Masitinib for the treatment of mild to moderate Alzheimer's disease

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Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Nandini Loganathan on 06/05/15 For personal use only.

Masitinib for the treatment of mild to moderate Alzheimer’s disease Expert Rev. Neurother. 15(6), 587–596 (2015)

Jaume Folch1, Dmitry Petrov2, Miren Ettcheto2, Ignacio Pedros1, Sonia Abad2, Carlos Beas-Zarate3,4, Alberto Lazarowski5, Miguel Marin6, Jordi Olloquequi7, Carme Auladell8 and Antoni Camins*2,6 1

Unitat de Bioquimica i Biotecnologıá, Facultat de Medicina i Cie`ncies de la Salut, Universitat Rovira i Virgili, Reus, Tarragona, Spain 2 Unitat de Farmacologia I Farmacogno`sia, Facultat de Farma`cia, Institut de Biomedicina (IBUB), Centros de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas (CIBERNED), Universitat de Barcelona, Barcelona, Spain 3 Departamento de Biologıá Celular y Molecular, C.U.C.B.A., Universidad de Guadalajara and Division de Neurociencias, Sierra Mojada 800, Col. Independencia, Guadalajara, Jalisco 44340, Mexico 4 Centro de Investigacion Biomedica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Jalisco 44340, Mexico 5 Instituto de Investigaciones en Fisiopatologıá y Bioquı´mica Clıńica (INFIBIOC), Facultad de Farmacia y Bioquı´mica, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina 6 Centro de Biotecnologıá, Universidad Nacional de Loja, Av. Pıó Jaramillo Alvarado y Reinaldo Espinosa, La Argelia, Loja, Ecuador 7 Facultad de Ciencias de la Salud, Universidad Autonoma de Chile, Talca, Chile 8 Departament de Biologia Cellular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain *Author for correspondence: [email protected]

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Alzheimer’s disease (AD) is a degenerative neurological disorder that is the most common cause of dementia and disability in older patients. Available treatments are symptomatic in nature and are only sufficient to improve the quality of life of AD patients temporarily. A potential strategy, currently under investigation, is to target cell-signaling pathways associated with neurodegeneration, in order to decrease neuroinflammation, excitotoxicity, and to improve cognitive functions. Current review centers on the role of neuroinflammation and the specific contribution of mast cells to AD pathophysiology. The authors look at masitinib therapy and the evidence presented through preclinical and clinical trials. Dual actions of masitinib as an inhibitor of mast cell–glia axis and a Fyn kinase blocker are discussed in the context of AD pathology. Masitinib is in Phase III clinical trials for the treatment of malignant melanoma, mastocytosis, multiple myeloma, gastrointestinal cancer and pancreatic cancer. It is also in Phase II/III clinical trials for the treatment of multiple sclerosis, rheumatoid arthritis and AD. Additional research is warranted to better investigate the potential effects of masitinib in combination with other drugs employed in AD treatment. KEYWORDS: Alzheimer . inflammation . masitinib . neurodegeneration . tau

Alzheimer’s disease (AD) was first described over a century ago by the physician Alois Alzheimer, but still, more than 100 years later, the root cause of the disorder is not completely understood [1]. Currently available pharmaceutical interventions are inadequate and provide only slight improvement in disease symptoms [2,3]. Recently, researchers have made a number of breakthroughs in uncovering the molecular mechanisms involved in disease pathogenesis [4,5]. This work has led to the identification of novel molecular targets and drug candidates, some of which are already on the market, with others in various stages of preclinical and clinical development. As the loss of cholinergic neurons in the frontal cortex and the hippocampus is a prominent histopathological feature of AD and other dementias, initial drug development efforts have focused on restoring central cholinergic transmission [3]. Acetylcholinesterase inhibitors (AchEIs), which include donepezil, rivastigmine and galantamine, are indicated for the treatment of patients with mild to moderately severe Alzheimer’s dementia [2,3]. These

10.1586/14737175.2015.1045419

compounds increase cholinergic transmission by inhibiting acetylcholinesterase at the synaptic cleft. Unfortunately, the therapeutic efficacy of AchEIs is limited and the available drugs in this class do not halt disease progression [2,3,6]. Cognitive decline in AD patients has also been linked to neuronal damage as a result of excitotoxicity caused by the persistent overactivation of N-methyl-D-aspartate receptor (NMDAR) by the amino acid glutamate [7,8]. Memantine is an NMDAR antagonist administered for the treatment of moderate to severe AD, which reduces glutamatergic excitotoxicity [3,9]. However, just as with AchEIs, the beneficial effects of memantine are modest, and the treatment is largely palliative. Another key aspect of AD pathology which has been the subject of intensive research interest (with vast financial resources invested) concerns elucidating the exact role b-amyloid peptide plays in disease progression. It is well known that AD is neuropathologically characterized by senile (amyloid) plaques, consisting of extracellular deposits of b-amyloid protein, and by the intraneuronal neurofibrillary tangles, comprising

