Posts Tagged → GSK
Watch this space on Sunday as I cover the public unveiling of five drug candidates’ structures. I’ll be liveblogging the “First Disclosures of Clinical Candidates” symposium at the San Diego ACS National Meeting, which runs from 2PM to 5PM Pacific.
1:30PM It’s half an hour before the start of the session and the big ballroom is still pretty empty. Expect that to change in short order.
Company: Lexicon Pharmaceuticals
Meant to treat: type 2 diabetes
Mode of action: dual inhibitor of sodium glucose transporters 1 and 2, which play key roles in glucose absorption in the gastrointestinal tract and kidney
Medicinal chemistry tidbits: this drug candidate had Lexicon’s chemists refamiliarizing themselves with carbohydrate chemistry. Most inhibitors of sodium glucose transporters incorporate D-glucose in some way. Lexicon’s chemists realized they could try something different– inhibitors based on the scaffold of L-xylose, a non-natural sugar. The team has already published a J. Med. Chem paper (2009, 52, 6201–6204) explaining that strategy. LX4211 is a methyl thioglycoside-the team went with a methyl thioglycoside because upping the size too far beyond a methyl lost activity at SGLT1.
Status in the pipeline: LX4211 is currently completing Phase IIb trials.
Company: Bristol-Myers Squibb
Meant to treat: migraine
Mode of action: antagonist of the receptor for calcitonin gene-related peptide- increased levels of this peptide have been reported in cases of migraine
Medicinal chemistry tidbits: This team recently published an orally bioavailable CGRP inhibitor, BMS-846372 (ACS Med. Chem. Lett., DOI: 10.1021/ml300021s). However, BMS-846372 had limited aqueous solubility, something that might make its development challenging. To improve that solubility, the BMS team sought to add polar groups to their molecule, something that’s been tough to do with CGRP inhibitors historically. In the end, the team managed to add a primary amine to BMS-846372′s cycloheptane ring while maintaining CGRP activity, leading to BMS-927711.
Status in the pipeline: Phase II clinical trials
3:05 lots of questions from the audience for this talk! One questioner notes (as was noted in talk) that 4 CGRP inhibitors had gone before this drug in the clinic, and not made it through. Speaker notes that this candidate is more potent than others at CGRP (27 picomolar).
3:53 We’re a bit behind schedule but got plenty of good chemistry…
Meant to treat: tumors with loss-of-function in the tumor suppressor protein PTEN (phosphatase and tensin homolog)- 2nd most inactivated tumor suppressor after p53- cancers where this is often the case include prostate and endometrial
Mode of action: inhibitor of phosphoinositide 3-kinase-beta (PI3K-beta). Several lines of evidence suggest that proliferation in certain PTEN-deficient tumor cell lines is driven primarily by PI3K-beta.
Medicinal chemistry tidbits: The GSK team seemed boxed in because in 3 out of 4 animals used in preclinical testing, promising drug candidates had high clearance. It turned out that a carbonyl group that they thought was critical for interacting with the back pocket of the PI3K-beta enzyme wasn’t so critical after all. When they realized they could replace the carbonyl with a variety of functional groups, GSK2636771 eventually emerged. GSK2636771B (shown) is the tris salt of GSK2636771.
Status in the pipeline: Phase I clinical trials
Company: Gilead Sciences
Meant to treat: chronic infection with hepatitis B and C viruses
Mode of action: agonist of Toll-like receptor 7, which recognizes RNA from viral sources
Medicinal chemistry tidbits: The team paid a lot of attention to particular sidechain in their drug candidates– they examined a range of pKa’s from the acidic side of the scale to the basic side, and learned that a basic amine was important for agonist activity.
Status in the pipeline: Phase Ib clinical trials
Company: Bristol-Myers Squibb
Meant to treat: hepatitis C
Mode of action: inhibitor of viral NS5B replicase
Medicinal chemistry tidbits: This drug candidate is an allosteric inhibitor– early on in the program BMS researchers had evidence to suggest that allosteric inhibition of the replicase would be feasible, and would provide an alternative to the nucleoside analogs that constitute the vast majority of replicase inhibitors. The team started with fused indole lead structures which bound to the thumb site 1 allosteric site in the replicase (Bioorg. Med. Chem. Lett., DOI: 10.1016/j.bmcl.2011.03.067). Adding a morpholine amide enhanced potency, and adding substituents to it abrogated transactivation of the pregnane X receptor (PXR). Ultimately this group was replaced with a methylated piperazine, with substituents stitched together to give another ring. A cyclopropane adjusted the shape of the molecule to jibe with information gathered from an X-ray co-crystal structure.
