↓ Expand ↓

Posts Tagged → GlaxoSmithKline

GSK’s R&D Review: Successes & Lessons Learned

Three years after reorganizing its discovery research activities into small, multi-disciplinary units, GlaxoSmithKline is providing a first peek at how its new approach to R&D is faring. A healthy chunk of its year-end earnings presentation yesterday was devoted to discussing the productivity of its research engine, and what can be expected out of its labs in the next three years.

As we described, the goal of its 2008 revamp was to create a biotech-like, entrepreneurial feel within the walls of a big pharma firm:

After being one of the first drug companies to create research hubs, or what it calls “centers of excellence in drug discovery,” GSK last year created “discovery performance units” (DPUs) within each hub. Each of the 38 DPUs operating now has a multidisciplinary team of up to 60 scientists focusing on a therapeutic area, a disease pathway, or some aspect of basic biology.

GSK also formed a “discovery investment board” that makes funding decisions for the research projects in each DPU. The idea is to bring diverse perspectives on the merits of each project: In addition to [GSK R&D head] Slaoui, the board includes a biotech company CEO, a senior public health official, and GSK’s heads of drug discovery, late-stage development, and business development.

DPUs are intended to operate like a biotech company housed in a big pharma firm. Much as a biotech gets funded by venture capitalists, a DPU receives an initial bolus of money and then extra cash when certain project goals are met. Each DPU had an initial review after a year of operation and will undergo another review this month, the 18-month check point. The board meets a last time at the three-year mark.

GSK says there are clear signs that the DPU approach is working. Although the company is spending less on R&D and has raised the bar for moving a drug candidate into late-stage development, it has increased the number of molecules in its late-stage pipeline, Patrick Vallance, GSK’s president of R&D told the Haystack. Under the new R&D regime, 22 molecules have moved into late-stage development, and Vallance wants to see 30 molecules pushed forward in the next three years.

And in what Vallance believes is a sign that scientists are becoming more ambitious and attempting to do genuinely novel early research, roughly 17 publications in came out of GSK’s labs last year. Prior to the DPU approach, basically no papers were being submitted to prestigious journals, he says.

The board, which had its final review in November, decided to shut down three DPUs, and create four new DPUs. Funding for six existing DPUs was upped by more than 20%, while five units saw funding decrease by more than 20%. Overall, 40 DPUs were funded for the next three-year cycle, with a budget that has remained unchanged.

So what has GSK learned at the end of three years? On a practical level, reviewing all projects on the same schedule “is just too complicated,” Vallance says.

And the largest DPUs, which had 60 to 70 scientists, need scaling back in order to maintain their focus, he says. “What some of those units did was filled the activity to meet the number of people rather than the size of the opportunity,” he says. And the number of scientists needed for a DPU is entirely project dependent, “I do think there is an upper limit, beyond which the returns become diminishing,” he adds. “When you get above 60, I don’t think you see more, I think you see less.”

The review process also brought some surprises. Some DPU heads told the board “we don’t think you should reinvest,” either because the project didn’t get as far as originally planned or the scientific problem turned out to be different than they expected, Vallance says. “The confidence of people to say, ‘This isn’t right, cut it and move on to something else,’ was a positive surprise.”

Leaders also came from unexpected places. Vallance points to the case of a bench chemist who came before the board with a proposal for a DPU that was so strong that not only did the project get funded, but the chemist is now heading it up.

Other big phama firms surely keeping a close watch on how GSK fares—and how investors respond to their pipeline progress. Since GSK unveiled the model in 2008, several others have adopted similar strategies.

*story amended on 2/9/12: Patrick Vallance is currently president of R&D for GSK.

Genentech Says Experimental Cancer Combo is Safe

Genentech this week unveiled promising results from a Phase I study suggesting it is possible to safely combine two cancer drug candidates, its MEK inhibitor GDC0973 and its PI3K inhibitor GDC0941. In addition to a relatively clean safety profile, there were also early signs that the combination is combating cancer.