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Folch, Petrov, Ettcheto et al.

filaments of a phosphorylated form of a microtubule-associated protein (tau) [10]. Senile plaques are formed around an extracellular core of amyloid protein surrounded by dystrophic neurites and reactive glial cells. The plaque core is mainly composed of fibrillary aggregates of the b-amyloid peptide, generated by proteolytic cleavage of the transmembrane amyloid precursor protein (APP). The amyloid cascade hypothesis suggests a central role for APP in disease pathogenesis [7,10–13]. The hypothesis relies, in part, on the observation that the early-onset (familial) AD occurs as a result of the excessive accumulation of b-amyloid protein due to genetic mutations in the APP, presenilin 1 and presenilin 2 genes [10–12]. Shortly after its postulation over 20 years ago, the amyloid cascade hypothesis took center stage, and has remained the dominant paradigm in the field of AD research until very recently [12–15]. According to this, the neurotoxic effects of excessive accumulation of both the insoluble b-amyloid peptide and the soluble oligomeric forms of it serve as an initial trigger for AD, subsequently causing synaptic dysfunction, neuronal death and the formation of neurofibrillary tangles [10,11]. Because the hypothesis provided a coherent framework for understanding AD etiology, several disease-modifying therapeutic approaches targeting amyloid peptides had been proposed [13–15]. A number of drug candidates (including bapineuzumab) not only directed at removal of insoluble b-amyloid but also at the prevention of b-amyloid plaque formation have even entered clinical development [2,3,7,13–15]. Likewise, soluble b-amyloid monomers (solanezumab) and oligomers had also been targeted [16]. Unfortunately, all these studies have failed at significantly improving AD symptoms [2]. While the exact causes for the failure of these compounds are unclear, some investigators have suggested that the treatment began too late, at a stage when there was already a significant and presumably permanent neuronal loss [7]. AD has proven to be rather tricky to treat and virtually all of the available, as well as most of the investigational drugs have less-than-desirable therapeutic profiles. The need to generate novel molecules that do not only slow down neurodegeneration but are also capable of halting disease process altogether clearly remains unmet. First and foremost, the pharmaceutical industry and the broader scientific community have to be able to coherently answer the following questions: What are the reasons for the past failures of investigational drugs? Which class/classes of molecules may be more suitable for delaying AD pathology? How can effective neuroprotection be achieved? The answer to these questions is not going to be simple as it is becoming increasingly evident that AD is a multifactorial disorder involving the interactions among various biological and environmental factors [4,5,8,12,17,18]. Metabolic abnormalities, such as peripheral and central insulin and cholesterol signaling deregulation, as well as pathological glial cell activation could all play a role in AD initiation and progression [19,20]. Further studies are necessary to evaluate the genetic influences, which may help to understand the precise mechanisms involved in the AD pathogenesis, thus potentially leading to the development of new arrays of therapeutics with disease-modifying potential. 588

