Impact of CFTR Modulator Therapy on inflammatory response in Cystic Fibrosis: A longitudinal Cohort Analysis

<bold>Background:</bold> We investigated the impact of CFTR modulator treatment on the pattern of C-reactive protein (CRP) in a longitudinal (10+years) single centre cohort of adults with Cystic Fibrosis (awCF) database, with the characteristic trends modelled and compared before and during modulator treatment. <bold>Methods:</bold> 446 awCF, (median 80 CRP measurements/person over 13 years), were categorised into three distinct CFTR modulator treatment progressions: never (n=192), none-double-triple (n=157) and none-triple (n=97). Linear modelling of the change in CRP as a function of CFTR treatment pathway, was performed with characteristic trend direction categorised where Pr(>t)<0.05 on the predicted slope over time. Periods of CRP instability were assessed and compared across each modulator treatment phase by logistic regression. <bold>Results:</bold> Pre-modulator therapy, 148/446 (33%) awCF demonstrated longitudinally increasing CRP levels compared with 13/254 (5%) following commencement of triple therapy. 63/254 (25%) demonstrated a significant reduction in CRP within the first 90 days of treatment. These improvements were primarily seen with triple therapy. Furthermore, among eligible patients, 41/64 experienced a rapid drop in CRP instability, moving towards a stabilised trajectory. This response was associated with lower Pre-modulator BMI, higher age, and female gender (p=0.11, 0.07, and 0.13, respectively). <bold>Conclusion:</bold> CFTR triple therapy rapidly decreases inflammation in some awCF, stabilising CRP variability post-treatment, contrasting with limited change in double therapy. Supported by EU/EFPIA IMI iABC grant n° 115721 and by Gilead Sciences Limited, Grant n°15307