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Array-Based Alzheimer’s Dx Development Takes Three Steps Forward as Teams Commit to Tests

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Two companies and one academic/commercial collaboration separately announced last week that they are moving ahead with plans to develop tests for early-stage diagnosis of Alzheimer’s disease. All three used microarrays to discover the markers in their prospective tests and are leaning towards using the technology as the platform for delivering any resulting diagnostics to market.
 
DiaGenic, ExonHit Therapeutics, and a team of researchers from the Translational Genomics Institute, Banner Alzheimer's Institute, and contract research firm Kronos Science Laboratory are developing tests for early-stage Alzheimer’s and that future diagnostics arising from these projects may be based on arrays.
 
For DiaGenic and ExonHit, array-based research-use-only tools for Alzheimer’s that will act as a springboard to future clinical use could become available as soon as next year. Both firms have developed blood-based, gene-signature expression assays that they claim can help identify early-stage Alzheimer’s disease and guide better treatment and therapy options.
 
In DiaGenic’s case, the Oslo, Norway-based firm presented a prototype of its Alzheimer’s detection assay at the Alzheimer’s Association International Conference on Prevention of Dementia, held in Washington, DC, last week.
 
DiaGenic similarly presented two assay prototypes — one based on Applied Microarrays’ CodeLink platform and another using Applied Biosystems TaqMan assays — at an Alzheimer’s conference in Salzburg, Austria, in March (see BAN 3/27/2007).
 
This week, the company committed to having an RUO version of the assay on the market by the first half of 2008 — the first time it has provided any details of its development timeline. In the past DiaGenic has shied away from speculating on launch dates for its tests.
 
Company officials also said this week that after DiaGenic launches the RUO assay, it plans to pursue both European and US regulatory clearance for its Alzheimer’s test, which it believes may be able to shave costs off the roughly $100 billion spent on caring for Alzheimer’s patients in the US each year.
 
Current testing methods, including imaging, are only able to diagnose Alzheimer’s late in the development of the disease. DiaGenic hopes its tests could be used in conjunction with potential drugs to help diagnose and treat Alzheimer’s patients sooner.
 
“We will make the test available for diagnostic use, by CE marking in Europe, by the second half of 2008,” DiaGenic’s Managing Director Erik Christensen wrote in an e-mail to BioArray News this week. “Subsequent, but without a communicated date from DiaGenic, an approval from FDA will be pursued,” he wrote.
 
DiaGenic plans to support the roll-out of the test, which will be available as either a TaqMan assay or on the CodeLink platform, from its headquarters in Oslo, although the company does not plan to limit itself to the European market, Christensen wrote.
 
“The test will be available for selected partners for research use later this year,” he wrote. “The final marketing strategy for the research-use-only product is in development, and the product consists of both a selected gene set and proprietary statistical software. The business will thus initially be handled through Oslo and we are focusing on the global market and not restricting ourselves to Europe only.”
 
As part of preparing for the market launch, DiaGenic is continuing with several studies to “build documentation on the prototypes.” He cited DiaGenic’s involvement with the Norwegian government-funded Functional Genome Research project, which focuses on early detection of Alzheimer’s disease, “including conversion to AD from mild cognitive impairment and on test specificity in other dementias.”
 
DiaGenic is also establishing research collaborations with university groups in the US that could “be a valuable contribution to successfully develop[ing] a sensitive and specific diagnostic assay,” Christensen wrote.
 
La Maladie d'Alzheimer
 
DiaGenic was not the only firm to commit to a launch date for its Alzheimer’s test last week. For the first time, French diagnostics firm ExonHit Therapeutics said it will seek certification in Europe and market clearance in the US for its test “as soon as 2009.”
 
ExonHit’s assay is a 60-marker, multi-gene expression test assisted by an algorithm to produce a score that determines whether the patient has Alzheimer's disease. Like DiaGenic’s, ExonHit’s test uses patient sera in its assay.
 
In the past, ExonHit had not committed to launching its test on an array platform versus an RT-PCR platform like TaqMan. However, John Jaskowiak, the company’s vice president of business and marketing, told BioArray News in an e-mail this week that it is likely that ExonHit’s test will be on an array.
 
“The number of probe sets used by our signature directs [us] towards an array-based test,” he wrote. ExonHit has not disclosed which array platform its test will be based on, although the firm does have ties to both Agilent Technologies and Affymetrix, which both manufacture its line of splice variant arrays.
 