Neuroinflammation: role of mast cell–glia interactions

Because mast cells (MCs) are a component of the immune system which operates at a whole-body level, pathophysiological changes in these cells affect multiple organ systems. In the CNS, MCs’ contribution to neuroinflammatory disease pathology is undisputed, but less is known about their role in neurodegenerative diseases such as AD and Parkinson’s disease [21–23]. MCs are derived from bone marrow and released into the blood stream as immature MC progenitors, with the maturation process completed in peripheral tissues [21,24,25]. MCs serve an important physiological function and are implicated in both the innate and adaptive immunity and inflammation, especially allergic inflammation [24]. Committed MC progenitors found in peripheral blood are characterized by surface receptors: the tyrosine kinase receptor (TKR) c-kit (CD117), CD34, CD13 and Fc"RI, acquired during the beginning of differentiation and maturation [21,25]. The process of differentiation in the bone marrow is under the influence of c-kit ligand (stem cell factor [SCF]) and IL-3. Once the committed MC reaches its target site, the maturation process is completed by the acquisition of its effector phenotype depending on the type of resident tissue [21]. Activated MCs are capable of synthesis and secretion of diverse types of inflammatory mediators, such as TNF-a, serotonin, histamine, heparin and the proteolytic gelatinase enzymes MMP-2 and MMP-9 [21,24–26]. The precise mechanisms whereby MCs contribute to cerebral inflammation are not yet fully described. MCs are localized to surrounding blood vessels and may promote alterations in blood–brain barrier permeability due to their capacity to synthesize and secrete vasoactive agents in an activated state [21,23–27]. An inflammatory cascade likely includes activation of chemoattractants and their receptors, adhesion of blood-borne leukocytes to cerebral vessels and the extravasation of inflammatory cells into the CNS. Blood–brain barrier disruption is known to precede many pathological and clinical symptoms of neurodegenerative diseases [22]. Moreover, MCs modulate the T cell response directly by interaction with the T-cell receptor and via interactions among co-stimulation molecules such as OX40/OX40L and 4-1BB/1-4BBL or indirectly via the production of cytokines [21,23,25,27]. Furthermore, MCs modulate the humoral response by interacting with B cells via CD40/CD40L and certain cytokines, thereby inducing B cell activation and proliferation [21]. MC–microglia interaction is also a possibility. During the inflammatory process, MCs mature quickly resulting in a rapid release of inflammatory mediators. Importantly, MCs contain preformed TNF-a (which activates microglia), and it is the only cell type to do so [21,22,28]. Several recent in vitro studies examined the nature of MC–glia interactions in some detail (reviewed in [26]). For example, it has been shown that MCs can release ATP which favors the activation of P2 purinergic receptors in microglia, provoking the secretion of IL-33. IL-33 can then bind to MC cell membrane receptors, causing the release of IL-6, IL-13 and monocyte chemoattractant protein-1, which in turn may regulate the activity of microglia [25,26]. Thus, the cytokine Expert Rev. Neurother. 15(6), (2015)


Masitinib for the treatment of mild to moderate AD

IL-33 provides a direct link in a modulatory cross-talk between the glia and MCs [26,29,30]. Activated in this manner, MCs alert innate immune system to the site of potential injury, with a resulting increase in vascular permeability that is likely to play a role in neuroinflammation [29,30]. Similarly, MCs release tryptase, which is a natural agonist of protease-activated receptor 2 in glial cells, activation of which can facilitate the release of reactive oxygen species and proinflammatory cytokine mediators such as TNF-a and IL-6 [21,23–27]. Furthermore, MC activation leads to upregulation of P2X purinoceptor 4 receptors on the microglia, resulting in the release of brain-derived neurotrophic factor [21]. Moreover, additional molecules and receptors which may form a part of MC–glia axis include complement component 5a receptor, chemokine (CXC motif) receptor 4/12 (CXCR4 and CXCL12) and toll-like receptors [21,23,25,27]. Taken together, these data suggest that brain MCs which are readily detectable in the hippocampus, leptomeninges, dura mater, choroid plexus, and the parenchyma of the thalamic– hypothalamic region (generally along the blood vessels) may play a prominent role in regulating the neuroinflammatory process [31–33]. Therefore, it seems likely that glial cell (both astrocytes and microglia) regulation is inextricably linked to MC signaling in the CNS [26]. MCs–glia axis appears to play an essential role in neuronal life support and contributes to the blood–brain barrier structure [21,26,32]. The delicate balance between the secretion of neurotrophic/neuroprotective and the potentially toxic pro-inflammatory molecules is at the crux of understanding the mechanism of action (MOA) of drugs which selectively target MCs. The c-kit receptor tyrosine kinase

Initial interest in the c-kit receptor (also called CD117), which belongs to class III of TKR family, was in the field of cancer research (mainly in veterinary therapy), since its activation promoted the growth of gastrointestinal stromal tumors (GIST) [34–36]. Since then, c-kit gain-of-function mutations have been linked to cancer transformation in a variety of human malignancies and tumor progression in several human tissues [34]. This particular TKR is closely related to the colony stimulating factor 1 receptor (CSF1R/M-CSFR), plateletderived growth factor receptor (PDGFR) and fms-related tyrosine kinase 3 receptor [35]. SCF is a natural c-kit agonist promoting receptor dimerization and kinase domain activation [35]. c-kit regulates cell survival, proliferation, differentiation and migration [34–36]. All class III TKRs are characterized by the presence of five extracellular ligand-binding immunologlobulin-like domains and a kinase insert sequence of 70–100 amino acids that resides in the middle of the intracellular tyrosine kinase (TK) domain. In the case of c-kit, the kinase insert region is 80 amino acids long [35]. Extracellular immunoglobulin-like portion of c-kit specifically recognizes SCF and regulates receptor dimerization [37–39]. Once dimerized, c-kit undergoes a conformational change that allows informahealthcare.com

