FROM NEW ENGLAND JOURNAL OF MEDICINE
A new drug that targets the cystic fibrosis transmembrane conductance regulator protein could significantly improve lung function and other symptoms in patients with cystic fibrosis.
In a phase 3 double-blind, placebo controlled crossover trial, researchers examined the effects of tezacaftor – a cystic fibrosis transmembrane conductance regulator (CFTR) corrector – in combination with the CFTR potentiator ivacaftor, compared with ivacaftor alone or placebo.
According to a paper published in the New England Journal of Medicine, the 248 patients enrolled in the study were heterozygous for the Phe508del mutation, which is associated with more severe disease, but also had a CFTR mutation that meant they still had some residual CFTR function.
“The addition of the CFTR corrector tezacaftor was hypothesized to enhance clinical benefit in patients with these mutations by increasing overall CFTR function,” wrote Dr. Steven M. Rowe of the division of pulmonary, allergy, and critical care medicine at the University of Alabama at Birmingham, and his coauthors. “This combination treatment is particularly important for restoring activity to those carrying two copies of the Phe508del CFTR mutation, as shown for the approved corrector-potentiator combination lumacaftor-ivacaftor, and may provide benefit to patients with other CFTR mutations.”
After two 8-week treatment periods in which patients were randomized to two of the three regimens, separated by an 8-week washout period, researchers saw significant improvements in predicted forced expiratory volume in 1 second (FEV1), both with tezacaftor-ivacaftor and ivacaftor alone, compared with placebo (N Engl J Med. 2017 Nov 23;377:2024-35. doi: 10.1056/NEJMoa1709847 ).
From baseline to the average of week 4 and 8, the combination of tezacaftor-ivacaftor was associated with a 6.8-percentage-point absolute change, and there was a 4.7-percentage-point improvement with ivacaftor alone compared with placebo. The difference between the tezacaftor-ivacaftor combination and ivacaftor monotherapy was also statistically significant in favor of the combination treatment.
Researchers also saw significant improvements in the secondary endpoint of absolute change in the Cystic Fibrosis Questionnaire–Revised score; the combination treatment was associated with an 11.1 point improvement compared with placebo, and monotherapy achieved a 9.7-point improvement. In the combination therapy group, 65% of patients achieved a clinically important difference of 4 points or greater, compared with 58% of patients in the monotherapy group and 33% of patients in the placebo group.
“These findings confirm the benefits of potentiator therapy in patients with residual CFTR function mutations and the added benefit conferred by corrector-potentiator combination therapy in this population,” the authors wrote.
The investigators also saw a lower rate of pulmonary exacerbations in the combined therapy group, but this did not reach statistical significance.
The rate of adverse events was similar across all three groups. Most were considered mild or moderate in severity and were largely clinical manifestations of cystic fibrosis.
Vertex Pharmaceuticals, which manufactures tezacaftor and ivacaftor, funded the study. Twelve of the thirteen authors reported receiving various kinds of support from Vertex, including personal fees, grant support, and nonfinancial support. Several authors reported ties to other industry sources.
