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Heptares solves first X-ray structure of Family B GPCR, but full details not yet public

GPCR family tree

The new structure adds a new section of GPCR space amenable to computer modeling (big blue circle), a space which includes sought-after drug targets. Previously determined GPCR structures, which are all from the same family, are highlighted in small blue and red circles. Image courtesy Heptares

In what might be the year’s biggest molecular teaser, Heptares Therapeutics has announced that it has solved the first X-ray crystal structure of a G-protein coupled receptor in the Family B subclass. The work provides the first structural insights into a protein family that includes sought-after drug targets such as GLP-1 for diabetes and CGRP for migraine.

Largely because of that drug discovery relevance, however, Heptares is choosing to keep its structure somewhat close to the vest. Officials presented views of the structure, of a GPCR called Corticotropin Releasing Factor (CRF-1) receptor, at conferences on Friday and Monday. But Heptares CEO Malcolm Weir says his team has no immediate plans to publish the structure or to deposit coordinates into the repository known as the Protein Data Bank.

The structure, Weir says, is another success for Heptares’ GPCR stabilizing technology, StaR. The technique involves targeted mutations that help to trap a GPCR in a single biologically-relevant state. In the case of CRF-1, Weir says, the stabilized receptor is captured in the “off” state.

The structure itself, which is at a resolution of 3 Ångstroms, has the 7-helix membrane-spanning structure typical of GPCRs. However, CRF-1′s architecture is rather different from receptors in Family A, the only GPCR family for which X-ray structures had been available until now, Weir says. “The overall shape of the receptor looks different, the orientation of the helices looks different, and there are detailed differences within helices that are at analogous positions in Family A receptors,” he says. He notes that there are differences in helices 6 and 7, which undergo important motions during GPCR activation.

“This is an important breakthrough, although fine details of the structure and release of coordinates may still be some time away,” says Monash University’s Patrick Sexton, an expert in Family B GPCRs who was at Friday’s talk. The structure, he says, confirmed researchers’ expectations that the major differences in membrane-spanning helices between Family A and Family B receptors would occur on the extracellular side. “There was a very open and relatively deep extracellular binding pocket, with the receptor having a ‘V’ shaped appearance,” he says. This open pocket likely contributes to medicinal chemists’ difficulties obtaining high affinity small molecule ligands for Family B receptors, he suggests.

That open pocket might be involved in another Family B GPCR mystery, according to Roger Sunahara, also in attendance Friday, who studies GPCRs’ molecular mechanisms at the University of Michigan, Ann Arbor. All Family B GPCRs, including CRF-1, have a large domain at their amino-terminus that contains large portions of their ligand binding sites. That domain was not included in this structure, he says, but “it would appear that deleted globular N-terminal domain would fit quite nicely into the open pocket.”

The CRF-1 receptor is a drug target for depression and anxiety, but at least one CRF antagonist failed to show benefit compared to placebo in a clinical trial. Weir says the impact of the CRF-1 structure for drug discovery will not necessarily be in CRF-1 drug discovery per se, but in the ability to develop relevant computer models of related targets.

It hasn’t been possible to make accurate models of Family B receptors with Family A information, explains Ryan G. Coleman, a postdoctoral fellow at UCSF who develops GPCR models, but who was not in attendance at the talks. Quality models could streamline small molecule drug discovery for the entire family, he explains. Most of the natural ligands for Family B receptors are long peptides, which are notoriously tough to replace with small molecule drugs.

Experts like Coleman will have to wait for some time to learn about the structure for themselves, unless they happened to have a friend in the audience at Heptares’ talks. It’s not unheard of for there to be a gap of several months to two years between a structure’s announcement and publication.

“We’re delighted to have such an informative structure,” Weir says. “It’s very exciting.” He adds says Heptares is progressing toward a structure of the biggest fish in family B, GLP-1, in the “on” state.

What Pfizer’s Bapineuzumab Failure Means for Parkinson’s Disease Research

The spectacular—and largely anticipated—failure of the Alzheimer’s treatment bapineuzumab has caused an outpouring of stories questioning what went wrong and what it means about pharma’s approach to R&D. Pfizer, Johnson & Johnson, and Elan, the developers of bapineuzumab, are taking a beating in the press for investing so heavily, not to mention raising the hope of so many patients, in a therapy that had not shown strong signs of efficacy in early trials.

