ABSTRACT
BACKGROUND: Investigation of novel cystic fibrosis transmembrane conductance regulator (CFTR) potentiators, such as GLPG1837, for CF patients with gating mutations is challenging as trials require patients to withhold ivacaftor, the current standard of care. This study explored the feasibility of such a study and the impact of one-week ivacaftor withdrawal. METHODS: This open-label, single-arm study aimed to enrol 32 adults ≥18â¯years of age with CF and at least one p.Gly551Asp (G551D) mutation. Patients received three increasing GLPG1837 dosages twice-daily for two 7-day and one 14-day period following a one-week ivacaftor washout. The primary outcome was safety; secondary outcomes were changes in sweat chloride concentration, spirometry outcomes, and pharmacokinetics. RESULTS: Twenty-six patients enrolled; 24 completed the study. Adverse events were reported by 53.8-76.9% of patients (dosage-dependent), with respiratory adverse events most common. Mean sweat chloride concentrations decreased from 97.7â¯mmol/L (baseline) to 68.7â¯mmol/L (end of GLPG1837 treatment). In ivacaftor-pre-treated patients, mean sweat chloride concentrations rose from 42.5â¯mmol/L at screening to 98.5â¯mmol/L after ivacaftor washout. Levels were decreased following GLPG1837 treatment (to 68.8â¯mmol/L at treatment end). Percent predicted forced expiratory volume in 1â¯s declined from 73.3% at screening to 68.5% after ivacaftor washout but returned to screening level at treatment end (73.1%). CONCLUSIONS: Patient willingness to participate in the study suggests that the need for a short period of ivacaftor withdrawal may not be a barrier to development of novel potentiators, such as GLPG1837. A one-week ivacaftor washout was generally well tolerated, but resulted in a decline in lung function, which was reversed with GLPG1837 treatment to pre-washout levels. Combined with the concentration-dependent decrease in sweat chloride concentration, results show that GLPG1837 increases CFTR activity in G551D-CF patients. FUND: This work was supported by Galapagos NV. CLINICAL TRIAL REGISTRATION NUMBERS: NCT02707562; EudraCT 2015-003291-77.
Subject(s)
Aminophenols , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis , Drug Substitution , Pyrans , Pyrazoles , Quinolones , Withholding Treatment , Adult , Aminophenols/administration & dosage , Aminophenols/adverse effects , Chloride Channel Agonists/administration & dosage , Chloride Channel Agonists/adverse effects , Cystic Fibrosis/diagnosis , Cystic Fibrosis/drug therapy , Cystic Fibrosis/genetics , Dose-Response Relationship, Drug , Drug Monitoring/methods , Drug Substitution/adverse effects , Drug Substitution/methods , Female , Humans , Male , Pyrans/administration & dosage , Pyrans/adverse effects , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Quinolones/administration & dosage , Quinolones/adverse effects , Respiratory Function Tests , Sweat/chemistry , Treatment OutcomeABSTRACT
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 29â¯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: -17.6â¯mmol/L [GLPG2222 200â¯mg], pâ¯<â¯0.0001; ALBATROSS: -7.4â¯mmol/L [GLPG2222 300â¯mg], pâ¯<â¯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.
