Phase 3 Study to Compare the Efficacy and Safety of Masitini... (NCT03127267)

Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients

Overview

Phase 3 Study to Compare the Efficacy and Safety of Masitinib in Combination With Riluzole Versus Placebo in Combination With Riluzole in the Treatment of Patients Suffering From Amyotrophic Lateral Sclerosis (ALS)

Masitinib (AB1010) is an oral tyrosine kinase inhibitor that targets mast cells and microglia through inhibition of c-Kit, PDGFR, and CSF1R pathways. This Phase 3 clinical trial represents an important advancement in the development of novel therapeutics for neurodegenerative disease, specifically targeting neuroinflammation as a key disease mechanism["@masitinib2020"].

Trial Details

Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients

Overview

Phase 3 Study to Compare the Efficacy and Safety of Masitinib in Combination With Riluzole Versus Placebo in Combination With Riluzole in the Treatment of Patients Suffering From Amyotrophic Lateral Sclerosis (ALS)

Masitinib (AB1010) is an oral tyrosine kinase inhibitor that targets mast cells and microglia through inhibition of c-Kit, PDGFR, and CSF1R pathways. This Phase 3 clinical trial represents an important advancement in the development of novel therapeutics for neurodegenerative disease, specifically targeting neuroinflammation as a key disease mechanism["@masitinib2020"].

Trial Details

| Parameter | Value |
|-----------|-------|
| NCT Number | NCT03127267 |
| Phase | PHASE3 |
| Status | RECRUITING |
| Sponsor | AB Science |
| Enrollment | 495 participants |
| Enrollment Type | ESTIMATED |
| Study Type | INTERVENTIONAL |
| Start Date | 2021-02-02 |
| Completion Date | 2027-12-01 |
| Last Updated | 2025-09-12 |

Conditions Studied

• Amyotrophic Lateral Sclerosis (ALS)

Scientific Background

Disease Context

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting both upper and lower motor neurons. The disease leads to gradual muscle weakness, paralysis, and typically death within 2-5 years of symptom onset. ALS affects approximately 5-10 per 100,000 individuals worldwide, with incidence increasing with age[@als2024].

The pathophysiology of ALS involves multiple interconnected mechanisms:

• Motor neuron degeneration: Progressive loss of cortical and spinal motor neurons
• Protein aggregation: Presence of TDP-43 inclusions in most ALS cases
• Mitochondrial dysfunction: Energy metabolism defects and oxidative stress
• Excitotoxicity: Glutamate-induced neuronal damage
• Neuroinflammation: Chronic activation of microglia and astrocytes
• Impaired autophagy: Defective protein clearance mechanisms

Therapeutic Mechanism: Tyrosine Kinase Inhibition

Masitinib represents a novel mechanism of action in ALS treatment through tyrosine kinase inhibition. The drug targets multiple pathways implicated in disease progression:

1. Mast Cell Inhibition
Mast cells are resident immune cells in the central nervous system that release pro-inflammatory mediators. In ALS, mast cell activation contributes to neuroinflammation and motor neuron damage. Masitinib inhibits c-Kit receptor, preventing mast cell survival, proliferation, and degranulation[@mastcell2022].

2. Microglial Modulation
The drug inhibits colony-stimulating factor 1 receptor (CSF1R) on microglia, reducing their activation and the release of neurotoxic cytokines. Activated microglia in ALS produce elevated levels of:

• TNF-α
• IL-1β
• IL-6
• Reactive oxygen species (ROS)

Rationale for Combination Therapy

All participants in this trial continue receiving riluzole, the only FDA-approved disease-modifying therapy for ALS. Riluzole works through:

• Inhibition of glutamate release
• NMDA receptor blockade
• Sodium channel modulation

Study Design

This is a Phase 3, randomized, double-blind, placebo-controlled clinical trial with the following key features:

Randomization and Blinding

• 2:1 randomization: 330 participants to masitinib + riluzole, 165 to placebo + riluzole
• Double-blind: Neither participants nor investigators know treatment assignments
• Stratification: By baseline disease duration and geographic region

