Amyotrophic lateral sclerosis (ALS) is a neurodegenerative, life-threatening disease characterized by progressive muscular paralysis reflecting degeneration of motor neurons. While the average survival time is 3 years, about 10 percent of people with ALS will survive 10 years.
Preclinical studies show that masitinib is capable of exerting neuroprotection in both the central and peripheral nervous systems by inhibiting the functionality of different cells implicated in ALS progression. AB Science has completed a phase 2/3 human clinical trial with promising results in a population accounting for about 85% of ALS patients. A confirmatory phase 3 study will be launched in 2019.
In recognition of the critical need for new treatments, masitinib received orphan drug designation for ALS from both the European Medicine Agency (EMA) and the U.S. Food and Drug Administration (FDA).
Because of its potent and selective activity against CSF1R, masitinib is able to inhibit the CSF1/CSF1R signaling pathway thereby regulating CSF1R-dependent cells such as microglia. By merit of its activity against c-Kit, LYN and FYN, masitinib is also able to inhibit the function of mast cells. The development of masitinib in Amyotrophic Lateral Sclerosis is therefore based on the pharmacological action of masitinib in microglia cells and mast cells, thereby slowing microglial-related disease progression, reducing neuro-inflammation, and modulating the neuronal microenvironment in both central and peripheral nervous systems.It is through this multifaceted therapeutic approach that masitinib appears capable of generating the beneficial treatment effects observed in humans (as evidenced by significant improvement in relevant clinical measures of disease progression from clinical assessment) and also from appropriate preclinical animal studies [Trias 2016, Trias 2017, Trias 2018 ].
Summary of clinical program
Phase Design Population Primary Target Patient Target IDMC recommandation Study Status Related publications 2/3 Prospective, double-blind, placebo-controlled, parallel groups study Patients suffering from Amyotrophic Lateral Sclerosis Change from baseline to week 48 in Amyotrophic Lateral Sclerosis functional rating scale (ALSFRS)-Revised 400 NA Study completed -
Phase 2/3 studyAB Science completed a phase 2/3 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).The masitinib in combination with riluzole showed the following significant activity in the normal progressor population of ALS patients:
The masitinib safety profile in ALS was in line with the known masitinib safety profile.In order to confirm the findings of this phase 2/3 study, AB Science plans to launch a confirmatory phase 3 study in ALS.Amyotrophic lateral sclerosis is a rare degenerative disorder that results in progressive wasting and paralysis of voluntary muscles. There are approximately 50,000 people with ALS in the European Union and in the US, with more than 16,000 new cases diagnosed each year in Europe and in the US. Almost 80% of ALS patients die within 5 years and 90% die within 10 years.Mast cells and neutrophils mediate peripheral motor pathway degeneration in ALS.
- 27% slowing of ALSFRS-R deterioration at week 48 (primary analysis)
- 29% slowing of deterioration in quality-of-life (ALSAQ-40)
- 22% slowing of deterioration in respiratory function (FVC)
- 25% delay in disease progression (survival-to-event analysis)
Trias E, King PH, Si Y, Kwon Y, Varela V, Ibarburu S, Kovacs M, Moura IC, Beckman JS, Hermine O, Barbeito L.
JCI Insight. 2018 Oct 4;3(19). pii: 123249. doi: 10.1172/jci.insight.123249.
Evidence for mast cells contributing to neuromuscular pathology in an inherited model of ALS.
Trias E, Ibarburu S, Barreto-Núñez R, Varela V, Moura IC, Dubreuil P, Hermine O, Beckman JS, Barbeito L.
JCI Insight. 2017 Oct 19;2(20). pii: 95934. doi: 10.1172/jci.insight.95934.
Post-paralysis tyrosine kinase inhibition with masitinib abrogates neuroinflammation and slows disease progression in inherited amyotrophic lateral sclerosis.
Trias E, Ibarburu S, Barreto-Núñez R, Babdor J, Maciel TT, Guillo M, Gros L, Dubreuil P, Díaz-Amarilla P, Cassina P, Martínez-Palma L, Moura IC, Beckman JS, Hermine O, Barbeito L.
J Neuroinflammation. 2016 Jul 11;13(1):177. doi: 10.1186/s12974-016-0620-9.
ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment?
Petrov D, Mansfield C, Moussy A, Hermine O.
Front Aging Neurosci. 2017 Mar 22;9:68. doi: 10.3389/fnagi.2017.00068. eCollection 2017. Review.
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Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS). Multiple sclerosis in its progressive forms is characterized by continuous progression of disease, without relapses or remissions. Progressive forms of MS are considered to be more severe than relapsing-remitting MS with very few treatment options to reduce disability progression. There is a high unmet medical need in those with progressive forms of MS.
Growing evidences suggests that mast cells play a crucial role in neuroinflammatory processes and the subsequent degeneration of nerve cells observed in patients suffering from MS. Mast cell inhibition is therefore an attractive therapeutic approach in the treatment of MS.
Masitinib is currently investigated in progressive forms of MS with an ongoing phase 2/3 study.
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 studyAB 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.Masitinib treatment in patients with progressive multiple sclerosis: a randomized pilot study.
Vermersch P, Benrabah R, Schmidt N, Zéphir H, Clavelou P, Vongsouthi C, Dubreuil P, Moussy A, Hermine O.
BMC Neurol. 2012 Jun 12;12:36. doi: 10.1186/1471-2377-12-36.
