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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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September 28, 2006

The Horse Latitudes

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Posted by Derek

I haven't given any updates on my side project recently because, well, there hasn't been much to update. Progress has stalled, for several reasons - instrument difficulties, power outages, people (including me) being out of town, resources being shifted around. This sort of work is particularly vulnerable to that sort of thing, because it exists through the sufferance of others. It's always been a "work on this after everything else is taken care of" project, and recently everything else has been having its innings.

I have a backlog of completed experiments in the freezer, waiting for a chance to get run, and I'm working on the design of several more. One thing that window-of-opportunity projects force you to do is make the most of the chances you get, so experimental design becomes more crucial than ever. I can't just run the first thing that comes into my head - odds are that it won't be the optimum use of the time and resources. I can usually think up something better if I spend more time thinking about it. Even so, I've had about all the time to think that I can handle for now, and I'm working on ways to get things going again.

Another odd feature of this work is the solo nature of it. I'm used to working in teams, which is how the drug industry operates the overwhelming amount of the time. That's because we have to have people who specialize in so many different areas, but there's an operational aspect to it that doesn't get mentioned much. In a team environment, people have to get things done because someone else is waiting on them. The biologists running the assays are waiting on the medicinal chemists for compounds, who are waiting on the assay numbers to see what to do next, and the same goes for formulations, metabolism, the in vivo assays, and all the rest of it.

But working alone is another story. No one is waiting on these results in the same way as in a normal drug discovery project. Many of my colleagues are interested in what's going on, but I'm the main customer for my own data, for now. If I completely stopped doing this project- walked away and never came back - some folks would eventually ask me about whatever happened to that wild idea of mine, but most wouldn't. And it wouldn't take long for the memory of the whole thing to get buried under the steady pile-up of new work.

No, no one's pressing me to do this but me. It's a different sensation from the industrial research I'm used to. For everything else I've worked on, I've known that if I left the project it would roll along without me, but not this time. This idea would die immediately if I took my shoulder off the wheel, but I'm not going to let that happen.

Comments (1) + TrackBacks (0) | Category: Birth of an Idea

September 27, 2006

Nobel Fever Is Upon Us

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Posted by Derek

As we move into October, we enter what scientists know as Nobel Season. The Chemistry prize will be announced next Wednesday, so it's time for the annual sport of figuring out who will get it. For those keeping score at home, here's the list of previous winners.

Last year I looked around for a betting market, but the action was pretty thin. I haven't detected any great amounts of money hitting the table this year, either, but Thomson ISI does have their poll going again. But it's next to useless, as far as I can tell, because I don't see any of their listed choices as front-runners for the award this year. (Nature's Sceptical Chymist blog agrees).

For example, I have nothing against Dave Evans and Steve Ley, who are both top-rank synthetic organic chemists. But if they're on the list in that category, there are several others who should be, too - not that I think it's necessarily going to be a synthetic organic year. And it wouldn't surprise me to see Stuart Schreiber eventually win a Nobel, but I think the committee can safely wait on that one, too, since his resume is still lengthening nicely. And as for Tobin Marks, it would surprise me to see another organometallic-themed award right after last year's. No, if Thomson's site had a secure connection to put my credit card down on a bet, I'd take the field rather than their choices and feel very happy about it.

Over at the Endless Frontier, Paul Bracher has his money down on either the green fluorescent protein folks (Tsien et al) or perennial pick George Whitesides. Keep in mind, though, that he works for Whitesides, so he may not have the most objective opinion there. I wouldn't object to a win for him, though, but I'd like to see how the committee would phrase it - the traditional line on a Whitesides pick is that he's contributed to too many areas to pin down. More Nobels have gone to hedgehogs than to foxes.

The green fluorescent protein suggestion is a good one, though. And perhaps this will be the year that the committee recognizes RNA interference, which could land in the chemistry award as easily as anywhere else. My runner-up to those suggestions is nanoscale structures (Stoddart et al.), but I have that pick running substantially behind the other two. That's mainly because the other two have demonstrated some real-world utility, but hey, fullerenes. Add your own picks in the comment section, and let's see who calls it.

Comments (26) + TrackBacks (0) | Category: General Scientific News

September 26, 2006

Smell the Vibrations

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Posted by Derek

Mentioning the C. S. Sell article on odors and molecules the other day leads me to talk about Luca Turin. I don't think you can seriously take up the topic of chemicals and their smells without mentioning him, although those mentions tend to be anything but neutral.

Turin is (in)famous for suggesting that there's more to smell than molecular shapes and functional groups. He has an impressive list of structures that provide almost the same scent, but have very different shapes, along with a complementary set of nearly identical molecules with very different ones. These, along with several other arguments (vide infra) have led him to propose that the human body responds not only to shapes, but to vibrational spectra. Your nose, by this theory, is smelling the infrared spectra of the molecules that reach it.

This isn't a new idea - it was first proposed in 1938, and again in the early 1980s. Both times it was shot down, though, primarily by counterexamples such as enantiomeric molecules (mirror-image, for the non-chemists) which smell different while having identical vibrational spectra. Another problem was that no one could figure out how an olfactory receptor could be sensing vibrational spectra, since, to the best of human knowledge, the majority of noses contain neither a source nor detector of infrared light.

Luca proposed that electron tunnelling might provide the answer, and took a cue from solid state electronics. If the receptor was senstive to electron flow, it could function as a switch. An unoccupied receptor would have no current, but if a molecule whose vibrational mode energy was the same as the energy gap between its filled and unfilled levels, then electrons could drop to the lower state by tunnelling across. The receptors wouldn't scan the range themselves - rather, each one would be tuned to a different energy gap. Whether or not a given molecule worked for a given receptor would depend on its size and shape (to fit into the active site) but also on its charge distribution (and thus its functional groups) and its vibrational spectrum. The most complete published version of his theory can be found here.

In 2003, a book came out extolling Luca's work: The Emperor of Scent. It goes into detail about how the vibrational theory was received, which was mostly with great scepticism. Reviews of the book itself were all over the place, from enthusiastic to vitriolic. In that last category was the one from Nature Neuroscience (subscriber link here). The author, Chandler Burr, must have known that he was going to be in for a rough time when the reviewer started things off by quoting "Good Vibrations" by the Beach Boys.

