Evaluating Long-Term Effectiveness of Cystic Fibrosis Modulator Therapies After Rapid Adoption: A Dual-Approach Study

Modulator therapies like ivacaftor have revolutionized clinical management of cystic fibrosis (CF), showing marked short-term benefits in trials but heterogeneous findings in long-term observational studies. Since newer modulators have become the standard of care for the majority living with CF in the U.S., characterizing long-term effectiveness with real-world data is increasingly difficult due to the lack of contemporary comparator groups for performing between-subjects analyses. To determine the extent to which ivacaftor preserves long-term lung function and compare the results of within- and between-subject analyses for evaluating its real-world effectiveness. This retrospective cohort study used data from the US Cystic Fibrosis Foundation Patient Registry (2003-2016). We employed two approaches to evaluate ivacaftor effectiveness on percent predicted forced expiratory volume in 1s (ppFEV1): i) within-subject comparisons of ppFEV1 before and after ivacaftor initiation and ii) comparisons between ivacaftor-treated and untreated individuals with similar disease pathology. We modeled data from 560 ivacaftor-treated individuals with the G551D variant. For between-subject comparisons, we used propensity scores to match the treated group with 2,800 untreated F508del homozygous individuals. Modulator initiation bias was assessed and accounted for in each model. Our results showed an initial average improvement in ppFEV1 in ivacaftor-treated children and adults (ranging from 4.54 to 6.53% predicted based on within-subject comparison of before vs. after ivacaftor initiation). There was a slower decline in adults, compared to children. These ivacaftor-treated cohorts experienced less decline relative to their F508del homozygous counterparts (between-group differences in treated vs. control ranged from 0.36 to 0.64% predicted). Both the within- and between-subject comparisons demonstrated similar levels of ivacaftor effectiveness. However, small differences between the two approaches were observed in younger individuals. Ivacaftor was associated with improved ppFEV1 across all age groups, with the magnitude of improvement roughly 50% of that observed in clinical trials. The results support the need to account for modulator initiation bias and the use of within-subject analysis in future CFTR modulator effectiveness studies, but caution is advised in younger individuals due to developmental changes that may affect pre- and post-treatment comparability.