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 1s (ppFEV1), and Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Symptom Score (RSS). RESULTS: Single and multiple doses of inhaled eluforsen up to 50mg 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 50mg dosed 3 times per week for 4weeks 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.
- Drevinek, P.
- Pressler, T.
- Cipolli, M.
- De Boeck, K.
- Schwarz, C.
- Bouisset, F.
- Boff, M.
- Henig, N.
- Paquette-Lamontagne, N.
- Montgomery, S.
- Perquin, J.
- Tomkinson, N.
- den Hollander, W.
- Elborn, J. S.
Keywords
- *Antisense oligonucleotide
- *cfq-r rss
- *Clinical trial
- *Delta F508
- *Pulmonary medicine
- Therapeutics. NP-L and NH were full-time employees of ProQR Therapeutics during
- design development, execution and reporting of this study, and SM was full-time
- employee of ProQR Therapeutics during execution and reporting of this study. FB
- and MB are or were statistical consultants paid by ProQR Therapeutics. KDB report
- grants related to the submitted work. KDB and JSE report grants outside the
- submitted work. KDB and JSE report activity on advisory boards during the conduct
- of the study and outside the submitted work. PD, KDB and JSE received fees for
- consultancy. CS, MC and TP have no disclosures.