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

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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.

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