I'll say this for the idea: this theory is well-made, because it's wide-ranging enough to accommodate a lot of the puzzling data about chemical odors, while at the same time making some specific predictions. Counterexamples can be found to just about any simple theory of odor, but this one is harder to get rid of. Not that people haven't tried, though. In 2004, a group at Rockefeller University reported some tests of Luca's predictions in Nature Neuroscience, a journal that must have been happy to see their manuscript. Three of his proposals took a good pounding: that mixtures of guiacol and benzaldehyde take on a vanilla odor not found in either compound alone, that straight-chain aldehydes with an odd number of carbons smell different from even-numbered ones, and that deuterated acetophenone smells different from the parent compound. The group reported failure on all three counts. The accompanying editorial was especially nasty, and to my mind, rather uncalled-for.

Turin has addressed some of these results, and it can be inferred that he didn't care for the Rockefeller group's experimental design. (He's partnered with a British statistician to analyze past data in the field and propose new designs for such tests). It does seem though, from the available data, that many animals from insects to dogs can in fact distinguish deuterated compounds from their lighter analogs. Turin's also proposed deuterated/nondeutreated dimethyl sulfide as a more distinguishable pair of compounds (see this long but interesting review article). That one's from 2003, before the latest results, but even at that point he's pointing out that vibrational theory, taken by itself, can't explain many important things about odors (such as their perceived intensity). At the same time, though, he maintains that the standard "odotope" theory is even more lacking.

Turin has now come out with a book of his own, which is getting better treatment from the scientific press so far (here's the Science review for subscribers). He's also put his money where his, er, nose is by forming his own company, Flexitral, with the intention of finding new odorants more efficiently. So far, the company has several commercial products, which are claimed to be improvements over the existing analogs in stability and allergenicity.

As for me, I'm willing to believe that vibrational spectra might be a component of odor, although shape is clearly a factor, too. But I'm betting that downstream neural processing will be just as large an influence, if not greater. For now, I'm going to see if I can get some deuterated dimethyl sulfide, and if I do, I'll report back.

Comments (23) + TrackBacks (0) | Category: Chemical News

September 25, 2006

A Spray-Painted Crystal Ball

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Posted by Derek

Looking through my files, I found a chart which I clipped out of Genetic Engineering News back in late 2004 or so. It's a table of expected drug launches and sales potentials, based on data from Mehta Partners (a well-known and often-quoted pharmaceutical-sector investment and consulting firm).

Now that we're in the last quarter of 2006, this little document has gone from looking hopeful to looking downright creepy. The Y axis is sales potential, divided into eight tiers, and the X axis is a timeline, quarter-by-quarter. Let's take it from the upper left corner and look at the expected big winners from 2005 and 2006:

Macugen: Expected launch 1Q 05, sales potential 1.25 to 1.5 billion. The reality: the launch went off pretty much as expected, but the sales, well. . .they're running at about 10% of that peak estimate. OSI bought the drug's developer, Eyetech, and people wondered at the time what they were thinking. Maybe they're wondering now, too. . .

Indiplon: Expected launch 4Q 05, sales potential 1.25 to 1.5 billion. The reality: oh, dear. Neurocrine is trying to go it alone until they find a new partner, and they're still in there pitching, but this has been a real development disaster.

Let's pause a moment to note that both of these were printed in green type, which the chart helpfully informs us were considered "low risk" at the time. After meditating on the implications of that statement, we move on to:

Edifoligide: Expected launch 4Q 05, sales potential 1.25 to 1.5 billion. The reality: Aaargh. The drug, an oligonucleotide "decoy" designed to tie up a particular set of transcription factors involved in vein graft failure, completely missed its clinical endpoints in a major trial. Bristol-Meyers Squibb dropped it; its developer (Corgentech) went through a near-death experience and emerged with a changed name and an (appropriate) focus on pain management.

Accomplia: Expected launch 1st half 06, sales potential 1.5 to 2.75 billion. The reality: the drug is slowly, slowly creeping into the market in Europe. But no one has any idea of when it might be approved in the US (where most of that money is going to be made, if it ever is), and Sanofi-Aventis has been extraordinarily uncommunicative on the issue. It won't be 2006, that's for sure. Next year? That's what they thought last year. . .

Plavix (for Japanese market): Expected launch 1st half 06, sales potential 1.25 to 1.5 billion. The reality: they made it in May of this year, but the cost has been heavy. And, of course, Plavix and its profits have been making the news for other reasons entirely.

Asoprisnil: Expected launch 2nd half 06, sales potential 1.25 to 1.5 billion. The reality: who knows? Takeda/Abbott and Schering, after some clinical difficulties, have written off 2006 and refuse to say when the uterine bleeding drug might be submitted for approval. Judging from the lack of recent statements, the outlook isn't good.

Not a pretty picture. Just think of how many investment decisions were made based on forecasts like this - it's enough to give you the shivers. But I'm not really blaming Mehta Partners for this - after all, they did what they could with the information they had from the companies involved. And the companies aren't completely to blame, either - many of them really believed that these things were going to work, or at least do better than they have, and they put a lot of their own money on those opinions. No, it's hard to find someone to take the entire fall. Research and development ishard.

Comments (4) + TrackBacks (0) | Category: Clinical Trials | Drug Development

September 24, 2006

Touch Me Not

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Posted by Derek

I see that Dylan found an old bottle of L-DOPA in his stockroom - I'd handle that one with gloves, but that's the medicinal chemist in me talking. He segues into a discussion of the MPTP story, which I talked about here a while back. Every med-chemist who's done work on central nervous system drugs knows the story, in my experience.

But that knowledge doesn't seem to be universal. I once, some years ago, had a lab associate from another group mention to me casually that he'd just made a batch of an intermediate, which when he drew it out on the hood sash, turned out to be the para-bromo analog of MPTP. I couldn't believe my eyes, and I stared at him in horror, wondering if this was some sort of joke. "You what?" It was then his turn to stare at me, wondering what was wrong. He had never heard of MPTP, of the irreversible Parkinson's syndrome that it causes, had no idea that there was a problem, and so on.

