Research
Masitinib as an adjunct therapy for mild-to-moderate Alzheimer's disease: a randomised, placebo-controlled phase 2 trial
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* Corresponding authors: François Piette francois.piette@cfx.aphp.fr - Olivier Hermine ohermine@gmail.com
1 Hôpital Charles Foix, Service de Médecine, Bâtiment Louis Ramond, 7 avenue de la République, 94205 Ivry-Sur-Seine, France
2 Hôpital Charles Foix, Service de Gériatrie et Consultation Mémoire, Hôpital Charles Foix, 7 avenue de la République, 94200 Ivry-sur-Seine, France
3 Université UPMC-Paris 6, 4 place Jussieu, 75005 Paris, France
4 Centre d'investigation libéral des troubles de mémoire, 6 av Alsace-Lorraine, 92500 Rueil Malmaison, France
5 Hôpital Pitié-Salpêtrière et Université UPMC-Paris 6, Centre de Gériatrie, 47-83 bd de l'Hôpital, 75651 Paris, France
6 Centre Hospitalier de la Région de St Omer, Neurologie et Gériatrie, Route des Blendecques, 62505 Helfaut, France
7 Medforma, 108 bis Bd A. Blanqui, 75013 Paris, France
8 Laboratory of Allergy and Immunology, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
9 Inserm U891, Centre de Recherche en Cancérologie de Marseille, Signalisation, Hématopoïèse et Mécanismes de l'Oncogenèse, Centre de Référence des Mastocytoses, 13009 Marseille, France
10 Institut Paoli-Calmettes, 13009 Marseille, France
11 Université de la Méditerranée, 27 Bd Leï roure, 13009 Marseille, France
12 AB Science, 3 avenue George V, 75008 Paris, France
13 Service d'hématologie adulte, centre de référence sur la mastocytose, CNRS UMR 8147, Hôpital Necker Assistance publique hôpitaux de Paris, Université Paris V - René Descartes, 149 rue de Sèvres, 75015 Paris, France
Alzheimer's Research & Therapy 2011, 3:16 doi:10.1186/alzrt75
Published: 19 April 2011Abstract
Introduction
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.
Methods
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.
Results
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.
Conclusions
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.
Trial registration
Clinicaltrials.gov NCT00976118