Masitinib Retreats Across Three Fronts: Regulatory History and Competitive Moat Expose Structural Disadvantage

AB Science Terminates Three Masitinib Studies for Prioritization

AB Science has announced the formal termination of three clinical studies for its tyrosine kinase inhibitor, masitinib, in immune-mediated diseases. The terminated trials include a mid-stage study in mast cell activation syndrome (MCAS), a late-stage trial in mastocytosis, and a Phase 3 study in progressive multiple sclerosis. The French biotech stated that this decision was made to prioritize resources on its main clinical programs and was not driven by any safety concerns with masitinib, as enrollment for these trials had previously been paused with no rapid resumption in prospect.

• AB Science is discontinuing three masitinib clinical trials: a Phase 2 study for mast cell activation syndrome (MCAS), a Phase 3 trial for mastocytosis, and a Phase 3 study for progressive multiple sclerosis. These programs were designated as 'non-priority' by the company.
• The decision to terminate these studies was primarily a matter of resource prioritization, with CEO Stéphane Ledermann noting that enrollment had been paused and there was no prospect of rapid resumption. AB Science explicitly stated that the discontinuation was not due to any safety issues with masitinib.
• Following these terminations, AB Science will focus on its two main clinical programs: masitinib for amyotrophic lateral sclerosis (ALS) and the investigational microtubule destabilizer AB8939 for acute myeloid leukemia (AML). The company also has ongoing masitinib programs for Alzheimer’s disease (Phase 3) and sickle cell disease (Phase 2), along with a preclinical candidate for sarcoma and solid tumors.

Understanding Masitinib's Safety Profile Across Its Clinical Programs

Across masitinib's clinical development program, the safety profile has been characterized predominantly by adverse events of mild to moderate severity, with an initial higher incidence that tends to attenuate with continued treatment. In rheumatoid arthritis, the overall incidence of adverse events was high at 95%, though the majority were mild or moderate in intensity and declined considerably after 12 weeks of treatment; only two nonfatal serious adverse events were reported. The patient withdrawal rate of 37% — which necessitated last observation carried forward (LOCF) data imputation — was attributed in part to a heightened cautious response to adverse events, given that this represented masitinib's first evaluation in a non-oncologic setting. A recommended starting dose of 6.0 mg/kg/day administered orally in two divided intakes was identified based on potency and tolerability trends. In Alzheimer's disease, adverse events occurred more frequently with masitinib than placebo (65% vs. 38% of patients), yet most were mild to moderate and transient; severe adverse events occurred at a comparable frequency across arms (15% vs. 13%), with masitinib-associated events including gastrointestinal disorders, oedema, and rash.

In the oncology setting, masitinib demonstrated a notably favorable tolerability profile relative to comparator agents. In gastrointestinal stromal tumor (GIST), patients receiving masitinib experienced significantly lower rates of severe adverse events compared to sunitinib (52% vs. 91%, P = 0.008) over a median follow-up of 14 months, supporting a positive benefit-risk ratio. In veterinary oncology, adverse effects were observed in 64.1% of dogs treated for mast cell tumors, with serum alanine aminotransferase elevation (23.1%) and vomiting (15.4%) being the most frequent findings; masitinib was nonetheless characterized as well-tolerated and effective. In canine atopic dermatitis, premature discontinuations in the masitinib arm (28.2% vs. 26.0% for control) were driven primarily by adverse events (13.4% vs. 4.8%), and 16.0% of masitinib-treated dogs experienced severe adverse events versus 7.7% in the control group. Notably, masitinib was associated with a risk of reversible protein loss; however, regular surveillance of blood albumin and proteinuria enabled timely discontinuation before clinical manifestation of toxicity.

The most recent evidence, from a 2024 meta-analysis of five randomized controlled trials across multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis, indicates a statistically significant elevation in overall adverse event incidence in the masitinib group versus control (RR = 1.12, 95% CI [1.07–1.17], P < 0.01). This elevated risk was consistent across both the 3 mg/kg/day (RR = 1.13, P = 0.01) and 4.5 mg/kg/day (RR = 1.11, P < 0.01) dose levels. Adverse events categorized as severe, non-fatal serious, leading to dose reduction, or resulting in permanent discontinuation were all significantly more frequent in the masitinib arm (P ≤ 0.01). However, no statistically significant difference was observed between the 3 mg/kg/day dose and placebo specifically with respect to severe and non-fatal serious adverse events, suggesting a potential dose-dependent modulation of risk that may inform future dosing strategies in neurodegenerative indications.

Masitinib's Ongoing Journey: Beyond Terminated Immune Trials

Masitinib's clinical development programme extends well beyond mast cell activation syndrome, spanning oncology, neurology, inflammatory, and infectious disease indications. The breadth of intervention models — from randomised placebo-controlled phase 3 trials to preclinical mouse models — reflects the drug's multi-target mechanism across mast cell, tyrosine kinase, and neuroinflammatory pathways.

Addressing Unmet Needs in Mast Cell Activation Syndrome

Despite growing recognition of MCAS as a clinically significant multisystem disorder, substantial gaps remain in its diagnosis, treatment, and patient management. The condition continues to be underdiagnosed due to heterogeneous presentations, restrictive diagnostic criteria used by some clinicians, and limited awareness across specialties — leaving many patients undertreated or misclassified for years.