We established that he'd made a good-sized load of the stuff, but that he hadn't been handling it to any great degree (and had been wearing gloves when he worked up the reaction). I put the fear into him, warning him under no circumstances to touch the stuff or mess with any glassware involved, and contacted the toxic waste disposal folks. They charge quite a bit to haul things like that away, I think.

In the meantime, I read up on the structure-activity relationships that had been worked out for these compounds. A key paper by Mabic and Castagnoli in J. Med. Chem. (39, 3694) showed that the 4-bromo compound was, unfortunately, an "excellent substrate" for MAO-B, the enzyme that turns these structures into the neurotoxic species, so odds were excellent that the compound was trouble.

But not once it was taken away and destroyed, anyway. The person who made it developed no symptoms over the next couple of years that I was able to observe him, as far as I could see. (And I believe that you need a pretty good internal dose to get into trouble - light skin contact probably won't do it). Memos went out to everyone reminding them of these structures and why they shouldn't be messed with. But I still wonder how many people might stumble across these compounds and whip up a batch of something that shouldn't be made. That's another argument for electronic lab notebooks. You could set the things to start honking and flashing if you entered such a target structure into them, to alert the clueless. . .

Comments (23) + TrackBacks (0) | Category: The Central Nervous System | Toxicology

September 22, 2006

Darn Photons

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Posted by Derek

No time for a post for today, unfortunately - I was up late last night, trying to see this from my backyard. No dice - like most amateur astronomers, I need a darker sky. Even if I'd been able to see the galaxies, they wouldn't exactly look like that photo from Kitt Peak, though - visually in my 11-inch scope, they're going to be a lot more like the first one of this series. And as for this view: well, not without my own space program.

Coming up next week: more Ariad craziness, and we'll tackle (in a separate post!) the perplexing question of whether you have an infrared spectrometer in your nose or not.

Update: forgot to mention this. I've noticed that the comment spam filters seem to be set a bit more aggressively here these days. A number of comments are wrongly ending up in the junkpile. I'm rescuing them, but often not in a very timely manner. This weekend I'll try to tweak things back a bit.

Comments (2) + TrackBacks (0) | Category: Blog Housekeeping

September 20, 2006

Imclone, Drama Queen of Biotech

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Posted by Derek

So, it turns out that Imclone doesn't actually own a key patent covering uses of its only money-maker, Erbitux. This case has been dragging on for years in one form or another, a bizarre story well chronicled here at Fortune. This is another case of prior art invalidating a patent:

The trial is the culmination of a strange 20-year saga. It pits three distinguished scientists from Israel's Weizmann Institute against ex-colleague Joseph Schlessinger. . .The scientists accuse Schlessinger of absconding with their idea of combining a monoclonal antibody with chemotherapy, taking it to a corporate predecessor of Sanofi-Aventis, and secretly applying for a patent on it. While the application was pending, Aventis licensed the rights exclusively to ImClone. (Schlessinger denied impropriety and claimed credit for the antibody and the combination.)

ImClone had reason to question who the inventor was as early as 1994, when the U.S. Patent Office rejected its application on the grounds that the Weizmann scientists had published an article describing the combination idea before Aventis filed for the patent. ImClone told the patent office it would provide support for its claim, then dropped the application. The company later refiled, and the patent office relented.

Imclone was never able to back up that claim in the end, so out goes their patent. (The Israeli scientists, as Yeda Research and Development, still have a valid patent of their own which they just licensed to Amgen). This is the sort of thing that I don't think should be patented to start with - I have a big problem with broad method-of-treatment claims - but the prior publication makes that a moot point in this case as far as Imclone's concerned. Analysts are estimating that this loss could cut Imclone's earnings by 10 to 20 per cent, which they certainly don't need.

Carl Icahn, the company's largest individual shareholder (behind Bristol-Meyers Squibb), has seen enough. He was elected to the board of directors today, and lost no time sending an open letter calling for the CEO's head. Icahn's no fool as an investor, but I have to question his judgment in hanging on to his Imclone position with such tenacity. Not that Big Carl cares, but I've been telling people to sell the stuff for a long time now, because I don't like their prospects.

I didn't count on this patent loss, though - I just had them downrated in general. And it seems this opinion is shared by others in the industry. Back earlier this year Imclone announced with great blasts of trumpets that it would entertain offers to be bought. Reaction to this opportunity didn't meet their expectations, though, because in August they took themselves off the block, saying that the offers they'd received had been inadequate. It's especially notable that Bristol-Meyers Squibb didn't see fit to buy them out, especially considering that many of Imclone's stockholding fanatics have always seen that as a safety net.

So if BMS, who know Imclone inside out, doesn't want them, why does Carl Icahn? The stock did make it back to $40 per share after I last stuck my tongue out at it around $34. But now it's at $29. . .

Update: as per the comments, here's an excellent and detailed summary of this litigation from PatentBaristas. There are a lot of odd features to the case - check out the part where the Imclone scientist had a suspiciously good memory of a key conversation from twenty years ago. . .

Comments (10) + TrackBacks (0) | Category: Business and Markets | Cancer

September 19, 2006

By Any Other Name

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Posted by Derek

There's a paper in the latest Ang. Chem. that will be of interest to everyone who's into the way that various chemicals smell. And hey, what organic chemist isn't?

It's by a flavor and fragrance chemist, who lists many tables of compounds that have very minor structural variations but completely different smells. One noteworthy example is geraniol, which is a large component of the scent of roses. Adding a methyl group next to its primary allylic alcohol coverts it to an analog with an "intense fungal odor", which I don't think I'm going to be lining to up sample any time soon. And you'd have thought that the smell of geraniol would be pretty robust - you can saturate the allylic double bond, and it's still rosy. Take that compound and substitute an aryl group for the isobutenyl on the other end - still rosy. But don't mess with that primary alcohol.

