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Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation
  1. J P Clancy1,
  2. Steven M Rowe2,
  3. Frank J Accurso3,
  4. Moira L Aitken4,
  5. Raouf S Amin1,
  6. Melissa A Ashlock5,
  7. Manfred Ballmann6,
  8. Michael P Boyle7,
  9. Inez Bronsveld8,
  10. Preston W Campbell5,
  11. Kris De Boeck9,
  12. Scott H Donaldson10,
  13. Henry L Dorkin11,
  14. Jordan M Dunitz12,
  15. Peter R Durie13,
  16. Manu Jain14,
  17. Anissa Leonard15,
  18. Karen S McCoy16,
  19. Richard B Moss17,
  20. Joseph M Pilewski18,
  21. Daniel B Rosenbluth19,
  22. Ronald C Rubenstein20,
  23. Michael S Schechter21,
  24. Martyn Botfield22,
  25. Claudia L Ordoñez22,
  26. George T Spencer-Green22,
  27. Laurent Vernillet22,
  28. Steve Wisseh22,
  29. Karl Yen22,
  30. Michael W Konstan23
  1. 1Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  2. 2Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
  3. 3Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado, USA
  4. 4Division of Pulmonary and Critical Care, Department of Medicine, University of Washington, Seattle, Washington, USA
  5. 5Cystic Fibrosis Foundation, Bethesda, Maryland, USA
  6. 6Department of Pediatrics, Hannover Medical School, Hannover, Germany
  7. 7Johns Hopkins University School of Medicine, Johns Hopkins Adult Cystic Fibrosis Program, Baltimore, Maryland, USA
  8. 8Department of Pulmonology and Tuberculosis, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands
  9. 9University of Leuven, Belgium
  10. 10Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  11. 11Division of Pulmonary Medicine, Children's Hospital Boston, Boston, Massachusetts, USA
  12. 12Department of Medicine, Minnesota Cystic Fibrosis Center, University of Minnesota School of Medicine, Minneapolis, Minnesota, USA
  13. 13The Research Institute, The Hospital for Sick Children and Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
  14. 14Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
  15. 15Division of Pediatric Pulmonology, Université Catholique de Louvain, Brussels, Belgium
  16. 16Nationwide Children's Hospital, Columbus, Ohio, USA
  17. 17Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA
  18. 18Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  19. 19Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
  20. 20Division of Pulmonary Medicine and Cystic Fibrosis Center, Children's Hospital of Philadelphia, and Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
  21. 21Department of Pediatrics, Emory University and Children's Healthcare of Atlanta, Atlanta, Georgia, USA
  22. 22Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts, USA
  23. 23Department of Pediatrics, Division of Pulmonology, Case Western Reserve University School of Medicine, Rainbow Babies and Children's Hospital, Cleveland, Ohio, USA
  1. Correspondence to Dr JP Clancy, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA; john.clancy{at}


Background VX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTR in vitro.

Methods A randomised, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacodynamics of VX-809 in adult patients with cystic fibrosis (n=89) who were homozygous for the F508del-CFTR mutation. Subjects were randomised to one of four VX-809 28 day dose groups (25, 50, 100 and 200 mg) or matching placebo.

Results The type and incidence of adverse events were similar among VX-809- and placebo-treated subjects. Respiratory events were the most commonly reported and led to discontinuation by one subject in each active treatment arm. Pharmacokinetic data supported a once-daily oral dosing regimen. Pharmacodynamic data suggested that VX-809 improved CFTR function in at least one organ (sweat gland). VX-809 reduced elevated sweat chloride values in a dose-dependent manner (p=0.0013) that was statistically significant in the 100 and 200 mg dose groups. There was no statistically significant improvement in CFTR function in the nasal epithelium as measured by nasal potential difference, nor were there statistically significant changes in lung function or patient-reported outcomes. No maturation of immature F508del-CFTR was detected in the subgroup that provided rectal biopsy specimens.

Conclusions In this study, VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland. Additional data are needed to determine how improvements detected in CFTR function secondary to VX-809 in the sweat gland relate to those measurable in the respiratory tract and to long-term measures of clinical benefit.

Clinical trial number NCT00865904

  • Cystic fibrosis
  • ion transport
  • sweat chloride
  • protein folding disorders
  • paediatric lung disaese
  • respiratory infection
  • bronchiectasis
  • cystic fibrosis
  • atypical mycobacterial infection

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  • See Editorial, p 4

  • Funding Supported by Vertex Pharmaceuticals and grants CTSA UL1 RR024134 to the Children's Hospital of Philadelphia; NIH 1UL1 RR025744 to Stanford University; NIH K23 DK075788 to SMR; IUL1 RR025777 to Dr Guay-Woodford; CFF CLANCY09YO to SMR; AMIN09YO to RSA; NIH/NCRR/CTSA Grant UL1 RR024153 to the University of Pittsburgh; UL1 RR024992 from the National Center for Research Resources (NCRR), a component of the NIH, and NIH Roadmap for Medical Research; NIH grants UL1 RR024989 and P30 DK27651 to Case Western Reserve University; UL1 RR025747 from the NCRR. M01 RR00400 from the NCRR from Harvard Catalyst/The Harvard Clinical and Translational Science Center (NIH Award #UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic health care centres). UL1 RR 025005 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research to the Johns Hopkins School of Medicine. CTSA (Clinical and Translational Science Award) Grant number is 1UL1 RR025014 to the University of Washington. CFFT Durie 06A0. CTSA grant: UL1RR025747 to the University of North Carolina Chapel Hill. CTSA 1UL1 RR025780 to University of Colorado. Washington University ICTS/CTSA Grant Number UL1 RR024992 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research to Washington University in St. Louis. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centres, the NCRR or the NIH.

  • Correction notice This article has been corrected since it was published Online First. The author name Kris DeBoeck has been corrected to Kris De Boeck.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Institutional Review Board at each site.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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