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  • Periodic Reporting for period 1 - Respiratory-ImmunoDx (Clinical validation of host biomarker signature for distinguishing bacterial versus viral lower respiratory tract infections (LRTI) in adults at the point-of-need)

Respiratory-ImmunoDx Report Summary

Project ID: 684589

Periodic Reporting for period 1 - Respiratory-ImmunoDx (Clinical validation of host biomarker signature for distinguishing bacterial versus viral lower respiratory tract infections (LRTI) in adults at the point-of-need)

Reporting period: 2015-12-01 to 2016-11-30

Summary of the context and overall objectives of the project

Lower respiratory tract infection (LRTI), primarily pneumonia and bronchitis, is the third leading cause of death worldwide. The incidence of LRTIs in Europe is 30 million, greater than diabetes mellitus (2 million) and malignant neoplasms (2.4 million) combined leading to 230,000 deaths, and over 1 million hospitalizations. The attendant economic burden of LRTI in Europe is estimated at €46 billion annually (direct and indirect costs). LRTI presents a diagnostic challenge due to the difficulty in pathogen sampling and the often indistinguishable clinical symptoms of bacterial and viral etiologies. This uncertainty leads to antibiotic misuse, both overuse (typically for bronchitis) and underuse (often for community-acquired pneumonia, CAP). Overuse of antibiotics may expose the patient to unnecessary adverse side effects and contributes to emergence of antimicrobial resistance, currently a major global health threat. Underuse may cause the patient to suffer prolonged disease and increases the likelihood of hospitalization and mortality, with attendant health and economic costs. In the case of CAP, late treatment with antibiotics has been shown to directly impact mortality.

Older adults are at risk for LRTIs due to immunosenescence and co-morbidities, as reflected by increasing incidence with age. In view of the aging European population, the human and economic burden of LRTI is predicted to increase in the coming years. Since most adult LRTIs are managed on an outpatient basis, innovative approaches are warranted that will provide the clinician with actionable information at the point-of-need (community clinic and emergency department [ED]) – to treat or not to treat with antimicrobial therapy – with the goal of promoting 'healthy aging'.
Today, LRTI patient management at the point-of-need is guided mainly by clinical symptoms, and in some cases, by the circulating levels of biomarkers, including procalcitonin, C-reactive protein (CRP), and Interleukin-6 (IL-6). However, the diagnostic performance of each biomarker alone is often restricted. Furthermore, as all these biomarkers are predominantly bacterially-induced, their combination leads to limited diagnostic improvement.

To address this, MeMed has previously identified a three host-biomarker signature that comprises a novel viral induced protein called TRAIL, which at that time was not in clinical use. Based on this proprietary biomarker signature, MeMed developed and received EU regulatory approval (CE-IVD) for a diagnostic test called ImmunoXpert™. This test uses microplates to measure serum levels of the three proteins (TRAIL, IP-10 and CRP) and applies proprietary software to integrate their values and generate viral and bacterial likelihood scores. In a prospective clinical study with over 1000 patients MeMed demonstrated that ImmunoXpert™ accurately distinguished viral versus bacterial acute infections across different group ages, physiological systems (e.g., upper respiratory, urinal and gastrointestinal) and a broad range of pathogens (56 strains), significantly outperforming traditional tests.

Two main objectives are pursued as part of this project with the aim of facilitating wide adoption of the ImmunoXpert™ test for managing LRTI adult patients at the point-of-need:

Objective (1): To clinically validate the biomarker signature for accurate diagnosis of viral versus bacterial LRTI, in a multi-center, prospective pan-European study enrolling 1100 adults in EDs and clinics.

Objective (2) To develop, validate and obtain EU regulatory clearance for a new point-of-need device (to be called ImmunoDx™), that will allow rapid measurements (15 minutes) of the signature from a drop of blood.

For further reading see:

1. The burden of lung disease - ERS. <>
2. WHO | The top 10 causes of death. WHO at <>
3. Welte, T., Torres, A. & Nathwani, D.. Thorax 67, 71–79 (2012).
4. WHO | Global burden of disease. <>
5. Pneumonia - ERS. <>
6. Gibson, G. J., Loddenkemper, R., Lundbäck, B. & Sibille, Y. Eur. Respir. J. 42, 559–563 (2013).
7. The economic burden of lung disease - ERS. <>
8. Millett, E. R. C., Quint, J. K., Smeeth, L., Daniel, R. M. & Thomas, S. L. PLoS ONE 8, e75131 (2013).
9. Healthy ageing. <>
10. Oved, K. et al. PLoS ONE (2015).
11. Eden, E et al. J of Infection (2016)
12. van Houten , C et al. Lancet Infectious Diseases (2016)

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

During this reporting period, significant progress was made in respect to the project objectives: To clinically validate the biomarker signature for accurate diagnosis of viral versus bacterial LRTI, a multi-center, prospective pan-European study enrolling 1100 adults is carried out in the UK, Israel and Germany, and is one of the largest clinical studies ever to be conducted in the field. In the first reporting period a clinical protocol agreed on all three clinical leaders from the participating institutions was generated. The clinical protocol was reviewed and approved by the ethical committee (IRB) of Rambam Health Care Campus, in which the majority of patients of the study are recruited, and patients recruitment is expected in the coming weeks. Similar steps were initiated at the two additional recruiting medical centers.
During the first reporting period MeMed has been working to continue the transition of the ImmunoXpert™ ELISA format into the ImmunoDx™ format, to attain the overarching goal of a rapid and reliable host-based POC platform for distinguishing bacterial and viral infection in general, and LRTIs in particular. Key milestones in the product development process have already been accomplished, including: (i) Completion of rigorous design-input process to capture market and user requirements; (ii) Development of the cartridge and the underlying chemistry to attain the required level of analytical sensitivity for each of the three proteins and reproducibility; (iii) Reduction of assay time for measuring all three proteins to 15 minutes; and (iv) Down selection of reader concept design and creation of functional prototype.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Attainment of the project two synergistic objectives is highly aligned with the goals of the Horizon 2020 SME instrument and MeMed’s business strategy, and will allow a pioneering product to achieve accelerated market adoption, initially in Europe and then globally. The validated signature, measured using the new ImmunoDx™ device, will give physicians, simple, accurate, and actionable information to improve the management of LRTI adult patients, at the place and time where it is most needed. This tool has the potential to profoundly impact the quality of life for patients by reducing adverse effects due to antibiotics overuse and reducing complications and mortality due to underuse, by reversing the trend of increasing hospitalization and its associated economic burden, and on the societal level, by slowing the emergence of antibiotic resistant bacteria – one of today's major public health threats.

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