Dr Joel BraunsteinJoel Braunstein, MD
C2N Diagnostics was recently granted breakthrough device designation by the FDA for its brain amyloidosis blood test, which is a blood-based in vitro diagnostic being developed to predict amyloid PET scan results in individuals being assessed for an Alzheimer disease diagnosis. The test will provide initial screening information to aid doctors in determining the need for further diagnostic testing.

The test is currently being investigated in the Plasma Test for Amyloid Risk Screening (PARIS) study to evaluate and validate the tests’ clinical diagnostic performance. If approved by the FDA, the test could be the first blood-based screening test to predict brain amyloid PET scan results with memory complaints or dementia.

Joel Braunstein, MD, CEO of C2N Diagnostics, spoke with NeurologyLive in an interview to further explain C2N Diagnostics’ proprietary brain amyloidosis blood test, its clinical impact, and the PARIS study.

NeurologyLive: Can you describe the process of the amyloid blood test?

Joel Braunstein, MD: The C2N blood test uses plasma, which is obtained through a traditional blood sampling technique. The collected blood sample is sent to a centralized lab, that being C2N Diagnostics. Theoretically, any clinical laboratory that has the proper instrumentation and adequate training would be able to perform this. For our initial rollout of the test, we would expect the test to be performed in a single centralized laboratory.

The blood sample arrives at C2N. We process the sample and then ultimately run the plasma component through a mass spectrometer to obtain a readout of two peptide markers: amyloid beta (Aβ) 42 and Aβ40. We then calculate a ratio of Aβ42 over Aβ40. That ratio will produce a value that we ultimately categorize into a normal/abnormal, or positive/negative test result. We would expect to provide the numerical test value and result back to the clinician, who would then use that information to aid in further evaluation of the patient. The specific interpretation of the test is something that could still evolve as we learn more about the performance of the test in ongoing clinical studies; however, the general premise here is that if you have a negative test that would ideally present a low concern for Alzheimer disease pathology in someone who's at risk. A positive result would suggest that further diagnostic testing is warranted out of potential concern for Alzheimer pathology. The diagnostic process really lies in the hands of the neurologist or the clinician who's taking care of the patient. We hope that the results of our test will substantially aid in the overall evaluation and ultimately, management, of that patient.

Mass spectrometers are instruments that have a tried-and-true history of being used in the research setting. These instruments are a primary tool for many researchers to look at the quantitation and metabolism of proteins and other biomolecules implicated in human disease processes. In our case, we use mass spectrometry to measure the analytes of interest. There are other platforms that can be used for looking at proteins or peptides, but our group is particularly focused on mass spectrometry as the platform. We believe that mass spectrometry offers some unique insights into peptides and proteins of interest, and we believe that the platform has other attributes that make it ideal for using as part of an in vitro diagnostic test. Two benefits to mass spectrometers include: 1) their specificity, and 2) their precision. In scientific terms, specificity means that in the context of measuring a biomarker, you are actually measuring the biomarker that you are interested in measuring. Other platforms for quantifying biomarkers can be less specific than the mass spectrometer, which is really the gold standard for specificity. In our case, we're interested in identifying Aβ42 and Aβ40 in the plasma, and the mass spectrometer is very specific for picking out those two analytes. A second special attribute of mass spectrometers, once you lock down the methodology for measuring those markers, is the high precision of the measurement. So, not only are mass spectrometers specific, meaning you can measure what you're intending to measure, but they're also precise. This means that if you were to take the same sample and run it 2 separate times, you should get a similar read-out of the reported values. That's important when you're dealing with a condition as complicated as Alzheimer disease and trying to detect amyloid pathology in the brain using a plasma test—plasma is a complex matrix, and it's hard to pull out the analytes of interest from that matrix. You want to ensure that you have a precise and specific method to measure something as challenging to detect as Aβ42 and Aβ40.

Are you studying this diagnostic in clinical trials?

We are currently studying performance of the test in a clinical study among individuals who are deemed to be at high risk for Alzheimer disease. We are using specific criteria that identifies the person who is at high risk for Alzheimer disease. These individuals have subjective memory complaints and have presented to their clinician due to concern for potential Alzheimer disease. A number of conditions may explain the cognition concerns. Certainly, the early stages of Alzheimer disease or mild cognitive impairment (MCI) could be a cause for the cognition decline. However, a variety of other neurodegenerative diseases can also explain the cognition concerns and masquerade as Alzheimer.

