Jane C Davies1, Olivier Van de Steen2, Silke van Koningsbruggen-Rietschel3, Pavel Drevinek4, Nico Derichs5, Edward F McKone6, Desirée Kanters2, Lisa Allamassey2, Florence Namour7, Herman de Kock2, Katja Conrath8. 1. Imperial College London and Royal Brompton and Harefield NHS Foundation Trust, London, UK. 2. Galapagos NV, Mechelen, Belgium. 3. CF Center, University Children's Hospital and Faculty of Medicine, University of Cologne, Cologne, Germany. 4. Department of Medical Microbiology, Motol University Hospital and 2nd Faculty of Medicine, Charles University, Prague, Czech Republic. 5. Charité Universitätsmedizin Berlin, Pediatric Pulmonology and Immunology, Berlin, Germany. 6. St. Vincent's University Hospital and University College Dublin School of Medicine, Dublin, Ireland. 7. Galapagos SASU, Romainville, France. 8. Galapagos NV, Mechelen, Belgium. Electronic address: Katja.Conrath@glpg.com.
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 ≥18 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 97.7 mmol/L (baseline) to 68.7 mmol/L (end of GLPG1837 treatment). In ivacaftor-pre-treated patients, mean sweat chloride concentrations rose from 42.5 mmol/L at screening to 98.5 mmol/L after ivacaftor washout. Levels were decreased following GLPG1837 treatment (to 68.8 mmol/L at treatment end). Percent predicted forced expiratory volume in 1 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.
BACKGROUND: Investigation of novel cystic fibrosis transmembrane conductance regulator (CFTR) potentiators, such as GLPG1837, for CFpatients 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 ≥18 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 97.7 mmol/L (baseline) to 68.7 mmol/L (end of GLPG1837 treatment). In ivacaftor-pre-treated patients, mean sweat chloride concentrations rose from 42.5 mmol/L at screening to 98.5 mmol/L after ivacaftor washout. Levels were decreased following GLPG1837 treatment (to 68.8 mmol/L at treatment end). Percent predicted forced expiratory volume in 1 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-CFpatients. FUND: This work was supported by Galapagos NV. CLINICAL TRIAL REGISTRATION NUMBERS: NCT02707562; EudraCT 2015-003291-77.
Authors: N Mayer-Hamblett; S van Koningsbruggen-Rietschel; D P Nichols; D R VanDevanter; J C Davies; T Lee; A G Durmowicz; F Ratjen; M W Konstan; K Pearson; S C Bell; J P Clancy; J L Taylor-Cousar; K De Boeck; S H Donaldson; D G Downey; P A Flume; P Drevinek; C H Goss; I Fajac; A S Magaret; B S Quon; S M Singleton; J M VanDalfsen; G Z Retsch-Bogart Journal: J Cyst Fibros Date: 2020-06-07 Impact factor: 5.482
Authors: Iris A L Silva; Tereza Doušová; Sofia Ramalho; Raquel Centeio; Luka A Clarke; Violeta Railean; Hugo M Botelho; Andrea Holubová; Iveta Valášková; Jiunn-Tyng Yeh; Tzyh-Chang Hwang; Carlos M Farinha; Karl Kunzelmann; Margarida D Amaral Journal: Biochim Biophys Acta Mol Basis Dis Date: 2020-07-28 Impact factor: 5.187
Authors: Andrea Gramegna; Martina Contarini; Stefano Aliberti; Rosaria Casciaro; Francesco Blasi; Carlo Castellani Journal: Int J Mol Sci Date: 2020-08-16 Impact factor: 5.923