The take-home lesson is that there are no major SAR trends in odor that you can count on. A substitution that works in one series can do nothing when applied to a closely related compound, or it can take the odor off in a completely unexpected direction. That aryl-for-isobutenyl switch I mentioned, for example, isn't silent if you try it on benzylacetone (4-phenyl-2-butanone). The starting ketone smells "sweet and floral", but the corresponding methylheptenone is described as "pungent, green, herbaceous".

The reason for all this craziness is that there are hundreds of olfactory receptors, most of which appear to respond to huge numbers of compounds as agonists. (There's that induced fit again)! And it's not like the agonists all smell the same, either. There also appear to be multiple binding sites involved, and possibly other protein cofactors as well. The structural complexities are bad enough, but there are probably neural processing effects laid on top of them, which makes the author predict that "consistently accurate prediction of odors will not be possible for a very considerable time". He's quick to point out that it's not like the flavor and fragrance industry has to money to underwrite the work needed to do it, either.

Does this remind you of anything, fellow medicinal chemists? If the perception of smell is the physiological readout in this case, how different is this from all the physiological states we're trying to produce with our small drug molecules? How well do we really understand their binding, and how much can we trust our SAR models? Hey, the fragrance people have big advantages on us - they can immediately test their molecules just by sticking them under their noses, which is like a five-second clinical trial with no FDA needed. And they're still as lost as geese. A lot of the time, so are we.

Comments (24) + TrackBacks (0) | Category: General Scientific News | Life in the Drug Labs

September 18, 2006

Tenderbutton Calls It Quits

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Posted by Derek

So I see that Dylan Stiles is going to close down his blog next month. I'll miss it, but I can't say that I'm completely surprised by his decision. He's in the home stretch of his PhD work in a demanding group, and there will doubless be some stretches in the next few months where he'll be lucky to have time to go to the john, much less update a blog. I wish him luck, and hope that his eventual transition to Dr. Stiles is as quick and painless as possible.

And yes, that's my theory as to why he's calling a halt. I'm sure that questions of future employment and so on have crossed his mind, but his kind of site definitely won't hurt his prospects, should he decide to go into industry. Dylan obviously knows his synthetic chemistry, enjoys doing it, and can pick up new material quickly - those are some of the key things that you look for when you're hiring. I second the suggestion made by one of the commenters on his site that anyone who's offended by the blog is someone you wouldn't want to work for, anyway.

When I first linked to him, I wrote that it was a good thing that the internet didn't exist when I was a grad student. I meant that two ways - first off, I'd have wasted huge amounts of time rooting around on the web, naturally, not that I didn't make do with what was at hand. But the second problem would have been that I would have probably been tempted to start a blog myself, which would have taken up even more time that I couldn't have afforded. As I've written here before, the purpose of graduate school is to prove that you can get out of graduate school. After allowing for a certain amount of down time needed to maintain your sanity, things that distract you from that main purpose are not your friends.

If I'd had a blog, I'd have spent a good amount of time venting. That surely would have gotten me in trouble sooner or later, given the amount of steam that I had available. I'm pretty sure that I wouldn't have wanted future employers reading what I had to say after I messed up some reaction at 3 AM, what I wanted to do to my summer undergrad student after he blew us all up, or after one of my ever-helpful labmates had stolen a lab jack out from under a distillation of mine while it was still going. No one knowingly hires someone who sounds like a cranky, hyperverbal maniac, which is what I sounded like much of the time back then. (My current co-workers who read this site can, I hope, restrain themselves from further comment).

As for my situation now, well, I blog mostly at night, and I post from home. That's because "night" and "home" are real times and real places now, as opposed to graduate school, when they were crammed over into that little area on the left-hand side of the dial marked "Not in the lab, for some reason". Life's extras fit into place better after you've had the time to get a life to fit them into.

Comments (8) + TrackBacks (0) | Category: Graduate School

September 17, 2006

Tough Targets

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Posted by Derek

Novartis has been looking pretty impressive lately. They've announced promising data for their odd immunosuppresive drug Fingolimod (FTY720) in multiple sclerosis therapy. The study isn't very large (255 patients), but the statistics versus placebo look pretty strong. The compound is also showing promise in transplantation, and no doubt the company is looking into other autoimmune disorders as well.

I should note that the drug's target (which appears to be a sphingosine phosphate receptor) wasn't known for many years. It started out as a structural variation on another compound with known effects, it but turned out to have a different (and more useful) profile. This one, if it works, will be more a triumph of persistance and deep pockets rather than drug design, but we'll take 'em where we can get 'em.

The company also has reported data on a new bisphosphonate (Aclasta, aka Reclast) for osteoporosis, notable because it's only dosed once a year. This one had over seven thousand patients, followed for three years, so it's a substantial piece of work, with what appear to be very strong statistics indeed. Novartis appears ready to hammer Fosamax (aledendronate), which has been coining money for Merck for many years now, since they specifically studied a subgroup of patients who were switched from that drug.

One of the notable things about these two drugs is that they're addressing chronic, slow-moving diseases with difficult clinical endpoints. These therapeutic areas are tough to work with in the clinic, and very costly to explore. There are many companies in the industry that would immediately try to outlicense a new osteoporosis clinical candidate rather than try to develop it themselves. You won't see many small biotechs trying to go it alone in areas like this, that's for sure.

So even though I make fun of Pfizer (especially) for being too huge, Novartis is one of the counterexamples. They (along with Merck and GlaxoSmithKline) show that size can have advantages, if you use some of that muscle in the research buildings. FIguring out why some large research organizations are more productive than others, and what part of that isn't due just to chance, has stumped better pundits than me, though. . .

Comments (5) + TrackBacks (0) | Category: Business and Markets | Clinical Trials

September 14, 2006

Take Your Shots

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Posted by Derek

It's taken a while, but a traditional science publisher is starting to make the leap to blog-style comments for scientific papers. Nature has begun offering authors the option of having their paper commented upon by the teeming masses of researchers while it's still in the review phase. (Tyler Cowen speculated on the pluses and minuses of this idea earlier this year). (Update: and does again here in response to an article on this very experiment).

Nature's been talking about peer review and its evolution for a while now - see this section and this blog at their site. They seem to have decided that debate is all very well, but that we're not going to know how well these ideas work until we put them into practice, thus their peer review trial site.

