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Speedier Screening

GSK’s Discovery Fast Track program looks inside academia for promising but risky drug targets

by Lisa M. Jarvis
November 3, 2014 | A version of this story appeared in Volume 92, Issue 44

Charlie Mo (left) and Matt Culyba, postdocs from UPenn professor Rahul Kohli, work on an antibacterial project partnered with GSK.
Credit: Rahul Kohli/Penn
Kohli’s postdocs Charlie Mo (left) and Matt Culyba work on an antibacterial project partnered with GSK.

Biomedical scientists in academia spend a good portion of their careers illuminating a single problem or phenomenon, such as the role of a specific protein in disease or the way in which bacteria acquire resistance to a drug. But after reaching their goal, researchers find themselves in a quandary: Do do they stop there, keeping it as a purely academic pursuit, or push the boundaries to translate that basic knowledge into a potential therapy?

GlaxoSmithKline might be making it easier to decide. Last year, the company launched its Discovery Fast Track program, which pairs an academic scientist who has a well-described drug target with GSK scientists who have expertise in drug discovery. Together, they run a screen on the drug firm’s sizable compound library to see if any good starting points for a drug campaign emerge.

If they do come up with good starting points, the relationship can potentially be continued through GSK’s Discovery Partnerships with Academia (DPAc) unit, which works with academia to turn more developed ideas into drug candidates.

GSK hopes the Discovery Fast Track program will bring in novel ideas at a very early stage, swiftly assessing their merit. “The very first risk you take when running a project is usually a screen,” says Pearl Huang, head of GSK’s DPAc unit. This program “is a way to discharge that risk very quickly.”

GSK is one of several drug companies helping academic scientists gain access to screening capabilities. Approaches differ: Some companies want guaranteed ownership of any discoveries made out of a screen, whereas other partnerships are initially forged more loosely; some involve academic and industry scientists working side by side, whereas others use a middleman to cultivate projects. But the companies have the same goal: better access to innovative science in an increasingly competitive environment.

Given that environment, GSK wasn’t sure what to expect when it first solicited applications for the Discovery Fast Track program last year, Huang says. “We thought we’d get at least some wacky stuff—like high school kids applying or something. We were shocked by the quality of what we saw.”

GSK fielded about 140 applications. Though most were of high quality, few were ready to advance. GSK tried to give investigators with interesting ideas that didn’t make the cut a clear picture of the kind of work needed to get a project to the point where an investment from big pharma would make sense.

Credit: GSK
GSK screens partners’ assays against roughly 1 million compounds.
Well plates at a GlaxoSmithKline high throughput screening facility.
Credit: GSK
GSK screens partners’ assays against roughly 1 million compounds.

What makes a project ripe for investment? Huang says GSK’s “number one criteria” is a strong hypothesis. “We look for targets that are not just associated with disease, but that have some data that suggest they’re causal of disease,” she says. Programs that home in on how a genetic malfunction is linked to or responsible for a disease progression are ideal.

And having the right tools to actually broach a target is key. “Drug discovery is essentially a set of problems that need to be solved, and if they’re problems we’re pretty good at solving and we think we can rise to it, we’ll do it,” Huang says. If the project is intriguing, but the technology to solve those problems is 20 years away, it is scratched off the list.

Last, someone inside GSK needs to want to commit to being the “champion” for the project. As Huang points out, drug discovery takes several years, and a successful project needs someone willing to keep pushing it forward.

The first set of winners—eight in total—came to GSK with projects spanning a range of therapeutic ideas, tackling everything from oncology to malaria to male fertility.

One of those winners, Rahul Kohli, a principal investigator at the Perelman School of Medicine at the University of Pennsylvania, had been trying to come up with small molecules that target the pathways by which bacteria acquire resistance. His lab developed an assay and had an idea of its robustness after some 2,000 compounds were screened against it at the local Penn screening facility.

Kohli also had support for the project. In 2012, he was awarded one of the National Institutes of Health’s New Innovator Awards, a five-year grant totaling $2.4 million meant to fuel the search for small molecules to block the enzymes that allow bacteria to adapt to drugs.

But GSK offered Kohli more than just money. The program complemented the work he was doing with academic partners while also quickly pushing the project forward, Kohli says. GSK has employed both its traditional high-throughput screening capabilities and its DNA-encoded smallmolecule libraries against Kohli’s assay. Moreover, the company has a depth of practical knowledge about drug discovery that simply isn’t found in universities.

“We’ve done maybe two screens in my lab, on two different targets,” Kohli says. “Their experience, their knowledge of things that can go wrong, things they look for, permutations of different options—it’s something that can only come with experience.”

GSK recently transferred several lead compounds, which are still confidential, to Kohli, whose lab is preparing to test their promise in an orthogonal assay. The partners plan to meet at the end of October to discuss the results and determine whether and how to move forward.

