Cystic fibrosis (CF), the most common lethal genetic disease in Caucasians, is 
characterized by chronic bacterial lung infection and excessive inflammation, 
which lead to progressive loss of lung function and premature death. Although 
ivacaftor (VX-770) alone and ivacaftor in combination with lumacaftor (VX-809) 
improve lung function in CF patients with the Gly551Asp and del508Phe mutations, 
respectively, the effects of these drugs on the function of human CF macrophages 
are unknown. Thus studies were conducted to examine the effects of lumacaftor 
alone and lumacaftor in combination with ivacaftor (i.e., ORKAMBI) on the 
ability of human CF ( del508Phe/ del508Phe) monocyte-derived macrophages (MDMs) 
to phagocytose and kill Pseudomonas aeruginosa. Lumacaftor alone restored the 
ability of CF MDMs to phagocytose and kill P. aeruginosa to levels observed in 
MDMs obtained from non-CF (WT-CFTR) donors. This effect contrasts with the 
partial (~15%) correction of del508Phe Cl- secretion of airway epithelial cells 
by lumacaftor. Ivacaftor reduced the ability of lumacaftor to stimulate 
phagocytosis and killing of P. aeruginosa. Lumacaftor had no effect on P. 
aeruginosa-stimulated cytokine secretion by CF MDMs. Ivacaftor (5 µM) alone and 
ivacaftor in combination with lumacaftor reduced secretion of several 
proinflammatory cytokines. The clinical efficacy of ORKAMBI may be related in 
part to the ability of lumacaftor to stimulate phagocytosis and killing of P. 
aeruginosa by macrophages.