NEW YORK – Over the last several years, advances in both treatments for Alzheimer's disease and technologies for measuring biomarkers linked to the condition have driven growing interest from the diagnostics industry.
This is especially true of blood-based Alzheimer's tests, a territory that, to date, has largely been the province of academic researchers and smaller life science firms but has recently seen an uptick in activity from big diagnostics players like Roche and Sysmex as well as midsized companies like Fujirebio and clinical labs like Quest Diagnostics.
This investment on the part of such firms is a vote of confidence of sorts — an indication that blood-based testing for Alzheimer's is broadly viewed as a viable business proposition. It also raises questions about how the smaller companies that have pioneered the space will fit if it becomes dominated by larger outfits.
"There are companies looking at [Alzheimer's] and thinking, this could be the next oncology in terms of biomarkers," said Kristen Amanti, a partner with Newtown, Massachusetts-based healthcare consulting firm Health Advances. "There are some who predict that in the future Alzheimer's is going to be divided into biomarker-defined segments that will guide treatment, and so there is a potentially huge opportunity for diagnostics companies here."
Two developments have been key to accelerating this opportunity. Recent US Food and Drug Administration approvals of Biogen's Alzheimer's drug Aduhelm (aducanumab) and Eisai's Alzheimer's drug Leqembi (lecanemab) have raised the possibility that physicians will in the near future need Alzheimer's screening methods to identify patients who may benefit from these and/or future treatments.
Meanwhile, advances in biomarker discovery and measurement have made it possible to detect analytes linked to Alzheimer's in patient blood, raising the possibility of diagnostics that, unlike existing cerebrospinal fluid or PET imaging tests for the condition, can be run inexpensively and at scale in large, potentially asymptomatic populations.
"I think the moment we have all been waiting for was the availability of a disease modifying therapy, and that certainly will have a significant impact on the need for testing," said Bruce Jordan, international business leader for personalized healthcare solutions, neurology, and general medicine at Roche Diagnostics.
"And when you talk about [testing] in plasma, if you go back three or four years, I think the field was asking, 'Is this actually possible, to identify signs of [brain] amyloid [characteristic of Alzheimer's] in the peripheral blood?'" he added. "And I think the data has shown over the years that this is possible."
St. Louis-based C2N Diagnostics has been a major player in pushing plasma-based Alzheimer's testing forward. A spinout of Washington University in St. Louis, the company was founded in 2007 and has been working on plasma-based tests for the condition for more than a decade. In 2020, it brought its PrecivityAD assay to market as a laboratory-developed test. The assay uses mass spectrometry to measure levels of amyloid beta (Aβ) 40, Aβ 42, and apolipoprotein E4 (ApoE4) in patient blood and combines those measures with patient age to assess the likelihood that they have the brain amyloid pathology characteristic of Alzheimer's.
Immunoassay firm Quanterix has also been active in the blood-based Alzheimer's biomarker space, which the company sees as a good fit for its high-sensitivity Simao technology. It currently offers CLIA-based blood tests for the Alzheimer's marker phosphorylated tau 181 (pTau 181) and neurofilament light chain (NfL), a marker of neuronal damage that could be useful in early detection of the disease.
Both C2N's and Quanterix's tests were used as biomarkers in the primary clinical studies for Leqembi. Individuals treated with the drug showed an increase in plasma Aβ 42/40 and reduction in plasma pTau 181 — both indicating effectiveness — compared to individuals given a placebo. In prescribing information for the drug, however, the FDA noted that the Aβ 42/40 and pTau 181 results "should be interpreted with caution due to uncertainties in bioanalysis."
Bresso, Italy-based Diadem has also been active in the plasma Alzheimer's testing space, developing a mass spec-based test called Alzosure Predict that measures an Alzheimer's-linked variant of the protein p53 that it is positioning for identification of patients likely to develop the disease well before the onset of symptoms. The company, which has received breakthrough device designation from the FDA for the test as well as a $2.5 million grant from the US National Institutes of Health to validate the assay, aims to begin sales in the US and Europe this year.
With blood-based tests either on the market or nearing commercialization, these small firms have a head start on many of their larger competitors, but the space could quickly become a crowded one. At the end of 2022, Kobe, Japan-based diagnostics firm Sysmex received approval from Japan's Pharmaceuticals and Medical Devices Agency for its blood-based HISCL β-Amyloid 1-42 Assay Kit and HISCL β-Amyloid 1-40 Assay Kit, which are intended for use on its automated HISCL-Series immunoassay instruments.
In March, Roche announced a collaboration with Eli Lilly to develop its Elecsys Amyloid Plasma Panel (EAPP), an immunoassay-based test measuring pTau 181 and ApoE4.
Midsized diagnostics firm Fujirebio currently offers research-use-only plasma tests for Aβ 42/40 ratio and pTau 181 and is developing assays for pTau 217 and NfL. The company is still assessing which of these markers will prove most useful clinically.
Amanti said she suspects there are other companies looking at the space that have not yet made their plans public. She suggested, though, that the opportunity will likely prove large enough to sustain a variety of players serving different parts of the market.
"I think there's probably room for both platform companies [like Roche] and the specialty diagnostics laboratories," Amanti said. "If we're talking about mass spec-based testing that has an algorithm attached to it, I think that kind of testing will remain in the specialty lab. But I also think there will be a use case for, 'Hey, this patient needs to go on therapy. They have to be positive for amyloid beta. We need to do a quick blood test.'"
