Although the precise pathogenesis of multiple sclerosis (MS) is not fully understood, MS can be classified as an autoimmune neurodegenerative disorder. More than a century ago, Neumann reported that mast cells accumulation is found at the edge of MS plaques. Recently, the presence of mast cells and of an increased concentration of mast cell constituents have been confirmed in MS plaques [Krüger, 2001]. In recent years, there are growing evidences that mast cells are playing a crucial role in the inflammatory process and subsequent demyelination in MS.
Recent work in animal studies has shown that mast cells act at multiple levels to influence both the induction and the severity of MS. Inhibitors of mast cells (e.g. hydroxyzine) have been reported to effectively inhibit the progression and severity of clinical signs of experimental allergic encephalomyelitis (EAE) and limit the extent of mast cells degranulation [Dimitriadou, 2000]. Nedocromyl sodium, a mast cell stabilizer, has also successfully delayed and prevented the development of EAE [Seeldrayers, 1989]. An EAE model in mast cell-deficient W/Wv mice exhibited significantly reduced disease incidence, delayed disease onset, and decreased mean clinical scores [Secor, 2000]. In addition, several mast cell constituents, including proteases, are capable of effecting demyelination and degradation of myelin proteins, with breakdown products stimulating further mast cell degranulation and contributing to activation of Myelin Basic Protein (MBP)-reactive lymphocytes [Dietsch and Hinrichs, 1991]. Estradiol and MBP have been shown to synergistically act upon mast cell secretion, with in vitro evidence of early brain demyelination as a result (quadrilaminar myelin sheaths regarded exclusively as an early stage of demyelination both in EAE and MS) [Theoharides, 1993].
The hypothesis is that degranulation of mast cells adjacent to myelin serves as a focus for inflammatory demyelination, leading to damage of myelin sheath by proteolysis, secretion of vasoamines and release of chemoattractants that could recruit circulating blood cells. This would make mast cells a unique therapeutic target for MS. And consequently, masitinib by inhibiting mast cell degranulation represents a promising therapeutic approach in the treatment of MS.
Summary of progressive multiple sclerosis clinical program with masitinib
Phase |
Design |
Population |
Primary Target |
Patient Target |
IDMC recommandation |
Study Status |
Related publications |
2a |
Double-blind, placebo-controlled, parallel-group study |
Patients with primary progressive or relapse-free secondary progressive multiple sclerosis |
Response on MSFC, which measures symptoms of patients on three aspects: movement of the lower limbs, movement of the upper limbs, and cognitive tests |
35 |
NA |
Study completed |
Vermersch, 2012 |
2/3 |
Prospective, double-blind, placebo-controlled, 2-parallel groups study |
Patients with primary progressive or relapse-free secondary progressive multiple sclerosis |
Change in EDSS (Expanded Disability Status Scale), which is a scale used for quantifying disability in multiple sclerosis |
650 |
Continuation of the study without resampling option (based on interim analysis performed on one dosage and safety data) |
Recruitment completed |
– |
Phase 2a proof of concept
Clinical phase 2a proof of concept with masitinib in patients with progressive multiple sclerosis supported the development of masitinib in progressive forms of multiple sclerosis. The phase 2a study showed that for the primary endpoint of MSFC (which measures symptoms of patients on three aspects: movement of the lower limbs, movement of the upper limbs, and cognitive tests), 32% of patients treated with masitinib were responders as compared with 0% with placebo. A clinical response was defined as > 100% change from baseline in MSFC score.
Phase 2/3 study
AB Science launched a phase 2/3 study to assess the safety and efficacy of masitinib in patients with primary progressive or relapse-free secondary progressive multiple sclerosis.
The Independent Data Safety and Monitoring Committee (IDMC) has, on each occasion, recommended the continuation of this phase 3 study based on the analysis of the safety data.
In March 2018, an interim analysis was performed and the IDMC did not request implementation of the protocol resampling option.
Study recruitment was completed with 656 enrolled patients.
Four principal courses of MS are currently defined according to clinical characteristics; namely: Relapsing Remitting MS (RRMS), Secondary Progressive MS (SPMS), Primary Progressive MS (PPMS), and Progressive Relapsing MS (PRMS). The disease typically presents as RRMS, with more than 50% of RRMS patients entering a progressive phase (SPMS) following a highly variable delay. Approximately 10 to 15% of patients present with PPMS, which is characterized by continuous disease progression from the onset of disease, i.e. without relapses and remissions, for which prognosis is considered as poor due to the relatively rapid development of advanced disability as compared with RRMS.
Altogether, the progressive forms of multiple sclerosis represent around 60% of patients, hence around 400,000 patients in the USA and in the EU alone.