Masitinib, a c-kit/PDGF receptor tyrosine kinase inhibitor, improves disease control in severe corticosteroid-dependent asthmatics
Masitinib, a c-kit/PDGF receptor tyrosine kinase inhibitor, improves disease control in severe corticosteroid-dependent asthmatics
复制标题
DOI：
10.1111/j.1398-9995.2009.02122.x
复制
发表时间：
2009-08-01
期刊：
影响因子：
12.4
通讯作者：
Chanez, P.
中科院分区：
文献类型：
--
作者：
Humbert, M.;de Blay, F.;Chanez, P.
背景：Masitinib是一种酪氨酸激酶抑制剂，靶向干细胞因子受体（c-kit）和血小板衍生生长因子受体（PDGF），它们分别在肥大细胞和支气管结构细胞等多种细胞类型上表达。我们假设c-kit和PDGF受体抑制可能会减少支气管炎症并干扰气道重塑，这是严重哮喘的重要特征。目的：主要终点是口服皮质类固醇治疗16周后与基线相比的百分比变化。哮喘控制（哮喘控制问卷）、加重率、肺功能检查、抢救用药需求和安全性的变化是次要终点。方法：对44例重度皮质类固醇依赖性哮喘患者进行了为期16周的随机、剂量范围（3、4.5和6 mg/kg/天）的安慰剂对照研究，这些患者尽管有最佳的哮喘管理，但控制仍很差。结果：在治疗16周时，马西替尼和安慰剂组的口服皮质类固醇减少量相当（马西替尼组和安慰剂组的中位减少量分别为-78%和-57%）。尽管有类似的减少，但与安慰剂组相比，马西替尼组的哮喘控制问卷评分明显更好，在第16周减少了0.99个单位（P < 0.001），而安慰剂组则减少了0.43个单位。马西替尼治疗与更多的暂时性皮疹和水肿相关。结论：马西替尼是一种c-kit和pdgf受体酪氨酸激酶抑制剂，可能是治疗皮质类固醇依赖性哮喘的一种创新途径。这些初步结果为进一步的重症哮喘长期临床研究提供了依据（ClinicalTrials.gov标识符：NCT00842270）。
Background: Masitinib is a tyrosine kinase inhibitor targeting stem cell factor receptor (c-kit) and platelet-derived growth factor (PDGF) receptor, which are expressed on several cell types including mast cells and bronchial structural cells, respectively. We hypothesized that c-kit and PDGF receptor inhibition may decrease bronchial inflammation and interfere with airway remodeling, which are crucial features of severe asthma.Objectives: The primary endpoint was the percent change from baseline in oral corticosteroids after 16 weeks of treatment. Change in asthma control (asthma control questionnaire), exacerbation rate, pulmonary function tests, rescue medication requirement and safety were secondary endpoints.Methods: A 16-week randomized, dose-ranging (3, 4.5, and 6 mg/kg/day), placebo-controlled study was undertaken in 44 patients with severe corticosteroid-dependent asthma who remained poorly controlled despite optimal asthma management.Results: At 16 weeks of treatment, a comparable reduction in oral corticosteroids was achieved with masitinib and placebo (median reduction of -78% and -57% in the masitinib and placebo arms, respectively). Despite this similar reduction, the Asthma Control Questionnaire score was significantly better in the masitinib arm as compared to placebo with a reduction by 0.99 unit at week 16 (P < 0.001) vs 0.43 unit in the placebo arm. Masitinib therapy was associated with more transient skin rash and edema.Conclusions: Masitinib, a c-kit and PDGF-receptor tyrosine kinase inhibitor, may represent an innovative avenue of treatment in corticosteroid-dependent asthma. These preliminary results warrant further long-term clinical studies in severe asthma (ClinicalTrials.gov Identifier: NCT00842270).