Most stories are focused on the implications for Alzheimer’s research and, more generally, the pharma business model given the hundreds of millions of dollars the three companies sank into bapineuzumab. But news of its failure also resonated in research communities focused on other neurogenerative diseases, like Parkinson’s disease and Huntington’s disease, marked by protein aggregation.

I checked in with Todd Sherer, CEO of the Michael J. Fox Foundation to understand what Parkinson’s researchers might learn from the disappointing data from bapineuzumab. Sherer believes there are scientific and business ramifications of the results, both of which might have a chilling effect on neuroscience research.

From a scientific perspective, some are declaring the failure of bapineuzumab the nail in the coffin of the amyloid hypothesis, the theory that the beta-amyloid, the protein responsible for the plaque coating the brains of people with Alzheimer’s disease, is the primary cause of neuron death in the disease. Bapineuzumab, which blocks beta-amyloid, was one of a handful of treatments to test the hypothesis in the clinic. So far, every drug to reach late-stage trials has failed.

Sherer isn’t convinced bapineuzumab is the nail in the amyloid hypothesis coffin. “Obviously the results are very disappointing given the level of interest and investment that’s been put forward for this therapy,” Sherer says. “I don’ think that the result is a definitive answer to the amyloid hypothesis because there are many different ways to target amyloid aggregation therapeutically.”

Parkinson’s researchers are also trying to learn from the setbacks in Alzheimer’s and apply that to studies of drugs targeting alpha synuclein, the protein that clumps together in the brains of people with Parkinson’s disease. “One of the things that is a learning for us in Parkinson’s is really to try to be as smart and informative as we can be in the early clinical trials,” he says.

In Alzheimer’s, for example, the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a collaboration between government, academic, and industry scientists, was formed in 2003 to identify biomarkers that can be used both in the diagnosis of the diseases and in the clinical development of Alzheimer’s drugs. However, Sherer points out that while progress in the ADNI initiative has been promising, it was started too late for many companies, which had already jumped into larger clinical trials of Alzheimer’s therapies.

The Fox Foundation already has a biomarker initiative for Parkinson’s ongoing. The goal is that when the first clinical trial for a vaccine alpha-synuclein, to be led by the Austrian biotech Affiris with support from the non-profit, starts later this year, the tools will be in place to conduct a highly informative study.

On the business side, Sherer worries about the impact of more bad news in Alzheimer’s at a time when many companies are already moving out of drug discovery in many areas of neuroscience. “One of the concerns I have is that investors like big pharma companies and others are already showing a trend towards risk aversion,” Sherer says. “That will just get reinforced by these large trials not succeeding.”

Although basic research is uncovering new therapeutic avenues in diseases like Alzheimer’s and Parkinson’s, companies may decide the bar for understanding the biological relevance for each drug target needs to be set much higher. But when it comes to Parkinson’s disease, he adds, “we are not going to have the luxury of knowing everything about the disease and the biochemical pathways before we need to push forward with therapies.”

One hope Sherer has is that companies will make much of the data from these failed trials available to the research community to try to understand what didn’t work, and what the results really mean. “It’ll be a goldmine of information for other Alzheimer’s trials, but also for other genetic diseases like Parkinson’s disease and Huntington’s disease.”


TEDMED and Alzheimer’s: Gregory Petsko, Reisa Sperling, and the next Al Gore

Petsko (TEDMED)

Gregory Petsko knows why he came to TEDMED. “I’m looking for Al Gore,” he told me flat-out over lunch. Folks who know Petskoknow the former Brandeis University biochemistry department chair isn’t one to mince words. And he’s nailed the reason why an academic might want to look outside traditional conferences and soak up some of the TEDMED aura. He’s looking for a charismatic champion to take up a biomedical cause: in Petsko’s case, it’s support for research in Alzheimer’s disease.

Petsko and Reisa Sperling, director of the Center for Alzheimer’s Research and Treatment at Brigham and Women’s Hospital, talked about Alzheimer’s at TEDMED on Wednesday. Both talks were cast as calls to action. Just consider the introduction Petsko got from TEDMED chair and Priceline.com founder Jay S. Walker: “This is a man who hears a bomb ticking.”

