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, 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 cystic fibrosis in the United States, characterizing long-term effectiveness with real-world data is increasingly difficult because of 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-subjects analyses for evaluating its real-world effectiveness.

This retrospective cohort study used data from the U.S. Cystic Fibrosis Foundation Patient Registry (2003-2016). We used two approaches to evaluate ivacaftor effectiveness on percent predicted forced expiratory volume in 1 second (ppFEV1): 1) within-subject comparisons of ppFEV1 before and after ivacaftor initiation; and 2) 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-subjects 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 with 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-subjects comparisons demonstrated similar degrees 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 (cystic fibrosis transmembrane conductance regulator) modulator effectiveness studies, but caution is advised in younger individuals because of developmental changes that may affect pre- and post-treatment comparability.