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ATP binding, autophosphorylation and the initiation of a downstream signaling cascade through subsequent binding of adaptor proteins and additional TKRs. Alternatively spliced c-kit isoforms are characterized by the presence or absence of a Gly-Asn-Asn-Lys tetrapeptide sequence within the extracellular juxtamembrane domain, which affects the kinetics and the magnitude of activation of the intracellular kinase. The intracellular portion, responsible for signal transduction, contains proximal and distal kinase domains separated by an interkinase region. The cytoplasmic domain also controls the rate of spontaneous dimerization. Moreover, the receptor can be cleaved and released from the cell membrane, giving rise to a soluble c-kit, consisting of only the extracellular domain [37,39–41]. The SCF/c-kit interaction leads to receptor dimerization and autophosphorylation with the initiation/activation of multiple signal transduction pathways. Among the well-characterized signaling pathways activated by the SCF/c-kit, we highlight the phosphatidylinositol 3-kinase/AKT, SRC kinases, Janus kinases/ STAT, phospholipase-Cg and MAPK. All of these kinases transmit signals generated by c-kit activation to the nucleus through a series of intermediates that also become phosphorylated. Pathophysiological activation of these pathways has also been linked to cancers. For example, aberrant activation of ERK (a member of MAPK family) in cancer cells results in cell cycle dysregulation [35–37,40,41]. Thus, c-kit became a viable target in cancer research, with some successful applications of tyrosine kinase inhibitors (TKIs), which also inhibit c-kit, currently in use in both the veterinary and human medicine [42,43]. TKIs were originally developed in order to inhibit aberrant TK activity which was present in some cancers. Among these compounds, imatinib (Gleevec) was the first non-selective c-kit inhibitor, which also targets platelet-derived growth factor receptor PDGFRa/b, BCR/ABL TK, CSF-1R and spleen TK (SyK). Imatinib is approved for use in human patients for the treatment of Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia, as well as for c-kit positive unresectable and/or malignant gastric GIST [42–44]. Several of the currently used multiselective anticancer drugs, for example, sorafenib and sunitinib, include c-kit in their lists of known targets [34,35,43,45]. Therapeutic potential of masitinib in human disease

Masitinib, also known as AB1010, is a novel oral, potent and selective phenylaminothiazole-type TKI that was originally approved for veterinary therapeutics for the treatment of MC tumors in dogs (FIGURE 1) [46,47]. Masitinib is currently under investigation for the treatment of human tumors [48,49]. However, potential clinical use of masitinib in non-oncological applications is gaining attention due to the involvement of the SCF receptor/c-kit in MC-mediated inflammatory pathogenesis [21,23–26,50,51]. c-kit is the primary target of masitinib, but it also exhibits weak inhibitory activity toward fibroblast growth factor receptor 3, lymphocyte-specific kinase (Lck), Lck/Yesrelated protein (Lyn), focal adhesion kinase and the Fyn TKR. The latter four TKRs belong to the sarcoma (Src) family proteins. Even though masitinib presents with some off-target 589

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H3C

O N H

HN

S

N N


N

N CH3

Figure 1. Chemical structure of masitinib.

binding, it is nevertheless one of the most selective commercially available kinase inhibitors, as determined in a study involving 178 kinase inhibitors against a panel of 300 protein kinases [45]. It goes without saying that the drug’s selectivity and specificity is a crucial determinant of its potential sideeffect profile and a necessary prerequisite for approval by regulatory agencies. In human medicine, masitinib is considered as a treatment for cancer, inflammatory diseases including rheumatoid arthritis (RA), inflammatory bowel disease, asthma and mastocytosis [52–55]. In recent years, a new potential application of masitinib in neurodegenerative diseases, such as AD and multiple sclerosis (MS), has emerged [9,56]. As mentioned previously, a TKI inhibitor (imatinib) is approved for use in human c-kit+ GIST patients (reviewed in [42]). It is thought that most, if not all, GIST tumors harbor a gain-of-function c-kit mutation, which results in persistent c-kit activation. Because masitinib is a much more selective c-kit inhibitor, its potential for the treatment of GIST is clear. The results of a Phase II clinical trial demonstrated favorable outcomes with 7.5 mg/kg/day of oral masitinib as a first-line treatment in imatinib-naive GIST patients [57]. Encouraging results were obtained in another Phase II trial in imatinib-resistant/intolerant GIST patients. Masitinib at a dose of 12 mg/kg/day significantly improved prognostic outcomes in these patients and exhibited a better safety profile when compared to sunitinib (another TKI). An international Phase III trial of masitinib in imatinib-resistant patients with advanced GIST is currently in progress [58]. The safety and efficacy of masitinib has also been evaluated for the treatment of pancreatic cancer [49]. In this type of cancer, increased MC activity in the tumor microenvironment has been linked to poor prognosis. In an international Phase III trial, 9 mg/kg/day masitinib was administered in combination with gemcitabine. Results indicate a significant survival advantage in patients who received a combination therapy, compared to gemcitabine alone. In the case of RA, it has been shown that MCs can represent over 5% of the synovial cell population [51]. At such high levels of MCs, treatment with first-line drug methotrexate (MTX) and 590

