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.”
Targeting Early-Stage Disease
Alzheimer disease (AD) is the principal cause of dementia in an aging population and, as such, is the main focus of ongoing research into biomarker and drug development targeting the neurodegenerative disorders characterized as “dementias” due to their effects on cognition and memory.
A primary goal of this research is the detection of biomarkers associated with predementia—the pathophysiologic changes in the brain that precede clinical, symptomatic disease.
Professor Colin Masters, University of Melbourne, described amyloid plaque, a hallmark of Alzheimer disease, as a “signpost,” a preclinical biomarker of disease that “may occur well before the onset of clinical symptoms.” But even amyloid plaque is a relatively late marker of AD, and biomarker research is focusing on more upstream processes: the initial misfolding of amyloid protein—in particular, beta-amyloid (Aß), and more specifically Aß(1-42)—which leads to protein aggregation and dimer, trimer, and oligomer formation, triggering neuroinflammatory processes and having a toxic effect on neuronal synapses.
Professor Masters spoke about “dramatic progress” during the past several years toward the goal of validating biomarkers of predementia. This includes the use of labeled ligands for detecting Aß and associated advances in positron emission tomography (PET) imaging, as well as the development of strategies for measuring levels of Aß and tau protein in CSF.
The correlation of blood-based biomarkers to preclinical disease is an ongoing challenge, but “we’re closing in,” said Professor Masters, noting that the focus is not only on Aß and tau levels in the blood, but also other surrogate markers such as molecules associated with inflammation that are emerging from proteomics studies.
In addition, there is growing interest in phosphorylated tau protein (phospo-tau), as well as other proteins that may be more reactive and destructive than Aß or tau.
As amyloid accumulates in plaques in the brains of AD patients, Aß levels in the CSF decrease while phosphorylated tau protein levels increase, with resulting cell death and neuronal loss, explained Dr. Hutcheson. The company has used biomarkers to show in real time and in a dose-dependent fashion the ability of certain drugs to knock down Aß(1-42).
“Transformation of Aß into soluble synaptotoxic oligomers is the main underlying neuropathology in AD,” said Mark Treherne, Ph.D., CEO of Senexis, and the therapeutic goal is to modulate Aß aggregation. In his talk, Dr. Treherne described the company’s work in developing orally bioavailable small molecule inhibitors that can penetrate the CNS and both block and reverse the toxic effects of Aß oligomerization.
SEN1500 is Senexis’ lead compound in development for AD. It binds directly to Aß monomers and oligomers and inhibits aggregation. At the conference, Dr. Treherne presented recent functional and physiological data that follow on previous behavioral findings for SEN1500 and a follow-up compound, SEN1576. He described the correlation between biochemical markers and the pharmacological effects of the compounds, which the company hopes will help translate these results into human subjects and support a future Phase II trial.
Senexis is also developing SEN1176, which suppresses Aß(1-42)-induced production of inflammatory compounds by macrophages, such as nitric oxide, TNF-α, IL-1β, and IL-6. It has shown good oral bioavailability and in vivo efficacy in a model of learning and memory.
We have demonstrated that our compounds are neuroprotective, and “preserving synaptic integrity is essential to having a drug that works,” added Dr. Treherne.