Alzheimer’s statistics are sobering and Petsko used them to dramatic effect. People who will reach 80 by the year 2050 have a 1 in 3 chance of developing the disease if nothing is done, he told the audience. “And yet I hear no clamor,” he said. “I hear no sense of urgency.”

Petsko shared some not-yet-published work with TEDMED’s audience. Continue reading →

Wither Neuroscience R&D? Pfizer’s Ehlers Doesn’t Think So

In this week’s issue, I look at the perceived exodus by pharma companies from neuroscience R&D. Between AstraZeneca’s recent cutbacks, the closure of Novartis’ neuroscience research facility in Basel, and earlier moves by GSK and Merck, industry watchers are understandably worried that the neuroscience pipeline will dry up.

One person who isn’t worried is Michael Ehlers, Pfizer’s chief scientific officer for neuroscience research. Ehlers came to Pfizer a year and a half ago from Duke, with the explicit mission to revamp how the company finds and develops drugs for brain diseases. The scientist is convinced that the field is ripe for new and better drugs, and that by staying in the game, Pfizer will be in a good position to capitalize on what he believes will be a healthy flow of new discoveries.

Many drug companies argue that the risk in neuroscience simply doesn’t justify the investment. The overarching sentiment is that the brain is still a black box: good targets are few and far between; clinical trials are long and unpredictable; regulatory approval is tough; and generic competition is plentiful. For many big pharma firms, the math just doesn’t add up.

“I personally don’t find that calculus to give you the total picture,” Ehlers says. Shifting resources away from neuroscience to focus on areas like oncology, where the environment looks favorable—clear clinical trial endpoints, the opportunity for fast-track approval, an easier chance for reimbursement from payors—only makes sense in the short term, Ehlers says. But that thinking “is short sighted as to where the fundamental state of biology is in neuroscience,” he says.

Why is Ehlers so encouraged about a field that so many are walking away from? He believes that neuroscience is poised to benefit from the kind of genetic links that generated so many targets—and eventually so many targeted-drugs—in oncology. “There is going to be kind of a revolution in the next five years—it’s not going to be tomorrow…but you have to think about that inflection of opportunity over the five-to-ten year time horizon.”

To take advantage of each new genetic clue, Ehlers has revamped Pfizer’s approach to neuroscience R&D. As this week’s story explains:

In the past, big pharma often gave its scientists a mandate to work in areas such as Alzheimer’s or schizophrenia, regardless of tractable drug targets. Now at Pfizer, Ehlers says, his team is “indication agnostic.” Any program that Pfizer undertakes must have a critical mass of biological knowledge—for example, human genetics, human phenotyping, and evidence of dysfunctional neurocircuits—to convince Ehlers it’s worth pursuing. “We start there,” he says. “That hasn’t always been the case.”

Moreover, Pfizer no longer relies on mouse models as predictors for responses in humans. “We’ve for the most part stopped all rodent behavior as a model for disease and are much more about what’s happening in the brain,” he says. Scientists measure human responses to prove experimentally that a drug works.

Pfizer’s goal, according to Ehlers, is to tackle fewer projects but have more confidence in their potential for success. The result should be a drug pipeline “rooted in something more than optimism.”

He cites Huntington’s disease as one area that, even before coming to Pfizer, he saw as a prime scientific opportunity. “You know the gene, you know a fair bit about what’s going on, you have a wealth of data, tons of models, a clear clinical course, and an identifiable patient population,” he says. “If we can’t deal with that, we’re in trouble.”

Biogen Idec Reveals Clinical Data for (Really) Small Oral MS Drug BG-12

Biogen Idec made a splash last week when its oral medication for multiple sclerosis (MS), BG-12, was found to reduce relapses in 44-53% of nearly 3,800 patients in two separate Phase 3 clinical trials (CONFIRM and DEFINE, respectively). Continued hopes for an orally available, non-injectable MS treatment have created a race between Biogen Idec and several other firms, as C&EN’s Lisa Jarvis examines in a 2009 MS cover story. In fact, so much has changed in 2 years that two of the six Phase 3 drugs mentioned in that article – Teva’s laquinimod and Merck’s cladribine – have already been withdrawn from competition.

