CORDIS - EU research results

Validation of a Novel Diagnostic Biomarker for Dry Eye Syndrome based in nucleotides detection

Periodic Reporting for period 1 - DryEye (Validation of a Novel Diagnostic Biomarker for Dry Eye Syndrome based in nucleotides detection)

Reporting period: 2015-06-01 to 2016-01-31

The project “Validation of a Novel Diagnostic Biomarker for Dry Eye Syndrome based in nucleotides detection” in which we were worked is related to our biomarker for the diagnosis of Dry-Eye syndrome and the monitoring of the effectiveness of its treatment.
Our biomarker is associated with a method in which is assessed the concentration in human tears, of a molecule called diadenosine tetraphosphate (Ap4A). Ap4A is an intracellular signal molecule that is produced due to harsh environmental factors. In our studies we have discovered that Ap4A is released from the corneal epithelium stimulating tear production, and is a physiological modulator of tear secretion. We have proved that its aberrant presence in the tears is closely related to the signs and symptoms of the Dry Eye syndrome.
The objectives presented to the Project Proposal were:
Objective 1. To carry out a clinical evaluation of the Ap4A biomarker on human samples, to validate it in comparison to the gold standard of tear osmolarity test and the inflammation.
Objective 2. After the test we will assess the results, to evaluate if the compound is existing in sufficient concentration on the variety of the patients and to verify the precision and repeatability of our biomarker.
Specific objectives as next steps after the termination of the Phase 1 of the project:
S. Objective 1. Transformation of the biomarker in a medical device and preparation of a prototype.
S. Objective 2. Validation of the prototype in a wide clinical trial to establish all the prerequisites for a medical biomarker as described in the DEWS report (DEWS report is the official report of the Dry Eye Work-Shop). Regulatory requirements to obtain the CE market approval: biocompatibility studies included.
S. Objective 3. Production and commercialization of the device.
According to the project proposal we had to evaluate our biomarker for Dry Eye syndrome (diadenosine tetraphosphate-Ap4A) in a clinical trial on 30 subjects. In order to achieve wide-ranging statistical results, we decided to raise the subjects to 52. The study was organized from June to September 2015 and it started in October 2015. After 4 months of intensive work on human subjects, the trial terminated in December 2015. The process of the results took two months, from January to February 2016.
In the study participated 52 subjects, divided taking according to their respective score on the McMonnies tests. They were divided in two groups of symptomatic (25) and asymptomatic (27) subjects. Table 1 below, depicts the statistic results obtained for each of the tests.
We noticed, statistically significant differences between the two groups for the symptoms parameters (McMonnies and OSDI tests), and for the tear stability (TBUT) in the measurement of diadenosine tetraphosphate (Ap4A). On the other side, neither the existing diagnostic tests of TearLabTM osmolarity test nor the InflammaDryTM-concentration of MMP-9, showed significant differences when comparing symptomatic to asymptomatic patients.
In the case of TearLabTM-osmolarity test, the values obtained in both groups were above the cut-off values of dry eye, according to the parameter of 312 mOsm/l.
In the case of InflammaDryTM-concentration of MMP-9 test, the values found, were below the cut-off in both groups (considered at 40 ng / ml).
In the case of Ap4A, if we consider that the cut-off value to include a subject as dry eye patient, was 0.5 uM, it was found that:
24 of 25 subjects of the asymptomatic group (96%) had Ap4A concentrations below that cut-off value. This means we can consider that the Ap4A has a specificity of 96% on discarding the syndrome.
20 of 27 subjects in the symptomatic group (74%) had concentrations above that Ap4A cut-off value. This means we can consider that the Ap4A has a sensitivity of 74% to diagnose the syndrome.
There were statistically significant differences in the concentration of diadenosine tetraphosphate (Ap4A) between symptomatic and asymptomatic patients.
The sensitivity and specificity of the diadenosine tetraphosphate biomarker is high enough to suggest it as objective marker for the dry eye syndrome.
The user needs addressed by our biomarker are having to do with the improving of the quality of life of millions of people in Europe and worldwide. The prevalence of the diagnosed patients with dry eye in the EU is between 70 and 165 million. The diagnostic tests represent a cost between 15% and 54%, of the whole management of the disease and depending on the country could reach amounts between 32€ and 278€ per patient in 2003/04 prices. It is difficult to calculate the exact annual costs for Dry Eye diagnosis in Europe, but certainly they range between several hundred millions to some billions of euros.
It is of extreme importance the accurate diagnosis of the Dry Eye syndrome in order to select the correct corresponding treatment and thus improve the quality of life of the patients and reduce the health and social costs in the European Union. Another interesting factor is that the prevalence of the syndrome is growing, following the surge of the life expectancy of the population. It is obvious that Dry Eye diagnosis represents a significant cost for the patient and the social security and there is an urgent market need for a precise reduced cost medical diagnostic devise. Concerning the complex presentation and variety of signs and symptoms, is evident the need for an inexpensive, readily available, and reproducible diagnostic test for Dry Eye. In such a case we foresee an immense market opportunity for a novel product to a target a specific group of consumers.
Our diagnostic tool will fill the gap between the traditional diagnosis made in specific laboratories, and the inexpensive specific test. The method has the potential to improve the decision making, accelerate future Dry Eye drug development and reduce development costs of the new drugs, because is a rapid simple and inexpensive test, able to substitute the current unspecific, inaccurate and costly diagnostic process for Dry Eye syndrome.
Examining a patient during the clinical trial