This study is a randomized, double-blind, placebo-controlled, ascending oral multi-dose study to evalute the efficacy, safety and pharmacokinetics of CPX administered to adult patients with mild to moderately severe cystic fibrosis. Background: Cystic fibrosis is the most common, fatal, autosomal recessive disease affecting the Caucasian population. Overall, 5% of Caucasians in the U.S. are heterogeneous for the defective gene responsible for the disease. The disease is caused by a single defective gene or chromosome 7 that codes for a 1480 amino acid protein called cystic fibrosis transmembrane conductance regulator (CFTR). The manifestations of cystic fibrosis in the lung are characterized by thickened airway secretions that result from abnormal epithelial ion transport. The abnormality is based on defective cyclic adenosine monophosphate (cAMP) mediated C1- secretion, which is exacerbated by physiological Na absorption. Paracellular water transport in the airways is consequently reduced. The resulting lumenal dehydration is thought to be a damage signal to the pulmonary epithelium causing increased mucin secretion. The water-poor lumen environment itself induces an abnormal physical state of the secreted mucins. The result is a vicious cycle leading to an accumulation of excessively viscous mucus, bacterial overgowth, and infection. Although cystic fibrosis is a whole body disease manifesting in different ways throughout the body as a dysfunction of epithelial cells, it is usually the lung problem that is principally responsible for the invariably fatal outcome of this illness, for which there is currently no cure. 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 rreceived support from a number of recent experiments. CPX is a new drug in the class of protein-repair therapeutics which may interact directly with the CFTR. CPX was discoverd by Harvey Pollard, M.D., Ph.D. and Kenneth Jacobson, Ph.D. 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 F508 mutant CFTR, and activates outward chloride currents from primary cultures of cystic fibrosis human airway cells. Pollard et al hypothesized that compounds which bind to CFTR close to the F508 location should induce a local conformation that could affect protein-lipid interactions, and might affect the trafficking, maturation and overall level of CFTR in the cell. CPX is the only cystic fibrosis drug in clinical development that promotes CFTR trafficking and stimulates chloride ion transport.
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