Objective 2007: Become Goddess of PowerPointery

Long time no see.
I took something of a hiatus from the hootacular environs of the Refuge due to the Most Wonderful Time of the Year at DOPI:* performance reviews for 2006 and objectives setting for 2007. I know. I shouldn’t whine and bitch about this, seeing how much work you academics put into the grant writing process in the unending effort to suck at the NIH/NCI/NSF/IYAH** teat, and I can appreciate how difficult that is. After seeing my grad advisor lose a significant grant (since regained) during the heyday of Ronnie Reagan years when 0.0000037% of all NIH grants were funded, I was utterly convinced there was no f’ing way I would be hippity hopping down the academic trail.

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Big Pharma Screws the (Fat) Pooch

Let’s see, the Biz shot its right foot with the Vioxx debacle, then its left foot with Zyprexa (and others, but that’s a recent one), so now it must look for another site for further damage of its tattered n’ shattered image. Hmmm, how about lobbing off a couple of fingers? The FDA’s approval of Slentrol, Pfizer’s new chemical entity (NCE) for treatment of obese dogs ought to do the trick. Zing! There go the fingers.
As a minion of the dark overlords, I have to say that the announcement made me cringe for a number of reasons, the primary one being that this further solidifies the perception that “all drugs from pharma are for frivolous indications.” This past weekend, I visited a close friend, a sr. director of chemistry of a company in the Boston area, and we lamented this latest flappery not only for the bad PR, but also because of its sheer lack of necessity. After all, a typical American dog’s diet is in the control of its owner; likewise, so is its level of activity. Jeez, people. Just take the dog and yourself out for a walk.
The subject has been covered by other Science Bloggers, Pharma Watch Dogs amoung them. See effect measure, Corpus callosum, and Retrospectacle. I’ve already made my opinions on drugs for human obesity known (And now a word from obesity’s big fat corporate sponsor), but that won’t stop me from weighing in (har) on fat doggies and Pfizer’s strategy.
Now Shelley’s post in Retrospectacle is a fine screed, but if one is to speak of “the truth” regarding Pfizer’s NCE for canines, then the following “despite it seeming to fill an non-existent market” is not quite accurate.

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A Healthy Dose of Skepticism

With the latest Big Pharma debacle (“Hey, let’s shoot ourselves in the other foot”) from the Prozacasaurus’ overmarketing of Zyprexa (see Grrl’s, Jake’s, and David’s (addendum, 12/21) blog entries on the subject), this recent (and free access) article from PLoS Medicine: Educating Health Professionals about Drug and Device Promotion: Advocates’ Recommendations seems particularly relevant.

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Thorazine for some and Quaaludes for all your patients!

Over at Terra Sigillata, Abel Pharmboy dissects the deeper meaning of the Rozarem ad which features Abe Lincoln, a beaver and a scuba diver telling an insomniac how much they miss him. The ad is hawking Takeda Pharm’s latest little sleeping pill. The Rozarem campaign is a departure from the usual direct-to-consumer drug advertising. It’s certainly edgier and more surreal than Mandy Patinkin looking sincerely into the camera and urging you to “ask your doctor about Crestor.”
I am not a fan (to say the least) of pharma’s DTC advertising, but I’ll leave my frothing rant on that subject for another time. When I first started in the Biz 18 years ago this month, ads for prescription drugs were confined to JAMA, The Lancet, or speciality journals. These were the days before e-journals and pdf’s. There were some pretty intriguing ones to be found as glossy color prints or more subdued black and white tones. When I worked on targets for prostate cancer, I often read, appropriately enough, The Prostate, and also the Journal of Urology. Some of the ads in the latter were eyebrow-raising. Who knew there were, uh, gadgets like that for male plumbing? Honestly, the impact of phosphodiesterase-5 inhibitors cannot be underestimated. Then there was the article on cosmetic surgery to reverse circumcision, complete with figures and diagrams.

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A pant-hoot of appreciation goes out to United Kingdom bonobo, grimupnorth, for passing this along.

Adam Kay is a junior doctor from the UK who passes his limited spare time by writing songs, including one about a new wonder-drug called Paracetamoxyfrusebendroneomycin.
He’s built up a cult following, and he’s currently selling out at the Edinburgh festival.
There are some clips from the songs on this site:
The Friday Project (“Paracetamoxyfrusebendroneomycin” contained therein – Doc Bushwell)
He gives all proceeds from his album sales to a cancer charity.
See what you think.