even with TNF-a antagonists may not be fully effective [51,59]. Tebib et al. published a study, the purpose of which was to evaluate the efficacy of two different concentrations of masitinib in patients with active RA who had shown an inadequate response to treatment with a single disease-modifying antirheumatic drug (DMARD), which includes either MTX or anti-TNF-a [60]. In this Phase II clinical trial, masitinib was administered orally to 43 patients at initial randomized dosing levels of 3 and 6 mg/kg/day over a 12-week period. The results were generally positive. Drug tolerance was acceptable and the adverse events (AEs) were mild or moderate (skin rashes, edema, nausea and diarrhea). A 24-week follow-up clinical trial to evaluate the efficacy of masitinib when compared to DMARD treatment is currently recruiting patients. It aims to compare the safety and clinical efficacy of masitinib (ClinicalTrials.gov Identifier: [61]) at 3 and 6 mg/kg/day doses to MTX (alone or in combination with any other DMARDs) in patients with active RA and showing inadequate response to MTX or other DMARDs. The management of asthma with masitinib with the aim to control the symptoms and optimizing respiratory function is another area of interest with this drug. Humbert et al. reported positive Phase II results when oral masitinib was administered to patients with severe corticosteroid-dependent asthma (ClinicalTrials.gov Identifier: [62]). This was a 16-week, randomized, dose-ranging (3, 4.5 and 6 mg/kg/day), parallel-group, placebo-controlled study in 44 patients poorly controlled despite using optimal treatment for asthma [63]. The goals were to assess the pharmacokinetic profile of masitinib, its clinical and biological safety parameters, the decrease in corticosteroid therapy and the asthma control improvement (symptomatic scores, rescue medication intake, respiratory function). The study demonstrated that masitinib was safe in patients with severe asthma, and it also improved daily symptoms of asthma and reduced asthma exacerbations. Deregulated activity of the SCF/c-kit pathway in mastocytosis (either cutaneous or systemic) is related to gain-of-function mutations in the c-kit receptor. In a relatively small Phase II trial in patients with systemic or cutaneous mastocytosis, Paul et al. demonstrated a significant improvement in disease symptoms following a 12-week treatment with 3 or 6 mg/kg/day of masitinib [64]. With reference to MS, Vermersch et al. have recently published a multicenter, randomized, placebo-controlled proof-ofconcept trial with masitinib that was administered orally at 3–6 mg/kg/day for 12 months in MS patients. The aims of the study were to evaluate the clinical benefits of masitinib in the treatment of primary progressive MS or relapse-free secondary progressive MS. In this study, 35 patients were randomized to receive masitinib (n = 27) or placebo (n = 8) [53]. Masitinib was relatively well tolerated with the most common AEs being asthenia, rash, nausea, edema and diarrhea. The authors reported that masitinib has a positive effect on MS-related impairment for primary progressive MS and relapse-free secondary progressive MS patients [56]. The clinical trials, in general, demonstrate a favorable sideeffect profile for masitinib in comparison to other TKIs, Expert Rev. Neurother. 15(6), (2015)



especially regarding cardiotoxicity and genotoxicity. For example, it has been reported that imatinib showed cardiotoxic effects due to its strong inhibition of the Abelson kinase (ABL). However, masitinib is only a weak inhibitor of cardiotoxic kinases (ABL, vascular endothelial growth factor receptor), which results in an improved cardiovascular safety profile, compared to other TKIs. Besides, preclinical studies have also shown that masitinib is not genotoxic [65]. Pharmacodynamics, pharmacokinetics & metabolism of masitinib

