When Joshua Soldo and John Forrest met with Alzheimer’s specialist Khalid Iqbal, PhD, at the Alzheimer’s International Conference in Amsterdam two summers ago, it would alter the future of Veravas, their company that had created sample transformation and biomarker purification technology.
“I asked [Iqbal], ‘What do you think of these diagnostic tests [for Alzheimer’s]?’” Soldo told Inside Precision Medicine. “He said, ‘They’re all rubbish because they’re all measuring the wrong thing—it’s not plaque that matters, it’s the tau pathology that leads to the breakdown of the neural network and neural generation. If you were going to have a test [for Alzheimer’s], you should be looking for tau pathology because that’s what matters.’”
Tau is a protein that stabilizes microtubules. When tau becomes hyperphosphorylated, it sequesters and competes with normal tau, preventing the structure from stabilizing and pulling it off the microtubules. This tau pathology, which begins as seeding in the prion-like manner of hyperphosphorylated tau binding normal tau, eventually forms these tau tangles and microtubular filaments, which are indicative of cognitive decline and one of the hallmarks of Alzheimer’s disease.
Soldo continued, “In [Iqbal’s] mind, if we could develop a test to measure tau pathology—that binding of hyperphosphorylated tau to normal tau—it would be a clinically meaningful test. So, I thanked him for his time, got his business card, and had the long flight home to the U.S. I thought about what [Iqbal] was saying and asked, Can we do that with our technology? By the time I landed, I already had the concept for an assay design, so I called him up and said, Dr. Iqbal, I think you and I should meet.”
Iqbal, who also co-founded and serves as the CSO of Phanes Biotech, an early-stage biotech company developing treatments for neurodegenerative diseases, took Soldo up on the meeting. The result was a patent application for a tau-binding assay that was filed and then developed into a blood-based test by Veravas and Phanes Biotech.
Fast-forward to today and Veravas has announced the analytical verification of this test, called the VeraBIND Tau Assay, to measure Alzheimer’s tau pathology in blood. According to the announcement, the VeraBIND Tau Assay showed 92% agreement with gold-standard tau PET imaging in samples from patients with normal cognitive function, mild cognitive impairment, or dementia.
“The big difference is we’re not measuring the level of [tau],” said Soldo. “Most companies would capture the biomarker on the beads and then say, ‘How much should we capture?’ Then, they report the result in nanograms or picograms per milliliter. We don’t answer that question. We say, ‘Is it present, and if it is, is it active?’ If it’s active, you got it. If you don’t have symptoms, you probably need to look at the modifiable risk factors that are out there to try to delay the onset of this disease… and hopefully, one or more of these tau-directed therapies to clear this tauopathy and maybe stop the disease from progressing that are at different clinical trial phases of trials will come out in the next three to five years.”
The quest for truth
Joshua Soldo has had a prolific career in the diagnostic space over the past 25 years. At Beckman Coulter, he developed and patented the solid-phase technology used in their access immunoassay platform and also developed some of the very first cardiac assays for acute myocardial infarction. At his next stop, DiaSorin, he got involved in making the world’s first fully automated test for vitamin D. “That kind of blew up,” Soldo told Inside Precision Medicine. “At one point, we’re doing over 40 million vitamin D tests annually in the U.S. alone. It was a pretty exciting time.”
According to Soldo, the disadvantage of releasing a test at that rate is that it increases the likelihood of total diagnostic failures. It was through the failures of this test that Soldo became aware of interferences—substances such as lipids, free hemoglobin, and bilirubin (also known as globulins and drugs) that affect the results of clinical pathologic tests as they are performed.
Before his next job, a stint at Roche, Soldo devised an inventive method for pre-analytically cleaning patient samples to remove interferences before testing. As Soldo put it, “Instead of trying to design around it, what if you just get rid of the interferences to begin with?” That biomarker purification technology, VeraBind—a portmanteau of the Latin word for truth (“vera”) and the word for bind—is the foundation of Veravas, which Soldo co-founded with Forrest in 2017.
In some ways, that was the extent of Soldo’s ambition for the project. However, a series of events, including Soldo’s mother experiencing a brain injury from an aneurysm, drew him back into the world of diagnostics, culminating in that fateful summer day in Amsterdam.
False positive silver lining
To validate the VeraBIND Tau Assay, Soldo and Veravas teamed up with PET imaging expert Bernard Hanseeuw, MD, PhD, associate head of the Memory Clinic, neurology department, Saint Luc University Hospital in Brussels and instructor at Mass General Hospital in Boston. According to Soldo, Hanseeuw had gotten wind of the VeraBIND Tau Assay and met Forrest co-founder John Forrest at the 2023 Human Amyloid Imaging Conference in Miami, leading to an introduction and conversation with Soldo.