For its part, Roche plans to position its EAPP as a rule-out test, likely for use in a relatively broad patient population. Jordan said that in the company's discussions with the FDA it had become clear that the agency wants "to see the test explored not only in a specialist setting but also earlier in the care journey, moving toward being inclusive of more primary care settings."
Roche sees its Elecsys Beta-Amyloid (1-42) CSF II and Elecsys Phospho-Tau (181P) CSF assays, which received 510(k) clearance from the FDA in December 2022, as confirmatory tests that can be used to follow up results from the EAPP or other blood tests.
Fujirebio also offers an FDA-cleared CSF Alzheimer's test, its Lumipulse G β-Amyloid Ratio (1-42/1-40) immunoassay.
As these larger firms target the market for plasma Alzheimer's testing, C2N is looking to stay ahead by continuing to innovate and add to its portfolio while also working to scale its operations to enable widespread use of its tests, said Joel Braunstein, the company's president and CEO. The company has developed a second-generation version of its PrecivityAD test called PrecivityAD2 that adds mass spec measurement of plasma pTau 217/unphosphorylatedTau 217 ratio to the components of the original test.
In data presented at the AD/PD 2023 International Conference on Alzheimer’s and Parkinson’s Diseases this month, the test distinguished between amyloid positive and negative individuals in a cohort of 307 patient seen at primary care sites in Sweden with an area under the curve of 0.94. In a separate cohort of 281 cognitively unimpaired individuals, the test detected brain amyloid with an AUC of 0.96. The study also looked at the ability of plasma biomarkers to predict cognitive decline, finding that pTau 217 ratio was the most effective of the markers evaluated.
"We view our task as continuing to be innovators for the field," Braunstein said. He added that while many view plasma-based tests as primarily useful as an initial screening tool, C2N believes its technology could ultimately serve as a confirmatory diagnostic.
"Our vision from the get-go was that we can develop really high-quality assays that would enable us to completely obviate the need for a subsequent test," he said. "Delay of diagnosis is a big issue [as is] the complexity of the diagnostic journey for patients. … We want to be able to provide a single solution that greatly simplifies that process."
Scaling its testing capacity is also "an important part of our future growth and is an active area of development for us," Braunstein said. He cited recently announced partnerships with lab companies in Brazil and Australia to bring the Precivity Test to those markets and said that C2N planned to announce additional similar deals this year.
Quanterix is also pushing its plasma Alzheimer's pipeline forward, generating data for a pTau 181 FDA submission through the Global Alzheimer's Platform Foundation Bio-Hermes study and working on assays for other Alzheimer's markers including pTau 217 and pTau 231.
CEO Masoud Toloue said the company expects the market will accommodate multiple test providers, particularly as "more disease modifying treatments become available" and added that "Roche's entry into the Alzheimer's diagnostic landscape is complementary to Quanterix's presence in the space."
Braunstein similarly suggested that Roche's move into plasma Alzheimer's markers could benefit other smaller players by raising the profile of such testing.
"When a company like Roche commits to developing a program like this, they are going to do a lot in the area of education," he said. C2N has also made similar educational efforts, and as a smaller firm, its global footprint is limited, and raising awareness is "an absolutely critical issue," Braunstein said.
Charlotte Teunissen, a professor of neuroscience at Amsterdam University Medical Centers, noted that Roche's large instrument installed base and its integration into existing clinical laboratory workflows give it an advantage, particularly where higher volume testing is concerned.
"While the technology of C2N is really outstanding, and they have developed the test extremely well, it is not a technology that you can export easily to a lot of other labs and put into their routine clinical laboratories," she said. "That is what the bigger companies are good at. Their technologies fit well into routine clinical chemistry laboratories."
That doesn't necessarily mean Roche will take over the market, Teunissen said. She noted that while she initially thought the company would dominate CSF-based Alzheimer's testing in Europe, Fujirebio has become the leading provider there. The relative simplicity and smaller footprint of that company's immunoassays analyzers have likely contributed to its advantage in this area, she noted.
Then there is the question of how immunoassays like those being developed or offered by firms including Roche, Sysmex, and Fujirebio will stack up to the performance of mass spec-based tests like C2N's.
In particular, this could prove an issue for tests measuring plasma Aβ 42/40 ratio, where the difference between patients with and without amyloid pathology is typically only 10 to 15 percent and where drugs commonly used in older populations can significantly impact patient ratios. Some studies have indicated that this difference may be too small for tests to reliably detect and that inclusion of other markers may be necessary to provide the required performance.
Research has also shown that mass spec-based assays for Aβ 42/40 ratio do have high performance for identifying amyloid positive individuals, whereas the immunoassays evaluated did not.
Indeed, Roche moved on from a prototype immunoassay for assessing plasma Aβ 42/40 ratio due to the small difference in levels between patients with and without amyloid pathology and the challenge of measuring that difference consistently, Jordan said.
C2N does have a large competitor in the mass spec space as Quest Diagnostics last year launched its AD-DETECT product, a mass spec-based laboratory-developed test that measures Aβ42/40 ratio in plasma.
It also remains unclear how existing plasma-based tests and proposed markers will hold up when tested in larger, more diverse populations. Some studies, for instance, have indicated that markers like pTau 181, pTau 231 and NfL may perform differently in different ethnic groups.
Researchers have also seen factors like kidney function and body mass index impact results delivered by plasma markers, said Rebecca Edelmayer, senior director of medical and scientific relations at the Alzheimer's Association.
Plasma tests "need to be something that are testing broadly across a variety of individuals, across broad populations to show that the predictive value of these tests is helpful to clinicians and patients who have to make decisions about their health," she said.