Status in the pipeline: Phase II clinical trials
4:52 That’s it folks! Watch for additional coverage of these talks in an April issue of C&EN.
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.
Well, 2011 is in the books, and we here at The Haystack felt nostalgic for all the great chemistry coverage over this past year, both here and farther afield. Let’s hit the high points:
1. HCV Takes Off – New treatments for Hepatitis C have really gained momentum. An amazing race has broken out to bring orally available, non-interferon therapies to market. In October, we saw Roche acquire Anadys for setrobuvir, and then watched Pharmasset’s success with PSI-7977 prompt Gilead’s $11 billion November buyout. And both these deals came hot on the heels of Merck and Vertex each garnering FDA approval for Victrelis and Incivek, respectively, late last spring.
2. Employment Outlook: Mixed – The Haystack brought bad employment tidings a few times in 2011, as Lisa reported. The “patent cliff” faced by blockbuster drugs, combined with relatively sparse pharma pipelines, had companies tightening their belts more than normal. Traffic also increased for Chemjobber Daily Pump Trap updates, which cover current job openings for chemists of all stripes. The highlight, though, might be his Layoff Project. He collects oral histories from those who’ve lost their jobs over the past few years due to the pervasive recession and (slowly) recovering US economy.. The result is a touching, direct, and sometimes painful collection of stories from scientists trying to reconstruct their careers, enduring salary cuts, moves, and emotional battles just to get back to work.
3. For Cancer, Targeted Therapies – It’s also been quite a year for targeted cancer drugs. A small subset of myeloma patients (those with a rare mutation) gained hope from vemurafenib approval. This molecule, developed initially by Plexxikon and later by Roche / Daiichi Sankyo, represents the first success of fragment-based lead discovery, where a chunk of the core structure is built up into a drug with help from computer screening.From Ariad’s promising ponatinib P2 data for chronic myeloid leukemia, to Novartis’s Afinitor working in combination with aromasin to combat resistant breast cancer. Lisa became ‘xcited for Xalkori, a protein-driven lung cancer therapeutic from Pfizer. Researchers at Stanford Medical School used GLUT1 inhibitors to starve renal carcinomas of precious glucose, Genentech pushed ahead MEK-P31K inhibitor combinations for resistant tumors, and Incyte’s new drug Jakifi (ruxolitinib), a Janus kinase inhibitor, gave hope to those suffering from the rare blood cancer myelofibrosis.
4. Sirtuins, and “Stuff I Won’t Work With – Over at In the Pipeline, Derek continued to chase high-profile pharma stories. We wanted to especially mention his Sirtris / GSK coverage (we had touched on this issue in Dec 2010). He kept up with the “sirtuin saga” throughout 2011, from trouble with duplicating life extension in model organisms to the Science wrap-up at years’ end. Derek also left us with a tantalizing tidbit for 2012 – the long-awaited “Things I Won’t Work With” book may finally be coming out!
5. Active Antibacterial Development – In the middle of 2011, several high-profile and deadly bacterial infections (Germany, Colorado, among others) shined a spotlight on those companies developing novel antibacterials. We explored front -line antibiotics for nasty Gram-negative E.coli, saw FDA approval for Optimer’s new drug Fidiclir (fidaxomicin) show promise against C. difficile and watched Anacor’s boron-based therapeutics advance into clinical testing for acne, and a multi-year BARDA grant awarded to GSK and Anacor to develop antibacterials against bioterrorism microorganisms like Y. pestis.
