BMS and Pfizer’s blood thinner beats aspirin- now, what can it really do?
Jun11

BMS and Pfizer’s blood thinner beats aspirin- now, what can it really do?

Yesterday, Bristol Myers Squibb and Pfizer agreed to stop AVERROES, a late-stage clinical trial of an experimental blood thinner, early. It's relatively rare for a trial to be stopped for positive reasons, but that is what happened here. An independent analysis concluded that the blood thinner, called apixaban, was more effective than aspirin at reducing strokes and blood clots anywhere outside of the brain in patients with atrial fibrillation, a common abnormal heart rhythm. Stroke is a major complication for patients that have this heart problem, and drug companies would like to find a more manageable way to reduce patients' chances of having one. Apixaban is one of a slew of potential new blood thinners in the pipeline that is an oral inhibitor of Factor Xa, a protease enzyme that sits at a key point in the body's complicated blood coagulation cascade. Matthew Herper at Forbes recently broke down how another drug in this same class, Merck's betrixaban, works. One thing to keep in mind is that none of the 5600 patients in this study were taking warfarin, a decades-old blood thinner that's still one of the gold standards for preventing stroke. For patients with atrial fibrillation, warfarin, a vitamin K antagonist that interferes with the coagulation cascade, is generally considered to be a more effective option than aspirin, which prevents blood platelet activation. The patients in the AVERROES trial, BMS's press release explains, were either unable to take or chose not to take warfarin. I can understand the perspective of the folks choosing not to go that route. Warfarin works, it's cheap, and it's also an oral medication, but it's far from perfect. People who take it must be very carefully monitored by a physician, because other drugs and even foods in the diet can alter its effects in the body. And with blood thinners, you're always walking a tightrope- too high a dose can lead to excessive bleeding. Also, some genetic differences can affect how well warfarin will work. Patients who have that genetic makeup might want to have another option that they can take in the form of a pill. But apixaban is still an investigational agent- FDA has yet to approve it. The news in this trial was good news, but given the relative effectiveness of aspirin I'm not sure how surprising it really was to those following this field closely. To get a complete picture of what apixaban can do, it will be good to see what comes of the ongoing ARISTOTLE trial. That trial, like AVERROES, is a Phase III, randomized, double blind clinical trial in patients with atrial fibrillation. But instead of...

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Untangling Tau & Alzheimer’s
Apr08

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...

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Harnessing the Alzheimer’s Pipeline
Apr05

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...

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California Dreaming of Macrocycles
Apr02

California Dreaming of Macrocycles

When I go to a 'first disclosure' talk, where drug candidates' structures are publicly revealed for the first time, I try to do my homework in advance. But there are always a few surprises. Take the candidate unveiled at the ACS meeting by Paul M. Scola of Bristol Myers-Squibb. BMS-650032 is a potential Hepatitis C treatment. It inhibits a protease that's essential for the hepatitis C virus's replication. I'd learned from the team's abstract that BMS had already advanced another compound (BMS-605339) to clinical trials, and that that compound was discontinued because of some mild adverse findings. So I tried to figure out what parts of BMS-605339 the team might've adjusted to resolve those effects. I thought I'd found a clue in a recent patent from the BMS team (WO/2009/140500). They patented compounds that contained a large ring, a macrocycle. This got my attention for a few reasons. Two years ago, we covered the disclosure of Merck's MK-7009, another potential treatment for hepatitis C that blocks the same protease. MK-7009 contains a macrocycle. Also, macrocycles, when applied strategically, can be beneficial in drug discovery, enhancing metabolic stability or binding affinity for a given drug target, as Scola and a few other experts told us last year. "It's got to be a macrocycle," I thought. Well, I thought wrong. BMS-650032 doesn't contain a macrocycle, after all- the only modifications that the team made to the original clinical candidate, BMS-605339, to arrive at 650032 were very subtle substituent changes to an isoquinoline ring. But the team did indeed examine macrocycles, Scola told me in San...

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ArQule Shares Surge on Met-Inhibitor Data
Mar31

ArQule Shares Surge on Met-Inhibitor Data

ArQule’s stock has doubled this morning on new data from a Phase II trial of its lead drug candidate ARQ197, in patients with tough-to-treat lung cancer. ARQ197 targets the Met receptor, a protein involved in helping cancer spread. As we wrote a few years back, in the pantheon of tyrosine-kinase receptors implicated in cancer, Met comes off as a particularly sinister protein. "Met is one of the highest and most frequently occurring gene products in tumors," George Vande Woude, research director of the Van Andel Institute, a cancer research center in Grand Rapids, Mich., and discoverer of the c-Met gene, told us at the time. In ArQule’s trial, a combination of Genentech’s targeted lung cancer drug Tarceva, which blocks the EGFR receptor, and ARQ197 kept the disease from spreading for 16.1 weeks versus a delay of 9.7 weeks in patients given Tarceva alone. The results results were more striking in a subset of the population with a specific cell type. You might look at the data and think, hmm, an extra two months, that’s not much. But its important to remember that these patients are in the latest stages of the disease, and have already been treated with many other drugs that have failed to slow down the cancer. “I think it does provide validation for Met,” says Needham & Co. analyst Mark Monane. “This is solid Phase II data in combination with Tarceva, that’s two targeted therapies together.” ArQule is also studying using the drug in combination with other targeted agents, like Bayer/Onyx’s Nexavar and Eli Lilly’s Gemzar. “Is this the beginning of a beautiful friendship between 197 and commonly used agents? Could be,” Monane says. Those who have been keeping an eye on the c-Met landscape might recall that Exelixis has two of its own c-Met inhibitors in the clinic. However, the South San Francisco-based company is taking a different approach, and rather than potently hitting that one receptor, is blocking several proteins at once. XL184, partnered with Bristol-Myers Squibb and in Phase III trials, hits MET, VEGFR2, and RET, while XL880, partnered with GlaxoSmithKline, inhibits MET and VEGFR2. “I think the jury is out on whether you want a single, targeted c-Met inhibitor or something more promiscuous,” Monane...

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