Elexacaftor-tezacaftor-ivacaftor is efficacious in treating cystic fibrosis patients with Phe508del-minimal function genotypes

1. In this multicenter, phase 3 study of cystic fibrosis patients who were previously unresponsive to modulator regimens, triple-combination therapy with the next-generation corrector elexacaftor resulted in a significantly improved percentage of predicted forced expiratory volume in one second versus placebo after 4 and 24 weeks.

2. Improvements were also shown in sweat chloride concentration, the rate of pulmonary exacerbations, and the respiratory domain score on the Cystic Fibrosis Questionnaire-Revised.

Evidence Rating Level: 1 (Excellent)

Study Rundown: While hundreds of disease-causing mutations have been discovered for cystic fibrosis, the vast majority of people with the condition exhibit a three base deletion resulting in the absence of a phenylalanine residue (Phe508del) that is essential for intracellular trafficking and native stability of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Concurrent use of CFTR correctors and potentiators has been effective for patients possessing two Phe508del alleles but markedly less so for those with only one copy in addition to a second mutation that is unresponsive to modulator therapy (minimal function). This phase 3 study tested the effects of the triple-combination regimen of the next-generation corrector elexacaftor, the corrector tezacaftor, and the potentiator ivacaftor on CF patients with a single Phe508del allele, finding that treatment with these modulators resulted in significant improvements in forced expiratory volume in one second (FEV₁) versus placebo. Patients who received elexacaftor-tezacaftor-ivacaftor treatment also reported dramatic improvements in quality of life based on the Cystic Fibrosis Questionnaire-Revised (CFQ-R) and had a significantly lower risk of pulmonary exacerbations. Adverse events were generally mild to moderate and rarely resulted in discontinuation of treatment. This study was bolstered by high adherence as well as stratification by numerous factors including percentage of predicted FEV₁, age, and sex. Additionally, findings were supported by a concurrent trial that demonstrated similar outcomes in homozygous Phe508del patients. While this modulation is likely to benefit a large portion of the CF population, further research is still necessary to extend these benefits to younger children or those with less common responsive mutations.

Click here to read the study in NEJM

Relevant Reading: Unravelling the Regions of Mutant F508del-CFTR More Susceptible to the Action of Four Cystic Fibrosis Correctors

In-Depth [randomized controlled trial]: This multicenter, double-blind, phase 3 trial randomly assigned 403 patients 12 years of age or older with cystic fibrosis and Phe508del-minimal function genotypes to receive either placebo or a combination of elexacaftor (200 mg once daily), tezacaftor (100 mg once daily), and ivacaftor (150 mg every 12 hours) for 24 weeks. Patients treated with the CFTR modulators performed significantly better relative to placebo based on absolute change in percentage of predicted FEV₁ after 4 weeks (mean treatment difference, 13.8; 95% CI, 12.1 to 15.4) and 24 weeks (mean treatment difference, 14.3; 95% CI, 12.7 to 15.8). Treatment with elexacaftor-tezacaftor-ivacaftor also resulted in a significantly lower rate of pulmonary exacerbations (rate ratio, 0.37; 95% CI, 0.25 to 0.55) and lower concentration of sweat chloride in mmol/liter (mean treatment difference, −41.8; 95% CI, −44.4 to −39.3). Finally, patients treated with the modulators experienced superior nutritional outcomes (mean treatment difference in BMI, 1.04; 95% CI; 0.85 to 1.23) and self-rated higher on the CFQ-R respiratory domain (mean treatment difference, 20.2; 95% CI, 17.5 to 23.0). 9.4% of patients in the exacaftor-tezacaftor-ivacaftor group experienced a severe adverse event compared to 7% in the placebo group, but roughly 90% of adverse events in both groups were of mild to moderate severity. In the modulator-treated group, the most common adverse event was infective pulmonary exacerbation (21.8%), followed closely by sputum increase (19.8%), headache (17.3%), and cough (16.8%).

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