Adam Kay has a future in direct-to-consumer pharma advertising. Thanks, grim. I owe you a grooming session.

Fixing the drug approval process: a sea change or tilting at windmills?

After being buggery-augered with no lube by the New England Journal of Medicine’s finest, it’s refreshing for us minions of Big Bad Pharma and our small company lampreys to read an article in that august journal which moves beyond Angellic knee jerk histrionics.
Alastair J.J. Wood, M.D. offers a proposal for radical changes in the drug-approval process. As Joseph j7uy5, proprietor of Corpus Callosum notes, this is a free access article and a worthwhile read.
Wood’s proposals include severe kicking of the tires for me-too drugs, follow-up on safety after a drug’s launch, demonstration of a real clinical benefit, and encouraging discovery and development of first-in-class drugs. The prospect of extended exclusivity past a drug’s patent lifetime would in theory give the pharma companies incentive to engage in these activities. This might cause some bristling among consumer activists (check out the link below to Boldrin and Levine’s treatise on the evils of intellectual property) since branded drugs are more costly than generics, and exclusivity keeps the higher preiced med out there that much longer. Keep in mind that although generics are cheaper, they do not encourage nor pay for innovation, and honestly, that’s what pharma really needs to focus on now: innovative drugs which will be a genuine benefit for unmet medical needs.
Speaking from the discovery bench monkey’s perspective, there are some notions in Wood’s article which are pant-hootworthy. I particularly like Wood’s incentives for discovery of first-in-class drugs.

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Somewhat less gleeful Gleevec

When Gleevec hit the market in 2001 for chronic myelogenous leukemia , it was hailed as a major breakthrough in cancer treatment. Gleevec, which inhibits bcr-abl kinase, was the harbinger of targeted chemotherapy and represented a departure from the cytotoxics which, although effective, possess a broad array of adverse effects. A History of STI 571, written by Brian Druker, M.D., the principal investigator who championed the compound, not only illustrates the genesis of the drug itself but also the interdisciplinary teamwork required for drug discovery. Behind Gleevec came Iressa, Astra-Zeneca’s EGFR (a receptor tyrosine kinase) inhibitor.
Among the attractions of drugs like Gleevec and Iressa is their specificity toward a defined protein target which in theory should decrease toxicity from off target interactions. Because many pre-clinical compounds interact with the ATP binding region of the protein kinase active site, there is spillover to non-target kinases, but a surprising degree of specificity can be engineered into the molecules. This specificity may wind up being more critical for protein kinases validated as targets for inflammation as opposed to cancer in which some degree of toxicity may be more acceptable in the clinic.
Most drug tox results from off-target effects, i.e., some other protein is inhibited by the compound. Quite a number of drugs exhibit cardiotoxicity by blocking of the hERG ion channel. Screening compounds for hERG activity is common practice in the drug discovery biz. Gleevec passed this hurdle. Sometime a drug’s adverse effects only become apparent after more patients are exposed to the med. As reported in Monday’s the New York Times on Monday (7/24; see Warning Issued on Drug for Leukemia), some patients on Gleevec suffer serious heart damage. In this case, the adverse effect is not due to off target liabilities such as hERG antagonism, but instead it is mechanism based.
The original study is reported in Kerkela et al.’s paper, “Cardiotoxocity of the cancer therapeutic agent imatinib mesylate” which appears as an advance of print online publication in Nature Medicine. It’s nicely executed, and parses the connections between in vitro mechanism to in vivo effects. The swapping in of the imatinib resistant c-Abl domain, which then allowed cell survival in the presence of imantinib, is a pretty nifty bit. As an aside, this is something I love to see as part of target validation…stick in a mutant analog of target protein and examine the results of cell phenotype; siRNA just ain’t enough.
Here’s the abstract of the Nature Medicine paper:

