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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - ADVANTAGE (ADvanced Validation of A Novel TB Active disease diagnostic to address Global unmet needs: a European consortium approach)

Teaser

Summary

Tuberculosis (TB) remains the single biggest communicable disease affecting 10.4m people in 2015 and causing 1.8m deaths globally. TB is preventable and curable, but despite significant investment and decades of research, diagnosis is not a simple procedure. The current tools available for the diagnosis have various limitations means that the diagnosis of active TB remains a long and difficult first step to its management. As Active TB is highly contagious rapid diagnosis and early start of treatment will help to prevent the spread of the disease. WHO has identified the need for a simple, rapid, POC blood test for TB suitable for use in a minimally resourced setting. It is this challenge that project â€˜ADVANTAGEâ€™ seeks to address.
The overall objectives of the three-year project are:
- Migrating the proof of concept from the laboratory to the POC platform
- Validating and improving the biomarker signature
- Developing proprietary antibodies to the biomarkers in the panel
- Retrospective clinical trials to confirm diagnostic accuracy
- Prospective clinical trials in Europe, India and BRICS countries
- Commercial planning including regulatory readiness.

Work performed

The key tasks during period 2 focused on developing the Biosensia platform and developing specific reagents for the test. Biosensia could not overcome various technical issues and the project team has concluded that Biosensia should withdraw from the project. ProteinLogic have identified and tested an alternative platform that is well developed technically. ProteinLogic will be seeking formal approval to substitute this platform with a view to validating its biomarker signature in clinical studies in Europe, S.Africa and Brazil.Whilst there was some success with development of specific reagents, the task was much more challenging. We have agreements in principle for long term supply of the reagents for commercial thus removing a potential obstacle to commercialisation of the test.

During this period there has been a major break-through. Analysis of a large number of well-characterised clinical samples has successfully shown discrimination between active TB and non-TB samples, with a high degree of accuracy. This achievement is unprecedented as the level of accuracy exceeds those currently required by the W.H.O for a rule-out test for Active TB (sensitivity > 90%, specificity >70%). A rule-out test for active TB is the top priority test in the fight to eradicate TB, as such a test has the potential to help clinicians quickly prioritise those patients with symptoms who are more likely to have Active TB. This would then lead to the treatment of those affected, thus reducing further spread of the disease. This break-through therefore indicates the huge potential of the biomarker signature. A conservative estimate of the annual global market for a rule out TB test is 80million tests per annum at an estimated market value of >$1bn per annum.

Despite the delays in the platform development, ProteinLogic has continued activities to fulfil the objectives of the project. Visits to S.Africa, India and China have provided first hand insights on how to gain market access for its test.
The project has demonstrated the potential for utilising the ProteinLogic biomarker signature as the basis of an innovative â€˜rule outâ€™ test to discriminate between TB and non-TB. The funding has allowed us to engage several people thus contributing to train the next generation of excellent researchers. The funding has also allowed us to develop cutting-edge research algorithm which will be of interest to doctoral students and postdoctoral researchers. Transferring of analytical assays from high quality, expensive research platforms used in research laboratory to a point-of-care platform is extremely challenging. Some important lessons have been learnt. Lesson 1: â€œBegin with the end in mindâ€. It is worth considering a top-down approach i.e devote efforts in an initial assay optimization step to confirm that a single assay on the POC platform could detect biomarkers in relevant clinical samples .Lesson 2: Access to human clinical samples is critical to validation of biomarkers. Collect good quality prospective clinical samples, under careful collection and storage protocols and have a sufficient number of disease, sick and healthy controls + full clinical history. Multiple aliquots will be required for assay development as well as for the biomarker signature. These are important components of translational biomarker research platforms. Lesson 3: Decisions regarding whether or not to seek regulatory approval also significantly influence translational research structures, depending on the specific regulatory regimen. Lesson 4: The development of a commercial test utilising multiple biomarkers requires the resolution of many interwoven issues and knowledge and expertise from very diverse areas â€“ scientific, clinical, regulatory and commercial, to name but a few.

Final results

During this period there has been a major break-through. Analysis of a large number of well-characterised clinical samples has successfully shown discrimination between active TB and non-TB samples, with a high degree of accuracy. This achievement is unprecedented as the level of accuracy exceeds those currently required by the W.H.O for a rule-out test for Active TB (sensitivity > 90%, specificity >70%). A rule-out test for active TB is the top priority test in the fight to eradicate TB, as such a test has the potential to help clinicians quickly prioritise those patients with symptoms who are more likely to have Active TB. This would then lead to the treatment of those affected, thus reducing further spread of the disease. This break-through therefore indicates the huge potential of the biomarker signature. A conservative estimate of the annual global market for a rule out TB test is 80million tests per annum at an estimated market value of >$1bn per annum.
The availability of a simple, rapid and affordable POC test for TB will have major impact on morbidity, mortality and economic wellbeing of affected individuals and families in the developed and developing world. The project has demonstrated the potential for utilising the ProteinLogic biomarker signature as the basis of an innovative â€˜rule outâ€™ test to discriminate between TB and non-TB. Results to date using high quality European clinical samples, indicate performance better than the W.H.O guidelines; this work is on-going with the objective of increasing accuracy (specificity) level even further.
As part of the reagent development program, we have identified a monoclonal antibody pair against one of the biomarkers in the panel; these monoclonals show high performance assay characteristics and may have high potential as novel reagents for research, clinical applications and potentially therapeutic use.
The impact of ProteinLogic\'s work was mentioned in a recent Unitaid Report, entitled TUBERCULOSIS Diagnostics Technology Landscape 5th Edition, May 2017.
The project co-ordinator attended a course in mid-2016, on TB Research held in Montreal, Canada. This also facilitated discussions with healthcare professionals on the ground dealing with TB. There were attendees across 160 Countries and ProteinLogic had an opportunity to make a non-confidential presentation to the â€˜TB Tech Pitch Forumâ€™.Further dissemination of knowledge was also facilitated by attendance at conferences in Dubai and Brussels.