NEW YORK – After years of development based on research originally begun at the US National Institutes of Health, Synaps Dx is preparing to fully launch its skin-based Alzheimer's disease diagnostic test.
Drawing on preclinical work done at the NIH and licensed from the former Blanchette Rockefeller Neuroscience Institute, now part of West Virginia University, Synaps Dx is building on a beta launch in Texas and aiming to target the rest of the southern US in the near future.
The firm's Discern test uses three biomarkers — two proteomic and one imaging biomarker — to diagnose Alzheimer's disease and differentiate it from other forms of dementia. The primary diagnosis is based on morphometric imaging, which measures how cells grow, Synaps President and CEO Frank Amato said. Fibroblasts are cultured from a patient's skin sample and imaged, and the total cell aggregates and area of cell aggregates are measured and read out at different time points to see how they change. Fewer large aggregates are formed in a patient with Alzheimer's than a patient without, and the cells begin to clump together and fall into themselves in Alzheimer's patients, Amato said. In a Scientific Reports paper published in November, the morphology assay showed 100 percent sensitivity and specificity when compared to autopsy diagnosis.
The "anchor" of the test and the first confirmatory diagnosis after morphometric imaging, according to Amato, is the protein kinase C epsilon biomarker, which is a "hallmark driver of synaptic change." Synaptic loss tracks closely with the development of Alzheimer's disease, but the protein degrades quickly in a patient's blood. In comparison, it is much more stable in skin, Amato said, which led the developers to use skin punch biopsy samples. The fibroblasts cultured from the skin samples are exposed to a toxic oligomer, and the changes in PKC epsilon are measured via ELISA — when treated with the oligomer, PKC epsilon levels are upregulated in Alzheimer's patients and downregulated in patients with non-Alzheimer's dementia, Amato said. When validated against autopsy diagnosis, the test had 100 percent sensitivity and 96 percent specificity.
The other proteomic biomarker and second confirmatory assay, if the imaging and PKC epsilon tests disagree, is the measurement of phosphorylated ERK-1 and ERK-2. The properties of the proteins change between cells depending on whether a patient is healthy, has Alzheimer's, or has non-Alzheimer's dementia. In this test, the fibroblasts are exposed to an inflammatory agonist, which highlights changes in the amounts of phosphorylated ERK-1 and ERK-2. Those levels are measured using western blot testing and quantified with an index that differentiates between Alzheimer's and non-Alzheimer's dementia. Validation against autopsy diagnosis in a paper published in PNAS in 2006 found the test had 97 percent sensitivity and 94 percent specificity.
The combination of the assays' results is used to determine whether a patient has Alzheimer's disease or non-Alzheimer's dementia, as well as a breakdown of the results from each assay. The entire process takes about eight to 10 weeks, Amato said, owing to the fact that culturing the cells takes six weeks. He noted that traditional work-ups for Alzheimer's disease, which often include PET imaging and cerebrospinal fluid-based testing, can take up to about 12 weeks total, but said that Synaps Dx is "always looking at ways to automate and speed up" its testing process.
The test is also able to differentiate between mixed dementia patients, or patients with more than one cause of dementia, Amato said. In the same Scientific Reports paper from November, researchers found the imaging assay was able to correctly diagnose Alzheimer's even when patients had other comorbidities.
The company began seriously working toward commercialization after raising $10 million in its Series A financing round in 2021 and is currently planning a Series B round targeting healthcare venture capital groups, Amato said. It has also received its own reimbursement codes from the Centers for Medicare and Medicaid Services: one for the cell culturing, imaging, and PKC epsilon tests, which is priced at $2,215, and one for the ERK assay if the first two tests don't agree, priced at $511. The test only has Medicare coverage right now, and the company has not sought private payor coverage, but Amato noted that the majority of the Alzheimer's population is covered by Medicare anyway.
Synaps Dx began offering its test in a beta launch in Texas last year, providing the assay to 16 doctors and getting 340 samples to test in its CLIA laboratory in Maryland, Amato said. The company plans to use the funding from its Series B round to launch the test more broadly in Texas, then move to Florida, North Carolina, and the rest of the South. The firm started its launch in Texas because it had previous sales connections in the state and because Texas is often an early adopter of healthcare technology, Amato said. It is moving to Florida next due to the large population of elderly people and retirement communities in the state, he added.
Right now, the assay is being offered as a laboratory-developed test, but Amato said the company hopes to gain de novo clearance from the US Food and Drug Administration for one of its tests, likely the imaging assay. It will then seek 510(k) clearance for the other two assays.
Although it is targeting the US first, the company's intellectual property is patented or has patents pending in multiple countries, including Japan, Canada, South Korea, and countries accepting the CE mark, he said. Due to its small size, the firm would likely need a partner to expand globally, but the size of the US market is enough for now, Amato said. It is also considering partnerships with diagnostic companies who have more commercial infrastructure in the US, with Amato saying the firm has had conversations with larger companies and there is potential for M&A activity in the future.
Synaps Dx is also exploring partnerships with pharmaceutical companies, particularly as more Alzheimer's drugs, such as Biogen's Aduhelm (aducanumab) and Eisai's Leqembi (lecanemab), are approved and brought to market. There is ample opportunity to market the test to patients with mild cognitive impairment before they're diagnosed with dementia — a market that pharma companies are also targeting, Amato said. The firm is finalizing a partnership with an undisclosed pharma partner that will be announced soon, he added.
Currently, Alzheimer's is diagnosed through a combination of symptom observations, tests using cerebrospinal fluid, and brain imaging technologies. Also, many companies have developed or are developing blood-based tests for the disease. Japanese firm Fujirebio received FDA clearance in 2022 for its Lumipulse G β-Amyloid Ratio (1-42/1-40) assay, which detects amyloid plaques in cerebrospinal fluid, and the company is working on plasma-based tests, as well. C2N Diagnostics, meantime, has developed its PrecivityAD test that measures plasma Aβ 42/40 and apolipoprotein E protein, and Quanterix offers blood-based LDTs for pTau 181 and neurofilament light, both of which have received breakthrough device designation from the FDA.
Italian diagnostic firm Diadem has also received breakthrough device designation for its mass spectrometry-based plasma test AlzoSure Predict. Quest Diagnostics currently offers its Quest AD-Detect Amyloid Beta 42/40 Ratio test for plasma, and Roche nabbed FDA clearance last year for two cerebrospinal fluid-based Alzheimer's tests measuring beta-amyloid and tau proteins.
For Amato, the biggest differentiator between Discern and other Alzheimer's disease tests, besides the use of skin as a sample, is that its biomarkers have been validated with autopsies and have been clinically confirmed as indicative of a patient having Alzheimer's. Early validation of the test used about 150 skin samples that were taken when patients were diagnosed with dementia and then validated against their autopsies, he said.
Many Alzheimer's tests are measuring proteins that are hallmarks of Alzheimer's disease, such as amyloid plaque and neurofilament light, but that haven't unequivocally been proven to cause Alzheimer's, he said. "Without those two proteins, you wouldn't have Alzheimer's disease, but they don't cause the disease," he added. "When an individual has plaque and tau in their brain, that doesn't mean they're going to have Alzheimer's disease."