Lumacaftor/ivacaftor in people with cystic fibrosis with an A455E-CFTR mutation

J Cyst Fibros. 2021 Sep;20(5):761-767. doi: 10.1016/j.jcf.2020.11.007. Epub 2020 Nov 26.

Abstract

Background: Previous in vitro organoid data showed A455E-CFTR, a rare CFTR mutation with 4.1% prevalence in the Netherlands, responds to lumacaftor/ivacaftor (LUM/IVA). We explored LUM/IVA's clinical efficacy in people with CF and ≥1 A455E-CFTR mutation.

Methods: Participants aged ≥12 years were randomized to 1 of 2 treatment sequences (LUM/IVA→placebo or placebo→LUM/IVA) with an 8-week washout period between. Primary endpoint was absolute change in ppFEV1 from study baseline through 8 weeks. Additional endpoints were change in sweat chloride concentration (SwCl) and CFQ-R respiratory domain score. Correlations between organoid-based measurements and clinical endpoints were investigated.

Results: Twenty participants were randomized at 2 sites in the Netherlands. Mean absolute change in ppFEV1 from study baseline through Week 8 showed a treatment difference of 0.1 percentage points (95% CI, -2.5 to 2.7; P = 0.928) between LUM/IVA (within-group mean change, 2.7) and placebo (within-group mean change, 2.6). The mean absolute change in SwCl concentration from study baseline through Week 8 showed a treatment difference of -7.8 mmol/L between LUM/IVA and placebo (P = 0.004), while the absolute change in CFQ-R respiratory domain score showed a treatment difference of 3.5 between LUM/IVA and placebo (P = 0.469). The in vitro organoid-based assay demonstrated a concentration-dependent swelling increase with LUM/IVA. Exploratory correlation analyses between organoid swelling and ppFEV1 and SwCl outcomes showed correlation coefficients of 0.49 and -0.11, respectively.

Conclusions: In this exploratory study, LUM/IVA elicited an in vitro response in organoid swelling and in vivo response in SwCl in participants with CF and ≥1 A455E-CFTR mutation. The primary endpoint (ppFEV1) did not show a statistically significant difference between LUM/IVA and placebo; correlations between in vitro and in vivo responses were not established (NCT03061331).

Keywords: A455E–CFTR; Crossover study; Cystic fibrosis; Lumacaftor/ivacaftor.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aminophenols / therapeutic use*
  • Aminopyridines / therapeutic use*
  • Benzodioxoles / therapeutic use*
  • Cross-Over Studies
  • Cystic Fibrosis / drug therapy*
  • Cystic Fibrosis / genetics*
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Double-Blind Method
  • Drug Combinations
  • Female
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Quinolones / therapeutic use*
  • Young Adult

Substances

  • Aminophenols
  • Aminopyridines
  • Benzodioxoles
  • CFTR protein, human
  • Drug Combinations
  • Quinolones
  • lumacaftor, ivacaftor drug combination
  • Cystic Fibrosis Transmembrane Conductance Regulator

Associated data

  • ClinicalTrials.gov/NCT03061331