Research Article: Masitinib as an adjunct therapy for mild-to-moderate Alzheimer’s disease: a randomised, placebo-controlled phase 2 trial

Date Published: April 19, 2011

Publisher: BioMed Central

Author(s): François Piette, Joël Belmin, Hélène Vincent, Nicolas Schmidt, Sylvie Pariel, Marc Verny, Caroline Marquis, Jean Mely, Laurence Hugonot-Diener, Jean-Pierre Kinet, Patrice Dubreuil, Alain Moussy, Olivier Hermine.


Neuroinflammation is thought to be important in Alzheimer’s disease pathogenesis. Mast cells are a key component of the inflammatory network and participate in the regulation of the blood-brain barrier’s permeability. Masitinib, a selective oral tyrosine kinase inhibitor, effectively inhibits the survival, migration and activity of mast cells. As the brain is rich in mast cells, the therapeutic potential of masitinib as an adjunct therapy to standard care was investigated.

A randomised, placebo-controlled, phase 2 study was performed in patients with mild-to-moderate Alzheimer’s disease, receiving masitinib as an adjunct to cholinesterase inhibitor and/or memantine. Patients were randomly assigned to receive masitinib (n = 26) (starting dose of 3 or 6 mg/kg/day) or placebo (n = 8), administered twice daily for 24 weeks. The primary endpoint was change from baseline in the Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-Cog) to assess cognitive function and the related patient response rate.

The rate of clinically relevant cognitive decline according to the ADAS-Cog response (increase >4 points) after 12 and 24 weeks was significantly lower with masitinib adjunctive treatment compared with placebo (6% vs. 50% for both time points; P = 0.040 and P = 0.046, respectively). Moreover, whilst the placebo treatment arm showed worsening mean ADAS-Cog, Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory, and Mini-Mental State Examination scores, the masitinib treatment arm reported improvements, with statistical significance between treatment arms at week 12 and/or week 24 (respectively, P = 0.016 and 0.030; P = 0.035 and 0.128; and P = 0.047 and 0.031). The mean treatment effect according to change in ADAS-Cog score relative to baseline at weeks 12 and 24 was 6.8 and 7.6, respectively. Adverse events occurred more frequently with masitinib treatment (65% vs. 38% of patients); however, the majority of events were of mild or moderate intensity and transitory. Severe adverse events occurred at a similar frequency in the masitinib and placebo arms (15% vs. 13% of patients, respectively). Masitinib-associated events included gastrointestinal disorders, oedema, and rash.

Masitinib administered as add-on therapy to standard care during 24 weeks was associated with slower cognitive decline in Alzheimer’s disease, with an acceptable tolerance profile. Masitinib may therefore represent an innovative avenue of treatment in Alzheimer’s disease. This trial provides evidence that may support a larger placebo-controlled investigation. NCT00976118

Partial Text

Alzheimer’s disease (AD) is a degenerative neurological disorder and the most common cause of dementia and disability in the older patient [1]. With no known cure and the currently available treatments only able to temporarily ease symptoms, additional therapeutic options are required. New therapeutic approaches include minimising accumulation of amyloid-beta (Aβ) peptides in the brain [2,3] or targeting cells and signalling pathways implicated in neuronal destruction associated with neuroinflammation [4-6].

Within the limitations inherent to such relatively small phase 2 studies, these results suggest that oral masitinib may have benefits in patients with mild-to-moderate AD. The mechanisms underlying this response remain to be elucidated; as orally administered masitinib is unlikely to have effectively penetrated the BBB, however, we may assume its mechanism of action must be indirect, originating outside the BBB [18]. A growing body of evidence implicates Aβ peptides (predominantly Aβ42) as being the main mediator of neurotoxicity in AD [2,3]. Additionally, neuroinflammation is thought to be a major contributor in the pathogenesis of AD [4-6]. Therapies are therefore being sought that reduce Aβ-peptide accumulation and inflammatory response in the brain [19]. Moreover, it has been proposed that blood-borne Aβ peptides could represent a substantial and chronic source of soluble, exogenous Aβ peptides [11]. Although plasma levels of Aβ peptides are about 20-fold lower than cerebrospinal fluid levels, altered BBB function could provide a route for blood-borne Aβ peptides to contribute to AD. The brain is usually protected from this reservoir of Aβ peptides by the BBB; however, there is evidence suggesting that the BBB is defective in AD patients [11-14], conceivably allowing an influx of exogenous Aβ peptides and other blood-borne compounds. Therapies to maintain or reinforce the integrity of the BBB could thus be beneficial in AD.

Masitinib, an oral tyrosine kinase inhibitor with high activity against mast cells, administered as add-on therapy to standard care during 24 weeks showed promising signs of retarding the rate of cognitive decline of AD with an acceptable tolerance profile. Masitinib may therefore represent an innovative avenue of treatment in AD. Confirmatory phase 3 trials are justified to further investigate the long-term efficacy and safety of masitinib as an adjunct therapy with cholinesterase inhibitors and/or memantine for treatment of mild-to-moderate AD.

Aβ: amyloid beta; AD: Alzheimer’s disease; ADAS-Cog: Alzheimer’s Disease Assessment Scale – cognitive subscale; ADCS-ADL: Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory; AE: adverse event; BBB: blood-brain barrier; CDR: Clinical Dementia Rating; CIBIC-plus: Clinician’s Interview-Based Impression of Change-plus caregiver input; LOCF: last observation carried forward; MMSE: Mini-Mental State Examination; PDGFR: platelet-derived growth factor receptors.

The present study was financially supported by AB Science. Masitinib is under clinical development by the study sponsor, AB Science (Paris, France). The sponsor was involved in the study design; data collection, analysis, and interpretation; and manuscript preparation and submission. AM is an employee and shareholder of the study sponsor. OH and PD are consultants and shareholders of the study sponsor. JB and LH-D have received honorarium from AB Science. No other conflicts of interest have been declared.

FP, JB, HV, NS, SP, MV, CM, and JM participated in the study design, enrolled patients, collected data, and were involved in editing the manuscript. LH-D participated in the patient evaluation forms and editing of the manuscript. J-PK, PD, AM, and OH contributed to the study design and editing of the manuscript. All authors critically reviewed and approved the final manuscript.