CFTR activity is enhanced by the novel corrector GLPG2222, given with and without ivacaftor in two randomized trials

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dc.contributor.author Bell, Scott C.
dc.contributor.author Barry, Peter J.
dc.contributor.author De Boeck, Kris
dc.contributor.author Drevinek, Pavel
dc.contributor.author Elborn, J. Stuart
dc.contributor.author Plant, Barry J.
dc.contributor.author Minić, Predag
dc.contributor.author Van Braeckel, Eva
dc.contributor.author Verhulst, Stijn
dc.contributor.author Muller, Karine
dc.contributor.author Kanters, Desirée
dc.contributor.author Bellaire, Susan
dc.contributor.author de Kock, Herman
dc.contributor.author Geller, David E.
dc.contributor.author Conrath, Katja
dc.contributor.author Van de Steen, Olivier
dc.contributor.author van der Ent, Kors
dc.date.accessioned 2019-11-19T12:30:36Z
dc.date.available 2019-11-19T12:30:36Z
dc.date.issued 2019-05-03
dc.identifier.citation Bell, S.C., Barry, P.J., De Boeck, K., Drevinek, P., Elborn, J.S., Plant, B.J., Minić, P., Van Braeckel, E., Verhulst, S., Muller, K. and Kanters, D. (2019) 'CFTR activity is enhanced by the novel corrector GLPG2222, given with and without ivacaftor in two randomized trials'. Journal of Cystic Fibrosis, 18(5), pp.700-707. doi:10.1016/j.jcf.2019.04.014 en
dc.identifier.volume 18 en
dc.identifier.issued 5 en
dc.identifier.startpage 700 en
dc.identifier.endpage 707 en
dc.identifier.issn 1569-1993
dc.identifier.uri http://hdl.handle.net/10468/9100
dc.identifier.doi 10.1016/j.jcf.2019.04.014 en
dc.description.abstract Background Several treatment approaches in cystic fibrosis (CF) aim to correct CF transmembrane conductance regulator (CFTR) function; the efficacy of each approach is dependent on the mutation(s) present. A need remains for more effective treatments to correct functional deficits caused by the F508del mutation. Methods Two placebo-controlled, phase 2a studies evaluated GLPG2222, given orally once daily for 29 days, in subjects homozygous for F508del (FLAMINGO) or heterozygous for F508del and a gating mutation, receiving ivacaftor (ALBATROSS). The primary objective of both studies was to assess safety and tolerability. Secondary objectives included assessment of pharmacokinetics, and of the effect of GLPG2222 on sweat chloride concentrations, pulmonary function and respiratory symptoms. Results Fifty-nine and 37 subjects were enrolled into FLAMINGO and ALBATROSS, respectively. Treatment-related treatment-emergent adverse events (TEAEs) were reported by 29.2% (14/48) of subjects in FLAMINGO and 40.0% (12/30) in ALBATROSS; most were mild to moderate in severity and comprised primarily respiratory, gastrointestinal, and infection events. There were no deaths or discontinuations due to TEAEs. Dose-dependent decreases in sweat chloride concentrations were seen in GLPG2222-treated subjects (maximum decrease in FLAMINGO: –17.6 mmol/L [GLPG2222 200 mg], p < 0.0001; ALBATROSS: –7.4 mmol/L [GLPG2222 300 mg], p < 0.05). No significant effects on pulmonary function or respiratory symptoms were reported. Plasma GLPG2222 concentrations in CF subjects were consistent with previous studies in healthy volunteers and CF subjects. Conclusions GLPG2222 was well tolerated. Sweat chloride reductions support on-target enhancement of CFTR activity in subjects with F508del mutation(s). Significant improvements in clinical endpoints were not demonstrated. Observed safety results support further evaluation of GLPG2222, including in combination with other CFTR modulators. Funding Galapagos NV. Clinical trial registration numbers FLAMINGO, NCT03119649; ALBATROSS, NCT03045523 en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher Elsevier B.V. en
dc.relation.uri https://www.sciencedirect.com/science/article/pii/S1569199319300736
dc.rights © 2019 The Authors. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society en
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/ en
dc.subject Cystic fibrosis en
dc.subject F508del en
dc.subject Gating mutation en
dc.subject GLPG2222 en
dc.subject Ivacaftor en
dc.subject CFTR modulator en
dc.title CFTR activity is enhanced by the novel corrector GLPG2222, given with and without ivacaftor in two randomized trials en
dc.type Article (peer-reviewed) en
dc.internal.authorcontactother Barry Plant, Department of Medicine, University College Cork, Cork, Ireland. +353-21-490-3000 Email: b.plant@ucc.ie en
dc.internal.availability Full text available en
dc.description.version Published Version en
dc.contributor.funder Galapagos NV, Belgium en
dc.contributor.funder AbbVie, Inc, USA en
dc.description.status Peer reviewed en
dc.identifier.journaltitle Journal of Cystic Fibrosis en
dc.internal.IRISemailaddress b.plant@ucc.ie en
dc.identifier.eissn 1873-5010


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© 2019 The Authors. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society Except where otherwise noted, this item's license is described as © 2019 The Authors. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society
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