So what’s the secret sauce behind BG-12? Many pharmaceuticals are small molecules with multiple heteroatoms and aromatic rings, but not BG-12: it’s just dimethyl fumarate! A search for ‘fumarate’ on pubs.acs.org returned >4800 hits, which gives you an idea of its common use in several organic reactions: [3+2] cycloadditions, Diels-Alder reactions, and Michael additions. Interestingly, dimethyl fumarate is the all-E stereoisomer; the Z-configuration, where the two esters are on the same side of the central double bond, goes by the tagline ‘dimethyl maleate’ and does not seem to possess anti-MS effects.

Very small molecules such as BG-12 (molecular weight = 144) are notoriously tough to use as drugs: they hit lots of enzymatic targets, not just the intended ones, and tend to have unpredictable side effects (see Derek Lowe’s 2005 article regarding the FDA “approvability” of several common drugs today). Toss in BG-12’s alkylating behavior to boot (fumarates can interact with nucleophilic amines or sulfides at multiple sites, including enzyme active sites), and you have to wonder how it functions in the body. Well, so do scientists. A 2011 review implicates up to 3 potential biochemical mechanisms – the Nrf2 pathway Lisa mentioned in the 2009 piece, T-helper phenotype 2 interleukin upregulation (IL-4, IL-10, IL-5, which “change gears” for immune system functioning), and CD62E inhibition, which controls adhesion of blood cells to inflammation sites.

Side notes: Flavoring chemists have added fumaric acid, the parent diacid of BG-12, to industrially-prepared foodstuffs such as baking powder and fruit juices since the 1930s. A darker side of dimethyl fumarate emerges when you consider its non-medicinal use: certain furniture companies applied it to new upholstered chairs and sofas to stop mold growth. This unfortunately caused several cases of severe skin irritation, which a 2008 exposé in London’s Daily Mail likened to actual burns.


Lazy Cakes And Melatonin: The Sleepy Snack

Brownie packaging, front and back

SeeArrOh has the straight dope on a controversial snack product. SeeArrOh is a Ph.D. chemist working in industry.

(An homage to Terra Sigillata; it might normally be covered on his beat.)

Astute readers of the New York Times may have noticed a front-page article from a few weeks back, highlighting a new late-night snack: Lazy Cakes.  Taking a cue, perhaps, from the substance-laced brownies popular in the late ‘60s, these brownies pack a decidedly sleepy secret: each contains a “proprietary calming blend” of ingredients, chief among which is melatonin. 

Melatonin is a hormone usually secreted by the pineal gland (a pinecone-shaped gland located just above the cerebellum) in humans and other mammals, in response to dark surroundings.  (Note: Although they sound similar, melatonin should not be confused for melanin, the skin pigment formed by sunlight exposure) In mammals, melatonin induces the circadian rhythms associated with sleep, affects the onset of puberty and may help regulate DNA transcription.1,2 Biologically derived from tryptophan, the amino acid and purported suspect of the Thanksgiving “turkey coma”, melatonin has been shown clinically to have benefits for memory loss, in addition to antioxidant potential.  Melatonin capsules have been sold over-the-counter for insomnia and jet lag since the 1980s. 

Technically speaking, the product is labeled a dietary supplement, and as such skirts regulation by the FDA.  One valid concern are possible interactions that melatonin, like other supplements, could have with prescription drugs, a topic addressed both by Terra Sig and C&E News.  More controversy over the soporific snacks springs from their colored packaging and wide availability.  This intrepid blogger ventured out into the wild to recover a sample for analysis.  The packaging, upfront, has a distinctly comic-book appeal: purple and green swirls, a trippy logo evoking That ‘70s Show, and a cartoon brownie mascot leaned back for a snooze.  The brownie itself is compact, and has quite a bit of heft for your average baked good.  The back of the wrapper evokes language usually associated with cigarette labeling: multiple tiny lines of serious text stating Recommended for Adults Only, and Do Not Drive or Operate Heavy Machinery.     

