NEW YORK — With the recent publication of two peer-reviewed papers, Alzheimer's testing firm C2N Diagnostics continues to build the case for its blood-based test for the condition, PrecivityAD.
The company also saw this week a development that could have a notable impact on its fortunes and that of the Alzheimer's testing space more generally, as the US Food and Drug Administration approved Biogen's anti-amyloid Alzheimer's treatment Aduhelm (aducanumab).
C2N and its collaborators published in May a study in Molecular Neurodegeneration that looked at the performance of its test in 414 plasma samples collected from six different US cohorts, finding that it predicted amyloid status with 86 percent accuracy when ApoE4 copy number and age were included in the test model. Also in May, the St. Louis-based company and collaborators published a study in Clinica Chimica Acta detailing the analytical characteristics of the assay, finding that it had levels of precision, accuracy, sensitivity, and linearity suitable for clinical testing.
Both studies are what Joel Braunstein, cofounder, president, and CEO of C2N, described as an ongoing effort to build a body of evidence supporting use of the test, which the company launched in October as a laboratory-developed test.
The PrecivityAD test uses mass spectrometry to measure blood amyloid beta (Aβ) 40, Aβ 42, and apolipoprotein E levels along with patient age to generate a score of 0 to 100, with a higher score indicating a higher likelihood of the amyloid brain plaques characteristic of Alzheimer's disease. The test is the first commercially available blood test for detecting the presence of brain amyloid.
"Since the day we introduced this test, we knew it would be an imperative for us to have well-documented evidence and that that evidence would ultimately drive adoption," Braunstein said. "The opportunity [for users] to see peer-reviewed publications provides I think a lot of assurances that it is a robust test and has been peer-reviewed. It's imperative for physicians to be able to review results from clinical studies that evaluate the test in a variety of different clinical contexts and different patient populations."
The Molecular Neurodegeneration study in particular addressed this latter point, Braunstein said, noting that the six centers the samples were taken from varied in the patient populations, sample collection conditions, and exact PET imaging techniques they used to assess amyloid status.
"Even in the presence of that heterogeneity, the test performs very well," he said.
Moving forward, the company has a number of additional studies and datasets it plans to publish for peer review, including the data set used to derive and validate the specific model of the test it is offering out of its CLIA facility. It is also exploring how the test performs across different ethnicities as well as questions around whether it can indicate amyloid pathology in patients without Alzheimer's symptoms or who are in the prodromal stage of the disease. Additionally, Braunstein said the company and its collaborators have begun to study questions of clinical utility, such as how test results impact patient care.
The FDA's approval of aducanumab also opens up a potential future market for PrecivityAD tests and others like it. It remains to be seen what regulators and payors will require in terms of testing to select patients who qualify for the treatment, but it seems likely that some form of amyloid testing will be needed, said Douglas Scharre, a neurologist and director of the division of cognitive neurology at Ohio State Wexner Medical Center, which was involved in clinical trials for aducanumab.
While the FDA approved the drug for treating Alzheimer's generally, clinical trials evaluated it only in individuals with early-stage Alzheimer's who tested positive for brain amyloid by PET scan. Scharre noted that now payors like Medicare and private insurers would begin hashing out the criteria patients must meet to qualify for reimbursement for the drug. He said that he expected testing to show amyloid positivity would be part of payor requirements.
"I can't imagine them just saying, 'OK, the doctor thinks that you have it, we'll just pay for it,'" he said.
PET imaging is the gold standard for assessing amyloid status, but it is expensive, costing as much as $10,000, depending on the center, Scharre said, exposes patients to radiation, and is generally not covered by insurers. Effective tests for diagnosing Alzheimer's based on measurements of Aβ in cerebrospinal fluid exist and are far less expensive than PET imaging. These tests, however, require a spinal tap, which some patients are reluctant to undergo and which may be dangerous in patients on drugs like blood thinners, Scharre said.
"I would love to have a blood-based test," he said, though he noted that, unlike PET and CSF amyloid testing, PrecivityAD is not yet FDA-cleared. He added that while it was substantially less expensive than PET, it was still expensive. The list price for PrecivityAD is $1,250, though C2N offers financial assistance that can bring the price down to between $25 and $400.
Braunstein said that, generally speaking, the approval of aducanumab "will certainly escalate the priority and need for being able to better identify those patients who truly have Alzheimer's disease pathology."
"The existing tools, CSF-based measurements and PET scans, are just not a solution that is going to be accessible to as many people who it may be appropriate to test," he said. "And that is part of the drive for blood-based biomarkers, that it really opens up the window to many, many more patients being able to get evaluated."
A number of companies and academic researchers other than C2N are also exploring plasma-based markers for Alzheimer's. Researchers from the Alzheimer's Precision Medicine Initiative have shown that plasma measurements of Aβ 40 and Aβ 42 made using Quanterix's Simoa platform could identify cognitively normal individuals with brain amyloid.
In 2019, researchers at IBM identified a plasma protein signature predictive of CSF Aβ42 levels. The same year, a team led by researchers at King's College London identified a panel of 12 blood proteins that could distinguish between asymptomatic subjects with high and low levels of brain Aβ deposits with a sensitivity of .78 and specificity of .77. In 2018, researchers at Japan's Center for Development of Advanced Medicine for Dementia identified a series of Aβ precursors and variants measured using immunoprecipitation combined with MALDI-TOF mass spec that could help detect and monitor Alzheimer's disease.
With regard to PrecivityAD specifically, Braunstein said that the company would need to collect data demonstrating that its test could be useful for stratifying and identifying people most likely to benefit from treatment.
"The data has to be examined, and you have to be able to demonstrate with evidence that the test can work in that capacity," he said, though he didn't say if the company had any immediate plans to begin investigating this question.
Braunstein said that currently the test is most heavily used in research settings by pharmaceutical companies, for example, that are trying to enroll patients in clinical trials.
"There is very good data at this point to support the premise that one can use a blood test like this to markedly speed enrollment in clinical studies," he said. "So there has been significant demand for using the test in that context."
He said the company has also seen strong demand from academic investigators researching aspects of Alzheimer's disease who need biomarker work as part of their study.
"What typically happens there is that we become a subcontractor on those grants to provide the biomarker measurements," Braunstein said.
The test is less widely used in the clinic at this point, but Braunstein said he expected that as the test gained reimbursement clinical uptake would grow.
He added that in addition to diagnosing Alzheimer's, the test has proved useful clinically for ruling out the disease. "We've had a number of individuals who wind up getting a low score that is inconsistent with amyloid presence that compels the physician to look for other causes, and we've seen a number of cases where that has led to concrete changes in [patient] management," he said.
FDA clearance will likely also be important for driving uptake of the test, particularly, as Scharre suggested, with regard to the potential use of the test as part of evaluating patients for treatment with aducanumab or other anti-amyloid drugs that may come to market in its wake. The company is pursuing FDA 510(k) clearance for the test, which received breakthrough designation from the agency in 2019.