Long-term reductions in inflammation in people with cystic fibrosis treated with elexacaftor/tezacaftor/ivacaftor.

RATIONALE: Inflammation is a hallmark of cystic fibrosis (CF) and associated with bronchiectasis and lung disease progression. The effects of elexacaftor/tezacaftor/ivacaftor (ETI), a CF transmembrane conductance regulator modulator therapy, on inflammation remain incompletely understood.

OBJECTIVES

Investigate 2-year changes in airway and systemic inflammation in adolescents and adults with CF clinically prescribed ETI and the relationships between inflammatory changes and clinical outcomes.

METHODS

PROMISE is a prospective, multicenter, observational study in people with CF aged ≥12 years. Assessments of sputum and blood inflammatory markers occurred before and through 24-30 months of ETI therapy in participants who enrolled in the PROMISE-Inflammation substudy. Changes in inflammation were tested with mixed-effects models. Relationships between inflammatory markers and clinical outcomes were examined using Spearman correlations.

RESULTS

The study cohort comprised 223 participants. ETI was associated with sustained reductions in sputum neutrophil elastase activity, calprotectin, IL-1β, and IL-8, increases in sputum IL-6 through 24/30 months of therapy, and reductions in circulating high-sensitivity CRP (hsCRP) through 12/18 months of therapy. Sputum NE activity reductions correlated with percent predicted forced expiratory volume in 1 second (ppFEV1) and respiratory symptom score improvements at 24/30 months post-ETI. Sputum IL-6 increases correlated with ppFEV1 improvements. Serum hsCRP reductions were associated with ppFEV1 and respiratory symptoms improvements at 12/18 months post-ETI, and circulating calprotectin reductions were associated with respiratory symptom improvements.

CONCLUSIONS

Airway and systemic inflammation decreases through 2.5 years of ETI therapy in adolescents and adults with CF. Reductions in inflammation correlate with clinical improvements. These changes in inflammation represent a disease-modifying benefit of this transformative therapy.

CLINICAL TRIALS REGISTRATION: NCT04038047.