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A blood based biomarker identifying early Alzheimer Disease's pathology

Periodic Reporting for period 3 - VERDAD (A blood based biomarker identifying early Alzheimer Disease's pathology)

Okres sprawozdawczy: 2020-12-01 do 2021-11-30

Alzheimer’s Disease (AD) is a global pandemic, representing a €300 bn yearly expenditure in EU and affecting ~10% of its population above 65 years old. However, it has been estimated that a five-year delay in the disease onset could reduce the disease prevalence – and its costs – by up to 33% over the next decades, representing potential savings over €100 bn in EU alone.

The disease progression could be delayed by combining compounds to block the initial stages of the neurodegenerative cascade and by lifestyle adjustments; however, current drug pipeline does not trigger sizeable improvements in AD patients. This is primarily due to irreversible brain damage in later AD stages. Over 2,000 various AD interventions have been or are being tested in the World according to around 600 of those in Europe, to compete in a growing, €2Bn market. But how to test the if those interventions are working in a quick, reliable and cost-efficient way? How to effectively select the patient cohorts for the tests?

Therefore, the need for early diagnosis before symptoms arises become apparent, both to delay AD progression and to test the large pipeline of potential breakthrough medications. Despite the high need for early diagnosis, only 36 trials for AD detection are registered at Will any of these work? Are they cost-effective?

In July 2018 Biogen and Eisai announced positive topline results of the final analysis for their drug candidate BAN2401 at 18 months, with new data providing compelling evidence to further support amyloid hypothesis as a therapeutic target for Alzheimer's disease. The recent progress within drug development triggers an increased demand for better diagnostic tools.

Currently, the detection options are cerebral fluid test (detects beta-amyloid (Aβ)) - a neurotoxic metabolite that is the initiator of AD’s neurodegenerative cascade, as well as Tau and pTau biomarkers; it is invasive and costs around €5,000 and PET imaging (detects Aβ plaques, relies on radioactive isotope injection and costs around €3,000. Both tests show amyloid burden which is not well correlated with the clinical symptoms. These are not suitable for mass screening and are therefore used when AD has progressed.

Our solution:
Contrary to existing AD blood tests, PreADx (currently at TRL6) provides a direct indication of a dysfunctional immune system leading to AD's pathological process quickly and at low cost. PreADx detects reduced clearance of Aβ, through the combination of efficient isolation of blood monocytes and proprietary sheep monoclonal antibodies combined with human recombinant anti-complex antibodies to quantify Aβ degradation through an accurate immunoassay test. This indication is available years before clinical symptoms onset, allowing for the first time to understand the disease dynamics with time and allow timely prescription of AD medications as well as follow up AD’s progression.

Expected impact:
VERDAD project's primary outcome is the world’s first in-vitro diagnostic (IVD) blood test for accurate AD diagnosis – PreADx - which is expected to become:
• Key technological enabler for the pharma industry, enabling to monitor the disease dynamics with time, test the effects of an early drug prescription in AD progression and assist the selection of patients in clinical trials - representing a €750K savings potential for an average-sized clinical trial, which can surpass €6Mn for large phase III trials;
• Clinical cornerstone to monitor patients at risk of developing AD, allowing early interventions, and reduce the probability of disease aggravation and onset of cognitive impairment;
• Widely used test for early AD identification, exploring the existing customer demand for accurate early AD diagnosis.
The Project was initiated in June 2019 and is operational according to the schedule
PreADx's Stakeholder Groups are:
1) pharmaceutical and nutraceutical companies plus R&D groups dedicated to developing new AD therapies,
2) physicians and caregivers bringing those to practice in public and private hospitals, and nursing homes
3) AD patients, their families and society in general and citizens looking for early diagnosis
4) healthcare system in general.

In detail, for Stakeholder Group 1, there is 99% attrition rate of human-tested compounds targeting AD failing to reach the market; among the highest in any therapeutic area . Thus, R&D efforts are currently shifting to better understanding the disease progression and possibly target early disease mechanisms to delay the onset of the disease. In these studies, repeated CSF analysis or PET imaging are not applicable due to high cost and low compliance, and thus a blood-based test is ideally suited– which is driving pharm players to strongly seek for cost-effective methods for patient selection and follow-up of therapeutic interventions. Lastly, US Food and Drug Administration released a new guidance document earlier in 2018 highlighting the importance of biomarkers in early AD studies.

For Stakeholder Group 2, time-limited improvement of cognitive function from current therapies underlines the near impossibility of counteracting irreversible brain damage. Current routine diagnostics of AD takes 6-12 months and only begins after the first symptoms appear, due to prohibitive costs of screening. Quick and affordable tests can capture the disease progress early in a screening routine and delay the disease progression.

For Stakeholder Group 3, there is a very high demand for early diagnosis, even if no real efficacious drugs for AD available now. Early and reliable diagnosis will allow to prepare the senior’s life plan, which is the key concern for individuals and their families.

For Stakeholder Group 4, reduction of costs associated with AD is of high importance. Indeed, AD’s Costs to Society were estimated by Alzheimer’s Europe at staggering €177Bn already in 2008; the corresponding costs in the USA were estimated at €167Bn.

This stems from the fact that as of 2013, according to Alzheimer’s Europe, estimated 8.7Mn people living with AD in Europe. Further, according to World Alzheimer’s Report 2015, 46.8Mn are living with dementia worldwide, with a staggering nearly three-fold prevalence increase until 2050.

In addition, AD is the top health condition responsible for overall prevalence of both disability and dependence in the elder population, as the onset of cognitive impairment quickly compromises their ability to carry out complex but essential. Moreover, AD’s progression quickly escalates the need for care, accelerating the costs and the economic burden of the disease – above and beyond other leading diseases such as stroke, heart disease and cancer, both in EU and in the USA .