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.
Extensive medicinal chemistry and iterative structure-activity relationship (SAR) studies to evaluate potency, selectivity, and pharmacokinetic properties resulted in the identification of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770, 48, ivacaftor), an investigational drug candidate approved by the FDA for the treatment of CF patients 6 years of age and older carrying the G551D mutation.
We conclude that G551D- and G1349D-CFTR have distinct pharmacological profiles and speculate that drug therapy for CF is likely to be mutation-specific.
After several successful clinical trials the potentiator, ivacaftor, is now licenced for use in adults and children (>six years), with CF bearing the class III G551D mutation and FDA licence was recently expanded to include 8 additional class III mutations.
Two cystic fibrosis transmembrane conductance regulator mutations have different effects on both pulmonary phenotype and regulation of outwardly rectified chloride currents.
In people with CF bearing G551D or R117H mutations, ivacaftor did not change the average ASL pH; however reductions in sweat Cl- concentration correlated with elevations of ASL pH.
STRIVE, a double-blind, placebo-controlled randomized trial, evaluated ivacaftor (150 mg) in CF patients aged 12+ with the G551D-CFTR mutation for 48 weeks.
Cystic fibrosis patients bearing both the common missense mutation Gly----Asp at codon 551 and the delta F508 mutation are clinically indistinguishable from delta F508 homozygotes, except for decreased risk of meconium ileus.
Ivacaftor was approved by the Food and Drug Administration (FDA) to be taken orally at a dose of 150 mg twice a day in G551DCF patients older than 6 years.
Changes of CFTR functional measurements and clinical improvements in cystic fibrosis patients with non p.Gly551Asp gating mutations treated with ivacaftor.
The G551D mutation is reasonably common in the CF patient population and produces a CFTR protein that localizes normally to the plasma membrane, but fails to open in response to cellular cues.