6. Obesity, Diabetes, and IBS – Drugs for metabolic disorders have been well-represented in Haystack coverage since 2010. Both Carmen and See Arr Oh explored the vagaries of Zafgen’s ZGN-433 structure, as the Contrave failure threatened to sink obesity drug development around the industry. Diabetes drugs tackled some novel mechanisms and moved a lot of therapies forward, such as Pfizer’s SGLT2 inhibitors, and Takeda’s pancreatic GPCR agonist. Ironwood and Forest, meanwhile, scored an NDA for their macrocyclic peptide drug, linaclotide.
7. The Medicine Show: Pharma’s Creativity Conundrum – In this piece from October, after Steve Jobs’ passing, Forbes columnist Matt Herper both eulogizes Jobs and confronts a real ideological break between computer designers and drug developers. His emphasis? In biology and medical fields, “magical thinking” does not always fix situations as it might in computer development.
We hope you’ve enjoyed wading through the dense forest of drug development with Carmen, Aaron, Lisa, and See Arr Oh this past year. We here at The Haystack wish you a prosperous and healthy 2012, and we invite you to come back for more posts in the New Year!
GlaxoSmithKline recently announced a contract with the Biomedical Advanced Research and Development Authority (BARDA), a US government preparedness organization (Note: it’s not often pharma-relevant press releases come from the Public Health Emergency website!). The award guarantees GSK $38.5 million over 2 years towards development of GSK2251052, a molecule co-developed with Anacor Pharma a few years back, as a counter-bioterrorism agent. The full funding amount may later increase to $94 million, pending BARDA’s future option.
The goal here is to develop “GSK ‘052”, as it’s nicknamed among med-chemists, into a new antibiotic against especially vicious and virulent Gram negative bacteria, such as the classic foes plague (Yersinia pestis) or anthrax (Bacillus anthracis).
So what’s so special about this molecule? Usually, med-chemists “color” with the same atomic “crayons”: some carbon, sulfur, nitrogen, oxygen, and hydrogen, with a few halogens or transition metals every now and then (luckily, the golden age of mercury and arsenic therapies has largely passed on!). But seeing boron ensconced in a lead molecule rings alarm bells . . . you don’t usually see boron in pharmaceutical scaffolds!
Look closely at GSK’052 (shown above): that’s a boron heterocycle there! Anacor, a company specializing in boron based lead compounds, first partnered with GSK in 2007 to develop novel benzoxaborole scaffolds. This isn’t the first company to try the boron approach to target proteins; Myogenics (which, after several acquisitions, became Millennium Pharma) first synthesized bortezomib, a boronic acid peptide, in 1995.
Stephen Benkovic (a former Anacor scientific board member) and coworkers at Penn State first discovered Anacor’s early boron lead molecules in 2001, with a screening assay. The molecules bust bacteria by inhibiting leucyl-tRNA synthetase, an enzyme that helps bacterial cells to correctly tag tRNA with the amino acid leucine. Compounds with cyclic boronic acids “stick” to one end of the tRNA, rendering the tRNA unable to cycle through the enzyme’s editing domain. As a result, mislabeled tRNAs pile up, eventually killing the bacterial cell.
Inhibition of synthetase function turns out to be a useful mechanism to conquer all sorts of diseases. Similar benzoxaborozoles to GSK ‘052 show activity against sleeping sickness (see Trypanosoma post by fellow Haystack contributor Aaron Rowe), malaria, and various fungi.
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!
Last year’s JP Morgan Healthcare conference brought a flood of proclamations and projections about growth in emerging markets. Although the topic is now more of a given rather than a new arm of drug companies’ strategies, it seemed worth compiling some of the comments on emerging markets made at this year’s event. Of note? With many of the best assets in developing countries already snatched up and so much attention on what remains, prices are rising. Several big pharma CEOs underscored the need to grow at a profit, instead of just for the sake of growing. Time will tell if companies can heed their own advice.
GlaxoSmithKline is very deliberately shifting resources away from the U.S. and into emerging markets. In just a few years, the number of sales reps in the U.S. is down to 5,000 from 9,000, while the number of reps in emerging markets has grown from about 8,500 to 13,000, said GSK’s chief strategy officer David Redfern.
Of the 17 significant M&A deals undertaken by GSK since mid-2008, nine were in emerging markets. When asked whether that pace would continue, Redfern said the company no longer needed acquisitions to gain entry into those markets. And while bolt-on deals are still possible, he notes that
“There’s no doubt prices are going up in emerging markets and we’ll maintain our discipline,” Redfern said. “In 2008 we did quite a few deals. We’ve walked away from a lot more deals last year.”
