The combination of ivacaftor and the investigational agent tezacaftor is effective and has a favorable safety profile in patients with cystic fibrosis homozygous for the Phe508del CFTR mutation, according to results of a 24-week randomized, placebo-controlled clinical trial.

Patients receiving the tezacaftor-ivacaftor combination experienced a mean increase in their percentage of predicted forced expiratory volume in 1 second of 3.4 percentage points, compared with a mean decrease of 0.6 percentage points in the control group, at the end of the trial (P less than .001). The pulmonary exacerbation rate was 35% lower in the tezacaftor-ivacaftor treatment arm than in the placebo arm (P = .005), data show. These results were recently published in the New England Journal of Medicine (2017 Nov 3. doi: 10.1056/NEJMoa1709846 ).

Most adverse events were mild to moderate, and serious adverse events occurred less frequently in the tezacaftor-ivacaftor treatment arm, compared with the placebo arm, reported Jennifer L. Taylor-Cousar, MD, of National Jewish Health, Denver, and her coinvestigators.

Ivacaftor was the first approved modulator of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and tezacaftor is an investigational CFTR corrector. Tezacaftor demonstrated efficacy in a previous phase 2 trial that included patients either homozygous for the Phe508del mutation or heterozygous for the Phe508del and G551D mutations, Dr. Taylor-Cousar and her coauthors said in their report.

The combination of ivacaftor and another CFTR corrector, lumacaftor, is already available to treat cystic fibrosis patients who are homozygous for the Phe508del CFTR mutation. However, not all patients can receive lumacaftor-ivacaftor because of its respiratory side effects, and lumacaftor is associated with “prohibitive drug-drug interactions” due to considerable cytochrome P-450-3A induction, according to the study authors.

“The improved safety profile of combination therapy with tezacaftor-ivacaftor, as compared with currently available therapy, in addition to its effect on multiple efficacy end points, supports its use in a broad range of patients with cystic fibrosis,” wrote Dr. Taylor-Cousar and her colleagues.

The phase 3 trial included 509 cystic fibrosis patients at least 12 years of age who were homozygous for the CFTR Phe508del mutation. The mean percentage of predicted forced expiratory volume in 1 second of the patients was 60.0, at baseline.

All patients were randomized to combination therapy with tezacaftor 100 mg once daily and ivacaftor 150 mg twice daily, or matched placebo. A total of 475 patients completed the 24-week trial. The incidence of serious adverse events was just 12.4% of tezacaftor-ivacaftor–treated patients, compared with 18.2% in the placebo arm, and no serious adverse events led to treatment discontinuation.

“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,” Dr. Taylor-Cousar and her colleagues wrote.

Treatments that modulate CFTR are promising, according to the authors, because they treat the underlying cause of cystic fibrosis.

Vertex Pharmaceuticals supported the study. Dr. Taylor-Cousar reported personal fees from Vertex Pharmaceuticals outside of the submitted work. Full disclosures for all authors were published on the New England Journal of Medicine website .


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