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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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July 29, 2010

Craig Venter, Venting

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Posted by Derek

Craig Venter has never been a person to keep a lot of things bottled up inside him. But check out this interview with Der Speigel for even more candor than usual. For instance:

SPIEGEL: Some scientist don't rule out a belief in God. Francis Collins, for example …

Venter: … That's his issue to reconcile, not mine. For me, it's either faith or science - you can't have both.

SPIEGEL: So you don't consider Collins to be a true scientist?

Venter: Let's just say he's a government administrator.

There's more where that came from. The title is "We Have Learned Nothing From the Genome", and it just goes right on from there. Well worth a look.

Comments (78) + TrackBacks (0) | Category: Biological News

Let's Just Spread This Deal Out All Over the Paper, Why Don't We?

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Posted by Derek

Fierce Biotech has it right - the management at Sanofi-Aventis is "leaking like an old wooden ship". That's why we're seeing so many reports from highly placed sources, and people familiar with the negotiations, and so on. Here's the latest, and no doubt phones are even at this moment ringing over at the Wall Street Journal and Bloomberg with updates. . .

Comments (4) + TrackBacks (0) | Category: Business and Markets

New from OSI / Astellas

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Posted by Derek

When last we heard about the takeover of OSI by Astellas, everyone was standing around wondering what was going to happen. Some of that uncertainly seems, unfortunately, to be vanishing. A source tells me that the OSI people have been informed that their Ardsley headquarters and the Melville site on Long Island are to close. The fate of the Farmingdale site on LI is still unclear. Ardsley used to be where Purdue Pharma had a lot of people, and I don't think that OSI has been there that long, actually.

I've also heard that development staff at OSI have been told that they're being let go, but are free to re-apply to Astellas - that could mean several things, none of them particularly good, but that's all I have so far.

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

Open-Source Pharmaceutical Babble

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Posted by Derek

The topic of "open-source" drug discovery is an interesting (and potentially important) one. It just keeps coming up, but one of the problems with it is that it presents a terrible opportunity for vagueness. Too much of what I've read on the subject is hand-waving.

I'm afraid that the key parts of this column fall into the same category. It's by Jackie Hunter, formerly of GlaxoSmithKline. The lead-up parts of the piece are fine, where she lays out some of the problems facing the industry. But then we get this vision:

In the future, the most effective pharmaceutical companies will be hubs at the center of a network of collaborators and suppliers, focusing internally on their core competencies, which might include medicinal chemistry, execution of clinical trials, or sales and marketing. They will facilitate interactions across their network to stimulate the development of innovation ecosystems.

The resulting opportunities to expand beyond traditional products and markets will enable pharmaceutical companies to evolve into companies that offer a range of health-care solutions. These will include not only prescription medicines, but also diagnostics, branded generics, and technologies that support personalized medicine, as well as so-called “neutraceuticals” and other “wellness options.”

And that's it; that's the payoff. We'll all just hop to it, enabling and facilitating, expanding and evolving, stimulating and focusing. None of those are concrete verbs suggesting real courses of action. Whenever you see someone slip into that sort of talk, you can be sure that (at the very least) they have difficulty communicating whatever specific ideas they have. Or (more likely) that they don't have any specific ideas to tell you about at all.

Not that I can blame Jackie Hunter. I don't have a lot of good suggestions at the moment, either. But if you read that column closely, it says (on the one hand) that the problems of the industry are so large that single drug companies probably can't deal with them. Fine. Then it goes on to say that dealing with them will probably reduce the size of drug company R&D organizations. The connection between those two ideas is presumably hidden in that ball of fuzz I quoted above.

Comments (36) + TrackBacks (0) | Category: Drug Development | Drug Industry History

July 28, 2010

Out in the Public

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Posted by Derek

I wanted to mention a couple of meetings that I'll be attending over the next month or so, in hopes of meeting people there. First off, this weekend I'll be at the 2010 Sci Foo Camp, out at Google's headquarters in Mountain View, CA. I'm happy to have received an invitation to this one, and I'm looking forward to seeing what it's like.

And in August, I'll be attending some of the sessions at the Boston ACS meeting, and speaking at a "Lunch and Learn" session on scientific blogging and communication. It's on Tuesday, August 24, from 12 to 2 at the Boston Convention Center. Here's a PDF flyer for the event. My fellow lunch-and-learners will be Ed Silverman of Pharmalot, David Kroll (aka "Abel Pharmboy" of Terra Sigillata, and Michael Tarselli of Scripps Florida. I hope to meet some of you there!

Comments (12) + TrackBacks (0) | Category: Blog Housekeeping

PPAR: A Veil Is Lifted, At Last

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Posted by Derek

I used to work on compounds targeting the PPAR family (and nuclear receptors in general). I knew nothing about the field when I started, which is the traditional situation a medicinal chemist is in, but I picked it up. And picked it up. . .and picked up still more information, on and on, as it dawned on me that the whole field was quite possibly beyond our ability to deal with in an organized fashion.

Not that people didn't try, famously Glaxo. They cranked up a huge effort to go after these targets with the full toolbox - structure, pharmacology, med-chem, animal models, the lot. Merck and others did the same, but Glaxo's team were out there front and center at every conference, presenting data and mentioning in asides that they had X dozen crystal structures of that receptor, and this-many compounds heading into development, and so on. Very little has emerged out on the money-making end from all this work, by all the companies who've tried it. Avandia (rosiglitazone) and Actos (pioglitazone) are still the only PPAR-targeting drugs on the market, with Avandia in serious trouble, and they were both developed before anyone knew what their target was.

