6:39 PM
May 03, 2019
 |  BioCentury  |  Product Development

Amyloid: how did we get here and what can we learn?

Lessons for industry from nearly 20 years of amyloid failures

Unlike any other theory in drug development, the amyloid hypothesis of Alzheimer’s disease has maintained an almost cult-like following, despite two decades littered with a long line of late-stage failures and not a single success. But the storied history holds valuable lessons that, if heeded, could improve the odds of the next wave of therapies, both for AD and other neurodegenerative diseases.

Since 2002, amyloid-lowering compounds have been tested in at least 30 failed Phase II or Phase III trials, many of which were explained away by bad trial designs, lack of biomarkers or the need for better compounds (see Table: “Full of Fail”).

One issue that’s clouded the picture is that the disease is defined by the presence of amyloid deposits in the brain, making a circular argument out of questions about the peptide’s role.

Still, multiple lines of genetic data converge on β amyloid as the primary driver of AD, creating a case for the target that some in the field find air tight.

The assumption has been that targeting the disease-causing agent will translate into a disease-modifying therapy. One of the biggest lessons is that this logic can no longer be taken for granted.

This is particularly true in neurodegenerative diseases, because they lie undetected for decades, recruiting additional pathological mechanisms along the way. After symptoms have started, it may be too late to target the initial trigger.

Amyloid failures also call into question the viability of targeting protein aggregates, or at least any single aggregation-prone protein, a common approach in neurodegenerative diseases.

The silver lining is that the amyloid work has led to better tools for selecting AD patient populations, confirming target engagement, and monitoring therapeutic response. Alongside mechanism-specific biomarkers, these tools stand to increase the efficiency of AD trials for new MOAs, enabling companies to answer questions about these mechanisms faster than they did for amyloid.

Table: Full of fail

During the past 17 years, at least 30 Phase II and III trials testing the β amyloid hypothesis in Alzheimer’s disease have enrolled nearly 40,000 patients only to fail to improve or even worsen cognition. A few have seen improvements in biomarkers of amyloid plaque formation and other signals, prompting new trials at different doses or in different patient groups, notably to earlier stage AD or in biomarker-enriched populations. The table below is grouped by program and lists the details of the failed trials in chronological order starting with the first in 2002. Duration listed is for readout of primary endpoint. CSF = cerebrospinal fluid markers of β amyloid; PET = positron emission topography imaging of amyloid plaques using radiolabeled contrast agents; (A) Elan Corp. plc sold its Alzheimer’s programs to Johnson & Johnson (NYSE:JNJ) in 2008; Wyeth was acquired by Pfizer Inc. (NYSE:PFE) in 2009. Source: BCIQ: BioCentury Online Intelligence, ClinicalTrials.gov, Journal of the American Medical Association, Neurology, New England Journal of Medicine, company websites

CompanyProductTargetTrialData reportedPopulationPtsDuration Cognition resultAmyloid resultAmyloid measureCompleted?
Elan Corp. plc / Wyeth (A)AN-1792Aβ, all formsPh IIa Study AN1792(QS-21)-201March 2002Mild to...

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