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

Summary

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.

Findings

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).

Interpretation

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.

Funding

Faron Pharmaceuticals, National Institute for Health Research University College Hospitals Biomedical Research Centre, the Finnish Academy, the Sigrid Juselius Foundation, and the Arvo and Inkeri Suominen Foundation.

Introduction

Acute respiratory distress syndrome (ARDS) is characterised by pulmonary inflammation, diffuse non-cardiogenic bilateral pulmonary oedema, and refractory hypoxaemia. The severity of ARDS is defined by the ratio between the partial pressure of arterial oxygen (PaO₂), in kPa, divided by the inspired fraction of oxygen (FiO₂; PaO₂/FiO₂ ratio): mild (39·9–26·7 kPA), moderate (26·6–13·4 kPa), and severe ARDS (≤13·3 kPa).¹ Triggered by a variety of extra-pulmonary or pulmonary disease states, ARDS is often seen in patients in intensive care units, affecting nearly 200 000 critically ill patients a year in the USA alone.² Associated fiscal, mortality, and morbidity burdens are substantial: health-care costs about US$5000 dollars per patient per day in intensive care,2, 3 and some 35–40% of patients with ARDS die.² Survivors have impaired functional capacity and increased health-care costs extending up to 5 years or more after discharge.⁴ Treatment, however, remains supportive, and although paralysis with drugs such as cisatracurium might have a role in improving outcome,⁵ no mechanistically or disease-specific pharmacotherapies have been shown to improve outcome.6, 7

One key pathophysiological event in ARDS is an early increase in pulmonary capillary permeability, causing plasma exudation into the alveolar space and thus (potentially life-threatening) hypoxaemia. Ecto-5′-nucleotidase (cluster of differentiation 73, or CD73) is an enzyme expressed on vascular endothelium, epithelial cells, and a leucocyte subset. Through dephosphorylation of adenosine monophosphate), CD73 yields anti-inflammatory adenosine,⁸ which binds to its A2B receptor that is diversely expressed in tissues including the lung,⁹ mediating anti-inflammatory effects such as the prevention of vascular leakage and the inhibition of leucocyte recruitment into sites of inflammation.10, 11, 12 Such endogenous protective mechanisms are enhanced in the presence of hypoxia.¹³ Thus adenosine receptor knockout mice are especially vulnerable to acute lung injury and pulmonary vascular leakage,12, 14 and CD73 reduces pulmonary vascular leakage in acute lung injury in animal models.¹¹

We have previously shown that interferon-beta (IFN-beta) decreases vascular permeability by upregulating CD73 expression and activity on cultured endothelial cells.¹⁵ Moreover, severity of experimental acute lung injury is greater in CD73-deficient mice than in wild-type mice, and can be alleviated with IFN-beta treatment in only wild-type mice, indicating that IFN-beta exerts its effect via CD73.¹⁵ Thus, findings from cell-culture and rodent studies suggest that up-regulation of CD73 by IFN-beta has the potential to ameliorate pulmonary vascular leakage and to improve outcome in ARDS. We assessed whether these findings were true in human beings—we sought to confirm that human IFN-beta could increase CD73 expression in human lung samples before doing a phase 1–2 clinical study.