CPX (ORAL, MULTIDOSE) IN ADULTS W/ MILD TO MODERATELY SEVERE CYSTIC F

囊性纤维化蛋白修复疗法是一种利用药物恢复突变CFTR分子功能的新方法。有可能激活囊性纤维化细胞中驻留的突变CFTR的概念得到了最近的一些实验的支持。CPX(8-环戊基-1，3-二丙基黄嘌呤)是蛋白质修复类药物中的一种新药，可直接与CFTR相互作用。CPX是由美国国立卫生研究院(NIH)国家糖尿病、消化和肾脏疾病研究所(NIDDK)的医学博士哈维·波拉德和博士肯尼斯·雅各布森发现的。CPX是一种A1受体拮抗剂，它与突变的DF508突变CFTR的第一个NBF结构域(NBF-1)的508位核苷酸结合折叠(NBF)具有高度的特异性和亲和力，并激活原代培养的囊性纤维化人呼吸道细胞的外向氯电流。CPX是临床开发中唯一一种可促进囊性纤维化(CFTR)转运和刺激氯离子转运的囊性纤维化药物。本研究的主要目的是评价口服多次递增剂量的环磷酰胺治疗成人轻中度囊性纤维化患者的安全性和有效性。疗效测定将以鼻上皮跨膜电位差和氯化汗作为替代标志物。第二个目标是评估多次口服递增剂量的环磷酰胺在轻、中度囊性纤维化成人患者中的药代动力学。

Cystic fibrosis protein-repair therapy is a new approach using drugs to restore function to mutant CFTR molecules. The concept that it might be possible to activate mutant CFTR resident in the cystic fibrosis cell has received support from a number of recent experiments. CPX (8-cyclopentyl-1,3-dipropylxanthine) is a new drug in the class of protein-repair therapeutics which may interact directly with the CFTR. CPX was discovered by Harvey Pollard, MD,PhD and Kenneth Jacobson, PhD, of the National Institute of Diabetes and Digestive and Kidney Disorders (NIDDK) of the National Institutes of Health (NIH). CPX, an A1-receptor antagonist, binds with high specificity and affinity to the nucleotide-binding fold (NBF) at position 508 in the first NBF domain (NBF-1) of DF508 mutant CFTR, and activates outward chloride currents from primary cultures of cystic fibrosis human airway cells. CPX is the only cystic fibrosis (CF) drug in clinical development that promotes CFTR trafficking and stimulates chloride ion transport. The primary objective of this study is to evaluate the safety and efficacy of multiple ascending oral doses of CPX administered to adult patients with mild to moderately severe cystic fibrosis. Efficacy determination will use nasal epithelial transmembrane potential difference and sweat chloride as surrogate markers. The secondary objective is to evaluate the pharmacokinetics of multiple oral ascending doses of CPX administered to adult patients with mild and moderate cystic fibrosis.