Genentech is one of several companies running a trial to test the safety of combining inhibitors of the lipid kinase PI3K, part of the PI3K/AKT/mTor pathway, and drugs blocking the protein kinase MEK, part of the KRas/MAP signalling pathway. As we discuss in our upcoming April 11th cover story on PI3K inhibitors, the rationale for knocking down both pathways  is compelling: both are considered to be crucial in cancer cells’ survival, and blocking only one pathway has more often than not proven ineffective.

As Robert Abraham, CSO of Pfizer’s oncology research unit, explains in Monday’s story:

“KRas mutations are associated with many of the deadliest cancers,” including colorectal and pancreatic, Pfizer’s Abraham says. Yet they are incredibly resistant to conventional chemotherapy, and based on preclinical studies of the mutations, are expected to be resistant to the new batch of mTor/PI3K inhibitors as well, he adds. The working hypothesis is that knocking out two of the major drivers of cancer—the KRas and PI3K pathways—could have a significant effect on the most recalcitrant tumors.

To date, there are at least six Phase I trials planned or ongoing that combine MEK inhibitors with compounds that block some aspect of the mTor/PI3K pathway. Merck and AstraZeneca made headlines in 2009 when they said they would partner to test Merck’s AKT inhibitor with AstraZeneca’s MEK inhibitor. Sanofi-Aventis has meanwhile teamed with Merck Serono to explore the potential of combining two of its PI3K inhibitors in combination with Merck Serono’s MEK inhibitor. GlaxoSmithKline has two of its own drugs in a combination trial, and its MEK inhibitor GSK1120212 is also being tested in combination with Novartis’ PI3K inhibitor BKM120. And while Pfizer has yet to initiate such a study, Abraham said the company is “keeping two eyes on that combination.”

We go into much more detail in Monday’s cover story about the efforts to match PI3K inhibitors with other drugs, and the rationale behind different flavors of compounds (mTor/PI3K inhibitors vs. pan-PI3K inhibitors vs. single-isoform inhibitors). Stay tuned!

GSK Abandons Resveratrol, Focuses on Next Generation Compounds

GlaxoSmithKline has reportedly abandoned work on SRT501, or resveratrol, the controversial drug based on the ingredient found in red wine that has been said to reverse the aging process. The news came as no real surprise—the company has been quiet about the compound since May, when it halted a clinical trial of the drug in multiple myeloma after cases of kidney failure occurred. (find background on that news and other controversies around the drug herehere, and here.). But confirmation that SRT501 is officially done for is prompting many to wonder about what else Sirtris has up its sleeve—specifically, what exactly is going on with the follow-on compounds it has put in the clinic. The news is also reinvigorating a debate over the value of Sirtris. As you’ll recall, GSK paid $720 million for Sirtris in 2008, and industry folk have been questioning the hefty price tag ever since.

Just before Thanksgiving, GSK had a group of reporters into the Sirtris offices to provide an overview of its externalization strategy for R&D. Given the very public debate over the value of its technology, it was an interesting choice of venue. But their offices were spacious, and we got a tour of their labs, which house about 70 people who operate fairly autonomously from the overall GSK operation. I can attest that there were indeed chemists in lab coats makin’ compounds while I was there.

The day included a presentation by George Vlasuk, former vice president of metabolic disease and hemophelia research at Wyeth who last year came over to GSK to lead Sirtris. He was brought on to keep pursuing “the dream,” of resveratrol, “but do it in a slightly different way,” Vlasuk said. Prior to GSK’s purchase of Sirtris, “the science, in some regards, didn’t get as fully elaborated as it could have,” he acknowledged.  His job was to “make sure the science was solid and we were going down a path you could really develop drugs from.

From the presentation, it was clear that work on SRT501 was dead in the water, as the focus of Vlasuk’s talk was squarely on the next set of compounds. Continue reading →

GSK Highlights Rare Diseases Approach

GlaxoSmithKline today outlined its strategy in rare diseases, while also unveiling its latest licensing deal in the area.

Created in February, the rare diseases unit will focus on four therapeutic areas–metabolism, central nervous system and muscle disorders, immunoinflammation, and rare malignancies and hematology—and will initially chase treatments for 200 diseases. “We believe that focusing on 200 diseases is a good compromise between the enormity of the task and what we can really address with the team we have in place,” Marc Dunoyer, head of GlaxoSmithKline’s rare diseases unit said on a call with reporters this morning.

