Impact of lumacaftor/ivacaftor and tezacaftor/ivacaftor on treatment response in pulmonary exacerbations of F508del/F508del cystic fibrosis.

Background: Pulmonary exacerbations (PEx) remain a major cause of morbidity and mortality in people with cystic fibrosis (PWCF). Although the combination cystic fibrosis transmembrane conductance regulator (CFTR) modulators lumacaftor/ivacaftor and tezacaftor/ivacaftor have been shown to reduce PEx frequency, their influence on clinical and biochemical responses to acute PEx treatment is unknown.

Methods: We performed a secondary analysis of STOP2, a large multicenter randomized controlled trial of antimicrobial treatment durations for adult PWCF presenting with PEx. Propensity score matching was used to compare outcomes in antibiotic-treated F508del/F508del PWCF receiving lumacaftor/ivacaftor or tezacaftor/ivacaftor with those observed in antibiotic-treated F508del/F508del controls not receiving CFTR modulator therapy. The primary outcome measure was the change in percent predicted FEV (ppFEV) following completion of intravenous (IV) antibiotics, with post-antibiotic changes in symptoms, serum C-reactive protein (CRP) concentrations and weight included as secondary endpoints.

Results: Among 982 PEx events in randomized PWCF, 480 were homozygous for F508del, of whom 289 were receiving lumacaftor/ivacaftor or tezacaftor/ivacaftor at initiation of antibiotic therapy. Modulator-treated F508del/F508del PWCF did not demonstrate greater improvements in ppFEV, symptoms, serum CRP or weight following antibiotic treatment compared to modulator-naïve controls matched for age, sex, baseline ppFEV, genotype, body mass index, initial CRP, initial symptoms, exacerbation history, diabetic status, randomization arm and concomitant medical therapy.

Conclusion: In the acute setting, CFTR modulator therapy with lumacaftor/ivacaftor or tezacaftor/ivacaftor does not convey additional clinical or biochemical advantage above standardized PEx treatment in F508del/F508del PWCF.