But there's absolutely no doubt that PPAR subtypes are major metabolic players; it's just that we don't quite know how to untangle the huge number of effects they have. Now a paper from one of the longtime leaders in the field, Bruce Spiegelman, might restore some order. And it does so in an unexpected way.

Upstream of all the hideously complex transcriptional effects, subtly modulated by ligand, by cell type, by time of day and who know what else, Spiegelman's groups has found that it's the phosphorylation of PPAR-gamma by the kinase CDK5 that might be the key. That doesn't alter the broad strokes of transcription, but it does alter specific genes that are associated with obesity and the metabolic syndrome. (It's known that the PPARs associate with a host of other protein cofactors, and this phosphorylation probably affects some protein-potein binding surface).

High-fat diets in rodents crank up CDK5 activity, and a whole list of effective PPAR compounds, it turns out, keep the receptor from being phosphorylated by it. Moreover, insulin sensitivity correlates quite well with the degree of phosphorylation. It really does look as if the code has been cracked - we may finally know what the primary PPAR-linked event is that affects type II diabetes. So, forget all those other assays: just measure the amount of serine-273 phosphorylation and you've done what you need to do?

This work has doubtless caused plenty of people in the metabolic disease field to drop whatever they were holding and start thinking things all over again. There are a lot of questions to answer: what happens if you dose a CDK5 inhibitor? In what other tissues does a high-fat diet alter CDK5 activity? Could you get all the insulin-sensitization effects of a glitazone drug without the side effects, by targeting a drug development program differently? Does CDK5 have anything to do with the cardiac side effects that everyone's so worried about with Avandia? And so on. It's a great result, one of those papers where you really come away knowing something crucial that you didn't before.

Comments (12) + TrackBacks (0) | Category: Diabetes and Obesity

Genzyme: On the Other Hand. . .

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Posted by Derek

In his classic Where Are the Customers' Yachts?, Fred Schwed mentions that the option market can be a good corrective when you're talking yourself into some investment idea. Take a look at it, he says, and you can see how many people are putting their own money down on the proposition that you might be wrong.

Someone's doing just that with the Genzyme takeover speculation, according to the Wall Street Journal. Some trader opened up thousands of option contracts the other day, selling a pile of $75 October call options and opening up a January put spread between 55 and 65. I know that this is gibberish to most people who don't think about this stuff all the time, but what it means is that whoever this is doesn't think that Genzyme is going to make 75 by the end of October (or wants to be protected against the possibility that it won't), and will start to really clean up if the stock starts moving down below 55 again sometime before the end of January.

The options market is a zero-sum game (as opposed to stocks), so whoever this trader is has sold these option contracts to people who think otherwise about Genzyme's probable moves, or to some market maker who's willing to assume the risk for the given price. For any option transaction, eventually someone will be completely right, and the other guy will be completely wrong. We'll see. . .

Comments (1) + TrackBacks (0) | Category: Business and Markets

July 27, 2010

How Sleazy It Can Get

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Posted by Derek

I've written several times about pharma/biotech companies whose stock promotion strategies seem suspect. But there are always more layers below. A reader sends along this headache-inducing promotion for a company called A5 Laboratories (no link from me to their website). They have, you'll all be interested to hear, a wonderful new method to produce "natural" interferon, which is going to turn them into a multi-billion dollar behemoth.

Sure it is. If you look through that come-on, you notice that it starts diverging from consensus reality very quickly, and never looks back. It's clearly written for people who know no biology, no medicine - in fact, for people who know as little as possible save that they want to get rich. Rich fast. And who believe, for some reason, that breathlessly touted penny stocks are the way to do it. Alas, these sorts of advertisements are generally paid for by some of the existing shareholders of such companies, in order to recruit a fresh generation of investors to take a few truckloads of stock off everyone's hands. This is the bottom of the pond, folks.

Need I note that the CRO assets that the company excitedly announces purchasing were controlled by A5's sole director and officer? And that both companies have the same address in Quebec? Or that A5 Laboratories itself was formerly known as El Palenque Vivero, incorporated in 2006 to run a plant nursery in Cuernavaca, Mexico? Could I make such stuff up myself? No, I could not. My imagination is vivid, but it has limits. Shameless avarice, on the other hand, has none.

Comments (34) + TrackBacks (0) | Category: Business and Markets | The Dark Side

Genzyme Telling Sanofi-Aventis to Buzz Off?

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Posted by Derek

That's what Bloomberg is reporting. Meanwhile, the Wall Street Journal reported that GlaxoSmithKline has expressed interest in the recent past, and that J&J might get involved as well. If a deal goes through, no matter who ends up making it, it'll be a lot more expensive than it looked like being. But isn't that ever the way in M&A? The problem is, everyone except the buyer has a great interest in seeing things go off at the highest possible price.

Comments (4) + TrackBacks (0) | Category: Business and Markets

Alzheimer's and Amyloid, Again

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Posted by Derek

I wanted to mention this good article in the New York Times on the amyloid hypothesis and Alzheimer's. That's a topic I've covered often here, but this is a good overview of the field. And it's a good overview of the field's big questions, too: is amyloid really the cause of Alzheimer's? Do we have any therapies that can slow amyloid deposition, or not? If so, do any of them actually show any real-world benefit to patients?

