Quick takes: Q&A with Jeff Evelhoch on Imaging Biomarkers for Alzheimer’s Disease
Jeffrey L. Evelhoch
Alzheimer’s Disease (AD) is a growing health issue that will continue unabated as the population ages. Despite significant resources and the best efforts to develop therapeutics for AD, little success has been realized – much to the frustration of researchers. Between 2002 and 2019, over 250 new drugs were tested in clinical trials and only memantine, a symptomatic treatment, was approved by the FDA. Otherwise, all new drugs aiming to modify the course of AD have failed in long and costly clinical trials. The prevailing hypothesis for these failures is that once symptoms point to a diagnosis of AD, it is too late to intervene with any of the existing therapies.
The AD amyloid hypothesis, the most studied and tested, has become a Phase 3 graveyard. Many questions remain unresolved – e.g. are amyloid plaques causative of or merely correlative with the disease? Could plaques even be detected and treated early enough to avoid further cognitive loss? Does plaque removal result in restoration of cognitive functions?
A corner may have been turned with a focus more on defining AD by its underlying pathologic processes and an improved understanding of the disease through better tools and methods. In 2018, FDA offered guidelines incorporating biomarkers for the selection of early-onset or at‑risk AD patients for enrollment into clinical trials.1 These guidelines are a sea change in diagnosing AD, placing more weight on biomarkers and biomarker characterization rather than solely by clinical symptoms.
Consequently, resources are being used to develop biomarkers to diagnose and stage AD as early as possible; those biomarkers (and others) might then be incorporated into the development of therapeutic interventions for AD subjects. Moreover, new infrastructures and frameworks have been established, e.g., defining a common nomenclature of categories to group biomarkers: aggregated b-amyloid, aggregated tau, and neurodegeneration or neural injury (see also Questions 2 and 3).
At the 2019 Companion Diagnostics Forum, we were fortunate to have Jeff Evelhoch present on his work at Merck about using novel biomarkers and positron emission tomography (PET) biomarkers in AD patients. He also highlighted the field in general, including the current and future status of research and development for clinical applications.
Jeff agreed to follow up with the Journal to address a few questions on his presentation points
Jeff, you summarize thinking on the current treatment of AD in two clear, concise points:
So far, all new drugs aiming to modify the course of AD have failed in long and costly Phase III trials.
JE (comment): Based on retrospective analysis of data late last year from the Aducanumab trials that were stopped last spring after the data monitoring committee reviewed the data (summarized in presentation at CTAD in December*), Biogen has decided to file **with the FDA. Given it is a retrospective analysis, it is not clear if it will be reproduced prospectively. However, it does bring hope and clearly Biogen does not think it has failed.
Once symptoms permit a diagnosis of AD is made, it may be too late to intervene with existing therapies.
In light of these observations, we pose the following questions:
What have biomarkers (imaging or otherwise) taught us about why current drugs have failed to stem the disease? Have biomarkers helped clarify the root cause of drug failures?
As is common in drug development, biomarkers are used to provide information needed to ensure the proof of concept trial adequately tests the therapeutic hypothesis. Thus far, the large majority of drugs tested have focused on the amyloid hypothesis. For some drugs pharmacodynamic biomarkers have provided clear evidence of target engagement (e.g., dose-dependent reduction in Ab42 for BACE inhibitors, dose-dependent reduction in amyloid plaque for some antibodies targeting amyloid oligomers) so we can be sure the drug did not fail due to lack of target engagement. Following on the failure in a well-executed proof of concept trial, researchers in this field realized that a better understanding of the root cause of drug failure would require studies to test specific hypotheses, which may use biomarkers, to develop a deeper understanding of the biology.
A couple of your presentation slides on biomarker readout as a function of clinical stage are reproduced here. Could you please explain how, in practice, the disease might be assayed by a biomarker readout and the readout conveyed in a format that is clear to clinicians?
As the authors of the NIA AA 2018 Research Framework: Toward a biological definition of Alzheimer’s disease2 stated, “it is premature and inappropriate to use this research framework in general medical practice”. That is primarily because there is still much to learn about how the biomarkers, individually or together, can inform the future course of disease for an individual patient.
As that information becomes clearer, a better format will, in turn, be developed to convey assay results to clinicians. At the simplest extreme, a positive or negative classification for presence of amyloid plaque and tau neurofibrillary tangles in the brain, with cut-offs determined to identify patients who will suffer progressive cognitive decline, could be used to identify patients with AD.
