Effects of Chronic Masitinib Treatment in APPswe/PSEN1dE9 Transgenic Mice Modeling Alzheimer’s Disease

Li, Tengfei; Martin, Elodie; Abada, Yah-Sé; Boucher, Céline; Cès, Aurélia; Youssef, Ihsen; Fenaux, Grégory; Forand, Yona; Legrand, André; Nachiket, Nadkarni; Dhénain, Marc; Hermine, Olivier; Dubreuil, Patrice; Delarasse, Cécile; Delatour, Benoı̂t

doi:10.3233/jad-200466

Cited by 36 publications

(25 citation statements)

References 19 publications

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“…33 Indeed, neuroprotection associated with masitinib's therapeutic targeting of these cells in other neurodegenerative disorders suggests that reduction of neuronal damage in MS is also probable. 13,15 In conclusion, masitinib at 4.5 mg/kg/d can benefit patients by slowing EDSS-based disability worsening; however, validation of these findings via a confirmatory phase 3 study will be necessary, in part because neuroimaging data were not collected during the current study and also due to an absence of signal on secondary end points. Overall, study AB07002…”

Section: Discussionmentioning

confidence: 89%

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Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis

Vermersch

Brieva-Ruiz

Fox

et al. 2022

Neurol Neuroimmunol Neuroinflamm

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Background and ObjectivesMasitinib is a selective tyrosine kinase inhibitor, targeting innate immune cells (mast cells and microglia) that are involved in the pathophysiology of progressive multiple sclerosis (MS). Study AB07002 assessed oral masitinib in patients with progressive MS who were progressing but not clinically active.MethodsThis randomized, double-blind, 2 parallel-group, placebo-controlled trial assessing 2 dose levels of masitinib vs equivalent placebo was conducted at 116 hospital clinics and specialized MS centers in 20 countries. Randomization (2:1) with minimization was performed centrally using an automated system. Patients, physicians, and outcome assessors remained masked to treatment group allocation. Patients with primary progressive MS (PPMS) or nonactive secondary progressive MS (nSPMS) without relapse for ≥2 years, aged 18–75 years, with baseline Expanded Disability Status Scale (EDSS) 2.0–6.0, and regardless of time from onset were treated for 96 weeks. The primary end point was overall EDSS change from baseline using repeated measures (generalized estimating equation, timeframe W12–W96, measured every 12 weeks), with positive values indicating increased clinical deterioration. Efficacy and safety were assessed in all randomly assigned and treated patients.ResultsA total of 611 patients were randomized; 301 in the masitinib 4.5 mg/kg/d parallel group and 310 in the uptitrated masitinib 6.0 mg/kg/d parallel group. Masitinib (4.5 mg/kg/d) (n = 199) showed significant benefit over placebo (n = 101) according to the primary end point, 0.001 vs 0.098, respectively, with a between-group difference of −0.097 (97% CI −0.192 to −0.002); p = 0.0256. Safety was consistent with masitinib's known profile (diarrhea, nausea, rash, and hematologic events), with no elevated risk of infection. Efficacy results from the independent uptitrated masitinib 6.0 mg/kg/d parallel group were inconclusive, and no new safety signal was observed.DiscussionMasitinib (4.5 mg/kg/d) can benefit people with PPMS and nSPMS. A confirmatory phase 3 study will be initiated to substantiate these data.Trial Registration InformationThe first participant was randomized to study AB07002 on August 25, 2011. The trial was registered with the European Clinical Trials Database (#EudraCT 2010-021219-17) on July 1, 2011 (clinicaltrialsregister.eu/ctr-search/trial/2010-021219-17/ES) and with ClinicalTrials.gov (#NCT01433497) on September 14, 2011 (clinicaltrials.gov/ct2/show/NCT01433497).Classification of EvidenceThis study provides Class II evidence that masitinib 4.5 mg/kg/d decreased progression of disability, measured by the EDSS, in adults with PPMS or patients with nSPMS (with no exacerbations in the last 2 years).

