Universität zu Köln

Davies, Jane C., Van de Steen, Olivier, van Koningsbruggen-Rietschel, Silke, Drevinek, Pavel, Derichs, Nico, McKone, Edward F., Kanters, Desiree, Allamassey, Lisa, Namour, Florence, de Kock, Herman and Conrath, Katja (2019). GLPG1837, a CFTR potentiator, in p.Gly551Asp (G551D)-CF patients: An open-label, single-arm, phase 2a study (SAPHIRA1). J. Cyst. Fibros, 18 (5). S. 693 - 700. AMSTERDAM: ELSEVIER. ISSN 1873-5010

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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 >= 8 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 pharmacoldnetics. 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. (C) 2019 The Authors. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Davies, Jane C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Van de Steen, Olivier UNSPECIFIED UNSPECIFIED UNSPECIFIED van Koningsbruggen-Rietschel, Silke UNSPECIFIED UNSPECIFIED UNSPECIFIED Drevinek, Pavel UNSPECIFIED UNSPECIFIED UNSPECIFIED Derichs, Nico UNSPECIFIED UNSPECIFIED UNSPECIFIED McKone, Edward F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kanters, Desiree UNSPECIFIED UNSPECIFIED UNSPECIFIED Allamassey, Lisa UNSPECIFIED UNSPECIFIED UNSPECIFIED Namour, Florence UNSPECIFIED UNSPECIFIED UNSPECIFIED de Kock, Herman UNSPECIFIED UNSPECIFIED UNSPECIFIED Conrath, Katja UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-141851
DOI:	10.1016/j.jcf.2019.05.006
Journal or Publication Title:	J. Cyst. Fibros
Volume:	18
Number:	5
Page Range:	S. 693 - 700
Date:	2019
Publisher:	ELSEVIER
Place of Publication:	AMSTERDAM
ISSN:	1873-5010
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CYSTIC-FIBROSIS; DOUBLE-BLIND; IVACAFTOR; SAFETY; EFFICACY; MUTATION; BIOMARKER Multiple languages Respiratory System Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/14185