Long-term reductions in inflammation in people with cystic fibrosis treated with elexacaftor/tezacaftor/ivacaftor
Scott D. Sagel, T. Spencer Poore, Brandie D. Wagner, Jing Xie, Sonya L. Heltshe, Mary Cross, Preston E. Bratcher, Jennifer L. Taylor‐Cousar, Alexandra Wilson, Kimberly McBennett, Sarah J. Morgan, Pradeep K. Singh, David P. Nichols, Andrea Kelly, George M. Solomon, PROMISE Study Group, Richard Ahrens, Moira Aitken, Raouf Amin, Joanne Billings, Andrew Braun, Holly Carveth, Subramanyam Chittivelu, James Chmiel, Elliott Dasenbrook, Joan DeCelie-Germana, Daniel Dorgan, Henry Dorkin, Allen Dozor, Marie Egan, Deborah Froh, Ronald Gibson, Gavin Graff, Ann Granchelli, William Hunt, Sugeet Jagpal, Raksha Jain, Larry Johnson, Claire Keating, Kevin Kirchner, Dana Kissner, Kate Larson-Ode, Jorge Lascano, Kelvin MacDonald, Michelle Mann, Kimberly McBennett, Susanna McColley, Nighat Mehdi, Joel Mermis, Carlos Milla, Susan Millard, Peter Mogayzel, Samya Nasr, Julie Noe, Gregory Omlor, Krishna Pancham, Deepika Polineni, Christopher Richards, Dion Roberts, Scott Sagel, Iman Sami, Michael Schechter, Karen Schultz, Alvin Singh, Varsha Taskar, Jennifer Taylor-Cousar, Heather Thomas, Karen Voter, Patricia Walker, Daniel Weiner, Mark Wurth
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.