Lilly's Alzheimer's R&D Relies on Updated, Better Biomarkers and Diagnostic Tools

Eli Lilly's most notable progress in Alzheimer's disease came last year when the U.S. Food and Drug Administration (FDA) approved its amyloid plaque-targeting therapy Kisunla. However, beyond drug development for this complex disease, the company is also working on developing more sensitive and clinically meaningful diagnostic tools to help identify patients and drive more effective treatments.

Dr. Anthony “Nino” Sireci, Eli Lilly's senior vice president of clinical biomarkers, laboratories and diagnostics, transitioned into Alzheimer's disease from the oncology field. He previously worked at Loxo Oncology, which was acquired by Eli Lilly in 2019. Sireci witnessed numerous advances in precision oncology, and now he sees similar but faster-moving developments in this memory-destroying disease.

Using lung cancer as an example, Sireci notes that despite genetic testing capabilities existing for the past 20 years, about 80% of patients still haven't undergone comprehensive genomic profiling. In Alzheimer's disease, he sees the same shift happening, but faster, as pharmaceutical companies, healthcare systems, and patients gradually adapt to newer diagnostic technologies.

"How do we break through this ceiling in Alzheimer's disease? How do we ensure every patient gets tested? Because that's the only way to realize the full potential of our progress," Sireci said. "We don't want to settle for the status quo seen in oncology, because we can do better."

Eli Lilly used multiple diagnostic tools in the development of Kisunla. From PET scan imaging agents to ultra-sensitive blood tests, Eli Lilly works both with partners and through its LillyDirect platform to promote earlier diagnosis and expand access to these diagnostic tools.

"Our next goal must be to identify patients with amyloid pathology at the earliest possible stage, even before symptoms appear."

— Dr. Anthony "Nino" Sireci, Senior Vice President, Clinical Biomarkers, Laboratories and Diagnostics, Eli Lilly

We spoke with Sireci about advances in Alzheimer's disease testing, how these advances fit into drug development at Eli Lilly and the broader research community, and how he hopes diagnostic tools will help identify patients and disease in the future.

This interview has been edited for length and style.

PHARMAVOICE: What changes have occurred in the Alzheimer's disease field over the past decade or so?

Dr. Anthony “Nino” Sireci:There was a time when using blood tests to help diagnose Alzheimer's disease was a distant dream, but gradually, we developed methods to detect biomarkers like Aβ40 and Aβ42, and these tests have been on the market for years. In my view, the real shift began when we started focusing on phosphorylated tau protein, which is very useful for diagnosing amyloid pathology through blood. Two post-translationally modified tau fragments—p-tau181 and p-tau217—correlate with the presence of amyloid in the brain. This was a game-changing discovery, especially p-tau217, whose test performance has approached a 90% positive predictive value. If the test is positive, we are 90% confident that amyloid pathology is present; if negative, we are 90% confident in ruling it out.

I've witnessed the immense value of biomarker evolution, and we began exploring their value to clinicians early on.

Another area in Alzheimer's disease that is progressing faster than in oncology is coding and payer coverage. Because even with the best technology and drugs, what good are they if patients can't afford them or can't access them?

Why are these leaps in understanding the disease happening now?

First is technology. These protein fragments used as biomarkers require ultra-sensitive detection techniques not only in high-end academic labs but also in clinical laboratories. Our ability to measure substances in the blood has improved.

Second is understanding these biomarkers. We didn't know about p-tau217 until a few years ago, and understanding what measurable tau tangles and amyloid plaques in the blood truly mean required a great deal of meticulous and painstaking work.

We are in a new era: we understand the pathology, we have diagnostic technology, and we have potential treatment options—the combination of these three has made the field of Alzheimer's diagnosis flourish.

At a company like Eli Lilly that spans drug development and diagnostics, how does biomarker research integrate into drug development?

Biomarkers play multiple roles in drug development and ultimately in commercialization and access. In the development phase, they first serve as markers for patient identification and clinical trial enrollment. In Kisunla's Trailblazer-Alz 2 (Phase 3 clinical trial), we used PET as a visual biomarker to identify patients. In Trailblazer-Alz 3 (a Phase 3 trial for preclinical patients), we used blood biomarkers to define the population. Thus, we can use biomarkers to assess whether a drug is working, rather than relying solely on final outcome measures like symptom progression.

In Alzheimer's disease, we haven't fully discussed the role of biomarkers in terms of drug resistance, but in oncology we do this often. In oncology, biomarkers can serve as potential surrogate endpoints in trial design to assess progression and patient response to drugs. We haven't discussed it that way in Alzheimer's yet, but I can imagine that in the future we will start considering certain biomarkers as endpoints. The FDA has set a high bar for such applications, but thinking in that direction is not unrealistic.

Where does Eli Lilly currently stand in the Alzheimer's diagnostic space, and what's next?

Our first FDA-approved test is Lumipulse p-tau217/Aβ42, intended for early symptomatic patient populations. That's significant. Additionally, several in vitro diagnostic manufacturers are advancing FDA submissions, and we're excited about that. We also have multiple laboratory-developed tests, and there are guidelines specifying the performance standards these tests should meet—90% specificity, with an indeterminate range below 20% in asymptomatic or symptomatic populations. We know how to validate and what performance characteristics to focus on, and these advances are happening quickly.

Our next goal must be to identify patients with amyloid pathology at the earliest possible stage, even before symptoms appear. We know that amyloid deposition in the brain occurs before neuronal death—so how do we identify these patients? Developing blood tests or leveraging existing ones would be significant and would open the door for patients to get tested before symptoms arise.

How can healthcare systems use these biomarkers to provide testing for patients?

From an access and regulatory standpoint, we are in a favorable position. Although adoption is faster than in oncology, it's not yet widespread and likely hasn't reached most patients. Part of the reason is a lack of physician confidence or restrictions in guidelines on when to use the tests. So, we need to think about how to demonstrate or support the use of these tests in broader patient populations. Their utilization is far below where it should be, and the key to achieving that lies in continued publication of research, updated guidelines, and enhanced patient education.

How does Eli Lilly plan to closely integrate Alzheimer's diagnosis with treatment pathways to achieve more precise treatment in the future?

First, Eli Lilly is working with partners to drive further validation and approval of Alzheimer's biomarkers and to ensure appropriate, high-quality testing is available globally. Getting these tests to patients and paving the way for earlier diagnosis is our top priority. Perhaps one day, it will become part of routine annual blood work for people over 50 or 65. That would be an exciting point for diagnostics to make an impact, and it must be blood-based.