The pharmacokinetics of masitinib was studied in both animal models and humans. In Beagle dogs, the dose of 12.5 mg/kg/day was the maximum tolerated. Following oral administration of masitinib, the drug was rapidly absorbed, reaching a peak plasma concentration of 895 ng/ml, with a time-to-peak concentration (Tmax) of approximately 2 h. The mean area under the curve for plasma concentration was 5.70 (±1.93) mg h/ml. The mean elimination half-life (T½) was 3.24 (±0.42) h. It was established that masitinib is approximately 90% bound to plasma proteins. Masitinib is metabolized predominantly by N-dealkylation. Elimination is principally in the bile and gastrointestinal tract. In vitro studies in human liver microsomes indicate that masitinib inhibits the activity of cytochrome P450 isozymes CYP2C9, 2D6, 3A4 and 3A5. Thus, it should be administrated with caution with the simultaneous use of drugs metabolized by CYP450 isoforms [47,48,63]. Masitinib had been evaluated in clinical trials in humans in four doses: 3, 6, 9 and the maximum recommended dose of 12 mg/kg/ day. Soria et al. [66] reported on the human pharmacokinetic profile of free base masitinib and its active metabolite, AB3280. The gastrointestinal absorption of masitinib was rapid with a mean Tmax of between 1.7 and 4.7 h. Plasma samples collected on days 1 and 14 of treatment were analyzed by dose cohort (in mg/day) and by weight-adjusted dose levels (in mg/kg/day). The mean plasma half-life averaged 24 h (range 18–36 h) without accumulation after 14 days of orally administered masitinib. Apparent clearance and volume of distribution of masitinib were high. Following repeated administration of masitinib, pharmacokinetics data demonstrated that on the last day of evaluation, Cmax had shown higher levels in the concentration of masitinib compared with AB3280. In feces, the principal characterized metabolites with suspected biological activity were the N-desmethyl derivative and a sulfate conjugate of mono-hydroxy-masitinib. The main conclusion in human studies with masitinib was that it is safe to administer to patients with asthma, cancer, AD and other diseases. Therapeutic potential of masitinib in AD

Previously reported studies support the hypothesis that MCs play a role in the pathogenesis of AD. Niederhoffer et al. demonstrated that b-amyloid 1-42 was able to promote MC degranulation through the interaction with CD47/b1-integrin membrane complex [52]. Maslinska et al. detected a significant accumulation of reactive astrocytes around the senile plaques in informahealthcare.com

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postmortem AD brains. Intriguingly, reactive astrocytes and tryptase-containing MC infiltrates were also detected in brain areas where the amyloid deposits were not present, suggesting a generalized, rather than the senile plaque-specific inflammatory response [53]. These studies demonstrate a likely involvement of a MCs–glia axis in AD development. Results of a randomized, placebo-controlled Phase II study in AD patients receiving masitinib for 24 weeks as an adjunct therapy were recently reported [9]. An addition of 3–6 mg/kg/day of masitinib to the existing treatment with either anticholinesterase inhibitors (donepezil, rivastigmine or galantamine) and/or memantine significantly improved the Alzheimer’s Disease Assessment Scale-cognitive subscale test response. The Alzheimer’s Disease Assessment Scale-cognitive subscale was designed to assess changes associated with cognitive impairment in clinical trials of AD. The Alzheimer’s Disease Assessment Scale-cognitive subscale includes a battery of 11 tests that measure memory capacity, level of understanding, temporal and spatial orientation, and alterations in spontaneous language. This scale is used because of its high sensitivity in detecting small degrees of change in cognitive function. In this study, the addition of masitinib improved cognition, when compared to placebo. Likewise, masitinib improved the score on the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL); however, this improvement was no longer statistically significant at week 24. The outcomes of the Mini Mental State Examination test, which is commonly used for identification of cognitive impairments, were also improved after treatment with masitinib. Mini Mental State Examination is useful to clinicians as it aids in dementia diagnosis and allows an accurate assessment of its progression and severity. The main conclusions of this modest study were that oral masitinib is beneficial in patients with mild to moderate AD, and that additional studies are necessary to confirm the efficacy of this drug for AD treatment. That study was the first to demonstrate the clinical efficacy of a combination therapy with a drug that targets the MCs selectively [9]. Interestingly, apart from targeting SCF/c-kit signaling on MCs, which likely results in an inhibition of the MCs–glia interactions, masitinib may have another MOA useful in AD treatment. Even though we previously mentioned that masitinib is highly selective in c-kit inhibition, it nevertheless is also capable of blocking the Src family TK Fyn in a nanomolar range. As Fyn is involved in tau phosphorylation, it is possible that masitinib could prevent neurofibrillary tangles formation. Shirazi and Wood [54] demonstrated that Fyn is upregulated in AD brain, and recent studies showed the presence of a Fyn phosphorylation site in the paired helical filament tau, supporting a role for Fyn in AD neuropathogenesis [55,67]. Fyn is also involved in the cell cycle regulation, and inappropriate neuronal cell cycle reentry has been previously linked to AD and other neurodegenerative diseases [68–70]. Seward et al. reported that b-amyloid promotes tau phosphorylation and cell cycle re-entry by activating Fyn and two additional kinases (PKA and CaMKII) [71]. Thus, it 591

