TY - JOUR
T1 - CFTR activity is enhanced by the novel corrector GLPG2222, given with and without ivacaftor in two randomized trials
AU - Bell, Scott C.
AU - Barry, Peter J.
AU - De Boeck, Kris
AU - Drevinek, Pavel
AU - Elborn, J. Stuart
AU - Plant, Barry J.
AU - Minić, Predag
AU - Van Braeckel, Eva
AU - Verhulst, Stijn
AU - Muller, Karine
AU - Kanters, Desirée
AU - Bellaire, Susan
AU - de Kock, Herman
AU - Geller, David E.
AU - Conrath, Katja
AU - Van de Steen, Olivier
AU - van der Ent, Kors
N1 - Funding Information:
We thank all patients and investigators involved in the studies. Medical writing support (including development of a draft outline and subsequent drafts in consultation with the authors, assembling tables and figures, collating author comments, copy-editing, fact-checking, and referencing) was provided by Kate Wicks PhD at Aspire Scientific (Bollington, UK), and funded by Galapagos NV (Mechelen, Belgium).
Publisher Copyright:
© 2019 The Authors
PY - 2019/9
Y1 - 2019/9
N2 - 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.
AB - 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.
KW - Administration, Oral
KW - Adult
KW - Aminophenols/administration & dosage
KW - Benzoates/administration & dosage
KW - Benzopyrans/administration & dosage
KW - Biological Availability
KW - Chloride Channel Agonists/administration & dosage
KW - Cystic Fibrosis Transmembrane Conductance Regulator/genetics
KW - Cystic Fibrosis/diagnosis
KW - Double-Blind Method
KW - Drug Monitoring
KW - Drug Therapy, Combination/methods
KW - Female
KW - Humans
KW - Male
KW - Mutation
KW - Quinolones/administration & dosage
KW - Respiratory Function Tests/methods
KW - Sweat/chemistry
KW - Treatment Outcome
UR - http://www.scopus.com/inward/record.url?scp=85065025887&partnerID=8YFLogxK
U2 - 10.1016/j.jcf.2019.04.014
DO - 10.1016/j.jcf.2019.04.014
M3 - Article
C2 - 31056441
AN - SCOPUS:85065025887
SN - 1569-1993
VL - 18
SP - 700
EP - 707
JO - Journal of Cystic Fibrosis
JF - Journal of Cystic Fibrosis
IS - 5
ER -