Sanofi-Aventis is also bolstering its sales force in emerging markets at the expense of jobs in the U.S. and Europe. Chris Viehbacher said there has been a 40% reduction in pharmaceutical operations between 2009 and 2011, and a significant overhaul of its European operations is underway. Meanwhile, headcount in emerging markets is expected to increase by 40% in that same timeframe. As a result, “in 2011, we expect to sell more in emerging markets than we do in Europe or the U.S.”
Merck said it had also “significantly reduced” the number of sales reps in developed markets. The company’s goal is to grow sales in emerging markets from 18% to 25% by 2013.
“We’ve been frank to say that companies are ahead of us,” Merck’s CEO Ken Frazier said. However, he pointed out that it’s still an open field: the leading player in China only has about 3% of the market share.
Frazier also stressed the importance of achieving profitable growth in those regions, a nod to the rising prices for assets. “We think value-creating partnerships are the right way to go, because that way our partners have a strong stake in the growth and success of our business,” he added.
Eli Lilly & Co. is avoiding pure generics, and instead is trying to expand its presence in emerging markets by increasing sales of its existing product portfolio in six key markets–China, Russia, Brazil, Mexico, Turkey, and Korea. After doubling its sales force in China, among other efforts, the company has doubled sales in emerging markets in the past five years. Sales in emerging markets, now over 10% of total Lilly revenues, are expected to double again in coming years, said Lilly CEO John Lechleiter.
“We will add nominally medicines to our offerings, primarily in our core therapeutic areas, through product acquisitions, licensing deals, or co-marketing arrangements,” Lechleiter said. “We will pursue alliances, possibly including company acquisitions, to bolster our ability to capture growth in areas where our infrastructure is not fully developed.”
Lastly, big biotech is starting to at least think about, if not fully outline its strategy to expand globally. In a passing comment during his presentation, Amgen CEO Kevin Sharer said emerging markets will be an important part of the company’s future, but “not the future tomorrow morning, but the strategic future.”
This Friday, we’re looking back at 2010′s big news in pharma and biotech, both the good and the bad. Check out our picks and be sure to weigh in on what you think we missed.
1. Provenge Approved
In April, Dendreon’s Provenge became the first approved cancer immunotherapy. Dendreon CEO Mitch Gold called it “the dawn of an entirely new era in medicine.” And while prostate cancer patients are excited for a new treatment option, the approval is perhaps most exciting for its potential to reignite interest in cancer immunotherapy research. There’s a lot of room for improving the approach—Provenge is, after all, expensive and highly individualized. Now that immunotherapy have been proven to work, there’s hope that the lessons learned in both its discovery and clinical development will aid scientists in inventing even better cancer vaccines.
2. Obesity Field Slims
The obesity drug race played out in dramatic fashion in 2010, with three biotech companies-Vivus, Arena, and Orexigen, each making their case for its weight-loss medication before FDA. As of this writing, Orexigen’s drug Contrave seems to be on the surest footing to approval, but longtime obesity-drug watchers know that caution seems to rule the day at FDA, so nothing is a sure bet.
Orexigen’s Contrave and Vivus’s Qnexa are both combinations of already-approved drugs, whereas Arena’s Lorqess is a completely new molecule. When C&EN covered the obesity race in 2009, it seemed that Lorqess (then going by the non-brand-name lorcaserin) had the cleanest safety profile, but Qnexa was best at helping patients lose weight.
But FDA’s panels didn’t always play out the way folks expected. There were safety surprises- notably the worries about tumors that cropped up in rats on high doses of Lorqess, and the extensive questioning about birth defect risks from one of the ingredients in Vivus’ Qnexa. The fact that FDA’s panel voted favorably for Orexigen’s Contrave, a drug that’s thought to have some cardiovascular risks, generated discussion because FDA pulled Abbott’s Meridia, a diet drug with cardiovascular risks, from the market in October.
