A Study Looking at the Safety, Tolerability and Efficacy of the Combination of the Study Drugs GLPG2451 and GLPG2222 With or Without GLPG2737 in Patients With Cystic Fibrosis. (FALCON)
Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a cAMP-regulated anion channel expressed primarily at the apical plasma membrane of secretory epithelia. Over 2,000 mutations in the CFTR gene have been identified, which are grouped into 6 classes (class I-VI). The F508del mutation is by far the most common CFTR mutation globally, especially in the Caucasian population. Approximately 80 to 90% of CF patients in the United States and Europe have at least one copy of this mutation on one allele, with almost half of them being F508del homozygous (i.e., the mutation is present on both alleles). The F508del mutation impairs CFTR folding, stability at the endoplasmic reticulum and plasma membrane, and chloride gating. Thus, the F508del mutation results in very little to no CFTR protein in the apical membrane. CFTR dysfunction results in increased chloride concentration in sweat and viscous secretions that are difficult to clear, affecting most exocrine glands, notably the pancreas, intestine, liver, and bile duct. However, most morbidity and mortality results from dehydration of the airway surface liquid and impaired airway mucociliary clearance, which leads to cycles of bacterial infection, chronic inflammation, bronchiectasis and progressive decline in pulmonary function.
There is a high unmet medical need for subjects with CF, especially for subjects that are either homozygous or heterozygous for the F508del mutation (with a potentiator non-responsive mutation on the second allele). GLPG2451, GLPG2222 and GLPG2737 are in clinical development for the oral treatment of CF, and represent the components of a potentiator/correctors triple combination therapy targeting the F508del CF subject population.