Antisense oligonucleotide eluforsen improves CFTR function in F508del cystic fibrosis

Abstract Background Cystic 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 . Methods This 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. Results In 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. Conclusions In F508del- CFTR homozygous subjects, repeated intranasal administration of eluforsen improved CFTR activity as measured by NPD, an encouraging indicator of biological activity.