Masitinib in Neurology

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	Piette, 2011
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 study

AB 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.

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Masitinib in Neurology

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