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

J Cyst Fibros. 2023 Sep;22(5):875-879. doi: 10.1016/j.jcf.2023.06.012. Epub 2023 Jul 6.

Abstract

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 FEV1 (ppFEV1) 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 ppFEV1, symptoms, serum CRP or weight following antibiotic treatment compared to modulator-naïve controls matched for age, sex, baseline ppFEV1, 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.

Keywords: CFTR modulator; Clinical trial; Cystic fibrosis; Ivacaftor; Lumacaftor; Pulmonary exacerbation; Respiratory infection; Tezacaftor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aminophenols / therapeutic use
  • Anti-Bacterial Agents / therapeutic use
  • Benzodioxoles / therapeutic use
  • Chloride Channel Agonists / therapeutic use
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / therapeutic use
  • Cystic Fibrosis* / diagnosis
  • Cystic Fibrosis* / drug therapy
  • Cystic Fibrosis* / genetics
  • Drug Combinations
  • Female
  • Humans
  • Male
  • Multicenter Studies as Topic
  • Mutation
  • Randomized Controlled Trials as Topic

Substances

  • Aminophenols
  • Anti-Bacterial Agents
  • Benzodioxoles
  • Chloride Channel Agonists
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Drug Combinations
  • ivacaftor
  • lumacaftor
  • tezacaftor