Phase 2 study of VX-770 in Cystic Fibrosis Subjectswith G551D

描述(由申请人提供)： 该项目是评估VX-770在囊性纤维化受试者中的安全性和耐受性、药代动力学和药效学的第二阶段研究。VX-770是Vertex制药公司发现的一种小分子，正在开发用于治疗囊性纤维化(CF)，这是高加索人群中最常见的致命遗传性疾病之一，影响着美国约3万名儿童和成年人。尽管辅以营养补充剂、抗生素和粘液剂的治疗，CF患者的预计存活年龄中值为35岁左右。Vertex已经获得FDA的快速通道和孤儿药物称号。 本研究的目的是促进VX-770治疗囊性纤维化患者的发展。囊性纤维化是由囊性纤维化跨膜传导调节基因(CFTR)缺陷引起的。VX-770已被证明在体外通过有缺陷的CFTR氯离子通道在多种细胞系统中增加氯离子的转运，包括来自CF供体呼吸道的人支气管上皮(HBE)细胞。 两项已完成的健康受试者和CF受试者的临床研究表明，VX-770达到了建模表明可能与临床相关的血浆水平。这些研究还表明，VX-770的耐受性一般也很好，只有一个显著的不良事件，那就是皮疹的发生。 目前的第2阶段研究题为“A阶段2a，随机、双盲、安慰剂对照的VX-770研究，以评估G551D型囊性纤维化(CF)受试者的安全性、药代动力学和CFTR活性的生物标记物。”主要终点将是安全性和耐受性。次要终点将是鼻电位差(NPD)、氯化汗、1秒用力呼气量(FEV1)和药代动力学参数。这些参数将评估VX-770在以III、IV和V类CFTR突变为特征的CF受试者中的临床和功能效果。基于非临床数据，这些缺陷的CF患者最有可能对VX-770‘S独特的作用机制产生反应。 VX-770通过增加细支气管壁上皮细胞的CFTR通道氯电导，可能有助于恢复呼吸道分泌物的特性，减少粘液堵塞、感染和炎症的循环。这些作用可能有助于保护肺功能，减少与进行性肺损伤相关的发病率，并延长CF患者的生存时间。

DESCRIPTION (provided by applicant): This project is a Phase 2 study assessing the safety and tolerability, pharmacokinetics, and pharmacodynamics of VX-770 in cystic fibrosis subjects. VX-770, a small molecule discovered by Vertex Pharmaceuticals Incorporated, is being developed for treatment of cystic fibrosis (CF), one of the most common lethal inherited disorders in Caucasian populations that affects approximately 30,000 children and adults in the United States. Despite adjunctive treatments with nutritional supplements, antibiotics, and mucolytics, the median predicted age of survival for a person with CF is in the mid-30s. Vertex has received FDA fast track and orphan drug designation. The intention of this research is to advance the development of VX-770 for the treatment of patients with cystic fibrosis. CF is caused by a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. VX-770 has been shown to increase chloride ion transport through defective CFTR chloride ion channels in vitro in multiple cellular systems, including human bronchial epithelial (HBE) cells from CF donor airways. Two completed clinical studies with healthy subjects and subjects with CF demonstrated that VX-770 reaches plasma levels that modeling suggests could be clinically relevant. These studies also demonstrated that VX-770 was also generally well tolerated with only one significant adverse event, which was the occurrence of a rash. The present Phase 2 study is entitled "A Phase 2a, Randomized, Double-Blind, Placebo- Controlled Study of VX-770 to Evaluate Safety, Pharmacokinetics, and Biomarkers of CFTR Activity in Cystic Fibrosis (CF) Subjects with Genotype G551D." Primary endpoints will be safety and tolerability. Secondary endpoints will be nasal potential difference (NPD), sweat chloride, forced expiratory volume in 1 second (FEV1), and pharmacokinetic parameters. These parameters will assess the clinical and functional effects of VX-770 in CF subjects characterized by Class III, IV and V CFTR mutations. Based on nonclinical data, CF patients with these defects are the most likely to respond to VX-770's unique mechanism of action. By increasing CFTR channel chloride conductance in bronchiolar epithelia, VX-770 may help restore properties of airway secretions and decrease cycles of mucus plugging, infection and inflammation. These effects may help preserve pulmonary function, decrease morbidity associated with progressive lung impairment/damage, and prolong survival in CF patients.