Alzheimer’s disease is an irreversible, neurodegenerative disorder leading to disabling impairment of memory and thinking skills. Alzheimer’s disease is the most common cause of dementia among older adults.
Masitinib is currently investigated in mild to moderate forms of Alzheimer’s disease with an ongoing phase 2/3 study. The rationale for evaluating masitinib in Alzheimer’s disease is based on the inhibition of c-Kit and Fyn kinase signaling pathways, which in turn inhibit different disease related processes.
There is no approved drug given as an add-on to cholinesterase inhibitors or memantine in mild to moderate forms of Alzheimer’s disease.
Recently, the importance of the blood brain barrier (BBB) in the pathology of Alzheimer Disease has been recognized [Gosselet, 2013]. Furthermore, neuroinflammation is thought to be a major contributor in the pathogenesis of Alzheimer Disease [Skaper, 2014]. Mast cells are found on both sides of the blood brain barrier (BBB) and also have the ability to rapidly cross the BBB, thereby increasing their numbers in response to physiological stimuli [Nautiyal, 2008; Theoharides, 2004; Silverman, 2000]. It is well-established that mast cells play a prominent role in sustaining the inflammatory network of the central nervous system [Hendriksen, 2017], in part by releasing large amounts of proinflammatory mediators and also modulate BBB permeability [Zhuang, 1996].Alzheimer Disease is also associated with the pathological aggregation of amyloid-beta (Aβ) plaques and tau-positive neurofibrillary tangles. Mast cells can be activated by a range of stimuli including amyloid-β peptides [Niederhoffer, 2009], which could contribute to greater BBB permeability, thereby increasing the accumulation of β-amyloid peptides. By restoring the BBB integrity, via inhibition of mast cell activity, masitinib can perhaps reduce the influx of blood-bourne amyloid-β peptides and proinflammatory mediators into the brain. [Clifford, 2007]. Additionally, several lines of evidence implicate Fyn in the pathogenesis of Alzheimer Disease through its dual role in Aβ signaling and Tau phosphorylation [Folch, 2015], making it a potential target.Hence, the therapeutic benefit of masitinib in Alzheimer Disease is expected to be exerted through multiple mechanisms of action: via its inhibition of mast cell activity, which will impact on neuroinflammation and regulation of the BBB permeability; and also, inhibition of the protein kinase Fyn, which is involved in Aβ signaling and Tau phosphorylation.
Summary of Alzheimer Disease 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 mild to moderate Alzheimer Disease Change on ADAS-Cog, which measures the effect on cognition and memory 34 NA Study completed
2/3 Prospective, double-blind, placebo-controlled, parallel groups study Patients with mild to moderate Alzheimer Disease Change on ADCS-ADL, which measures self-care and activities of daily living, and change on ADAS-Cog, which measures the effect on cognition and memory 720 Continuation of the study (based on futility analysis and safety data) Recruitment completed -
Phase 2a proof of concept
Clinical phase 2a proof of concept with masitinib in Alzheimer Disease supported the development of masitinib in Alzheimer Disease. In this phase 2a study, the decline of cognitive function, as assessed by the ADAS-Cog responder rate, was higher in the placebo arm compared with the masitinib treatment arm after 12 and 24 weeks (50% vs. 6% for both; P = 0.040 and P = 0.046, respectively). Also, the proportion of responders showing an improvement in daily living activities, defined as an ADCS-ADL increase ≥ 3, was higher in the masitinib treatment arm compared with the placebo arm at weeks 12 and 24; respectively, 50% versus 0% (P = 0.051) and 60% versus 16.7%, (P = 0.149).
Phase 2/3 studyAB Science launched a phase 2/3 study to assess the safety and efficacy of masitinib in patients with confirmed mild to moderate Alzheimer Disease. In this study, masitinib is given as add-on therapy to cholinesterase inhibitor (donepezil, rivastigmine or galantamine) and/or memantine.The Independent Data Safety Monitoring Committee (IDMC) has, on each occasion, recommended the continuation of this phase 2/3 study based on the analysis of the safety data, and once based on the result of an efficacy futility test.Recruitment was completed with 721 enrolled patients. A pre-planned interim analysis is planned once 75% of the patients have completed the treatment period.
Alzheimer Disease remains a major health problem with between 5 and 10 million people affected in the USA and Europe. Alzheimer Disease is the most common type of dementia among western countries, corresponding to about 60% of cases. Alzheimer Disease is already the sixth leading cause of all deaths in USA and the fifth cause among Americans aged more than 65 years. Worldwide it is thought that there are more than 15 million people affected by Alzheimer’s disease.Masitinib as an adjunct therapy for mild-to-moderate Alzheimer's disease: a randomised, placebo-controlled phase 2 trial.
Piette F, Belmin J, Vincent H, Schmidt N, Pariel S, Verny M, Marquis C, Mely J, Hugonot-Diener L, Kinet JP, Dubreuil P, Moussy A, Hermine O.
Alzheimers Res Ther. 2011 Apr 19;3(2):16. doi: 10.1186/alzrt75.
Masitinib as an adjunct therapy for mild-to-moderate Alzheimer's disease: a randomised, placebo-controlled phase 2 trial.
Folch J, Petrov D, Ettcheto M, Pedrós I, Abad S, Beas-Zarate C, Lazarowski A, Marin M, Olloquequi J, Auladell C, Camins A.
Expert Rev Neurother. 2015 Jun;15(6):587-96. doi: 10.1586/14737175.2015.1045419. Epub 2015 May 11. Review.