So, how's it working? Looking it over, I can see (as of today) ten current papers that are available for comments, posted roughly since the beginning of this month. None have attracted any comments at all, which is a situation that many bloggers will be all too familiar with. The site, though powered by Movable Type, doesn't seem to have date-driven archive pages as such, although it does have categories. Looking at the "Recent Comments" sidebar, though, will take you back to the last paper that attracted some, which was posted on August 29th. The navigation links at the top of its page will then take you back, paper by paper.

Digging through the stack in this manner, the only papers with substantial comments are found here, here, here, here, and especially here. That takes us back to early July, and the first papers seem to have appeared about a month before. The great majority of papers have attracted no comments at all - I wonder what sort of traffic the site is getting?

It's interesting to compare the behavior patterns there with those at a regular blog. There are a few "nice paper!" one-liners, which out here in the rest of the world are the sign of spam, but which appear to be sincere (if not very useful) communications on the Nature site. The comments are moderated, and I'd like to know just how many they've had to excise. I ask because there are still some off-topic oddities that make it through, like this, where a Chinese researcher makes a rambling complaint of harassment by his government. And there's a planetary science paper here, two of whose five comments are clearly by loons, which must please the original authors no end.

Where real comments appear, they're often done in the style of a peer reviewer, starting with the obligatory "The authors present interesting data on the. . ." type of sentence, and going on in rather stilted fashion. It seems clear that very few of the commentors have much exposure to the regular blog world, or if they do, they're taking great pains to not allow any of that experience to leak over into the exalted world of Nature.

I wish them luck with the experiment. What I'd like to see is an idea that's been proposed before, but never implemented in chemistry: comments on papers after they've published. Think of how interesting Organic Letters would be with comments after each paper in the table of contents - heck, I'd go all out and put a hit counter on each paper, so you could see what's getting attention and what isn't. Does the ACS have the nerve?

Comments (13) + TrackBacks (0) | Category: The Scientific Literature

September 13, 2006

Spectroscopic Days

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Posted by Derek

Talking about my old optical spectroscopy class brought a couple of other things to mind. One of them is that I have never used a good solid 95% of the material I learned there, ever again. Not even once. I worked on a big ol' honking normal coordinate analysis for a class project during that time, and looking back at it, I'm shocked to see the stuff in my handwriting. I supposed there must have been some benefit to learning all of this material, but it is a benefit that time has managed to obscure.

The main thing I took out of the class was the incident I spoke of earlier in the week - hitting the wall of what I had already learned or could pick up on the fly. I'd been warned for years, while growing up, that I was going to have to buckle down and study someday, which news I absorbed in an abstract sort of way. I thought that the prediction had come true in college, but in those courses I could still show up unprepared and understand what was going on. This spectroscopy class was a different order of experience, and a useful one. Fortunately, I left academia before running into the experience of a subject that not only could not be understood in real time, but couldn't be understood after long and careful thought, either. I am reliably informed that they're out there.

The other result of the class was the following work of art, which I composed one day in lieu of doing the assignment. I posted some of this a few years ago, but many readers will not have seen it. It is, of course, a parody of Lewis Carroll's White Knight's song from Through the Looking Glass, which is in turn a parody of Wordsworth, who seems to have tuned up many parodists to concert pitch.


He waved his hands and asked me why
Some peak would polarize
But I was thinking of my lunch
And looked up in surprise.

He then showed me a diagram
And I found to my shame
I didn't know what good it was,
And couldn't say its name.

And if now I chance to put
My tongue in super-glue
Or madly cram my chiral foot
In its enantiomeric shoe,
I weep, for it reminds me so
Of that old class I used to know,
Of ligand fields and planar nodes
And symmetries of normal modes.

Comments (4) + TrackBacks (0) | Category: Graduate School

September 12, 2006

Walking the Plank at Bristol-Myers Squibb

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Posted by Derek

As had been expected for several days, Bristol-Myers Squibb CEO Peter Dolan was ousted today, along with general counsel Richard Willard. This is part of the fallout over the Apotex disaster, and it was looking increasingly like the company was either going to have to fire these two or face possible charges.

I can recommend this analysis by Robert Steyer at TheStreet.com. As he points out, the abortive Apotex deal was both stupid and embarrassing. BMS had already been in trouble over channel stuffing, inflating its wholesale numbers to meet targets, so it wasn't the best time to sign an envelope-pushing deal with a competitor to restrict supply.

Bristol-Myers Squibb, for its part, has released a statement on the Apotex deal, which contains this ringing declaration of principle:

". . .there is no evidence from which to conclude that the company or any of its employees acted unlawfully."

Well, OK then! Actually, I'm sure that's true. But if you restrict that statement to the boardroom and replace the word "unlawfully" with "intelligently", we could have some room to negotiate here. There have been signs for years now. Under Dolan, BMS has grievously overpaid for several assets (in my view and that of many others) and made some serious high-level mistakes. It's also been a rather grim investment during his tenure. I mean, I mock Pfizer for its stock performance, but you'd have been better off owing it than BMS over the last few years - heck, you'd have been better off owning Merck and riding out the Vioxx news. Don't believe me? (To be fair, your best investment choice among those three would have been to bury your money in a coffee can in the backyard, but you don't often get that option from the typical financial advisor).

Now, I made the argument here a month or two ago that CEOs don't matter as much as people think they do - but I left myself some room to maneuver, because that statement applies to anyone reasonably competent. Some of my readers made the point that the people at the top can set the tone for an entire organization, for better or worse, and perhaps this is a good example. I hope the company gets its act together, because it should be a bigger force in the industry than it is. The past few years, from what I can see, have been a wasted opportunity, and this is no time to be wasting them.

Comments (7) + TrackBacks (0) | Category: Business and Markets

September 11, 2006

Enzymes Do Whatever They Want To

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Posted by Derek

It's been a while since I wrote about the neuraminidase inhibitors (Tamiflu and Relenza, oseltamavir and zanamivir). As we start to head into fall, though, I'm sure that avian flu will invade the headlines again, if nothing else (and I hope it's nothing else).

