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Posts Tagged → Novartis

Liveblogging First-Time Disclosures of Drug Structures from #ACSNOLA

Bookmark this page now, folks. On Wednesday, April 10, I will be here, liveblogging the public debut of five drug candidates’ structures. The “First Time Disclosures” Session at the ACS National Meeting in New Orleans runs from 2PM-4:55PM Central time. I am not able to conjure up a permalink to the session program, so here’s a screengrab instead.
NOLAblog-program
1:20PM I’m in hall R02, where the session’s set to begin in about 40 minutes. Found a seat with a power outlet nearby, so I’m good to go!
2:29PM
IMG_3813
BMS-906024
Company: Bristol-Myers Squibb
Meant to treat: cancers including breast, lung, colon, and leukemia
Mode of action: pan-Notch inhibitor
Medicinal chemistry tidbit: The BMS team used an oxidative enolate heterocoupling en route to the candidate– a procedure from Phil Baran’s lab at Scripps Research Institute. JACS 130, 11546
Status in the pipeline: Phase I
Relevant documents: WO 2012/129353
3:02PM
IMG_3810
LGX818
Company: Novartis Institutes for Biomedical Research and Genomics Institute of the Novartis Research Foundation
Meant to treat: melanoma with a specific mutation in B-RAF kinase: V600E
Mode of action: selective mutant B-RAF kinase inhibitor
Status in the pipeline: Phase Ib/II
Relevant documents: WO 2011/023773 ; WO 2011/025927
3:47PM
IMG_3812
AZD5423
Company: AstraZeneca
Meant to treat: respiratory diseases, in particular chronic obstructive pulmonary disease
Mode of action: non-steroidal glucocorticoid receptor modulators
Medicinal chemistry tidbit: This compound originated in part from a collaboration with Bayer Pharma.
Status in the pipeline: Phase II
Relevant documents: WO 2011/061527 ; WO 2010/008341 ; WO 2009/142568
4:17PM
IMG_3811
Birinapant (formerly known as TL32711)
Company: TetraLogic Pharmaceuticals
Meant to treat: cancer
Mode of action: blocks the inhibitor of apoptosis proteins to reinstate cancer cell death
Status in the pipeline: Phase II
Relevant documents: US 8,283,372
5:00PM
IMG_3814
MGL-3196 (previously VIA-3196)
Company: Madrigal Pharmaceuticals, acquired from VIA Pharmaceuticals, licensed from Roche
Meant to treat: high cholesterol/high triglycerides
Mode of action: mimics thyroid hormone, targeted to thyroid hormone receptor beta in the liver
Medicinal chemistry tidbit: this molecule was discovered at Roche’s now-shuttered Nutley site.
Status in the pipeline: completed Phase I trials
Relevant documents: WO 2007/009913 ; WO 2009/037172

And that’s it, folks! Watch the April 22nd issue of C&EN for more on this session.

Pharma & Biotech Job Cuts Mount in 2012

For those keeping track, yesterday’s layoffs at AstraZeneca add to an already substantial list of cuts in the pharma and biotech industries since the beginning of the year. By our tally, nearly 13,000 job cuts, many in R&D, have been announced so far–and we’re barely into February. Here’s where we’re at (and do let us know if we’ve missed any):

–AstraZeneca is chopping 7,300 jobs, including 2,200 R&D positions, by 2014. Neuroscience research is being revamped and focused on external partnerships; the company’s Montreal R&D site will be shuttered, and research activities ended at its Södertälje site in Sweden.

–Genzyme gave the pink slip to an unspecified number of R&D scientists this week. The layoffs come as Sanofi integrates its big biotech acquisition.

–Alnylam is trimming 61 jobs, or 33% of its workforce, in order to save roughly $20 million this year.

–BioSante Pharmaceuticals is shedding 25% of its staff, or 21 employees and contractors, after disappointing Phase III results for its female sexual dysfunction treatment LibiGel.

–Takeda is axing 2,800 jobs, or 9% of its workforce, following its acquisition of Swiss drugmaker Nycomed. The bulk of the layoffs, which cut across R&D, commercial, operations, and administrative positions, will occur in Europe.

