Novel Therapeutic Approaches in IPF

描述(由申请人提供)： 特发性间质性肺炎(IIP)是一组病因不明的急性和慢性弥漫性肺病。特发性肺纤维化(IPF)是最致命、最常见的IIP类型。随着我们对IPF认识的发展，IPF显然是一种异质性疾病。我们先前证明，在同一患者体内经常存在多种组织病理学类型的IIP。同样，同一患者可能同时出现炎症和纤维化区域，这取决于所检查的肺部区域。 IPF是没有治愈方法的。目前推荐的治疗方案是抗炎的，并将细胞毒剂(如硫唑嘌呤或环磷酰胺)与泼尼松联合使用(美国胸科学会，2000)。虽然一些患者似乎有反应或稳定，但根据目前的诊断指南，很少有严格的数据清楚地阐明该方案对被诊断为IPF的患者的有效性和安全性。目前治疗方法的失败反映了缺乏对参与IPF发病机制的多个生物学上可信的靶点同时、多方面的攻击，这是合理的。我们假设，利用IPF的特定病理生理特征设计的新疗法将被证明具有最大的治疗成功。考虑到这些概念，我们建议对以前未治疗的IPF患者进行两项新的治疗试验。 IPF的特点是促纤维化的白三烯产生过多，而抗炎PGE2产生不足。我们的第一个方案比较了选择用来纠正这种失衡的两种药物的组合：齐留通+N-乙酰半胱氨酸和标准疗法+硫唑嘌呤+泼尼松。与其他类型的IIP相比，IPF的特征还包括促纤维化细胞因子IL-13受体的表达增加。我们的第二个方案通过利用由人IL-13和突变形式的假单胞菌外毒素组成的雾化融合蛋白来加强这一观察。这种融合蛋白的内化导致细胞凋亡。这两项试验都是随机、双盲、安慰剂对照试验。每个试验的主要终点是死亡或FVC下降10%的组合。次要终点包括安全性、肺功能变化、生活质量、呼吸困难、六分钟步行距离、六分钟步行试验期间饱和度的变化以及呼吸系统住院。这些方案将定义标准治疗的作用，测试靶向联合治疗的疗效，并探索设计和交付IPF治疗剂的新方法的前景。(摘要结束)

DESCRIPTION (provided by applicant): The idiopathic interstitial pneumonias (IIP) represent a group of acute and chronic diffuse parenchymal lung diseases of unknown etiology. Idiopathic pulmonary fibrosis (IPF) is the most deadly and common type of IIP. As our understanding IPF evolves, it is evident that IPF is a heterogeneous disease. We previously demonstrated that multiple histopathologic patterns of IIP often exist within the same patient. Similarly, the same patient may exhibit areas of both inflammation and fibrosis, depending on the area of lung examined. There is no cure for IPF. The current recommended treatment regimen is anti-inflammatory and combines a cytotoxic agent (such as azathioprine or cyclophosphamide) with prednisone (American Thoracic Society, 2000). Although some patients seem to respond or stabilize, there are few rigorous data clearly elucidating the efficacy and safety of this regimen for patients diagnosed with IPF using current diagnostic guidelines. It is plausible that the failure of current therapeutic approaches reflects the lack of a simultaneous, multi-faceted assault against multiple biologically plausible targets involved in the pathogenesis of IPF. We hypothesize that novel therapies engineered to exploit specific pathophysiologic features of IPF will prove to have the greatest therapeutic success. With these concepts in mind, we propose two novel therapeutic trials for previously untreated patients with IPF. IPF is characterized by the overproduction of pro-fibrotic leukotrienes and underproduction of anti-inflammatory PGE2. Our first protocol compares the combination of two agents selected to correct this imbalance: zileuton plus N-acetyl cysteine versus standard therapy with azathioprine plus prednisone. IPF is also characterized by increased expression of the profibrotic cytokine IL-13 receptor compared to other types of IIP. Our second protocol advantages this observation by utilizing an aerosolized fusion protein comprised of human IL-13 and a mutated form of Pseudomonas exotoxin. Internalization of this fusion protein results in cellular apoptosis. Both trials are randomized, double-blind, placebo-controlled trials. The primary endpoint in each trial is a combination of death or decline in FVC of >10%. Secondary endpoints include safety, changes in pulmonary function, quality of life, dyspnea, six-minute walk distance, change in saturation during a six-minute walk test, and respiratory hospitalizations. These protocols will define the role of standard therapy, test the efficacy of targeted combination therapy, and explore the promise of a novel approach to the design and delivery of therapeutic agents for IPF. (End of Abstract)