Pursuing treatments for 200 diseases seems ambitious. After all, the rare diseases unit is comprised of just 30 people who work with scientists in GSK’s 38 discovery performance units as well as leverage outside opportunities.

But Dunoyer pointed out that roughly 3,000  rare diseases are rooted in genetics, which provides natural starting points for drug discovery campaigns. Further, the company appears to be looking for deals that bring technologies that can be applied across a range of diseases.

The company has already established a small network of partners with edgy drug discovery technology. Prior to the creation of the unit, GSK paid $25 million upfront for Prosensa’s PRO051, an RNA-based therapeutic now in Phase II trials for the treatment of Duchenne muscular dystrophy. GSK then bought the rights to a number of enzyme replacement therapies from JCR Pharmaceuticals. In March, GSK signed a broad pact worth up to $1.5 billion to use Isis Pharmaceuticals’ antisense technologies to develop therapies for rare diseases.

Today, GSK announced a partnership with Italian charity Fondazione Telethon and research organization Fondazione San Raffaele for the development of gene therapies based on the patient’s own bone marrow. In exchange for $14 million upfront and the promise of milestones, GSK gains access to a gene therapy that has completed Phase I/II trials in ADA severe combined immune deficiency, more commonly known as “bubble boy disease,” which affects just 350 children worldwide. The organizations will use the stem cell technology to develop treatments for a variety of other rare diseases based on single-gene mutations.

GSK isn’t the only drug company with a newfound interest in rare diseases. In December, Pfizer started a rare diseases unit, which recently set up an R&D group in Cambridge, Mass. Sanofi-Aventis has for months been trying to buy Genzyme in order to bolster its rare diseases portfolio. Novartis has also become interested in rare diseases as a foothold into larger markets.

From Pisces To Prodrugs: An Obesity Story

Sockeye salmon (Shutterstock)

When it comes to obesity, the drug race between Arena’s lorcaserin, Vivus’s Qnexa and Orexigen’s Contrave is at the forefront of folks’ minds these days.

But yesterday at the ACS National Meeting in Boston, I sat in on part of a session in the Division of Medicinal Chemistry that gave me a broad overview of other strategies for developing treatments for obesity. I heard a neat story from Donald L. Hertzog of GlaxoSmithKline that I thought I’d share.

GSK is focusing on the melanin concentrating hormone receptor protein as a target for obesity drugs. When I read the abstract, I thought I’d made a mistake. What in the world could the pigment melanin have to do with obesity?

It turns out there’s a fascinating connection. Continue reading →

Scientists On The Move

I like taking the time to read the fine print in journal articles. When I first read the antibiotic work I posted about yesterday, I noticed that a few of the authors on the paper had little crosses next to their names. If you go to said fine print, you will find that they are no longer at GSK, but are located elsewhere. I’m no Chemjobber or Electron Pusher, but I try to pay attention to researchers’ moves.

Drake S. Eggleston, Fabrice Gorrec, Earl W. May & Alexandre Wohlkonig
Present addresses: Innovalyst, 1000 Centre Green Way, Suite 200, Cary, North Carolina 27513, USA (D.S.E.); MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 0QH, UK (F.G.); OSI Pharmaceuticals, 1 Bioscience Park Drive, Farmingdale, New York 11735, USA (E.W.M.); Vrije Universiteit Brussel, VIB Department of Molecular and Cellular Interactions, Pleinlaan 2, 1050 Brussels, Belgium (A.W.).

Platensimycin On My Mind

Yesterday we posted a Latest News item that heralds a potential new class of antibiotics. This is a topic near and dear to my heart, because I worked on the total synthesis of a potential new antibiotic in graduate school. Of course, my time in grad school also taught me not to trumpet ‘potential new antibiotics’ as the next big wonder drugs, because the molecules in question almost always have yet to be tested in people, a process that seldom goes perfectly smoothly.

There was a slightly different twist to this story that made me think it deserved attention: it seems to be nudging researchers and saying, “Don’t get so caught up in the hoopla of fancy genomics technology that you ignore old antibiotic targets that still need exploring.”

