BACKGROUND: Eluforsen is an antisense oligonucleotide designed to bind to the mRNA region around the F508-encoding deletion and restore the cystic fibrosis transmembrane conductance regulator (CFTR) protein function in the airway epithelium. We assessed the safety and tolerability, pharmacokinetics and exploratory measures of efficacy of inhaled eluforsen in cystic fibrosis (CF) patients homozygous for the F508del-CFTR mutation. METHODS: This randomised, double-blind, placebo-controlled, dose escalation 1b study recruited adult CF subjects with a FEV1 > 70% predicted in four single ascending dose cohorts and four multiple ascending dose cohorts. Primary objectives were safety and tolerability. Secondary endpoints included pharmacokinetics, percent predicted forced expiratory volume in 1 s (ppFEV1), and Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Symptom Score (RSS). RESULTS: Single and multiple doses of inhaled eluforsen up to 50 mg were safe and well tolerated. A maximum tolerated dose was not established. Systemic exposure was low in all cohorts and lung function remained stable throughout the study. Three of four eluforsen-treated groups in the MAD study demonstrated an improvement in CFQ-R RSS at end of treatment with adjusted mean change from baseline values ranging from 6.4 to 12.7 points. In comparison, there was a mean decrease of 6.5 points in the placebo group from baseline to end of treatment. CONCLUSIONS: Inhaled eluforsen up to 50 mg dosed 3 times per week for 4 weeks was safe and well tolerated, showed low systemic exposure, and demonstrated improvement in CFQ-R RSS, a relevant measure of clinical benefit in CF patients.

Charité Universitätsmedizin Berlin Mittelallee 4 Augustenburger Platz 1 Berlin 13353 Germany

Copenhagen University Hospital Rigshospitalet Blegdamsvej 9 Copenhagen 02100 Denmark

Cystic Fibrosis Centre Azienda Ospedaliera Universitaria Integrata di Verona P le Stefani 1 Verona 37126 Italy; Cystic Fibrosis Centre Azienda Ospedaliera Universitaria di Ancona via Conca 71 Ancona 60020 Italy

Cytel Route de Pre Bois 20 1216 Geneva Switzerland

Cytel Route de Pre Bois 20 1216 Geneva Switzerland; GSK Consumer Health Route de l'Etraz 2 1260 Nyon Switzerland

Department of Medical Microbiology and Department of Paediatrics Motol University Hospital and 2nd Faculty of Medicine Charles University 5 Uvalu 84 Prague 15006 Czech Republic

Faculty of Medicine Health and Life Sciences 90 Lisburn Road Belfast BT9 6AG Northern Ireland

ProQR Therapeutics Zernikedreef 9 2333 CK Leiden the Netherlands

ProQR Therapeutics Zernikedreef 9 2333 CK Leiden the Netherlands; Blueprint Medicines Corporation 45 Sidney St Cambridge MA 02139 USA

ProQR Therapeutics Zernikedreef 9 2333 CK Leiden the Netherlands; Breath Therapeutics Inc 633 Menlo Ave Ste 230 Menlo Park CA USA

ProQR Therapeutics Zernikedreef 9 2333 CK Leiden the Netherlands; Gyroscope Therapeutics Stevenage Bioscience Catalyst Gunnels Wood Road Stevenage Herts SG1 2FX UK

University Hospital of Leuven University of Leuven Herestraat 49 3000 Leuven Belgium

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