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

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dc.contributor.authorBell, Scott C.
dc.contributor.authorBarry, Peter J.
dc.contributor.authorDe Boeck, Kris
dc.contributor.authorDrevinek, Pavel
dc.contributor.authorElborn, J. Stuart
dc.contributor.authorPlant, Barry J.
dc.contributor.authorMinić, Predag
dc.contributor.authorVan Braeckel, Eva
dc.contributor.authorVerhulst, Stijn
dc.contributor.authorMuller, Karine
dc.contributor.authorKanters, Desirée
dc.contributor.authorBellaire, Susan
dc.contributor.authorde Kock, Herman
dc.contributor.authorGeller, David E.
dc.contributor.authorConrath, Katja
dc.contributor.authorVan de Steen, Olivier
dc.contributor.authorvan der Ent, Kors
dc.contributor.funderGalapagos NV, Belgiumen
dc.contributor.funderAbbVieen
dc.date.accessioned2019-11-19T12:30:36Z
dc.date.available2019-11-19T12:30:36Z
dc.date.issued2019-05-03
dc.description.abstractBackground 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, NCT03045523en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationBell, 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.2019.04.014en
dc.identifier.doi10.1016/j.jcf.2019.04.014en
dc.identifier.eissn1873-5010
dc.identifier.endpage707en
dc.identifier.issn1569-1993
dc.identifier.issued5en
dc.identifier.journaltitleJournal of Cystic Fibrosisen
dc.identifier.startpage700en
dc.identifier.urihttps://hdl.handle.net/10468/9100
dc.identifier.volume18en
dc.language.isoenen
dc.publisherElsevier B.V.en
dc.relation.urihttps://www.sciencedirect.com/science/article/pii/S1569199319300736
dc.rights© 2019 The Authors. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Societyen
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectCystic fibrosisen
dc.subjectF508delen
dc.subjectGating mutationen
dc.subjectGLPG2222en
dc.subjectIvacaftoren
dc.subjectCFTR modulatoren
dc.titleCFTR activity is enhanced by the novel corrector GLPG2222, given with and without ivacaftor in two randomized trialsen
dc.typeArticle (peer-reviewed)en
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