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Merck Taps Luminex to Develop CDx to Stratify Patients for Alzheimer's Drug Trials

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Originally published March 19.

Merck has selected Luminex to develop a multi-marker companion test to select patients for clinical trials of its investigational BACE inhibitor MK-8931, which is being developed to prevent or delay the symptoms of Alzheimer's disease.

In a deal announced last week, Merck said it would work with Luminex to develop a companion test based on the firm's xMAP platform that will be used to stratify patients into clinical trials involving MK-8931. According to the terms of the collaboration, Luminex will be responsible for the test's development, regulatory approval, and commercialization.

In turn, Merck researchers will use the test to identify patients with mild cognitive impairment who are at heightened risk of developing Alzheimer's based on the concentration levels of the biomarkers amyloid-beta42 and total tau protein in their cerebrospinal fluid. The drug developer plans to enrich clinical trials for MK-8931 with patients at greater risk of developing the disease.

Published data suggest that variable levels of Aβ42 and t-tau in CSF of patients with mild-cognitive impairment may be a way to identify those at high risk of developing Alzheimer's disease and may enable doctors to treat patients early to stave off symptoms.

MK-8931 inhibits the beta amyloid precursor protein site cleaving enzyme, or BACE, which is thought to be implicated in the production of amyloid beta peptide, which causes the accumulation of amyloid plaque that many researchers believe to be the underlying cause of Alzheimer's disease. As such, Merck is betting that as a BACE inhibitor, MK-8931 will block the formation of amyloid plaque deposits in the brain and delay or prevent Alzheimer's disease.

A significant portion of drug development in Alzheimer's has focused on this so-called amyloid hypothesis, which holds that drugs that can prevent the formation of amyloid plaque can also prevent disease symptoms, such as dementia. But the strategy hasn't panned out for many drug makers.

For example, Johnson & Johnson and Pfizer's bapineuzumab, a monoclonal antibody designed to bind to and clear beta amyloid, failed late-stage clinical trials last year. The drug was being studied as a treatment for mild to moderate Alzheimer's disease in APOE4 carriers, which is associated with increased risk for Alzheimer's. The companies halted research on the drug based on the study results.

In the case of Eli Lilly's solanezumab, which is also designed to bind to the beta-amyloid protein and remove it from the brain before it forms amyloid plaque, the drug failed to slow the rate of cognitive decline in two separate studies. However, the study results suggested that the drug may be effective in staving off memory decline in patients with mild to moderate disease. Further clinical trials are exploring the drug's efficacy in this subpopulation.

Meanwhile, Roche is taking a protein biomarker-driven strategy, like Merck, but for a monocolonal antibody called gantenerumab. The company is conducting a 770-patient study, called Scarlet Road, in which researchers will measure Tau/Aβ levels in study participants' spinal fluid to identify early onset or prodromal Alzheimer's patients and treat them with gantenerumab. Roche is developing a companion test to gauge Tau/Aβ levels in trial participants. Results from Scarlet Road are expected in 2015 (PGx Reporter 9/12/2012).

Roche subsidiary Genentech is testing another monoclonal antibody, crenezumab, to see if it can prevent Alzheimer's in a population genetically predisposed to getting the disease. Genentech, in collaboration with Banner Alzheimer's Institute and the National Institutes of Health, is conducting a Phase II trial investigating crenezumab in the residents of Medellin, Colombia, where people share a common ancestor and have a high prevalence of mutations in the presenelin 1 gene. Those harboring the dominant gene mutation will start to lose their memory in their mid-40s and their cognitive functions will deteriorate by age 50.

The five-year study will involve approximately 300 participants, of whom approximately 100 mutation carriers will receive crenezumab and another 100 mutation carriers will receive a placebo. In a third arm, approximately 100 participants who don't carry the mutations will receive a placebo. Study investigators will begin recruiting patients for this study next year.

Merck believes that its BACE inhibitor has a mechanism of action that is substantially different from antibodies targeting a-beta, and as such might able to succeed in preventing Alzheimer's where other agents failed.

In a Phase I study, MK-8931 reduced the levels of beta-amyloid in the cerebrospinal fluid of Alzheimer's patients and healthy volunteers without dose-limiting side effects. Based on the results from this early study, Merck has initiated a Phase II/III trial, called EPOCH, to investigate the safety and efficacy of MK-8931 in patients with mild to moderate Alzheimer's. The Phase II portion of EPOCH is slated for completion by year end. The company expects to enroll nearly 2,000 patients into the trial, which is expected to be completed in January 2017.

Merck's decision to partner with Luminex to develop the companion test for MK-8931 on the xMAP platform will enable the company to gauge multiple markers from a single patient sample at once. Multiplex tests are quicker and potentially less costly than testing individual markers separately. Merck also chose the multiplex bead-based immunoassay due to the fact that the technology has been used in protein research applications and has been validated in multiple published studies. Additionally, a number of Luminex's xMAP technologies have garnered FDA clearance.

Alzheimer's Disease International estimates that there are more than 5 million people in the US currently living with the disease. A diagnosis of Alzheimer's can only be confirmed by looking at the histopathological features and beta amyloid deposits in the brain after a person has died. Currently, there are no available treatments that prevent the disease.

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