The dust still hasn’t fully settled. Arena and Vivus received Complete Response Letters from FDA for Lorqess and Qnexa. Vivus has submitted additional documentation and a followup FDA meeting on Qnexa is happening in January. Also to come in January is the agency’s formal decision on Contrave. And if you’re interested in learning about the next wave of obesity drugs coming up in clinical trials, read this story in Nature News.
3. Sanofi & Genzyme: The Neverending Story
Speaking of drama, Sanofi’s pursuit of Genzyme has been in the headlines for months now, and promises to stretch well into 2011. The story goes something like this: Genzyme had a tumultuous year, as it struggled to correct the manufacturing issues that created product shortages and eventually led to a consent decree with FDA. In walked Sanofi, who offered—in a friendly way—to buy the company for $18.5 billion. Genzyme refused to consider what it viewed as a lowball offer. Weeks passed, they remained far apart on price with no signs of anyone budging, until Sanofi finally went hostile. Genzyme suggested it would be open to an option-based deal, which would provide more money later on if its multiple sclerosis drug candidate alemtuzumab reached certain milestones. Sanofi stuck to its $18.5 billion guns and is now trying to extend the time period to convince shareholders to consider its offer.
4. Final Stretch in HCV Race
This year, the industry finally got a peek at late-stage data for what are likely be the first drugs approved for Hepatitis C in more than two decades. Based on Phase III data, analysts think Vertex’s telaprevir will have an edge over Merck’s boceprevir once the drugs hit the market. Meanwhile, the next generation of HCV drugs had a bumpier year, with several setbacks in the clinic. Still, the flood of development in HCV has everyone hoping that eventually people with HCV can take a cocktail of pills, rather than the current harsh combination of interferon and ribavirin.
5. Pharma Covets Rare Diseases
Historically, research in rare diseases has been relegated to the labs of small biotechs and universities. But in 2010, big pharma firms suddenly noticed that if taken in aggregate, a pretty sizable chunk of the public—on the order of 6%–suffer from rare diseases. They also noticed that when there’s a clear genetic culprit, drug discovery is a bit more straightforward. Further, rare disease can sometimes be a gateway to approval in larger indications, making them all the more appealing. With that, Pfizer and GlaxoSmithKline both launched rare diseases units and made a series of acquisitions and licensing deals (Pfizer/FoldRx, GSK/Amicus, GSK/Isis, etc) to accelerate their move into the space. Meanwhile, Sanofi is trying to jump in with both feet through its proposed acquisition of Genzyme.
6. MS Pill Approved
Novartis gained approval in September for Gilenya, the first treatment for multiple sclerosis that is a pill rather than an injection. In even better news for people with MS, there more pills are rounding the corner towards FDA approval: Sanofi’s teriflunomide, Teva’s laquinimod, and Biogen’s BG-12. All of these drugs come with safety caveats, but the idea of new treatment options after years depending on interferons has gotten everyone in the MS field pretty excited.
7. Antibody-Drug Conjugates Prove Their Mettle
The concept of linking a powerful chemo drug to a targeted antibody, thereby creating something of a heat-seeking missile to blast tumor cells, isn’t new. But antibody-drug conjugate technology has finally matured to a point where it seems to be, well, working. Seattle Genetics presented very positive results from mid-stage studies of SGN-35 in two kinds of lymphoma. And ImmunoGen provided clear data showing its drug T-DM1 could significantly minimize side effects while taking down breast cancer.
8. Pharma Forges Further into Academia
With nearly every pharma firm paring back internal research, the focus on external partnerships has never been greater. Broad deals with universities are becoming more common, and Pfizer has arguably gone the furthest to evolve the model for working with academic partners. In May, Pfizer announced a pact with Washington University under which the academic scientists will look for new uses for Pfizer drug candidates. As part of the deal, they gain unprecedented access to detailed information on Pfizer’s compound library. And last month, Pfizer unveiled the Center of Therapeutic Innovation, a network of academic partnerships intended to bridge the “valley of death,” between early discovery work and clinical trials. The first partner is University of California, San Francisco, which scores $85 million in funding over five years, and the network will eventually be comprised of seven or eight partners, worldwide. Most notable is that Pfizer is planting a lab with a few dozen researchers adjacent to the UCSF campus to facilitate the scientific exchange.
