Combination Therapy in Patients with Cystic Fibrosis Targets Underlying Dysfunction
Louis M. Bell, MD reviewing Wainwright CE et al. N Engl J Med 2015 May 17.
Two new drugs used in combination improved pulmonary function, reduced pulmonary exacerbations, and increased body-mass index in a selected cohort of patients older than 12 years.
Mutations in the gene for cystic fibrosis transmembrane conductance regulator (CFTR) protein, an anion channel in the epithelial cell membrane, result in abnormal amounts or activity of the protein. About 45% of patients with cystic fibrosis are homozygous for the most common CFTR mutation (Phe508del); median survival among this cohort in the U.S. is 37 years.
Researchers studied a combination of a recently approved drug, ivacaftor, and an investigational drug, lumacaftor, in two phase III, randomized, double-blind, placebo-controlled, industry-sponsored trials. Lumacaftor, a CFTR corrector, increases the amount of protein on the epithelial cell surface in vitro. Ivacaftor, a CFTR potentiator, increases the percentage of time the anion channels are open.
In the two trials, 1108 patients homozygous for the most common CFTR mutation received placebo or the combination of oral lumacaftor (600 or 400 mg per day) plus ivacaftor (250 mg every 12 hours) for 24 weeks. About one quarter of the patients were 12 to 17 years of age.
The mean absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline to 24 weeks (the primary outcome) was significantly greater in the study-drug groups than the placebo group, ranging from 2.6 to 4.0 percentage points higher. The rate of pulmonary exacerbations was significantly lower in the study-drug groups, by 30% to 39%. In addition, mean body-mass index increased in the study-drug groups. The rate of serious adverse events was similar between the study-drug groups (17% to 23%) and the placebo group (29%). Overall, 93% of the study-drug cohort finished the trial.
Citation(s):
Wainwright CE et al. Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med 2015 May 17; [e-pub].