–Novartis unveiled plans to shed some 1,960 positions in the U.S. as it braces for generic competition for Diovan, a blood pressure medicine that brought in more than $6 billion in 2010, and an expected drop in demand for its renin inhibitor Rasilez following questions about the drug’s safety.

–Human Genome Sciences said it would cut 150 jobs, or about 14% of its workforce, in a move that affects manufacturing, R&D, and administrative activities.

–Xoma is shedding 84 workers, or 34% of its staff, as it shifts to outsourcing late-stage and commercial manufacturing, as well as some research.

–SkyePharma is cutting 20% of the 101 employees at its site in Muttenz, Switzerland.

–Sanofi plans to layoff 100 workers at its Monteal site as part of an overhaul of its Canadian operations.

–J&J will trim 126 workers as it closes its Monreal R&D center.


AstraZeneca to Shed 2,200 R&D Jobs

AstraZeneca wielded a heavy ax to its workforce today as it prepares for tougher times ahead. The British-Swedish drugmaker is chopping 7,300 jobs, including 2,200 R&D positions, in hopes of achieving $1.6 billion in annual cost savings by 2014.

This is the third round of major cutbacks at AstraZeneca. In 2010, the company announced plans to slash 8,000 jobs over four years, a move that added to the elimination of 15,000 jobs between 2007 and 2009. This specific round girds against an onslaught of generic competition for key products and accounts for several disappointments in the company’s late-stage pipeline. In the coming months, the company will lose patent protection in various markets for the anti-psychotic Seroquel IR, the anti-cholesterol drug Crestor, and the blood thinner Atacand. Meanwhile, AstraZeneca’s late-stage pipeline has faltered. The recent setbacks (adding to earlier ones) include ending development of the PARP inhibitor olaparib, which prompted it to take a $285 million charge; a failed Phase III trial for the antidepressant TC-5214; and a thumbs down from FDA last month for dapagliflozin, a Type II diabetes drug being developed with Bristol-Myers Squibb.

R&D has taken a heavy hit in each round of cuts. During the Q&A session following AstraZeneca’s earnings presentation, one analyst said his back of the envelope calculations suggest the company will have shed 7,600 R&D jobs between 2006 and 2014. Based on comments by AstraZeneca’s R&D chief Martin Mackay, small molecule research has born the brunt of those cuts. He noted that headcount in biologics research has grown, and pointed out that biologics now account for 40% of the company’s early-stage pipeline (candidates in studies earlier than Phase II), up from 15-20% in recent years.

The latest R&D revamp will be primarily focused on AstraZeneca’s neuroscience activities, where the risk of investment is seen as particularly high. “It’s a really tough area,” Mackay said.  “The industry hasn’t produced enough and we haven’t produced enough.”

The challenge was highlighted in November, when TC-5214, an anti-depressant being developed by Targacept and AstraZeneca, failed to show benefit in a Phase III trial. The bad news came as a surprise, as TC-5214 had demonstrated strong efficacy in smaller trials. Three other Phase III trials are underway, but analysts are skeptical that the program can be salvaged. “Prospects appear grim,” Leerink Swann analyst Joshua Schimmer said in a note last month.

AstraZeneca is creating a small team of 40 to 50 scientists that will work with external partners in academia and industry to discover and develop neuroscience drugs. The adoption of this new strategy means that the company’s Montreal R&D facility will be shuttered, and it will end R&D at its Södertälje site in Sweden.

AstraZeneca’s overhaul of its neuroscience activities is the latest in what appears to be a big pharma exodus from internal central nervous system R&D. In December, Novartis said it would close its neuroscience research facility in Basel, Switzerland, and GlaxoSmithKline two years ago decided to end research in certain central nervous system areas, such as depression and pain.

Novartis’s Afinitor helps Pfizer’s Aromasin to Delay Breast Cancer

Looks like Afinitor (everolimus), a drug marketed by Novartis for various cancers, may soon have a new indication. Already approved for a variety of diseases – kidney cancer, pancreatic tumors, and organ rejection prevention – Afinitor shows new promise for breast cancer patients. Clinical data released Monday demonstrate marked improvement for hormone-resistant breast cancer patients when Afinitor, an mTOR inhibitor, is used in combination with the aromatase inhibitor Aromasin (exemestane). Patients receiving both drugs delayed disease progression an average of 7 months, versus 3 months for Aromasin alone.