There's an interesting report in Nature (subscriber link) on how these drugs work. Bird flu is a Type A influenza, but there are two broad groups inside that class, which are defined by what variety of neuraminidase enzyme they express. (There are actually nine enzyme variants known, but four of them fall into one group and five into the other).

The drugs were developed against group-2 enzymes, but they're also effective against group-1 influenzas. Since the X-ray crystal structures showed the the drugs bound in the same way to all the group-2 neuraminidases, and since the active sites of all the subtypes across the two groups are extremely similar, no one ever thought that their binding modes would be different. Well, until last month, anyway, when the X-ray crystallographic data came in.

And what it showed was that the active sites of the group-1 enzymes, sequence homology be damned, have a much different structure than the group-2s. As it turns out, though, they can adopt a similar shape when an inhibitor binds to them, which is why the marketed inhibitors still work on them, but they're fundamentally quite different.

I can't resist the urge to use this example to illustrate some of the real problems in our current state of the art for computation and modeling. The differences between these two enzymes are due to their different amino acid residues far away from the active site, which makes modeling them much, much more difficult (and makes the error bars much, much wider when you do). That's why no one realized how far off the group-1 and group-2 neuraminidases were until the X-ray structure was available: modeling couldn't tell you. Any modeling efforts that tried would probably have decided, incorrectly, that the two groups were nearly identical. Why shouldn't they be?

But if we'd had that X-ray data from the start, modeling would very likely have told you, incorrectly, that there was little chance that either Relenza or Tamiflu would work on the group-1 enzyme variants. Why should they? The "induced fit" binding modes, where the enzyme changes shape significantly as the ligand binds, are understandably very difficult to model. There are just too many possibilities, too many of which are within each other's computational error bars.

Now, it's true that this latest work isn't based on molecular modeling at all. (You have to wonder how close these guys got, though). But plenty of projects that are using it are just as much in the dark as a neuraminidase team would have been, and they may not even realize it. Most molecular modelers are well aware of these limitations, but not all of them - or all of the managers over them - are willing to accept them. And when you get out to investors or the general public, it's all too easy for modelers or managers to act as if things are perfectly under control, when in reality they're lurching around in the dark. Like the rest of us. . .

Comments (11) + TrackBacks (0) | Category: In Silico | Infectious Diseases

September 10, 2006

If You Want Your Explanations Overnight, It'll Cost You

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Posted by Derek

OK, the votes in the comments to the Explain This! post came out with NMR/MRI as the clear winner, with a strong plurality wanting to make sure that Fourier transforms are part of the explanation. So that's what I'll take on, but it's not going to appear this week. I'm going to try to pitch the explanation to an intelligent lay reader who doesn't have any particular physics, chemistry, or math skills. I'm out of my mind.

In second place were various suggestions about X-ray crystallography, and perhaps that'll be topic number two. Chirality would be tied with that, except there were actually more votes against it than for it, with people finding it not all that hard to explain. (They've clearly never tried to explain to someone whose specialty is running a Morris water maze assay why all the compounds flipped from R to S just because a group changed out on the far end of the molecule). Other multiple-vote getters were Woodward-Hoffman/FMO, structure determination in general, and antibiotic resistance.

Many of the single-vote topics would be good as well, and some of them would be quite tricky. The person who suggested point group symmetry, though, brought back some memories. I'd never covered anything in that area as an undergraduate, for one reason or another. So there I am in my first year, taking an optical spectroscopy class, and on about the second day the professor launches into a discussion of symmetry operations and their relevance to infrared absorption bands (which is considerable).

And this was the first lecture I had ever heard where I understood nothing but the common verbs and the minor parts of speech. I listened to the whole thing with mounting alarm. It had taken me all the way to graduate school to come definitively to the limits of my knowledge, but the pavement ran out right there. I was so stunned I couldn't even take notes - I'd never tried to take notes on something that I wasn't comprehending at all, so I didn't know how.

That evening, I stalked over to the chemistry library and checked out, among other things, Harry Gray's book on group theory, renowned as the first one on the subject "that you could read in bed without a pencil in your hand". And I didn't go to bed myself until I understood just what I'd been listening to that morning, because I didn't enjoy the experience one bit, and wanted to make sure that it never happened again.

Comments (3) + TrackBacks (0) | Category: General Scientific News | Graduate School

September 7, 2006

Inherently Obvious - It's Obviously Inherent

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Posted by Derek

Note: This is part 2 of tonight's Ariad-fest. Part 1 is below.

The Ariad reexamination itself makes for entertaining reading, if you have a sufficiently geeky worldview, which I do. I was incorrect in my first look at this the other night, when I thought that the rejections were largely on means-plus-function grounds. All of the claim rejections are based on 35 U.S.C. 102, which is good ol' prior art, and 35 U.S.C. 103, which is obviousness. If something has been publicly described, you can't patent it. The bulk of the document is a case-by-case recitation of the various publications which anticipated the patent's claims or rendered them obvious.

By my count, there are fifty-three of them cited. Since the patent's claims are written in the pounding, repetitive, unbalanced-washing-machine style favored by many attorneys, most of these citations turn around and invalidate great swaths of them, over and over. Not only are there the expected papers from the primary literature, but various textbooks and reference handbooks (the PDR, Goodman and Gilman) make an appearance as well.

The actions and literature descriptions of the mechanisms of cyclosporin, glucocorticoids, various antibiotics, and many other substances are adduced. My favorite section is on pages 46-49, on the effect of substances such as resveratrol, found in grapes and in red wine. (More on resveratrol here and here). The examiner cites the King James Bible as invalidating prior art, along with several more conventional citations, and points out that:

"In short, any time someone, over the last several hundred or thousand years, drank even a moderate amount of red wine with food containing significant fats (e.g., the typical French diet) they were reducing NF-kB acitivity (and concomitant NF-kB mediated gene expression) that had been induced by the fat content in the food."

