1. Tezacaftor-Ivacaftor significantly improves lung function and reduces the frequency of pulmonary exacerbations in cystic fibrosis (CF) patients homozygous for the Phe508 deletion (Phe508del).
2. Unlike safety outcomes reported for lumacaftor-invacaftor, there was no increased incidence of adverse respiratory events in the tezacaftor-ivacaftor group compared to placebo.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Cystic fibrosis is caused by a loss of function in the cystic fibrosis transmembrane conductance regulator (CFTR) protein which results in thick mucus secretions negatively impacting various organ systems. For individuals with CF found to be homozygous for the Phe508del mutation, previous studies (TRAFFIC and TRANSPORT trials) demonstrated a modest improvement in lung function and reduction in pulmonary exacerbations with the combination of CFTR modulators lumacaftor-invacaftor. However, the treatment was associated with a relatively high frequency of adverse respiratory events and drug discontinuation compared to placebo. This trial reports the efficacy and safety of a next generation CFTR modulator, tezacaftor-ivacaftor, in CF patients homozygous for the Phe508del mutation. The efficacy of tezacaftor-invacaftor in improving lung function and reducing the rate of pulmonary exacerbations was significantly greater than placebo. Furthermore, tezacaftor-invacaftor was not associated with increased adverse respiratory events compared to placebo and there were no discontinuations of the trial due to respiratory events. The improved safety profile and similar efficacy of tezacaftor-invacaftor, compared to lumacaftor-invacaftor, provides a new treatment options for CF patients homozygous for Phe508del.
This was a phase 3, randomized, double-blind, multicenter, placebo-controlled, parallel-group trial based on CF patients homozygous for the Phe508del age 12 and older. Preclinical studies have also demonstrated the efficacy of tezacaftor-invacaftor in patients heterozygous for Phe508del and G551D mutations. However, there are still numerous CF mutations for which effective treatment does not exist.
In-Depth [randomized controlled trial]: This international phase 3 trial randomized 510 patients age 12 and older with confirmed homozygous Phen508del CF to tezacaftor-ivacaftor (n = 251) or placebo (n = 258) in a 1:1 ratio. Randomization was stratified by age, sex, and percentage of predicted FEV1. The primary trial endpoint was efficacy of treatment compared to placebo, based on absolute percentage change in the predicted forced expiratory volume in one second (FEV1) through week 24 of the trial. FEV1 values were obtained at baseline, day 15, and weeks 4,8,12,16, and 24 during treatment. Secondary endpoints included additional markers of efficacy such as relative change in percentage of predicted FEV1, number of pulmonary exacerbations, change in body mass index (BMI), and change in the respiratory domain score on the CF questionnaire-revised (CFQ-R), and an assessment of safety.
Among the 510 patients randomized, 504 were included in the efficacy analysis (248 and 256 in the tezacaftor-ivacaftor and placebo groups, respectively), which was based on results at week 24 of the trial. The mean difference in absolute percentage change of predicted FEV1 from baseline was 4.0 percentage points higher in the tezacaftor-ivacaftor group compared to the placebo group (3.4 with tezacaftor-ivacaftor, -0.6 with placebo; 95% confidence interval [CI], 3.1 to 4.8; p < 0.001). The relative difference in the change of predicted FEV1 was 6.8 percentage points higher in the treatment group (95% CI, 5.3 to 8.3; P<0.001). Treatment with tezacaftor-ivacaftor was also associated with a significant reduction in the annualized rate of pulmonary exacerbations (0.64 tezacaftor-ivacaftor vs. 0.99 placebo events/year; rate ratio, 0.65; 95% CI, 0.48 to 0.88; p = 0.005). Treated patients reported a higher CFQ-R respiratory domain score than those in the placebo group (mean difference, 5.1 points; 95% CI, 3.2 to 7.0). There was no significant difference in the change in BMI between trial groups. The most common adverse events occurred more frequently in the placebo group compared to tezacaftor-ivacaftor, including prespecified respiratory events of special interest (13.1% vs. 15.9% with placebo). The safety profile of tezacaftor-ivacaftor was consistent across all trial subgroups.
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