“[Hanseeuw] was super excited about the assay and said, ‘Wow, if you guys can do a blood-based version of a tau imaging test, which is not easy for me to run in my practice and clinic and everything, that would be a game changer,’” said Soldo. “So, we agreed to do a clinical study together where, based on his clinical cohort and samples, he would identify samples that were tau PET negative and positive based on his imaging as well as amyloid PET negative and positive, and where he also had full cognitive assessment testing done on these patients to know if they are cognitively normal or impaired with MCI or dementia and knew their genetic predisposition (if they’re ApoE4 positive or negative).”
Hanseeuw was flush with data and sent samples to Veravas to test the VeraBIND Tau Assay and compare the results retrospectively to the tau PET imaging (F18MK6240 tau) results. With 100 patient samples—including 52 confirmed positive for Alzheimer’s tau pathology via F18MK6240 tau PET imaging (of which 19 had normal cognitive function, 21 had mild cognitive impairment, and 12 had dementia), 38 healthy controls, and 10 patients positive for beta-amyloid plaques but negative by tau PET—the data showed 94.2% sensitivity and 89.6% specificity, resulting in an overall VeraBIND Tau assay agreement of 92.0% against tau PET imaging. Though they weren’t perfect, Soldo said that for a single cutoff—a “yes/no” assay—the VeraBIND Tau Assay demonstrated inspiring results. However, what Soldo is really impressed by comes from a more detailed analysis of the false results.
Soldo said, “In the samples that we were false-positive, which meant tau PET was negative and our test was positive, some of these patients had dementia and went on to develop Alzheimer’s. So, it showed that we were more sensitive than the tau PET, and [Hanseeuw] is using a second-generation towel tau PET tracer that’s supposed to be more specific and sensitive for tau pathology. [Hanseeuw] is excited because it looks like our assay may potentially improve sensitivity over imaging. Again, imaging can only detect how it will light up when it’s at a certain density in the brain, so this is a blood-based assay. It’s possible we could have improved sensitivity even over tau PET imaging. We felt that this was a pretty exciting assay for an analytical verification study to show with a single cutoff over 90% accuracy against tau PET.”
RUO first, FDA-approved IVD second
The next step is to bring the VeraBIND Tau Assay to the market as a laboratory developed test (LDT) with the CLIA lab partner. However, with the FDA’s classification of LDTs as in vitro diagnostics (IVDs), which subject them to device regulation, Soldo stated that the short-term path to market is as a research use only (RUO) test, followed by work on transitioning from analytical validation (i.e., presence of a molecule) to clinical validation (i.e., presence of a disease) and meeting with the FDA to discuss clinical trials. Soldo’s take on the FDA’s oversight of laboratory development tests is that high-complexity labs that are Clinical Laboratory Improvement Amendments (CLIA) and College of American Pathologists (CAP) accredited believe they already have regulatory supervision and oversight for high-quality, highly accurate tests. Still, the FDA disagrees, thinking that some commercialized LDTs are subpar and may not meet the standards of other diagnostic tests.
Soldo said, “There’s this battle right now between the FDA and especially the large reference labs, like LabCorp and Quest, and Academic Centers of Excellence with many LDTs on their menu. If you tell the Mayo Clinic that they have a junk test, they will say, ‘FDA, you’re not going to tell us that our LDT is of high quality and high accuracy; we’re the Mayo Clinic.’ In fact, [the Mayo Clinic] wrote a long letter to the FDA saying they have over 1,500 LDTs, and they said we are not submitting our 1500 LDTs to the FDA. That’s just not going to happen. And so if you’re in the Mayo Clinic, I guess you can have those discussions. We would never say that to the FDA—we’re not the Mayo Clinic.”
Before the FDA’s ruling, using an LDT required a license to be a part of a high-complexity Clinical Laboratory Improvement Act (CLIA) certified laboratory. That process necessitates a complete validation of the assay in which a lab develops its own clinical cutoffs and performance metrics (e.g., accuracy, precision, and sensitivity), which must be produced during an audit. To stay current, Soldo stated that some labs enroll their LDTs in CAP, which sends out surveillance efficiency samples that can eventually show the accuracy of their assays.
“LDTs are a way to bring novel diagnostics to the market faster because you never know how long it’s going to take to get an assay through the FDA, what kind of data they’ll want, or what kind of studies they’ll expect. Since Alzheimer’s is the wild, wild west right now, and there aren’t any blood tests approved yet by the FDA for Alzheimer’s. So, we don’t know how long it will take for that to progress. We feel this test has a way of making a clinical impact today, addressing an unmet clinical need. We say that our test is not on the market every day, we are not improving patient lives.”
At the end of the day, Soldo said that by taking the RUO route, Veravas will collect real-world evidence, which the FDA allows in IVD submissions, to show clinical validation. And that’s the route they will take to strengthen their future submission to the FDA.
