Lung function improvement on triple modulators: high-resolution, nationwide data from the Danish Cystic Fibrosis Cohort

Abstract

Background: People living with cystic fibrosis in Denmark had early, universal access to triple modulator treatment with elexacaftor/tezacaftor/ivacaftor. Close monitoring allowed us to assess the impact of treatment on lung function and progression of lung disease in an unselected nationwide cystic fibrosis population from 6 years of age.

Methods: Data were analysed using linear mixed-effect models to assess changes in levels and annual rates of change (slopes) in percent predicted (pp) forced expiratory volume in 1 s (FEV₁), forced vital capacity (FVC) and forced expiratory flow at 25-75% of FVC (ppFEF_25-75%) between the 12 months pre-treatment and treatment periods. Subgroup analyses assessed the impact of elexacaftor/tezacaftor/ivacaftor among those with/without previous modulator treatment, normal/mild/moderate/severe lung disease at treatment initiation, children/adults and birth cohorts.

Results: We included 392 people living with cystic fibrosis with a median (interquartile range) 12 (nine to 15) spirometry measurements per person. The mean (95% CI) improvement in ppFEV₁ was 13.0 (11.3-14.6) 12 months after initiation of elexacaftor/tezacaftor/ivacaftor treatment. The annual rate of change improved from -1.4 (-2.1 - -0.6) ppFEV₁ in the pre-treatment year to 2.7 (1.8-3.5) ppFEV₁ per year during treatment. Similarly, ppFVC increased by 8.0 (7.1-8.9) and FEF_25--75% by 19.5 (17.0-21.9).

Conclusions: Using high-resolution data from a nationwide real-world setting, our study documents the impact of elexacaftor/tezacaftor/ivacaftor on lung function across subgroups based on age, disease severity and treatment history. These findings point towards a new period of consistent lung function improvement among people living with cystic fibrosis on elexacaftor/tezacaftor/ivacaftor.

FIGURE 1

Selection of people with cystic fibrosis (CF) in the Danish Cystic Fibrosis Cohort for analysis. ETI: elexacaftor/tezacaftor/ivacaftor.

FIGURE 2

Graphs based on two-piece linear mixed models adjusted for sex and age including percent predicted forced expiratory volume in 1 s (ppFEV₁) measurements 12 months before and during elexacaftor/tezacaftor/ivacaftor (ETI) treatment (random effects: participant identifier and cystic fibrosis (CF) centre). a) Total population; b) previous cystic fibrosis transmembrane conductance regulator modulator (CFTRm) treatment; c) children/adults; d) severity of lung disease; e) birth cohorts. Data on lung function obtained within 21 days following ETI initiation were excluded from analysis. Estimates and slopes are presented in tables 2 and 3. Children represent people with CF aged 6–17 years at baseline. Severity of lung function is based on ppFEV₁ at ETI initiation.