Imatinib mesylate (Gleevec) is a small-molecule inhibitor of the fusion protein Bcr-Abl, the causal agent in chronic myelogenous leukemia. Here we report ten individuals who developed severe congestive heart failure while on imatinib and we show that imatinib-treated mice develop left ventricular contractile dysfunction. Transmission electron micrographs from humans and mice treated with imatinib show mitochondrial abnormalities and accumulation of membrane whorls in both vacuoles and the sarco- (endo-) plasmic reticulum, findings suggestive of a toxic myopathy. With imatinib treatment, cardiomyocytes in culture show activation of the endoplasmic reticulum (ER) stress response, collapse of the mitochondrial membrane potential, release of cytochrome c into the cytosol, reduction in cellular ATP content and cell death. Retroviral gene transfer of an imatinib-resistant mutant of c-Abl, alleviation of ER stress or inhibition of Jun amino-terminal kinases, which are activated as a consequence of ER stress, largely rescues cardiomyocytes from imatinib-induced death. Thus, cardiotoxicity is an unanticipated side effect of inhibition of c-Abl by imatinib.

Gleevec remains a breakthrough drug, and the principal investigator for the imatinib induced cardiotox study says as much:

“Gleevec is a wonderful drug, and patients with these diseases need to be on it,” Thomas Force, who led the study, said in a statement.

The results give a heads up to clinicians using Gleevec as part of their pharmacopoeia and for emerging drugs which target Abl and other non-receptor kinases.
It just goes to show that in the world of new drugs, to quote Roseanne Roseannadanna: “It’s always something.” For protein kinase targets, the imatinib results emphasize the need to understand (as much as can be) the signaling pathways in which a target kinase is entwined.
For a good overview of Gleevec’s arrival on the scene and the potential for protein kinase inhibitors as drugs, check out Approval heralds new generation of kinase inhibitors? from Nature Biotechnology (2001).

Pernicious influences at the FDA…and what’s new about this?

So the Union of Concerned Scientists issued a press release, and the media bleats “FDA Scientists Blast Agency Priorities.” In the interest of brevity, the qualifier that these blasts emanated from 20% of those surveyed was omitted. Presumably, the other 80% were cowed into submission by their hyperpolitically charged overlords or were just too busy and overworked to be bothered. Of the 20%, various responses indicated various misgivings as noted in the survey summary on the UCS web site.
Job dissatistisfaction at the FDA? Undue influence by outside interests? Poor morale? Suppression of scientific candor? Well, stop the presses!
At the risk of sounding like an acerebrate Fox News cretin, a more fair and balanced approach by the media would be welcome as opposed to making it sound like the FDA is on the verge of implosion. It’s not. The FDA has never been free from problems. The difficulties just seem to change with the political farts, I mean, winds of the moment.

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And now a word from obesity’s big fat corporate sponsor.

Doc Bushwell here, pharmaceutical bogeyperson of the fast food-pharma-medical establishments’ collusion against the fundamentalist fat activists (FFAs). Yes, that’s right. We bench monkey pharma researchers lie awake at night, tossing, turning and vigorously scratching our nether regions, while we plot new ways of wresting money and adipose tissue from these hapless souls.
Truth be told, many large pharmaceutical companies have major obesity research programs which have fed, and intend to feed, the pipeline with compounds as clinical candidate hopefuls in the war against obesity. Some, like Sanofi-Aventis’ rimonabant/Accomplia, the CB-1 receptor antagonist, have moved far into the clinic in the hopes of replacing nastier entities like fen-phen. The purveyors of the newer meds hope to claim a sizeable chunk of this sizeable market.
Although we bench monkeys would like to think that good science drives target selection in discovery research, and in fact this is not an uncommon event, the pecuniary creatures in market analysis have increasingly worked their wiles into the earlier stages in the drug discovery process. Good science, although of paramount importance to us discovery types…

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Never send in a chimp when a human will do: assays in discovery research

What a day! Between the scintillating launch of the new blogs (really, I am all aquiver) and doing my best to be irksome in my actual day job, I am more than ready to knock back a dry vodka (Grey Goose, preferably) martini at my favored watering hole in Einsteinville.
Part of my job is to pass judgment on protein targets gearing up for screening campaigns. “Screening” refers to high throughput screening which is the bread and butter of discovery research in Big Bad Pharma. It’s an automated process in which the general idea is to increase that needle in the haystack factor. This is accomplished by assaying huge numbers of compounds (typically 1 million plus) against an enzyme or receptor target of therapeutic interest.

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