Standard therapy for breast cancer includes treatment with estrogen receptor antagonists, such as Aromasin and tamoxifen, which bind in the estrogen receptor pocket of cancer cells, slowing proliferation (see the excellent NCI website for more information on breast cancer treatment). Aromasin itself has a very similar structure to estrone (a natural body hormone that binds to estrogen receptors) except that it irreversibly modifies the receptor pocket upon binding, making Aromasin a so-called “covalent” or “suicide” inhibitor (see Lila Guterman’s article from Sept. 5, 2011 issue of C&EN for more on drugs that bind for keeps).

Like Aromasin, Afinitor follows the trend of being structurally related to a natural binder of a key cancer target protein. mTOR (mammalian target of rapamycin), the protein target of Afinitor and related macrolides, was first discovered through binding studies using rapamycin, a polyketide natural product found in a soil bacterium from Easter Island (its Polynesian name is Rapa Nui, hence, rapamycin). Rapamycin also goes by the generic name sirolimus, of which so many analogues have been prepared that all go by the catch-all “limus drugs.” The attachment of a hydroxyethyl (CH2CH2OH) tail to rapamycin produces everolimus, which compared to sirolimus demonstrates better pharmacokinetic properties, including higher bioavailability (greater proportion of drug reaching target sites) and a shorter plasma half-life (meaning the drug doesn’t stick around as long, which can help curb toxicity or other side effects).

Note: Please see Sally Church’s post on Pharma Strategy Blog for more info on mTOR pathway biology and coverage of ECCO 2011 conference information regarding everolimus.

Is Vernalis’ Hsp90 Destined to Be a Blockbuster?

Vernalis shares shot up today after Novartis gave a shout out to AUY922, which blocks a molecular chaperone called Hsp90, in a discussion of its second-quarter results. The Swiss pharma major identified AUY922 in a list of potential blockbusters, a distinction that may seem ambitious to those who have been watching compound after compound targeting Hsp90, which helps stabilize stressed-out proteins, crash and burn.

So what makes the Vernalis drug so interesting? We took a look at the field back in 2007, and at the time it was clear the Vernalis compound differed from most of the other drugs in or poised to enter clinical studies. The first and second-generation Hsp90 inhibitors were all based on geldanamycin, an antibiotic found in soil microorganisms. On its own, the natural product is a poor drug candidate—a quinine moiety renders it highly reactive and highly insoluble. Much of the early discovery work was focused on engineering out those issues, leading to drug candidates from Kosan Bioscience (bought by Bristol-Myers Squibb in 2008, work on the Hsp90 drug, however, seems dead in the water), Conforma Therapeutics (bought by Biogen Idec in 2006, after which the Hsp90 compound was put on the backburner), and Infinity Pharmaceuticals.

But, as we wrote, Vernalis sidestepped geldanamycin altogether:

Vernalis deployed fragment-based drug discovery technology to find low-molecular-weight compounds with a weak binding affinity for Hsp90. Guided by X-ray crystal structures of prospective compounds bound to Hsp90, company researchers optimized the compounds into leads. The end result is a range of drugs that do not all fall under the geldanamycin umbrella.

That’s the structure piece, but another piece of the puzzle is that researchers appear to be figuring out how best to use these compounds. On their own, Hsp90 inhibitors have shown limited to no therapeutic benefit. “It is abundantly clear that with rare exceptions we did not see a lot of single agent activity” with Hsp90 inhibitors,  Julian Adams, president of R&D at Infinity, told me last month at the ASCO annual meeting. The lack of activity might have been predicted, he adds, given that it was known that blocking Hsp90 only activated another protein-folding chaperone called Hsp70.

Indeed, evidence is emerging that Hsp90 inhibitors could find use in combinations with other targeted agents and for specific patient populations. Infinity did a deep dive into the data gathered from a Phase I trial combining Infinity’s lead Hsp90 inhibitor retaspimycin and Taxotere in lung cancer patients. The result: signs of strong activity in people with the ALK mutation (the target of Pfizer’s lung cancer drug crizotinib), in heavy smokers, and in people who carried the normal KRas gene.

