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

Rationale: 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.

Objectives: 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.

Methods: 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.

Results: 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.

Conclusions: 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.