#BIO2012: Pfizer’s academic push by the numbers

The evolution of the model for academic-pharma collaboration has been a topic of much discussion as more companies try to tap into university talent for early-stage research (recent examples of collaborations can be found here and here). Industry observers question whether anything tangible will come out of the efforts (see here for a recent critique), believing the divergent missions and cultural differences of each organization inevitably sidelines these pacts. Pfizer is making one of the more aggressive pushes through its Centers for Therapeutic Innovation. Under the CTI model, Pfizer has set up labs in research hotbeds like Boston and San Francisco, where, through partnerships with various academic institutions, its scientists work side-by-side with university scientists to discover new biologics-based drugs. This week at BIO, I sat down with Tony Coyle, CTI’s chief scientific officer, to talk about CTI’s progress. A more in-depth look at the CTI model will come in the pages of the magazine, but in the meantime, I wanted to share some facts and figures that came out of our chat: Number of CTIs formed: Four (San Francisco, San Diego, New York, Boston) Number of academic centers involved: 20 Number of Pfizer scientists across each of its dedicated labs: roughly 100 (Coyle says about 75% were hired from the outside, coming from biotech, academia, with a few from big pharma) Number of proposals reviewed in the last year: 400 Percentage of proposals overlapping with internal Pfizer efforts: <5% Number of proposals funded so far: 23 Number of therapeutic areas being studied: 4 (rare diseases, inflammation, cardiovascular disease, and oncology) Facts and figures aside, Pfizer is trying to move as quickly as possible given the learning curve of teaming with academia. Coyle said he’s promised his bosses that by the third year of the effort, at least four drugs will be in human studies across multiple therapeutic areas. “We’re well on our way to identifying a number of candidates, and I have no doubt that in the next 18 months, we’ll be in our first patient studies,” he added. Those numbers could change in 2013, when Pfizer potentially expands its CTI outside the U.S. “Ex-U.S is still our ambition,” Coyle says. “2012 has been a period of ‘lets build the group, get the programs and start executing on the pipeline.’ For 2013, we will be and are looking at opportunities ex-U.S., and have had some pretty good discussions to date...

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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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Bristol-Myers, Pfizer’s Apixaban Tops Warfarin In Anticoagulant Face-Off
Aug29

Bristol-Myers, Pfizer’s Apixaban Tops Warfarin In Anticoagulant Face-Off

Over the weekend Bristol-Myers Squibb and Pfizer announced that their blood-clot-preventing drug candidate, Eliquis (apixaban), bested the workhorse anticoagulant Coumadin (warfarin) in a large clinical trial. The results were announced at the European Society of Cardiology congress and simultaneously published in the New England Journal of Medicine. This is the first time that one of the cadre of anticoagulants seeking to replace warfarin has been shown to be superior to warfarin at preventing dangerous blood clots that can lead to strokes while also having a lower rate of bleeding compared to warfarin. In the 18,201 patient Phase III clinical trial, called ARISTOTLE, apixaban reduced the risk of stroke in patients with an abnormal heart rhythm called atrial fibrillation by 21 percent, major bleeding by 31 percent, and mortality by 11 percent. More statistics are available in the announcement, the journal article, and in this Forbes report, which plucks out these illustrative numbers: The investigators calculated that for every 1000 patients treated with apixaban instead of warfarin for 1.8 years •stroke would be avoided in 6 patients, •major bleeding would be avoided in 15 patients, and •death would be avoided in 8 patients. Analysts reacted positively to the data, with Leerink Swann analyst Seamus Fernandez raising his 2017 sales estimate for apixaban by $1.1 billion to $4.1 billion in a note to investors. We’ve previously explained how apixaban works– briefly, it blocks Factor Xa, a protease enzyme near the end of the complex biochemical pathway that regulates blood clotting. Another Factor Xa inhibitor, rivaroxaban, has been approved in Europe but awaits FDA approval. Pradaxa (dabigatran), which blocks the enzyme thrombin, has been approved by FDA for reducing the risk of stroke associated with atrial fibrillation. So what’s the secret of apixaban’s success? In 2010, we spoke with Ruth R. Wexler, executive director of cardiovascular diseases chemistry at Bristol-Myers Squibb, who explained how apixaban was designed with pharmacokinetic properties (the properties that reflect how the body affects a drug’s fate after administration) in order to reduce the risk of off-target effects. The extent to which an anticoagulant gets distributed through the body also matters, says Ruth R. Wexler, executive director of cardiovascular diseases chemistry at Bristol-Myers Squibb. “Coagulation factors are in the blood,” she says. So there’s no need for a drug candidate that blocks a coagulation factor, such as Factor Xa, to be distributed beyond the bloodstream and reach other tissues and organs. “Getting into other tissues and organs is frequently the reason why there are off-target safety issues,” she says. This was one of many concerns BMS had in mind as it developed its most advanced Factor Xa inhibitor,...

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BMS-AstraZeneca Dapagliflozin Diabetes Drug Falls Short; Pfizer’s Answer on the Horizon?
Jul29

BMS-AstraZeneca Dapagliflozin Diabetes Drug Falls Short; Pfizer’s Answer on the Horizon?

