01 Feb 2019

St. Louis-based C2N announced this week that the Food and Drug Administration has fast-tracked review of its blood test for amyloid pathology, granting it Breakthrough Device designation. This status is reserved for devices that could improve treatment or diagnosis of a life-threatening or debilitating disease that has no such options. As part of the approval process, the Plasma Test for Amyloid Risk Screening (PARIS) trial will test how well blood Aβ42/Aβ40 measured by the mass spec test correlates with brain amyloid detected by PET. The goal is to develop an inexpensive and noninvasive test for Aβ pathology that can be used in clinical trial recruitment and in clinical diagnosis.

Scientists have made huge strides toward a blood test for Alzheimer’s disease in recent years (Nov 2018 conference news). C2N’s mass spectrometry-based approach is one of several in the works. Others include an enhanced immunoassay based on the single molecule optimized array (SIMOA) detection being developed by researchers at VU University, Amsterdam, and ADx Neurosciences, Ghent, and another mass-spectrometry-based test from Japanese and Australian researchers (Aug 2018 conference news; Feb 2018 news). These tests are all based on detecting Aβ42 and Aβ40 in the blood. A low Aβ42/Aβ40 ratio suggests ongoing amyloid accumulation in the brain.

The Breakthrough Device designation speeds up the review process. “This will give C2N more frequent correspondence with the agency as we develop the test,” said C2N CEO and co-founder Joel Braunstein. “This will help to ensure that we are designing our clinical studies properly and are performing the correct analytical validation to satisfy regulatory requirements.”

The PARIS study will enroll more than 500 people who have at least one established risk factor for AD and who have subjective memory problems. The primary goal is to see how well the blood test picks up brain amyloid pathology detected on PET scans. The company has nearly completed enrollment, drawing from patients seeking treatment at memory clinics in the U.S. Researchers are in the process of collecting blood samples and PET scans from each. Details about the study, including baseline characteristics of participants, will be presented at the Alzheimer Association International Conference in Los Angeles in July. A number of ancillary studies, including ongoing cohort studies, will contribute more samples to bring the total tested for regulatory submission to more than 1,000, Braunstein said.

At this point, C2N analyzes all samples at its St. Louis facility. After blood is collected using a standardized procedure, it is immediately frozen and later shipped to the company for analysis. Over the long term, C2N will partner with other mass spec labs for commercialization of the assay.

“The central lab design is important at this stage; this is definitely not a ‘plug and play’ assay yet,” noted Henrik Zetterberg, University of Gothenburg, Sweden, who is not involved in this work. “The relatively small difference in plasma Aβ42/40 between brain amyloid-positive and brain amyloid-negative groups puts very high demands on the performance of a plasma assay.” He emphasized the need to replicate findings and work out the pre-analytic sample handling and assay stability.

In contrast, the ADx SIMOA-based AMYBLOOD assay is being designed so that labs can analyze samples on site. ADx has already correlated the ratio of plasma Aβ42/40 with Aβ in cerebrospinal fluid, and plans to correlate against amyloid PET in the next few months in samples from different cohorts, according to company co-founder Hugo Vanderstichele. Researchers are currently optimizing procedures for collection and storage of samples and developing robust test methods. The company is beginning discussions on how to commercialize the test, said Vanderstichele.—Gwyneth Dickey Zakaib