This gets into the broader question of biomarkers as well. The FDA is insisting, as they should, that any potential Alzheimer's therapy should show improvements in memory or cognition, not just improvements in number of plaques or the like. Getting that sort of data is very difficult, but it's really the only way to avoid yet another "You'd Have Thought That. . ." moment. We've been having too many of those over the last few years. As the FDA's director of neurology puts it:

“You only care if down the road the patient gets better,” Dr. Katz said. “What we are concerned about is approving a drug based on a lab test and being wrong about what happens to the patient clinically.”

With Alzheimer’s, Dr. Katz said, “the great fear is that maybe amyloid has nothing to do with the disease.” If that were the case, and the agency approved a drug that blocked amyloid formation, millions of healthy people could end up taking something useless or even dangerous. And because it takes so long for Alzheimer’s to develop, it could be decades, if ever, before anyone knew the drug did not work.

“It is a conundrum,” Dr. Katz said. “We all hope to get to the point in our understanding of the disease process where everyone in the field says: ‘Look. We know it now. Amyloid causes Alzheimer’s, and we have drugs that decrease amyloid.’ But we are not there yet.”

Biomarkers, ideally, are supposed to speed up drug development. But validating a good one might just as slow a process as if you didn't have a biomarker at all. What I worry about is a situation where the first people to discover these things end up with no chance to benefit from their work, but actually end up helping out other groups much more. And while there's a place for altruism in medical research, I doubt if making it the driving force will lead to success. . .

Comments (17) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials

July 26, 2010

Biosimilars: Not Easy, But Not Impossible, Either

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Posted by Derek

So we actually had two converging stories on Friday afternoon - the news that Sanofi-Aventis is going after Genzyme, and the news that tiny Momenta Pharmaceuticals finally got FDA approval for a biogeneric of Lovenox (enoxaparin). . .a big seller for Sanofi-Aventis.

I knew something was going on with those folks - I'm close enough in Cambridge that I could hear them whooping and popping champagne corks. They've got backing from Novartis, who will actually be making the stuff using Momenta's techniques, but this was make-or-break news for them, and they've been waiting for quite a while to hear it. Meanwhile, Sanofi-Aventis has been hoping just as long that this day wouldn't come.

And they're not alone. A lot of companies have built their business model around the fact that it's very hard to produce biosimilars, so anything that chips away at that is a potential attack on their profits. Genzyme is very much one of those companies, and Shire is one of the companies hoping to move them into the new world.

Every biologic product is different, though, and some of them are going to be harder to break than others. But the financial incentives for doing so are there, and Friday's approval makes them more definite than ever. As a small-molecule guy, I'm not all that sad about this, although that may be an unworthy emotion. I think that some sort of exclusivity (which we now grant mostly through the patent system) is necessary for research companies to turn a profit. But that exclusivity shouldn't be perpetual, either. Everyone should have an incentive to look for the next new thing - hoofbeats, coming up from behind, should be the constant background sound.

Comments (12) + TrackBacks (0) | Category: Business and Markets | Regulatory Affairs

July 23, 2010

Aventis: Is It Genzyme?

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Posted by Derek

Genzyme's stock has jumped straight up this afternoon, and word is that they're the target of the rumored Sanofi-Aventis takeover move. This is being attributed to "people with knowledge of the matter", which is generally shorthand for "people that we know are highly placed insiders but that we've agreed not to name".

You have to think that if GENZ hadn't had their manufacturing woes that this wouldn't be happening.

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

Vivus, Qnexa, Arena, Lorcaserin and the FDA

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Posted by Derek

One big story from the last week was the FDA advisory panel's "No" decision on Qnexa, the drug-combo obesity therapy developed by Vivus. This is the one that's a combination of phentermine and topiramate, both of which have been around for a long time. And clinical trials showed that patients could indeed lose weight on the drug (with the required diet and exercise) - but also raised a lot of questions about safety.

And it's safety that's going to always be a worry with any obesity drug, even once you get past the (rather large) hurdle of showing efficacy. That's what took the Fen-Phen combination off the market, and what torpedoed Acomplia (rimonabant) and the other CB-1 compounds before they'd even been property launched. The FDA panel basically agreed that Qnexa helps with weight loss, but couldn't decide how bad the side effects might be in a wider patient population, and whether they'd be worth it:

But the drug has side effects, both known and theoretical. It may cause birth defects, it may increase suicide risk, it can cause a condition called metabolic acidosis that speeds bone loss, it increases risk of kidney stones, and may have other serious effects.

"It is difficult if not impossible to weigh these issues as the clinical trials went on only for a year, and patients will use this drug for lifetime," (panel chair Kenneth) Burman said. "It is impossible to extrapolate the trial data to the wider population."

That's a problem, all right, and it's not just Vivus that has to worry about it. When the potential number of patients is so large, well, any nasty side effects that are out there will show up eventually. How do you balance all these factors? Is it possible at all? As that WebMD article correctly points out, a new obesity drug will come on the market with all kinds of labeling about how it's only for people over some nasty BMI number, the morbidly obese, people with other life-threatening complications, and so on. But that's not how it's going to be prescribed. Not after a little while. Not with all the pent-up demand for an obesity drug.

Although that's probably the worst situation, this problem isn't confined to obesity therapies - any other drug that requires long-term dosing has this hanging over it (think diabetes, for one prominent example). That brings up the question that anyone looking over clinical trial data inevitably has to face: how much are the trials telling us about the real world? After all, the only way to be sure about how a drug will perform in millions of people for ten years is to dose millions of people for ten years. No one's going to want to pay for any drugs that have been through that sort of testing, I can tell you, so that puts us right where we are today, making judgment calls based on the best numbers we can get.

