A lot has changed in how new treatments are developed for Alzheimer’s Disease (AD). With the 2021 approval of Biogen’s Aduhelm™, the FDA has clearly demonstrated a willingness to use imaging biomarkers as primary endpoints in AD, something that has never occurred before in the CNS space.
“As the technology and our understanding of AD pathophysiology evolves, we expect to see advanced approaches for assessing treatment effect in clinical development, ultimately enabling more effective Alzheimer’s Disease treatments.”
– Rohit Sood, MD, PhD, VP Scientific & Medical Services, Calyx
How is the research behind AD treatment development evolving?
We as an industry are still trying to understand the pathophysiology of Alzheimer’s. Although we’re continuously updating our knowledge based on new information coming out of the labs, it hasn’t yet been appropriately delineated.
Over the last decade our understanding was that beta amyloid was the primary protein responsible for the underlying pathophysiology of AD. Although the contribution of abnormal protein deposition to AD is widely recognized and currently accepted by the scientific community, the exact pathogenesis of AD is complex, and more effort needs to be put into understanding the pathophysiology of AD for the development of therapeutic agents. Moreover, as pharmaceutical clinical trials tailored toward the removal of beta amyloid have failed to demonstrate significant response, there is increasing interest in the role of Tau protein aggregates and beta amyloid plaque, with an emphasis on anti-Tau antibodies.
In addition, there is a school of thought that neuroinflammation plays a role and today, industry is in the process of developing radioisotope tags so that we can identify neuroinflammation and whether there’s a change in the extent of neuroinflammation with drug intervention.
All of these are important factors for trial sponsors to consider when deciding what to target in their AD development programs. But the decision on how to best assess treatment response is not always clear cut. There is an increasingly complex array of potential digital radiology biomarkers that look at brain perfusion and diffusion changes, and volumetric analysis of the hippocampus and other limbic regions including amygdala and entorhinal cortex.
As the technology and our understanding of AD pathophysiology continues to evolve, we expect to see advanced approaches for assessing AD treatment effect in clinical development, ultimately enabling the availability of more effective Alzheimer’s Disease treatments.
“Sponsors and CROs should partner with a core imaging lab whose scientists are experienced in AD study design and understand the optimal imaging modalities needed to demonstrate drug efficacy efficiently, effectively, and economically.”
– Stephen M. Bravo, MD, Chief Medical Officer, Calyx
Is medical imaging currently required in AD studies?
Neuromaging modalities such as PET and MRI have been used to detect pathological changes associated with AD and have played an important role in the development of noninvasive biomarkers of disease progression and assessment of response to therapy in clinical trials. Detection of early neurodegenerative changes associated with AD has been possible due to the development of neuroimaging measures of brain atrophy and brain structures such as hippocampus and cortex. Novel image analysis algorithms for characterizing and classifying AD and Mild Cognitive Impairment (MCI) have been developed and applied to MR images. MRI is also currently used for safety assessment of AD drug therapies, especially important in the development of monoclonal antibody therapies, which can cause life threatening changes in the brain. But now medical imaging is also going to be a requisite for primary efficacy endpoint data collection in order for FDA to consider new drug approvals.
What’s changing in how we assess drug efficacy in AD clinical trials?
Traditionally, efficacy in AD trials is evaluated via rater analysis by clinical doctors who are considered experts in the field of dementia – as well as geriatric, psychiatric, and neurology experts – using the mini mental status examination or other clinical tools to determine baseline disease level and progression or regression. Because these tools are very subjective and produce tremendous amounts of interobserver variability, rater analysis is becoming outdated and, while it will likely never disappear, will likely become less relevant in future trials.
The utilization of radiology biomarker data removes this subjective analytic bias and is a far more rigorous scientific methodology to determine drug effects. Currently, there are AI/machine learning techniques that are being developed to measure subtle changes that are difficult for the human eye to detect, delivering more perspective and a more scientifically rigorous data set that stands up to statistical scrutiny in determining treatment response.
How can Calyx help sponsors leverage medical imaging to demonstrate AD treatment efficacy?
Calyx’s Medical Imaging scientists have significant experience in Alzheimer’s Disease drug development and broad knowledge of the emerging modalities to improve drug response evaluation. They routinely help AD researchers:
1. Determine the best radiological biomarker to evaluate
2. Identify how the radiology modalities used can help to drive identification of an enriched study subject population yielding greater rates of enrollment/randomization
3. Identify digital radiological biomarkers which can be quantified and tracked longitudinally to provide more scientifically rigorous data supporting drug efficacy to the FDA
4. Produce reliable data to support regulatory submissions through the Blinded Independent Central Review (BICR) of imaging reads
What do you see in the future re: the impact medical imaging will have on AD treatment development?
As our understanding of AD advances, so does the technology that we’ll use to develop more effective treatments for it. We see medical imaging delivering additional value in two ways:
- Validating the companion diagnostics required to identify patients who will be best served by treatment of the drug being trialed. This drives the economic rational/model which allows for CMS (Medicare/Medicaid) and commercial US insurance reimbursement decisions.
- Driving further quantitative analysis of MR and PET/CT images to derive even more sophisticated biomarker analysis to help determine the velocity of drug effects and to predict drug effect on an individual basis (supporting the notion of individualized medicine being applied to the clinical research/life sciences space).
FDA’s recognition of using imaging as an objective, noninvasive biomarker is a big step forward for Alzheimer’s Disease research. Clinical trial sponsors should partner with a core imaging lab whose medical imaging scientists are experienced in AD study design and understand the optimal imaging modalities needed to demonstrate drug efficacy efficiently, effectively, and economically.