9. Finally, New Blood Thinners
This year saw the FDA approval of a viable alternative to coumadin (aka warfarin), a 50-plus-year-old workhorse blood thinner that interacts with many foods and herbal supplements.
Boehringer’s Pradaxa (dabigatran) got a unanimous thumbs-up from an FDA panel for preventing stroke in patients with a common abnormal heart rhythm called atrial fibrillation. FDA approved the drug in October. The next new warfarin alternative to be approved could be Xarelto (rivaroxaban), which has had favorable results in recent Phase III clinical trials, as David Kroll over at Terra Sig explained. Both Xarelto and Pradaxa had already been approved for short term use outside the US.
Rivaroxaban and dabigatran work at different stages of the biochemical cascade that leads to clotting, as we illustrated here. Another drug candidate in the warfarin-alternative pipeline is BMS’s and Pfizer’s apixaban. Check out coverage of apixaban trials here and at Terra Sig. And in a separate blood-thinner class, FDA today rejected Brilinta, a possible competitor to mega-blockbuster Plavix.
10. Alzheimer’s Progress & Setbacks
Alzheimer’s disease has been a tough nut to crack, and news in 2010 has done little to dispel this reputation. This year Medivation’s Dimebon, which started life as a Russian antihistamine and showed some promise against Alzheimer’s, tanked in its first late-stage clinical trial. Later in the year, Eli Lilly halted development of semagacestat after the compound actually worsened cognition in Alzheimer’s patients. Semagacestat targeted the enzyme gamma-secretase, and the New York Times and other outlets reported the news as shaking confidence into a major hypothesis about what causes Alzheimer’s and how to treat it– the amyloid hypothesis.
But not everyone agreed with that assertion. Take Nobel Laureate Paul Greengard, who told C&EN this year (subscription link) that semagacestat’s troubles may have been due to the drug’s incomplete selectivity for gamma-secretase.
This year Greengard’s team discovered a potential way to sidestep the selectivity issue, by targeting a protein that switches on gamma-secretase and steers it away from activities that can lead to side effects. Greengard thinks the amyloid hypothesis is very much alive. But the final word on the amyloid hypothesis will come from trial results in next year and beyond, for drugs such as BMS-708163, Bristol Myers Squibb’s gamma-secretase inhibitor.
11. Avandia (Barely) Hangs On
Avandia was once the top selling diabetes medication in the world, but in 2010 long-running rumblings about the drug’s cardiovascular risks reached fever pitch. By the fall, Avandia was withdrawn from the European Union market and heavily restricted in the US.
Avandia (rosiglitazone) helps diabetics control their blood sugar levels by making cells more responsive to insulin. Widespread scrutiny of Avandia dates back to 2007, when a study led by Vioxx-whistleblower and Cleveland Clinic cardiologist Steve Nissen suggested Avandia increased the risk of heart attacks. In February 2010, a leaked government report that recommended Avandia be pulled from the market made headlines. In July, an FDA advisory panel voted on what to do about Avandia, and the results were a mixed bag, with most panel members voting either to pull the drug entirely or add severe restrictions. In the end, FDA sided with the “restrict” panelists- Avandia is still on the market, but it can only be prescribed to patients who can’t control their blood sugar with a first-line medication.
Clearly, researchers still have a lot to learn about how the drugs in Avandia’s class work. But we enjoyed reading Derek Lowe’s self-characterized rant about just how much effort has been put in so far. Among several other drugs in Avandia’s class, Rezulin (troglitazone) was pulled from the market many years ago because of adverse effects on the liver, but Actos (pioglitazone) remains on the market and appears to be safe.
12. Executive Musical Chairs
The year after a trio of mega-mergers and at a time when patent losses are piling up, drug companies shook up their management. The most notable changes came at Pfizer: First, the company abandoned its two-headed approach to R&D leadership and picked Michael Dolsten, former head of R&D at Wyeth, to lead research. Martin Mackay, Pfizer’s head of R&D, meanwhile jumped ship to lead R&D at AstraZeneca. Then, in a move that took everyone by surprise, Pfizer’s CEO Jeff Kindler suddenly stepped down and Ian Reade took over. At, Merck, president Kenneth Frazier will take over as CEO in January; Richard T. Clark will stay on as chairman of Merck’s board. And just this week, Sanofi-Aventis saidformer NIH director Elias Zerhouni would replace Marc Cluzel as head of R&D, while Merck KGaA appointed Stefan Oschmann as head of pharmaceuticals. Oschmann comes on from Merck & Co., where he was president of emerging markets.