The FDA itself still has that call to make on Qnexa, and they could still approve it with all kinds of restrictive labeling and follow-up requirements. What about the other obesity compound coming along, then? A lot of people are watching Arena's lorcaserin (which I wrote about negatively here and followed up on here). Arena's stock seems to have climbed on the bad news for Vivus, but I have to say that I think that's fairly stupid. Lorcaserin may well show a friendlier side-effect profile than Qnexa, but if the FDA is going to play this tight, they could just let no one through at all - or send everyone back to the clinic for bankrupting.

As the first 5-HT2C compound to make it through, lorcaserin still worries me. A lot of people have tried that area out and failed, for one thing. And being first-to-market with a new CNS mechanism, in an area where huge masses of people are waiting to try out your drug. . .well, I don't see how you can not be nervous. I said the same thing about rimonabant, for the same reasons, and I haven't changed my opinion.

Since I got a lot of mail the last time I wrote about Arena, I should mention again that I have no position in the stock - or in any of the other companies in this space. But I could change my mind about that. If Arena runs up in advance of their FDA advisory panel in the absence of any new information, I'd consider going short (with money I could afford to lose). If I do that, I'll say so immediately.

Comments (24) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity | Regulatory Affairs | The Central Nervous System | Toxicology

July 22, 2010

Back in Business

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Posted by Derek

I wanted to let everyone know that I'm back from my break, and will resume regular blogging tomorrow. I have a few topics queued up, but in case I've missed something - any big stories out there that we should be talking about?

Comments (20) + TrackBacks (0) | Category: Blog Housekeeping

July 13, 2010

Midsummer

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Posted by Derek

I wanted to let everyone know that posting is going to be scanty around here for the rest of the week and into the first part of next. Any gigantic events that may happen I'll try to cover, but otherwise I'll be fairly scarce. . .

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

Avandia: Was the Evidence Buried?

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Posted by Derek

The New York Times has added to the arguments over Avandia (rosiglitazone) this morning, with an above-the-fold front page item on when its cardiovascular risks were first discovered. According to leaked documents, that may have been as early as the end of 1999 - just a few months after the drug had been approved by the FDA.

According to Gardiner Harris's article, SmithKline (as it was at the time) began a study that fall, and "disastrous" results were in by the end of the year that showed "clear risk" of cardiovascular effects. (They must have been disastrous indeed to show up in that short a time, I have to say). He quotes a memo from an executive at the company:

“This was done for the U.S. business, way under the radar,” Dr. Martin I. Freed, a SmithKline executive, wrote in an e-mail message dated March 29, 2001, about the study results that was obtained by The Times. “Per Sr. Mgmt request, these data should not see the light of day to anyone outside of GSK,” the corporate successor to SmithKline.

The only possible way I can see this being taken out of context would be if the rest of the memo talked about how poorly run the study was and how unreliable its data were - in which case, someone was an idiot for generating such numbers. But that puts the company in the situation of "idiots" being the most benign (and least legally actionable) explanation. Which is not where you want to be.

Without seeing the actual material, it's hard to comment further. But what's out there looks very, very bad.

Comments (29) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | The Dark Side | Toxicology

Hmmm: The Gates Foundation Bails

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Posted by Derek

According to this piece, the Gates Foundation unloaded basically all of its pharma and biotech stock holdings during the second quarter. Merck/Schering-Plough, J&J, Lilly, through Vertex and all the way to InterMune, Allos, and Auxilium - they held millions of shares of these, and it's all gone.

I presume that this is some sort of sector-rotation move by the foundation's investment advisors. But they certainly seem to have rotated good and proper - according to the article, the only life-science investment left is Seattle Genetics. It's certainly not a ringing vote of confidence in the financial prospects of the industry, at any rate. . .

Comments (4) + TrackBacks (0) | Category: Business and Markets

July 12, 2010

Natural Products: Not the Best Fit for Drugs?

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Posted by Derek

Stuart Schreiber and Paul Clemons of the Broad Institute have a provocative paper out in JACS on natural products and their use in drug discovery. As many know, a good part of the current pharmacopeia is derived from natural product lead structures, and in many other cases a natural product was essential for identifying a target or pathway for a completely synthetic compound.

But are there as many of these cases as we think - or as there should be? This latest paper takes a large set of interaction data and tries to map natural product activities on to it. It's already know that there are genes all up and down the "interactome" spectrum, as you'd expect, with some that seem to be at the crossroads of dozens (or hundreds) of pathways, and others that are way out on the edges. And it's been found that disease targets tend to fall in the middle of this range, and not so much in the too-isolated or too-essential zones on either side.

That seems reasonable. But then comes the natural product activity overlay, and there the arguing can start. Natural products, the paper claims, tend to target the high-interaction essential targets at the expense of more specific disease targets. They're under-represented in the few-interaction group, and very much over-represented in the higher ones. Actually, that actually seems reasonable, too - most natural products are produced by organisms as essentially chemical warfare, and the harder they can hit, the better. Looking at subsets of the natural product list (only the most potent compounds, for example) did not make this effect vanish. Meanwhile, if you look at the list of approved drugs (minus the natural products on it), that group fits the middle-range interactivity group much more closely.