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Inhibition of neuroinflammatory process

modulation. On the other hand, cognitive improvements as a result of Fyn inhibition are likely independent of b-amyloid production and amyloid plaque load (FIGURE 2).

Glial cells

Safety & tolerability Mast cells Masitinib Neuron


Modulation of NMDA receptor Inhibition of tau phosphorilation Inhibition of FYN kinase Memory process improvement Prevention of cell cycle re-entry

Figure 2. A proposed mechanism whereby masitinib could exert neuroprotective effects in Alzheimer’s disease. Fyn signaling in the hippocampus is, at least partially, regulating cell cycle re-entry, neuronal memory process, tau phosphorylation and also NMDA receptor. In addition, masitinib inhibits c-kit receptor in mast cells and, thus, the neuroinflammatory process. NMDA: N-methyl-D-aspartate.

has been hypothesized that phosphorylated tau could trigger a neurodegenerative cascade that may require the expression of cell cycle markers in neurons prior to the apoptotic process [72]. Moreover, Fyn overexpression was found to accelerate synapse loss and the onset of cognitive impairment in the J9 (APPswe/ Ind) transgenic AD mouse model, while blocking the Fyn expression rescued synapse loss in the J20 (APPswe/Ind) mice [73]. While tau is generally considered an axonal protein, it does have a role in dendrites as well. It has been demonstrated that tau participates in postsynaptic targeting of Fyn to dendrites [74,75]. In dendrites, Fyn is capable of interacting with NMDARs, thus regulating receptor activity [75,76]. Fyn kinase could potentiate the neurotoxic process through the phosphorylation of the subunit 2 (NR2B) of the NMDAR in dendritic spines, which results in stabilization of the receptor’s interaction with the postsynaptic density protein PSD-95. The exact mechanism of b-amyloid–Fyn–NMDAR interaction likely involves the formation of the complex between b-amyloid, the prion protein (PrP) and the metabotropic glutamate receptor 5 (mGluR5) which can promote Fyn activation, ultimately leading to the phosphorylation of the NR2B [74,77–79]. As mentioned above, tau plays a key role by delivering Fyn postsynaptically. Interestingly, saracatinib (AZD0530) is another Src inhibitor which targets Fyn. Although at the beginning this drug was developed for cancer treatment, it was abandoned for this application. Currently, two clinical trials are testing the efficacy of saracatinib in early-stage AD ([80] and [81]). In conclusion, treatment with masitinib may provide dual benefits in AD pathology. On the one hand, inhibition of the MCs may reduce neuroinflammation via MCs–glia axis 592

Based on a number of clinical trials which considered masitinib for a range of conditions including AD, the drug appears to be well tolerated in humans. The majority of the reported AEs are consistent with other TKIs already on the market. Edema, rash, nausea, vomiting and diarrhea are commonly reported. However, these AEs are generally transient and are well within the acceptable thresholds for this type of symptomatic treatment. For an in-depth overview of the safety data reported in clinical trials, refer to Table 4 of [9] and Table 3 of [47]. Conclusion

The failure of AD treatments developed over the last few decades demonstrates the complexity of the underlying pathology. Masitinib may not be an all-encompassing cure-all for the disease, but depending on the results of ongoing and future clinical trials, it may have a chance to become an additional disease-modifying compound in the arsenal of physicians aiming to treat this debilitating condition. Expert commentary

