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Periodic Report Summary 2 - TRAUMAKINE (Interferon-beta treatment of acute respiratory distress syndrome (ARDS))

Project Context and Objectives:
The TRAUMAKINE project aims at the EU Marketing Authorisation Application for an orphan indication of the biopharmaceutical interferon-beta (IFN-beta), to treat moderate and severe acute respiratory distress syndrome (ARDS). ARDS is a sudden clinical syndrome of life-threatening acute respiratory failure with bilateral pulmonary infiltrates of non-cardiac origin with severe hypoxemia.
The primary aetiology of ARDS is varied and approximately half of the diagnosed cases have a background of sepsis, one third have pneumonia and the rest are mostly caused by traumas. In all cases the predominant feature of this condition is vascular injury that increases capillary permeability, leading initially to formation of interstitial protein-rich lung fluid followed by leukocyte migration from the blood circulation. The final stage of this deterioration is fibril accumulation, scarring and permanent loss of lung function. Despite the much improved mechanical ventilation techniques and supportive therapies, ARDS presently kills 30-45% of the 175000 annual European patients. Many different approaches and numerous clinical trials have failed in ARDS treatment and this condition still has no approved pharmacological treatment in Europe even if the suspected underlying cause is being treated. Patients are ventilated and the immediate goals of the treatment are supportive care and prevention of complications.
Prevention of vascular leakage has not been targeted in ARDS previously even though it is known to be the very first pathological step leading to infiltration of inflammatory cells and accumulation of fibrils.
Adenosine is one of the physiological regulators of endothelial cell permeability but its therapeutic use has been very limited due to its short half-life in circulation. Even though adenosine turnover is high, its beneficial effects have been demonstrated in different animal models. It reduces extra-vascular lung water, increases endothelial cell barrier and down regulates inflammation. During episodes of inflammation, multiple cell types release adenine nucleotides and CD73 is the rate-limiting enzyme controlling local adenosine availability.
The key finding leading to the TRAUMAKINE project has been the identification of IFN-beta as an activator of the CD73 gene, leading to increased de novo synthesis of CD73 and its expression on the surface of endothelial cells. The increased presence of CD73 on the cell surface has been shown to result in increased adenosine levels and enhanced endothelial barrier function. Thus, IFN-beta can be used to significantly prolong the beneficial effects of adenosine in the circulation.
These findings encouraged Faron Pharmaceuticals Ltd to conduct a phase I/II study to test safety, tolerability and initial efficacy of IFN-beta with ARDS patients. The phase I part of the study tested the safety and pharmacokinetics of IFN-beta using four different doses and the phase II was then continued with the optimal tolerated dose (OTD). This study turned out to be extremely successful.
The key finding was a strong reduction of the odds of mortality (by 82%), never seen previously with ARDS trials. Only three of the 37 patients treated with the IFN-beta died resulting in all cause mortality of only 8.1%. Also many secondary end points supported the good efficacy of the IFN-beta treatment while no drug related adverse events were observed with the OTD. These results have been published in The Lancet Respiratory Medicine (Bellingan et al. (2014) The Lancet Res.Med.2(2):98-107). Based on these results Faron has proceeded with the clinical development and a high-class scientific and clinical partner network was established. The core of the TRAUMAKINE project was quickly formed with four partners and the team was privileged to receive the European Union 7th Framework Programme grant for the project. The Team has now constructed a pan-European ADRS trial called INTEREST to complete clinical development in Europe.