The “calming blend” also includes valerian root, which is commonly found in teas and herbal supplements.  Containing sugar-decorated polycyclic lactones called iridoids, as well as valerenic acid3 derivatives, the extracts have been shown clinically to reduce anxiety and relieve insomnia.4 Passion flower extract brings a dose of alkaloids into the bedtime mix; well-known sleep inducers opium and morphine are part of this general molecular family.  The other ingredients, however, seem to just be along for the ride: current “superfruits” goji berry and açai, with the old Vitamin C standby of rose hips.

For my part, I don’t believe that a baked good packing a pharmaceutical punch should be sold in colorful wrappers, next to the candy bars.  However, having experienced my share of late-night grad school anxiety, I can’t blame someone for wanting a good solid nap, any way they can.

1. Fox, Stuart Ira.  Human Physiology, Sixth Ed. Boston: WCB / McGraw Hill, 1999.  pp. 289, 315. 
2. Merck & Co., Inc.  The Merck Index, 13th Ed. New Jersey, 2001. p. 5841
3. Ramharter, J.; Mulzer, J. Org. Lett. 2009, 11, 1151-1153.
4. NIH Dietary Supplement Fact Sheet: Valerian.  2008.  Downloaded from http://ods.od.nih.gov

Drug Candidate Structures Revealed At #ACSAnaheim

1PM Pacific: There’s one hour left before chemists will pack a ballroom in Anaheim to see potential new drugs’ structures unveiled for the first time. Watch this space for updates.

2:39PM Pacific: CEP-26401
This drug candidate now has a name: irdabisant
company: Cephalon
meant to treat: deficits in cognition and/or attention in diseases such as Alzheimer’s and schizophrenia
mode of action: inverse agonist of histamine H3 receptor, which regulates several neurotransmitter pathways involved in cognition, attention, memory
medicinal chemistry tidbits: Cephalon’s goal was to bring a high quality compound to the clinic to define the utility, if any, of H3 antagonists for these indications. The team studied compounds in this area that failed. Among the things they learned was that several adverse events could be tied to drug candidates’ lipophilicity. So the team prioritized lipophilicity and other such characteristics in its discovery workflow. status in the pipeline: completing Phase I in the beginning of April 2011, advancing to Phase II
structure coming soon!
UPDATED 3/29 with structure:


3:16PM Pacific: BMS-663068
company: Bristol-Myers Squibb
meant to treat: HIV
mode of action: inhibits HIV attachment to host cells by binding to the viral envelope gp120 protein and interfering with its attachment to host CD4 receptors
medicinal chemistry tidbits: potency and getting the drug candidates to reach the bloodstream efficiently were key. Replacing a methoxy group on with heterocycles, such as triazoles, gave a big boost in potency.
status in the pipeline: Completed Phase IIa clinical trials. Phase IIb studies are planned for later this year.


4:24PM Pacific:LX1031
company: Lexicon
meant to treat: irritable bowel syndrome
mode of action: blocks a subtype of tryptophan hydroxylase, the rate-limiting enzyme in serotonin synthesis, in the gut.
medicinal chemistry tidbits: Lexicon started their medchem program with an open mind. They could have made a molecule that was exquisitely selective for the subtype of tryptophan hydroxylase in the gut, they could avoid hitting the other subtype by making their molecule stay out of the brain, or both. They ultimately ended up using the latter strategy, making molecules slightly on the heavy side (above 500 or 550 molecular weight) and adding groups like a carboxylic acid, that tend to keep things out of the brain.
status in the pipeline: Completed Phase IIa clinical trials.

5:30PM Pacific: MK-0893
company: Merck
meant to treat: type 2 diabetes
mode of action: blocks the receptor for the hormone glucagon. Glucagon is released by the pancreas in response to falling glucose levels.
medicinal chemistry tidbits: Merck kept several chemical scaffolds in play during this research program. But the team’s big breakthrough was adding a methyl group to the benzylic position of a promising compound, which greatly improved potency. This methyl group strategy hadn’t worked for previous compound series, but the team revisited it anyway.
status in the pipeline: Completed some Phase II trials, according to clinicaltrials.gov

company: Elan
meant to treat: Alzheimer’s disease
mode of action: blocks gamma-secretase, a key enzyme in the production of amyloid-beta, the peptide behind the plaques that mar Alzheimer’s patients’ brains.
medicinal chemistry tidbits: Adding a cyclopropyl group and a trifluoromethyl group enhanced molecules’ metabolic stability.
status in the pipeline: discontinued because of adverse liver side effects unrelated to its mode of action.