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis

Vermersch

Brieva-Ruiz

Fox

et al. 2022

Neurol Neuroimmunol Neuroinflamm

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“…Although masitinib treatment did not affect the amyloid plaque load nor the IL-1β concentration in older animals treated daily for almost 2 months, it promoted the recovery of spatial learning performance. Additionally, the decrease of synaptophysin immunoreactivity detected in APP/PS1dE9 mice was completely recovered to normal values after MC depletion or treatment with masitinib, suggesting an additional synaptic protection [115]. Thanks to the AB Bioscience support, the anti-inflammatory effect of masitinib is currently considered for the treatment of diverse diseases in which inflammation is either the cause or the consequence of the condition, including cancer, rheumatoid arthritis, inflammatory bowel disease, asthma, multiple sclerosis, ALS, and AD [116][117][118][119].…”

Section: Alzheimer's Diseasementioning

confidence: 87%

“…A recent study evaluated the chronic effect of masitinib on APP/PS1dE9 mice progression [115]. Although masitinib treatment did not affect the amyloid plaque load nor the IL-1β concentration in older animals treated daily for almost 2 months, it promoted the recovery of spatial learning performance.…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Mast Cell and Astrocyte Hemichannels and Their Role in Alzheimer’s Disease, ALS, and Harmful Stress Conditions

Harcha

Garcés

Arredondo

et al. 2021

IJMS

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Considered relevant during allergy responses, numerous observations have also identified mast cells (MCs) as critical effectors during the progression and modulation of several neuroinflammatory conditions, including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). MC granules contain a plethora of constituents, including growth factors, cytokines, chemokines, and mitogen factors. The release of these bioactive substances from MCs occurs through distinct pathways that are initiated by the activation of specific plasma membrane receptors/channels. Here, we focus on hemichannels (HCs) formed by connexins (Cxs) and pannexins (Panxs) proteins, and we described their contribution to MC degranulation in AD, ALS, and harmful stress conditions. Cx/Panx HCs are also expressed by astrocytes and are likely involved in the release of critical toxic amounts of soluble factors—such as glutamate, adenosine triphosphate (ATP), complement component 3 derivate C3a, tumor necrosis factor (TNFα, apoliprotein E (ApoE), and certain miRNAs—known to play a role in the pathogenesis of AD, ALS, and other neurodegenerative disorders. We propose that blocking HCs on MCs and glial cells offers a promising novel strategy for ameliorating the progression of neurodegenerative diseases by reducing the release of cytokines and other pro-inflammatory compounds.

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“…Masitinib (Masivet, Kinavet, AB1010) is a selective tyrosine kinase inhibitor (TKI) known to modulate neuroinflammation mediated by mast cells. Li et al, in 2020 demonstrated that chronic treatment with masitinib could restore spatial learning and synaptic density in the hippocampus in the APP/PS1 mouse model of amyloidosis [ 115 ]. AB Science® conducted a phase 2b/3 clinical trial from 2012 to 2020 to compare masitinib 4.5 or 6 mg/kg/day dosing with placebo in 721 confirmed mild to moderate AD subjects receiving a ChE inhibitor and/or memantine in twenty one mostly European countries.…”

Section: Therapeutic Strategies For the Development Of Anti-ad Drugsmentioning

confidence: 99%

Recent advances on drug development and emerging therapeutic agents for Alzheimer’s disease

2021

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Graphic Abstract Alzheimer’s disease (AD) is a neurodegenerative old age disease that is complex, multifactorial, unalterable, and progressive in nature. The currently approved therapy includes cholinesterase inhibitors, NMDA-receptor antagonists and their combination therapy provides only temporary symptomatic relief. Sincere efforts have been made by the researchers globally to identify new targets, discover, and develop novel therapeutic agents for the treatment of AD. This brief review article is intended to cover the recent advances in drug development and emerging therapeutic agents for AD acting at different targets. The article is compiled using various scientific online databases and by referring to clinicaltrials.gov and ALZFORUM (alzforum.org) websites. The upcoming therapies act on one or more targets including amyloids (secretases, Aβ 42 production, amyloid deposition, and immunotherapy), tau proteins (tau phosphorylation/aggregation and immunotherapy) and neuroinflammation in addition to other miscellaneous targets. Despite the tremendous improvement in our understanding of the underlying pathophysiology of AD, only aducanumab was approved by FDA for the treatment of AD in 18 years i.e., since 2003. Hence, it is concluded that novel therapeutic strategies are required to discover and develop therapeutic agents to fight against the century old AD.

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Effects of Chronic Masitinib Treatment in APPswe/PSEN1dE9 Transgenic Mice Modeling Alzheimer’s Disease

Cited by 36 publications

References 19 publications

Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis

Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis

Mast Cell and Astrocyte Hemichannels and Their Role in Alzheimer’s Disease, ALS, and Harmful Stress Conditions

Recent advances on drug development and emerging therapeutic agents for Alzheimer’s disease

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