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Boost in Use of Biomarker-Based Alzheimer's Diagnostics Expected From Shift in Guidance

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NEW YORK (360Dx) – Synergies between new draft regulatory guidance and a recently released research framework on Alzheimer's disease are expected to increase the use of biomarker diagnostics in evaluating Alzheimer's disease, experts said.

In February, the US Food and Drug Administration released draft guidance that established new diagnostic criteria to define the population with Alzheimer's disease, including "the earliest stages characterized only by pathophysiological changes" which "are typically demonstrated by an assessment of various biomarker measures."

In April, the National Institute on Aging at the US National Institutes of Health, together with the Alzheimer's Association released a new research framework that defines Alzheimer's disease by brain changes rather that clinical symptoms. The framework was published in the April issue of Alzheimer's & Dementia: The Journal of the Alzheimer's Association.

"What the framework is going to help us with, in addition to clinical presentations, is more quantitatively identifying those individuals with biomarkers that we can associate with disease at both late stages, and hopefully very early stages," said Edward Ginns, medical director, neurology at Quest Diagnostics. "One of the unmet needs at this point is to identify those that are even having mild cognitive impairment that can progress to Alzheimer's, or in the future, those who are at risk for Alzheimer's to actually start interventions and treatments earlier."

The timing of the FDA's draft guidance along with the research framework's emphasis on brain changes could be significant for the industry, according to Jeffrey Cummings, director of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas and Cleveland, and a fellow of the American Academy of Neurology.

"By defining these very early stages, like the preclinical stage, the FDA is encouraging pharma'ceutical and biotechnology and academic investigators to concentrate, or at least work, in this area of preclinical disease," Cummings said. "I think there is synergy between the regulatory evolution and the biomarker evolution that is both allowing these studies to go ahead with biomarkers and encouraging them to go ahead by establishing regulatory standards."

The shift in Alzheimer's disease toward the use of biomarker diagnostics rather than diagnosing the disease from clinical symptoms has been prompted by failures in treating patients with clinical symptoms in later stage of disease, and by the biomarkers themselves, according to Cummings.

"The advances in biomarkers have allowed us to identify patients who have the Alzheimer protein amyloid in the brain [which begins] to accumulate protein about 15 years before [patients] develop symptoms, so there is quite a long preclinical phase," he said. "The evolution of biomarkers has allowed us to envision a preclinical phase of Alzheimer's that was invisible to us before."

While there is currently no medication to cure Alzheimer's disease or stop it from progressing, the FDA has approved two types of medications, cholinesterase inhibitors and memantine to treat cognitive symptoms such as memory loss and confusion, according to the Alzheimer's Association.

Currently, Alzheimer's disease diagnostics are used to assess where a patient stands in the progression of the disease and to determine whether they have Alzheimer's disease or another metabolic disorder "masquerading" as Alzheimer's, such as metabolic disease, thyroid dysfunction, or even trauma, according to Quest's Ginns.

Quest offers several Alzheimer's diagnostic tests, including its Admark phospho-tau/total-tau/Ab42 Enzyme Linked Immunosorbent Immunoassay (ELISA) test, and its beta-amyloid 42/40 ratio mass spectrometry test, both of which test cerebrospinal fluid, as well as genetic testing for genes associated with earlier onset of the disease.

In the summer, Great Neck, New York-based accountable care organization Primary PartnerCare will pilot a new screening and diagnostic program for Alzheimer's and dementia developed by Quest and the University of California San Francisco, which will include lab testing; a tablet-based neurobehavioral assessment sensitive to mild cognitive impairment; and MRI imaging. Findings of the pilot study are expected to be available in mid-2019, according to a company spokesman.

The research framework and FDA guidance are also expected to encourage use of biomarker diagnostics for research purposes, including the development of companion diagnostics, and the identificatiol8n of patients with early-stage disease for clinical trial participation. Quest is currently working with both academic institutions and commercial pharmaceutical companies and is participating with partners in clinical trials, according to Ginns. He declined to disclose details of trials for confidentiality reasons.

Genentech, which has several Alzheimer's disease medications in its pipeline, welcomed the new FDA draft guidance and NIA-AA research framework and the categorizations of patients based on biological changes.

"Diagnostics are an essential part of our development strategy in AD, as we aim to tailor treatments to specific patient subgroups, and identify which patients are most likely to benefit from our medicines," said Tobias Bittner, biomarker lead neuroscience at Genentech.

Genentech is currently developing cerebrospinal fluid and blood-based immunoassays as well as Tau PET imaging to more accurately determine Alzheimer's pathology in the brain, Bittner said.

"We were the first to use biomarkers to define early-stage AD in clinical trial and are continuing to explore high-performing diagnostic and disease monitoring solutions," Bittner said.

Genentech is developing its capabilities and building strategic alliances to match the right treatments and correct dosages to the right patients, according to Bittner.

"Our vision is to unlock the full potential of personalized healthcare through the development of biomarkers and leading diagnostics," he said.

While diagnostic lab tests for Alzheimer's disease currently involve testing cerebrospinal fluid, a future goal is to offer blood-based Alzheimer's disease tests, Quest's Ginns noted.

"We are looking at innovative ways to earlier and earlier identify onset," he said. "From a diagnosticians point of view, if we can back up and make that accumulation of data more sensitive and also move from cerebrospinal fluid to blood tests, it will not only facilitate the accumulation of data in clinical studies but also perhaps we can use some of the tests that we currently have earlier so that we can make a better dent in progression of the illness."

Cummings expects the recent increased emphasis on biomarker diagnostic will lead to a an increase in the use of cerebrospinal fluid-based diagnostics and a larger increase in amyloid brain imaging, which has been used for a long time to measure neurodegeneration. However, blood based lab diagnostics once developed, would likely see much greater use than either imaging or cerebrospinal fluid tests, he said.

"The blood tests were not included in the diagnostic framework because they are not advanced enough yet, but there is a general acknowledgement in the field that that would be a much better solution than either imaging or spinal fluid," Cummings said.

Blood tests would avoid the inconvenience of lumbar puncture and the high cost of brain imaging, he noted. In addition, imaging can slow the evaluation of patients for clinical trials, because of limits of how many people can be scanned in a day.

Currently, there is need for more diagnostics for early-stage disease that are easier to access and cheaper to administer because Alzheimer's disease drug development is costly and has a high failure rate, Cummings said. A paper he coauthored in Alzheimer's Research and Therapy in 2014 showed that the failure rate of Alzheimer's disease drug development was 99 percent.

The goals is that eventually a rise in biomarker usage supported by the recent framework will lead to much larger increase in biomarker diagnostics use as new diagnostic and treatment options emerge.

"The hope is, not only will it impact moving more quickly to identify companion diagnostics that will be more efficacious, but as we learn more and more about the correlation of biomarkers with imaging and disease presentation, the hope is that biomarkers will play more and more of a role in the clinic also," Ginns said.