Lumacaftor/ivacaftor in people with cystic fibrosis with an A455E-CFTR mutation
Berkers, Gitte; van der Meer, Renske; Heijerman, Harry; Beekman, Jeffrey M; Boj, Sylvia F; Vries, Robert G J; van Mourik, Peter; Doyle, Jamie R; Audhya, Paul; Yuan, Zheng Jason; Kinnman, Nils; van der Ent, C Kors
(2021) Journal of Cystic Fibrosis, volume 20, issue 5, pp. 761 - 767
(Article)
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
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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).
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Keywords: A455E–CFTR, Crossover study, Cystic fibrosis, Lumacaftor/ivacaftor, Pulmonary and Respiratory Medicine, Pediatrics, Perinatology, and Child Health, Journal Article
ISSN: 1569-1993
Publisher: Elsevier
Note: Funding Information: All authors received nonfinancial support (assistance with manuscript preparation) from ArticulateScience LLC, which received funding from Vertex Pharmaceuticals Incorporated. Additional disclosures are as follows: JRD, ZY, and NK are employees of Vertex Pharmaceuticals Incorporated and may own stock or stock options in Vertex Pharmaceuticals Incorporated; PA was employed by Vertex Pharmaceuticals Incorporated at the time the study was conducted; HH reports personal fees from Gilead, PTC, Teva, and Vertex Pharmaceuticals Incorporated, and clinical trials with AbbVie and Vertex Pharmaceuticals Incorporated; JMB reports grants from Eloxx and Proteostasis, travel support from Proteostasis and Vertex Pharmaceuticals Incorporated, and royalties from the Royal Netherlands Academy of Sciences and Arts; RGJV is the CEO of Hubrecht Organoid Technology, a company based on the commercial implementation of the organoid technology, and reports grants and advisory board membership from Vertex Pharmaceuticals Incorporated; CKvdE reports grants from Eloxx, Galapagos NV, Gilead, GSK, Nutricia, ProQR, Proteostasis, Teva, and Vertex Pharmaceuticals Incorporated, and a patent (10006904) with royalties paid. SFB does not have any other disclosures to report. Publisher Copyright: © 2020
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