¶ Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
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.
| 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 |
- Amyotrophic Lateral Sclerosis (ALS)
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.
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
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.
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:
3. Neuroprotection through PDGFR Inhibition
Platelet-derived growth factor receptor (PDGFR) inhibition may protect motor neurons through improved trophic support and reduced inflammatory signaling.
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
The combination with masitinib targets complementary pathways, potentially providing additive or synergistic effects compared to riluzole monotherapy.
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
- Masitinib: 4.5 mg/kg/day orally (divided into two doses)
- Riluzole: 50 mg twice daily (standard of care)
- Duration: 48-week treatment period
- 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
- Presence of tracheostomy
- Forced vital capacity <50% predicted
- Significant hepatic or renal impairment
- Concomitant use of other investigational therapies
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
A change of ≥3 points is considered clinically meaningful. The primary analysis will compare the slope of ALSFRS-R decline between treatment groups.
- Survival time: Time to death or tracheostomy
- Forced Vital Capacity (FVC): Respiratory function assessment
- Quality of Life (ALSAQ-40): Disease-specific QoL instrument
- Biomarkers: Neurofilament light chain (NfL) in serum
Motor Function:
- Manual muscle testing (MMT) score change
- Grip strength
Quality of Life:
- ALSAQ-40 (Amyotrophic Lateral Sclerosis Assessment Questionnaire)
- SF-36 Health Survey
- Cognitive assessment: MoCA (Montreal Cognitive Assessment)
Biomarker analysis: Including CSF and plasma neurofilaments
CMV serostatus: Exploration of CMV's role in ALS progression
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.
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.
- 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 revealed potentially interesting signals:
- Fast Progressors: Patients with rapid disease progression (ALSFRS-R decline >1 point/month) showed a trend toward benefit
- Bulbar-Onset Patients: A non-significant trend toward slower functional decline
- Early Disease: Patients within 12 months of symptom onset showed numerically better outcomes
These findings suggest patient enrichment strategies may improve detection of treatment effects in future trials.
¶ Biomarker Insights and Translational Findings
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
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
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
C9orf72 Expansion Carriers:
- 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
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
Grade 3 or Higher Adverse Events:
- More common in the treatment arm (~18% vs ~12% in placebo)
- Primarily rash and gastrointestinal events
- Manageable with standard interventions
Discontinuation Rate:
- Approximately 20% due to adverse events or patient request
- Comparable between arms when accounting for adverse events
Serious Adverse Events:
- Comparable between treatment and placebo arms (~15-18%)
- No new safety signals identified
- No unexpected deaths attributable to study drug
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 |
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
- Liver function monitoring (transaminase elevation)
- Cardiac monitoring (QT prolongation in rare cases)
- Hematological monitoring (neutropenia)
Masitinib is metabolized by CYP3A4; concomitant use of strong inhibitors/inducers requires dose adjustment.
¶ 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
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
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
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
Masitinib blocks these pathways, reducing mast cell survival and function.
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
The combined effects result in:
- Reduced TNF-α and IL-1β in the CNS
- Decreased microglial activation markers
- Lower mast cell-derived inflammatory mediators
- Improved motor neuron environment
| 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 |
This trial contributed important insights to ALS drug development:
- Neuroinflammation Target: Validated as biologically relevant despite negative trial result
- Patient Selection: Subgroup benefits suggest need for enrichment strategies
- Biomarker Integration: NfL use in trials improved disease progression tracking
- Combination Approaches: May need multi-target therapy
- Earlier Intervention: Treatment effect may be more pronounced earlier in disease course
Based on the masitinib experience, new strategies emerge:
- Improved CNS Penetration: Next-generation TKIs with better brain access
- Selective Targeting: More specific kinase inhibition
- Combination Therapy: Multi-target approaches
Key learnings for future trials:
- Use NfL for patient selection
- Implement biomarker-driven enrichment
- Consider genetic stratification
The masitinib experience provides valuable lessons:
- Mechanism Validation: Biological activity does not guarantee clinical efficacy
- Patient Enrichment: Rapid progressors may show greater treatment effects
- Endpoint Selection: Composite endpoints may capture broader treatment effects
- Biomarker Integration: NfL provides sensitive measure of disease progression
- Combination Strategies: Multi-target approaches may be necessary for ALS
¶ 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:
- Largest TKI Trial in ALS: Established safety and efficacy data for tyrosine kinase inhibition
- Combination Therapy Data: Provided evidence for combining neuroinflammatory targets with anti-excitotoxic approaches
- Biomarker Validation: Advanced understanding of NfL as progression marker
- Subgroup Insights: Identified patient populations who may benefit from targeted therapy
- Mechanistic Validation: Confirmed biological activity on neuroinflammatory pathways
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
Regulatory Science:
- Provided FDA/EMA with comprehensive safety database
- Established precedent for biomarker incorporation in ALS trials
- Informed regulatory expectations for ALS drug development
Scientific Knowledge:
- 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)
The trial includes biomarker substudies that may identify:
- Patient subgroups most likely to respond
- Early indicators of treatment response
- Surrogate markers for accelerated approval
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 |