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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/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:

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?

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.

Obesity Musings On Alkermes, J&J News

I am always on the lookout for news in the obesity drug area. But lately two of the molecular components of experimental obesity drugs in late-stage clinical trials-naltrexone and topiramate- are in the news for other reasons.

Alkermes announced this morning that it will receive priority review from FDA for VIVITROL, an injectable extended-release formulation of naltrexone, for treating opioid-dependent patients, with a PDUFA date of October 12, 2010. The idea is that a once-monthly injection of VIVITROL would be given to lower cravings in people with a dependence on opioids such as heroin, Vicodin, or Oxycontin. VIVITROL is already approved for treating alcohol dependence.

It’s Alkermes’s formulation that’s new. Naltrexone as a chemical entity has been around for some time. DuPont originally marketed it as Trexan in 1984 but that form is now off-patent, as C&EN’s Ann Thayer wrote back in 2006. I also promised that there was an obesity connection here, and indeed there is. Naltrexone is one of the two components in Orexigen’s experimental obesity medication, Contrave, as I explained last year. Orexigen has developed its own proprietary sustained-release formulation of naltrexone and the experimental drug’s other active ingredient-bupropion, an antidepressant and smoking-cessation aid that boosts dopamine signaling.

Ortho-McNeil Pharmaceutical, a subsidiary of Johnson & Johnson, has agreed to pay $81 million (that’s $6.1 million in criminal fines and $75.37 million from civil suits) for promoting its epilepsy medication Topamax for several uses not approved by FDA. This story has been in the news for nearly a month now (see Pharmalot’s entry about it here) but the company pled guilty to the illegal marketing just last Friday, placing this item back at the top of my Google News list.

One of the off-label indications J&J was promoting turns out to be obesity, according to the whistleblower who brought the case. Read the legal documents here [pdf format]. Thanks to Jim Edwards at BNET for posting these.

Topiramate (the active ingredient in Topamax) is one of the two active ingredients in Vivus’s experimental obesity drug Qnexa. But Vivus’s formulation uses topiramate at a much lower dose than would be taken as a standalone drug.

Addex Dishes About J&J Deal

Merck wasn’t the only company holding an R&D Day today- Swiss pharmaceutical firm Addex Pharmaceuticals also held a briefing for investors and journalists. (I didn’t get to go to Geneva, but I did watch the webcast and downloaded the presentations here.)

Addex has dedicated its entire pipeline to allosteric modulators- drug candidates that work at protein sites other than the ones where the body’s chemicals typically bind. Last fall we wrote about Addex’s strategy and its potential usefulness in tackling G-protein coupled receptors (GPCRs), one of the biggest (if not the biggest) classes of drug targets.

Today Addex updated attendees on a few different drug candidates. But the biggest news was that it disclosed the terms of its schizophrenia drug partnership with Ortho-McNeil-Janssen Pharmaceuticals, a unit of Johnson & Johnson. According to the terms of the deal, Addex could get as much as 112 million euros subject to successful completion of development and regulatory milestones. In addition, Addex is eligible for low double-digit royalties on sales of the possible schizophrenia drug it discovered, subject to regulatory approval and successful commercial launch. Addex’s stock jumped up 8.75% on the news, to 13.05 Swiss francs (about $11.75)

In the deal, Ortho gets to fund and perform preclinical and clinical development for Addex’s potential schizophrenia drug, known as ADX71149. The molecule dials up the activity of a GPCR that responds to glutamate, called mGluR2. The dialing-up part is what’s thought to be important. It’s the whole point of taking an allosteric approach. Instead of just turning a receptor on or off, you adjust its activity to acceptable levels. The philosophy at Addex is that this more subtle approach will restore more normal glutamate signaling in schizophrenia patients, with fewer of the kinds of side effects that result from an all-or-nothing, on-or-off approach. Of course all that remains to be seen for ADX71149. Phase II clinical trials (which can give an indication of therapeutic potential) for the molecule are slated to start later this year.

This nuanced approach to disease was clearly attractive to J&J, but it’s also one that many, including Addex, have stumbled over. Last December, Addex had a big disappointment when they had to stop development of their lead drug candidate, ADX10059, because of safety concerns. The molecule was in clinical trials for migraine and heartburn associated with gastroesophageal reflux disease. But a safety monitoring turned up signs of liver abnormalities in people receiving ADX10059.

Untangling Tau & Alzheimer’s

While researching the ins and outs of beta-amyloid and Alzheimer’s, we of course wanted to know what other targets pharma companies had up their sleeves. The most obvious next big target is tau, the other hallmark pathology in the brains of people with Alzheimer’s.

As we wrote, most of big pharma’s eggs are in the beta-amyloid basket, with nearly every drug in the Alzhiemer’s pipeline looking to block the production of or somehow clear the peptide. But in addition to beta-amyloid filled plaques, the brains of people with Alzheimer’s are marked by “tangles,” or clumps of an abnormal form of the protein tau. The beauty of tau as a drug candidate is that “it doesn’t rise and fall with the amyloid hypothesis,” Charles Albright, group director of neuroscience biology at Bristol-Myers Squibb, told us. In other words, because overproduction of tau hasn’t been definitively linked to overproduction of beta-amyloid (though some researchers do believe the link exists), it could still be a viable target if none of the beta-amyloid blockers in the clinic prove effective.