In the study, researchers at GlaxoSmithKline, in collaboration with the Wellcome Trust’s Seeding Drug Discovery Initiative and the U.S. Defense Threat Reduction Agency, found a small molecule that blocks DNA gyrase, or type IIA topoisomerase, in an entirely new way. The molecule was effective against a panel of drug resistant bacteria and revealed new nuances of the gyrase mechanism to boot.

Since the news story discussed revisiting old antibiotic targets, I thought I’d spend some time reminding Haystack readers of a search for a new one. Over the last few years, C&EN has extensively covered the story of platensimycin, a promising antibacterial with an exciting target, first isolated from a South African soil sample.

Here’s an abbreviated platensimycin timeline:

May 2006: Merck researchers report the structure of platensimycin and describe its intriguing activity- it blocks FabF, an enzyme involved in fatty acid synthesis, one that has never before been targeted by antibiotics used in the clinic.

October 2006: K.C. Nicolaou group at Scripps Research Institute reports the first total synthesis of racemic platensimycin, setting the stage for making analogs for exploring its bioactivity.

April 2008: Lisa Jarvis’s C&EN cover story counts platensimycin among the natural product antibiotics in development.

March 2009: Microbiologists report that pathogens can scavenge lipids from their mammalian hosts, suggesting that platensimycin’s target (part of the lipid synthesis pathway) may not be a viable target for an antibiotic, after all.

August 2010: I contacted Merck to ask about the current status of platensimycin. Here is what Dr. Sheo Singh, Merck Research Labs Director of Medicinal Chemistry, who led the discovery team on platensimycin in 2006, had to say: “As part of the merger integration of Merck and Schering-Plough, platensimycin is being evaluated and prioritized along with all the other compounds in the early stage pipeline.”

More On Malaria Open Innovation Announcement

A slew of molecules that might lead to the next antimalarial drug are up for grabs, now that GlaxoSmithKline, the Genomics Institute of the Novartis Research Foundation, and a consortium led by a St. Jude Children’s Research Hospital team have released their data into the public domain. As I wrote today, this is great news for the malaria community, which has to do drug discovery on a shoestring compared to, say, the oncology community.

But a large-scale data free-for-all like this one (GlaxoSmithKline says that their collection is the largest one that a pharmaceutical company has made universally available) is bound to set some precedents. We’ve blogged about open innovation for neglected diseases before, noting that skeptics may wonder if these efforts will lead to a warm fuzzy feeling rather than tangible scientific progress.

Researchers need to think carefully about how they release and curate their data so that doesn’t come to pass, says Sean Ekins of Collaborative Drug Discovery, the US-based informatics service provider that is one of the hosts for GSK’s dataset. Collaborative Drug Discovery (CDD) is a spinout of Eli Lilly & Company that is now working with the Gates Foundation to foster collaboration and open innovation approaches for tuberculosis, while CDD are also working with researchers on other neglected diseases. CDD worked closely with GSK to make the malaria data broadly available to the scientific community.

“How can we ensure that the next datasets that come through will have a high value? How can we avoid False positive and false negative issues in assays?” Ekins asks. The issues he raises, to me, are similar to the ones Derek Lowe brought up a few months back, when GSK first announced they would be making their data public.

Another important issue that still needs examining is that of coordination, Ekins adds. Consortia and public-private partnerships have emerged to fill up the thin malaria pipeline, but there is still more that can be done, he says.

“The bigger picture here should be the acceleration of hits to drugs,” Ekins says. “How this data will work to catalyze malaria drug discovery is a matter of discussion, but releasing the data is an important first step.”

On a related note, on our previous open innovation blog entry Jean-Claude Bradley commented: “Are the biotechs trying to generate any income from participating – or is this strictly a humanitarian contribution?”

I don’t know about every case, but for this case I asked GSK: Suppose one of these compounds is successful in clinical trials and becomes a bona fide drug one day. How are the rights to the compound distributed?

Here’s the reply I got from the company.
GSK would hope that scientists will contribute any new findings/data to the online data source and to donate any IP into a patent pool for diseases of the developing world. We will have the principles of use including our approach to IP outlined on the websites where the data will be hosted. We would hope that anyone generating knowledge from this or IP would comply with the spirit of our initiative.

