R&D, Research Institutes

After yet another PhIII Alzheimer’s failure, experts try to map a path out of the wrecking field

Pushed by a 15-year record of clinical failures and pulled by an FDA searching for a practical new path forward for Alzheimer’s drug research, a joint committee organized by the NIH’s National Institute of Aging and the Alzheimer’s Association is suggesting a biomarker-based approach to defining the illness that can guide new development efforts.

Eliezer Masliah

In place of the old toxic protein debate that once divided the field into two camps for amyloid beta and tau, the group believes that the presence of both should be a hallmark of Alzheimer’s, along with physical evidence of neurodegeneration or neuronal injury. By mixing and matching the biomarkers, they want to be able to highlight the development of the disease into a set of distinct stages that can be used to test the effectiveness of new drugs and combination therapies even before symptoms appear.

So amyloid beta by itself would be evidence of disease pathology. Added to the presence of tau you could diagnose someone as having Alzheimer’s. And signs of neurodegeneration could be used to highlight the advance of the disease. They’re also leaving the door open to other biomarkers for the disease as research continues and the field evolves.

By centering on biomarkers that can be identified through brain imaging, along with a standard approach to defining cognition, they believe they have a foundation to build a new wave of studies that can find new drugs to help the millions of people who unknowingly have the first telltale signs of a lethal disease that wipes out a person’s memories.

“We have to focus on biological or physical targets to zero in on potential treatments for Alzheimer’s,” explained Eliezer Masliah, director of the division of neuroscience at the NIA. “By shifting the discussion to neuropathologic changes detected in biomarkers to define Alzheimer’s, as we look at symptoms and the range of influences on development of Alzheimer’s, I think we have a better shot at finding therapies, and sooner.”

Their proposal is critical to a big R&D field that has been shaken by a series of major drug studies that have gone far to prove that researchers don’t have a clear understanding of the biology of the disease. 

Lon Schneider

“You can’t get around that people can have the pathology of Alzheimer’s disease and not have clinical symptoms,” Lon Schneider, a researcher at USC’s Keck School of Medicine, told me recently as I explored where the field was headed. “They can have a head full of amyloid and be at risk of developing dementia,” but then never experience symptoms of the disease.

The news on Alzheimer’s R&D is all bad. Merck’s recent decisive failure on BACE, cutting off the supply of amyloid beta to the brains of patients, has helped disprove a theory that has spurred billions in fresh research spending. Just yesterday little vTv threw in the towel on an attempt to repurpose a failed drug from Pfizer for the disease, another chronic loser among various development strategies. And Pfizer, after spending billions of dollars on various projects, opted to simply drop out, joining an industry retreat that has already claimed the lion’s share of the work at AstraZeneca and GlaxoSmithKline. 

Richard Hodes

At the same time, the FDA has been encouraging the field to define a standard set or biomarkers that could help define a path for researchers to reasonably define the disease and demonstrate progress in slowing it down, ahead of symptoms defined by the gold standard of Phase III programs centered on cognition and function. 

“In the context of continuing evolution of Alzheimer’s research and technologies, the proposed research framework is a logical next step to help the scientific community advance in the fight against Alzheimer’s,” said NIA Director Richard Hodes. “The more accurately we can characterize the specific disease process pathologically defined as Alzheimer’s disease, the better our chances of intervening at any point in this continuum, from preventing Alzheimer’s to delaying progression.”

Their work is in the April 10 issue of Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.


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