EPS2.01Challenges in evaluating the Long-term effectiveness of cystic fibrosis modulator therapies after rapid and widespread adoption: a dual-approach study

Abstract

Objectives: CFTR modulators like ivacaftor have revolutionised cystic fibrosis (CF) management by partially restoring CFTR function, showing marked short-term benefits in clinical trials. However, as these therapies become the standard of care, controlling for a real-world long-term evaluation is difficult, limiting traditional between-subject analyses. This study compares within-subject and between-subject analyses without contemporary controls to evaluate the long-term effectiveness of ivacaftor in preserving lung function. Methods: This retrospective cohort study used data from the US CF Foundation Patient Registry (2003–2016). We evaluated the 6-year effectiveness of ivacaftor in ppFEV1 through: (i) within-subject comparisons of ppFEV1 before and after ivacaftor initiation and (ii) comparisons between ivacaftor-treated and untreated individuals with similar disease pathology. Results: We modelled 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. Results showed an initial improvement in ppFEV1, followed by a slower decline in adults. Within-subject analysis estimated an initial improvement ranging from 3.50 to 5.58 (95% confidence interval [CI]), with a change in the annual rate of decline from -0.33 to 0.77 (95% CI). The within- and between-subject comparisons were broadly consistent, although small differences highlight the influence of underlying assumptions, particularly for younger individuals. Conclusion: Ivacaftor was associated with improved ppFEV1 across all age groups, with the magnitude of improvement approximately 50% of that observed in clinical trials. The results support the use of within-subject analysis in future modulator effectiveness studies, but caution is advised in younger individuals due to developmental changes that may affect pre- and post-treatment comparability.