But what does that mean for natural products as drug leads? There would appear to be a mismatch here, with a higher likelihood of off-target effects and toxicity among a pure natural-product set. (The mismatch, to be more accurate, is between what we want exogenous chemicals to do versus what evolution has selected them to do). The paper ends up pointing out that additional sources of small molecules look to be needed outside of natural products themselves.

I'll agree with that. But I suspect that I don't agree with the implications. Schreiber has long been a proponent of "diversity-oriented synthesis" (DOS), and would seem to be making a case for it here without ever mentioning it by name. DOS is the idea of making large collections of very structurally diverse molecules, with an eye to covering as much chemical space as possible. My worries (expressed in that link above) are that the space it covers doesn't necessarily overlap very well with the space occupied by potential drugs, and that chemical space is too humungously roomy in any event to be attacked very well by brute force.

Schreiber made a pitch a few years ago for the technique, that time at the expense of small-molecule compound collections. He said that these were too simple to hit many useful targets, and now he's taking care of the natural product end of the spectrum by pointing out that they hit too many. DOS libraries, then, must be just in the right range? I wish he'd included data on some of them in this latest paper; it would be worthwhile to see where they fell in the interaction list.

Comments (58) + TrackBacks (0) | Category: Drug Assays | Drug Industry History | Toxicology

July 9, 2010

Lechleiter's Prescription for Science

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Posted by Derek

John Lechleiter of Eli Lilly has an op-ed in today's Wall Street Journal on innovation in the US. Needless to say, he's worried:

A recent study ranked the U.S. sixth among the top 40 industrialized nations in innovative competitiveness, but 40th out of 40 in "the rate of change in innovation capacity" over the past decade. The ranking, published last year by the Information Technology and Innovation Foundation, measured what countries are doing—in higher education, investment in research and development, corporate tax rates, and more—to become more innovative in the future. The U.S. ranked dead last.

He goes on to say that we need a climate that appreciates new technology (which I certainly think we have), the financial system to support it (which is where he makes the case for favorable tax treatment), and the people who can do it. That's the longest single section of the whole piece:

The final and most important elements are the seeds of innovation, which equate to talented people and their ideas. Human beings—with their talent and energy, creativity and insights—are a priceless resource, but one that is woefully underdeveloped in this country.

There are three policies necessary to cultivate these seeds of innovation. First, with our kids falling further behind on international comparisons in education, we've got to get serious about broad improvement in science and math instruction in our grade schools and high schools.

Second, we need immigration laws that allow and encourage top scientists from other countries to choose to work in the United States. This does not entail drastic changes, but a sensible increase in visas for highly skilled immigrants and a shorter, simpler green-card application process.

Third, we need a well-funded basic research infrastructure within academic and government labs. What's required is not some new "Manhattan Project," but a long-term funding commitment necessary to attract more outstanding scientists to basic research and keep them engaged in productive work throughout their careers.

Well, there are going to be a lot of people reading this who will snort and say "Great, domestic science policy advice from Lilly, the company that's outsourcing everything short of what has to be picked up by a crane". And that call for better science education, together with the immigration reform paragraph, takes us into the "Danger! Undersupply of Scientists!" territory that drives many actual scientists crazy as they scan the employment ads and reformat their CVs.

I agree that science and engineering should be valued more in this country. But given our culture, what would make it so would be the perception that these fields are great places to have lucrative jobs, and that perception is currently taking an awful beating. Justifiably. So I'm not seeing this as a supply-of-scientists problem, as much as I see it as a shortage-of-ways-for-scientists-to-make-a-living one. . .

Comments (61) + TrackBacks (0) | Category: Business and Markets | General Scientific News | Press Coverage

The Horror Of Asking For Data

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Posted by Derek

A reader in the UK sent along this item from the BBC, and those of us in the drug industry will enjoy it very much. An EU regulation is forcing health food and supplement companies to. . .wait for it. . .actually provide evidence that their advertising claims are true.

For those of us living in Orrin Hatch's world here in the US, this will certainly be a change of pace. US readers know how it works - listen to the ads, with the first two sentences delivered as a low-decibel mutter: "Sold as a nutritional supplement only. Not intended to treat, cure, or modify any disease. But the hell with that! It'll grow hair, regenerate your liver, detoxify your colon, improve your memory, and boost your immune system! You'll lose weight, have more energy, sleep better, and you'll have to fight off the attentions of the opposite sex with whatever weapons come to hand! And it's all-natural! Call now for a free thirty-day supply!"

No, the EU isn't letting this stuff pass. Want to claim that your cranberry drink reduces the risk of urinary tract infection? Show us your clinical data - and no, not from someone else's study. From yours, with your product. Glucosamine for arthritis? Got some data to back that up? Green tea for cholesterol, or as an antioxidant? Show them some numbers, or go home. The marketers aren't too happy:

Ioannis Misopoulos, director general of the International Probiotics Association (IPA), is openly hostile.

"It can take three years to get these kinds of human studies together but in the meantime the claims are going to be wiped away," he said. "The regulation is killing this industry and the job losses are already being felt."

Cry me a procreating river, dude. Or come over here to where you can't get near the market without going through the clinic first - and for a lot longer than three years, I might add. And where every claim you make for your product is hammered out with the regulatory authorities, and if they catch you stretching out past them you can get fined out the wazoo. So they won't even let you keep running the ads while you go fetch some evidence, eh? Well, it gets worse:

Not surprisingly, the process has left many manufacturers here in the UK angry. Some say EFSA is demanding the same kind of clinical evidence which prescription medicines would require.

