ARDS: IV Interferon-beta-1a Effect on Mortality

Prof Sirpa Jalkanen MD, PhD MediCity Research Laboratory and Department of Medical Microbiology University of Turku Turku, FinlandMedicalResearch.com Interview with:
Prof Sirpa Jalkanen MD, PhD
MediCity Research Laboratory and Department of Medical Microbiology
University of Turku Turku, Finland

MedicalResearch.com: What are the main findings of the study?

Answer: Pulmonary vascular leakage occurs early in acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Mortality is high (35-45%), but no effective pharmacotherapy exists. Production of anti-inflammatory adenosine by ecto-5’-nucleotidase (CD73) maintains endothelial barrier function. Interferon-beta-1a (IFN-beta) increases CD73 synthesis and might thus reduce vascular leakage and mortality in ALI/ARDS. We tested this hypothesis and the findings were as follows:

1.IFN-beta increased the number of CD73-positive vessels in human lung culture (4- and 14.3-fold on days 1 and 4 respectively, p=0.04 and 0.004).

2. The optimal tolerated FP-1201 dose (a unique intravenous formulation of interferon-beta 10 μg /day for six days) caused a significant rise in serum MxA (a marker for interferon response) and CD73 levels and a fall in interleukin-6 (an inflammatory cytokine) concentration.

3. Most importantly, odds of 28-day mortality was 81% lower in the treated than untreated subjects (8% vs 32%, OR[95% CI]0.19[0.03 to 0.72], p=0.01).


MedicalResearch.com: Were any of the findings unexpected?

Answer:  Although preclinical studies with mouse models suggested a good effect of interferon-beta in acute lung injury, the beneficial effect in the clinical trial was surprisingly strong. This is especially encouraging in the light that no effective specific pharmacotherapy is available for ARDS.

MedicalResearch.com: What should clinicians and patients take away from your report?

Answer:  Our human ex-vivo data are consistent with those from cell lines and animal studies, suggesting that IFN-beta-1a increases CD73 synthesis in pulmonary tissue and results in decrease of pulmonary vascular leak. This mechanism is most likely behind the reduced mortality in patients with ARDS. Although conclusive proof of efficacy needs to be obtained from randomised controlled trials, our human in-vivo data suggest a beneficial effect. If proven to be effective in future trials, IFN-beta-1a would be the first clinically effective mechanistically targeted and disease-specific treatment for ARDS. Until the results of future trials are available, clinicians should continue with best practice in supportive care.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Answer: Therapeutic potential must be substantiated in large-scale prospective randomised trials. FP-1201 has been granted an orphan drug status for the treatment of ALI/ARDS with interferon-beta by the European Commission and European Medicines Agency (EMA) and is waiting for EMA advise to start phase III studies. We are also currently evaluating the role of CD73 as a marker for disease severity and therapeutic response in ARDS.

Citation:

The effect of intravenous interferon-beta-1a (FP-1201) on lung CD73 expression and on acute respiratory distress syndrome mortality: an open-label study

The effect of intravenous interferon-beta-1a (FP-1201) on lung CD73 expression and on acute respiratory distress syndrome mortality: an open-label study
Geoff Bellingan MD,Mikael Maksimow PhD,David C Howell MD,Martin Stotz MD,Richard Beale MB,Monika Beatty MD,Timothy Walsh MD,Alexander Binning MD,Alan Davidson MD,Martin Kuper MD,Sanjoy Shah MD,Jackie Cooper MSc,Matti Waris PhD,Gennady G Yegutkin PhD,Juho Jalkanen PhD,Prof Marko Salmi MD,Ilse Piippo MD,Markku Jalkanen PhD,Prof Hugh Montgomery MD,Prof Sirpa Jalkanen MD
The Lancet Respiratory Medicine – 23 December 2013
DOI: 10.1016/S2213-2600(13)70259-5

 

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