And as the official Manual of Patent Examining Procedure makes clear, something old doesn't become patentable just because you've finally discovered the scientific reason for its effects. If the use or property you're trying to claim is inherent in the prior art, it's unpatentable. As long as the inherent characteristic necessarily flows from the prior art, and is not just one of many other possibilities, the claim can be rejected. Once this happens, the burden of proof is on the applicant to show that there's a difference that isn't obvious. That will be Ariad's only recourse at the USPTO, which is why they're also going outside and petitioning the US District Court.

From my perspective, they're not going to have an easy time of it. The rejection of the NF-kB claims seems pretty comprehensive, and it's hard for me to think of arguments that would refute enough of the examiner's contentions to matter. Left unspoken in the office action is the clear inference that the original patent should never have been granted in the first place, which is what I thought back in 2002. Looking back, that post seems downright psychic, if I do say so myself.

Comments (10) + TrackBacks (0) | Category: Patents and IP

Move On, Move On - Nothing To See Here. . .

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Posted by Derek

I seem to have set off all kinds of interest with that Ariad patent item from the other day (thanks to the folks from the Dow Jones news wire for citing me as a source, by the way). I'm not sure when the reexamination actually showed up on the USPTO site, but I was alerted to it this week by an email from a regular reader.

And that when-did-people-know question is an interesting one. Some of the fans of Ariad's stock have been claiming that this is all old stuff, that the company has already disclosed this information, no news here, already priced in, etc. Ariad's management seems to be taking roughly the same tack, according to Peter Loftus at Dow Jones:

"An Ariad spokeswoman referred inquiries to comments made by company executives on a conference call in August. "This action is a routine and expected step in the re-examination procedure and does not represent the final ruling," Ariad Chief Executive Harvey Berger said on the call, according to a transcript. "The PTO action invites a response from the patentees which will be filed in due course." He also said the patent remains valid and enforceable during the re-examination process."

Berger is right that this isn't the final ruling, of course. I believe that Ariad has one shot at an appeal through the Patent Office, though, before this becomes final. Since early June, they've also tried to stop the whole thing through legal action (a request to enjoin the PTO from continuing the reexamination, and a request for summary judgment on their complaint) in the U.S. District Court (Eastern Virginia). A hearing was set for September 1, and a dollar or so spent this evening on the PACER document retrieval system tells me that the motion was argued on that day, but no court order has been recorded yet.

So, are Ariad's fans correct that all this is old news? If you go back to Ariad's most recent 10-Q form, you find the whole painful topic glossed over a bit on page 23:

As a result of the PTO orders described above, Lilly's ex parte request has been merged into a single action with the ex parte request filed on December 2, 2005 (the "Merged Requests"). The Merged Requests question the patentability of certain claims of the '516 Patent by newly cited references which (i) either inherently or expressly disclose the use of a variety of prior art compounds as reducing NF-?B activity and resulting gene expression, or (ii) are directed to the use of oligonucleotides having an NF-?B binding site for reduction of NF-?B activity. The PTO issued a first office action affirming the Merged Requests on August 2, 2006.

And that's that. You have to go to the PTO to find out that "affirming the merged requests" means "agreeing with them wholeheartedly, to the tune of throwing out most of the patent's claims, including all the ones that were used as the basis for the lawsuit". (See the next post for the details). Despite this oblique acknowledgement of the PTO's decision, the rest of the 10-Q form carries on as if nothing had happened. Referring to the uncertainty surrounding the patent, the quarterly report cites:

. . .The timing and ultimate outcome of Plaintiff's motion for summary judgment enjoining the PTO from proceeding with the reexamination of the Merged Requests, and the consequent reexamination of the Merged Requests by the PTO if the motion is denied . . ."

And says that:

Although we have prevailed at trial in the Lilly litigation, the damages we have been awarded by the jury may be eliminated or limited by an adverse finding upon appeal or in the event that the claims of the '516 Patent are invalidated by the PTO.

Emphasis added in both cases. Now, I'm sure that legally Ariad is within its rights to talk this way, because the reexamination process isn't finished until they've had a right to reply and the PTO has issued its final action. But you wouldn't know from reading this that large sections of their patent had already been ripped out by the seams, and that the task before Ariad now was to make this go away rather than to keep it from happening in the first place.

Comments (1) + TrackBacks (0) | Category: Patents and IP

September 6, 2006

Tell 'Em You Work On Something Else

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Posted by Derek

When I tell people that I work for a drug company, they often want to know what disease I'm working on. I've been able to give all kinds of answers over the years, and most of them go over well. Everyone's glad to hear that you're doing research on diabetes, cancer, Alzheimer's or other widespread high-profile problems. Of the areas I've spent time in, cancer probably has the most cachet on this scale, since almost everyone knows of someone who's had serious trouble with one form or another.

The antithesis of cancer's situation is probably obesity. No matter how many headlines come out on its epidemic nature, huge public health consequences, and so on, it still doesn't get you the respect that other indications do. There are several reasons for this, the first of which is the seriousness of the disease, as defined by life expectancy. For better or worse, obesity patients are going to survive for much longer periods than cancer patients.

Scientifically, this actually makes the field more difficult to work in. Frankly, with most of the current cancer therapies, all we can offer is a few more months or (in some cases) years of life for most patients, so until recently long-term side effect issues haven't been a big concern. (Note, though, that this is changing). But obesity therapies are going to be used for longer periods of time. Obesity is associated with a shorter lifespan, true, but the level of obesity that some people are wanting to treat doesn't have that great an effect on mortality, and the survival rate with even morbid obesity is one heck of a lot better than with most kinds of cancer.

Getting back to the seriousness problem, another issue is that for many people, it's hard to shake the image of obesity as something that could be better treated by just eating less food and getting off the couch. I realize that that's not always a fair judgement, and my heart does indeed go out to people who put on weight more easily than the average person. But that said, there can be little doubt that eating fewer calories and doing a bit more exercise would take off untold numbers of pounds nationwide. The question is, as physicians will tell you, is whether anyone is going to do those things. If they can be more motivated by taking an obesity drug along with changing their diet and doing some exercise, then perhaps the drugs will have partially proved their worth. Of course, you could argue that similar effects at that level might be obtained by pills filled with, say, oat bran, billed as wonderful new obesity therapies: Placebatrim, anyone?

