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

VX-770 在囊性纤维化受试者中与 G551D 的 2 期研究

• 批准号: 7368521
• 负责人: CLAUDIA ORDONEZ
• 金额: $ 35万
• 依托单位: VERTEX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7368521
• 关键词: Phase; study; VX; 770; Cystic

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.

描述（由申请人提供）： 本项目是一项II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），这是高加索人群中最常见的致命遗传性疾病之一，影响了美国约30，000名儿童和成人。尽管使用营养补充剂、抗生素和粘液溶解剂进行了连续治疗，但CF患者的预测生存年龄中位数为30多岁。 Vertex已获得FDA快速通道和孤儿药认定。 这项研究的目的是促进VX-770治疗囊性纤维化患者的发展。 CF是由囊性纤维化跨膜传导调节因子（CFTR）基因缺陷引起的。 VX-770已被证明在多种细胞系统（包括来自CF供体气道的人支气管上皮（HBE）细胞）中通过体外缺陷CFTR氯离子通道增加氯离子转运。 在健康受试者和CF受试者中进行的两项已完成的临床研究表明，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通常耐受性良好，仅发生1起显著不良事件，即皮疹。 本II期研究的标题为“一项在基因型为G551 D的囊性纤维化（CF）受试者中评价VX-770的安全性、药代动力学和CFTR活性生物标志物的IIa期、随机化、双盲、安慰剂对照研究”。“主要终点将是安全性和耐受性。 次要终点是鼻电位差（NPD）、汗液氯化物、1秒用力呼气量（FEV 1）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应。根据非临床数据，具有这些缺陷的CF患者最有可能对VX-770的独特作用机制产生反应。 通过增加细支气管上皮细胞中CFTR通道氯离子传导，VX-770可能有助于恢复气道分泌物的性质，并减少粘液堵塞、感染和炎症的周期。 这些作用可能有助于保护肺功能，降低与进行性肺损伤/损害相关的发病率，并延长CF患者的生存期。