In the biotech world, the most notable shift came in June, when George Scangos moved over from leading Exelixis totake the top job at Biogen Idec.
13. RNAi Rollercoaster
The year has been a tumultuous one for RNAi technology. Leaders in siRNA technology are experiencing growing pains as they try to turn promising science into commercialized products. Alnylam, arguably the best-known and biggest player in the RNAi arena, laid off 25% of its staff after Novartis decided not to extend its pact with Alnylam. Things only got worse when Roche announced it was exiting RNAi research, a move that hit its development partners Alnylam and Tekmira. Roche seemed to be primarily worried about delivery, an issue that is holding the field back from putting more RNAi-based therapeutics into the clinic.
But it’s not all bad news: the year brought a spate of big-ticket deals for companies developing other kinds of RNAi technology. GSK signed on to use Isis Pharmaceuticals’ antisense technology, which uses single-stranded rather than double-stranded oligonucleotides. And Sanofi entered into a pact with Regulus, the microRNA joint venture between Isis and Alnylam, worth $740 million. Further, Isis and Genzyme made some progress with mipomersen, the cholesterol drug developed using Isis’ antisense technology.
14. Revival of Interest in Cancer Metabolism
In cancer research, the old was new again in 2010, with a flurry of publications about depriving cancer cells of their energy source by taking advantage of quirks in their metabolism. That idea has been around since the 1920′s- when German biochemist Otto Warburg noticed differences in how cancer cells and normal cells deal with glucose. This year, Celgene handed over $130 million upfront for access to any cancer drugs that come out of Massachusetts biotech Agios Pharmaceuticals’ labs. One target in Agios’s crosshairs is an enzyme involved in glucose metabolism- pyruvate kinase M2. In addition to the Celgene/Agios deal, we noted that AstraZeneca and Cancer Research UK are in a three-year pact related to cancer metabolism, and the technology behind GlaxoSmithKline’s much-talked-about $720 million purchase of Sirtris has to do with depriving cells of energy.
15. More Job Cuts
Not to end this list on a sour note, but it wouldn’t be complete without acknowledging the ongoing narrative of layoffs and retooling at drug companies. This year brought brutal cuts at AstraZeneca, GSK, Bristol-Myers Squibb, and Abbott, along with the widespread and ongoing layoffs at Pfizer and Merck. Several features in C&EN looked at the impact the cuts are having on chemists:
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. Continue reading →
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.
After years of debate over the safety of GlaxoSmithKline’s diabetes drug Avandia, U.S. and European regulatory agencies have finally made a decision about the future of the drug. European authorities have recommended suspending marketing of the drug, while FDA is severely restricting access to the drug, but seems to be leaving the door open to further actions. GSK, meanwhile, issued a press release saying it would stop promoting Avandia worldwide.
Today’s announcements mark yet another chapter in the Avandia saga, which began in May 2007, when Cleveland Clinic cardiologist Steve Nissen published an analysis of the combined data from 42 previous clinical trials of GSK’s diabetes drug. The results weren’t pretty: Nissen’s article in the New England Journal of Medicine claimed that patients taking Avandia were 43% more likely to have a heart attack than those who were not on the pill. The next three years brought a series of safety alerts, conflicting data analyses, advisory panels, and questions over whether GSK tried to cover up the cardiovascular safety risk associated with the drug.
In July, a panel of FDA advisors had mixed views on Avandia: 12 of the 33 panelists voted to remove the drug from the market, while 10 said it could stay on the market with strong restrictions on prescribing the drug.
FDA today sided with those 10 panelists and imposed strict limitations on who can take Avandia. The agency will also adjust the drug’s label to reflect the safety risk. Under a risk evaluation and mitigation strategy, or REMS, Avandia can only be prescribed to new patients if they have been unable to control their blood sugar with other diabetes drugs. Continue reading →