David Cox leads one of Pfizer’s “biotech-like” research units.
By John Russell
January 20, 2009 | Start with a person who should be sick but isn’t. Use DNA variation to hunt for broken genes that are keeping this person well. Set up a vigorous hypothesis generation and killing machine to mercilessly winnow through the options. Make drugs informed by the rare surviving hypothesis and race them through proof of concept.
To a considerable extent, this is what Pfizer’s year-old Biotherapeutics and Bioinnovation Center (BBC), which recently broke ground on a headquarters in the Mission Bay district of San Francisco, is trying do with its Target Generation Unit (TGU), led by David Cox. Like his new boss and BBC president Corey Goodman (see, “Can Academics Save Pharma?” Bio•IT World, November 2007), Cox has a sparkling academic resume. He was the former co-director of the Stanford University Genome Center before co-founding the Affymetrix off-shoot Perlegen (see, “Taking Data Storage to Infinity and Beyond,” Bio•IT World, January 2003). Much of the TGU is located at the BBC Research Technology Center (RTC), in Cambridge, Mass.
If drug finding is still largely searching for needles in a haystack, Cox is using a genetics magnifying glass to find them. But this is not the whole formula. The BBC seeks the nimbleness of biotech and a new, more effective approach to collaborating with academia (see, “BBC’s University Challenge”). The result, Pfizer desperately hopes, will be faster, less expensive, less problematic biotherapeutic discovery and development, and possibly the emergence a new paradigm that is adopted throughout the Pfizer organization.
Watching the BBC
The BBC is actually a federation of small, independent biotech-like research units that aims to harness the strengths of biotech and pharma to discover and develop biotherapeutics through clinical proof-of-concept. One of those units is Rinat, a spinout from Genentech with cutting-edge antibody technology expertise. Another is CovX in San Diego, which is pursuing an emerging technology, uniting the therapeutic attractiveness of peptides with the beneficial clinical properties of antibodies.
The third unit is comprised of the RTC and Coley in Düsseldorf, Germany, which is building Pfizer’s capability in RNA interference. “Each of these research units are focused on a novel and growing technology area, each unit harnessing its small size, unique culture, and entrepreneurial drive to discover and develop breakthrough science in the most productive way,” says Cox.
While those sites will feature cell-based and animal in vivo studies, Cox says the TGU was set up to complement those activities by putting human genetics on the front end of that process. “Human genetics has never been very successful by itself, so it needs human cell-based models and it needs systems biology approaches to be really useful.” Cox says the TGU will put a premium on integrating the genetics, cell-based models and systems approaches “to maximize that synergy.”
After several years at Perlegen, Cox was drawn to the Pfizer opportunity by “the ability to plug human genetics into a situation that can impact medicine. It’s remarkable what’s happened in human genetics over the past five or ten years. But the actual impact on health outcomes, to date, has been pretty pathetic.” Human genetics can play a role in picking treatment options and use them more effectively, Cox says. “But the way our society is set up, it’s really hard to have that make commercial and regulatory sense. What I realized is that it’s going to be really hard doing it in a diagnostics way, so why not apply human genetics to make new medicines for unmet medical needs? That is what attracted me to this opportunity.”
The TGU approach will start with an important clinical question and outcome, then use genetics as a way of linking that outcome to a specific biological pathway. As an example, Cox offers this intriguing question: Why do some diabetes patients have such a high risk of dying from heart attacks? No current diabetes drugs impact the incidence of heart attack, so what biological pathway or target is the key to dealing with that medical need?
This is where the human genetics comes in. Cox’s team is starting with unusual diabetes patients that for some reason do not develop cardiovascular disease—patients that should have developed the side effect but didn’t. “By doing DNA sequencing quite globally on a large number of genes, we’re looking to see if there is evidence of rare DNA variations that may be the reason why these diabetics didn’t get cardiovascular disease,” says Cox. “We’re looking for the broken genes in the people who didn’t get sick.”
In many cases, Cox suspects, the mutation will have partially reduced the effect of the gene. “It doesn’t give you a home run, but it parachutes you in specifically to the biology you’d like to look at.”
From there, TGU is positioned to study cell-based models to study the effects of knocking out that gene. “Here’s where the systems biology comes in: you perturb the system with that very focused initial gene and now you say, based on the output of that perturbation, are there better things within that aspect of biology that you should be looking at then the initial gene that you used?”
