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

描述（由申请人提供）： 该项目是一项 2 期研究，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。 VX-770 是 Vertex Pharmaceuticals Incorporated 发现的一种小分子，正在开发用于治疗囊性纤维化 (CF)，囊性纤维化是白种人群体中最常见的致命遗传性疾病之一，影响着美国约 30,000 名儿童和成人。尽管采用营养补充剂、抗生素和粘液溶解剂等辅助治疗，CF 患者的预计生存年龄中位数为 30 多岁。 Vertex 已获得 FDA 快速通道和孤儿药指定。 这项研究的目的是推进 VX-770 的开发，用于治疗囊性纤维化患者。 CF 是由囊性纤维化跨膜电导调节因子 (CFTR) 基因缺陷引起的。 VX-770 已被证明可以在体外多个细胞系统（包括来自 CF 供体气道的人支气管上皮 (HBE) 细胞）中增加氯离子通过有缺陷的 CFTR 氯离子通道的转运。 两项针对健康受试者和 CF 受试者的已完成临床研究表明，VX-770 达到了建模表明可能具有临床相关性的血浆水平。这些研究还表明，VX-770 通常也具有良好的耐受性，只有一个显着的不良事件，即出现皮疹。 目前的 2 期研究标题为“VX-770 的 2a 期、随机、双盲、安慰剂对照研究，用于评估基因型 G551D 囊性纤维化 (CF) 受试者的 CFTR 活性的安全性、药代动力学和生物标志物”。 主要终点是安全性和耐受性。 次要终点是鼻电位差 (NPD)、汗液氯化物、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 对具有 III、IV 和 V 类 CFTR 突变特征的 CF 受试者的临床和功能影响。根据非临床数据，具有这些缺陷的 CF 患者最有可能对 VX-770 独特的作用机制产生反应。 通过增加细支气管上皮中的 CFTR 通道氯电导，VX-770 可能有助于恢复气道分泌物的特性，并减少粘液堵塞、感染和炎症的循环。 这些作用可能有助于保护肺功能，降低与进行性肺损伤/损伤相关的发病率，并延长 CF 患者的生存期。

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.