This is where an Alzheimer pathology screening test has the potential to aid the doctor’s evaluation of the patient.

The PARIS Study is a study that we're using as a pivotal trial to demonstrate the safety and efficacy of the device. Per the FDA requirements to be able to get marketing clearance or marketing authorization for a test, a sponsor must demonstrate that the test meets a certain level of diagnostic performance in the target patient population. The PARIS Study is designed to help us define that performance level.

While the PARIS Study will provide us with key data that we would ultimately submit to the FDA, we are also going to be submitting data from other studies. These studies are evaluating the performance of the test in other patient groups than those included in PARIS. Those studies are also helping us to answer a variety of other research questions beyond those that will be answered in PARIS. It is our hope that all of the information we accumulate will support a solid package for the FDA to make its decision about the suitability of our test.

We have already conducted some studies with this test. The early data is encouraging, but the PARIS Study represents the pivotal study, which we've broken into two phases. Also, we expect any studies that are happening in parallel to the PARIS Study to also be important pieces of information for the ultimate application to FDA.

We haven't indicated our specific timeline. It's our hope that we can be looking at 2020 for submitting the test for review by the FDA, and ultimately, a clearance or approval. This, of course, is subject to many different assumptions, but we believe that we are making very good progress. We have been actively enrolling in PARIS and so we've made a lot of progress in the conduct of that study. The next stage after completion of enrollment is the evaluation of the samples. Like I indicated at the beginning of our talk when an individual has their blood taken, the blood gets sent over to C2N. We then store those samples under frozen conditions until we're ready to do the analysis. So there's enrollment of individuals into the clinical trial and then there's analysis of the samples, which occurs at a later date. The sample analysis at C2N is what actually yields the measurements that we’re interested in reporting.

We're excited about the work at C2N. We think that this test has potential to serve as an important tool for clinicians to use when a patient that falls into a certain risk category for Alzheimer disease presenting to a memory specialist with subjective memory complaints. We want the physician to have a widely accessible tool that is cost effective and will enable timely and efficient screening for amyloid pathology in the brain as detected by PET. Based on the test information, we hope that the clinician will be better equipped to recommend the patient for further analysis for Alzheimer disease pathology; or, decide that it makes more clinical sense to evaluate the patient for other conditions besides Alzheimer that might explain the cognition problem. Existing diagnostic tests for Alzheimer disease have various limitations. Some of these tests are expensive and logistically complicated to administer. Amyloid PET imaging, for instance, is costly, difficult to access for certain people in parts of the country, and exposes individuals who do not have Alzheimer disease to unnecessary radiation. The ability to provide a screening test with a blood draw has potential to improve the speed and efficiency of the overall diagnostic process.

C2N was recently granted breakthrough device designation, what’s this mean for the test?

The FDA granted us a Breakthrough Device Designation, and we're enthusiastic about that. This identifies the test as addressing an important unmet medical need, an important public health problem, and it allows for more timely and potentially speedier access to the market. There's still the statutory requirement to demonstrate safety and efficacy even with the breakthrough designation; however, when you have that designation, it demonstrates that the FDA considers your program a priority and important with the potential to provide a significant impact on clinical care. At the same time, it affords us at C2N better communication and more interactions with the FDA. Thus, as we're making progress with our development program, we can have more correspondence with the FDA to improve our chances of staying on track and optimizing our chances of introducing a safe and effective diagnostic test for the clinic.

There's growing data to suggest that someone's awareness of having Alzheimer disease or even just having amyloid pathology will lead to better care for that patient. It's our hope that a test like ours will also allow doctors to provide better care of their patients. This will have to be demonstrated in clinical studies, but it is our goal with development of the test to substantially aid in the diagnostic process. In turn, we think that could translate to into better planning and better management of the patient, whether that patient has Alzheimer disease or another condition causing the subjective memory complaint. Also, when more effective Alzheimer’ therapies come onto the market, we believe that these therapies will be most effective at the earliest stages of the disease. A widely accessible screening test could be helpful for identifying those people who are presenting with early stages of the disease. Earlier detection could lead to earlier intervention.