Project Results:
The final goal of the TRAUMAKINE project is to get the EU Marketing Authorisation Application for an orphan indication of the biopharmaceutical IFN-beta, to treat moderate and severe ARDS. For this purpose the project has been divided into four main objectives. The first main objective is the successful execution of the pan-European phase III clinical trial (FPCLI002) for the treatment of ARDS using IFN-beta. The second main objective is the clinical and biomarker data analysis. In order to significantly expand the output of the clinical trial, the obtained data will be related to more features than just the primary clinical end point (the all cause mortality at day 28). This in mind, the third main objective is the development of new assays and ARDS biomarker panel and the fourth main objective involves the genetic analysis of the CD73 gene, NT5E, in ARDS patients. These additional themes will hopefully lead to new developments on ARDS treatment and diagnosis.
Most of the work during the 36 months has involved the first two objectives and many important goals have been reached leading to the start of the FPCLI002 study (INTEREST). The clinical trial steering committee has been established and several meetings have been held. This steering committee consists of well-known national key opinion leaders from each of the seven participating countries. Scientific advise for the FPCLI002 study was requested from the European Medicines Agency (EMA) based on the excellent phase I/II study results. All the required documentation was prepared for the advice process with the help of the steering committee and other experts. The final EMA scientific advice was received in December 2013 and it provided many answers and regulatory opinions to the specific questions presented. The implications of the advice on the study protocol were carefully considered and amendments were made accordingly before the protocol was finalised.
The steering committee also recommended the best suitable sites for the study from each participating country. The suitability of the recommended sites based on their recruitment capability and ability to provide the harmonised treatment and care of the ARDS patients was confirmed by the selected contract research organisation resulting in the final site list of 55 sites. When all the sites were selected, the clinical trial study groups in each country were established and the first meetings were held. In these meetings the different aspects of the study including the protocol design and the harmonisation and standardisation of supportive care were introduced and discussed. Simultaneously, the site contracting process has been on-going and some of the sites have already been initiated and are presently recruiting patients. It can therefore be concluded that the FPCLI002 trial has started, which is the most important goal reached thus far.
The aim of the development of new assays and ARDS biomarker panel is to develop a fit-for-purpose ARDS biomarker panel, which could be used to predict the disease severity, ARDS progression and length of hospitalisation as well as response to IFN-beta and other supportive therapies. Based on the original treatment hypothesis, the induction of CD73 levels are of great interest and CD73 is one of the candidates in the biomarker panel. Therefore, a robust CD73 ELISA assay and reference standard material production process has been developed and optimised. This CD73 assay has been transferred to a specialised central laboratory where the CD73 levels in FPCLI002 clinical study patient samples will be measured. The performance of the assay has been tested thoroughly and a pancreatitis and an acute kidney injury sample cohorts have been measured to gain experience for the FPCLI002 patient sample analysis. This preparatory work has provided the needed tools for the measurement of CD73 levels in the IFN-beta treated patients in the FPCLI002 clinical trial.

Potential Impact:
The potential impact of the final results can be extremely important. If the IFN-beta treatment proves effective in ARDS patients, it will be the first pharmacological treatment for this sudden and potentially deadly condition. There are approximately 175.000 annual ARDS patients in the EU, a high orphan disease figure and therefore any effort to help these patients medically would have a major impact to our current practices with these patients. In addition to the reduction of the mortality rate and improvement of the quality of life among these patients there will be significant pharmaco-economical impact to the society, as the ARDS patients are the most expensive ones to hospitals due to long time spent at ICU and the intensive supportive care. We also anticipate generating a much better understanding of the disease progress that leads to mortality and which biomarkers and other clinical parameters are important during this deadly process. Furthermore, this project should result in rapid screening of ARDS risk factors using the diagnostic ARDS panel that can be taken into account when supportive therapies are applied. CD73 plus some other biomarkers could become surrogate markers for ARDS and treatment with IFN-beta. The TRAUMAKINE project is also a significant business opportunity. As there is no existing ARDS treatment, one can anticipate significant market penetration following the pan-European trial INTEREST. The Manufacturing of IFN-beta drug substance and drug product is also done in EU so most of the business will stay in EU.
All scientific achievements will be published in a timely manner in the relevant and appropriate scientific journals, preferably in those practicing open access-policy. Knowledge about the new possibilities to prevent ARDS will be distributed through key presentations at relevant scientific Symposia Meetings and Workshops. Updated information can also be found from the project web-pages at

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