Biomarker Q&A: The landscape and outlook for precision medicine in neurology

Labcorp has continued to invest in the technology, innovation and expertise globally to support clients focused on bringing life-changing treatments to patients with neurological diseases. We recently spoke with Robert Martone, scientific discipline director for neurology with the Biomarker Solution Center, to learn about the acceleration and expansion of biomarkers and diagnostic development related to neurological disease.

Tell us about the current biomarker landscape in neurology?
 

We are seeing an extraordinarily dynamic time of acceleration and expansion in biomarker and diagnostic developments in neurology. 

This is due to a convergence of a number of factors

• First, there is increasingly a focus in neurology on the biological definition of diseases, rather than on behavioral or functional impairments. For example, the NIA and Alzheimer’s Association proposed a biological definition of Alzheimer’s disease. This included the presence of Aβ amyloid pathology with varying contributions of tau pathology and evidence of neurodegeneration. They termed this the “ATN” framework, for amyloid pathology (A), tau pathology (T) and neurodegeneration (N). Similarly, a recent position paper in Lancet Neurology provided a biological definition of Parkinson’s disease as neuronal α-synuclein disease. 

In part, this focus on biological changes rather than functional impairments is driven by the remarkable resilience of human brain function, which leads to a disconnect between chronic progressive neurodegenerative processes and functional impairment. For example, it is well known that in Parkinson’s disease, a significant amount of cell death occurs in the substantia nigra long before any motor symptoms occur. By the time symptoms appear, the underlying damage may be irreversible. Following the biomarkers of that disease process rather than the functional impairments offers the hope for early interventions that might stem the progression of disease prior to significant loss of function.

Tofersen offers an example of this reliance on biomarkers rather than functional endpoints for disease modification: Tofersen was approved by the FDA for the treatment of amyotrophic lateral sclerosis (ALS) resulting from mutations in SOD1 based upon clinical studies that showed significant changes in levels of the biomarker neurofilament light (NFL), a biomarker of axonal injury and neurodegeneration, absent any significant functional changes.

• There has also been a drive to improve outcomes and reduce trial expenses by identifying peripheral biomarkers that have concordance with brain pathology and employing them in patient selection. In Alzheimer’s disease, for example, definitive diagnosis of disease often requires amyloid PET scans, which are expensive, involve exposure to radiation and require proximity to a cyclotron. Quite often, the initial clinical evaluation fails to be confirmed by the more definitive PET scan. The rate of these enrollment failures can reach up to 60%, leading to significant cost as well as risk and exposure to the patients. 

Recently, we’ve seen the development of fluid biomarkers, both in CSF and blood. While the CSF assays are regarded as a diagnostic equivalent to amyloid PET scans, and are much less expensive, they require lumbar puncture and patient reluctance can become a challenge. 

• There have, however, been exciting advances in blood-based biomarkers. Although somewhat less accurate than CSF assays, they are increasingly being used to triage subjects entering clinical trials, while the highly accurate CSF assays are being used as a replacement for amyloid PET imaging. All of these drug discovery efforts have led to the first FDA-approved disease modifying therapies for Alzheimer’s and ALS with other potential therapies following close behind. With those therapies come the need to accurately identify the most appropriate patients for access to those drugs. For example, in Alzheimer’s disease, an amyloid targeting drug should only be given to a patient who has amyloid pathology. As I mentioned, CSF assays are concordant with PET scans and cost thousands of dollars less. Labcorp offers blood-based biomarkers that can aid in the diagnosis of Alzheimer’s disease, as well as diagnostic CSF assays. Thus, the power of fluid biomarkers are being developed into diagnostics for clinical practice. Finally, none of these achievements would have been possible without advances in assay platforms that now offer a number of robust reproducible high-throughput ultra-high sensitivity assays. We are often able to offer assays targeting the same biomarker on multiple competing platforms.

Compared with other therapeutic areas, what are the key differences for the development of a biomarker for neurology?

Fundamentally, neurology biomarkers are an attempt to relate changes in a certain biological marker with impairments in the enormously complex repertoire of human behavior.

More operationally, the brain is relatively unique in being isolated from the bloodstream or systemic circulation by the blood-brain barrier. Because brain proteins need to cross this barrier, brain biomarkers are found in very low concentrations in blood and require high sensitivity assays for detection. 

Neurology biomarker discovery often requires first establishing the importance of a biomarker in CSF which, as mentioned, can only be obtained by a far more invasive procedure than a blood draw.

Neurology biomarkers themselves often have challenging characteristics. They tend to aggregate, stick to tubes, and are often sensitive to mixing. It has taken years of collaborative international research to establish the necessary pre-analytical handling procedures for many of these biomarkers. 

What impact will advancements in neurology biomarkers have in the next several years?

Over the next several years, neurology biomarkers will increasingly find their way into clinical practice and will be developed as clinical diagnostics. This progress will be accelerated by the availability of minimally invasive blood biomarkers. What individual biomarkers might lack in sensitivity or specificity could be compensated for with combinations of biomarkers combined into an algorithm.

While focus on the biological definition of disease may help advance therapeutic development, it is not without controversy. New criteria from an Alzheimer’s Association working group may lead to the testing of asymptomatic people for the first hints of Alzheimer’s disease pathology. This is contentious because there is a stigma associated with dementia, and there are risks associated with a diagnosis of dementia such as loss of insurance or employment, isolation, life disruption, and self-censoring. Although disease modifying therapies have begun to reach the market, they are expensive and pose significant risks. Because of these challenges, it is unclear what would be gained by such early testing at this time.

Increasingly, we will see the use of digital biomarkers that will screen for subtle changes in brain function and activity measured through computer interface in addition to the fluid biomarkers that reflect changes in levels of proteins and other analytes. Some of these tools might be deployed in the comfort and privacy of the home and help guide the patient journey.

We’ll also see the application of biomarkers to measure brain health, perhaps as a routine component of healthcare. There is an epidemic of brain injury in this country resulting from falls, accidents, sports and abuse and much of it goes unreported, inviting even more extensive, often permanent injury. Labcorp now offers a lab-developed test for neurofilament light, a marker for nerve injury regardless of cause, and we’re investigating other makers as well that could be useful to monitor concussion, for example. Imagine someone who suffers a concussion while playing sports having a test that will inform whether it is safe to return to play. We believe that's in our future within the next few years.

Learn more about how Labcorp offers our biopharma partners many laboratory-developed tests (LDTs) across the ATN framework, including ultrasensitive Aβ assays, and pTau217, which has high concordance with amyloid pathology.