Cox says there are two very different ways of thinking about systems biology. The approach he’s advocating starts with one part of the universe and expands out. The other collects the data and reverse engineers how everything works. “They’re both absolutely fine intellectual constructs and they both undoubtedly contribute really useful information, but one is much more focused than the other,” he says.
Cox sees important roles for in silico biology, although he says the problem with ’omics approaches is that “they aren’t tied to the fundamental clinical outcomes that we care about. The reason for looking at the DNA variation is because you can associate that in a casual way with the clinical outcomes that you care about.”
The goal is to use various approaches to draw links between DNA variations and clinical outcomes. “Without understanding the mechanism, the chances that things are going to work in humans as a drug are very unlikely.” Cox intends to “keep pushing at the mechanism until we are confident that we have enough understanding that when we put that in humans, it’s actually going to have the effect we want.“
The success of the BBC will ultimately be judged, Cox says, by “how many things that we put into humans in clinical trials show positive proof of concept in patients. Period. There’s no intermediate success.” He expects to have some idea in a year or two, but as for proof of concept in humans, “it’s unrealistic to think that we will have the answer in less than three. But it better be a lot faster than ten years!”
Cox does not see Pfizer’s size and bureaucracy hindering his group’s goals. “We have a tremendous opportunity to show how this can work,” he says, arguing that the BBC represents a truly innovative operating model both for Pfizer and the pharmaceutical industry in general. The BBC will work closely with the rest of Pfizer R&D “to maximize platform line, therapeutic area and technology expertise to drive the development of high-value compounds across both organizations.”
He foresees plenty of interaction between the two groups. “The BBC will take compounds through proof of concept. We have our own clinical unit. But for all of the phase III trials and all of what needs to get leveraged from big pharma, that’ll be part of the Pfizer organization. So we leverage the strengths of the big organization but we stay separate enough that we can use a biotech approach for the first parts of research and development.”
Maintaining a sense of independence for the BBC is important. “We want to preserve the unique cultures of these sites and maintain their entrepreneurial spirit,” says Cox. “The notion is to have groups that you can get everybody together in a small auditorium and talk to everybody without a microphone—they’re all focused on the technology, and it becomes really exciting.”
There will still be a priority on reaching the go/no-go decision early. “The motive to kill projects is very high for us because we expect most of our ideas are going to be not very good,” Cox admits. “No matter how good our ideas are, if we do the right science, most of them are going to go away. That’s just the way science works.”
Systems and in silico biology approaches will help scrutinize ideas that appeared promising but based on kinetic parameters or mass action, tell the TGU not to bother to do a single experiment because it’s dead on arrival. “Lowering clinical attrition is the key,” says Cox. “If we can put biotherapeutics into the clinic that have a higher probability of making it to the market to become human drugs, that will be a win for Pfizer, and a big win for human health.”
BBC’s University Challenge
Pfizer is focusing on six priority areas based on the perceived likelihood of success and unmet medical needs: oncology, Alzheimer’s disease, schizophrenia, pain, rheumatoid arthritis, and diabetes. The BBC is no different, but will initially focus on diabetes and oncology.
A key component will be a directed emphasis on external collaborations. Historically, Cox says, “pharma has given money to academics but often hasn’t given any real detailed knowledge about what they are trying to accomplish. And the academics are happy to take the money but they aren’t really interested in the questions the pharma industry is interested in and they use it to do whatever they want.”
Cox says Pfizer and the BBC are going to find the scientists with the right expertise to complement its internal strengths, but in a much more directed fashion. “We’re going to say, ‘We’re really interested in your models for this particular purpose and that we’d like to work with you to get this particular answer.’” That’s quite a departure from the traditional way of doing things, says Cox, because in general big pharma has been reluctant to divulge its specific interests and strategies. “I think that leveraging what’s out in the biomedical world in an effective way is really, really important.”
Cox mentions a new relationship with UCSF as an example. Pfizer entered a three year collaboration with the California Institute for Quantitative Biosciences (QB3), headquartered at UCSF. The idea is that UCSF scientists can propose ideas based on their research. If a Pfizer scientist feels that idea could be interesting, those two scientists can submit a joint proposal to a review team. “The new collaboration intimately links the scientific talent of UCSF with the extraordinary expertise of Pfizer,” says Cox. J.R.
This article also appeared in the Jan-Feb 2009 issue of Bio-IT World Magazine.
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