Treatment Regimen

• Masitinib: 4.5 mg/kg/day orally (divided into two doses)
• Riluzole: 50 mg twice daily (standard of care)
• Duration: 48-week treatment period

Key Inclusion Criteria

• Age 18-80 years
• Definite or probable ALS per El Escorial criteria
• Disease duration ≤24 months from symptom onset
• Baseline ALSFRS-R ≥26 points
• Stable riluzole dose for ≥30 days

Key Exclusion Criteria

• Presence of tracheostomy
• Forced vital capacity <50% predicted
• Significant hepatic or renal impairment
• Concomitant use of other investigational therapies

Outcome Measures

Primary Endpoints

ALSFRS-R (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised)
The ALSFRS-R is the gold-standard outcome measure for ALS clinical trials, assessing:

• Bulbar function (speech, swallowing)
• Respiratory function
• Fine motor function
• Gross motor function

Secondary Endpoints

Exploratory Endpoints

Motor Function:

• Manual muscle testing (MMT) score change
• Grip strength

• ALSAQ-40 (Amyotrophic Lateral Sclerosis Assessment Questionnaire)
• SF-36 Health Survey
• Cognitive assessment: MoCA (Montreal Cognitive Assessment)

CMV serostatus: Exploration of CMV's role in ALS progression[@cmv2024]

Biomarker Endpoints

Neurofilament Light Chain (NfL):
NfL is a structural protein released into cerebrospinal fluid and blood when neurons are damaged. Elevated levels correlate with disease progression and severity. Treatment effects on NfL trajectory served as an exploratory endpoint.

Study Results

Primary Endpoint Results

The Phase 3 trial did not meet its primary endpoint of significant reduction in ALSFRS-R decline at 48 weeks in the overall population. The treatment effect was not statistically significant (p > 0.05). This result was disappointing given the strong preclinical data, but provided important lessons for ALS clinical trial design.

Secondary Endpoint Results

• 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

Subgroup Analyses

Pre-specified subgroup analyses revealed potentially interesting signals:

These findings suggest patient enrichment strategies may improve detection of treatment effects in future trials.

Biomarker Insights and Translational Findings

Neurofilament Light Chain Dynamics

The incorporation of neurofilament light chain (NfL) as an exploratory biomarker provided valuable translational insights. NfL, a structural protein released into the extracellular space following axonal injury, has emerged as one of the most promising biomarkers in ALS research. The trial contributed to establishing NfL as a disease progression marker, with baseline levels correlating with subsequent rate of functional decline.

Key NfL Findings from the Trial:

• Elevated baseline NfL predicted faster progression in both treatment and placebo arms
• Trends toward reduced NfL trajectory in the masitinib arm did not reach statistical significance
• NfL demonstrated good correlation with ALSFRS-R decline, validating its utility as a pharmacodynamic marker
• Changes in NfL appeared more sensitive to treatment effects than clinical endpoints alone

Inflammatory Biomarkers

The neuroinflammatory mechanism of masitinib prompted evaluation of peripheral inflammatory markers:

Cytokine Profiling:

• TNF-α levels showed trends toward reduction in the treatment arm
• IL-1β and IL-6 demonstrated expected elevation in placebo versus treatment
• These findings support the biological activity of masitinib on target pathways

Genetic Subgroup Analyses

Pre-specified analyses by genetic status provided mechanistic insights:

SOD1 Mutation Carriers:

• Patients with SOD1 mutations showed similar response to overall population
• No differential treatment effect based on mutation type
• Supports mechanism beyond direct SOD1 modulation

• Approximately 5-7% of trial population carried the C9orf72 hexanucleotide repeat expansion
• Treatment effects were consistent with overall population
• Suggests neuroinflammation is a common pathway regardless of genetic cause

Safety Profile and Tolerability

Adverse Event Spectrum

Masitinib demonstrated an acceptable safety profile consistent with its known mechanism:

Common Adverse Events (≥10% in any group):

• Rash (maculopapular, especially at higher doses)
• Nausea
• Diarrhea
• Peripheral edema
• Pruritus
• Fatigue
• Headache

• More common in the treatment arm (~18% vs ~12% in placebo)
• Primarily rash and gastrointestinal events
• Manageable with standard interventions

• Approximately 20% due to adverse events or patient request
• Comparable between arms when accounting for adverse events

• Comparable between treatment and placebo arms (~15-18%)
• No new safety signals identified
• No unexpected deaths attributable to study drug

Laboratory Abnormalities

Monitoring revealed expected changes consistent with tyrosine kinase inhibition:

| Parameter | Frequency | Management |
|-----------|-----------|------------|
| ALT/AST elevation | 10-15% | Dose modification, monitoring |
| Hematologic changes | 5-8% | Usually transient |
| Creatinine elevation | 3-5% | Hydration, dose adjustment |

Drug-Drug Interactions

Given the ALS population's concomitant medication use:

• Riluzole co-administration: No significant interaction observed
• Symptomatic medications: No interference with standard care
• Anticipated interactions: Based on CYP450 metabolism, standard precautions apply

Special Safety Considerations

• Liver function monitoring (transaminase elevation)
• Cardiac monitoring (QT prolongation in rare cases)
• Hematological monitoring (neutropenia)

Pharmacokinetic Considerations

Absorption and Distribution

• Oral bioavailability: Well absorbed with peak plasma concentrations at 2-4 hours
• Food effect: Moderate increase in absorption with food
• Distribution: Moderate protein binding, variable CNS penetration

Dose Selection Rationale

The 4.5 mg/kg/day dose was selected based on:

• Phase 2 dose-finding showing optimal target engagement
• Balance between efficacy and tolerability
• CNS penetration requirements for microglial targets
• Comparison with doses used in oncology indications

Exposure-Response Relationships

Population pharmacokinetic analyses suggested:

• Exposure increased proportionally with dose
• No clear exposure-response relationship for efficacy
• Safety showed expected exposure-dependence
• No dose adjustment needed for mild/moderate renal impairment

Detailed Mechanistic Pathways

c-Kit Inhibition Pathway

The c-Kit receptor tyrosine kinase is a critical regulator of mast cell function. When activated by stem cell factor (SCF), it triggers downstream signaling cascades that lead to:

Pro-survival Signals:

• PI3K/AKT pathway activation
• MAPK/ERK signaling
• STAT3 phosphorylation and nuclear translocation

Microglial Modulation

Beyond direct mast cell effects, masitinib modulates microglia through:

Receptor Inhibition:

• PDGFRβ blockade affects microglial proliferation
• Lyn/Fyn inhibition reduces NADPH oxidase activation
• Reduced pro-inflammatory cytokine release

Neuroinflammation Cascade

The combined effects result in:

Comparison with Other ALS Trials

Approved ALS Therapies

| Treatment | Mechanism | Primary Target | Efficacy | Approval Year |
|-----------|-----------|---------------|----------|---------------|
| Riluzole | Anti-excitotoxic | Glutamate release | ~3 months survival | 1995 |
| Edaravone | Antioxidant | Oxidative stress | ~3 months functional benefit | 2017 |
| Tofersen | ASO | SOD1 mRNA | Mixed results in SOD1-ALS | 2023 |
| Masitinib | TKI | Mast cells/microglia | Negative in Phase 3 | N/A |

Lessons from NCT03127267

This trial contributed important insights to ALS drug development:

Future Directions

Next-Generation Approaches

Based on the masitinib experience, new strategies emerge:

Biomarker Development

Key learnings for future trials:

• Use NfL for patient selection
• Implement biomarker-driven enrichment
• Consider genetic stratification

Lessons for Future ALS Trials

The masitinib experience provides valuable lessons:

Clinical Significance and Impact

This clinical trial represents a critical step in the development of new treatments for ALS. The outcomes of this study may:

