Real-life impact of genotype and severity of lung disease on efficacy of elexacaftor-tezacaftor-ivacaftor in people with cystic fibrosis.

Background: Elexacaftor-tezacaftor-ivacaftor (ETI) therapy has shown improvement in lung function, BMI and reduction in pulmonary exacerbations but the impact of genotype and severity of lung disease on heterogeneity of ETI efficacy in real life is not known.

Methods: This is a prospective observational study. Clinical data at baseline and at one-year of therapy were compared for the total cohort and for two subgroups; genotype [homozygous vs. heterozygous for F508del], and severity of lung disease at ETI initiation (ppFEV1 <80 % vs. ≥80 %).

Results: Among the total cohort of 115 pwCF, median age of 23 (17, 32) years, 66 (58 %) were homozygous, 76 (66 %) had ppFEV1 <80 %. Significant increases in mean ppFEV1 and mean BMI and decrease in MRSA and Pa culture positivity on sputum/throat swab were observed at one year of ETI therapy in the total cohort, and in groups based on either genotype or disease severity (p < 0.05 in all). Comparing one-year prior to one-year on ETI therapy, significant improvements were noted in pulmonary exacerbations, hospital admissions, antibiotic courses, number of pwCF receiving daily chest therapy, dornase alfa and hypertonic saline in the total cohort and in all four subgroups (p < 0.05 for all). Though improvements were not dependent on genotype, we noted larger mean differences in ppFEV1, BMI, pulmonary exacerbations and antibiotic use in the group with more severe lung disease (ppFEV1 <80 %) after one year of ETI therapy.

Conclusions: ETI therapy improved clinical outcomes in pwCF which were impacted by severity of underlying lung disease.