"EFSA is rejecting most of the proposed food supplement claims," says Jenny Baillie of the York-based health foods company Power Health, "even established claims like cranberry for urinary tract health, which will mean that there will be no information on packs for the consumer to assess what the product is supposed to do."

She believes the regulation may even drive consumers into buying from less reputable sources.

To which I am tempted to reply: Mundus vult decipi, ergo decipiatur. Except in the EU.

Comments (34) + TrackBacks (0) | Category: Snake Oil

July 8, 2010

Why Close One Research Site Over Another?

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Posted by Derek

There's been so much traffic here today that it's actually been a bit difficult to get in to write another post. And unfortunately it's all due to the Merck announcement. Some sites that have a long and distinguished history of drug discovery are set to be closed up as if they were so many redundant discount store locations.

And that shows you that no one in the business is thinking about these things - how hey, this site has really done a lot for us (or more than they should have, given their size), and maybe we should hold on to them. As past closings at other companies have shown, that's probably one of the last factors on the list, and most of the time it probably doesn't even come in at all.

What matters, I'd say, is what you'd think matters: the sheer accounting cost. How much does it cost to keep Facility X open? How much would it cost to close it? And how much would we save, compared to what we're giving up? It's that last part where the real arguing starts, because there are many people (I'm one, sometimes) that say that research cultures vary from place to place, and that some sites just seem to have a better history of discovery than others. They're not interchangeable.

But it's very hard to make that argument. This sort of thing doesn't show up in the financial statements, and it's hard to quantify. You also can't count on it, either, because some places will have a good run of many years, and then (for some reason) go flat. Despite what consultants will tell you, I don't think that anyone has figured out what exactly makes a research culture work. That makes fixing a broken one a tall order, and it also makes it very hard to raise one in the way that you want it. It's a combination of the individual people, their managers, the projects they get to work on, the experience that they have (or get) with success. . .all sorts of hard-to-deal-with variables.

It's not just in research institutes, either: why did Hungary produce its ferocious run of world-class scientists during the mid-20th century? Who wouldn't want to reproduce such a thing, or remake the old Bell Labs, or whatever your favorite success story might be. The fact that no one seems to be able to do this on demand argues strongly that no one knows how. And if no one knows how, no one's going to decide based on it, either. Sad.

Comments (52) + TrackBacks (0) | Category: Business and Markets | Who Discovers and Why

July 7, 2010

Merck Site Announcements - Closures and Otherwise

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Posted by Derek

A number of sources tell me that tomorrow (Thursday) will be the day that Merck makes a series of big announcements about site closures and re-alignments. I'll leave this comment thread open for news as it comes in. . .and good luck to all concerned. Having been through just this sort of thing myself, I can tell you that it will likely be a relief to finally have everything out on the table. . .

Comments (95) + TrackBacks (0) | Category: Business and Markets

XMRV and Chronic Fatigue: You Thought You Were Confused Before

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Posted by Derek

Time to revisit the chronic fatigue/XMRV controversy, because it's become even crazier. To catch up, there was a 2009 report in Science that this little-known virus correlated strongly with patients showing the clinical syndrome. Criticism was immediate, with several technical comments and rebuttals coming out in the journal. Then researchers from the UK and Holland strongly challenged the original paper's data and said that they could not reproduce anything like it.

Recently I (and a lot of other people who write about science) received an e-mail claiming that a paper was about to come out from a group at the NIH that confirmed the first report. I let that one go by, since I thought I'd wait for, you know, the actual paper (for one thing, that would let me be sure that there really was one). Now Science reports that yes, there is such a manuscript. But. . .

Science has learned that a paper describing the new findings, already accepted by the Proceedings of the National Academy of Sciences (PNAS), has been put on hold because it directly contradicts another as-yet-unpublished study by a third government agency, the U.S. Centers for Disease Control and Prevention (CDC). That paper, a retrovirus scientist says, has been submitted to Retrovirology and is also on hold; it fails to find a link between the xenotropic murine leukemia virus-related virus (XMRV) and CFS. The contradiction has caused "nervousness" both at PNAS and among senior officials within the Department of Health and Human Services, of which all three agencies are part, says one scientist with inside knowledge.

I'll bet it has! It looks like the positive findings are from Harvey Alter at NIH, and the negative ones are from William Switzer at the CDC. Having two separate government labs blatantly contradict each other - simultaneously, yet - is what everyone seems to be trying to avoid. Sounds to me like each lab is going to have to try the other's protocols before this one gets ironed out. I wouldn't be expecting either paper to appear any time soon, if that's the case.

Update: Well, as it turns out, the Retrovirology paper has been published - so what's holding up PNAS? Might as well get them both out so everyone can compare. . .

Comments (33) + TrackBacks (0) | Category: Biological News | Infectious Diseases

Drug Prices in the US: Not So High After All?

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Posted by Derek

So, who has the highest prescription drug prices in the industrialized world? Why, the US, of course - everyone knows that. (Our generic prices are among the lowest, but not everyone knows that). And how much more do we pay than those fortunate folks over in Europe? Why, double or more, right?

Wrong, apparently. There's a new study coming out from the London School of Economics, comparing prices of 68 drugs between the two regions. And what they find is that US prices are about 25% higher than Europe - but no more than that:

But the study confirms data released recently by several pharmaceutical groups, including AstraZeneca and GlaxoSmithKline. This data – confirmed informally by senior industry executives – suggests profits in the US are only marginally greater than in Europe.

