Hôpital Charles Foix, Service de Médecine, Bâtiment Louis Ramond, 7 avenue de la République, 94205 Ivry-Sur-Seine, France.
Alzheimers Res Ther. 2011 Apr 19;3(2):16. doi: 10.1186/alzrt75.
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.
Clinicaltrials.gov NCT00976118.
神经炎症被认为在阿尔茨海默病发病机制中起重要作用。肥大细胞是炎症网络的关键组成部分，参与调节血脑屏障的通透性。马替尼是一种选择性口服酪氨酸激酶抑制剂，能有效抑制肥大细胞的存活、迁移和活性。由于大脑富含肥大细胞，因此研究了马替尼作为标准治疗辅助疗法的治疗潜力。
对轻度至中度阿尔茨海默病患者进行了一项随机、安慰剂对照、2 期研究，患者接受马替尼作为乙酰胆碱酯酶抑制剂和/或美金刚的辅助治疗。患者被随机分配接受马替尼（n = 26）（起始剂量为 3 或 6 mg/kg/天）或安慰剂（n = 8），每日两次给药，持续 24 周。主要终点是根据阿尔茨海默病评估量表-认知子量表（ADAS-Cog）评估认知功能的变化，以及相关的患者应答率。
与安慰剂辅助治疗相比，马替尼辅助治疗后 12 周和 24 周时根据 ADAS-Cog 应答（增加>4 分）的临床相关认知下降率显著降低（分别为 6%和 50%；P = 0.040 和 P = 0.046）。此外，虽然安慰剂治疗组 ADAS-Cog、阿尔茨海默病合作研究日常生活活动量表和简易精神状态检查的平均评分恶化，但马替尼治疗组报告了改善，在第 12 周和/或第 24 周时治疗组之间具有统计学意义（分别为 P = 0.016 和 0.030；P = 0.035 和 0.128；和 P = 0.047 和 0.031）。根据第 12 周和 24 周时 ADAS-Cog 评分相对于基线的变化，治疗的平均效果分别为 6.8 和 7.6。马替尼治疗的不良事件发生率更高（分别为 65%和 38%的患者）；然而，大多数事件为轻度或中度且短暂。马替尼和安慰剂组严重不良事件的发生率相似（分别为 15%和 13%的患者）。马替尼相关的不良事件包括胃肠道疾病、水肿和皮疹。
在 24 周内作为标准治疗的辅助治疗给予马替尼与阿尔茨海默病的认知衰退速度较慢有关，具有可接受的耐受谱。因此，马替尼可能是阿尔茨海默病治疗的一种创新途径。这项试验提供的证据可能支持更大规模的安慰剂对照研究。
Clinicaltrials.gov NCT00976118。