5:31PM Pacific: That’s all for now, folks. I hope to update with more structure information later. Watch for my full story on this symposium in a mid-April issue of C&EN.

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.

Radiochemicals, Chemists, & a Potential Alzheimer’s Breakthrough

The NYTimes has a great piece today on a potential new dye that can detect amyloid plaque, the telltale sign of Alzheimer’s disease. As we’ve written, the pipeline is chock full of drugs to prevent amyloid from building up on the brain, but many neurologists believe those efforts could be for naught if the drugs aren’t tested early on in the progression of the disease. The problem is that its hard to separate dementia caused by Alzheimer’s from other neurological disorders. And by the time doctors can comfortably say that a person has Alzheimer’s, an awful lot of neurons have died. To date, there’s been no way to tell if someone showing signs of memory loss will indeed go on to develop the disease. Bottom line: this new dye could help identify the right patients, earlier on, ideally improving outcomes for drugs in development and ultimately patients.

The Times piece highlights the work of Daniel Skovronsky, CEO of Avid Radiopharmaceuticals, who along with University of Pennsylvania chemist Hank Kung developed a radioactive dye based on fluorine 18. Results from what could be a groundbreaking study will of the dye’s ability to detect amyloid plaque are going to be unveiled on July 11th at Alzheimer’s Association’s annual meeting.

We wanted to point readers to a piece our own Beth Halford wrote back in 2008 highlighting the genesis of three imaging agents labeled with 18F, including Kung and Avid’s dye and products by Bayer and GE Healthcare. More importantly, we wanted to point out some of the potential stumbling blocks to the development of newer agents and the field in general. While the NYTimes article discusses some of the ethical hurdles associated with developing and testing imaging agents for Alzheimer’s, Halford highlighted some of the larger picture worries—namely, a lack of basic research around nuclear medicine:

A report released last year by the National Academy of Sciences concluded that there was a “loss of federal commitment” to nuclear medicine. The Department of Energy, which has supported the bulk of nuclear medicine research since the 1950s, cut back its funding for the field by 85% from 2005 to 2006, and funding levels haven’t made any appreciable gains in the past two years.

PET researchers’ other chief complaint has particular relevance to C&EN readers. “What we’re missing in this field are chemists,” says Gilles Tamagnan, laboratory R&D director at Molecular NeuroImaging and associate professor of psychiatry at Yale University. “There’s plenty of nice chemistry to be done. There just aren’t enough people doing it,” he says.

PET researchers say more radiochemists are required to staff the rapidly growing number of PET centers (see page 68). They also note that only a handful of synthetic chemists are working on new methods to incorporate radionuclides into molecules. Medicinal chemists are also needed to expand the limited list of radiotracers currently available. “There are less than 20 teams developing new radiolabeled compounds for the brain,” Tamagnan notes, “and the brain is very big.”

In an entirely separate issue, the number of suppliers of radiochemicals has been shrinking, a situation that has some worried about the long-term availability of radiochemicals. As our own Mike McCoy wrote earlier this year, two major suppliers—Sigma-Aldrich and GE—exited the radiochemical business in 2008, moves that don’t exactly bode well for the long-term health of the industry. Although McCoy found several smaller suppliers that vouched for the stability of supply, a number of researchers, including Penn’s Kung, were feeling neglected. As McCoy writes:

There was a time when commercial radiochemical firms would replicate diagnostics developed in Kung’s lab and offer them to other scientists for use in research. But during the 2000s they lost interest in this business, he says, leaving his fellow researchers in the lurch. “I try to help them out, but I’m not set up to supply them on a regular basis,” he explains.

On a happier note, Kung says commercial supply houses seem a little more invested in helping out these days. Perhaps news of a breakthrough diagnostic is helping them to see the light. So chemists that use radiochemicals: are you having any trouble getting them? And do you buy into Tamagnan’s assertation that there’s a market for radiochemists out there?