What Pfizer’s Bapineuzumab Failure Means for Parkinson’s Disease Research
Aug10

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...

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Radiochemicals, Chemists, & a Potential Alzheimer’s Breakthrough
Jun24

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...

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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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