http://www.iconplc.com/icon-views/icon-views/2013/

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Biomarker Strategies for More Efficient Early-Phase Drug Development in Alzheimer's Disease

By Prof. Dr. Klaudius Siegfried, PhD, VP Global Leader, CNS Drug Research, ICON, plc.

The development of disease-modifying medication for Alzheimer's Disease (AD) has, to date, eluded medical science: Based on the available (pathological) evidence, there is a good consensus amongst AD researchers that the “amyloid cascade hypothesis” is likely to describe core elements of the pathophysiology of AD. However, in spite of this so far none of the potentially disease-modifying treatment approaches, based on this hypothesis, has turned out to be successful in clinical studies. One reasonable explanation for this outcome is that treatment was started too late, namely in patients with a diagnosis of AD or subjects with MCI (Mild Cognitive Impairment). An additional challenge is that AD, but even more so MCI, represents a pathophysiologically heterogeneous group of subjects with subgroups that cannot even be identified by a clinical diagnosis. People suffer from AD pathology for 15—and perhaps as many as 30—years before they become symptomatic and receive a clinical diagnosis. By that time in these subjects, the pathophysiological cascade of events may have proceeded so far that a treatment targeted at amyloidosis (or the removal of amyloid deposits) in the brain may come too late. We thus need biomarkers a) to identify patients at risk before they become symptomatic and b) that can be used as surrogate efficacy markers in (so far) asymptomatic subjects.

I recently moderated a [May 2013] webinar hosted by ICON through DIA’s Solution Provider Webinar platform: Biomarker Strategies for More Efficient Early-Phase Drug Development in Alzheimer's Disease.

Three distinguished speakers summarised the progress that researchers are making in using biomarkers to diagnose AD, stage the disease and select trial participants.

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Biomarkers in the Clinical Trial Development of Alzheimer Disease Agents: The Laboratory Perspective

John Allinson, VP Biomarker Lab Services, ICON Development Solutions, UK discussed a number of the analytical techniques used in the lab to detect AD, stressing that using different biomarkers in combination does, indeed, increase their sensitivity, specificity and positive/negative predictive values. Yet, the challenges are many:

There exists a dizzying array of analytical techniques and technology platforms available to measure AD pathology. It is difficult to choose the right combination from among 20+ methods and multiple technology platforms, especially as different methods/platforms will produce different results.
Other difficulties arise from the fact that there are still validation issues with certain methodologies, calibration materials are not yet fully standardized internationally although efforts are progressing in this arena, samples are difficult to collect, and at this point it is impossible to ensure that control groups are free of patients who are in pre-clinical stages of AD.

While progress is being made, no diagnostic process for AD is completely accurate; we do not have proven surrogate endpoints. Currently, the gold standard method for clinical diagnosis is still performed post mortem.

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