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...

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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...

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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 here, here, 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. Sirtris has developed a library of over 6,000 molecules that turn on SIRT1, the target of resveratrol, that are chemically unrelated to resveratrol, Vlasuk said. The company also recently published a paper on SIRT1 modulation, which can be found here. The first molecules to come out of that work are SRT2104 and SRT2379. Sirtris is wrapping up a series of clinical trials of those compounds and plans to discuss results from those early-stage studies in the first half of next year, he...

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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...

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From Pisces To Prodrugs: An Obesity Story
Aug25

From Pisces To Prodrugs: An Obesity Story

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. Researchers first found melanin concentrating hormone, a cyclic 19 amino acid peptide, in salmon. As you might expect, it plays a role in pigmentation of fish scales. In humans, however, the hormone doesn’t play a role in skin pigmentation. It’s made mostly in the human brain, in regions such as the hypothalamus. “When you see something released in the hypothalamus alarm bells should go off- because it could be important in feeding,” Hertzog said. That turned out to be the case. Researchers soon found that levels of the hormone go up during fasting in mice. And that mice lacking the receptor for the hormone were not only lean, they were resistant to diet induced obesity. GSK set out to make molecules that block melanin concentrating hormone receptor-1 as potential treatments for obesity. They found a promising molecule in GSK282254, which not only inhibited the receptor but as Hertzog put it, had “a lot of areas to get your hands on” for making analogs. When the GSK team replaced a simpler aromatic ring on GSK282254 with a bicyclic thienopyrimidone ring system, they saw a 15-fold boost in potency for inhibiting the receptor. After several more rounds of optimizing, they discovered GW856464, a compound that eventually made it to human clinical trials for treating obesity. Unfortunately, the molecule didn’t reach its site of action efficiently when taken orally. So GSK went back to the drawing board to find a way to improve the drug’s properties. They decided to try a prodrug approach-temporarily masking part of the drug candidate with a functional group that the body’s own enzymes will remove. Sure enough, when the team tacked the amino acid valine onto a hydroxyl group of GW856464, they made a prodrug with almost 6-fold higher bioavailability. This prodrug was selected for preclinical evaluation as a potential clinical candidate. Plenty of obesity drug strategies exist- it’ll be interesting to...

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