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Optimal use of hospital resources and intervention using suPAR for improving prognosis and care for patients with COVID-19

Periodic Reporting for period 2 - RISCinCOVID (Optimal use of hospital resources and intervention using suPAR for improving prognosis and care for patients with COVID-19)

Reporting period: 2021-08-01 to 2022-07-31

The overall objective of RISCinCOVID was to ensure optimal use of hospital resources and intervention using suPAR for improving prognosis and care for patients with COVID-19. This project has successfully managed to improve the use of hospital resources and an intervention guided by suPAR for the benefit of COVID-19 patients all over Europe.

One of the objectives was to identify low and high-risk patients that could benefit from therapy. The ESCAPE study successfully led to several learnings showing elevated suPAR levels in the study population, indicating a need to triage patients even earlier. suPAR was an excellent biomarker of high-risk patients with high prognostic value for 30-day mortality in the ESCAPE study. In addition, the study indicated a relevant therapy, namely anakinra. Both of these learnings from the ESCAPE trial were used in the design of subsequent studies that ultimately led to an EMA approval of suPAR-guided anakinra treatment leading to a 64% improvement in overall COVID-19 patient outcome. The work carried out in RISCinCOVID has been appreciated by scientists and doctors across Europe and the US and has resulted in suPAR being a recognized biomarker for the progression of patients infected with the SARS-CoV-2 virus.

Lastly, we have managed to successfully transfer manufacturing, upscale and implement the suPARnostic® technology across European hospitals to improve the risk stratification of COVID-19 patients and optimize hospital resources. Concerning the transfer of manufacturing and upscaling production, we successfully developed a validated European large-scale recipe for the turbidimetric product. Concerning the implementation of suPAR across hospitals in Europe, more than 20 hospitals were using suPAR-guided anakinra treatment to treat COVID-19 patients.

The work carried out in RISCinCOVID has been appreciated by scientists and doctors across Europe and the US, and has resulted in suPAR being a recognized biomarker for the progression of patients infected with the SARS-CoV-2 virus. As RISCinCOVID showed that suPAR is a strong marker in COVID-19, many publications and studies have followed. This has resulted in suPAR being approved by the EMA as a companion diagnostic for selecting patients that may benefit from immune modulation therapy. To date, suPAR is the only biomarker approved for personalized treatment of COVID-19.
WORK PACKAGE 1
This work package concerned the measurement of suPAR in acute medical patients at Hvidovre Hospital (subcontractor) and developing a RedCAP database for data gathering, analysis and development of guidelines. Furthermore, it concerned obtaining ethical approvals for doing so. REDcap database was built, and 6500 patients with symptoms of COVID-19 were included in the database, of whom +2000 had a positive RT-PCR test for SARS CoV-2. Ethical approvals have been obtained and uploaded to the Grant portal. A REDcap database and approval were obtained to add the clinical data, routine biomarkers, and outcome data.

Guidelines for suPAR in the Emergency Department have been created, and guidelines were implemented. The resulting guidelines are COVID-19 patients with a suPAR below 4 ng/ml are supportive of discharge (as low risk of developing severe COVID-19), while patients that present with COVID-19 and have suPAR above 6 ng/ml should receive increased clinical attention and treatment.

WORK PACKAGE 2
The ESCAPE study’s purpose of conducting a prospective open-label non-randomized trial of personalized immunotherapy in COVID-19 patients with high suPAR has successfully been accomplished. All patients screened had a high suPAR, and the study concluded that the “immune assessment resulted in favourable anakinra responses among critically ill patients with COVID-19 and features of MALS”.

The ESCAPE study has so far resulted in one important publication (Karakike et al, ESCAPE: an open-label trial of personalized immunotherapy in critically ill COVID-19 patients. Journal of Innate Immunity doi: 10.1159/000519090).

The ESCAPE trial provided four overall benefits for the international scientific society:
1. Knowledge that suPAR is highly elevated in the study population (progressed COVID-19 patients) of ESCAPE and therefore future studies should include patients with early COVID-19 disease.
2. suPAR appeared to be a strong tool to predict negative patient outcomes since more than 50% of the patients progressed to severe respiratory failure or mortality (higher share in comparator and tocilizumab arm), and all had high levels of suPAR.
3. suPAR did not increase significantly between day 1 before start of treatment and day 4 for patients receiving anakinra treatment. However, suPAR was significantly increased for patients receiving tocilizumab treatment (secondary study endpoint). This indicated that anakinra could be a superior treatment for high-risk COVID-19 patients which was important for design of future studies.
4. Thoughtful insights which stimulated the prompt clinical design of future research of the appropriate positioning of suPAR for the early detection of patients with COVID-19 at risk and treatment with anakinra (e.g. the SAVE and SAVE-MORE study leading to the EMA approval).

WORK PACKAGE 3
All ethics requirements have been successfully obtained. For the ESCAPE study, sufficient documentation for study protocol, registration, and approvals have been submitted. In addition, reports of posting results have been submitted as deliverables. Lastly, copies of authorizations for relevant facilities have been submitted and approved.

WORK PACKAGE 4
The transfer and further development of a new turbidimetric product based on the technologies from Japan was conducted successfully. During the first two quarters of 2021, deep technology know-how was acquired, and more than 200 different recipes were developed and tested. The recipe optimization presented several challenges and required substantial work. The production and validation process has been completed, and an associated development report was produced and submitted via the SyGMa grant agreement system in January 2022. Finally, the manufacturing and reproducibility and upscaling process have been conducted and validated, as evidenced in the final development and manufacturing report below. Both parties have signed a commercial agreement for the initial work in Japan. The manufacturing in Poland at Nutopi’s facilities will significantly decrease supply chain risk and lower production costs. The successful production has led to CE-IVD accreditation. The impact on the European healthcare system will be profound due to ensuring an adequate and timely supply of the suPARnostic® test for all COVID-19 patients and other acute care patients.
The ESCAPE study successfully led to several learnings used in subsequent studies' design. The project progressed beyond the state of the art by inspiring a phase 3 randomized controlled trial (SAVE-MORE) that ultimately led to an EMA approval. This important work has already saved many COVID-19 patient lives across European hospitals, which is considered a significant societal implication of the project.

The newly developed turbidimetric product measuring suPAR developed as part of WP4 is the first of its kind in Europe. The increased production of the product will result in further European jobs, and the use of suPAR will improve patient outcomes and reduce healthcare costs overall.
suPAR