Researchers from academia, pharma, and the biotech industry gathered at the National University Health System of Singapore last month for the “Translational Strategies for Therapeutics Discovery Through Dementia Biomarkers” conference.
Daniel Hutcheson, Ph.D., director of discovery research and head of neuroscience & CNS safety pharmacology at Maccine, and organizer of the conference, emphasized the important role various types of biomarkers are having and will have in the development of disease-modifying therapies that can intervene in the early stages of dementia.
In the future, clinicians will likely utilize an array of biomarkers that may include cerebrospinal fluid (CSF) sampling, imaging, cognitive testing, and measurement of changes in vasculature and blood flow to detect and monitor alterations in normal brain function.
Biomarkers can provide answers to critical questions, said Dr. Hutcheson. “Is my drug doing what I predict it will do? Is it impacting the target and can it modulate or prevent the progressive changes in the brain that underlie neurodegeneration?”
John Beaver, Ph.D., director of imaging at Maccine, talked about the company’s use of nonhuman primates to evaluate the effects of compounds intended to modulate CSF biomarkers believed to have a role in the pathophysiology of neurodegeneration. Placement of a cannula allows for serial sampling of relatively large volumes of CSF without causing stress to the animal, and supports the evaluation of pharmacokinetics and pharmacodynamics.
Eric Siemers, M.D., senior medical director of the Alzheimer global research team at Eli Lilly, identified three main roles for biomarkers in Alzheimer disease—more accurate diagnosis, which can also aid in patient selection for clinical trials; indicators of efficacy to inform decision making in Phase I and II trials; and, potentially, for use as surrogate markers to substitute for measures of, for example, cognition or performance of activities of daily living. Dr. Siemers noted a trend in the field toward the increasing consideration of putative surrogate biomarkers in Phase II trials.
We have “a toolbox of different biomarkers,” and the challenge is to select the best tool for a particular purpose,” observed Dr. Siemers. “Biomarkers allow you to be very much translational, to go back and forth between what you see in the laboratory and in the clinic.”
Despite the failure of Lilly’s gamma-secretase inhibitor semagacestat in Phase III testing last year, administration of the investigational drug was associated with a substantial change in plasma Aß levels, indicating that the drug was getting into the brain and “we knew we were hitting the target,” said Dr. Siemers.
Solanezumab, the Lilly monoclonal antibody drug in Phase III testing to assess its ability to delay progression of AD, selectively binds Aß. “After a single dose of solanezumab, data has shown that the concentration of Aß in the blood increases several hundred-fold.”