June 14, 2006 | Drug-induced vascular injury is a compound killer. Too often, a compound that looks promising, in terms of efficacy, is later cast aside when vascular injury turns up in animal testing. The FDA even established a task force on the problem a few years back, but made limited progress.

Now, in an important milestone for the systems biology community, Pfizer is publicly talking about promising work with Genstruct on vascular injury.

This particular Genstruct-Pfizer collaboration is around two compounds that produce profound vascular injury in rats. Pfizer did extensive profiling of the compounds (gene expression, proteomic, and metabolomic) and amassed a huge data set. Genstruct applied its inference-based modeling approach — the hallmark of which is interpreting large empirical data sets — and was able to define two key mechanisms having to do with the initial injury events and subsequent to the injury event, the initiation of inflammation.

Unsurprisingly, Genstruct CEO Keith Elliston is jubilant. “The [systems biology] industry has suffered from people going out and hyping what they think they might be able to do at some point in time rather than talk about what they actually accomplished,” says Elliston. “We really love that [Pfizer] is talking about [this.]” No doubt.

This project, which took only four months of Genstruct’s time, is part of a multi-pronged pilot program with Pfizer that began in 2003 and has now begun to bear public fruit.

“If you don’t understand the mechanism, how can you find out whether or not that’s going to be something that is going to be toxic in man? If you don’t have mechanisms, do you at least have biomarkers that you can use to identify the early events of vascular injury if you’re trying to do a first-in-man study or a dose escalation trial? No one has been able to define any biomarkers that have any kind of translational ability,” says Elliston.

Genstruct has proposed a series of biomarkers that Pfizer is now testing to determine if they can be used not only in animals but also in humans. Elliston says, “We defined a rationale that we think may enable these compounds to be developed in humans based on those mechanisms and how they operate differently in man than rats.”

Coming of Age
If the work proves out, it will constitute compelling evidence that modeling and simulation are coming of age. Indeed, the willingness of Pfizer to discuss the work publicly is a good sign. (Eugenia Floyd presented at the recent Society of Toxicology meeting in San Diego, according to Elliston, and Pfizer was scheduled to present at CHI’s World Biomarker Congress in late May).

Elliston says, “I think the promise of systems biology is to really help you identify things that you can capitalize on more efficiently, and faster. If you look at the vascular injury project, if you can identify why these PD4 inhibitors cause vascular damage, and we can identify early biomarkers to do this, we can start basically engineering out of these compounds the toxicity. Or if we find it’s not relevant to man, we can develop these compounds directly in man.”

Clearly, systems biology remains far from the mainstream, but among early adopters it’s becoming firmly entrenched. Consider that last March Novartis announced the elevation of Modeling and Simulation to departmental status and recruited Don Stanski, previously of Stanford University and the FDA, to lead the effort. He will report to the head of clinical development. The new department currently has 35 scientists (Novartis is recruiting more) and will be organized into three divisions — biology, pharmacology, and statistics.

“We’ve been doing this for about four years now, and we think now is the time to put the push on. You’ll see us doing a couple of aggressive moves over six to nine months. We’ve been able to demonstrate success with partners, and now it’s the time to turn it into a commercial push and see where it goes,” says Elliston.