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Wyeth’s Approach to Clinical Biomarkers

By Malorye Allison

Oct. 10, 2007 | Most companies have the same reasons for doing biomarker research. “We have to understand how a drug is working before we invest large sums of money into Phase II and III trials,” says J. Lynn Rutkowski, co-leader of clinical translational medicine at Wyeth Research. “If we can work through the mechanism, we can have much more confidence advancing the project.”

That’s the argument for using biomarkers, but how does that actually translate into specific programs? According to Rutkowski, it all begins early in development. “You need a strategy in place so you have time to do the research you need to fill in gaps and get biomarkers you have confidence in.”

Every compound at Wyeth — the company currently has 75 to 80 compounds in development — is evaluated for potential biomarkers. Rutkowski is responsible for the clinical development side of Wyeth’s translational medicine department. The team overseeing each compound includes a discovery biologist, clinical pharmacologist, and translational scientist. “There’s a dedicated person who is responsible for developing and delivering response biomarkers,” she says.

Last year, Wyeth initiated a collaboration with four Scottish universities (Aberdeen, Dundee, Edinburgh, and Glasgow) called the Translational Medicine Research Collaboration (TMRC). Wyeth is investing almost $86 million for biomarker discovery, including ten in cardiovascular and metabolic disease, four in inflammation, and seven in neuroscience.

“For each target, you want at least one biomarker unique to that target,” Rutkowski explains. Wyeth is continually developing new markers, which may take many forms. In stroke, for example, in addition to imaging technology, Wyeth is using rehabilitation tools to gauge patients’ responses. “We are taking advantage of robotic instrumentation for therapy that can also provide a quantitative assessment of motor-function recovery,” she says.

Alzheimer’s Advances
Alzheimer’s disease (AD) is a particularly important indication at Wyeth, which has 11 AD compounds in development. The company’s long-term strategy involves molecular markers, structural and functional brain imaging, and physiological, behavioral, and associative learning tests.

One problem is that it takes so long for AD patients to either show disease progression or improvement. And as it’s not possible to take samples of brain, molecular markers are picked out of cerebrospinal fluid or plasma. “If you are measuring something in a surrogate fluid, you still do not know exactly what is happening in the target tissue,” Rutkowski explains. However, the growth in biomarkers for AD is revealing new insights about the disease.

“We know there are familial forms of Alzheimer’s, and we know that mutations in gamma- and beta-secretase cause a build up in plaque,” Rutkowski says. Another hot target in AD are the neurofibrillary tangles seen in patients’ brains after autopsy. Plenty of markers are used to track the various states of molecules that play a role in plaque and tangle formation.

“Ideally, for a brain disorder, we would like to have a receptor ligand that could be the signal of some crucial event,” says Rutkowski. In concert with imaging, this would be a very specific approach. “We could verify that the drug gets to its target.”

Wyeth scientists are pursuing another type of plaque as an exciting new target — the so-called “vulnerable” plaque found in peripheral arteries that can rupture and cause heart attack or stroke. “Many of these cardiovascular diseases are linked,” Rutkowski says. “If you have lots of plaque, for example, you are at risk not only for ruptures; the vessels may get stiffer, causing high blood pressure.” Wyeth has several drugs that are targeting different processes, including inflammation.

Wyeth researchers are particularly interested in FDG-PET studies that will help monitor metabolic activity in these lesions without requiring biopsies, and are exploring different platform possibilities. The company’s scientists are also examining different ways of labeling macrophages to track their infiltration of the lesions. “We want these markers implemented in Phase I, and we already have a compound that is getting close to an IND,” Rutkowski says.

“At this point, we can do a Phase 0, which is like a Phase Ia/Ib/IIb type of study, something that allows more exploratory kind of research with additional add-on studies,” she says. With those completed, they should have some markers in hand, and feel confident that they are relevant to this condition.

Overall, Rutkowski doesn’t see many dominant approaches. “There are so many technologies emerging,” she says. “The moment you commit to one, there is another right behind it.”

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