Over the years, a number of hypotheses have been proposed to explain the etiology of AD. These include: the amyloid cascade hypothesis, mitochondrial hypothesis, dendritic hypothesis, cell cycle hypothesis and the inflammatory hypothesis [4–8,10–12,18]. If one assumes that each of these hypotheses describes an aspect of the disease, then the complexity of AD pathology becomes apparent. With the involvement of multiple signaling cascades, it is quite possible that a single drug could target more than one pathway. Such is the case of masitinib, a TKI which is capable of both c-kit and Fyn inhibition. Increased production of b-amyloid may be a cause of earlyonset familial AD. As a result of genetic mutations affecting APP processing, excessive accumulation of b-amyloid in the brain leads to senile plaque formation. Since amyloid plaques are clearly not a component of a healthy brain, immune system response is eventually activated. Indeed, previous studies have shown the existence of an inflammatory process around the plaques, which presumably favors the loss of neighboring neurons [82–87]. Activated microglia would then be responsible for the generalized cerebral inflammation. If that was the principal driving force behind AD-related neurodegeneration, then the NSAID treatment would be expected to be of great benefit to AD sufferers. This is not entirely the case, however, as only Expert Rev. Neurother. 15(6), (2015)



Drug Profile

some studies have demonstrated significant improvement in AD symptoms upon NSAID treatment, with others reporting a total lack of benefit in response to these compounds [88,89]. The clinical trial with masitinib demonstrates that MC inhibition contributes to cognitive improvements in AD patients. A similarly acting compound dasatinib, a dual Src/ Abl inhibitor (which also inhibits c-kit), used for treatment of chronic myeloid leukemia, improves cognition in APP/PS1 mouse model of AD by attenuating microgliosis and TNF-a [90]. Targeting the MCs–glia axis alone may provide some therapeutic benefits in AD treatment. However, we believe that an additional blockade of Fyn trafficking to the dendrites by masitinib and/or saracatinib will allow for further improvements in AD symptomatology. Previous studies suggest that cognitive deficits at early stages of AD are linked to synaptic loss/dysfunction and are not necessarily directly related to neuronal loss [91]. In fact, dendritic spine abnormalities may be an early sign of future neurodegeneration. Masitinib, in combination with other diseasemodifying compounds, could be instrumental in improving dendritic integrity in memory circuits. Dual actions of masitinib may lead to improvements in synaptic plasticity in patients with mild to moderate forms of AD.

decreasing pathologically elevated levels of the neurotransmitter glutamate. Both groups of drugs are indicated for the treatment of patients with moderate AD. However, it is clear that none of these approved drugs really represent a cure for the disease; their effect is only palliative and their efficacy decreases with time. In addition, some undesirable side effects, including vomiting and diarrhea, have been reported. More effective therapeutics, capable of slowing down the deterioration of cognitive functions in demented patients, are sorely needed. In this article, we have focused on clinical studies demonstrating the efficacy of blocking both the c-kit receptor in MCs (neuroinflammation) and Fyn (synaptic loss, tau, NMDAR) for the better management of AD. Masitinib may provide relief while not necessarily directly targeting the amyloid pathology. Masitinib’s MOA is to reduce both the neuroinflammation and dendritic spine defects present in AD. Results of the clinical trials involving masitinib demonstrate an improved safety profile over other TKIs in its class. Masitinib may also have applications in the treatment of other diseases such as cancer, RA, MS, asthma and mastocytosis. Masitinib’s selectivity and the fact that the drug was already approved in a number of Phase III clinical trials gives us a cautious hope that masitinib may be able to overcome the existing regulatory hurdles in its approval for AD treatment in the foreseeable future.

Five-year view

Financial & competing interests disclosure

There are currently just four drugs on the market approved for the treatment of AD. These belong to two groups: AChEIs and NMDAR antagonists. AChEIs include donepezil, rivastigmine and galantamine. The MOA of AChEIs is to increase cholinergic transmission by inhibiting acetylcholinesterase at the synaptic cleft. NMDAR antagonist memantine reduces excitotoxicity by

The authors were supported by the project ‘ Prometeo’ from SENESCYT (Government of Ecuador). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Key issues .

Current drug treatment of Alzheimer’s disease (AD) is symptomatic and is only effective for a short period of time.

.

The amyloid cascade hypothesis has dominated AD research field for decades. However, drugs targeting this pathway have failed.

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Immune response plays a role in AD. Until recently, glial cells were considered to be the main culprits.

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Mast cells contribute to neuroinflammation and participate in the regulation of the blood–brain barrier’s permeability.

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Masitinib, a selective tyrosine kinase inhibitor, blocks c-kit on mast cells.

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Masitinib also targets Fyn kinase, which may contribute to neuroprotection in AD.

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Phase II/III clinical trials with masitinib for the treatment of multiple disorders have been largely successful.

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Masitinib has potential applications in AD treatment.

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