• Underrecognition and misdiagnosis: MCAS remains historically underrecognized despite its estimated high prevalence, with patients frequently mislabeled as having unexplained inflammatory syndromes or somatization/primary psychiatric disorders. Some clinicians continue applying more restrictive diagnostic criteria, significantly compounding underdiagnosis of this complex but treatable condition.

• Diagnostic ambiguity and absence of reliable biomarkers: No clear biomarkers for MCAS have been established, and limited evidence supports the diagnostic utility of mast cell staining on gastrointestinal biopsies, with no validated cutoff for mast cell density. Access to specialized testing — including serum tryptase and urinary mediator assays — remains limited in resource-constrained settings, further complicating definitive diagnosis.

• Limitations of current therapeutic options: Existing mast cell stabilizers (cromolyn sodium, tranilast, nedocromil) are hindered by poor bioavailability, frequent dosing requirements, delayed onset of relief, and poorly understood mechanisms of action. Patients refractory to H1 antihistamines plus additional antimediator agents represent a critical population with high unmet need, and there is limited guidance on optimal sequencing or combination of available therapies.

• Patients with complex multisystem and overlapping comorbidities: Key populations under investigation include patients with co-occurring gastric dysmotility/SIBO, dysautonomia, hypermobile Ehlers-Danlos syndrome (hEDS) or hypermobility spectrum disorders (HSD), postural orthostatic tachycardia syndrome (POTS), and autoimmunity — conditions that frequently cluster with MCAS and complicate its management.

• Hereditary alpha-tryptasemia (HαT) patients: Patients with TPSAB1 copy number gain and concomitant mast cell disorders carry a notable clinical burden, including a 75% rate of severe anaphylaxis (predominantly drug-induced), and high frequencies of gastroesophageal reflux (87.5%), cutaneous symptoms (62.5%), neuropsychiatric features (62.5%), and autonomic dysfunction (37.5%). TPSAB1 genotyping has been recommended for routine evaluation to enable individualized management.

• Pediatric-onset MCAD populations: A first described pediatric-onset non-mastocytosis MCAD cohort (44 patients; mean age at onset 4.3 years) identified two distinct clinical profiles — persistent gastrointestinal symptoms triggered by food in those under 3 years, and episodic anaphylactic reactions in those over 3 years — underscoring the need for age-stratified diagnostic and treatment frameworks to reduce diagnostic delay.

• Patient experience and misinformation burden: Patients uniformly report feeling unheard during clinical encounters and commonly navigate care across multiple physicians and specialists, compounding the complexity of their management. Concurrently, a large proportion of MCAS-related content on social media platforms such as TikTok contains significant misinformation, with only 1 of the 50 most-watched videos (2%) referencing the validated Vienna diagnostic criteria, posing a risk of further diagnostic confusion and self-misdiagnosis.

• Research and infrastructure gaps: MCAS research remains in early stages, hampered by limited disease awareness, challenges in objectively assessing treatment response, and escalating misdiagnosis based on nonspecific criteria. There is a recognized need for next-generation mast cell stabilizers and prospective clinical trials that formally capture MCAS-specific endpoints, including anaphylaxis outcomes in patients receiving tyrosine kinase inhibitors.

Masitinib's Strategic Retreat from Key Immune Indications

The recent announcement from AB Science regarding the termination of three masitinib clinical studies in immune-mediated diseases—mast cell activation syndrome, mastocytosis, and progressive multiple sclerosis—marks a pivotal moment for the company and its lead asset. Masitinib, a selective tyrosine kinase inhibitor, has been investigated for its ability to modulate mast cell and microglial activity, offering a broad therapeutic promise across various conditions. Indeed, prior research has highlighted its potential, with a Phase 2a study in mastocytosis showing a 56% overall clinical response in patients with handicap, and a Phase 3 trial in progressive multiple sclerosis demonstrating a significant benefit in reducing disability progression.

However, the decision to halt these programs, despite some encouraging clinical signals, underscores the complex realities of pharmaceutical development. While AB Science attributes the move to resource prioritization rather than safety concerns, the implications are far-reaching. In mastocytosis, the competitive landscape has intensified with the recent approvals of other KIT inhibitors, potentially making masitinib's path to market more challenging. For progressive MS, a disease area with substantial unmet need, the withdrawal of a drug that showed positive Phase 3 data is a notable setback for patients and clinicians hoping for new treatment options.

This strategic realignment suggests a critical evaluation of masitinib's extensive pipeline, likely focusing on indications where the risk-benefit profile, market opportunity, and development pathway are most favorable. The development of tyrosine kinase inhibitors often involves managing a distinct pattern of adverse events, such as gastrointestinal issues, skin reactions, and hematologic events, as well as potential hepatotoxicity, which can add to the complexity and cost of clinical trials. While masitinib has generally been described as well-tolerated for long-term regimens after initial side effects, these inherent challenges in TKI development likely factored into the company's resource allocation decisions. Moving forward, the industry will watch closely to see how AB Science leverages its remaining masitinib programs and what this focused strategy means for its long-term growth.