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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TEDMED and Alzheimer’s: Gregory Petsko, Reisa Sperling, and the next Al Gore
Apr12

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

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. His team is looking at a less-trod path of Alzheimer's biology-- the role protein sorting defects might play in the development of the disease. Their focus is on a protein complex called the retromer, which Petsko likened to a truck driver, because its job is to sort and send proteins either to the golgi--the cell's recycling center, or to the lysosome for snipping. For Alzheimer's, the thought is that improper sorting can make the difference between normalcy and an accumulation of amyloid-beta, the protein thought to be a key player in developing the disease. Petsko told me that his collaborator, Scott Small of Columbia University Medical School, discovered that retromer played a role in Alzheimer's (Neuron, DOI: 10.1016/j.neuron.2006.09.001).   Petsko's team has developed small molecules that increase the level of active retromer complex in the cell. So far, their agents have been evaluated in cultured cells. Tests in mice are ongoing. It's important for the Alzheimer's field to look beyond amyloid-beta, says Kevin Sweeney, a TEDMED attendee who teaches at the University of California, Berkeley's Haas School of Business and is part of the Rosenberg Alzheimer's Project, a nascent organization that supports alternative avenues in Alzheimer's research. "For a while, at least, the Alzheimer's space looks like so many of the [clinical] trials have pursued a relatively narrow range of theories," he says. Even though those theories aren't fully played out, "we still think it's useful to start looking for other strands,"...

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Wither Neuroscience R&D? Pfizer’s Ehlers Doesn’t Think So
Mar19

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...

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Alzheimer’s Meds from Plants: Satori Digs up New Leads
Jul20

Alzheimer’s Meds from Plants: Satori Digs up New Leads

Earlier this week, Satori Pharmaceuticals reported from the 2011 Alzheimer’s Association International Conference two new promising lead molecules, SPI-1802 and SPI-1810. Both block gamma-secretase, one of several enzymes involved in snipping the lengthy amyloid precursor protein down to beta-amyloid, the peptide that makes up the plaques coating the Alzheimer’s brain. A slew of big pharma companies are pursuing compounds that inhibit the enzyme (see here for more on the subject). So, you ask: What’s so new about Satori’s approach? For starters, Satori is trying to be very specific about what their compounds target. The researchers claim their compounds promote selective degradation of a single type of brain plaque – Amyloid β-42, the plaque most commonly associated with the disease – without destroying other, shorter amyloid residues (Aβ-38 and -40) that may actually confer neural health benefits. A Satori patent from June 2010 shows the selective amyloid-destroying  abilities are due to six-ring structures isolated from flowering plants. Who says new drugs aren’t discovered from natural products anymore? The patent literature dug up by our gang suggests that Satori’s leads come from the earth; specifically that they are semisynthetic derivatives of compounds extracted from the roots of black cohosh (snakeroot). Native American and Chinese herbal medicine use preparations of this plant, usually brewed as root teas, to aid muscle cramps and pain associated with menstruation or menopause.  Just a casual glance at Satori’s lead structure evokes phytosterol hallmarks: cyclopropanation at C9-C10 (a precursor to B-ring expansion in compounds like cortistatin A, a sea sponge isolate), a highly oxygenated terpene end chain, and a glycosidic linkage off of carbon 1 (far left), coupled to a typical plant sugar such as arabinose or xylose. A major critique of early Alzheimer’s drugs was that it wasn’t clear they were actually binding to their intended enzyme targets, which could explain some of their disappointing clinical results. Indeed, Eli Lilly this week provided more data confirming semagacestat, its lead gamma-secretase inhibitor, actually worsened rather than ameliorated patients’ conditions. Interestingly, Satori’s lead molecules look nothing like most of the big pharma compounds: Semagacestat is a peptide-linked lactam, while Merck’s lead molecules are iminopyrimidones with heterocycles stapled on. It's still too early to tell if the major structural differences in these new lead compounds will overcome the issues associated with semagacestat. But Satori scientists have one selling point: their compounds do not interfere with Notch, a protein involved in a host of key cell–signaling processes, including helping to control cell differentiation, proliferation, and cell death. It also happens to be a substrate for gamma-secretase. The challenge of blocking gamma secretase without disrupting Notch has caused many drug companies to...

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Amusing News Aliquots
Jun23

Amusing News Aliquots

Silly samplings from this week's science news. Compiled by Bethany Halford and Lauren Wolf. Got a good story about late Chemistry Nobel Laureate William Lipscomb? The Annals of Improbable Research want to hear from you. [AIR] Your dishwasher is trying to kill you with fungus. Evil robots everywhere rejoice. [Physorg.com] Award-winning whisky maker is Kraft-chemist-turned-teacher-turned-distiller. “I decided that I really wanted to turn my chemistry from doing good to doing bad,'' he says.  "To turn to the dark side.'' [The Age] Hammocks rock ... you to sleep. And here’s the neuroscience to prove it. [NPR] Synthetic highs are big business for garage chemists. [Bloomberg Businessweek] Drinking coffee protects against Alzheimer’s disease. Yet another reason to have that fifth cup of the day. Or was it fourth? We can’t remember....

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