Clinical Pearls & Morning Reports

By Carla Rothaus

Published November 22, 2017


Cystic fibrosis is caused by a reduced quantity or function of cystic fibrosis transmembrane conductance regulator (CFTR) protein, owing to mutations in CFTR. CFTR modulators are a family of new compounds that target specific defects caused by mutations in CFTR and thereby treat the underlying cause of cystic fibrosis. Taylor-Cousar et al. conducted a phase 3 trial that evaluated the efficacy and safety of tezacaftor in combination with ivacaftor in patients with cystic fibrosis who were homozygous for the Phe508del mutation. Tezacaftor is an investigational CFTR corrector that, in combination with ivacaftor, has shown efficacy in preclinical studies. Read the latest NEJM Original Article.

Clinical Pearls

Q: What is the most common CFTR mutation in patients with cystic fibrosis?

A: Phe508del is the most prevalent CFTR mutation worldwide; approximately 46% of patients with cystic fibrosis in the United States are homozygous for this allele, as are 49% of those in Canada and 40% of those in Europe. The Phe508del mutation leads to greatly reduced CFTR protein activity owing to impaired processing and trafficking of CFTR to the epithelial-cell surface, as well as impaired function of the small quantity of the protein that is produced and trafficked to epithelial membranes.

Q: What are limitations of the CFTR modulators currently in use for cystic fibrosis?

A: Ivacaftor and the combination therapy lumacaftor–ivacaftor have both been associated with a rate of progressive decline in lung function that is lower than the rate observed among untreated, matched, control registry patients, which shows that effective CFTR modulators may modify the course of disease. However, not all patients who are homozygous for the Phe508del mutation can receive lumacaftor–ivacaftor because of its respiratory side-effect profile. In addition, strong cytochrome P-450-3A induction by lumacaftor causes prohibitive drug–drug interactions in some patients and limits the use of lumacaftor–ivacaftor in patients with ivacaftor-responsive mutations. Therefore, new CFTR modulator treatments for the population of patients who are homozygous for the Phe508del mutation are needed.

Morning Report Questions

Q: Is the combination of tezacaftor and ivacaftor effective for patients with cystic fibrosis who are homozygous for the Phe508del CFTR mutation?

A: In the study by Taylor-Cousar et al., the primary end point was the absolute change in the percentage of the predicted FEV1 from baseline through week 24. The use of tezacaftor–ivacaftor led to a significantly greater absolute change from baseline in the percentage of the predicted FEV1 than placebo (least-squares mean difference through 24 weeks, 4.0 percentage points; 95% confidence interval [CI], 3.1 to 4.8; P<0.001). Tezacaftor–ivacaftor also resulted in a significantly lower rate of pulmonary exacerbations than placebo. No significant difference in the body-mass index (BMI) at week 24 was noted between the tezacaftor–ivacaftor group and the placebo group.

Q: How did rates of adverse events in the tezacaftor-ivacaftor group compare to those in the placebo group in the trial by Taylor-Cousar et al.?

A: The rate of respiratory adverse events was not higher in the tezacaftor–ivacaftor group than in the placebo group, which shows that the safety profile for tezacaftor–ivacaftor is better than that reported for lumacaftor–ivacaftor. Serious adverse events were reported in 31 patients (12.4%) in the tezacaftor–ivacaftor group and in 47 (18.2%) in the placebo group. Seven patients (2.8%) in the tezacaftor–ivacaftor group and eight (3.1%) in the placebo group discontinued the trial regimen owing to adverse events. The commonly observed adverse events occurred more frequently in the placebo group than in the tezacaftor–ivacaftor group.

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