| Affiliation: | 1. INSERM U 1151, Université Paris Sorbonne, Hôpital Necker-Enfants Malades, 149 Rue de Sèvres, 75473, Paris, France;2. Cincinnati Children''s Hospital Medical Centre, 3333 Burnet Ave, Cincinnati, OH 45229, USA;3. University of Washington, 1410 NE Campus Parkway, Seattle, WA 98195, USA;4. National Jewish Health, 1400 Jackson St., Denver, CO 80206, USA;5. University of Leuven, Oude Markt 13, 3000 Leuven, Belgium;7. University Hospital Heidelberg, Im Neuenheimer Feld 156, 69120 Heidelberg, Germany;8. Charité-Universitätsmedizine Berlin, Auhustenburger Platz 1, 13353 Berlin, Germany;9. Berlin Institute of Health (BIH), Anna-Louisa-Karsch-Str. 2, 10178 Berlin, Germany;10. Cytel, 675 Massachussets Ave., Cambridge, MA 02139, USA.;11. Cytel, Route de Pre-Bois, 20, 1215 Geneva 15, Switzerland;12. ProQR Therapeutics, Zernikedreef 9, 2333, CK, Leiden, the Netherlands;13. Blueprint Medicines Corporation, 45 Sidney St., Cambridge, MA 02139, USA;14. Breath Therapeutics Inc., 90 Canal Street, 4th Floor, Boston, MA 02114, USA;15. Imperial College London, Kensington, London SW7 2AZ, UK;p. Queen''s University Belfast, University Rd., Belfast BT7 1NN, UK |
| Abstract: | BackgroundCystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. In this study we assessed the effect of antisense oligonucleotide eluforsen on CFTR biological activity measured by Nasal Potential Difference (NPD) in patients with the most common mutation, F508del-CFTR.MethodsThis multi-centre, exploratory, open-label study recruited adults with CF homozygous or compound heterozygous for the F508del-CFTR mutation. Subjects received intranasal eluforsen three times weekly for 4 weeks. The primary endpoint was the within-subject change from baseline in total chloride transport (Cl-free+iso), as assessed by NPD. Secondary endpoints included within-subject change from baseline in sodium transport.ResultsIn the homozygous cohort (n = 7; per-protocol population), mean change (90% confidence interval) in Cl-free+iso was ?3.0 mV (?6.6; 0.6) at day 15, ?4.1 mV (?7.8; ?0.4, p = .04) at day 26 (end of treatment) and ? 3.7 mV (?8.0; 0.6) at day 47. This was supported by improved sodium transport as assessed by an increase in average basal potential difference at day 26 of +9.4 mV (1.1; 17.7, p = .04). The compound heterozygous cohort (n = 7) did not show improved chloride or sodium transport NPD values. Eluforsen was well tolerated with a favourable safety profile.ConclusionsIn F508del-CFTR homozygous subjects, repeated intranasal administration of eluforsen improved CFTR activity as measured by NPD, an encouraging indicator of biological activity. |