There is also interest in combining Hsp90 inhibitors with Jak2 inhibitors, like ruxolitinib, conveniently being developed by Novartis and Incyte to treat rare blood disorders. Last fall, Memorial Sloan Kettering scientists showed that Jak2 is a very unstable protein, and blocking Hsp90, which ostensibly helps keep Jak2 pieced together, in combination could improve therapeutic outcomes.

Novartis is recruiting for a slew of clinical trials looking at the effect of combining AUY922 with other targeted agents. It’s early days for AUY922, which is still in Phase II trials. If all goes well, Novartis expects to file for regulatory approval for the compound in 2015.

So will an Hsp90 inhibitor finally make it to market? Detractors? Supporters? Speak up in the comments!

Haystack 2010 Year-In-Review

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/FoldRxGSK/AmicusGSK/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:

How some laid-off pharma chemists migrate to new careers

How academic programs are adapting

And the views from the ground in New England and California, two hotbeds of pharma/biotech (hint- it ain’t pretty).

For more jobs insight, join the discussions happening with Chemjobber and Leigh aka Electron Pusher, and check out their chemistry jobs blog roundtable, which just wrapped today.

This Week in Pharma Job Cuts…

As we know, its tough out there for scientists working in the pharmaceutical and biotech industries. This week brought yet another spate of drug industry cutbacks that seemed worth chronicling. For those keeping track:

Abbott Laboratories is getting rid of 3% of its workforce, or about 3,000 jobs, as it folds Solvay’s pharmaceuticals business into its operations. Most of the cuts will come from Europe: 300 jobs will be trimmed in Hannover, Germany; 500 in Weesp, the Netherlands; and Solvay’s U.S. headquarters in Marietta, Ga., will be shuttered. According to SEC filings, certain R&D programs will be discontinued (perhaps they can be auctioned off?).

Alnylam Pharmaceuticals, a leader in RNAi technology, is shedding 25-30% of its employees after Novartis decided not to opt-in to a technology licensing clause worth $100 million at the end of a five-year pact between the companies. The biotech raked in $125 million in funding during the lifetime of the pact, and had 25 full-time employees working on projects for Novartis. An interesting tidbit from a conference call held this morning from Alnylam: According to Alnylam’s CEO John Maraganore, Novartis now has 100 people working on RNAi technology at its site in Cambridge, Mass. Clearly they made a commitment to the field with their five-year pact with Alnylam, but somehow the sheer numbers were surprising. Alnylam expects to end the year with $320 million in cash on hand.

Bristol-Myers Squibb is cutting 3% of its workforce, estimated at around 800 jobs, as generic competition on its blood thinner Plavix looms. The company had already unveiled plans in 2008 to eliminate about 10% of its workforce, or about 3,700 jobs, by the end of this year. A 2007 cost-savings program had separately targeted 4,350 jobs.

Genzyme said last week it would eliminate 1,000 jobs over the next 15 months as it tries to right its manufacturing operations and combat takeover attempts.

Lundbeck is shedding 50 R&D jobs amid a reorganization of its R&D operations in Denmark and the U.S. The specialty pharma firm is shifting its focus to three main areas of biology– neurodegeneration, neuroinflammation and synaptic transmission—related to brain diseases, and will rely more on external partnerships.

Merck, meanwhile, appears to be having a tough time making cuts in the Netherlands, where it is essentially ridding itself of Organon’s R&D operations. According to Radio Netherlands, the big pharma firm is now negotiating with the Dutch government over the thousands of jobs slated to be lost in the region.

Novartis’ MS drug Gilenia gets the green light

The path to approval looks clear for Novartis’ Gilenia, which is poised to be the first oral treatment for multiple sclerosis on the market. Today, members of an FDA advisory panel unanimously gave the drug a positive vote, despite worries about its side effects.

Gilenia (also known as fingolimod or FTY720) is a derivative of myriocin, a compound found in a fungus that had been used for thousands of years in Chinese medicine. The drug taps into a concept similar to the one used by Biogen Idec’s Tysabri, both binding to proteins on the surface of immune cells. As we wrote last year:

Once activated in the lymphatic system, T cells and other immune cells travel the busy highway known as the bloodstream to get to their target tissues. Nature has provided them with a built-in GPS: proteins that sit on the surface of the cells and point them to the proper exit ramps during their journey. In the early 1990s, scientists realized they might be able to alter the course of the disease by disabling that GPS.

