title: The effect of intravenous interferon-beta-1a (FP-1201) on lung CD73 expression and on acute respiratory distress syndrome mortality: an open-label study.
abstract: BACKGROUND
  Pulmonary vascular leakage occurs early in acute respiratory distress syndrome (ARDS). Mortality is high (35-45%), but no effective pharmacotherapy exists. Production of anti-inflammatory adenosine by ecto-5'-nucleotidase (CD73) helps maintain endothelial barrier function. We tested whether interferon-beta-1a (IFN-beta-1a), which increases CD73 synthesis, can reduce vascular leakage and mortality in patients with ARDS.
  
  
  METHODS
  In ex-vivo studies, we first established that IFN-beta-1a induced CD73 up-regulation in cultured human lung tissue samples. We then tested the safety, tolerability, and efficacy of intravenous human recombinant IFN-beta-1a (FP-1201) in patients with ARDS in an open-label study (comprising dose-escalation and expansion phases). We recruited patients from eight intensive care units in the UK. Eligible patients were aged 18 years or older, had ARDS, and were being treated with assisted ventilation. We established an optimal tolerated dose (OTD) in the first, dose-escalation phase. Once established, we gave all subsequently enrolled patients the OTD of intravenous FP-1201 for 6 days. We assessed 28-day mortality (our primary endpoint) in all patients receiving the OTD versus 28-day mortality in a group of patients who did not receive treatment (this control group comprised patients in the study but who did not receive treatment because they were screened during the safety windows after dose escalation). This trial is registered with ClinicalTrials.gov, number NCT00789685, and the EU Clinical Trials Register EudraCT, number 2008-000140-13.
  
  
  RESULTS
  IFN-beta-1a increased the number of CD73-positive vessels in lung culture by four times on day 1 (p=0·04) and by 14·3 times by day 4 (p=0·004). For the clinical trial, between Feb 23, 2009, and April 7, 2011, we identified 150 patients, of whom 37 were enrolled into the trial and given treatment. The control group consisted of 59 patients who were recruited to take part in the study, but who did not receive treatment. Demographic characteristics and severity of illness did not differ between treatment and control groups. The optimal tolerated FP-1201 dose was 10 μg per day for 6 days. By day 28, 3 (8%) of 37 patients in the treatment cohort and 19 (32%) of 59 patients in the control cohort had died-thus, treatment with FP-1201 was associated with an 81% reduction in odds of 28-day mortality (odds ratio 0·19 [95% CI 0·03-0·72]; p=0·01).
  
  
  CONCLUSIONS
  FP-1201 up-regulates human lung CD73 expression, and is associated with a reduction in 28-day mortality in patients with ARDS. Our findings need to be substantiated in large, prospective randomised trials, but suggest that FP-1201 could be the first effective, mechanistically targeted, disease-specific pharmacotherapy for patients with ARDS.
authors: Critical Care, University College Hospital, London, UK; Department of Medicine, University College London and NIHR University College London Hospitals Biomedical Research Centre, UK.
authors: Geoff
authors: G
authors: Bellingan
authors: Faron Pharmaceuticals, Turku, Finland.
authors: Mikael
authors: M
authors: Maksimow
authors: Critical Care, University College Hospital, London, UK.
authors: David C
authors: DC
authors: Howell
authors: St Mary's Imperial College Hospital, London, UK.
authors: Martin
authors: M
authors: Stotz
authors: St Thomas's Hospital, London, UK.
authors: Richard
authors: R
authors: Beale
authors: Royal Infirmary Edinburgh, UK.
authors: Monika
authors: M
authors: Beatty
authors: Royal Infirmary Edinburgh, UK.
authors: Timothy
authors: T
authors: Walsh
authors: Victoria Infirmary Glasgow, UK.
authors: Alexander
authors: A
authors: Binning
authors: Western Infirmary Glasgow, UK.
authors: Alan
authors: A
authors: Davidson
authors: Whittington Hospital London, UK.
authors: Martin
authors: M
authors: Kuper
authors: Bristol Royal Infirmary, Bristol, UK.
authors: Sanjoy
authors: S
authors: Shah
authors: Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, UK.
authors: Jackie
authors: J
authors: Cooper
authors: Department of Virology, University of Turku, Finland.
authors: Matti
authors: M
authors: Waris
authors: MediCity Research Laboratory, University of Turku, Finland; Department of Medical Microbiology, University of Turku, Finland.
authors: Gennady G
authors: GG
authors: Yegutkin
authors: Department of Vascular Surgery, Turku University Hospital, Finland.
authors: Juho
authors: J
authors: Jalkanen
authors: MediCity Research Laboratory, University of Turku, Finland; Department of Medical Biochemistry and Genetics, University of Turku, Finland.
authors: Marko
authors: M
authors: Salmi
authors: Faron Pharmaceuticals, Turku, Finland.
authors: Ilse
authors: I
authors: Piippo
authors: Faron Pharmaceuticals, Turku, Finland.
authors: Markku
authors: M
authors: Jalkanen
authors: Department of Medicine, University College London and NIHR University College London Hospitals Biomedical Research Centre, UK; Whittington Hospital London, UK.
authors: Hugh
authors: H
authors: Montgomery
authors: MediCity Research Laboratory, University of Turku, Finland; Department of Medical Microbiology, University of Turku, Finland. Electronic address: sirpa.jalkanen@utu.fi.
authors: Sirpa
authors: S
authors: Jalkanen
mesh_terms: D015720:5'-Nucleotidase / Q000097:blood / Q000378:metabolism*; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured / Q000187:drug effects; D015331:Cohort Studies; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007362:Intensive Care Units; D000068556:Interferon beta-1a; D016899:Interferon-beta / Q000008:administration & dosage / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008168:Lung / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D012128:Respiratory Distress Syndrome / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality; D016896:Treatment Outcome; D006113:United Kingdom; D015854:Up-Regulation
chemical_list: D000276:Adjuvants, Immunologic; D015415:Biomarkers; D016899:Interferon-beta; D015720:5'-Nucleotidase; D000068556:Interferon beta-1a