As reported by Nature News and Forbes’ The Medicine Show  on July 20, dapagliflozin, a BMS-developed diabetes drug marketed with partner AstraZeneca, was given a “thumbs-down” by an FDA review panel on July 19. After the 9-6 final vote, panel members commented favorably on the drug’s new mechanism, but evidently felt that the safety profile could not be overlooked: the FDA committee meeting statement mentions increased risk of breast and bladder cancer, increased genital infections, and perhaps most seriously, potential for drug-induced liver injury (DILI). Dapagliflozin has been one of the rising stars of the new class of Sodium-Glucose cotransporter 2 (SGLT2) inhibitors for diabetes treatment, whose development roster includes Johnson & Johnson, Astellas, Boehringer Ingelheim, Roche, GSK, and Lexicon (Note: see Nat. Rev. Drug Disc. 2010, 551 for a full recap).  The excitement behind these drugs comes from a relatively new idea for diabetes treatment: inhibition of the SGLT2 enzyme stops the kidney from reabsorbing sugar, leading to excretion of the excess glucose in the urine, which in turn lowers blood sugar. Dapagliflozin, like most SGLT2 inhibitors, is a glucose molecule with a large aromatic group attached to the carbon atom in the spot chemists call the anomeric position. Such so-called C-glycosides are thought to have improved staying power in the bloodstream relative to O-glycosides (where the linkage point is at an oxygen atom, a more common scenario in sugars), since they are less susceptible to enzymatic breakdown. So, how do you improve these compounds? A paper Pfizer published last March (J. Med. Chem. 2011, 2952) may offer some hope.  Pfizer noted that some of the C-glycoside SGLT2 inhibitors gave a positive micronucleus test, indicating their potential to damage chromosomes. To work around this liability, their chemists  designed an analog of dapagliflozin where a second hydroxymethyl (CH2-OH) group is “tied” underneath the ring, forming a bicyclic compound that advantageously rigidifies the compound, increasing potency, while at the same time blocking a potential site of reactive metabolite formation (which might contribute to further DILI). The improved compound shows high potency for SGLT2 (~920 pm), a negative micronucleus test, and is now in Phase II  trials. Want to hear more? The lead author of Pfizer’s paper, Dr. Vincent Mascitti, will speak about the study as part of the Organic Division program at the ACS National Meeting in Denver – Sunday, August 28, 8:00 AM-8:30AM, Four Seasons...

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Pfizer: No Sacred Cows in R&D

Just when we thought it was over, the cost-cutting at Pfizer continues. In tandem with this morning’s fourth-quarter earnings announcement, Pfizer said it was closing its R&D site in Sandwich, U.K., and paring back research in Groton, Conn., both sites that had survived earlier cutbacks relatively unscathed. Upwards of 3,500 jobs are at risk in the cutbacks. First some details, and then some thoughts on what the new Pfizer research might shape up as. The details: –The closure of the Sandwich site will impact 2,400 jobs, although Pfizer says as the shutdown happens over the next 18-24 months, it hopes to move a few hundred folks over to other sites or to external partners. –Some 25% of the 4,400 employees at Pfizer’s Groton and New London campuses will be shed. –Internal research will be focused on a few core areas:  neuroscience, cardiovascular, metabolic and endocrine, inflammation and immunology, oncology, and vaccines. –Pfizer is creating dedicated units focused on pain and sensory disorders, biosimilars, and Asia R&D. –Pfizer is exiting research in multiple areas: allergy and respiratory, located in Sandwich, U.K.; internal medicine, which includes some research in lung, kidney, and genital urinary diseases, also located in Sandwich; oligonucleotides and tissue repair, in Cambridge, Mass.; and antibacterials, situated in Groton. –Regenerative medicine research in Cambridge, Mass., is also being dumped. However, similar work in Cambridge, U.K., will be part of a new pain and sensory disorder research unit. –The R&D budget for 2012 will shrink. The company previously expected to spend $8-$8.5 billion on research next year; now, it will shell out nearly 20% less, or between $6.5 and $7 billion. Remember back to 2008 and 2009, when R&D spending topped $10 billion? –Pfizer will establish external relationships for several activities, including manufacturing of active pharmaceutical ingredients and dosage forms, toxicology, and bioanalytics. –Pfizer is aligning its R&D network around a few hubs: Cambridge, Mass., San Francisco, New York, LaJolla, and Cambridge, U.K. As for the new “innovation engine” at Pfizer, CEO Ian Read today told investors he would be working closely with R&D chief Mikael Dolsten to overhaul the research culture at Pfizer. The idea is to empower research units with the decision making and also hold them accountable for the outcomes. Or as he put it, give scientists a feeling of “owning the money and owning the results.” This strategy sounds a lot like one that’s been taking shape over the last two years at GlaxoSmithKline and, more recently, at AstraZeneca. One analyst asked whether the research programs falling to the ax will be spun out into biotechs. The possibility seemed real, and it again sounded a lot...

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