Biogen’s Tysabri was the first drug approved to block one of those cell surface proteins, alpha-4-beta-1 integrin, which tells the immune cells when to leave the bloodstream and enter the brain and spinal cord.

Gilenia, meanwhile, binds to sphingosine-1-phosphate (S1P) receptor, a cell-surface protein that tells the immune cell to leave the lymph nodes. By doing so, some T cells are kept out of circulation, and preventing them from later reaching the nervous system.

Both drugs are very effective, but there are consequences to tweaking the immune system. Tysabri was temporarily sidelined after its launch after several patients died of a serious brain infection. The company is now working on an assay to predict whether a patient is susceptible to the virus that causes the infection, but in the meantime, the safety worries have limited widespread use of what is otherwise considered the most effective treatment on the market.

Gilenia, meanwhile, has its own set of side effects, including heart problems and weakened lung function. The FDA advisory panel will reportedly suggest that the company study a lower dose of Gilenia than that being proposed in Novartis’ new drug application, but the panel also said that study could be done after the drug was approved.

Assuming Novartis gets the greenlight from FDA, which usually follows the advice of its advisory panels, Gilenia will be the first pill approved to treat MS (it should be noted that Acorda’s pill Ampyra addresses the neurological symptoms of the disease, rather than the underlying inflammation that causes the brain lesions in people with MS.).

The race to get the first oral MS treatment had been neck-and-neck until last fall, when FDA rejected Merck Serono’s application for cladribine. This week, the German firm said it had resubmitted its application in the U.S., and will likely hear from European regulatory authorities in the third quarter of this year.

Cladribine takes more of a brute force method of suppressing lymphocytes. An intraveneous version of the drug, a purine nucleoside discovered at Scripps Clinic in La Jolla, Calif., was initially used to treat a rare form of leukemia. The toxicity issues, particularly cardiovascular effects, associated with a cytotoxic agent had some neurologists we spoke to last year thinking the drug would have a limited audience.

You might look at the side effect profiles of all these options and think: Whoa, kinda harsh. But people with MS are in desperate need for some new drugs. Aside from Tysabri, every other available treatment is elderly and simply an iteration of an interferon, which has proven only weakly effective at keeping the disease at bay.

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.

Array, Novartis Team for Mek-inhibitor

Boulder, Colo.- based Array BioPharma is again cashing in on its discovery platform for small molecules that block the protein kinase Mek. Novartis has agreed to pay $45 million out of the gate for ARRY-162, a MEK-inhibitor in Phase I cancer trials, and other back-up MEK-blocking compounds.

As part of the Novartis deal, Array could earn up to $422 million in additional milestones as the compound moves through the pipeline. Array is keeping a hand in the project, agreeing to pay for part of the development costs for the compound in exchange for what it calls “a significantly higher royalty rate” for U.S. sales of ARRY-162.

ARRY-162 blocks MEK, one of several protein kinases in a cell signaling pathway associated with cancer cell proliferation and survival. The compound is currently in an early-phase study in advanced cancer patients with solid tumors to determine the right dose and assess its safety.

ARRY-162 isn’t the first MEK inhibitor Array has married off. AstraZeneca licensed what is now known as AZD6224 as part of a long-standing collaboration around the protein target. Though AstraZeneca continues to develop AZD6224, most notably testing the drug in combination with Merck’s Akt inhibitor MK-2206, Array was freed from the exclusivity of the partnership last year. But in the six years of the pact, the biotech not only earned research funding, but pocketed some $96 million in milestone payments. From the looks of the Novartis deal structure, it looks like the Swiss drug major will pick up where AstraZeneca left off.

Array appears to be on a bit of a roll in scoring deals that wed reasonable upfront payments with research funding, while also keeping a healthy slice of future product sales. The biotech scored a $60 million upfront payment in December, when Amgen signed on to jointly develop ARRY-403, a second-generation glucokinase activator in Phase I. Glucokinase “senses” glucose in the pancreas by catalyzing the phosphorylation of glucose to glucose-6-phosphate, a critical first step in metabolizing sugar. Drugs like ARRY-403 enable the pancreas to better sense glucose, leading to increased insulin production. Amgen also agreed to provide funding over the course of a two-year research collaboration around glucokinase inhibitors.