Jaskowiak wrote that finding the right manufacturer is “currently work in progress’ and that “ExonHit will take all necessary licenses from the various commercial entities to bring products to market in the molecular diagnostics field.”
 
The firm continues to use its test in various studies, a process that is likely to intensify as it enters the clinical trials stage that is necessary to win regulatory approval from the US Food and Drug Administration.
 
For example, ExonHit presented new data at the meeting in Washington last week based on a recent study. “We have analyzed an additional group of non-AD, control individuals from a different site,” Jaskowiak wrote. “Contrary to our initial control group, these people were not systematically affected by cardiovascular pathologies. The combined use of these two control groups improved our ability to classify the AD patients,” he added.
 
In a statement released last week, ExonHit President Bruno Tocque said that the company’s ultimate plan is to partner with a larger diagnostics company to commercialize the test, perhaps even prior to clinical trials.
 
"Our objective is to rapidly have this test certified in Europe and to license it to an in vitro diagnostic company while retaining some marketing rights to assist the pharmaceutical industry with the recruitment of AD patients for clinical trials," Tocque said.
 

“If these types of tests will be applied prior to onset, the prospective trial will likely need to be very large and very long in duration to see who converts to AD.”

Tocque also said that ExonHit has the “financial resources needed to implement this strategy and to obtain the licenses [that] may be required for the commercialization of this test.” Indeed, the company recently issued 400,000 new shares worth €3.4 million ($4.5 million). The company has traded on the Alternext exchange in Europe under the ticker ALEHT since March 2006.
 
Jaskowiak wrote that the new funding from the stock issuance “reinforces our earlier strong cash position to invest appropriately in the development of our diagnostic programs.”
 
GAB2 
 
A different kind of Alzheimer’s discovery came out of a collaboration between the Translational Genomics Institute, the Banner Alzheimer's Institute, and Kronos Science Laboratory, all of which are based in Phoenix, Ariz.
 
The trio published a study this month in Neuron that identified a common gene that appears to increase a person's risk for developing Alzheimer's. In the paper, the group suggests that the gene — called GAB2 — modifies an individual's risk when associated with other genes, including apolipoprotein E varepsilon4, which has been shown to be associated with late-onset Alzheimer’s [Reiman E, et al. GAB2 Alleles Modify Alzheimer's Risk in APOE varepsilon4 Carriers. Neuron. 2007 Jun 7;54(5):713-720.]
 
The gene was identified after TGen and partners used Affymetrix 500K SNP arrays to screen through more than 1,000 brain samples.
 
According to paper co-author Dietrich Stephan, the “GAB2 finding, and all subsequent findings that allow pre-symptomatic risk assessment for common human disorders, gives us a window before onset to avoid known environmental risk factors, implement screening programs, identify and diagnose disease at its earliest signs and symptoms, and ultimately to develop well-tolerated prevention therapies.”
 
Stephan, head of the Neurobehavioral Research Unit at TGen, told BioArray News in an e-mail this week that in Alzheimer's disease, “giving individuals an option to know about their risk — and not being paternalistic about telling people what they may or may not be tested for — could prompt better cholesterol management, lifestyle changes such as staying mentally and physically fit, and strategically plan for the eventuality.”
 
“It is less clear as to the utility in disorders that are not ‘actionable,’ but again early risk assessment [and] detection forms the basis for prevention therapy development in the form of cost-effective clinical trials and outcomes research,” Stephan wrote.
 
To create that opportunity, Stephan is working with several undisclosed pharmaceutical companies to “develop and test efficacy [of compounds] in delaying the onset of AD.” Additionally, Stephan pointed out that TGen, as the IP holder for GAB2, is working with Kronos on diagnostic applications for the newly discovered gene.
 
He wrote that any tests TGen develops with Kronos “would be DNA-based diagnostics to assess carrier status of GAB2.” He said that such tests are “still a way out, though.”
 
With regards to the tests developed by DiaGenic and ExonHit, Stephan wrote that using array-generated expression signatures “to diagnose Alzheimer’s disease from a surrogate tissue such as circulating lymphocytes is certainly biologically reasonable and technically feasible.”
 
He cautioned, though, that it is “important to validate this type of test prospectively, in large numbers of cases and controls to accurately determine the sensitivity and specificity of the test.
 
“If these types of tests will be applied prior to onset, the prospective trial will likely need to be very large and very long in duration to see who converts to AD,” Stephan wrote.

 
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