PredARIA - A new biomarker system to predict ARIA adverse side effects from immunotherapies for Alzheimers disease

The US launch of new Alzheimer's Disease (AD) immunotherapies has put the spotlight on a serious side effect named “Amyloid Related Imaging Abnormalities (ARIA)”. AD is an irreversible progressive disorder that slowly destroys memory, thinking and function skills. Recently FDA approved the first new AD drug since 2003, which are based on Aß immunotherapy. Those new drugs have shown positive results in the removal of Aß plaques and reduction of cognitive decline. However, the clinical trials identified a dose-dependent increased risk of ARIA. All AD immunotherapies that target Aß plaque in the brain have an associated ARIA-risk for patients. ARIA is serious swelling/bleeding of the brain in patients as a response to amyloid-targeting immunotherapy. Up to 40% of patients eligible for treatment are at risk for ARIA. The mechanisms behind ARIA are not fully understood, but the drugs clear protein buildup in the brain, leading to subsequent deposits of toxic protein within cells lining the blood vessels, impairing their function. This results in localized brain swelling and in serious cases, bleeding and potential death. No tools are available for determining a patient’s ARIA risk. Our PreADx blood tests detect the amyloid fragments metabolized and deposited along blood vessels, and measures amyloid degradation capacity and the vitality of cells that clear amyloid protein. Our project aims to develop a blood test strategy for AD management that can detect risk for ARIA, thereby enabling personalized treatment optimization and prevention of ARIA. Our patented technologies, combining ongoing amyloid clearance assays with maximal clearance capacity assays - all in a blood sample - are ideally placed to predict susceptibility and diagnose ARIA. Our approach would enable safer use of the new immunotherapies, including opening for personalized strategies to individual dosage schemes.

The underlying idea of the project is to develop a new blood-based test strategy for Alzheimer’s Disease (AD) management that can detect susceptibility to serious adverse side effects of a newly approved drug and other immunotherapies, thereby enabling personalized treatment optimization and prevention of side effects occurring in up to 40% of patients. AD is an irreversible progressive disorder that slowly destroys memory, thinking and function skills. In 2021 FDA approved the first novel immunotherapy targeting the fundamental pathophysiology of AD, the first new treatment approved since 2003. The clinical trial demonstrated associations between clinical outcomes and a dose-dependent increased risk of severe adverse effects known as amyloid-related imaging abnormalities (ARIA). The European EMA regulatory body took issue with the safety profile: “It is not clear that the ARIA abnormalities can be properly monitored and managed in clinical practice”. Preventing ARIA corresponds well with our project goal. The mechanisms that underlie ARIA are yet not fully understood, but evidence suggests that antibody-mediated clearance of plaques release amyloid that is then deposited in cells lining the blood vessels, leading to angiopathy, perivascular inflammation and impaired clearance. Our blood test detects the distinct molecular signatures of Aß metabolized and deposited in vascular structures, and thus measures Abeta clearance capacity. Pre Diagnostic’s patented technologies, combining betaamyloid-clearance assays in an in-vitro IVD snapshot measurement with ex-vivo monocyte amyloid clearance capacity measurement, are ideally placed to predict ARIA susceptibility and diagnose ongoing side-effects that may harm the patient, including cancellation of treatment and lasting brain damage. This approach would enable safer use of the new immunotherapies, including opening up for personalized strategies to risk based drug dosage up-titration.