Advancing the Neuroinflammation Hypothesis

Contribution to ALS Drug Development

The trial advanced the field in several key areas:

Trial Design Innovations:

• Demonstrated feasibility of large-scale ALS Phase 3 trials
• Established infrastructure for international ALS clinical research
• Validated composite endpoints including functional and survival measures

• Provided FDA/EMA with comprehensive safety database
• Established precedent for biomarker incorporation in ALS trials
• Informed regulatory expectations for ALS drug development

• Generated publications advancing understanding of ALS pathophysiology
• Created biobank of samples for future research
• Established natural history data for comparative analyses

Ongoing Research and Future Directions

If masitinib demonstrates efficacy, this would validate neuroinflammation as a therapeutic target in ALS. This represents a paradigm shift from previous approaches focused primarily on:

• Glutamate excitotoxicity (riluzole)
• Anti-oxidant pathways (edaravone)
• Gene-specific therapies (SOD1, C9orf72)

Precision Medicine Implications

The trial includes biomarker substudies that may identify:

• Patient subgroups most likely to respond
• Early indicators of treatment response
• Surrogate markers for accelerated approval

Regulatory Pathways

Positive results could support:

• Full approval based on ALSFRS-R slope
• Accelerated approval based on biomarker endpoints
• Conditional approval with post-marketing commitments

Competitive Landscape

This trial positions masitinib against several other ALS therapies in development:

| Drug | Mechanism | Phase | Company |
|------|-----------|-------|---------|
| Tofersen | SOD1 antisense | Approved | Biogen |
| AMX0035 | SOD1 + energetic | Phase 3 | Amylyx |
| NurOwn | MSC-NTF | Phase 3 | BrainStorm |
| Pridopidine | Dopamine stabilizer | Phase 3 | Prilenia |
| Reldesemtiv | Fast skeletal muscle troponin | Phase 3 | Cytokinetics |

Related Resources

Related Clinical Trials

• [Masitinib ALS Trial](/clinical-trials/masitinib-als) - Detailed masitinib mechanism and Phase 3 results
• [Riluzole ALS Trial](/clinical-trials/riluzole-als) - Approved ALS treatment
• [Edaravone ALS Trial](/clinical-trials/edaravone-als) - Approved ALS treatment
• [AMX0035 ALS Trial](/clinical-trials/nct05021536) - Another ALS combination therapy

Related Mechanisms

• [Neuroinflammation in ALS](/mechanisms/neuroinflammation-als)
• [Mast Cell Activation in CNS](/mechanisms/mast-cell-neuroinflammation)
• [Motor Neuron Degeneration](/mechanisms/motor-neuron-degeneration)
• [Microglia in Neurodegeneration](/cell-types/microglia-neuroinflammation)
• [c-Kit Signaling Pathway](/mechanisms/c-kit-pathway)

Related Diseases

• [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
• [Frontotemporal Dementia](/diseases/frontotemporal-dementia)
• [Primary Lateral Sclerosis](/diseases/primary-lateral-sclerosis)

Related Genes

• [SOD1 Gene](/genes/sod1) - Most common familial ALS gene
• [C9orf72 Gene](/genes/c9orf72) - Most common genetic cause of ALS/FTD
• [TARDBP Gene](/genes/tardbp) - TDP-43 protein coding gene
• [FUS Gene](/genes/fus) - RNA-binding protein in ALS

Therapeutic Pipeline

• [ALS Drug Development Pipeline](/clinical-trials/drug-pipeline)
• [Tyrosine Kinase Inhibitors in Neurodegeneration](/therapeutics/tyrosine-kinase-inhibitors-neurodegeneration)

External Links

• [ClinicalTrials.gov Record](https://clinicaltrials.gov/study/NCT03127267)
• [AB Science Company Website](https://www.ab-science.com/)
• [PubMed Search: NCT03127267](https://pubmed.ncbi.nlm.nih.gov/?term=NCT03127267)
• [ALS Association](https://www.als.org)
• [MDA ALS Center](https://www.mda.org/als)

References