Diagnosing AD trials

Why diagnostics are key to the development of AD drugs

A battery of expensive late-stage failures has made it obvious to Alzheimer’s disease companies that more and better diagnostics will be essential to get new disease-modifying therapies to patients. But so far, the approaches being tested are too limited in number and too small in scope to provide the necessary tools.

After the first wave of molecules targeting beta amyloid failed in the clinic, companies began designing studies to enroll patients they believed were more likely to respond based on a confirmed diagnosis of AD and staging methods that suggested their disease had not yet passed the point of no return.

Strategies included enrolling patients believed to have earlier stage disease based on clinical diagnoses involving physicians’ assessments of cognition, confirming plaque deposition with PET imaging agents, and enrolling or stratifying patients based on the apolipoprotein E (APOE) epsilon 4 (APOE4) risk marker.

Even so, the tally of failures has only continued to grow. Three programs testing agents with three different mechanisms in early stage and/or high-risk populations have failed since September.

Part of the problem is that none of the diagnostic approaches are very sensitive.

“If we don’t have access to good diagnostics, we are handicapped in running state-of-the-art clinical trials.”

Andrea Pfeifer, AC Immune

The only validated and approved class of diagnostic tools - amyloid PET imaging agents - aren’t sufficient to definitively diagnose AD. Amyloid imaging cannot be used to stage AD because after plaques develop, some patients take years to show cognitive worsening, while others may develop full-blown AD within months.

In addition, Phase III trials of agents targeting amyloid that have used PET imaging to measure reductions in plaque burden have not established a correlation between plaques and clinical outcomes such as cognition and memory.

Without better tests, there is no good way to balance treatment and placebo arms to control for differences in risk of progression or to ensure that a trial doesn’t enroll too many patients who progress slowly and could not see a benefit during the time frame of a trial.

“If we don’t have access to good diagnostics, we are handicapped in running state-of-the-art clinical trials,” said Andrea Pfeifer, CEO of AC Immune S.A.

AD companies with therapeutic candidates in the clinic agree that a more diverse set of diagnostics are necessary to identify patients before amyloid plaques or tau tangles appear, and to measure disturbances in other causative pathways in AD that could be used to select patients for clinical trials based on the therapeutics’ mechanism

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