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Lumacaftor/ivacaftor in people with cystic fibrosis with an A455E-CFTR mutation.
- Source :
-
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society [J Cyst Fibros] 2021 Sep; Vol. 20 (5), pp. 761-767. Date of Electronic Publication: 2020 Nov 26. - Publication Year :
- 2021
-
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.<br />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 ppFEV <subscript>1</subscript> 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.<br />Results: Twenty participants were randomized at 2 sites in the Netherlands. Mean absolute change in ppFEV <subscript>1</subscript> 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 ppFEV <subscript>1</subscript> and SwCl outcomes showed correlation coefficients of 0.49 and -0.11, respectively.<br />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 (ppFEV <subscript>1</subscript> ) did not show a statistically significant difference between LUM/IVA and placebo; correlations between in vitro and in vivo responses were not established (NCT03061331).<br />Competing Interests: Declaration of Competing Interest 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.<br /> (Copyright © 2020. Published by Elsevier B.V.)
- Subjects :
- Adolescent
Adult
Cross-Over Studies
Cystic Fibrosis Transmembrane Conductance Regulator genetics
Double-Blind Method
Drug Combinations
Female
Humans
Male
Middle Aged
Mutation
Young Adult
Aminophenols therapeutic use
Aminopyridines therapeutic use
Benzodioxoles therapeutic use
Cystic Fibrosis drug therapy
Cystic Fibrosis genetics
Quinolones therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1873-5010
- Volume :
- 20
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society
- Publication Type :
- Academic Journal
- Accession number :
- 33249003
- Full Text :
- https://doi.org/10.1016/j.jcf.2020.11.007