Eli Lilly Designs P-Tau Biomarker Assay for Early Alzheimer’s Disease Diagnosis

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Biomarkers will be critical to developing precision medicine for Alzheimer’s disease. Although a few are out there, phosphorylated tau (P-tau) may enable even earlier and more accurate detection, according to Eli Lilly-associated researchers speaking at the Clinical Trials on Alzheimer’s Disease (CTAD) virtual conference in early November.

“They will help researchers mechanistically assess target engagement in clinical trials,” and also will be used in clinical practice to identify the right drugs for the right patients, Howard Fillit, M.D., CSO, Alzheimer’s Drug Discovery Foundation, said, introducing the conference symposium, “Latest Advances: Blood And Imaging Biomarkers Of Tau In Alzheimer’s Patients.”

Jeff Dage, Ph.D., senior research adviser at Eli Lilly and Company, presented the case for P-tau in blood as an accurate biomarker. “Recent literature has demonstrated P-tau levels are elevated many years prior to Alzheimer’s disease (AD) symptom onset and are in line with the detection of amyloid pathology.” Therefore, Eli Lilly is developing an assay that measures P-tau 217 in blood. Results collaborate those of tau PET analysis.

“We wanted a tau antibody that would bind to the expressed forms of tau, so we developed a very specific assay,” Dage said. The plasma assay elements include:

  • Capture – a biotin-labeled anti-phosphor-thr217-tau antibody
  • Detection – a ruthenium-labeled isoform-specific anti-tau antibody
  • Calibration – two antigen-specific synthetic peptides coupled with a PEG linker

Currently, this early assay is sensitive at 0.08 pg/mL, a measuring range of 0.08 to 2000 pg/mL, but less than 10% precision. Importantly, “It demonstrated a lack of drug interference for each drug studied,” Dage said.

In one of the many studies he recounted, a dose-based reduction in plasma P-tau217 levels accompanied the reduction in amyloid.

“This is encouraging as a pharmacodynamic biomarker in larger trials,” Dage said.

The assay is being explored for applications in clinical research, including new drug trials, based on its capability to identify patients with Alzheimer’s disease and also to predict their risk of progression.

“Future work will explore utility as a surrogate efficacy marker,” Dage said.

In a related presentation, Mike Devous, M.D., VP of imaging development at Avid Radiopharmaceuticals, a subsidiary of Lilly, compared flortaucipir, a tracer used in imaging studies, to neuropathy in Phase III trials. Results showed an association with the detection of cortical neurofibrillary tangles (NFTs) in a large autopsy study.

“We’re exploring whether an early tau region may be sensitive to early pathology and intermediate progression,” he said.

Avid’s clinical trials involving tau imaging using flortaucipir show comparable density and distribution of tau pathology when compared to autopsy literature. “Baseline flortaucipir correlates with 18-month cognitive and functional change measures, and tau visual read patterns interact with quantitation to enhance understanding of cognitive decline,” Devous said.

“In two pivotal trials, flortaucipir PET imaging had statistically significant sensitivity and specificity for predicting neurofibrillary tangle scores of B3 or Braak V/VI and high levels of Alzheimer’s disease neuropathologic change,” he said.

“Despite overall agreement with Braak stages, patients may have widely varying patterns of tau distribution. Those patterns appear in different regions of the brain, and are relevant in progression and decline,” Devous noted. Memory, language, and visuospatial abilities, for example, are affected.

Based on these studies, flortaucipir PET imaging appears to identify a therapeutic window. It seems to offer higher sensitivity than MRI imaging, and comparable specificity.

Identifying accurate biomarkers and applying them to the clinical treatment of Alzheimer’s patients could have a profound effect on therapeutics and the progression of disease.

As Takeshi Iwatsubo, M.D. professor of neuropathology, School of Medicine, University of Tokyo, underscored, “Alzheimer’s disease is a relentless, fatal disease, creating a health crisis for patients, families, and nations. If we can’t stop it, the cost to society will be great.

“As researchers, we understand that the hallmark pathologies of Alzheimer’s disease occur 10 to 20 years before clinical symptoms…and we believe that amyloid and tau are both part of a common disease cascade that can trigger neuroinflammation and neuronal death,” Iwatsubo  said. “And yet…our research findings are not translating into the realities of community practice and the broader patient experience.”

Biomarkers for amyloid, tau, and neuroinflammation already play important roles in stratifying risk for clinical trial populations, but they tend not to be used in clinical practice. Yet, when combined with clinical assessment, family history, and early detection practices, “these latest tau biomarker findings can change the face of clinical practice,” he said.

For example, Iwatsubo said this new generation of biomarkers could identify the pathology of Alzheimer’s disease long before symptoms become evident, thus allowing treatment earlier than is common today. That, in turn likely leads to better outcomes.

The University of Tokyo conducted a seven-year, 537-patient, Phase III trial sponsored by Eli Lilly, NIA, and AMED, Japan, dubbed the Japanese Alzheimer’s Disease Neuroimaging Initiative (ADNI). The protocol was identical to the U.S. ADNI trial. It found that Japanese and American patients have similar disease profiles, enabling harmonization of international trials. The trial also found APOE genotyping helpful for predicting ATN (amyloid, tau, neurodegeneration) classification.

Building on that, a Japanese trial-ready cohort is ready to study preclinical/prodromal Alzheimer’s disease. More than 4.5 thousand participants are enrolled in what ultimately is expected to be a 15,000- to 20,000-person trial to study variables in amyloid prediction based on A4 screening data. “We are wondering if similar predictions of risk are feasible based on tau biomarkers and this data,” Iwatsubo said.

Tau biomarkers are useful in diagnosing Alzheimer’s disease, these researchers agreed. But, as Iwatsubo cautioned, “We are at the early stages. Their potential as efficacy markers of disease-modifying therapies should be further demonstrated.”

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