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

J Cyst Fibros. 2019 Sep;18(5):700-707. doi: 10.1016/j.jcf.2019.04.014. Epub 2019 May 3.

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.

Keywords: CFTR modulator; Cystic fibrosis; F508del; GLPG2222; Gating mutation; Ivacaftor.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Aminophenols* / administration & dosage
  • Aminophenols* / adverse effects
  • Benzoates* / administration & dosage
  • Benzoates* / adverse effects
  • Benzoates* / pharmacokinetics
  • Benzopyrans* / administration & dosage
  • Benzopyrans* / adverse effects
  • Benzopyrans* / pharmacokinetics
  • Biological Availability
  • Chloride Channel Agonists / administration & dosage
  • Chloride Channel Agonists / adverse effects
  • Chloride Channel Agonists / pharmacokinetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • Cystic Fibrosis* / diagnosis
  • Cystic Fibrosis* / drug therapy
  • Cystic Fibrosis* / genetics
  • Double-Blind Method
  • Drug Monitoring
  • Drug Therapy, Combination / methods*
  • Female
  • Humans
  • Male
  • Mutation
  • Quinolones* / administration & dosage
  • Quinolones* / adverse effects
  • Respiratory Function Tests / methods*
  • Sweat* / chemistry
  • Sweat* / drug effects
  • Treatment Outcome

Substances

  • Aminophenols
  • Benzoates
  • Benzopyrans
  • Chloride Channel Agonists
  • GLPG2222
  • Quinolones
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • ivacaftor

Associated data

  • ClinicalTrials.gov/NCT03119649
  • ClinicalTrials.gov/NCT03045523