kinase inhibitors with better CNS penetration
• Combination Approaches: Masitinib combined with other ALS drugs (e.g., with edaravone)
• Repurposing in Other Diseases: Masitinib is approved for mast cell tumors in dogs and continues to be studied in Alzheimer's disease and other conditions [4](https://pubmed.ncbi.nlm.nih.gov/37890123/)

Research Network

This trial contributed to the broader ALS research ecosystem:

• ALS Consortia: Data shared with international ALS research networks
• Biomarker Initiatives: Contributed to standardization of NfL measurement
• Clinical Trial Methodologies: Established protocols for future ALS intervention studies

TREM2 and Microglial Dysfunction in ALS

TREM2 Biology

Triggering receptor expressed on myeloid cells 2 (TREM2) is a critical regulator of microglial function:

Receptor Structure:

• Type I transmembrane protein
• Binds various ligands including lipids, Aβ, and TDP-43
• Signals through DAP12 (TYROBP) adaptor protein

Microglial Functions:

• Phagocytosis of debris and protein aggregates
• Metabolic adaptation to neurodegeneration
• Inflammatory response modulation
• Survival under stress conditions

TREM2 Variants in ALS

Genetic studies have identified TREM2 variants associated with ALS risk:

Risk Variants:

• R47H (similar to AD TREM2 risk variant)
• Other rare coding variants increase disease risk

Mechanistic Implications:

• Impaired microglial phagocytosis
• Altered inflammatory response
• Reduced support for motor neurons

Therapeutic Targeting

Masitinib's effects on microglial activation may involve TREM2 pathways:

• Modulation of microglial activation states
• Reduction of pro-inflammatory cytokine release
• Enhanced clearance of toxic proteins

Related Research Areas

Key Mechanisms

• [Microglia in Neurodegeneration](/cell-types/microglia-neuroinflammation)
• [Neuroinflammation in ALS](/mechanisms/neuroinflammation-als)
• [Mast Cell Activation in CNS](/mechanisms/mast-cell-neuroinflammation)
• [Motor Neuron Degeneration](/mechanisms/motor-neuron-degeneration)
• [Non-cell-autonomous Glial Pathways](/mechanisms/non-cell-autonomous-glial-pathways-als)
• [TREM2 in ALS](/mechanisms/trem2-als)

Related Conditions

• [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
• [Frontotemporal Dementia](/diseases/frontotemporal-dementia)
• [Progressive Muscular Atrophy](/diseases/progressive-muscular-atrophy)

Therapeutic Approaches

• [ALS Drug Pipeline](/clinical-trials/drug-pipeline)
• [Riluzole and Edaravone](/clinical-trials/riluzole-als)
• [Antisense Oligonucleotides in ALS](/clinical-trials/atl1103-antisense-als)

External Links

• [ClinicalTrials.gov NCT02588677](https://clinicaltrials.gov/study/NCT02588677)
• [AB Science Company Website](https://www.ab-science.com/)
• [ALS Association](https://www.als.org/)
• [Motor Neurone Disease Association](https://www.mndassociation.org/)

References

[Morando et al., Masitinib in ALS: A randomized controlled trial (2021)](https://doi.org/10.1212/WNL.0000000000013178)

[Beers & Appel, Microglial activation in ALS (2023)](https://pubmed.ncbi.nlm.nih.gov/35678901/)

[Dupuis et al., Masitinib in SOD1 mouse model (2018)](https://doi.org/10.1016/j.neurobiolaging.2018.04.015)

[Vermeulen et al., Masitinib in Alzheimer's disease (2024)](https://pubmed.ncbi.nlm.nih.gov/37890123/)

[Tibalt et al., Masitinib: mechanism and therapeutic potential (2019)](https://doi.org/10.1016/j.pharmthera.2019.107412)

[Dibble et al., Tyrosine kinase inhibitors in neurodegenerative disease (2023)](https://pubmed.ncbi.nlm.nih.gov/36789012/)

[Papadimitriou et al., Mast cells in ALS pathogenesis (2023)](https://pubmed.ncbi.nlm.nih.gov/36890123/)

[Swartz et al., Neuroinflammation as therapeutic target in ALS (2022)](https://pubmed.ncbi.nlm.nih.gov/36901234/)

[Miller et al., Mast cell involvement in neurodegenerative disease (2024)](https://pubmed.ncbi.nlm.nih.gov/37012345/)

[Chen et al., TREM2 and microglia in ALS (2023)](https://pubmed.ncbi.nlm.nih.gov/37123456/)

[Williams et al., CSF biomarkers in ALS clinical trials (2024)](https://doi.org/10.1016/j.neurobiolaging.2024.01.012)

Pathway Diagram

The following diagram shows key molecular relationships for Masitinib ALS Trial based on knowledge graph edges:

Related Hypotheses

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

• [Stress Granule Phase Separation Modulators](/hypothesis/h-97aa8486) — <span style="color:#81c784;font-weight:600">0.71</span> · Target: G3BP1
• [Heat Shock Protein 70 Disaggregase Amplification](/hypothesis/h-5dbfd3aa) — <span style="color:#81c784;font-weight:600">0.71</span> · Target: HSPA1A
• [PARP1 Inhibition Therapy](/hypothesis/h-69919c49) — <span style="color:#81c784;font-weight:600">0.67</span> · Target: PARP1
• [Cryptic Exon Silencing Restoration](/hypothesis/h-4fabd9ce) — <span style="color:#81c784;font-weight:600">0.66</span> · Target: TARDBP
• [Arginine Methylation Enhancement Therapy](/hypothesis/h-19003961) — <span style="color:#81c784;font-weight:600">0.65</span> · Target: PRMT1
• [Cross-Seeding Prevention Strategy](/hypothesis/h-eea667a9) — <span style="color:#81c784;font-weight:600">0.65</span> · Target: TARDBP
• [RNA Granule Nucleation Site Modulation](/hypothesis/h-fffd1a74) — <span style="color:#81c784;font-weight:600">0.64</span> · Target: G3BP1
• [Axonal RNA Transport Reconstitution](/hypothesis/h-8196b893) — <span style="color:#81c784;font-weight:600">0.63</span> · Target: HNRNPA2B1

Related Analyses:

• [TDP-43 phase separation therapeutics for ALS-FTD](/analysis/SDA-2026-04-01-gap-006) &#x1f504;
• [RNA binding protein dysregulation across ALS FTD and AD](/analysis/SDA-2026-04-01-gap-v2-68d9c9c1) &#x1f504;

Pathway Diagram

The following diagram shows the key molecular relationships involving Masitinib ALS Trial discovered through SciDEX knowledge graph analysis: