New Combination Therapy for Cystic Fibrosis

A new combination of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, tezacaftor and ivacaftor, proved effective and safe in treating patients 12 years or older with CFTR gene mutations, according to 2 trials recently published in the New England Journal of Medicine. Tezacaftor, an investigational CFTR corrector, increases CFTR cell surface expression. Ivacaftor, an FDA-approved CFTR potentiator, enhances CFTR channel function.

In the first trial, 509 patients homozygous for the most common CFTR mutation that impairs CFTR cell surface expression, Phe508del, were randomly assigned to receive a combination of tezacaftor plus ivacaftor (100 mg of tezacaftor once daily and 150 mg of ivacaftor twice daily) or placebo. Throughout the 24-week trial, the tezacaftor-ivacaftor group had significant improvement in the primary outcome measure of lung function compared with the placebo group (3.4 vs −0.6 percentage points mean absolute change from baseline in forced expiratory volume in 1 second [FEV1]). Pulmonary exacerbation was 35% lower in the tezacaftor-ivacaftor group than in the placebo group.

The rate of serious adverse events was lower with tezacaftor-ivacaftor than with placebo (12.4% vs 18.2%).

The companion trial randomly assigned 248 patients heterozygous for the Phe508del deletion and a residual-function CFTR gene mutation to receive tezacaftor-ivacaftor therapy, ivacaftor monotherapy, or placebo. The residual-function mutation, present in approximately 5% of patients with cystic fibrosis, causes slower disease progression than does the Phe508del CFTR mutation.

Relative to the placebo group, the tezacaftor-ivacaftor group and ivacaftor-alone group had significant improvement in the primary outcome measure of lung function (6.8 vs 4.7 percentage points absolute change in the percentage of predicted FEV1). The difference in the primary outcome measure between tezacaftor-ivacaftor and ivacaftor alone significantly favored tezacaftor-ivacaftor. Rates of adverse events, which were mild or moderate, were similar in both intervention groups.

According to the authors, tezacaftor-ivacaftor therapy could offer an alternative to lumacaftor-ivacaftor therapy, which can cause adverse respiratory effects.