Past studies of drug price differences – including by the US General Accounting Office and by congressional officials – have suggested that US prices are at least one and a half times those of European prices.

Mr Kanavos says such comparisons are flawed, often comparing European list prices with US factory gate ones, which do not take into account the discounts negotiated between manufacturers and health insurers in the US. He says some previous studies have also taken unrepresentative samples.

Can this be correct? We'll have to check out the LSE study when it appears, but what if it is indeed on target? The Financial Times article mentions that this is embarrassing for the drug companies, who have maintained that the high US prices are needed to make up for lower prices elsewhere. But if the industry could have argued all along that prices aren't so high, why wouldn't it have done so to try to defuse the issue? Perhaps because no one wanted to go into great detail about all the various negotiated discounts along the supply chain? Speculation is welcome in the comments.

But it also seems embarrassing for people who've loudly been arguing the other side of the issue as well. What if the drug companies aren't as greedy as they look? And what if the European pricing regime, whose virtues have been pitched to me many times, wouldn't save much more money?

We'll take this up again when the study emerges. Until then, let the arguing commence! And thanks to FiercePharma for the tip to the story.

Comments (21) + TrackBacks (0) | Category: Business and Markets | Drug Prices

July 6, 2010

Commenting On Scientific Papers: How Come No One Does It?

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Posted by Derek

Why doesn't anyone comment on scientific papers? Let's narrow that down: why doesn't anyone comment on them when they have a comments field attached to them on a scientific publisher's web site?

Nature has been wondering about this for a while. In a new item about "Web 2.0" tools in science, they mention:

But deposition in arXiv is about as far as the scientific openness of even astronomers goes. The discussion that ensues is private. As Nature's experiment in open peer review showed (http://go.nature.com/N67mFk), and as can be seen from the lack of commenting on papers in Nature and other journals that encourage it, researchers see little to be gained from open discourse before or after publication. Not only are they busy, as the above quotes attest, but there's no credit to be gained, and some risk if one makes an erroneous or critical statement in public. What is more, astronomers and biologists register active discouragement of blogging — a form of communication that in their eyes carries no stamp of reliability or prestige. That picture of resistance to interactive discussion of science on the Internet is further amplified in a new survey, If You Build It, Will They Come? How Researchers Perceive and Use Web 2.0, to be published later this month by the UK Research Information Network.

Contrast that with a comment left here the other day, where a reader suggested that a great business plan might be to start a web site where people could comment on scientific publications. How to reconcile these world views? I think that one word goes a long way: anonymity. The first reaction to that is often a mental picture of the comments pages to (say) YouTube videos, and a brief shudder. And it's true that comments sections that allow easy anonymous accounts can attract all sorts of nasty stuff, as newspapers found out when they opened up their sites.

But anonymity has a long, distinguished history in science. Peer review! People will speak frankly about a paper under review, as long as they know that their comments will remain untraceable by the manuscript's authors. What makes it acceptable is that the editors of the journal know all the names involved, which (usually) keeps things above the midnight-ninja-assassination level.

So what would be needed, I think, would be a site where real e-mail and contact information would be required. You would be free to post under your real name, if you wanted to, or to take on whatever nom de guerre you wished, with the total assurance this this would not be revealed. At the same time, sheer invective and libel would be tossed out immediately, with the line to be drawn at the discretion of the site's editors. Personally, I'd delete comments that said only "This paper sucked", but I'd leave in the ones that said "This paper sucked because of X, Y, and Z." And the comments that started that way but then went on to talk about how the authors sucked in similar fashion would be truncated with some sort of standard mark meaning "ad hominem deleted".

That would be a lot of work. And there's a good chance that it would never take off at all, given the amount of trust involved. Would I wish to run such a site? No way - I already have a full-time job, thanks. But I'd like to see someone try.

Comments (38) + TrackBacks (0) | Category: The Scientific Literature

July 5, 2010

More From the Fourth

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Posted by Derek

And here's what we had at "In the Pipeline"'s headquarters for the Fourth - yep, a down-home old-fashioned Iranian kebab feast. Works just fine!
kebab%20feast%20small.jpg

Update: Since several people have pointed out that this is an experimental result without sufficient preparative details, here's the Supporting Information file: for the meat, you'll want beef tenderloin, cut into reasonable-size pieces (say, 3x4x4 cm). Chop up onions sufficient to cover the meat pieces (roughly one large onion per pound), and stir both of these together with salt (at your discretion, but roughly 10g per pound of meat), and lemon or lime juice - enough to moisten things, perhaps one half lemon per pound of meat. Let the meat marinate for at least two hours, then skewer it (broad Middle Eastern skewers work much better than the typical wiry ones you can get here). Whack the meat gently with the back (blunt) side of a cleaver once it's on the skewer and grill it over high heat, brushing it with a mixture of saffron (Iranian if you can get it, widely considered the best, at least by Iranians) steeped in hot water and melted butter.

As for the chicken, it gets a very similar treatment with the onions, salt, and lime juice. Brush that with the saffron as it grills (I just use the aqueous form, but feel free to use the butter mixture if you desire). You have now prepared kebab-e-bargh and juje kebab, either of which should be served with basmati rice. I was smart enough not to include a picture of that, so its recipe can wait until another time (!). Master those and the ground-meat kebab-e-kubideh and you can open a food stall for sure.

