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

Abstract

IntroductionNeuroinflammation 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.MethodsA 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.ResultsThe 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.ConclusionsMasitinib 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.Trial registrationClinicaltrials.gov NCT00976118

Mast cells: an expanding pathophysiological role from allergy to other disorders

“…Additionally, it has been demonstrated that fibrillar amyloid beta peptides are capable of directly activating the mast cells through a CD47/beta 1-integrin membrane complex to elicit mast cell degranulation, suggesting that mast cells may play a major role in AD pathogenesis (Niederhoffer et al 2009). Very recently, administration of masitinib mesilate, a selective tyrosine kinase inhibitor and efficient in controlling the survival, differentiation, and degranulation of mast cells, has been shown to slow cognitive decline in AD patients in phase II clinical trial (Piette et al 2011).…”

Evidence for mast cells contributing to neuromuscular pathology in an inherited model of ALS

“…Accordingly, clinical trials have shown therapeutic effects of masitinib in cases of mastocytosis, a rare disease characterized by abnormal accumulation and activation of mast cells in various tissues and organs (28). Masitinib was also shown to beneficially modulate CNS function in multiple sclerosis (29), stroke (30), and Alzheimer' s disease (31). In addition, a recent phase III clinical trial with masitinib in ALS has shown promising therapeutic effects in a significant group of patients, slowing the deterioration of motor functions and reducing the decline in quality of life (32).…”

Successes and Failures for Drugs in Late-Stage Development for Alzheimer’s Disease

“…No safety issues related to Cerebrolysin were indicated by the study's conclusion. As a result of the relative success of this trial, Ever Neuro Pharma GmbH is moving forward with a phase 4 study to compare the efficacy of Cerebrolysin to that of donepezil (NCT01822951) set to begin September 2013 (7). …”