(444) Elexacaftor/Tezacaftor/Ivacaftor Treatment Reduces Airway Inflammation in Cystic Fibrosis

Background: Airways disease in cystic fibrosis (CF) is caused by loss of CFTR mediated mucus hydration leading to inflammation and infection. The benefits of highly effective modulator therapies (HEMT) derive from restoration of CFTR activity; however, somewhat surprisingly prior studies of ivacaftor as HEMT have not demonstrated improvements in airway inflammation despite clear evidence of clinical benefit. Triple combination therapy (TCT) with elexacaftor, tezacaftor, and ivacaftor (Trikafta) has been approved as HEMT for a large proportion of PwCF and restores CFTR function more effectively that ivacaftor alone in individuals eligible for both therapies. To assess whether TCT alters airway pathophysiology, we compared bronchoalveolar lavage (BAL) markers of infection and inflammation in PwCF who had bronchoscopy performed before and after initiation of TCT.

Methods: A database of all PwCF on TCT was cross-referenced to a bronchoscopy database to identify all PwCF who underwent BAL while on TCT. The most recent bronchoscopy off TCT was chosen for comparison, with individuals excluded from further analysis if no bronchoscopy was performed within 5 years of the index procedure. Clinical information including demographics, genotype, indication for bronchoscopy, BAL findings were collected from the medical record. Bronchoscopies were characterized as surveillance if they were performed in conjunction with other sedated procedures with no recorded change in respiratory symptoms. Due to concern that the known increase in airway inflammation during a pulmonary exacerbation could confound the analysis, we also analyzed the subset of PwCF who had bronchoscopies performed as surveillance both on and off of TCT. Statistical analysis was performed with GraphPad Prism. Total and neutrophil cell counts were log transformed prior to analysis. This study was approved by the UNC IRB (#19-3264)

Results: 12 PwCF had bronchoscopies with BAL preformed both on and off TCT therapy, including one subject who had a procedure performed after discontinuation of TCT. Average age was 13.2±3.7 years at the time of bronchoscopy on TCT, and 10.1±4.2 years off of therapy. Average time BAL was performed while not on TCT until therapy start was 2.2±2.1 years. Average time subjects had been on TCT before BAL was performed was 0.9±0.7 years. BAL total cell count, neutrophil count, and % neutrophils were decreased in samples obtained from PwCF when on TCT relative to those preformed while not on this treatment (fig. 1A-C). Similarly, pathogens were recovered less often from BAL fluid while individuals were on TCT (fig. 1D). Respiratory symptoms suggestive of a pulmonary exacerbation were the indication for bronchoscopy in 5 of the 12 procedures performed while the individual was not on therapy, but only 1 of 12 of the procedures while on therapy. Decrease in inflammatory markers remained significant when examining only the 7 PwCF who had bronchoscopy performed for surveillance both pre and post TCT therapy.

Conclusions: This study demonstrates that use of TCT decreased markers of airway inflammation and frequency of positive cultures in PwCF. While not unexpected, these findings differ from prior studies of ivacaftor alone. Although this study is small, the findings suggest that TCT has a substantial impact on airway inflammation and infection consistent with its clinical benefit.

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