Post-BIO News Roundup

Been focusing on Chicago and this year’s BIO extravaganza all week? Here’s a sampling of news you might have missed.

Pirfenidone rejected

In a surprisingly twist, FDA refused to approve InterMune’s lung treatment pirfenidone, despite a positive recommendation from its advisory committee. The agency wants another lengthy trial to better demonstrate pirfenidone is effective at treating idiopathic pulmonary fibrosis, a debilitating and ultimately fatal lung disease for which there are no approved treatments in the U.S. or Europe. InterMune’s stock fell over 75% on the news. Check out this piece in Forbes’ health care blog on whether FDA is these days less likely to listen to its advisory panels.

Birth Control Pill Exalted

The mainstream media celebrated as “The Pill” turned 50. Technically, they’re celebrating the 50th anniversary of its approval by FDA. C&EN covered the chemistry story of the pill in “The Top Pharmaceuticals That Changed The World” special issue, back in 2005. Don’t miss the classy 1950s era photo of Carl Djerassi.

Resveratrol Trial Halted

A GlaxoSmithKline clinical trial studying a reformulated version of resveratrol was suspended on April 22 due to safety concerns, but company officials say the complications may or may not be related to the drug. The big question remains-what does this all mean for the effort to make drugs out of resveratrol, the trace component of red wine that’s been touted as a cancer fighter and a fountain of youth in a bottle? Continue reading →

Celgene Goes After Cancer’s Achilles’ Heel

The drug industry seems to be coming back around to the idea that cancer has an Achilles’ heel. In the latest deal related to cancer metabolism, Celgene is handing over $130 million upfront for access to oncology drugs coming out of Agios Pharmaceuticals‘ labs. Under the pact, Celgene, for a period of time, can opt-in on any drug candidate generated by Agios’ cell metabolism technology. Celgene can also put up extra cash to extend the opt-in period on a candidate.

Agios is focused on depriving cancer cells of their energy source by using small molecules to control critical metabolic enzymes. Those targets include isocitrate dehydrogenase (IDH1), shown to play a role in cancer formation, and pyruvate kinase M2 (PKM2), an enzyme involved in glucose metabolism. Carmen weighed in on their research in a piece on cancer metabolism back in February:

Agios researchers are looking at several metabolic enzyme targets. For example, they have found a surprising effect for brain-cancer-associated mutations in the enzyme isocitrate dehydrogenase 1. Rather than halting the enzyme’s dehydrogenase activity, the mutations cause it to catalyze a reduction, the researchers find (Nature 2009, 462, 739). The product of that reduction, a metabolite called 2-hydroxyglutarate, is over 100 times more abundant in tumors with the cancer-associated mutation. So the compound could be a useful marker in tests of a patient’s blood, urine, or cerebrospinal fluid to determine whether their tumor has the mutation. It could even be an indicator of whether certain experimental cancer drugs are working, says Joshua D. Rabinowitz, a coauthor of the work and consultant for Agios who studies metabolism at Princeton University.

The idea of targeting cancer metabolism isn’t new. As Carmen’s article notes, German biochemist Otto Heinrich Warburg first noticed a metabolic quirk in cancer cells—they break down glucose via an oxygen-free metabolic pathway, regardless of whether oxygen is available—in the 1920s.

There has been a revival of interest in the idea as researchers begin to understand the limitations of targeted therapies, molecules that often block a single protein kinase and, while effective in treating cancer for awhile, eventually stop working as resistance develops. In an editorial in the New York Times last August, James D. Watson, the granddaddy of DNA, advocated revisiting the concept of commonalities in cancer cells, specifically, how they metabolize glucose.

Now, interest is moving out of academic labs and into drug firms. In addition to the Celgene/Agios deal, AstraZeneca and Cancer Research UK are in a three-year research pact related to cancer metabolism. And the technology behind GSK’s questionable $720 million of Sirtris Pharmaceuticals is centered on depriving cells of energy.

Will any of this research pan out? Could there be a way to get to the very root of cancer?