And studies in animal models suggest that dampening tau production could improve the outcome for Alzheimer’s patients. “Certainly some of the experimental data suggests if you’re a demented plaque and tangled mouse and your tau level is knocked down, your behavior improves,” said Sam Gandy, associate director of the Mount Sinai Alzheimer’s Disease Research Center. Further, he noted that scientists have shown that at least some neurons die by a tangle-dependent process.

But when it comes to drug discovery, there are some key differences between beta-amyloid and tau. Beta-amyloid is a small peptide, whereas tau is a protein of about 50 kilodaltons. And despite clues, no one is really sure about a role for beta-amyloid outside of plaque-building, while tau is a rather ubiquitous protein that clearly binds to and stabilizes microtubules.

The bottom line for tau, is it is “very interesting, and very challenging,” Mene Pangalos said just weeks before leaving his job as Pfizer’s CSO in Neuroscience to head research at AstraZeneca.

One problem has been that the most obvious targets for tau are kinases that block the phosphorylation of tau. But it can be difficult to find selective kinase inhibitors without a lot of unpleasant side effects. “That’s where its been a struggle,” Pangalos added.

“It’s more challenging, but in a way, the target is common to more dementing processes than is amyloid, so it is important to keep hammering away at it,” Mount Sinai’s Gandy said.

Most companies involved in Alzheimer’s are indeed hammering away at it. David Michelson, vice president of clinical neuroscience and ophthalmology at Merck, believes that a range of drugs to test the tau hypothesis will be in the clinic in the next few years. “We and I’m sure others have very active programs looking at a lot of novel ways of trying to get at it, and I do believe that those will eventually bear fruit, but it probably will take a little longer.”

Bristol-Myers Squibb appears to have made some progress against the tough target. Francis Cuss, the company’s senior vice president for discovery and exploratory clinical research, recently told investors that the company would put a microtubule stabilizer targeting abnormal tau into Phase I trials later this year.

Meanwhile, Xconomy profiled the Vancouver, Canada-based Allon Therapeutics, which believes its peptide davunetide is the most advanced candidate to tackle tangles. Davunetide is in Phase IIa trials in Alzheimer’s, and early data has shown the therapy improved cognition in a small group of patients. Promising, to be sure, though other exciting early-stage results have taught the Alzheimer’s community to be cautious about expectations. The Haystack is curious whether Allon also measured tau in the cerebrospinal fluid, before and after dosing with its drug to show that it is having an effect on the protein.

Our own Sophie Rovner will take a more in depth look at the challenge and promise of tau in an upcoming issue. We’ll make sure to highlight the story when it comes out. Stay tuned!

Harnessing the Alzheimer’s Pipeline

In today’s issue, we have a package about drugs in development to treat Alzheimer’s disease. The main piece looks at the different kinds of drug candidates targeting beta-amyloid, the peptide responsible for the plaques coating the brains of people with Alzheimer’s. Despite a slew of molecules in the later stages of development, there are still questions about whether blocking beta-amyloid accumulation makes the most sense. As the article says:

“If the trials are successful—and the amyloid hypothesis is proven true—doctors will have a slew of new drugs that could slow the progression of the disease. If the trials fail, scientists will be forced back to the drawing board to develop new hypotheses and drug targets.”

The second piece is a case study of the complicated chemistry campaign involved in developing Merck’s most advanced BACE inhibitor. BACE is an enzyme used to cut down a larger peptide into beta-amyloid, and it has proven to be a tricky target.

The last piece asks whether Dimebon, the drug candidate being developed by Medivation and Pfizer, has any legs left in it after it performed miserably in a Phase III trial. The companies say the jury is still out, while most neurologists have less kind words for the drug.

Overall, the stories try to harness the pipeline for a market in which big pharma is anxious to have a presence. In its pipeline review at the beginning of the year, Pfizer touted the 10 compounds in development for Alzheimer’s, making it the second only to oncology in terms of therapeutic focus. Bristol-Myers Squibb devoted a good portion of its R&D day last month talking about BMS-708163, its gamma-secretase inhibitor expected to head into Phase III trials later this year. And the number of basic patent filings for Alzheimer’s drugs has jumped from 652 in 2000, to 1995 last year, according to Chemical Abstract Services.

Why all the interest? The market is vast and patients are greatly underserved. The two Alzheimer’s drugs currently on the market, Pfizer’s Aricept and Forest Laboratories’ Namenda, are at best mildly effective at temporarily easing the symptoms of the disease. Last year, Pfizer sold $432 million worth of Aricept, while Namenda sales totaled $949 million. With 5.3 Americans suffering from Alzheimer’s, imagine the potential for a drug that actually slowed the disease down. Now factor in the potential for that number of afflicted to quadruple by 2020, and the market for an Alzheimer’s drug starts to look pretty huge. Add in the likelihood that for a drug to have the most effect, it’ll probably need to be given before dementia sets in and for the rest of a person’s life, and it starts to look ginormous.

Throughout the week, we’ll try to post some bonus commentary from our reporting for the stories. Let us know if there’s anything specific you want to hear about!