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Antisense oligonucleotide eluforsen is safe and improves respiratory symptoms in F508DEL cystic fibrosis

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  • Pavel Drevinek
  • Tacjana Pressler
  • Marco Cipolli
  • Kris De Boeck
  • Carsten Schwarz
  • Florilene Bouisset
  • Marie Boff
  • Noreen Henig
  • Nicolas Paquette-Lamontagne
  • Sonya Montgomery
  • Jaakko Perquin
  • Nigel Tomkinson
  • Wilhelmina den Hollander
  • J Stuart Elborn
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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.

Original languageEnglish
JournalJournal of cystic fibrosis : official journal of the European Cystic Fibrosis Society
Volume19
Issue number1
Pages (from-to)99-107
Number of pages9
ISSN1569-1993
DOIs
Publication statusPublished - Jan 2020

Bibliographical note

Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

    Research areas

  • Antisense oligonucleotide, CFQ-R RSS, Clinical trial, Delta F508, Pulmonary medicine

ID: 59079776