Comparative Efficacy of CFTR Modulators: A Network Meta-analysis.

Abstract

Purpose: The objective was to study comparative efficacies of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, vanzacaftor-tezacaftor-deutivacaftor (VTD), elexacaftor-tezacaftor-ivacaftor (ETI), tezacaftor-ivacaftor (Tez-Iva), and lumacaftor-ivacaftor (Lum-Iva) in people with cystic fibrosis (pwCF), aged ≥ 12 years, carrying at least one F508del-CFTR-allele.

Methods: Data from randomized controlled or randomized active comparator trials were included in this network meta-analysis which used frequentist approach for comparing the efficacy of drugs and ranking based on P-scores. Outcomes of interest were mean differences in percentage-predicted forced expiratory volume in one second (ppFEV₁), CF questionnaire-revised respiratory domain (CFQ-R) scores, sweat chloride (SwCl) levels, and odds ratios (OR) for serious adverse events (SAE).

Results: Data from 13 studies were analyzed. Compared to placebo, the effects of VTD and ETI on ppFEV1 were almost quadruple of Tez-Iva and Lum-Iva (VTD: 12.78 [95% confidence intervals: 6.41; 19.15] and ETI: 11.95 [7.40; 16.50]) and almost seven times of Tez-Iva and Lum-Iva for CFQ-R (VTD: 21.23 [- 28.72; 71.18] and ETI: 19.27 [10.56; 27.98]). A statistically significant difference was noted between VTD and ETI in SwCl reduction (mean difference: - 8.59 [- 15.53; - 1.65]). There were no statistically significant ORs for SAEs for any CFTR modulators but VTD, ETI, and Tez-Iva were least associated with SAEs (ORs were 0.15 [0.01; 1.79], 0.49 [0.31; 0.78], and 0.74 [0.50; 1.09], respectively, as compared to placebo). Overall, P-score ranking ranked VTD as first and ETI as second, followed by others.

Conclusion: VTD and ETI were more efficacious than Tez-Iva and Lum-Iva in pwCF with at least one F508del-CFTR-allele.