Comments (13) + TrackBacks (0) | Category: Blog Housekeeping

Holiday

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Posted by Derek

Pretty much everyone in the US pharma/biotech industry has the day off today, added on for the Fourth of July. So here's one of my traditional posts for this holiday, never more true than now:

This, at least, I have observed in forty-five years: that there are men who search for it [truth], whatever it is, wherever it may lie, patiently, honestly, with due humility, and that there are other men who battle endlessly to put it down, even though they don't know what it is. To the first class belong the scientists, the experimenters, the men of curiosity. To the second belong politicians, bishops, professors, mullahs, tin pot messiahs, frauds and exploiters of all sorts - in brief, the men of authority. . .All I find there is a vast enmity to the free functioning of the spirit of man. There may be, for all I know, some truth there, but it is truth made into whips, rolled into bitter pills. . .

I find myself out of sympathy with such men. I shall keep on challenging them until the last galoot's ashore.

- H. L. Mencken, "Off the Grand Banks", 1925

Comments (9) + TrackBacks (0) | Category: Blog Housekeeping

July 2, 2010

Sanofi-Aventis Acquires. . .Somebody?

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Posted by Derek

This seems a bit premature: reports have leaked out that Sanofi-Aventis is planning some sort of big acquisition in the US, but no one's saying what it might be. Or if it's going to be done at all - just that they're working on it.

My impression over the years is that deals of this size are contemplated quite often, but that most of them never go through. The numbers don't pan out, the other party gets cold feet, unrelated other developments throw things off. . .there are a lot of things that can go wrong with a potential deal. But talking after-the-fact with some people who've been in a position to see such things, I've been struck by how many feelers are put out, all the time.

So this seems rather unprofessional of someone up there at Sanofi-Aventis. All this sort of leak can do is crank up the speculation about who the targets might be, and raise their stock prices just when you're working on a financial package. Smooth.

Update: the market seems to think that Allergan, Biogen, Genzyme, and possibly Celgene and Gilead are possible targets here. It's also worth noting that the original Bloomberg story cites five people as sources - but they don't all have to be from Sanofi-Aventis. A leak from the company being acquired is still fairly dumb, but it at least makes more sense. . .

Comments (15) + TrackBacks (0) | Category: Business and Markets

July 1, 2010

GSK's Biotechy World

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Posted by Derek

The Wall Street Journal is out today with a big story on GlaxoSmithKline's current research structure. The diagnosis seems pretty accurate:

Glaxo's experiment is a response to one of the industry's most pressing problems: the failure of gigantic research staffs, formed through a series of mega mergers, to discover new drugs. The mergers helped companies amass potent sales-and-marketing arms, but saddled their R&D with innovation-stifling bureaucracy. . .

The company's current strategy is to break things down into even smaller teams (often with their own names and logos) and to try to apply small-company incentives to them. That goes for both the positive and negative incentives:

The scientists in Glaxo's new biotech-esque groups know the clock is ticking. Called discovery performance units, or DPUs, the groups are about halfway through the three-year budgets they were given in 2008. Glaxo has made it clear that if the team members don't produce, they could get laid off. . .(the company also) says it's trying to get closer to the financial rewards of biotech. In some cases, it is setting aside "a pool of money" for scientists involved in a certain project. . .each time their experimental drug clears a certain hurdle, they get part of the money. . .

Of course, as the article also makes clear, the company has been through supposed newer-and-better re-orgs before. And that included schemes to break the company's research into more independent units. Those "Centers of Excellence in Drug Discovery" were supposed to be the last word eight or ten years ago, but apparently that didn't quite work out. The current philosophy seems to be that the idea didn't go far enough.

True or not? History doesn't give a person much reason for optimism when a large company says that it's going to get more nimble and less bureaucratic. You can make a very good living printing up the posters and running the training seminars about that stuff, but actually getting it to work has been. . .well, has anyone gotten it to work? Andrew Witty, the company's CEO says in the article that he doesn't see any contradiction in having "hugely successful entrepreneurial innovation" inside a big company, but real examples of that are thin on the ground - especially compared to the number of examples of such innovation being fought to the ground when it attempts to spring up.

That's not to say that this approach can't improve things at GSK. I think it's bound to be a good thing to turn people loose to make more of their own decisions, without feeling as if there's someone hovering over their shoulder all the time. But I don't know if it's going to be the revolution that they're hoping for (or the one that they might need).

Comments (62) + TrackBacks (0) | Category: Business and Markets | Drug Industry History | Who Discovers and Why

"Doctor's Data": Telling the Truth and Getting Sued For It

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Posted by Derek

I wanted to call attention to some legal action that appears to be underway - no, not against me. This is Quackwatch being sued by an outfit called "Doctor's Data" (no link from me).

These people perform urine tests for toxic metals, and seem to cater to all sorts of alternative practitioners, many of whom I'd regard as misled at best and fraudulent at worst (see the list of medical board actions and lawsuits near the end of that link). The biggest issue seems to be that the test is administered under "provoked" conditions (after infusing some sort of chelating agent), but the reference values are for normal conditions. People are then told that they have high levels of toxic metals, need lots of therapy, and so on. . .

It looks to me like Quackwatch's Stephen Barrett has performed a real service by detailing this problem and bringing together a lot of widely scattered information about it. But Doctor's Data is suing him for defamation and seeking to have him remove all such material from his site (and not to post any such anywhere else in the future). I've donated to his legal defense fund and would ask that others consider doing the same.

Comments (13) + TrackBacks (0) | Category: Snake Oil