Abstract
BackgroundPrevious 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. MethodsParticipants 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. ResultsTwenty 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. ConclusionsIn 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).
Highlights
Cystic fibrosis (CF) results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that reduce the quantity and/or function of the CFTR protein, which regulates chloride transport across epithelia in exocrine organs, in-cluding the lung and pancreas [1]
A455E mutations have been reported in
Three participants discontinued the study during the washout period due to adverse event (AE)
Summary
Cystic fibrosis (CF) results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that reduce the quantity and/or function of the CFTR protein, which regulates chloride transport across epithelia in exocrine organs, in-cluding the lung and pancreas [1]. P.Ala455Glu (A455E) is a class V mutation that generates CFTR protein with a shortened half–life, resulting in a reduction of mature CFTR protein [4,5,6]; in vitro studies suggest that the quantity of functional protein at the cell surface is 12% of wild type [7]. With this amount of functional protein, A455E–CFTR is considered a residual function mutation. We explored LUM/IVA’s clinical efficacy in people with CF and ≥1 A455E–CFTR mutation
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