No, we're not going to be able to get away with that one. That's a market for the "nutritional supplement" people. An obesity drug from a real pharmaceutical company is going to have to really do something to get past the FDA, and it's going to have to be extremely safe in order to stay on the market. (Thus the current state of the obesity drug market). Anything that meets these criteria will make a huge amount of money. But respect? Fair or not, that might be asking too much. . .

Comments (22) + TrackBacks (0) | Category: Cancer | Diabetes and Obesity

September 5, 2006

Ariad's Patent Eviscerated

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Posted by Derek

A correspondent has alerted me that the US Patent Office's re-examination of Ariad's huge NF-kB patent is complete. And 160 of its 203 claims have been rejected. This includes, I believe, all of the ones that Ariad used to make its recent case against Eli Lilly (#s 80, 95, 144, and 145). For example, it appears that only six of the first fifty claims are still standing.

You can find all the details here at the USPTO's PAIR site. (That 66-page "Re-exam Non-Final Action" is where the good stuff is). It appears that most of the claims have been dismissed due to over-broad functional language. There's a statement in there that most of the claims are "purely functional":

"With respect to claim 1 it is noted that the sole method step is function i.e. reducing NF-kB activity. Accordingly, the claims would encompass any in vitro or in vivo, natural (indirect) or man-made (direct) means of reducing NF-kB activity. Indeed, most of the method steps recited in the Baltimore patent are purely functional. . ."

This is an argument over the "means-plus-function" section of US patent law, 35 U.S.C. section 112, paragraph 6 if you want to get right down to it, which has been the subject of many a lawsuit. Here's a good discussion of the topic, and here's the Patent Office's take on it for its examiners, if you want to feel a throbbing sensation in your temples. Basically, I think the problem is that the patent is claiming a function (inhibition of NF-kB signaling) without specifying the means by which it is to be carried out.

And there's that nasty problem of prior art. The examiner notes a paper from the Journal of Biological Chemistry (265, 8339) which "teaches the reduction of NF-kB activity in induced cells". This reference, the office action goes on to state, expressly anticipates a large swath of the patent's claims right there. It makes for interesting reading, this re-exam, and I certainly don't have time to dig into all 66 pages of it tonight. But it'll be interesting to hear what Ariad (and its stock boosters) have to say in the morning. There's nothing on their web site tonight. . .

Update, September 6: Still nothing from the company on this - wouldn't an office action on a key piece of intellectual property qualify as a material event? One that affects ongoing litigation? Dated August 2, yet?

Comments (8) + TrackBacks (0) | Category: Patents and IP

September 4, 2006

Plavix Plot Twists

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Posted by Derek

The mighty Plavix battle has taken another unexpected twist. In the last installment, Canadian generic company Apotex had snookered (a completely accurate description) Bristol-Meyers Squibb and Sanofi/Aventis into an ill-advised agreement that ended up destroying the drug's patent protection. Apotex had begun gleefully shipping their generic, while the two larger companies sought relief in court from what appears to have been largely a problem of their own making.

To my surprise, that relief has been granted. Last week, a judge issued an injunction against further sales by Apotex in the U.S. until the patent infringement trial is completed. That's not even going to begin until early next year, and you can be sure that BMS and S-A are going to drag it out as much as possible. No legal bills can compare with the hit they've taken over generic Plavix. Sanofi-Aventis, for example, has lowered its profit forecast to a 2% increase over last year, instead of 12%, claiming that Apotex has clogged up all the distribution channels with their generic. I'm a little sceptical of the size of that effect - it's not unheard of for companies to unload other types of bad news under a convenient banner, given the chance - but there's no doubt that it's been a nasty experience.

Apotex may have just had its moment of glory, at least as far as Plavix is concerned. I'm sure that they made money during this adventure, so if they were going to lose the patent case anyway, they're still ahead. No doubt they'd have been even happier to go on selling it, but they'll take what they can get.

Meanwhile, the Federal Trade Commission is making threatening noises about investigating other pay-the-generic-to-go-away deals. The courts have ruled that such deals are legal if they don't push past the patent expiration of the drug, so I'm not sure what the FTC is going to be able to do. But they're clearly unhappy about the situation. For my part, I'd as soon see the generic companies go ahead and challenge the patent-holding ones, as long as the decisions are made in a competent legal venue. By which I mean, not like the one that upheld Ariad's patent. Keeping everyone on their toes is a good thing, as long as it's done fairly.

Comments (10) + TrackBacks (0) | Category: Cardiovascular Disease | Patents and IP

September 1, 2006

Merck: Unfigure-outable

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Posted by Derek

So, how are things going with the Merck/Vioxx situation? Short answer: confusingly. Earlier this month, Merck's winning verdict from last November was thrown out, and the whole case will have to be retried next year. To balance that out a bit, this week one of the company's big losses had its $51 million dollar award overturned - the judge says that Merck is still liable, but that the award was "grossly excessive".

To add to the uncertainty, another Merck loss in RioGrande City, Texas is coming under scrutiny. Today's Wall Street Journal has a front-page article (subscription link) reporting that one of the jurors in that trial had a history of borrowing money (thousands of dollars worth) from the plaintiff, a fact that certainly didn't come out during the voir dire. Merck, needless to say, is looking into having this verdict thrown out as well.

All this makes it impossible to say just what's happening. The reversals (and coming re-reversals, for all I know) just make it even harder to grasp. Even without these backtracks, the whole business is moving on a slower-than-human-attention-span time scale, which is the problem with a lot of important issues. Watching grass grow and paint dry can actually be very useful, but we're not equipped to do it very well.

For the time being, anyway, the flood of damaging information and bad decisions coming from Merck's side seems to have receded, perhaps because there wasn't much left to accomplish in that line. Interestingly, if you were a Merck shareholder before the Vioxx disaster hit, you're still underwater - but if you bought afterwards, you've done extremely well. This seems to reflect (understandable) panic at first, followed by relief that the company was capable of winning a case or two and not immediately disappearing beneath the flood waters. But if we're going to try every case at least twice, I don't see the stock making much headway for a while.

Comments (3) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Toxicology