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C2N Accelerating Development of Alzheimer's Early Detection Test, Phase III Clinical Trial Markers

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Neurology biomarker firm C2N Diagnostics is accelerating its test development efforts with the aim of commercializing protein markers for the early detection of Alzheimer's as well as for use as primary endpoints in Phase III clinical trials of therapies for the disease.

The company last month brought aboard Timothy Veenstra, the former director of the National Cancer Institute's Laboratory of Proteomics and Analytical Technologies, to spearhead these development efforts, focusing on establishing the tests' scalability, throughput, and internal validity, C2N CEO Joel Braunstein told ProteoMonitor.

Launched in 2007 to commercialize technology developed in the labs of Washington University researchers David Holtzman and Randall Bateman, C2N combines in vivo stable isotope labeling with mass spectrometry to track the production and clearance of proteins, particularly those associated with neurodegenerative disease.

The firm's primary focus is Alzheimer's, but it also has programs in conditions including Parkinson's, frontotemporal dementia, progressive supranuclear palsy, Huntington's, and amyotrophic lateral sclerosis, Braunstein said. C2N also provides services out of its bioanalytical research core lab, offering preclinical and clinical biomarker services in support of pharmaceutical research.

The company's internal biomarker development work currently centers around "about a dozen markers," Braunstein said, noting that due to the complexity of Alzheimer's, "it's hard to find a single marker" suitable for the various uses he and his colleagues are pursuing.

Like much Alzheimer's biomarker research, C2N's work has focused significantly on measuring levels of β-amyloid in cerebrospinal fluid. However, Braunstein noted, instead of looking at absolute levels of this molecule, the company uses stable isotope labeling to look at production and processing of Aβ. This, he said, offers the promise of a more sensitive, less variable look at patient Aβ levels.

An issue with tracking absolute Aβ levels, Braunstein said, "is that the hour-to-hour variability [of this measure] is incredibly high."

"Within a single individual, if you were to measure hourly [Aβ] levels over 24 hours, you can actually have variability ranging from 50 percent to 400 percent," he said.

Aβ production, on the other hand, "is very tightly regulated," Braunstein said, so that "by tagging the newly produced protein, you can follow its progression over time in the presence of all sorts of amyloid processing or metabolism, and you can pick up all sorts of subtle differences between individuals."

Braunstein also cited a study in the June edition of Science Translational Medicine published by researchers including Holtzman and Bateman that suggests that increased Aβ precedes amyloid deposition in the brain and, as such, tracking Aβ production could offer even earlier detection of Alzheimer's than approaches like PET imaging or measuring absolute Aβ levels in CSF.

Braunstein declined to say when C2N aims to launch its Alzheimer's early detection test, but, he noted, the company plans to do clinical validation studies for the markers in 2014. It has not yet determined if it will bring the test to market either as a laboratory-developed test, a US Food and Drug Administration-cleared in vitro diagnostic, or both, he said.

The company currently does not have a CLIA facility, but is working towards that goal, Braunstein said. Regarding an FDA-cleared version, he noted that the feasibility of such a product would hinge significantly on the continued progress of mass spectrometry into the clinic.

"I think clearly where the [mass spec] field is headed in proteomics is toward clinical applications," he said. However, he added, "right now our general feeling is that the world of specialized mass spec work is still centralized to a number of really good facilities."

That being the case, C2N plans for the time being to focus on internal development "to make sure we have very robust markers," Braunstein said, while also working on the markers with several "other parties with highly qualified mass spec capabilities… to replicate what we are doing and build a product that could theoretically be performed at multiple centers."

In July, the company inked an exclusive supplier agreement with Cambridge Isotope Laboratories for the stable isotopes used in its biomarker workflows. Under that agreement, C2N received from CIL an upfront payment, commercial milestone fees, a guaranteed supply of stable isotopes, and GMP-grade isotopically labeled leucine, which the company plans to use in upcoming clinical validation studies.

In addition to an early detection test for Alzheimer's, the company is also developing a marker for use as a surrogate endpoint in Phase III clinical trials. It already has markers in use for pre-clinical development and as primary endpoints in Phase I and Phase II Alzheimer's drug trials. Braunstein declined to name the pharma companies conducting these trials, but he did note that the firm had worked in the past with drug developers including Eli Lilly and ReXceptor.

C2N is also pursuing plasma-based Alzheimer's markers, which, as Braunstein noted, are desirable due to the expense of imaging methods and the difficulty inherent in obtaining CSF, which is typically taken via a lumbar puncture.

"A big challenge to the field is how do we develop markers that are easy to obtain and convenient to patients and affordable," he said. "[PET] imaging, while it can certainly help detect pathology, is not cheap and has logistical issues. And CSF measurements are quite good but also an inconvenience to patients."

Plasma-based markers would be ideal for screening larger cohorts of potentially at-risk patients "without having to put them through an invasive testing strategy," Braunstein said. He declined to disclose the particular proteins the company was looking at as plasma markers, but noted that they would not necessarily be the same as those in CSF.

"It's very clear that what is going on in the brain may not necessarily translate to what is going on in the blood," he said.

According to Braunstein, C2N currently has the equivalent of 10 full-time employees and is funded via a mix of service revenue, several anonymous donations, and grants from organizations including the Alzheimer's Drug Discovery Foundation, the Michael J Fox Foundation, and the National Institutes of Health.

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