At the other extreme, a score reflecting how much amyloid plaque, tau neurofibrillary tangles and neurodegeneration are present in the brain could be used to inform on their stage of disease progression. As noted in the 2018 NIA-AA Research Framework paper,2 “This level of granularity in biomarker classification, combined with genetic and clinical information, will presumably be useful in tailoring treatment to the individual when appropriate specific treatments become available.”
Could you discuss diagnosis and staging in terms of the framework2 of the three categories (aggregated b-amyloid, aggregated tau, and neurodegeneration or neuronal injury) related to the underlying pathologic processes?
Figure 4 of the 2018 NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease paper summarizes how the presence of aggregated amyloid-b (A+), aggregated tau (T+) and neurodegeneration are used for classifying research participants, which would presumably be the basis for future clinical use for diagnosis and staging. [Note: Figure 4, Tables 2 and 4 (for A, T nomenclature) are reproduced here or see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958625/].
Since aggregated amyloid-b is evident first and is not sufficient for progression of cognitive decline alone, A+ indicates Alzheimer’s pathological change, but not necessarily AD. In AD, aggregated amyloid-b is necessary for accumulation of aggregated tau, which is responsible for neurodegeneration, so A+T+ indicates AD, with or without evidence for neurodegeneration or cognitive decline. This is recognized as the earliest stage of AD since A+T+ subjects will ultimately have neurodegeneration.
As aggregated tau spreads from the medial temporal region to the cortex, the impact of the associated neurodegeneration on cognitive ability, which may not be evident in the earliest stages, increases. As more of the cortex is impacted by AD-related neurodegeneration, the ability of the patient to function normally is impacted increasingly. It should be noted that neurodegeneration and cognitive decline can occur for reasons other than AD, hence the presence of both aggregated amyloid and aggregated tau is critical to identify AD pathology but does not ensure other pathologies are absent.
Which imaging platforms and methods are currently used to assess AD patients?
Amyloid PET is used to detect aggregated Ab, tau PET is used to detect aggregated tau and both anatomic MRI and FDG PET are used to detect neurodegeneration.
Do you anticipate translating the observations, diagnosis, and staging made by imaging modalities to a profiling assay on body fluids – e.g., gene or protein panel measured from blood? cerebral spinal fluid?
In the CSF, assays already exist for: Ab42 and Ab42/Ab40 ratio, which are well correlated with amyloid PET measures of amyloid burden; phosphorylated tau, which correlates with tau PET measures of aggregated tau; and both total tau and neurofilament light chain (NfL), which are correlated with imaging measures of neurodegeneration. In the blood, both immunological and mass spectrometry assays are being developed for these biomarkers which should complement the imaging assays (e.g., identify which patients need to be imaged) or, in some cases, ultimately supplant them.
Would like to offer any summary comments on where you see this field in five to ten years?
We will have a better understanding of the heterogeneity of clinical AD (i.e., whether AD is the primary driver of cognitive decline or just one of multiple). Biomarkers will be used to identify cohorts of patients with a more consistent risk of progression due to AD that will enable proof of concept studies to be completed in much smaller cohorts and in less time than we have been able to do in the past. This will allow us to evaluate potential targets to impact AD disease progression more efficiently, which may lead to the identification of drugs that will impact this devastating disease to help patients, their families and caregivers.
Thank you for your responses, Jeff. I greatly appreciate your explaining the breadth and depth of the information that can be gleaned from imaging biomarker data. Not only do biomarkers provide diagnostic value, they also lead to understanding the underlying biological mechanisms of the stages of Alzheimer’s disease – both of which are critical for future development of precision medicine.
Dr. Jeffrey L. Evelhoch is Vice President and Head of Translational Biomarkers at Merck Research Laboratories (MRL). He was Professor of Internal Medicine, Oncology and Radiology at Wayne State University School of Medicine until 2002, when he began working in the biopharmaceutical industry with Pharmacia/Pfizer as Director of Structural Imaging. In 2004, he left Pfizer for Amgen, where he was Executive Director and head of Imaging Science until 2008, when he joined MRL as Vice President and Head of Imaging. In April 2015, he was named Vice President and Head of Translational Biomarkers. In his current role, Jeff, leads a group of more than 100 scientists, with expertise in quantitative molecular and imaging assays, who are responsible for development and qualification of novel biomarkers, use of biomarkers to inform pipeline decisions and the development and deployment of companion diagnostic tests.
- Early Alzheimer’s Disease: Developing Drugs for Treatment Guidance for Industry DRAFT GUIDANCE U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) February 2018 Clinical/Medical Revision 1 https://www.fda.gov/media/110903/download
- NIA-AA 2018 Research Framework: Toward a biological definition of Alzheimer’s disease paper, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958625/pmc/articles/PMC5958625/