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

Abstract

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.

Keywords: CFTR modulator; cystic fibrosis; inflammation; serum; sputum.

Figure 1.

ETI therapy was associated with sustained reductions in (a) sputum NE activity, (b) calprotectin, (c) IL-1β, and (d) IL-8, and a sustained increase in (e) sputum IL-6 through 24/30 months of therapy. Points correspond to least square mean estimates for each time point from the mixed models, the whiskers indicate the 95% confidence intervals around the least square means. **: p<0.01 compared with baseline (pre-ETI). Blue shading indicates values at or below the lower limits of detection of the assays.

Figure 2.

ETI therapy was associated with significant reductions in serum (a) hsCRP, (b) calprotectin, and (c) HMGB-1 at various time points through 12/18 months of therapy. Points correspond to least square mean estimates for each time point from the mixed models, the whiskers indicate the 95% confidence intervals around the least square means. **: p<0.01 compared with baseline (pre-ETI). Blue shading indicates values at or below the lower limits of detection of the assays.