Although Kohli had a reasonable amount of funding for his project before partnering with GSK, not every academic scientist has that backup support. For Pennsylvania State University biochemist Sarah Ades, the GSK program sustained a program that seemed to have hit a dead end. Ades had, through NIH’s Molecular Libraries Program, developed an assay for finding compounds that can disable gram-negative bacteria. But when the Broad Institute conducted a pilot screen using her assay, no hits came back, and she didn’t get follow-up funding to broaden the screen to the full NIH library.

Because a full screen is so expensive, Ades started to consider scaling back her efforts to a bigger pilot screen. As she decided between looking for funding or tabling the project, she learned about the GSK program.

Ades didn’t think she had a shot at winning, but the application was short, so she decided to throw her hat in the ring. And it was a good thing: Not only was she selected, but the screens of GSK’s vast compound library yielded hits. Ades and GSK scientists are now sifting through those hits to determine which compounds should be tested further.

GSK is well aware that many other big pharma companies are trying to woo academics with appealing drug discovery projects. “We know we’re not the only game in town,” Huang says. “We’ve tried to make our partnerships very attractive because we do offer access to resources, our whole chemical collection, our internal experts. Not everybody might find that valuable, but we think it’s really valuable.”

Drug firms are taking a variety of tacks to transition a well-developed idea into a drug candidate. Among GSK’s competitors, Pfizer has arguably made the biggest investment in partnering with academia. In 2010, the company launched its Centers for Therapeutic Innovation (CTI), a translational science effort centered on the notion that industry-academic pacts work best when partners can work side by side. Pfizer has set up R&D labs adjacent to four academic hubs—San Francisco, San Diego, Boston, and New York City—each of which works directly with scientists from a network of local universities and medical centers. The proximity to its partners also allows for quick translation into the clinic.

Last year, a treatment for inflammatory bowel disease became the first drug candidate developed in CTI to enter a clinical study. Two or three more compounds developed in conjunction with Memorial Sloan Kettering Cancer Center, New York University, and Brigham & Women’s Hospital are expected to enter the clinic in 2015, a pace CTI’s chief scientific officer, Anthony Coyle, expects to continue in 2016 and beyond.

Pfizer has also expanded the CTI program, which started off purely focused on biologics, to small molecules. Coyle says that in the past 18 months, 12 institutions have signed small-molecule pacts with Pfizer, with several projects already under way in oncology, inflammation, and cardiovascular disease.

In small molecules, Pfizer is focused on teaming with academics with novel targets that would benefit from the company’s deep experience in screening for and designing drugs. “The sophistication and diversity of our small-molecule libraries are as good as any other pharma’s, if not better in some spaces,” Coyle says, pointing out that Pfizer has commercialized more kinase inhibitors than any other company.

“We believe that we can screen faster with our libraries, make better molecules, but by doing that with an academic institution, we can really work in brand-new areas of biology and then really facilitate the progression of a new innovative concept.”

Although the CTI labs are fully equi­pped to do antibody drug discovery, screening for small molecules is done either at Pfizer facilities in Groton, Conn., or Kalamazoo, Mich., or performed by one of Pfizer’s partners.

In addition to expanding CTI to small molecules, Pfizer is broadening its reach beyond the 25 partner institutions located around its hubs. “There’s great science outside of those four major hubs,” Coyle says, and his team is now trying to figure out how to connect in a virtual way with key scientists and institutions outside of those areas. Part of that expansion includes linking with disease foundations such as JDRF, a nonprofit focused on type 1 diabetes, which last year teamed with CTI to cofund projects related to immune tolerance, diabetic nephropathy, and beta cell health. And Pfizer has also started a small effort in the U.K. focused on rare diseases.

Merck & Co.’s foray into accessing academic science took a different tack. Rather than connecting directly with a network of academic labs, Merck helped to start the California Institute for Biomedical Research (Calibr) in 2012.

Led by Scripps Research Institute California chemistry professor Peter G. Schultz, Calibr is a nonprofit organization that takes in academic drug discovery projects and cultivates them to the proof-of-concept stage, at which point Merck has an option to license the project. To date, Merck has not licensed any projects from Calibr.

Although competition for promising academic projects abounds, GSK was so encouraged by what it saw in the first year of its Discovery Fast Track program that it expanded it to Europe and the U.K. More than 250 applications came in from the other side of the Atlantic, while the number of applications from the U.S. and Canada grew to more than 200.

Next month, GSK will announce the 2014 winners. Meanwhile, it is in negotiations to bring some of the projects from 2013 into its DPAc unit, a complex process requiring a partnership that spans from drug discovery to commercialization.

Huang sees that broad commitment as another key to bringing in good projects in a competitive landscape. “For the academic who is really confident their idea will truly make an impact on a disease, or has spent their entire career explicating a target, they get a huge commitment of our time and resources to essentially help them prove they were right,” Huang says.  


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